Aggressive versus moderate lipid-lowering therapy in postmenopausal women with hypercholesterolemia: Rationale and design of the Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES) trial

Trial Design

Aggressive versus moderate lipid-lowering therapy in postmenopausal women with hypercholesterolemia: Rationale and design of the Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES) trial Paolo Raggi, MD,a Tracy Q. Callister, MD,b Michael Davidson, MD,c Francine K. Welty, MD,d Gloria A. Bachmann, MD,e Rachel Laskey, PhD,f Donald Pittman, PharmD,f Stephanie Kafonek, MD,f and Robert Scott, MDf New Orleans, La, Hendersonville, Tenn, Chicago, Ill, Boston, Mass, New Brunswick, NJ, and New York, NY

Background Electron beam tomography (EBT) is a noninvasive technique that allows the study of the entire coronary artery tree during a brief imaging session without the injection of any contrast media. Atherosclerosis is identified vicariously through the visualization of coronary calcific deposits. Quantitative assessments of calcium burden, such as calcium volume scores, have been shown to be a useful means to assess treatment-related changes in the extent of atherosclerotic plaques. Historically, the elderly female population has received less medical recognition regarding the risk and severity of coronary heart disease (CHD).

Methods In the BELLES (Beyond Endorsed Lipid Lowering with EBT Scanning) trial, the presence of asymptomatic CHD in 600 postmenopausal women will be assessed by EBT. In this 1-year, multicenter, randomized, double-blind, parallelgroup study, aggressive lipid-lowering treatment will be compared with moderate lipid-lowering treatment in postmenopausal women with hypercholesterolemia. The hypothesis we will test is that aggressive lipid-lowering therapy with 80 mg/d atorvastatin can produce greater reductions in atherosclerotic plaque burden as assessed by volumetric calcium scores than a moderate treatment with 40 mg/d pravastatin. The primary outcome measure will be the percent change from baseline in total CVS determined by EBT at 12 months.

Conclusions The results of the BELLES trial will help assess the actual incidence of CHD in postmenopausal women and the relative ability of two different lipid-lowering therapies to halt its progression. (Am Heart J 2001;141:722-6.)

Cardiovascular disease is the major cause of death for women, and the risk increases markedly in the postmenopausal period.1 Although the benefits of statins in women has been established in subgroup analyses of major clinical trials, to date there have been very few large prospective studies on the response of women to lipid-lowering therapies. The Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES) trial will test the hypothesis that aggresFrom aTulane University Health Sciences Center, New Orleans, La; bElectron Beam Tomography Research Foundation, Hendersonville, Tenn; cChicago Center for Clinical Research, Chicago, Ill; dHarvard Medical School, Boston, Mass; eUniversity of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ; and fPfizer Inc, New York, NY. Supported by Pfizer Central Research, Groton, Conn. Submitted September 12, 2000; accepted January 19, 2001. Reprint requests: Paolo Raggi, MD, Section of Cardiology, Tulane University Health Sciences Center, 1430 Tulane Ave SL48, New Orleans, LA 70112-2699. E-mail: [email protected] Copyright © 2001 by Mosby, Inc. 0002-8703/2001/$35.00 + 0 4/1/114372 doi:10.1067/mhj.2001.114372

sive cholesterol lowering with atorvastatin will produce a greater reduction in atherosclerotic plaque burden compared with moderately aggressive treatment with pravastatin in postmenopausal women with hypercholesterolemia. Treatment-related changes in the extent of atherosclerotic plaque will be studied by electron beam tomography (EBT). EBT is noninvasive, rapid, and relatively inexpensive, and it has the potential to become the method of choice for evaluating atherosclerosis progression.

Methods EBT imaging EBT imaging will be performed at 26 regional sites in the United States, with the use of C-150 Imatron scanners (Imatron, South San Francisco, Calif). A standard imaging protocol will be used: 36 to 40 continuous slices (slice thickness, 3 mm) will be obtained during a single breath-hold starting at the level of the carina and extending to the diaphragm. Imaging will be performed with 100-ms scanning time and will be

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Table I. Screening and follow-up of patients in the BELLES trial Visit Random assignment

Study period

Optional Baseline Screening screening EBCT

Procedure CHD risk factor profile Demographics, medical history, prior medications Vital signs* Complete clinical labs†‡§ Lipid profile Safety labs¶ Dispense drug Concomitant therapy Adverse events EBCT scan

Final EBCT

wk 0

wk 6

mo 3

mo 6

mo 9

X

X

X

X

X

X

X X

X X X X

X X X X X

X X X

mo 12 less 1 wk

mo 12

X X X X X X

X X

X X X

X X

X X

X

X X X X X X

*Height (at screening), weight, and blood pressure. †Serum chemistry and hematology by central laboratory (urinalysis at screening). ‡HbA1c at screening if the patient has diabetes mellitus type 1 or type 2. §Includes thyroid-stimulating hormone at screening. Includes total cholesterol, triglycerides, LDL-C, and HDL-C. ¶Includes transaminases (ALT, AST) and CPK.

triggered at 60% of the R-R interval. Calcified coronary artery areas will be identified as those with a minimum density of 130 HU and a minimum area of 3 pixels (1.03 mm2). Quantification of coronary artery calcification will be done by means of a highly reproducible volumetric calcium score method as previously described.2 In addition, patients will be required to have a total coronary calcium volume score (CVS) ≥30, as determined by EBT at the time of screening, to guarantee the best score reproducibility.2 The scans will be interpreted in a core laboratory by 2 independent readers blinded to patient treatment and each other’s interpretation. To guarantee the best image quality and the highest calcium score reproducibility, all scans showing motion artifacts will be repeated before shipping to the core laboratory. When this precaution is followed, there is no need for double scanning of the same patient in each occasion as recommended by others.3

Inclusion criteria Patients will be recruited by obstetricians and gynecologists, primary care physicians, internal medicine specialists, and cardiologists. Women will be 55 to 75 years of age and will be postmenopausal, defined as having amenorrhea for at least 1 year or currently receiving treatment with hormone replacement therapy (HRT) for at least 1 year. HRT is defined as the equivalent of ≥0.625 mg of oral conjugated estrogens given by any route of administration or in combination with progestin therapy. Women currently receiving HRT will continue to receive their current dosage for the remainder of the study. Women not receiving HRT may not begin such treatment during the study. Lipid entry criteria are low-density lipoprotein cholesterol (LDL-C) level ≥130 mg/dL (3.4 mmol/L) for women with clinical evidence of

coronary heart disease (CHD), peripheral vascular disease, or diabetes and LDL-C level ≥160 mg/dL (4.1 mmol/L) for all other women. As said above, patients will have a minimum CVS ≥30.

Exclusion criteria Patients will be excluded if they have a known contraindication to HMG-CoA reductase inhibitors (statins), for example, known hypersensitivity or hepatic dysfunction with aspartate transaminase (AST) or alanine transaminase (ALT) levels ≥1.5 times the upper limit of normal at any time between screening and randomization. Other exclusion criteria include treatment with lipid-lowering drugs other than HRT within 3 months of screening, evidence of secondary hyperlipidemia (as in nephrotic syndrome), renal dysfunction (creatinine ≥1.5 mg/dL), uncontrolled type 1 or type 2 diabetes mellitus (defined by an HbA1C >10%), uncontrolled hypothyroidism (defined by thyroid stimulating hormone >1.5 times the upper limit of normal), and plasma triglyceride levels >600 mg/dL (6.8 mmol/L). Individuals who have undergone a coronary artery bypass graft (CABG) at any time or percutaneous transluminal coronary angioplasty <12 months before screening or who have had a myocardial infarction <6 months before screening will not be eligible. Patients will also be excluded if they demonstrate evidence of other uncontrolled or concurrent conditions or medications that may affect the efficacy or safety comparisons, show the potential for noncompliance to therapy, or have body weight >300 pounds (136.2 kg). Concurrent therapy with any lipid-regulating medications (eg, niacin >500 mg/d, probucol, fibrates, bile-acid sequestering resins, other statins), drugs known to be associated with rhabdomyolysis in combination with statins, or systemic steroids is also prohibited.

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Screening and follow-up

Sample size

Patients will undergo an initial screening visit to include an assessment of their medical history, CHD risk factor profile, blood count, lipid profile, and urinalysis (Table I). If, after screening, patients are eligible for inclusion in the study, they will be scheduled for a baseline EBT scan within 3 working days at the designated regional EBT center. An optional second screening visit is allowed for patients who originally fail to qualify because of anomalous clinical laboratory results. If patients meet the inclusion/exclusion criteria at this second screening, they will then be eligible for the baseline EBT scan. Recorded baseline scans from all patients will be sent for evaluation within 2 working days to a central reading laboratory. Patients who successfully complete the screening visits and meet all inclusion and exclusion criteria will be randomly assigned within 1 week of screening to double-blind treatment with either 80 mg/d atorvastatin (2 × 40 mg) and matching pravastatin placebo or 40 mg/d pravastatin (1 × 40 mg) and matching atorvastatin placebo. Tablets will be taken at bedtime each day. After random assignment, patients will return for clinic visits at week 6 and at months 3, 6, 9, and 12 for efficacy and safety evaluations. A follow-up EBT scan will be performed 1 week before month 12 (Table I).

A sample size of 259 patients in each treatment group will have 90% power to detect a difference in mean CVS values of 10% (the difference between a 10% increase from baseline in coronary CVS for the pravastatin group vs 0% change in coronary CVS for the atorvastatin group), assuming that the common standard deviation is 35 with a 2-group t test with a .05 2-sided significance level. These calculations are based on a previous assessment of the effect of statins on coronary artery calcification by EBT.4 In that study, the average yearly CVS progression in untreated patients was +52% ± 36%, whereas the progression averaged 25% ± 22% in moderately treated patients and –7% ± 23% in aggressively treated patients. With an anticipated dropout rate of approximately 15%, enrollment of approximately 300 patients per treatment arm (total of 600) should provide an adequate number of evaluable patients.

Outcome measures The primary efficacy parameter is the percent change from baseline to month 12 in total coronary CVS determined by EBT. Analyses will be performed on the modified intent-totreat population. There will be two secondary efficacy parameters: (1) the percent change from baseline to month 12 in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, and triglycerides; (2) the percent change from baseline to month 12 in coronary CVS in each vessel: left main, left anterior descending, left circumflex, and right coronary artery determined by EBT.

Safety At each visit after screening, all adverse events will be recorded, grouped by body system and treatment group. The intensity and relation of each event to the study drug will also be summarized. Complete clinical laboratory evaluations will be performed by a central laboratory at screening and at month 12. Safety laboratory determinations alone (AST, ALT, creatine phosphokinase [CPK] levels) will be made at week 6 and at months 3 and 6. A clinically important laboratory abnormality will be reported as a serious adverse event and followed until the abnormality has been resolved or a satisfactory explanation for its occurrence has been obtained. Such an abnormality is defined as follows: CPK levels >10 times the upper limit of normal at 2 consecutive measurements 4 to 10 days apart accompanied by muscle tenderness or weakness; ALT or AST levels >3 times the upper limit of normal at 2 consecutive measurements 4 to 10 days apart. The following outcomes will also be recorded as serious adverse events: death; life-threatening adverse event; inpatient hospitalization or prolonged existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect.

Discussion Despite advances in the treatment of cardiovascular disease during the past decade, CHD remains the leading cause of death and a significant cause of morbidity among women in the United States.5 Although HRT has been shown to have a beneficial effect on plasma lipid levels in hypercholesterolemic women with CHD, the maximum reduction in LDL-C achievable with such therapy is only 10% to 15%,6,7 and the levels achieved are not always in the range recommended for the secondary prevention of CHD.8 Moreover, most of the data showing a favorable effect of HRT on coronary event reduction were collected in cohort studies and metaanalyses, and so far there is little evidence available from randomized, controlled clinical studies.6 The only controlled trial to date, the Heart and Estrogen/progestin Replacement Study (HERS), showed that HRT conferred no cardiovascular benefit over a 4.1-year treatment period despite a significant 10% decrease in LDL-C compared with placebo-treated patients.9 Furthermore, random assignment to active HRT was associated with an increased risk of cardiovascular events in women with established CHD. By contrast, the benefits of lipid-lowering therapy with statins on CHD events in women have been clearly demonstrated in a number of major clinical trials.10-13 Through their lipid-modulating effects, statins can reduce the risk of CHD events in both primary and secondary prevention patient populations while slowing the progression and in some cases inducing regression of coronary artery atherosclerosis. There is a growing body of evidence that aggressive reduction of LDL-C with statins yields enhanced clinical benefits over more moderate treatment strategies. In the Post-Coronary Artery Bypass Graft (Post-CABG) study, aggressive lowering of LDL-C with lovastatin to <100 mg/dL (2.6 mmol/L) reduced the progression of atherosclerosis in patients with CABG significantly more than moderate treatment, which lowered LDL-C

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to a level of approximately 130 mg/dL (3.4 mmol/L).14 More recently, the Atorvastatin Versus Revascularization Treatments (AVERT) trial demonstrated that in patients with stable CHD, robust LDL-C reduction with atorvastatin provided significantly greater cardiovascular benefit compared with angioplasty and usual care.15 Although results from trials such as post-CABG and AVERT are encouraging, they do not fully resolve the nature of the relation between the extent to which LDL-C is lowered and the reduction in clinical events. A definitive answer to the question of whether “lower is better” should be provided by the Treating to New Targets (TNT) study. TNT has enrolled more than 10,000 men and women with existing CHD and will investigate whether aggressive lowering of LDL-C beyond currently recommended target levels can confer additional clinical benefit. The BELLES trial has been designed to augment the findings of TNT and other lipid-lowering studies by focusing specifically on the effects of aggressive statin therapy in postmenopausal women without clinically evident CHD. Furthermore, a surrogate marker of atherosclerosis obtainable by noninvasive means such as EBT will be used for the first time in a large randomized trial. Several studies have shown that the majority of acute coronary events are caused by nonhemodynamically significant lesions.16-19 Furthermore, the benefit of lipid-lowering therapy in hypercholesterolemic patients, measured as reduction in coronary events, has often exceeded the degree of change in luminal diameter stenosis seen by coronary angiography.20,21 It has been suggested that these findings can be explained by “coronary artery remodeling,” which is known to occur in the early stages of atherosclerosis and causes outward displacement of segments of the external arterial walls.22-24 This adventitial enlargement prevents atheroma from encroaching on the lumen of the vessel, thereby concealing the presence or reducing the obstructive effect of plaques by angiography.17 A few noninvasive imaging technologies have been investigated to assess the extent of atherosclerosis. EBT, the most promising technique to date, can be used to study the entire coronary artery tree during a single imaging session.2–4 Unlike the helical scanners in wide use throughout radiology laboratories, EBT makes use of a novel radiologic technology that allows acquisition of images of the heart in only 100 ms. EBT has proved useful in the identification of coronary artery calcification, a marker of atherosclerosis,25,26 and the calcium score correlates well with the underlying atherosclerotic plaque burden.3,26,27 With the implementation of a volumetric score (CVS), the technique can be used to evaluate the effect of risk factors on atherosclerosis and to measure the effect of risk management on the stabilization/regression of atherosclerotic plaques.28 In one recent study, the extent to which atheroscle-

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rotic plaque size decreased, stabilized, or increased was found to be directly related to statin treatment and the resulting LDL-C levels.4 In the current trial, EBT and the CVS will be used to measure treatment-related changes in atherosclerotic plaque burden because this may provide important prognostic information. In fact, in a preliminary outcome study, patients with CVS progression on EBT had adverse cardiovascular events much more frequently than did patients without evidence of progression.29 The results of the BELLES trial are anticipated to add to the growing body of evidence demonstrating the ease and utility of EBT to track CHD progression, therefore enhancing acceptance of the technique for this application.

Conclusions The need for increased attention to primary and secondary prevention of CHD in women is clear. Because the postmenopausal years represent a period of marked atherosclerotic progression in women and because the health care of postmenopausal women is provided predominantly by obstetricians and gynecologists, there is a strong rationale for these specialists to assume a greater role in CHD risk management. However, the involvement of cardiologists, primary care, and internal medicine physicians will be vital to the successful recruitment of patients for this study. The BELLES trial is one of very few prospective studies investigating the effects of lipid-lowering therapy exclusively in women and is intended to raise awareness among physicians of the risk of untreated hypercholesterolemia in the postmenopausal population. Study data should provide evidence for the benefits of aggressive lipid lowering with statins in postmenopausal women as a safe and efficacious alternative or adjunct to HRT.

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