placebo: Probucol quantitative regression Swedish trial (PQRST): A status report

Development of Femoral Atherosclerosis in Hypercholesterolemic Patients During Treatment with Cholestyramine and ProbucolAPlacebo: Probucol quantitative Regression Swedish Trial (PQRST): A Status Report GOran Walldius, MD, PhD, Lars A. Carlson, MD, Uno Erikson, MD, Anders G. Olsson, MD, Jan Johansson, MD, JOrgen MOIgaard,MD, Sven Nilsson, MD, GOran Stenport, MD, Lennart Kaijser, Claes Lassvik, and Ingar Holme

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The Probucol Quantitative Regression Swedish Trial is being performed to investigate the effects of probucol on atherosclerosis in the femoral artery. Probucol is combined with cholestyramine and dietary management in hypercholestero!emic patients, and the effects of atheroma developing in the femoral artery will be followed by a quantitative angiographic technique. A randomly selected control group is also being managed by dietary therapy and cholestyramine, but receives placebo instead of probucol. The treatment time in this double-blind trial is 3 years, and femoral angiography is performed yearly. Detailed lipoprotein and apolipoprotein analysis are performed at monthly intervals. The basic study design is described here, and some results from the open prerandomization phase of the study are presented. (Am J Cardiol 1988;62:37B-43B)

From the King Gustaf V Research Institute and Department of Medicine, Karolinska Hospital and Karolinska Institute, Stockholm, the Department of Diagnostic Radiology, University Hospital, Uppsala, Department of Medicine, Faculty of Health Sciences, LinkSping, Department of Radiology, Faculty of Health Sciences,Link6ping,Department of Radiology,Faculty of Health Sciences,Link6ping,Department of Clinical Physiology,Karolinska Hospital, Stockholm, Department of Clinical Physiology, Faculty of Health Sciences, Link6ping Sweden, and the Rikshospitalet, Ulleval Hospibal,Oslo, Norway. This study was supported by grants from Merrell Dow Research Institute, Cincinnati, Ohio, the Swedish Medical Research Council 19X-204,19X-06962, the Swedish Margarine Industrial Association for Nutritional-Physiological Research, the King Gustaf V 80th Birthday Fund, the Nanna Svartz Fund, and the Gamla Tjanarinnors Fund, Stockholm, Sweden. Address for reprints: G6ran Walldius, MD, (co-ordinator of PQRST), King Gustaf V Research Institute, Box 60004, S-104 01 Stockholm, Sweden.

robucol lowers total and low-density lipoprotein (LDL) cholesterol levels. It also appears to have an antiatherogenic action, at least in animal models. Recent studies in Watanabe rabbits have shown that probucol prevents progression of atherosclerosis in vivo, probably by limiting oxidative modification of LDL and foam cell transformation of macrophages, as discussed by Kita, t Yamamoto, 2 Steinberg 3 and their co-workers. Probucol also lowers high-density lipoprotein (HDL) cholesterol levels. The lowering of HDL cholesterol levels by probucol may indicate that the drug enhances several steps in the reverse cholesterol transport process, as reported by Matsuzawa et al, 4 Sirtori 5 and Goldberg. 6 However, in humans, HDL cholesterol may protect against development and progression of atheroma. Therefore the benefit of lowering HDL with probucol has been questioned. The effects of probucol-induced cholesterol lowering on the development of human atherosclerosis are not well understood. In November 1985, a clinical trial in humans, the probucol Quantitative Regression Swedish Trial (PQRST), was begun to determine whether probucol can induce regression of atherosclerosis, retard its progression, or prevent the development of new lesions. The primary end point of the study is the atheroma volume of the femoral artery, as measured by a newly developed standardized electrocardiographic-triggered angiographic technique using computer-based quantitative densitometric scanning. 7 The trial is projected to end in 1992. This report describes the basic structure of the study design and presents some details of the study's current status. STUDY A I M S AND OBJECTIVES OF THE PQRST

The aim of the study is to determinewhether development of atherosclerosis in the femoral artery can be retarded, or regression induced, by altering serum lipoproteins with probucol, cholestyramine and dietary manage-

THE AMERICANJOURNALOF CARDIOLOGY JULY25,1988 37B

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PORS T

PRERANDOMIZATION PHASE DIAGNOSIS Referrals

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ment. A control group will follow the same regimen, but will receive placebo instead of probucol. The primary end point will be changes in atheroma volume of the femoral artery as estimated by annual measurements of angiograms quantified by densitometry. Several subsidiary angiographic and clinical physiologic techniques, as well as clinical manifestations of the disease, will be monitored. Changes in these end points will be related to the effects of therapy on cholesterol and triglyceride ceucentrations in various lipoprotein fractions measurea throughout the study. OVERVIEW OF THE TRIAL DESIGN Patients with hypercholesterolemia, with or without clinical signs and symptoms of peripheral artery disease, will be tested for inclusion and exclusion criteria. The study consists of a prerandomization period of approximately 8 months, followed by a 3-year trial. During the prerandomization phase, a diet aimed at reducing the serum levels of cholesterol will be started, followed by 2 periods of drug testing to select responders to cholestyramine and to probucol. Responders to these drugs will be investigated by femoral arteriography, and those with visible atherosclerosis (no occlusions) will be randomized to receive either probucol or placebo in the 3-year doublebli~d trial. All patients will receive cholestyramine and dietary therapy. Figures 1, 2 and 3 illustrate the structure of the study. PRERANDOMIZATION PHASE The prerandomization phase (Fig. 1) has 4 major components: clinical diagnosis, dietary management and 2 drug response test periods. Men and women younger than age 71 years at the time of referral will be considered. All must have total cholesterol levels >265 mg/dl (6.88 mmol/liter), LDL cholesterol levels >175 mg/dl (4.53 mmol/liter) and total triglyceride levels <350 mg/ dl (4.0 mmol/liter). Patients with hyperlipoproteinemia type III are excluded. Several other exclusion criteria are also considered (Table I): patients with diabetes, untreated thyroid disease, hypertension (diastolic blood pressure greater than 110 mm Hg), chronic renal failure, malignancy and recent myocardial infarction, several unstable hemodynamic conditions and some gastrointestinal diseases are also excluded. Eligible patients are given a prudent diet aimed at increasing intake of polyunsaturated fatty acids. The ra38B

FIGURE 1. Different phases of the prerandomization (open) part of the Probucol Quanffiarive Regression Swedish Trial (PQRS'r).

I

THE AMERICANJOURNAL OF CARDIOLOGY VOLUME62

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( THREE YEARS1

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Responders Clinical physiology Overview angiography Femoral a n g i o g r a p h y Visible atheroma Randomization - Risk - Sex - City

FIGURE 2. Investigations and activities at randomization into the trial phase of the Probucol Quantitative Regression Swedish Trial (PQRST).

PQRST TRIAL PHASE I Randomization Lipids Lipoproteins Apolipoproteins

x

x

x

x

x

x

x

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x

B i c y c l e ex. t e s t Tread m i l l t e s t Oscillo - plethysmo

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FIGURE 3. Investigations during the trial (double-blind) phase of the Probucol Quantitative Regression Swedish Trial (PQRST).

tio of polyunsaturated to saturated fats is increased from 0.2 to 0.5, and this increase is estimated to lower total cholesterol concentration by approximately 5%. Dieticians monitor the patients regularly throughout all parts of the trial. After 3 months of diet, patients are given 8 to 16 g of cholestyramine and 2 tablets of placebo daily. The dose of cholestyramine is individualized according to the patient's tolerance and expected compliance to the drug. Thus some patients are initially prescribed 8 or 12 g of cholestyramine.

TABLE I Exclusion Criteria During the Prerandomization Phase of the Probucol Quantitative Regression Swedish Trial Type III hyperlipoproteinemia* Diabetes Untreated thyroid disease Chronic renal failure (serum creatinine >2.0 mg/dl) Malignancy Myocardial infarction <6 months Unstable angina Major valvular heart disease Hypertension (diastolic BP >110 mm HG)

Peptic ulcers, GI diseases "Alcoholism" Blood chemistry abnormalities Signs/symptoms of TIA, stroke Pregnancy Other major diseases Severe aortofemoral atherosclerosis Other nonatherosclerotic arterial disease

"Very low density lipoprotein triglycerides >1.25 mmol/liter and simultaneous existence of a late pre-B III in agarose electrophoresis. BP = blood pressure; GI = gastrointestinal; TIA = transient ischemic attack.

After each component of the prerandomization period, lipoprotein analyses are performed in duplicate every other week. Patients whose total cholesterol concentration in serum decreases by 8% or more, compared with values after the diet, are considered responders to cholestyramine and continue with the same dose of cholestyramine for another 2 months. Probucol is given in a dose of 500 mg twice daily instead of placebo during this second 2 months, while the dose of cholestyramine is kept constant. Only patients with an additional lowering of total serum cholesterol of 8% or more during the probucol test period are considered responders to probucol and thus continue in the study. Before angiography, at the end of the prerandomization phase (Fig. 2), responders to both cholestyramine and probucol are subjected to a bicycle exercise test and a treadmill test to measure work capacity, electrocardiographic changes, and clinical signs and symptoms. Degree and localization of arterial involvement (atherosclerotic lesions?) are measured by pulse plethysmography, segmental blood pressure measurement and oscillometry. P R I M A R Y END-POINT DETERMINATIONS AND RANDOMIZATION An overview angiogram is recorded to visualize the arterial tree from the renal arteries down to the lower limbs. Arterial changes suggesting atherosclerosis are scored subjectively, as detailed by Erikson in the next article in this issue. 7 The primary end point--the atheroma volume of the femoral artery--is measured in those patients in whom visual inspection detects atherosclerosis. The patient is excluded if there is no visually apparent atherosclerosis, or if the femoral artery is completely occluded on both sides. The amount of atheroma volume is estimated twice. Roentgenograms are obtained from 2 injections 10 minutes apart. Each x-ray plate is synchronized to the R wave of the electrocardiogram to minimize artifacts induced by pulsative blood flow. A 20-cm segment of the artery is studied and the image converted into data elements by scanning. Algorithms are used to calculate atheroma volume, lumen volume, maximal and minimal widths of the vessels and edge roughness. 7 Eligible patients with atherosclerosis are then randomized and stratified by city (Stockholm or Link6ping),

sex, and degree of atherosclerosis evaluated by a scoring system (high or low risk). Patients are randomized in a double-blind fashion to receive either probucol or placebo. All continue to take cholestyramine and continue their diet, as in the prerandomization phase. The PQRST will randomize 240 patients. TRIAL PHASE OF THE STUDY Figure 3 illustrates the trial phase of the PQRST. Patients come for clinical evaluation and dietary monitoring every 3 months throughout the trial. Lipoprotein levels are measured at the same time. Each year the serum concentration of apolipoprotein AI and B are measured by enzyme immunoassay, and a full clinical physiologic evaulation (bicycle exercise test, treadmill test, oscillometry and plethysmography) is performed. Femoral arteriography is performed in duplicate at the start of the trial phase, then yearly during the 3-year study period. In the final year a full overview angiogram is added to these evaluations. SAMPLE SIZE AND STATISTICAL CONSIDERATIONS The size of the randomization group was calculated by considering the rate of patient exclusion during the prerandomization phase as a result of failure to meet inclusion criteria and drug response criteria. We estimated that approximately 1 of every 5 referred patients will enter the trial phase fulfilling all criteria. Thus, it will be necessary to screen about 1,350 to 1,500 patients to reach a randomized population of 240. Each of the 2 treatment groups will have 120 patients at the start of the trial period. We calculate that approximately 20 patients in each of these 2 groups will be withdrawn from the study (or die) as a result of severe medical problems or other problems. Thus, we expect that the final population after 3 years will be 100 patients in each of the 2 groups. At an a level of 0.05, and applying a 2-tailed test, the estimated power is 90% to detect a 5% greater annual change in atheroma volume in the probucol group compared with the placebo group. The crucial statistical variable for each person will be the slope of the regression coefficient (annual change in volume) by year of the 8 volume measurements. The primary hypothesis will be tested by looking for the difference in distribution of slopes between treatment groups. ORGANIZATION OF THE TRIAL The clinical part of the study is being carried out at the Departments of Medicine at Karolinska Hospital in Stockholm and in Link6ping. Clinical physiologic examinations are performed for each patient in those departments. The Stockholm patients are sent to Uppsala for angiography, while the Link6ping patients undergo angiography in Link6ping. All angiography x-ray findings are sent to Uppsala for evaluation. All lipid, lipoprotein and apolipoprotein analyses are performed at the King Gustaf V Research Institute of the Karolinska Institute in Stockholm. The coordinating center for all activities is the King Gustaf V Research InstiTHE AMERICAN JOURNAL OF CARDIOLOGY JULY25, 1988

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FIGURE 4. Referral rate according to month. Cross hatches indicate actual referrals. Solid line defines the referral rate necessary to reach a total of 1,460 referred patients after 3 years; dashed line defines the rate necessary to reach a total of 1 , 3 8 0 .

tute, where data processing is conducted on line with the QZ Data Center in Stockholm. The study's random code is open to a data and safety committee, consisting of 1 epidemio!ogist and 1 professor of medicine from the United States, 1 cardiologist and 1 radiologist from Sweden, in cooperation with a statistician/epidemiologist in Oslo. The committee continuously monitors the progress of the trial. PRESENT STATUS OF THE PQRST The trial began when the first patient was referred in August 1985. Figure 4 illustrates the pace of referrals; there were approximately 1,000 patients by October 1987. The figure shows that we are very close to the planned inflow of referrals. We closely monitor the exclusion rate and causes for exclusions during the prerandomization phase (Fig. 5). A so-called survival curve is constructed according to the Kaplan-Maier method to show how many patients are still eligible for the study at each of the 16 visits. The major reasons for dropout are the clinical exclusion criteria (Table I), which accounted for approximately 30% of the excluded subjects at visit 3. Approximately 11% are nonresponders to cholestyramine, i.e., their levels of serum cholesterol did not decrease by a minimum of 8% when they were receiving at least 8 g of cholestyramine. Approximately 30% are nonresponders to probucol, i.e., they did not respond by an additional 8% reduction in total cholesterol concentration compared with the level after 2 months of therapy with cholestyramine and placebo. About 20% of the patients who had no visible atherosclerosis or had double occlusions of the femoral artery 40B

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were excluded before randomization. Currently, we have approximately a 20% inclusion rate, i.e., 1 of every 5 patients referred to the study is randomized, as predicted by prestudy calculations. As of November 1987, 109 of the total planned 240 patients have been randomized. LIPID V A L U E S DURING THE OPEN P R E R A N D O M I Z A T I O N PHASE Table II lists initial values for cholesterol and triglycerides in total serum and in different lipoprotein fractions, as well as values during the prerandomization phase for those who were responders to both cholestyramine and probucol. Initial total cholesterol values were 351 mg/dl (9.1 mmol/liter). The combined regimen of cholestyramine, diet and probucol reduced total cholesterol by 37% and LDL cholesterol by 40%. There was no major effect on total triglyceride levels. Probucol lowered mean total cholesterol levels by an additional 17% when added to cholestyramine. Table III lists the effects of the combined treatment of diet, cholestyramine and probucol on total HDL, as well as HDL2 and HDL3. Total HDL cholesterol was decreased by 29% from about 57 rag/day (1.5 mmol/liter) to about 41 mg/day (1.1 mmol/liter). HDL2 decreased by 31% and HDL3 by 27%. Interestingly, patients who did not respond to probucol with a decrease in total plasma cholesterol did respond to probucol with a 25% decrease in their HDL cholesterol concentration. Results were similar for all lipoprotein variables regardless of sex or the presence of signs and symptoms of peripheral vascular disease. Based on reported drug use, our estimates of compliance to the prescribed drug dose are 95% for cholestyramine and 97% for probucol during

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F I G U R E 5. The " s u r v i v a l curve" showing the numbers of patients excluded at various points during the prerandomhudion phase. (d'mgnosis); D I E T : 3 months of diet; E X C L = excklsions as a result o f inclusion/exclusion criteria; Q + M a c = ¢holestyramine + placebo; q + PROB = cholestyramine + probucol. Random = randomization at visit 16.

the first year of the trial.

COMMENTS The Lipid Research Clinics Coronary Primary Prevention Trial has shown that an 8% decrease in total cholesterol concentration in hypercholesterolemic men protects against coronary heart disease. Therefore, for ethical reasons, cholestyramine is prescribed during the prerandomization period, and only those who can take at least 8 g and thereby lower their total cholesterol levels by at least 8% are eligible for addition of probucol and possible randomization into the trial. Thus, half of the patients randomized into the trial will be on a regimen of diet, cholestyramine and placebo. These patients may then benefit from the diet and cholestyramine, even though they do not receive probucol. During the rather extended prerandomization period, the patient makes 16 clinic visits for blood sampling and for discussions with a physician and a dietician. Because patients understand that they can lower their cholesterol levels through cholestyramine and diet therapy, they realize that they do riot run the risk of participating in a trial in which they might receive only placebo for 3 years. Therefore patients are generally very motivated to participate in the trial. Compared with the group of patients receiving placebo, those taking probucol during the trial phase will, by definition, have a different total cholesterol and most likely also different concentration of cholesterol in very low density lipoprotein, LDL and especially in HDL (which will be lower in the probucol group). The number of patients excluded so far in the prerandomization phase.suggests that referrals can cease by

T A B L E I I Cholesterol and Triglycerides in Total Plasma and VLDL and LDL in 143 Responders to Cholestyramine and Probucol During the Prerandomization Phase

Start Diet C + PI C + Pro

Weight

Tot. Chol.

VLDL Chol.

LDL Chol.

Tot. TG

73.3 72,5 71.9 71.7

9.11 8.81 7.03 5.81

0.89 0.84 0.93 0.74

6.68 6.38 4.47 3.95

2.04 1.94 2,24 1.91

Valueslisted are means;lipoproteinsin mmol/liter; weightin kg. C = cholestyramine;LDL ~ low-densityIipoprotein;PI = placebo;Pro = probucol; Tot. Chol. = total cholesterol;Tot, TG = total triglycerides;VLDL= verylow density lipoprotein.

T A B L E I I I Cholesterol in Total HDL and in HDL2 and HDL3 in 143 Responders to Cholestyramine and Probucol During the Prerandomization Phase (mmol/liter)

Total HDL

HDL2

HDL3

Start Diet C + PI C + Pro

1.47 1.45 1.51 1.05

0,66 0.65 0.79 0.45

0.82 0.80 0.73 0,60

Valueslisted are means. C = cholestyramine; HDL = high
mid-/late 1988 and that the trial can be expected to end in early or mid-1992.

MEMBERSHIP OF THE PQRST OVERVIEW AND MONITORING COMMITTEE Howard E. Eder (Chairman), Albert Einstein College of Medicine, New York, New York; Bengt W. Johansson, Department of Medicine, Malm6 General Hospital, THE AMERICAN JOURNAL OF CARDIOLOGY

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Malm6, Sweden; Hans Ringertz, Department of Radiology, Karolinska Hospital, Stockholm, Sweden; Herman A. Tyroler, University of North Carolina at Chapel Hill, Chapel Hill, NC.

REFERENCES 1. Kita T. Nagano Y, Yokode M, Ishii K, Noriaki K, Narumiya S, Kawai C. Prevention of atherosclerotic progression in Watanabe rabbits by probucol. Am J Cardiol 1988,62:I3B-19B. 2. YamamotoA, Hara H, Takaichi S, Wakasugi Jl, Tomikawa M. The effect of probucol on macrophages, leading to regression of xanthomas and atheromatous vascular lesions. Am J Cardiol 1988,62:31B-36B. 3. Steinberg D, Carew TE, Parthasarthy S. In vivo inhibition of foam cell

development by probucol in Watanabe rabbits. Am J Cardiol 1988,,62:6B-12B. 4. Matsuzawa Y, Yamashita S, Funahashi T, Tarui S. Selective reduction of cholesterol in HDL2fraction by probucol in familial hypercholesterolemia and hyperHDL2-cholesterolemia with abnormal cholesteryl ester transfer. Am J Cardiol 1988,62:67B-73B. 5. Sirtori CR. Changes in HDL subfraction distribution and increased cholesteryl ester transfer after probucol. Am J Cardiol 1988,62.'74B-77B. 6. Goldberg RB. Probucolenhances cholesterol efflux from cultured human skin fibroblasts. Am J Cardiol 1988,62:57B-59B. 7. Erikson U, NilssonS, Stenport G. Probucol Quantitative Regression Swedish Trial (PQRST): new angiographic technique to measure atheroma volume of the femoral artery. Am J Cardiol 1988,62:44B-47B. 8. DujovneCA, Krehbiel P, Chernoff SB. Controlled studies of the efficacy and safety of combined probucol-colestipol therapy. Am J Cardiol 1986;57:36H42H.

Discussion Question: In your study you do not have a group treated only with probucol. I would like to play the devil's advocate and suggest, based on the experience from Lipid Research Clinics Coronary Primary Prevention Trial, that about 25% of your patients may stop taking cholestyramine altogether by the end of the trial. In my own double-blind, placebo-controlled trial of resin with or without probucol, 81 found that patients taking resin with probucol do have better compliance than when they take resin alone. So there is the theoretical possibility that patients assigned to probucol plus cholestyramine may end up taking more cholestyramine than your cholestyraminetreated group. If that happens, how would you be able to interpret the results if that group happens to have a better angiographic response? I could postulate that they had a better response because they took more cholestyramine and not because probucol was part of the treatment. So, I would submit that the question you are asking is: Does cholestyramine cause more regression or better prevent progression of atherosclerosis with probucol or without probucol? You are not really asking if probucol causes more regression or better prevents atherosclerotic progression than cholestyramine alone. Dr. Walldius: We are well aware of the problem of taking cholestyramine for long periods of time because of side effects and falling compliance. That is why we made the prerandomization phase of the study long and why we accept patients only after we have tested their compliance on a dose of at least 8 g/day, which they claim they can tolerate for a long time. We realize that some patients can take only a low dose because of constipation or other gastrointestinal problems. Thus the 2-month test period should indicate whether the patient can tolerate the dose, and whether such a low dose will lower total cholesterol by at least 8%. Our experience so far is that 90% of patients can take at least 8 g of cholestyramine, and about 70% of patients can take 16 g with no--or at least tolerable--gastrointestinal side effects and other disturbances. Of course we cannot claim that they will continue to take and tolerate these same doses throughout the entire trial, but we hope 42B

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that the dose adjustment from the beginning of the trial will contribute to high compliance. Indeed, at the moment, the compliance to the prescribed dose of cholestyramine is about 95%. We can only hope that the probucol group ends up with the same doses of cholestyramine as the cholestyramine-only group at the end of the 3-year trial. Furthermore, subgroup analysis may make it possible to match the 2 groups according to their intake of cholestyramine to get a precise answer to the question of how much probucol affects the atherosclerotic process.

Question: In your prerandomization phase, how much more does probucol have to lower cholesterol for a patient to continue in the study? Dr. Walldius: A patient is considered to be a responder to probucol if his total cholesterol drops at least an additional 8% below its level after the cholestyramine test period. Our experience so far is that there are no problems with compliance to probucol therapy due to side effects or other problems during the prerandomization phase, since virtually all patients have a considerable drop in their HDL cholesterol. In view of the new and interesting results presented at this meeting proposing that lowering HDL may increase the rate of reverse cholesterol transport, and furthermore that tendinous xanthomas disappear more rapidly as HDL is lowered, one wonders whether lowering HDL cholesterol is in fact beneficial. It would be very interesting to follow patients who have a major lowering of HDL without a concomitant fall in LDL or VLDL cholesterol. However, our study design does not permit this, although we have been thinking a great deal about a possible substudy along those lines. Question: Your study would be more valuable if you could measure the effects of probucol on atherosclerosis in the coronary artery instead of the femoral artery. Such information would do more to further our understanding of probucol's lipid-lowering effects. Dr. Walldius: That is indeed a relevant question. When planning the study we discussed at length the possibility of doing quantitative coronary angiography, but soon realized that we would face several serious problems

if we did so. We have learned that the femoral artery is much more easily visualized by angiography than the coronary artery, since coronary arteries may be erroneously depicted and quantified if the pulsative blood flow is not standardized. We thought that it would be extremely difficult to standardize the quantification of coronary artery atheroma for several reasons: (1) The heart is moving. (2) The coronary artery has to be investigated by imaging from several angles. (3) Only a small part of the coronary arterial bed can be adequately visualized because the many crossing arteries make adequate estimates difficult. We realize that if you ask the simpler question of the degree of stenosis in 1 artery, the answer could be correctly calculated by densitometric scanning, at least after standardizing injection and film exposure according to the ECG cycle. However, how many laboratories do such standardizations today? I must emphasize that since our

main question is not primarily related to quantifying the degree of stenosis, but rather to estimating the atheroma volume and its change after therapy, we decided to chose the more easily measured femoral artery. Furthermore, we would have faced a major ethical problem in making annual measurements of coronary atherosclerosis, especially since many patients are subjectively healthy. Of course we want to have estimates of coronary artery atherosclerosis. Therefore we measure atherosclerotic manifestations indirectly through repeated bicycle exercise and treadmill tests to look for ST-segment depression (among other things). We hope that atheromatous changes in the femoral artery will correlate with overall estimations of atherosclerosis, as estimated by our socalled overview angiography. We also hope that the detailed atheromatous changes in the femoral artery correlate with other clinical physiologic estimates of atherosclerosis.

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