- Email: [email protected]
Antiatherosclerosis interventions in women1
Antiatherosclerosis Interventions in Women Howard N. Hodis,
MD,
Wendy J. Mack,
PhD,
Roger Lobo,
MD
Although important in reducing atherosclerosis progression and cardiovascular events in women, lowering of low-density lipoprotein cholesterol levels is not sufficient for optimum prevention. Additional potential targets for intervention include reducing levels of triglyceride-rich lipoproteins, increasing high-density lipoprotein cholesterol, and replacing certain hormones that decrease during menopause. Hormone replacement therapy (HRT) for the reduction of atherosclerosis progression and cardiovascular events has become complicated because of conflicting outcomes from recent surrogate end point studies and secondary prevention randomized clinical
trials. The key to HRT may be early intervention, when women first enter menopause and the atherosclerotic process appears to be relatively quiescent. Although many questions remain to be answered in this important area of women’s health, there is a fact that is certain: administration of HRT for the reduction of cardiovascular events is not a straightforward proposition. Powerful imaging tools for monitoring atherosclerosis progression exist that can be used to help address many questions relating to type, dose, regimen, and timing of HRT. 䊚2002 by Excerpta Medica, Inc. Am J Cardiol 2002;90(suppl):17F–21F
women as in men, atherosclerotic cardiovascular remains the number 1 cause of death. HowIever,ndisease there are potentially unique opportunities for the
MEASURING ANTIATHEROSCLEROSIS INTERVENTIONS IN WOMEN
prevention of atherosclerotic cardiovascular disease in women. Because most cardiovascular disease in women occurs in the postmenopausal phase of life, it appears that a protective factor or array of factors operative in premenopause may become inactive after menopause. Much of the current thinking hypothesizes that the protective factor present before menopause but not after menopause is estrogen.1–3 This simplification ignores other hormones and their metabolic products that diminish qualitatively, quantitatively, and in proportion to each other as a woman transitions into the menopause. It also ignores the biologic periodicity and, thus, the differences in hormonal exposure patterns between premenopause and menopause, as well as the sensitivity and responsiveness of the target end-organ tissue to the altered hormonal milieu as a woman transitions from premenopause to menopause.
From the Atherosclerosis Research Unit, Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, California, USA; and Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, New York, USA. Supported in part by a grant from the National Institute on Aging, R01AG18798. Disclosure: Dr. Hodis, Dr. Mack, and Dr. Lobo do not have a financial interest or other relationship with any manufacturer or commercial product. Discussion of unlabeled use of products: Estrogens and progestins are not labeled for reducing or slowing the progression of atherosclerosis. Address for reprints: Howard N. Hodis, MD, University of Southern California School of Medicine, Atherosclerosis Research Unit, 2250 Alcazar Street CSC 132, Los Angeles, California 90033. E-mail: [email protected]. ©2002 by Excerpta Medica, Inc. All rights reserved.
Although there may be different risk factors in women and men, the fundamental changes and stages of atherosclerosis that occur at the arterial wall level are, for the most part, indistinguishable. At its earliest stages of development, atherosclerosis may manifest as a physiologic change in vascular reactivity and/or stiffness. As the fatty streak begins to develop, so does wall thickening as a result of intima thickening and later hypertrophy of the media. Although progression from wall thickening to the fibrous plaque is typically the earliest manifestation of lumen loss, compensatory changes in the vascular wall can allow major lesion development and a heavy atherosclerosis burden before lumen obstruction and the onset of clinical symptoms. As atherosclerotic plaques progress to complicated lesions, they are marked by large lipid pools, hemorrhage, ulcerations, calcification, and, eventually, fissuring, plaque rupture, and thrombosis—the typical final common pathway to an acute cardiovascular event. All major stages of atherosclerosis progression can be measured.4 Physiologic measurements can be used to determine arterial vasoreactivity and stiffness by angiographic as well as noninvasive techniques. Arterial imaging allows direct quantitation of the atherosclerotic process. Serial coronary angiography can track lumen loss, an indirect measure of arterial wall changes, in the late phases of the atherosclerotic process. Noninvasive imaging can be used to directly measure arterial wall thickness in the earlier stages of atherosclerosis development. Cardiovascular events, the ultimate stage of atherosclerosis, can be measured in morbidity/mortality trials and observational studies. Although serial coronary angiography is the “gold standard” for measuring atherosclerosis change, this technique is limited to symptomatic individuals. Further, because this imaging endpoint is limited to lumen measurements, it can only be used to determine 0002-9149/02/$ – see front matter PII S0002-9149(02)02420-7
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the effects of interventions on the later stages of atherosclerosis progression. Regardless of these limitations, atherosclerosis progression measured by serial coronary angiography is predictive of clinical coronary events.5 Noninvasive direct quantitation of atherosclerosis is currently limited to peripheral vessels, such as the carotid and femoral arteries. The most well-established technique for direct quantitation of atherosclerosis is measurement of thickness of the carotid arterial wall by high-resolution B-mode ultrasonography.4,6 Through serial measurements of arterial wall thickness, progression of early atherosclerosis can be quantified and the effect of interventions on subclinical atherosclerosis determined. Progression of carotid arterial wall thickness correlates with progression of coronary artery atherosclerosis7 and is also predictive of clinical coronary events.6,8 For the determination of antiatherosclerosis interventions, the ultimate goal is to noninvasively quantitate coronary atherosclerosis. Current techniques, such as visualization of coronary calcium, only indirectly indicate the presence of atherosclerosis and are limited by a lack of data supporting application of this procedure to studies of antiatherosclerosis interventions. Technical issues, such as resolution, limit newer techniques, such as magnetic resonance imaging. Although a recognized hallmark of coronary atherosclerosis,9 coronary calcium appears predominantly in the late stage of atherosclerosis, and therefore, the lack of calcium in no way negates the presence of atherosclerosis. In fact, relative to the prevalence of atherosclerosis, the occurrence of coronary calcification is low, especially in women. In other words, coronary calcium is a surrogate for atherosclerosis that could be potentially useful as an endpoint in those individuals who have measurable calcium. Furthermore, serial measurement of calcium is plagued by very high variability, ranging from 30% to 50%, even when serial scans are performed over very short periods of time (⬍15 minutes).10 However, studies are under way to determine the applicability of serial coronary calcium quantitation as a noninvasive surrogate coronary atherosclerosis endpoint. These studies are being conducted with both electron-beam computed tomography and with the second-generation mechanical computed tomography imagers. With the latter, highresolution, subsecond, multirow scanning under either helical or sequential mode offers improved image acquisition through effectively faster scan times and improved signal-to-noise ratios.11 Whether the different types of imagers will make a difference in the applicability of coronary calcium quantitation as a trial endpoint remains to be determined. The growing availability of the second-generation mechanical computed tomography imagers, however, makes this tool for measuring coronary calcium more widely available. Once refined, magnetic resonance imaging has the potential for reproducibly and noninvasively imaging not only coronary artery lesions but also coronary arterial wall thickness. 18F THE AMERICAN JOURNAL OF CARDIOLOGY姞
ANTIATHEROSCLEROSIS INTERVENTIONS IN WOMEN
Reducing low-density lipoprotein cholesterol: The predominant intervention studied to date in the reduction of atherosclerosis and cardiovascular events in women has been the lowering of low-density lipoprotein cholesterol (LDL-C) with lipid-lowering medications. Although no study has been conducted solely in women, several trials have included women. In the approximately 18 serial coronary angiographic trials that reported the effects of lowering LDL-C on the progression of coronary atherosclerosis, approximately 12% of the 4,100 individuals randomized to these trials were women. Subjects who underwent LDL-C lowering in these trials were, overall, approximately twice as likely to demonstrate regression, 1.5 times more likely to demonstrate stabilization, and half as likely to demonstrate progression of coronary artery atherosclerosis relative to the placebo-treated subjects.4 Based on the reduction of progression of coronary artery atherosclerosis with LDL-C reduction, the larger morbidity/mortality trials have, as expected, shown a reduction in cardiovascular events with LDL-C lowering.12–16 In these morbidity/mortality trials, although women represented only approximately 19% of the total cohorts, they demonstrated the same degree of reduction in cardiovascular events (11% to 46%) as men (20% to 37%) in both primary and secondary prevention. However, when examined closely, the coronary angiographic trials indicate that, overall, 30% to 50% of treated subjects still demonstrated progression of coronary atherosclerosis, even under the most aggressive LDL-C lowering. In morbidity/mortality trials, LDL-C lowering resulted in only an approximately 30% reduction in cardiovascular events. Together, these trials indicate that, although important in reducing the progression of atherosclerosis and cardiovascular events, LDL-C lowering is not sufficient for optimum prevention. Other therapies may include reduction of triglyceride-rich lipoproteins, high-density lipoprotein cholesterol (HDL-C) elevation, and increasing postmenopausal hormonal levels. Reducing triglyceride-rich lipoproteins: As in men, triglycerides are a risk factor for cardiovascular events in women. This risk, however, is greater for women and is continuous and graded along the entire triglyceride range, beginning at 50 mg/dL.17 Triglycerides represent a polydisperse heterogeneous family of lipoprotein particles.18 These specific, partially delipidized lipoprotein particles may be more representative of risk and may be more appropriate targets for intervention than traditional lipid levels.19 Studies to further elucidate the role of these specific, partially delipidized lipoprotein particles in cardiovascular disease in women are in progress. Raising HDL-C: Several studies examining the role of elevating HDL-C, either as the primary hypothesis20,21 or secondarily through the reduction of triglycerides,22,23 have demonstrated the same degree of reduction in the progression of atherosclerosis and cardiovascular events as LDL-C lowering in men.
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Studies in women are thus far lacking. However, observational studies demonstrate the same degree of cardiovascular risk from the same range of HDL-C levels in men and women. Additionally, studies have indicated that up to 30% to 40% of the protective effect of estrogen replacement therapy in women is attributable to the increase in HDL-C level.
HORMONE REPLACEMENT THERAPY AND SECONDARY PREVENTION
Although there are ⱖ20 observational studies demonstrating that hormone replacement therapy (HRT) reduces cardiovascular events in postmenopausal women, randomized controlled trials have been less consistent. The Heart and Estrogen/progestin Replacement Study (HERS) demonstrated no significant reduction in cardiovascular events after 4.1 years of randomized, daily continuous combined conjugated equine estrogen (CEE) and progestin therapy relative to placebo in 2,763 postmenopausal women with established coronary artery disease.24 In a subgroup of 450 subjects, the investigators also reported that there was no effect of daily continuous combined CEE and progestin therapy relative to placebo on the progression of atherosclerosis, as assessed by serial carotid artery measurements of intima-media thickness over 4.1 years.25 The Estrogen Replacement and Atherosclerosis (ERA) trial, a randomized serial coronary angiographic trial, tested daily continuous combined CEE and progestin therapy (same regimen as HERS) and unopposed CEE therapy versus placebo in 309 women with preexisting coronary artery disease.26 After 3 years of randomized treatment, there was no effect of either daily continuous combined CEE and progestin or unopposed CEE therapy on the progression of coronary artery atherosclerosis, as measured by serial quantitative coronary angiography. The consistency of the measures of atherosclerosis progression with carotid intima-media thickness and coronary angiography with the morbidity/mortality outcome from HERS suggests that daily continuous combined CEE and progestin therapy and unopposed CEE therapy have no detectable effect on the progression of atherosclerosis in women with preexisting cardiovascular disease. The Postmenopausal Hormone Replacement Against Atherosclerosis (PHOREA) trial was a randomized, controlled, single-blind study of 321 healthy postmenopausal women 40 to 70 years of age preselected for a carotid intima-media thickness ⬎1 mm.27 The women were randomized to (1) 17-estradiol 1 mg every day plus gestodene (a progestin) 0.025 mg on days 17 to 28 of each 4-week cycle, (2) 17estradiol 1 mg every day plus gestodene 0.025 mg on days 17 to 28 of each third cycle only (every 3 months), or (3) placebo. After 48 weeks (or 12 cycles) of follow-up time, there was no difference in the progression of carotid intima-media thickness among the 3 treatment groups. Several important points should be noted about the PHOREA trial. First, although the women randomized to this trial were
“healthy,” defining the cohort with a carotid intimamedia thickness ⬎1 mm preselects individuals with advanced atherosclerosis.6 Second, there was no unopposed 17-estradiol arm in this trial. Third, although on the surface the results of PHOREA appear consistent with HERS and ERA, a treatment effect of any intervention lasting ⱕ1 year on the progression of atherosclerosis is not likely. Statistically significant treatment effects on the progression of atherosclerosis after 1 year of intervention have been noted with aggressive lipid alteration in post-hoc analyses,28 but these findings are not consistent. Reduction in cardiovascular events with antiatherosclerosis therapies consistently show divergence between intervention and placebo after 2 years of therapy.4,12–16 Thus, based on the results of many atherosclerosis and cardiovascular event trials, a significant treatment effect on the progression of atherosclerosis with 48 weeks of HRT is highly unlikely. On the other hand, physiologic parameters, such as arterial blood flow, vasoreactivity, and arterial stiffness improve over short intervals with HRT and established antiatherosclerosis interventions. Although arterial wall thickness was not significantly different between treatment arms in PHOREA after a 48-week treatment period, carotid arterial stiffness improved in the every-third-month progestin-estrogen arm relative to placebo; the effect was particularly apparent in women who were smokers.29 This has important implications, because aortic and carotid arterial stiffness are related to an increased risk of future cardiovascular and all-cause mortality, independent of established risk factors.30
ESTROGEN IN THE PRIMARY PREVENTION OF ATHEROSCLEROSIS The Estrogen in the Prevention of Atherosclerosis Trial (EPAT) was a randomized, double-blind, placebo-controlled, carotid artery ultrasound trial designed to test whether unopposed micronized 17-estradiol (1 mg/day) versus placebo reduces progression of subclinical atherosclerosis (carotid intima-media thickness) in healthy postmenopausal women without preexisting cardiovascular disease.31 All subjects were nonsmokers at randomization and remained so ontrial. Carotid artery ultrasonography was performed at baseline (2 visits) and every 6 months on-trial. The mean age of the 222 subjects randomized to EPAT was 61.1 years. The primary trial endpoint was the rate of change in the distal common carotid artery far wall intima-media thickness in computer image– processed B-mode ultrasonograms.32,33 At the end of 2 years of randomized treatment, there was a significant reduction in the progression of carotid intimamedia thickness in those women randomized to unopposed estrogen replacement therapy versus those randomized to placebo. The results of EPAT relative to HERS and ERA raise several interesting questions about the divergent outcomes and may be explained by differences in study populations. HERS and ERA were conducted in women with established cardiovascular disease, whereas EPAT was conducted in healthy women
A SYMPOSIUM: HORMONE REPLACEMENT THERAPY AND CARDIOVASCULAR DISEASE
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without preexisting cardiovascular disease. Additionally, women in EPAT were younger than those women randomized to HERS and ERA, and the interval from menopause to randomization was on average 23 years in HERS and ERA versus 13 years in EPAT. It is conceivable that HRT is an effective preventive therapy in slowing the progression of atherosclerosis while it is still limited to its early stages, but it may be less effective as a treatment once the atherosclerotic process has progressed to its later stages. These results are consistent with the pathologic findings in younger premenopausal women, in whom atherosclerosis tends to consist of more cellular fibrous tissue found in earlier stages of development, and less dense fibrous tissue found at later stages of development.34 Whether atherosclerosis is present for a shorter period of time before menopause or whether atherosclerosis develops rapidly as a woman enters menopause is unknown. Animal data suggest that lesions that develop quickly are predominantly composed of foam cells, whereas atherosclerosis that develops more slowly is composed primarily of fibrous tissue.35,36 If the loss of hormone activity permits rapid development or progression of atherosclerosis, then early intervention with HRT, perhaps in the perimenopausal period, will be more effective than initiating therapy years after menopause. This concept is similar to that used for bone protection, whereby HRT is far more effective in early menopause, when bone loss is most rapid. Thus, the younger age of the EPAT cohort relative to HERS and ERA could also be a possible explanation for the antiatherosclerosis effect seen in EPAT. The type of estrogen used in EPAT could also account for the antiatherosclerotic effect seen in EPAT versus HERS and ERA. CEE, used in HERS and ERA, is composed of many steroidal compounds, whereas micronized 17-estradiol represents the endogenous hormone produced by humans. This possibility will become more apparent later this year when the Women’s Estrogen-progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELLHART) is finalized. WELL-HART is a randomized, double-blind, placebo-controlled, serial coronary angiographic/ultrasonographic trial. A total of 226 postmenopausal women 63.5 years of age with established coronary artery disease were randomized to 1 of 3 treatment arms: (1) daily micronized 17-estradiol 1 mg/day plus medroxyprogesterone acetate placebo, (2) daily micronized 17-estradiol 1 mg/day plus active medroxyprogesterone acetate 5 mg/day for 12 sequential days of each month, and (3) daily 17estradiol placebo plus medroxyprogesterone acetate placebo. Coronary angiograms were obtained before randomization and repeated 3 years after randomized treatment under standardized protocol. The primary trial endpoint is the mean per-patient change in percent diameter stenosis determined by quantitative coronary angiography. In addition, carotid artery intimamedia thickness was determined under the same conditions and by the same protocol, methodology, technology, and imaging specialists as in EPAT. This trial will allow us to directly compare the effects of 20F THE AMERICAN JOURNAL OF CARDIOLOGY姞
17-estradiol on atherosclerosis progression in women who have established coronary artery disease versus women who do not have established disease in EPAT under very similar trial conditions and outcome measures using the same estrogen dose and regimen. WELL-HART will also provide information about whether sequentially administered medroxyprogesterone acetate attenuates the antiatherosclerosis effects of 17-estradiol in women with established cardiovascular disease. Whether progestogens negate the antiatherosclerosis effect of unopposed 17-estradiol in humans remains unanswered and is complicated by the many types, doses, and regimens available.
CONCLUSION Atherosclerosis remains the number 1 cause of death in women. Although the pathologic process of atherosclerosis is similar to that in men, the age at which women pass through the progressive stages of atherosclerosis may differ in that women appear to be in a relatively early stage of progress when they reach menopause. This provides an opportunity for intervention not offered biologically for men. If confirmed, EPAT results, along with observational, histologic, and animal data, would suggest that the best time for intervening in the atherosclerotic process in women may be early in the menopause transition, when the atherosclerotic process appears to be quiescent or relatively early. Whether all estrogen compounds and doses are equivalent needs to be determined. Whether the progestogen type, dose, or regimen negates the antiatherosclerosis effect of unopposed 17-estradiol in humans remains unanswered. A more complex question is, whether other hormones that women lack after menopause also need to be replaced before a maximal reduction in atherosclerosis progression will be realized. Although many questions remain unanswered in this important area of atherosclerosis prevention by hormone manipulation, this much remains certain: mimicking biology after menopause to capture the protection afforded women in premenopause is not a simple, straightforward proposition as previously believed. On the other hand, we have very powerful, precise, reproducible tools for tracking subclinical as well as late atherosclerosis that can be used to answer many of the questions before us.
1. Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med 1976;85:447– 452. 2. Grodstein F, Stampfer M. The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiovasc Dis 1995;38: 199 –210. 3. Grodstein F, Stampfer M. Estrogen for women at varying risk of coronary disease. Maturitas 1998;30:19 –26. 4. Blankenhorn DH, Hodis HN. Duff Memorial Lecture: arterial imaging and atherosclerosis reversal. Arterioscler Thromb 1994;14:177–192. 5. Azen SP, Mack W, Cashin-Hemphill L, LaBree L, Shircore A, Selzer RH, Blankenhorn DH, Hodis HN. Progression of coronary artery disease predicts clinical coronary events: long-term follow-up from the Cholesterol Lowering Atherosclerosis Study. Circulation 1996;93:34 – 41. 6. Hodis HN, Mack WJ. Carotid artery intima-media thickness and risk of cardiovascular events. Curr Pract Med 1999;2:171–174. 7. Mack WJ, LaBree L, Liu CL, Liu CH, Selzer RH, Hodis HN. Correlations
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between measures of atherosclerosis change using carotid ultrasonography and coronary angiography. Atherosclerosis 2000;150:371–379. 8. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu CL, Liu CH, Azen SP. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;128:262–269. 9. Blankenhorn DH. Coronary arterial calcification: a review. Am J Med Sci 1961;42:1– 49. 10. Wang S, Detrano RC, Secci A, Tang W, Doherty TM, Puentes G, Wong N, Brundage BH. Detection of coronary calcification with electron-beam computed tomography: evaluation of interexamination reproducibility and comparison of three image-acquisition protocols. Am Heart J 1996;132:550 –558. 11. Carr JJ, Crouse JR III, Goff DC Jr, D’Agostino RB Jr, Peterson NP, Burke GL. Evaluation of subsecond gated helical CT for quantification of coronary artery calcium and comparison with electron beam CT. AJR Am J Roentgenol 2000;174:915–921. 12. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301–1307. 13. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615–1622. 14. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383–1389. 15. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 16. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349 –1357. 17. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol 1992;70:3H–9H. 18. Alaupovic P. The biochemical and clinical significance of the interrelationship between very low density and high density lipoproteins. Can J Biochem 1981;59:565–579. 19. Hodis HN, Mack WJ. Triglyceride–rich lipoproteins and the progression of coronary artery disease. Curr Opin Lipidol 1995;6:209 –214. 20. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, for the Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410 – 418. 21. Brown BG, Zhao XQ, Chait A, Fisher LD, Dowdy A, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583–1592.
22. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK,
Kaitaniemi P, Koskinen P, Manninen V, et al. Helsinki Heart Study: primaryprevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987;317:1237–1245. 23. Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet 1996;347:849 – 853. 24. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605– 613. 25. Byington RP, Furberg C, Riley W, Applegate W, Herd A, Herrington D, Hunninghake D, Lowery M. Effect of estrogen and progestin on progression of carotid atherosclerosis in postmenopausal women with documented heart disease: HERS B-mode substudy [abstract]. J Am Coll Cardiol 1999;(suppl):265A. 26. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Givens DH, Waters D. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522–529. 27. Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis: a randomized controlled trial. Arterioscl Thromb Vasc Biol 2001;21:262–268. 28. Mack WJ, Selzer RH, Hodis HN, Erickson JK, Liu CR, Liu CH, Crawford DW, Blankenhorn DH. One-year reduction and longitudinal analysis of carotid intima-media thickness associated with colestipol/niacin therapy. Stroke 1993; 24:1779 –1783. 29. Angerer P, Kothny W, Stork S, von Schacky C. Hormone replacement therapy and distensibility of carotid arteries in postmenopausal women: a randomized controlled trial. J Am Coll Cardiol 2000;36:1789 –1796. 30. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999;99:2434 –2439. 31. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu CR, Liu CH, Azen SP, for the Estrogen in the Prevention of Atherosclerosis Trial Research Group. Estrogen in the Prevention of Atherosclerosis Trial: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939 –953. 32. Selzer RH, Hodis HN, Kwong-Fu H, Mack WJ, Lee PL, Liu CR, Liu CH. Evaluation of computerized edge tracking for quantifying intima-media thickness of the common carotid artery from B-mode ultrasound images. Atherosclerosis 1994;111:1–11. 33. Selzer RH, Mack WJ, Lee PL, Kwong–Fu H, Hodis HN. Improved common carotid elasticity and intima-media thickness measurement from computer analysis of sequential ultrasound frames. Atherosclerosis 2001;154:185–193. 34. Dollar AL, Kragel AH, Fernicola DJ, Waclawiw MA, Roberts WC. Composition of atherosclerotic plaques in coronary arteries in women ⬍40 years of age with fatal coronary artery disease and implications for plaque reversibility. Am J Cardiol 1991;67:1223–1227. 35. Wissler RW. Atherosclerosis: its pathogenesis in perspective. Adv Cardiol 1974;13:10 –31. 36. Wilson RB, Miller RA, Middleton CC, Kinden D. Atherosclerosis in rabbits fed a low cholesterol diet for five years. Arteriosclerosis 1982;2:228 –240.
A SYMPOSIUM: HORMONE REPLACEMENT THERAPY AND CARDIOVASCULAR DISEASE
21F
MD,
Wendy J. Mack,
PhD,
Roger Lobo,
MD
Although important in reducing atherosclerosis progression and cardiovascular events in women, lowering of low-density lipoprotein cholesterol levels is not sufficient for optimum prevention. Additional potential targets for intervention include reducing levels of triglyceride-rich lipoproteins, increasing high-density lipoprotein cholesterol, and replacing certain hormones that decrease during menopause. Hormone replacement therapy (HRT) for the reduction of atherosclerosis progression and cardiovascular events has become complicated because of conflicting outcomes from recent surrogate end point studies and secondary prevention randomized clinical
trials. The key to HRT may be early intervention, when women first enter menopause and the atherosclerotic process appears to be relatively quiescent. Although many questions remain to be answered in this important area of women’s health, there is a fact that is certain: administration of HRT for the reduction of cardiovascular events is not a straightforward proposition. Powerful imaging tools for monitoring atherosclerosis progression exist that can be used to help address many questions relating to type, dose, regimen, and timing of HRT. 䊚2002 by Excerpta Medica, Inc. Am J Cardiol 2002;90(suppl):17F–21F
women as in men, atherosclerotic cardiovascular remains the number 1 cause of death. HowIever,ndisease there are potentially unique opportunities for the
MEASURING ANTIATHEROSCLEROSIS INTERVENTIONS IN WOMEN
prevention of atherosclerotic cardiovascular disease in women. Because most cardiovascular disease in women occurs in the postmenopausal phase of life, it appears that a protective factor or array of factors operative in premenopause may become inactive after menopause. Much of the current thinking hypothesizes that the protective factor present before menopause but not after menopause is estrogen.1–3 This simplification ignores other hormones and their metabolic products that diminish qualitatively, quantitatively, and in proportion to each other as a woman transitions into the menopause. It also ignores the biologic periodicity and, thus, the differences in hormonal exposure patterns between premenopause and menopause, as well as the sensitivity and responsiveness of the target end-organ tissue to the altered hormonal milieu as a woman transitions from premenopause to menopause.
From the Atherosclerosis Research Unit, Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, California, USA; and Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, New York, USA. Supported in part by a grant from the National Institute on Aging, R01AG18798. Disclosure: Dr. Hodis, Dr. Mack, and Dr. Lobo do not have a financial interest or other relationship with any manufacturer or commercial product. Discussion of unlabeled use of products: Estrogens and progestins are not labeled for reducing or slowing the progression of atherosclerosis. Address for reprints: Howard N. Hodis, MD, University of Southern California School of Medicine, Atherosclerosis Research Unit, 2250 Alcazar Street CSC 132, Los Angeles, California 90033. E-mail: [email protected]. ©2002 by Excerpta Medica, Inc. All rights reserved.
Although there may be different risk factors in women and men, the fundamental changes and stages of atherosclerosis that occur at the arterial wall level are, for the most part, indistinguishable. At its earliest stages of development, atherosclerosis may manifest as a physiologic change in vascular reactivity and/or stiffness. As the fatty streak begins to develop, so does wall thickening as a result of intima thickening and later hypertrophy of the media. Although progression from wall thickening to the fibrous plaque is typically the earliest manifestation of lumen loss, compensatory changes in the vascular wall can allow major lesion development and a heavy atherosclerosis burden before lumen obstruction and the onset of clinical symptoms. As atherosclerotic plaques progress to complicated lesions, they are marked by large lipid pools, hemorrhage, ulcerations, calcification, and, eventually, fissuring, plaque rupture, and thrombosis—the typical final common pathway to an acute cardiovascular event. All major stages of atherosclerosis progression can be measured.4 Physiologic measurements can be used to determine arterial vasoreactivity and stiffness by angiographic as well as noninvasive techniques. Arterial imaging allows direct quantitation of the atherosclerotic process. Serial coronary angiography can track lumen loss, an indirect measure of arterial wall changes, in the late phases of the atherosclerotic process. Noninvasive imaging can be used to directly measure arterial wall thickness in the earlier stages of atherosclerosis development. Cardiovascular events, the ultimate stage of atherosclerosis, can be measured in morbidity/mortality trials and observational studies. Although serial coronary angiography is the “gold standard” for measuring atherosclerosis change, this technique is limited to symptomatic individuals. Further, because this imaging endpoint is limited to lumen measurements, it can only be used to determine 0002-9149/02/$ – see front matter PII S0002-9149(02)02420-7
17F
the effects of interventions on the later stages of atherosclerosis progression. Regardless of these limitations, atherosclerosis progression measured by serial coronary angiography is predictive of clinical coronary events.5 Noninvasive direct quantitation of atherosclerosis is currently limited to peripheral vessels, such as the carotid and femoral arteries. The most well-established technique for direct quantitation of atherosclerosis is measurement of thickness of the carotid arterial wall by high-resolution B-mode ultrasonography.4,6 Through serial measurements of arterial wall thickness, progression of early atherosclerosis can be quantified and the effect of interventions on subclinical atherosclerosis determined. Progression of carotid arterial wall thickness correlates with progression of coronary artery atherosclerosis7 and is also predictive of clinical coronary events.6,8 For the determination of antiatherosclerosis interventions, the ultimate goal is to noninvasively quantitate coronary atherosclerosis. Current techniques, such as visualization of coronary calcium, only indirectly indicate the presence of atherosclerosis and are limited by a lack of data supporting application of this procedure to studies of antiatherosclerosis interventions. Technical issues, such as resolution, limit newer techniques, such as magnetic resonance imaging. Although a recognized hallmark of coronary atherosclerosis,9 coronary calcium appears predominantly in the late stage of atherosclerosis, and therefore, the lack of calcium in no way negates the presence of atherosclerosis. In fact, relative to the prevalence of atherosclerosis, the occurrence of coronary calcification is low, especially in women. In other words, coronary calcium is a surrogate for atherosclerosis that could be potentially useful as an endpoint in those individuals who have measurable calcium. Furthermore, serial measurement of calcium is plagued by very high variability, ranging from 30% to 50%, even when serial scans are performed over very short periods of time (⬍15 minutes).10 However, studies are under way to determine the applicability of serial coronary calcium quantitation as a noninvasive surrogate coronary atherosclerosis endpoint. These studies are being conducted with both electron-beam computed tomography and with the second-generation mechanical computed tomography imagers. With the latter, highresolution, subsecond, multirow scanning under either helical or sequential mode offers improved image acquisition through effectively faster scan times and improved signal-to-noise ratios.11 Whether the different types of imagers will make a difference in the applicability of coronary calcium quantitation as a trial endpoint remains to be determined. The growing availability of the second-generation mechanical computed tomography imagers, however, makes this tool for measuring coronary calcium more widely available. Once refined, magnetic resonance imaging has the potential for reproducibly and noninvasively imaging not only coronary artery lesions but also coronary arterial wall thickness. 18F THE AMERICAN JOURNAL OF CARDIOLOGY姞
ANTIATHEROSCLEROSIS INTERVENTIONS IN WOMEN
Reducing low-density lipoprotein cholesterol: The predominant intervention studied to date in the reduction of atherosclerosis and cardiovascular events in women has been the lowering of low-density lipoprotein cholesterol (LDL-C) with lipid-lowering medications. Although no study has been conducted solely in women, several trials have included women. In the approximately 18 serial coronary angiographic trials that reported the effects of lowering LDL-C on the progression of coronary atherosclerosis, approximately 12% of the 4,100 individuals randomized to these trials were women. Subjects who underwent LDL-C lowering in these trials were, overall, approximately twice as likely to demonstrate regression, 1.5 times more likely to demonstrate stabilization, and half as likely to demonstrate progression of coronary artery atherosclerosis relative to the placebo-treated subjects.4 Based on the reduction of progression of coronary artery atherosclerosis with LDL-C reduction, the larger morbidity/mortality trials have, as expected, shown a reduction in cardiovascular events with LDL-C lowering.12–16 In these morbidity/mortality trials, although women represented only approximately 19% of the total cohorts, they demonstrated the same degree of reduction in cardiovascular events (11% to 46%) as men (20% to 37%) in both primary and secondary prevention. However, when examined closely, the coronary angiographic trials indicate that, overall, 30% to 50% of treated subjects still demonstrated progression of coronary atherosclerosis, even under the most aggressive LDL-C lowering. In morbidity/mortality trials, LDL-C lowering resulted in only an approximately 30% reduction in cardiovascular events. Together, these trials indicate that, although important in reducing the progression of atherosclerosis and cardiovascular events, LDL-C lowering is not sufficient for optimum prevention. Other therapies may include reduction of triglyceride-rich lipoproteins, high-density lipoprotein cholesterol (HDL-C) elevation, and increasing postmenopausal hormonal levels. Reducing triglyceride-rich lipoproteins: As in men, triglycerides are a risk factor for cardiovascular events in women. This risk, however, is greater for women and is continuous and graded along the entire triglyceride range, beginning at 50 mg/dL.17 Triglycerides represent a polydisperse heterogeneous family of lipoprotein particles.18 These specific, partially delipidized lipoprotein particles may be more representative of risk and may be more appropriate targets for intervention than traditional lipid levels.19 Studies to further elucidate the role of these specific, partially delipidized lipoprotein particles in cardiovascular disease in women are in progress. Raising HDL-C: Several studies examining the role of elevating HDL-C, either as the primary hypothesis20,21 or secondarily through the reduction of triglycerides,22,23 have demonstrated the same degree of reduction in the progression of atherosclerosis and cardiovascular events as LDL-C lowering in men.
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Studies in women are thus far lacking. However, observational studies demonstrate the same degree of cardiovascular risk from the same range of HDL-C levels in men and women. Additionally, studies have indicated that up to 30% to 40% of the protective effect of estrogen replacement therapy in women is attributable to the increase in HDL-C level.
HORMONE REPLACEMENT THERAPY AND SECONDARY PREVENTION
Although there are ⱖ20 observational studies demonstrating that hormone replacement therapy (HRT) reduces cardiovascular events in postmenopausal women, randomized controlled trials have been less consistent. The Heart and Estrogen/progestin Replacement Study (HERS) demonstrated no significant reduction in cardiovascular events after 4.1 years of randomized, daily continuous combined conjugated equine estrogen (CEE) and progestin therapy relative to placebo in 2,763 postmenopausal women with established coronary artery disease.24 In a subgroup of 450 subjects, the investigators also reported that there was no effect of daily continuous combined CEE and progestin therapy relative to placebo on the progression of atherosclerosis, as assessed by serial carotid artery measurements of intima-media thickness over 4.1 years.25 The Estrogen Replacement and Atherosclerosis (ERA) trial, a randomized serial coronary angiographic trial, tested daily continuous combined CEE and progestin therapy (same regimen as HERS) and unopposed CEE therapy versus placebo in 309 women with preexisting coronary artery disease.26 After 3 years of randomized treatment, there was no effect of either daily continuous combined CEE and progestin or unopposed CEE therapy on the progression of coronary artery atherosclerosis, as measured by serial quantitative coronary angiography. The consistency of the measures of atherosclerosis progression with carotid intima-media thickness and coronary angiography with the morbidity/mortality outcome from HERS suggests that daily continuous combined CEE and progestin therapy and unopposed CEE therapy have no detectable effect on the progression of atherosclerosis in women with preexisting cardiovascular disease. The Postmenopausal Hormone Replacement Against Atherosclerosis (PHOREA) trial was a randomized, controlled, single-blind study of 321 healthy postmenopausal women 40 to 70 years of age preselected for a carotid intima-media thickness ⬎1 mm.27 The women were randomized to (1) 17-estradiol 1 mg every day plus gestodene (a progestin) 0.025 mg on days 17 to 28 of each 4-week cycle, (2) 17estradiol 1 mg every day plus gestodene 0.025 mg on days 17 to 28 of each third cycle only (every 3 months), or (3) placebo. After 48 weeks (or 12 cycles) of follow-up time, there was no difference in the progression of carotid intima-media thickness among the 3 treatment groups. Several important points should be noted about the PHOREA trial. First, although the women randomized to this trial were
“healthy,” defining the cohort with a carotid intimamedia thickness ⬎1 mm preselects individuals with advanced atherosclerosis.6 Second, there was no unopposed 17-estradiol arm in this trial. Third, although on the surface the results of PHOREA appear consistent with HERS and ERA, a treatment effect of any intervention lasting ⱕ1 year on the progression of atherosclerosis is not likely. Statistically significant treatment effects on the progression of atherosclerosis after 1 year of intervention have been noted with aggressive lipid alteration in post-hoc analyses,28 but these findings are not consistent. Reduction in cardiovascular events with antiatherosclerosis therapies consistently show divergence between intervention and placebo after 2 years of therapy.4,12–16 Thus, based on the results of many atherosclerosis and cardiovascular event trials, a significant treatment effect on the progression of atherosclerosis with 48 weeks of HRT is highly unlikely. On the other hand, physiologic parameters, such as arterial blood flow, vasoreactivity, and arterial stiffness improve over short intervals with HRT and established antiatherosclerosis interventions. Although arterial wall thickness was not significantly different between treatment arms in PHOREA after a 48-week treatment period, carotid arterial stiffness improved in the every-third-month progestin-estrogen arm relative to placebo; the effect was particularly apparent in women who were smokers.29 This has important implications, because aortic and carotid arterial stiffness are related to an increased risk of future cardiovascular and all-cause mortality, independent of established risk factors.30
ESTROGEN IN THE PRIMARY PREVENTION OF ATHEROSCLEROSIS The Estrogen in the Prevention of Atherosclerosis Trial (EPAT) was a randomized, double-blind, placebo-controlled, carotid artery ultrasound trial designed to test whether unopposed micronized 17-estradiol (1 mg/day) versus placebo reduces progression of subclinical atherosclerosis (carotid intima-media thickness) in healthy postmenopausal women without preexisting cardiovascular disease.31 All subjects were nonsmokers at randomization and remained so ontrial. Carotid artery ultrasonography was performed at baseline (2 visits) and every 6 months on-trial. The mean age of the 222 subjects randomized to EPAT was 61.1 years. The primary trial endpoint was the rate of change in the distal common carotid artery far wall intima-media thickness in computer image– processed B-mode ultrasonograms.32,33 At the end of 2 years of randomized treatment, there was a significant reduction in the progression of carotid intimamedia thickness in those women randomized to unopposed estrogen replacement therapy versus those randomized to placebo. The results of EPAT relative to HERS and ERA raise several interesting questions about the divergent outcomes and may be explained by differences in study populations. HERS and ERA were conducted in women with established cardiovascular disease, whereas EPAT was conducted in healthy women
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without preexisting cardiovascular disease. Additionally, women in EPAT were younger than those women randomized to HERS and ERA, and the interval from menopause to randomization was on average 23 years in HERS and ERA versus 13 years in EPAT. It is conceivable that HRT is an effective preventive therapy in slowing the progression of atherosclerosis while it is still limited to its early stages, but it may be less effective as a treatment once the atherosclerotic process has progressed to its later stages. These results are consistent with the pathologic findings in younger premenopausal women, in whom atherosclerosis tends to consist of more cellular fibrous tissue found in earlier stages of development, and less dense fibrous tissue found at later stages of development.34 Whether atherosclerosis is present for a shorter period of time before menopause or whether atherosclerosis develops rapidly as a woman enters menopause is unknown. Animal data suggest that lesions that develop quickly are predominantly composed of foam cells, whereas atherosclerosis that develops more slowly is composed primarily of fibrous tissue.35,36 If the loss of hormone activity permits rapid development or progression of atherosclerosis, then early intervention with HRT, perhaps in the perimenopausal period, will be more effective than initiating therapy years after menopause. This concept is similar to that used for bone protection, whereby HRT is far more effective in early menopause, when bone loss is most rapid. Thus, the younger age of the EPAT cohort relative to HERS and ERA could also be a possible explanation for the antiatherosclerosis effect seen in EPAT. The type of estrogen used in EPAT could also account for the antiatherosclerotic effect seen in EPAT versus HERS and ERA. CEE, used in HERS and ERA, is composed of many steroidal compounds, whereas micronized 17-estradiol represents the endogenous hormone produced by humans. This possibility will become more apparent later this year when the Women’s Estrogen-progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELLHART) is finalized. WELL-HART is a randomized, double-blind, placebo-controlled, serial coronary angiographic/ultrasonographic trial. A total of 226 postmenopausal women 63.5 years of age with established coronary artery disease were randomized to 1 of 3 treatment arms: (1) daily micronized 17-estradiol 1 mg/day plus medroxyprogesterone acetate placebo, (2) daily micronized 17-estradiol 1 mg/day plus active medroxyprogesterone acetate 5 mg/day for 12 sequential days of each month, and (3) daily 17estradiol placebo plus medroxyprogesterone acetate placebo. Coronary angiograms were obtained before randomization and repeated 3 years after randomized treatment under standardized protocol. The primary trial endpoint is the mean per-patient change in percent diameter stenosis determined by quantitative coronary angiography. In addition, carotid artery intimamedia thickness was determined under the same conditions and by the same protocol, methodology, technology, and imaging specialists as in EPAT. This trial will allow us to directly compare the effects of 20F THE AMERICAN JOURNAL OF CARDIOLOGY姞
17-estradiol on atherosclerosis progression in women who have established coronary artery disease versus women who do not have established disease in EPAT under very similar trial conditions and outcome measures using the same estrogen dose and regimen. WELL-HART will also provide information about whether sequentially administered medroxyprogesterone acetate attenuates the antiatherosclerosis effects of 17-estradiol in women with established cardiovascular disease. Whether progestogens negate the antiatherosclerosis effect of unopposed 17-estradiol in humans remains unanswered and is complicated by the many types, doses, and regimens available.
CONCLUSION Atherosclerosis remains the number 1 cause of death in women. Although the pathologic process of atherosclerosis is similar to that in men, the age at which women pass through the progressive stages of atherosclerosis may differ in that women appear to be in a relatively early stage of progress when they reach menopause. This provides an opportunity for intervention not offered biologically for men. If confirmed, EPAT results, along with observational, histologic, and animal data, would suggest that the best time for intervening in the atherosclerotic process in women may be early in the menopause transition, when the atherosclerotic process appears to be quiescent or relatively early. Whether all estrogen compounds and doses are equivalent needs to be determined. Whether the progestogen type, dose, or regimen negates the antiatherosclerosis effect of unopposed 17-estradiol in humans remains unanswered. A more complex question is, whether other hormones that women lack after menopause also need to be replaced before a maximal reduction in atherosclerosis progression will be realized. Although many questions remain unanswered in this important area of atherosclerosis prevention by hormone manipulation, this much remains certain: mimicking biology after menopause to capture the protection afforded women in premenopause is not a simple, straightforward proposition as previously believed. On the other hand, we have very powerful, precise, reproducible tools for tracking subclinical as well as late atherosclerosis that can be used to answer many of the questions before us.
1. Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med 1976;85:447– 452. 2. Grodstein F, Stampfer M. The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiovasc Dis 1995;38: 199 –210. 3. Grodstein F, Stampfer M. Estrogen for women at varying risk of coronary disease. Maturitas 1998;30:19 –26. 4. Blankenhorn DH, Hodis HN. Duff Memorial Lecture: arterial imaging and atherosclerosis reversal. Arterioscler Thromb 1994;14:177–192. 5. Azen SP, Mack W, Cashin-Hemphill L, LaBree L, Shircore A, Selzer RH, Blankenhorn DH, Hodis HN. Progression of coronary artery disease predicts clinical coronary events: long-term follow-up from the Cholesterol Lowering Atherosclerosis Study. Circulation 1996;93:34 – 41. 6. Hodis HN, Mack WJ. Carotid artery intima-media thickness and risk of cardiovascular events. Curr Pract Med 1999;2:171–174. 7. Mack WJ, LaBree L, Liu CL, Liu CH, Selzer RH, Hodis HN. Correlations
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between measures of atherosclerosis change using carotid ultrasonography and coronary angiography. Atherosclerosis 2000;150:371–379. 8. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu CL, Liu CH, Azen SP. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;128:262–269. 9. Blankenhorn DH. Coronary arterial calcification: a review. Am J Med Sci 1961;42:1– 49. 10. Wang S, Detrano RC, Secci A, Tang W, Doherty TM, Puentes G, Wong N, Brundage BH. Detection of coronary calcification with electron-beam computed tomography: evaluation of interexamination reproducibility and comparison of three image-acquisition protocols. Am Heart J 1996;132:550 –558. 11. Carr JJ, Crouse JR III, Goff DC Jr, D’Agostino RB Jr, Peterson NP, Burke GL. Evaluation of subsecond gated helical CT for quantification of coronary artery calcium and comparison with electron beam CT. AJR Am J Roentgenol 2000;174:915–921. 12. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301–1307. 13. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615–1622. 14. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383–1389. 15. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 16. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349 –1357. 17. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol 1992;70:3H–9H. 18. Alaupovic P. The biochemical and clinical significance of the interrelationship between very low density and high density lipoproteins. Can J Biochem 1981;59:565–579. 19. Hodis HN, Mack WJ. Triglyceride–rich lipoproteins and the progression of coronary artery disease. Curr Opin Lipidol 1995;6:209 –214. 20. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, for the Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410 – 418. 21. Brown BG, Zhao XQ, Chait A, Fisher LD, Dowdy A, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583–1592.
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