Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis
David M. Herrington, M.D., M.H.S., David M. Reboussin, Ph.D., K. Bridget Brosnihan, Ph.D., Penny C. Sharp, Ed.D., Sally A. Shumaker, Ph.D., Thomas E. Snyder, M.D., Curt D. Furberg, M.D., Ph.D., Glen J. Kowalchuk, M.D., Thomas D. Stuckey, M.D., William J. Rogers, M.D., David H. Givens, M.D., and David Waters, M.D.
Background Heart disease is a major cause of illness and deathin women. To understand better the role of estrogen in the treatmentand prevention of heart disease, more information is neededabout its effects on coronary atherosclerosis and the extentto which concomitant progestin therapy may modify these effects.
Methods We randomly assigned a total of 309 women with angiographicallyverified coronary disease to receive 0.625 mg of conjugatedestrogen per day, 0.625 mg of conjugated estrogen plus 2.5 mgof medroxyprogesterone acetate per day, or placebo. The womenwere followed for a mean (±SD) of 3.2±0.6 years.Base-line and follow-up coronary angiograms were analyzed byquantitative methods.
Results Estrogen and estrogen plus medroxyprogesterone acetateproduced significant reductions in low-density lipoprotein cholesterollevels (9.4 percent and 16.5 percent, respectively) and significantincreases in high-density lipoprotein cholesterol levels (18.8percent and 14.2 percent, respectively); however, neither treatmentaltered the progression of coronary atherosclerosis. After adjustmentfor measurements at base line, the mean (±SE) minimalcoronary-artery diameters at follow-up were 1.87±0.02mm, 1.84±0.02 mm, and 1.87±0.02 mm in women assignedto estrogen, estrogen plus medroxyprogesterone acetate, andplacebo, respectively. The differences between the values forthe two active-treatment groups and the value for the placebogroup were not significant. Analyses of several secondary angiographicoutcomes and subgroups of women produced similar results. Therates of clinical cardiovascular events were also similar amongthe treatment groups.
Conclusions Neither estrogen alone nor estrogen plus medroxyprogesteroneacetate affected the progression of coronary atherosclerosisin women with established disease. These results suggest thatsuch women should not use estrogen replacement with an expectationof cardiovascular benefit.
Postmenopausal estrogen replacement has been recommended forthe secondary prevention of heart disease in women1,2,3 on thebasis of abundant observational data showing that women whoreceived postmenopausal hormone-replacement therapy had fewercardiovascular events than those who did not4,5 and numerousclinical and laboratory studies demonstrating favorable effectsof estrogen on cardiovascular risk factors and experimentalatherosclerosis.6,7 Thus, it was a surprise when the Heart andEstrogen/Progestin Replacement Study found no overall effectof 4.1 years of treatment with conjugated estrogen plus medroxyprogesteroneacetate on the risk of nonfatal myocardial infarction and deathfrom coronary heart disease among women with established coronaryatherosclerosis.8 These results were complicated by an earlyincrease and a late reduction in risk within the overall nulleffect.
Several hypotheses have been proposed to explain these results.Some have argued that a single, relatively short clinical trialmay not reliably predict long-term benefit, especially whenso much a priori evidence suggests that estrogen should be beneficial.9,10Others have wondered whether the favorable effects of estrogenare attenuated by medroxyprogesterone acetate.11 Finally, realbenefits of estrogen may have been offset by previously unrecognizedor underemphasized prothrombotic or proinflammatory effects— possibly limited to a subgroup of women.12 Such questionshave made it difficult for women and their physicians to knowhow to respond to these results. To clarify the role of estrogenin the secondary prevention of heart disease, more informationis needed about its effects on the underlying disease process— coronary atherosclerosis — and the extent to whichmedroxyprogesterone acetate may modify the effects of estrogen.
The Estrogen Replacement and Atherosclerosis trial is a randomized,double-blind, placebo-controlled clinical trial that has examinedthe effects of hormone-replacement therapy on the progressionof coronary atherosclerosis in women. A total of 309 postmenopausalwomen who had angiographically verified coronary artery diseaseat base line were randomly assigned to receive unopposed estrogen,estrogen plus medroxyprogesterone acetate, or placebo and werescheduled for coronary angiography about three years after randomization.In this report we describe the effects of treatment on the progressionof coronary atherosclerosis as measured by quantitative coronaryangiography.
Methods
Subjects
The study design was approved by institutional review boardsat the participating sites and has been described in detailelsewhere.13 Between January 1995 and December 1996, women wererecruited at one of six clinical sites (see the Appendix). Womenwere eligible if they were postmenopausal, were not currentlyreceiving estrogen-replacement treatment, and had one or moreepicardial coronary stenoses of at least 30 percent of the luminaldiameter, as measured by quantitative coronary angiography.Postmenopausal status was defined as the presence of one ofthe following conditions: an age of at least 55 years withoutnatural menses for at least five years; no natural menses forat least one year and a serum follicle-stimulating hormone levelof more than 40 IU per liter; documented bilateral oophorectomy;or self-reported bilateral oophorectomy, a follicle-stimulatinghormone level of more than 40 IU per liter, and a serum estradiollevel of less than 25 pg per milliliter (91.8 pmol per liter).The 28 women who were taking replacement estrogen at the screeningvisit were asked to stop for three months before being assignedto treatment.
Women were excluded if they had known or suspected breast orendometrial carcinoma, previous or planned coronary-artery bypasssurgery, a history of deep-vein thrombosis or pulmonary embolism,symptomatic gallstones, a serum aspartate aminotransferase levelmore than 1.5 times the normal value, a triglyceride level ofmore than 400 mg per deciliter (4.52 mmol per liter) while fasting,a serum creatinine level of more than 2.0 mg per deciliter (176.8µmol per liter), more than 70 percent stenosis of theleft main coronary artery, uncontrolled hypertension, or uncontrolleddiabetes. Of the 815 women screened, 309 (38 percent) were subsequentlyenrolled. In 150 of the 309 women (49 percent), the base-lineangiogram was obtained for clinical evaluation of ischemic heartdisease. In the others, base-line research angiography was performedto establish eligibility.
Treatment
After their informed consent had been obtained, the 309 eligiblewomen were randomly assigned to three groups by a permuted-blockrandomization procedure after stratification according to theiruse of lipid-lowering therapy and the clinical site. Each womanreceived two tablets daily. The women in the estrogen groupreceived one tablet containing 0.625 mg of conjugated equineestrogen (Premarin, Wyeth–Ayerst Research, Radnor, Pa.)and a placebo tablet. Those in the estrogen-plus-medroxyprogesteronegroup received a tablet containing 0.625 mg of conjugated equineestrogen plus 2.5 mg of medroxyprogesterone acetate (Prempro,Wyeth–Ayerst) and a placebo tablet. Those in the placebogroup received two placebo tablets.
Follow-Up
The participants were followed up in the clinic every six monthsand were contacted by telephone at three-month intervals betweenclinic visits. During each visit, compliance with study medicationwas assessed by pill count, and an interval medical historywas taken. For any suspected cardiovascular event, the admissionand discharge notes, electrocardiograms, cardiac-enzyme values,and data from cardiovascular testing and procedures were abstractedand sent to an independent end-point adjudicator who was unawareof the women's treatment assignments. The classification strategywas based on that used in the Heart and Estrogen/Progestin ReplacementStudy.13,14
At base line and annually thereafter, all the women underwentscreening mammography and gynecologic examinations, includingPapanicolaou smears and endometrial aspiration or vaginal ultrasoundexamination to detect subclinical hyperplasia. All gynecologicexaminations, data collection, and management of gynecologicadverse events were performed by staff and physicians otherthan those responsible for the collection of data on cardiovascularend points.
Angiographic data obtained at base line and a mean (±SD)of 3.2±0.6 years later were available for 248 of the309 subjects (80 percent). Twelve women (4 percent) died beforeundergoing follow-up angiography, and 44 (14 percent) droppedout or refused follow-up angiography; the base-line or follow-upfilms of 5 women (2 percent) were lost. Among the women forwhom angiographic follow-up data were available, those assignedto unopposed estrogen took 74 percent of their prescribed studymedication, as compared with 84 percent in the women assignedto estrogen plus medroxyprogesterone acetate and 86 percentin those assigned to placebo (P=0.03). Five women assigned toplacebo stopped taking the study drug and began taking open-labelestrogen during the trial.
Angiographic Evaluation
Base-line and follow-up coronary angiography was performed inidentical standardized fashion after the administration of 0.4mg of sublingual nitroglycerin (unless contraindicated by hypotension).A minimum of three sets of orthogonal views of the left coronaryartery and one of the right coronary artery were obtained atbase line and repeated exactly at follow-up. Clinically indicatedcoronary angiograms obtained within six months of the finalangiogram required by the study protocol were treated as finalangiograms to avoid the need to ask these women to undergo furtherangiography. For women who underwent percutaneous transluminalcoronary angioplasty or coronary-artery bypass grafting duringfollow-up (59 women [19 percent]), the angiogram obtained beforethe intervention was also analyzed. In 11 women (4 percent ofthe 309 women enrolled in the study), a clinically indicatedinterim angiogram without a subsequent invasive procedure wasthe only angiographic follow-up available.
Review and analysis of the paired films were performed witha previously validated system of cine projectors (SME-3500,Sony, Park Ridge, N.J.) and software (QCAPlus, Sanders DataSystems, Palo Alto, Calif.).15,16 With this system, the meanintraoperator difference between blinded duplicate measurementsof minimal diameter for vessels with lesions is 0.02 mm.16 Thereference, minimal, and average luminal diameters, as well asthe degree of stenosis as a percentage of the reference diameter,were obtained for 10 proximal and up to 11 optional epicardialcoronary segments, as explained in detail previously.13 If alesion was evident on either film, the analysis was directedto that portion of the segment. In segments with no obviouslesions, as much as possible of the proximal portion of thesegment in question was analyzed. In 84 subjects, one or moresegments could not be analyzed at base line or follow-up becauseof total occlusion or intervening coronary-artery bypass graftsurgery. The analyses were performed by operators who were unawareof the women's treatment assignments and the temporal sequenceof the films.
Statistical Analysis
The primary outcome was prespecified as the mean minimal coronary-arterydiameter within each subject at follow-up, analyzed on an intention-to-treatbasis.13 A mixed-model analysis of covariance was fitted, withadjustment for angiographic measurement at base line, locationof the segment in the coronary tree, length of follow-up, thespecific clinic, use of lipid-lowering therapy at base line,and a random subject effect. The analysis did not assume thatvariation in disease progression was the same across all locationsin the coronary tree and allowed for correlation in responsesof the segment within a given subject. Although the individualcoronary segment was the unit of measurement, group comparisonswere based on effects in the subjects, since the subject wasthe unit of randomization. Sensitivity analyses were performedto assess the effect of including subjects with clinically indicatedfollow-up angiography, segments measured before coronary-arterybypass grafting or percutaneous transluminal coronary angioplasty,and segments that were unavailable for analysis because of newtotal occlusions that occurred during follow-up.
Other angiographic outcomes included stenosis as a percentageof the reference diameter and the development of new lesionsin a patient, defined as the presence of one or more segmentswith less than 15 percent stenosis at base line and an increaseof 15 percentage points or more at follow-up. Models focusingon change in diameter were also examined. The study was designedto have 80 percent power to detect a difference of 0.054 mmin the degree of change in minimal luminal diameter from baseline to follow-up between the active-treatment groups and theplacebo group. All tests of hypotheses and reported P valuesare two-sided.
Results
Base-Line Characteristics
The base-line characteristics of the study population are summarizedin Table 1. The mean age was 65.8 years (range, 41.8 to 79.9).More women in the group receiving unopposed estrogen reportedusing nitrates at base line (P=0.01); however, this differencewas not statistically significant among the 248 women includedin the angiographic analysis. There were no other significantdifferences among the three treatment groups, with or withoutthe inclusion of women for whom angiographic data were not available.
Table 1. Base-Line Characteristics of the 309 Subjects According to Treatment Group.
Effects on Lipids
Among the 248 women for whom angiographic follow-up data wereavailable, those assigned to unopposed estrogen and those assignedto estrogen plus medroxyprogesterone acetate had reductionsin plasma levels of low-density lipoprotein cholesterol of 9.4±20.9 percent and 16.5±21.8 percent, respectively, ascompared with 1.3±21.5 percent in the placebo group (P=0.02for the comparison of estrogen with placebo, and P<0.001for the comparison of estrogen plus medroxyprogesterone acetatewith placebo). Similarly, women in both treatment groups hadsignificantly greater increases in plasma levels of high-densitylipoprotein cholesterol (18.8±20.8 percent and 14.2±17.1 percent, respectively) than women taking placebo (6.8±15.6percent; P<0.01 for both comparisons). Women in both treatmentgroups also had increased triglyceride levels (by 6.1±34.1percent and 10.1±36.0 percent, respectively); however,these increases were not significantly different from that inthe placebo group (2.2±39.0 percent, P>0.10 for bothcomparisons).
Effects on Angiographic Outcomes
The primary analysis included data on 2317 proximal coronarysegments in the 248 women with angiographic follow-up (a meanof 9.3 segments per subject). After adjustment for base-lineminimal diameter and other prespecified covariates, the within-subjectmean minimal coronary-artery diameters at follow-up were notsignificantly different between the active-treatment groupsand the placebo group (Table 2). Among women who took at least80 percent of their study medication, the results were the same.Parallel analyses with the percentage of stenosis as the outcomeof interest also yielded similar results. Expressing the datain terms of the change in mean minimal diameter from base lineto follow-up (after adjustment for the covariates in the primaryanalysis) also revealed no significant differences among groups.One or more new lesions developed in 30 percent of the patientstaking estrogen and 20 percent of those receiving combined therapyduring follow-up, as compared with 33 percent of those in theplacebo group (P=0.62 for the comparison of estrogen with placebo,and P=0.06 for the comparison of estrogen plus medroxyprogesteroneacetate with placebo). When data from all 3112 measurable coronarysegments were analyzed, the results were similar (data not shown).
Table 2. Mean (±SE) Base-Line and Follow-up Angiographic Results According to Treatment Group.
Because the effects of estrogen may differ in segments withminimal disease and in those with more extensive disease, analyseswere performed after stratification according to the severityof disease at base line. Among the 1067 segments with 0 to 24percent stenosis at base line, there were no significant differencesamong the groups in unadjusted or adjusted follow-up values;results were similar when analyses were limited to the 999 segmentswith 25 to 49 percent stenosis or the 251 segments with at least50 percent stenosis at base line.
To determine whether either of the active treatments might bemore efficacious in certain subgroups, the change in mean minimaldiameter was compared among treatment groups after stratificationaccording to age and various clinical characteristics (Table 3).No favorable effects of treatment were found in any of thesubgroups.
Table 3. Mean (±SE) Changes in Minimal Diameter, According to Treatment Group, in Selected Subgroups.
Cardiovascular and Other Clinical Events
Nine women died of coronary disease and 19 had nonfatal myocardialinfarctions during follow-up. There were no significant differencesamong the treatment groups in the rates of these events eitherduring the whole follow-up period or during the first year (Table 4).The rates of coronary revascularization, hospitalizationfor unstable angina, any coronary disease event, stroke or transientattack, and death from all causes were also similar among thegroups. Five women assigned to unopposed estrogen had venousthromboembolic events, as compared with two assigned to combinedtherapy and one assigned to placebo (P=0.11 for the comparisonof unopposed estrogen with placebo).
Table 4. Clinical Cardiovascular Events and Death during 3.2 Years of Follow-up, According to Treatment Group.
During follow-up, no women had evidence of endometrial carcinoma(Table 5). However, more women in the group assigned to unopposedestrogen had simple or complex hyperplasia (P<0.001) duringfollow-up. In addition, heavy or persistent vaginal bleedingoccurred in slightly more than half of the women taking unopposedestrogen who had a uterus; eight of these women (19 percent)ultimately required dilation and curettage. The rates of cholecystectomyand breast or other cancers were not significantly differentamong groups, although the incidence of these events was verylow. Fractures (at all sites) were more than twice as commonin the placebo group as in the active-treatment groups, butthis difference did not reach statistical significance (P=0.09).
Table 5. Gynecologic and Other Clinical Events during 3.2 Years of Follow-up, According to Treatment Group.
Discussion
Coronary atherosclerosis is the underlying cause of most deathand disability among women in the developed world. Effectivemeasures to slow its progression in both women and men are stillurgently needed. Several lines of evidence suggest that estrogenreplacement should be beneficial in postmenopausal women. However,our results indicate that a mean of 3.2 years of estrogen replacementdid not slow the progression of coronary atherosclerotic lesionsin women. These data are consistent with the results of theHeart and Estrogen/Progestin Replacement Study8 that showedno overall effect of estrogen plus medroxyprogesterone acetateon the risk of clinical cardiovascular events in women withestablished heart disease. These data go beyond previous workby demonstrating that unopposed estrogen was no more effectivethan estrogen plus medroxyprogesterone acetate in slowing diseaseprogression.
The clinical relevance of these angiographic findings is underscoredby the remarkable agreement between angiographic and clinicalresults in trials of lipid-lowering therapy17 and by the factthat subjects in other studies who were followed over time showeddramatic reductions in clinical events if they had slowing ofangiographically evident disease.18,19,20,21,22 Nonetheless,the progression of anatomically defined disease measures onlyone of several processes that combine to produce acute ischemicevents. Other studies are needed to elucidate the effects ofestrogen on ulceration and thrombosis of existing lesions.
How can the lack of a treatment effect in our study be explained,given the established effects of estrogen on lipid metabolism,endothelial function, and other factors involved in the pathogenesisand progression of atherosclerosis?6,7,23 One possibility isthat estrogen has proinflammatory effects that offset its beneficialeffects. Two recent epidemiologic studies24,25 and two clinicaltrials26,27 reported significantly higher levels of C-reactiveprotein in women using unopposed estrogen or estrogen with variousprogestins. Elevated levels of this protein, and the underlyinginflammation that it presumably reflects, are clearly associatedwith the risk of clinical cardiovascular events in women.28However, it is not known whether treatments that increase thelevels of C-reactive protein promote the progression of coronarydisease.
Another possible explanation for our results is that estrogenis more effective in preventing the development of atherosclerosisthan in slowing the progression of disease once it is established.In ovariectomized monkeys and rabbits in which atherosclerosishas not yet developed, estrogen inhibits the development ofdisease,29,30 yet similar studies in animals with establisheddisease have shown no effect on progression.15,31 In animals,the ability of estrogen to prevent the accumulation of cholesterolin the vessel wall appears to require a healthy endothelium.32Since atherosclerosis and aging are associated with impairedendothelial function,33 older women or women with establisheddisease may be less likely to realize a cardiovascular benefitfrom estrogen. The Women's Health Initiative, a large clinicaltrial in predominantly healthy women, will provide importantdata about estrogen use for the primary prevention of heartdisease.34
As in any clinical trial of the prevention of chronic disease,the conclusions of this study would be stronger with more subjectsand longer follow-up. However, the nearly identical rates ofdisease progression among the three groups after a mean of 3.2years offer little reason to suspect that a significant differencewould emerge with longer follow-up. Furthermore, the 95 percentconfidence limits for the differences between the active-treatmentand placebo groups in measures of minimal diameter at follow-upexclude benefits greater than 0.021 mm for estrogen plus medroxyprogesteroneacetate and 0.049 mm for unopposed estrogen.
Side effects, such as vaginal bleeding, especially in the groupreceiving unopposed estrogen, produced differential rates ofcompliance and opportunities for unblinding. However, the resultsof analyses of the subjects who complied with treatment werevirtually identical to intention-to-treat analyses, and assessmentsof angiograms and clinical cardiovascular events were performedby persons who had no contact with the women or knowledge ofthe treatment assignments. Despite random assignment to treatment,there was a nonsignificant trend toward more severe diseaseat base line among women assigned to combined therapy. Therefore,follow-up angiographic measures were compared after adjustmentfor base-line measurements.
Our trial did not have enough subjects to allow us to draw conclusionswith confidence about the effects of treatment on clinical events.In particular, there were not enough subjects for us to confirmor refute the pattern of excess risk of cardiovascular eventsthat was found during year 1 in the Heart and Estrogen/ProgestinReplacement Study and suggested in preliminary data from theWomen's Health Initiative (Rossouw J: personal communication).The nonsignificant trends toward more venous thromboembolicevents and fewer fractures in the active-treatment groups areconsistent with previously established effects of hormone therapy.
In summary, an average of 3.2 years of treatment with eitherunopposed conjugated estrogen (0.625 mg per day) or estrogenplus medroxyprogesterone acetate (2.5 mg per day) did not slowthe progression of coronary atherosclerosis in women with establisheddisease. These data are consistent with the overall null effectof estrogen plus medroxyprogesterone acetate on clinical eventsin the Heart and Estrogen/Progestin Replacement Study. On thebasis of these results, women with heart disease should notuse conjugated estrogen, alone or in combination with medroxyprogesteroneacetate, with an expectation of cardiovascular benefit. Unlessor until other data to the contrary emerge, it seems reasonableto extend this recommendation to other formulations of estrogenand progestin as well. Estrogen therapy may still be effectivefor the primary prevention of coronary heart disease, but thishas not yet been verified. In the meantime, women and theirphysicians should redouble efforts to use forms of treatmentand prevention already proved to slow the progression of coronarydisease and prevent cardiovascular events, including lipid-loweringtherapy when indicated.
Supported by a grant from the National Heart, Lung, and BloodInstitute (U01 HL-45488) and by a National Center for ResearchResources General Clinical Research Center grant (M01 RR07122).Study medications were provided by Wyeth–Ayerst Research.
We are indebted to Karen Potvin Klein, M.A., E.L.S., for hereditorial contributions.
Source Information
From the Section on Cardiology, Department of Internal Medicine (D.M.H.), the Department of Public Health Sciences (D.M.R., S.A.S., C.D.F.), the Hypertension and Vascular Disease Center (K.B.B.), the Department of Family and Community Medicine (P.C.S.), and the Department of Obstetrics and Gynecology (T.E.S.), Wake Forest University School of Medicine, Winston-Salem, N.C.; the Department of Cardiology, Carolinas Medical Center, Charlotte, N.C. (G.J.K.); LeBauer Cardiovascular Associates, Greensboro, N.C. (T.D.S.); the Division of Cardiology, University of Alabama at Birmingham, Birmingham (W.J.R.); Winston-Salem Cardiology Associates, Winston-Salem, N.C. (D.H.G.); and the Division of Cardiology, San Francisco General Hospital, San Francisco (D.W.).
Address reprint requests to Dr. Herrington at the Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1045.
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Appendix
The following were committee members, investigators, and staffof the Estrogen Replacement and Atherosclerosis Trial: DataSafety and Monitoring Board: T. Bush, C. Davis, C. Furberg (exofficio), D. Gordon (ex officio), A. Guerci (chair), A. Jacobs,C. Timmons, and R. Tong; Quantitative Coronary Angiography Consultants:G. Brown and W. Saunders; Internal Advisory Committee: G. Burke,T. Clarkson, W. Hazzard, and W. Little; Cardiovascular EndpointCommittee:B. Psaty; Steering Committee: B. Brosnihan, S. Folmar,C. Furberg (cochair), K. Geisinger, D. Herrington (cochair,principal investigator), D. Reboussin, P. Sharp, S. Shumaker,and T. Snyder; University of Alabama at Birmingham: W. Rogers,V. Bittner, R. Varner, A. Murphy, S. Rolli, and B. Vaughn; CarolinasMedical Center, Charlotte,N.C.: G. Kowalchuk, F. Harrison,J. Allan, and J. Smith; Forsyth Memorial Hospital, Winston-Salem,N.C.: D. Givens and T. Geralds; Moses Cone Health System, Greensboro,N.C.: T. Stuckey, J. Schaal, H. Smith III, M. Boozer, V. Bradsher,K. Cheshire, J. Khemlani, and S. Milks; Hartford Hospital, Hartford,Conn.: D. Waters, L. Chaffkin, S. Giri, A. Olivar, J. DeDominicis,J. Macer, J. Pazdar, and M. Siwy; Wake Forest University Schoolof Medicine, Winston-Salem, N.C.: D. Herrington, K. Geisinger,F. Kahl, P. Sharp, S. Shumaker, T. Snyder, K. Blinson, D. Combs,M. Davis, L. Doomy, M. Drum, L. Fan, S. Gorham, J. Griffin,J. Iannuzzi, P. Kelley, K. Klein, J. Lundy, B. Pusser, and V.Wilson; Data Coordinating Center: D. Reboussin, A. Florance,R. Fussell, M. James, C. Kancler, C. Kay, K. Lane, S. Reece,S. Slone, and T. Terrell.
Coronary Heart Disease in Women
Stevenson J. C., Flather M., Collins P., Assefi N. P., Rhoads C. S., Bassan M., Anderson P. W., Moscarelli E., Herrington D. M., Waters D., Hu F. B., Stampfer M. J., Willett W. C., Nabel E. G.
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343:1891-1894, Dec 21, 2000.
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