Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries: Design Features of a Clinical Trial with Carotid Atherosclerosis Outcome J.R. Crouse, MD, R.P. Byington, PhD, M.G. Bond, Ph.D., M.A. Espeland, PhD, J.W. Sprinkle, MS, M. McGovern, MD, and C.D. Furberg, MD Departments of Medicine (J. R.C.), Public Health Sciences (R. P.B., M.A.E., J, W. S., C. D.F.), and Neurobiology and Anatomy (M. G.B.), Bowman Gray School of Medicine, Winston Salem, North Carolina, and Bristol-Myers Squibb (M.M.)

ABSTRACT: The Pravastatin, Lipids, and Atherosclerosis in the Carotids trial (PLAC-II) was initiated in 1987 and is the first double-masked randomized clinical trial with progression of early extracranial carotid atherosclerosis as an outcome variable. The trial will compare a lipid-lowering agent (pravastatin, a hydroxyrnethylglutaryl CoA reductase inhibitor) with placebo for ability to retard the rate of progression of extracranial carotid atherosclerosis over 3 years. Inclusion criteria consisted of prevalent coronary artery disease, moderately elevated low-density lipoprotein (LDL) cholesterol (between the 60th and 90th percentiles), and the presence of at least one extracranial carotid artery atherosclerotic plaque that had an intimal-medial thickness (IMT) ~1.3 m m as visualized by B-mode ultrasound. Of approximately 650 patients w h o qualified on the basis of coronary disease and elevated LDL cholesterol, 55% were excluded because of B-mode criteria. One h u n d r e d and fifty-one males and females 50-75 years of age were recruited. Random allocation p r o d u c e d placebo-treated and test-treated groups that were similar for baseline historical data, physical findings, laboratory tests, lipid values, and B-mode characteristics. Baseline concentrations of plasma total cholesterol, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol were 234, 166, and 41 mg/dl, respectively. Baseline plasma concentration of triglyceride was 170 mg/dl. Despite selection of participants whose arteries, overall, were suitable for the trial, individual segments in some participants could not be visualized. Ninety-seven percent of the individual carotid artery segments were visualized in the c o m m o n carotid, 88% in the bifurcation, and 63% in the internal carotid artery. Far walls were slightly more often visualized than near walls, and nonvisualization was most c o m m o n for the near wall of the internal carotid. Nonvisualized segments were comparable between both

Address reprint requests to: ]ohn R. Crouse, MD, Departmentof Medicine, Bowman Gray Schoolof Medicine, 300 South Hawthorne, Winston Salem, NC 27103. ReceivedMarch 16, 1992; revisedJuly 29, 1992. Controlled ClinicalTrials 13:495-506(1992) © ElsevierScience Publishing Co., Inc. 1992 655 Avenue of the Americas, New York, New York 10010

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J.R. Crouse et al. treatment groups. The distribution of arterial walls with qualifying plaque of 91.3 mm IMT was similar for the two groups, and the two groups were also comparable for the primary outcome determinant, mean maximum IMT (mean of maximum of all visualizable sites, 1.32 mm for each treatment group). There are special problems related to recruitment and evaluation of patients for a clinical trial such as this, but the atherosclerosis outcome measurement markedly enhances power and compensates for difficulty in recruitment.

KEY WORDS: Reductase inhibitors, carotid, atherosclerosis, LDL cholesterol, clinical trials, ultrasound, intima-media thickness

INTRODUCTION Increasing confidence in the reliability [1-4], validity [5], and biological consistency [3, 6-17] of B-mode ultra sonography for noninvasively quantifying asymptomatic extracranial carotid atherosclerosis provided rationale for its use to evaluate antiatherogenic treatment effects in 1986. The test treatment chosen was pravastatin, a hydroxymethylglutaryl (HMG) CoA reductase inhibitor previously shown to be effective in lowering elevated serum lowdensity lipoprotein (LDL) cholesterol [18]. Previous case-control studies by the investigators had suggested that coronary patients older than 50 years of age are likely to show accelerated progression and that in this patient population LDL cholesterol is a risk factor for extracranial carotid atherosclerosis [6,8]. For this reason the protocol for the Pravastatin, Lipids and Atherosclerosis in the Carotids (PLAC-II) trial included males and females with moderately elevated LDL cholesterol and coronary artery disease manifested either by prior myocardial infarction or obstructive coronary disease documented by arteriography. Randomization began in February 1988 and was completed in February 1990. Follow-up is scheduled to end in December 1992. This paper describes the design of the trial, the baseline characteristics of the patient population, and the recruitment effort.

METHODS PLAC-II is a single-center trial and is one of two double-masked, placebocontrolled, randomized clinical trials initiated in 1986 to study the effect of pravastatin on atherosclerotic end points. For PLAC-II, the outcome variable is the rate of atherosclerotic progression in the extracranial carotid arteries measured noninvasively using B-mode ultrasonography. For the other trial (PLAC-I or Pravastatin Limitation of Atherosclerosis in the Coronary Arteries) the outcome measure is the rate of progression of coronary atherosclerosis measured indirectly by coronary angiography.

Eligibility Criteria One hundred and fifty-one patients with coronary artery disease between the ages of 50 and 75 were randomized. Inclusion criteria included coronary disease manifest by history of heart attack (a documented acute myocardial infarction with typical evolutionary ECG and enzyme changes) or by catheterization with evidence of >50% stenosis of a coronary artery. Potentially

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eligible participants were provided individual National Cholesterol Education Program NCEP Step I diet counseling by a nutritionist and LDL cholesterol after diet was required to be between the 60th and 90th percentiles for gender and age. For males between the ages of 50 and 54 this resulted in inclusion of patients with serum LDL cholesterol between 146 and 185 mg/dl, and for females of the same age the cut points were 148 and 192 mg/dl. For males and females older than 55 the corresponding cut points were 150 and 182 mg/dl (males) and 151 and 189 mg/dl (females) [19]. Exclusion criteria included plasma triglyceride concentration t 3 5 0 mg/dl, untreated hypo- or hyperthyroidism or other endocrine disease, secondary hyperlipidemia, recent myocardial infarction (~6 months), severe or unstable angina pectoris, uncontrolled congestive heart failure or hypertension, significant gastrointestinal disease or surgery that might interfere with drug absorption, excessive ethanol consumption, likelihood of moving from the community within 3 years, limited expected life span, and treatment with certain drugs including corticosteroids, androgens, other lipid-lowering agents, or antacids containing aluminum salts. Patients treated with thiazide diuretics and/or ~-adrenergic blockers were included if on stable dose. Patients who were initially qualified according to lipoprotein criteria underwent extensive dietary counseling (see below), and if they still qualified after the diet intervention, they underwent replicate baseline ultrasound examinations within 7 days to define characteristics of the near and far walls of the common carotid artery, the bifurcation, and the proximal internal carotid artery above the bulb. The ultrasound criterion for inclusion was at least one qualifying atherosclerotic lesion with an intimal-medial thickness (IMT) 91.3 mm. Patients with anatomically severe disease that precluded visualization of intra-arterial interfaces secondary to shadowing, or those with a bifurcation so near the mandible as to preclude visualization of the internal carotid artery, or tortuous vessels, or artery walls more than 4.0 cm deep were also excluded. Patients who qualified on LDL cholesterol and ultrasound criteria were eligible for entry into PLAC-II and were randomized to either pravastatin or matching placebo. Diet

As part of the screening process patients completed 5-day food records that were scored for fat and cholesterol content by a computerized nutrition program (Nutritionist III [20]). Based on the data from the food record, the patients were provided individual counseling in a phase I American Heart Association (AHA) diet [21] by a nutritionist. After 4--6 weeks they again completed 5-day food records and the above process was repeated until the food record and/or the nutritionist documented adherence to a phase I AHA diet. Ultrasound

The ultrasound methodology for the ultrasound trial was similar to that previously described [2]. A Biosound 2000 II s.a. high-resolution ultrasound unit equipped with an 8-MHz transducer was used. Images were transcribed on a SVHS ½videotape. A RMI 414B tissue-mimicking phantom was used to

498

J.R. Crouse eta|. monitor and assure instrument performance. Sonographers and ultrasound readers received 240 hours of training including 24 hours of lectures and 56 hours of practical experience prior to entering a certification program. The certification process continued for 2-4 months. During this period sonographers and readers in training carried out protocols with oversight by experienced supervisors and immediate feedback as regards any protocol deviation. Sonographers and readers are only certified after they have demonstrated the ability to define the intima-media at its thickest site on each of the 12 walls according to critique by an experienced reader. Upon satisfactory completion of this training, sonographers and readers were recertified yearly. Patients are examined in the supine position and each carotid wall and segment are interrogated independently from continuous angles to identify the thickest intima-media site. Each scan of the common carotid artery begins just above the clavicle and the transducer is moved cephalad through the bifurcation and along the internal carotid artery. Three segments are identified on each side: the distal 1.0 cm of the common carotid proximal to the bifurcation, the bifurcation itself, and the proximal 1.0 cm of the internal carotid artery. At each of the three segments for both near and far wall in the left and right carotid artery the sonographer identifies two interfaces: on the near wall the first interface (interface 2) is the adventitial-medial boundary, and the second (interface 3) is the intima-lumen boundary; on the far wall the first interface (interface 4) is the lumen-intima, and the second (interface 5) is medial-adventitial. Thus 2-3 and 4-5 define intimal-medial thicknesses on the near and far wall, respectively. When these interfaces have been demonstrated, the sonographer reduces gain and time gain control settings as low as possible to decrease artifact, and then records the video images that include the maximum 2-3 and 4-5 wall thickness at each of the 12 segments. Readers examine the videotapes and identify frames that demonstrate the maximum 2-3 and 4-5 wall thickness within each segment. Frames are captured electronically, displayed on high-resolution monitors, and wall maximum thicknesses are calculated at each site. All patients had duplicate ultrasound baseline readings within a week of each other and each patient is examined every 6 months during the 36-month treatment period with replicate final exams. Eligibility for randomization was based on the mean of duplicate readings.

Randomization Randomization took place within 2 weeks of qualifying for the trial. Patients were divided into two strata according to LDL cholesterol: patients with LDL cholesterol ~ 60th ~ 75th percentile; those with LDL cholesterol ~ 75th 90th percentile. Within each stratum patients were randomized to placebo or pravastatin.

Double-Masked Treatment and Follow-up Initial active treatment was 20 mg pravastatin once daily. a target LDL cholesterol of 90-110 mg/dl, provision was masked LDL cholesterol levels, to increase the dose of trial rag/day if LDL cholesterol had not fallen below 110 mg/dl, 10 rag/day if LDL cholesterol had fallen below 90 mg/dl.

In order to reach made, based on medication to 40 or decrease it to To maintain the

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mask, drug doses were also adjusted by the analysis center to match placebotreated patients with test-treated patients. At the end of the titration phase of the trial, 4% of the subjects were on 10 mg qd, 24% were on 20 mg qd, and 72% were on 40 mg qd. Patients were seen monthly for the first 3 months and at 3-month intervals thereafter. An ophthalmological exam was performed at baseline and at 6month intervals thereafter. Outcome/Statistical Analysis The primary objective of PLAC-II is to compare the effectiveness of pravastatin with that of placebo in reducing the rate of progression of early extracranial carotid atherosclerosis. Operationally, the primary outcome for the trial is the progression rate of the mean maximum IMT for 12 carotid walls (near and far walls of the common, the bifurcation, and internal segments, right and left sides of the neck) over a 3-year period. For each visit at which an ultrasound reading is obtained, the mean of these 12 maximum wall thicknesses is calculated for each patient. The primary outcome for the trial will be change in intimal-medial thickness between the two treatment groups over 36 months. RESULTS Patient Enrollment One hundred and fifty-one patients were enrolled in the trial. Recruitment through chart review, community screening, and advertisements in newspapers resulted in 25,000 initial contacts of w h o m 19,378 screened out immediately because of age and presence of other disease. An additional 3900 were excluded who resided over 90 miles from the medical center or w h o did not express interest in the trial. Of approximately 1700 patients who were interested in the trial, approximately 1000 were excluded on the basis of lipid and lipoprotein criteria (192 patients were on cholesterol-lowering medications, 591 had LDL that was below the 60th percentile, 105 had LDL above the 95th percentile, 108 had elevated triglyceride). Of approximately 650 patients with qualifying LDL, 55% were rejected because of the PLAC-II B-mode exclusion criteria, ie, normal carotid arteries (27%), complex plaque with shadowing (12%), high bifurcation, tortuous or too deep arteries of intra-arterial reference (16%). Of the remaining 292 patients, 141 were excluded or excluded themselves because of lack of interest (33%) or diet responsivity (23%), increased LDL (11%), drug therapy for dyslipidemia (11%), difficulty traveling to the clinic (11%), or laboratory abnormalities and other diagnoses (11%), and 151 were enrolled in the trial. Baseline Characteristics Baseline characteristics were similar for the placebo- and pravastatin-treated groups. Table 1 represents mean values for the two treatment groups. Patients' mean age was 63 years and 85% were male (reflecting the requirement

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Table 1

Baseline Characteristics of PLAC-II Subjects

Characteristics Age (y), mean Male (%): Smoking history, %: Current Former Never Female (%): Postrnenopausal Surgically Sterile Height (in.), mean Weight (lb.), mean Systolic blood pressure (ram Hg), mean Diastolic blood pressure (ram Hg), mean Glucose (mg/dl) Total cholesterol, mean LDL-C, mean HDL-C, mean TG, mean N

Treatment Group A

Treatment Group B

Z of Diff.

62.7 84.0

62.4 87.0

0.28 0.80

12.2 67.6 12.2

12.0 68.0 12.0

- 0.06

45.5 54.6 68.0 167.8 130.1

33.3 66.7 70.3 172.5 130.3

-1.65 - 1.12 - 0.05

39 61 69.2 170.1 130.2

77.7

77.1

0.42

77.4

92.93 235.0 167.2 42.2 159.9 75

94.41 233.3 164.2 40.4 182.9 76

0.55

- 0.93 0.47 1.01 1.22 - 1.84

Treatment Groups Comb. 62.6 85.3 12 68 12

93.68 234.2 165.7 41.3 171.5 151

for p r e v a l e n t c o r o n a r y disease at baseline). M e a n s e r u m total cholesterol concentration w a s 234 mg/dl, LDL cholesterol concentration w a s 166 mg/dl, H D L cholesterol concentration w a s 41 mg/dl, a n d triglyceride concentration w a s 172 mg/dl. T h r e e descriptions of baseline B - m o d e u l t r a s o u n d data are shown: comp l e t e n e s s of data at baseline, f r e q u e n c y of s e g m e n t s w i t h a baseline m a x i m u m IMT ~ 1 . 3 m m (the IMT that qualified the patient for the trial), a n d the g r o u p m e a n s for various wall thickness descriptors including a g g r e g a t e m e a n maxi m u m IMT (for 12 sites) a n d site-specific m e a n m a x i m u m IMT. Table 2 p r e s e n t s the p r e v a l e n c e of c o m p l e t e B-mode data at various sites in the t r e a t m e n t a n d control groups. Test a n d placebo-treated g r o u p s w e r e c o m p a r a b l e in this regard. For b o t h g r o u p s the m o s t c o m p l e t e data w e r e o b t a i n e d f r o m the c o m m o n carotid artery (97-100% w i t h data f r o m one or b o t h replicate scans), next m o s t c o m p l e t e f r o m the bifurcation (94-100% w i t h data f r o m one or b o t h replicate scans), a n d least c o m p l e t e f r o m the internal carotid artery (72-97% w i t h data f r o m o n e or b o t h replicate scans). Data o n the p r e v a l e n c e of maxi m u m IMT/>1.3 m m at various sites are s h o w n in Table 3. In b o t h the placeboa n d the p r a v a s t a t i n - t r e a t e d g r o u p IMT ~ 1 . 3 m m w a s m o s t p r e v a l e n t in the bifurcation, next m o s t p r e v a l e n t in the internal carotid, a n d least p r e v a l e n t in the c o m m o n carotid artery. The g r o u p m e a n s for the a g g r e g a t e m e a n m a x i m u m IMT ( m e a n m a x i m u m thickness in 12 sites) a n d s e p a r a t e l y for the m e a n m a x i m u m of the c o m m o n carotid, bifurcation, a n d internal carotid arteries are s h o w n in Table 4. This table also p r e s e n t s the g r o u p m e a n s for the single m a x i m u m IMT (this analysis includes o n l y o n e site, that of maxim u m thickness, for each participant). The a g g r e g a t e m e a n m a x i m u m IMT u s e d as the p r i m a r y o u t c o m e for this trial w a s the s a m e for b o t h t r e a t m e n t

Pravastatin Clinical Trial Table 2

501

P e r c e n t a g e of Patients with Visualization of a Site at N o n e , One, or Both Duplicate Readings at Baseline, b y Site, a n d G r o u p Treatment Group A N = 75 None

One

Both

Treatment Group B N = 76 None

One

Treatment Groups Combined N = 151

Both

None

One

Both

Left Side. Common Near Fat Bifurcation Near Far Internal Near Far

0 0

8 1

92 99

0 1

1 1

99 99

0 0

5 1

95 99

4 0

9 7

87 93

1 3

14 16

85 81

3 1

12 11

85 88

19 9

17 8

64 83

22 8

25 24

53 68

21 9

21 16

58 75

3 1

4 3

93 96

0 0

3 1

97 99

1 1

3 2

96 97

5 6

9 5

86 89

1 4

8 3

91 93

3 5

9 4

88 91

28 8

27 17

45 75

26 3

34 22

40 75

27 5

31 20

42 75

Right Side Common Near Far Bifurcation Near Far Internal Near Far

g r o u p s (Z = 0.12); individual sites w e r e also similar except for the far wall of the internal carotid artery (Z = 2.33). For the entire p o p u l a t i o n (placebotreated a n d test-treated) the m e a n absolute difference between duplicate scores for the m e a n m a x i m u m is 0.14 m m . O f these differences 95% are ~0.37 m m . Figure 1 s h o w s the distributions of individual m e a n m a x i m u m thicknesses ( m e a n of 12 sites) a n d Figure 2 the distribution of individual m a x i m u m thicknesses (one site p e r participant) for the entire population. The f r e q u e n c y h i s t o g r a m for the m e a n m a x i m u m IMTs is m o r e n o r m a l l y distributed t h a n that for the individual m a x i m u m thicknesses.

DISCUSSION W o r k carried out o v e r the last 5-8 years lends credibility a n d confidence to the use of n o n i n v a s i v e i m a g i n g to define intimal-medial thickness of the carotid arteries for use in epidemiological studies [1-17]. Pignoli [5] established the validity of the p r o c e d u r e , a n d his early w o r k as well as recent m o r e precise evaluations h a v e d e m o n s t r a t e d high reproducibility [1-4]. The m e t h o d has b e e n s h o w n to yield data that m a k e clinical " s e n s e " in that extensive carotid disease is related to the m a j o r c o r o n a r y risk factors a n d to p r e v a l e n t c o r o n a r y disease [5-17]. First u s e d in a case-control setting, the m e t h o d has n o w b e e n e x p a n d e d to e n c o m p a s s p o p u l a t i o n - b a s e d studies [3,11,14], cohort studies [22], and, m o r e recently, clinical trials [23,24]. In 1987 the first clinical trial utilizing this m e t h o d o l o g y w a s initiated with an aim to d e t e r m i n e the effect

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Table 3

Percentage of Scans with M a x i m u m Thickness 9 1 . 3 m m at Baseline Treatment Treatment Treatment Groups Group A Group B Combined a N = 75 N = 76 N = 151

Left Side Common Near Far Bifurcation Near Far Internal Near Far

22.7 25.3

23.7 18.4

23.2 21.9

63.9 70.7

74.7 77.0

69.4 73.8

49.2 45.6

37.3 28.6

43.3 37.0

17.8 23.0

14.5 26.3

16.1 24.7

54.9 80.3

72.0 87.7

63.7 84.0

37.0 65.2

32.1 50.0

34.6 52.3

Right Side Common Near Far Bifurcation Near Far Internal Near Far

aUsing the greater of the two values from both baseline exams. of a lipid-lowering agent (pravastatin) on the rate of progression of early carotid atherosclerosis. Lacking longitudinal data on which to estimate progression rate a n d its variance, cross-sectional data [7] w e r e u s e d for sample size calculation. These cross-sectional data suggested a trial in patients with existing coronary disease because they s e e m e d likely to have a high prevalence of carotid atherosclerosis and also to have an accelerated rate of progression, and because LDL cholesterol s e e m e d to be an i m p o r t a n t risk factor for carotid atherosclerosis. Subsequently, LDL cholesterol has b e e n recognized as a risk factor for prevalent carotid atherosclerosis in the K u o p i o Ischemic H e a r t Disease Risk Factor S t u d y [3], in the Arteriosclerosis Risk in C o m m u n i t i e s Study [14], and in individuals with familial hypercholesterolemia [17]. A luxury e n j o y e d b y investigators carrying out clinical trials c o m p a r e d to epidemiological cohort studies is the o p p o r t u n i t y to eliminate from the trial certain " p r o b l e m " patients and recordings. It has b e c o m e evident with the n e w B-mode m e t h o d o l o g y that certain scans are "difficult" to interpret [11], a n d patients with such scans were excluded from this trial. It is an i m p o r t a n t observation in PLAC-II that over 50% of otherwise eligible patients were excluded on the basis of our B-mode criteria alone. The focus in PLAC-II was on lesions w i t h o u t significant effect on blood flow. Thus, about half of those excluded h a d normal carotid arteries (insufficient plaque to enter the trial), and half had m o r e extensive plaques or plaques that were difficult to visualize. Exclusion of large n u m b e r s of patients on the basis of B-mode scan alone was unanticipated in PLAC-II a n d necessitated a more energetic recruitment effort than w o u l d otherwise have b e e n necessary.

Pravastatin Clinical Trial Table 4

503

Baseline C o m p a r i s o n s of B-Mode Variables ( m m )

B-Mode Variable (a) Mean maximum thickness in 12 walls Co) Mean max. of common (both near and far walls) (c) Mean max. of bifurcation (both near and far walls) (d) Mean max. of internal (both near and far walls) (e) Mean max. of common in near wail (f) Mean max. of common in far wall (g) Mean max. of bifurcation in near wall (h) Mean max. of bifurcation in far wall (i) Mean max. of internal in near wall (j) Mean max. of internal in far wall (k) Single maximum thickness

Treatment Group A N = 75

Treatment Group B N = 76

1.32

1.32

0.12

1.32

1.01

1.01

0.15

1.01

1.63

1.74

- 1.55

1.69

1.38

1.22

1.84

1.30

0.99

0.96

0.61

0.98

1.03

1.05

-0.37

1.04

1.49

1.58

- 1.15

1.54

1.76

1.87

- 1.16

1.82

1.15

1.11

0.57

1.13

1.50

1.25

2.33

1.38

2.64

2.46

1.38

2.55

Z of Diff.

Both Treatment Groups Combined N = 151

(Tmax) Patients in the t w o t r e a t m e n t g r o u p s w e r e c o m p a r a b l e in regard to baseline s y m p t o m status, physical e x a m features, a n d lipid a n d l i p o p r o t e i n concentrations. The a g g r e g a t e m e a n m a x i m u m IMT w a s similar for b o t h t r e a t m e n t g r o u p s as w e r e the majority of m e a n s of single-thickness m a x i m a for individual sites. Potential for individual sites to differ b e t w e e n t r e a t m e n t a n d control g r o u p s on the basis of chance alone ( w h e n several sites are s a m p l e d ) s u p p o r t s use of an a g g r e g a t e m e a s u r e of IMT as o u t c o m e variable rather t h a n m e a s u r e s at individual sites. Despite the effort described a b o v e to assess a g r o u p of patients suitable for B-mode evaluation of the carotid arteries, it w a s not possible to e v a l u a t e all 12 s e g m e n t s of all patients. In general, the c o m m o n carotid artery w a s visualized with f e w exceptions, followed b y the bifurcation, while the n e a r wails of the internal carotid arteries w e r e m o s t difficult to visualize and, in general, the far wall w a s m o r e readily visualized t h a n the n e a r wall. H o w e v e r , these p a t t e r n s w e r e similar for b o t h t r e a t m e n t g r o u p s . In addition, b o t h g r o u p s d e m o n s t r a t e d similar p a t t e r n s in p r e v a l e n c e b y site of an IMT J>1.3 m m (the qualifying lesion thickness). B-Mode u l t r a s o u n d m e t h o d s for quantifying atherosclerosis are particularly attractive b e c a u s e t h e y directly m e a s u r e wall thickness r a t h e r t h a n relying on l u m e n d i a m e t e r m e a s u r e m e n t s that infer the extent a n d severity of atherosclerosis. The latter a p p r o a c h , e m p l o y e d in a n g i o g r a p h i c studies or in studies utilizing D o p p l e r u l t r a s o u n d , is primarily suitable for s e m i q u a n t i t a t i v e identification of atherosclerosis u n d e r l y i n g stenotic lesions [25], since early ath-

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J.R. Crouse et al.

~0 ¢.c0 o (D

"6 E o0~ O O..

1.0

1.5

2.0

2.5

3.0

Thickness (mm)

Figure 1 Distribution of mean maximum thickness across 12 sites (ram) in PLAC-2. (From qualifying baseline B-mode, N = 151.)

10-¢-

O

O0

6--

O

E

42-

rl

0--

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

Thickness (mm)

Figure 2 Distribution of single maximum thicknesses across 12 sites (ram) in PLAC-2. (From qualifying baseline B-mode, N -- 151.)

erosclerosis is not associated with reduction in l u m e n diameter [26]. The noninvasive nature of the B-mode examination affords the o p p o r t u n i t y for replicate measures and sequential measures with the o p p o r t u n i t y for increased statistical power. U n d e r s t a n d i n g of the potential clinical relevance of preclinical disease that does not result in n a r r o w i n g of the arterial l u m e n is growing [27,28]. The data from this trial provide some assurance that carotid atherosclerosis progression is a reliable outcome measure. Randomization provides groups with comparable B-mode characteristics. H o w e v e r , recruitment for such trials

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m a y be m o r e difficult t h a n anticipated. Certain arterial s e g m e n t s are interp r e t e d w i t h a high d e g r e e of reliability while certain o t h e r wall s e g m e n t s are likely to be difficult to visualize, e v e n with the m o s t careful screening. Alg o r i t h m s h a v e b e e n d e v e l o p e d for interpolating data for m i s s i n g wall segm e n t s b a s e d o n available data [29], a n d the availability of the r e p e a t B-mode m e a s u r e m e n t s m a k e s possible a highly precise estimation of p r o g r e s s i o n rate a n d protects against loss of i n f o r m a t i o n d u e to late d r o p o u t or inability to follow u p on patients after 1 year. The authors acknowledge the help of Ms. Telle King, P.A., and Ms. Donna Hendrix for the clinical screening and recruitment of patients for this trial. In addition, the assistance of Rita Phillips, Ann Safrit, Rong Tang, M.D., Mitzie Spainhour, Billy Holley, Lisa Holley, Bo Xaio, and Jennifer Fitzsimmons in ultrasound scanning and reading were important to the completion of this trial. We also acknowledge the assistance of Ms. Misty Agientas and Ms. Margaret Browne in manuscript preparation. This study was supported by Bristol-Myers Squibb and by Preventive Cardiology Academic Award HL-01472 from the National Heart, Lung, and Blood Institute.

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