Conjugated equine estrogens and peripheral arterial disease risk: The Women's Health Initiative

Peripheral Vascular Disease

Conjugated equine estrogens and peripheral arterial disease risk: The Women’s Health Initiative Judith Hsia, MD,a Michael H. Criqui, MD, MPH,b David M. Herrington, MD,c JoAnn E. Manson, MD, DrPH,d LieLing Wu, MS,e Susan R. Heckbert, MD, PhD,f Matthew Allison, MD, MPH,b Mary McGrae McDermott, MD,g Jennifer Robinson, MD, MPH,h and Kamal Masaki, MD i for the Women’s Health Initiative Research Group Washington, DC; San Diego, CA; Winston-Salem, NC; Boston, MA; Seattle, WA; Chicago, IL; Iowa City, IA; and Honolulu, HI

Background Estradiol reduced progression of ultrasonographic carotid disease in a randomized trial. No trials of unopposed estrogen for prevention of lower extremity arterial disease or aortic aneurysm have been conducted. Methods The Estrogen Alone trial randomized 10 739 postmenopausal women with prior hysterectomy, mean age 63.6 F 7.3 years, to conjugated equine estrogens (CEE 0.625 mg/d) or placebo and documented health outcomes over an average of 7.1 F 1.6 years. Results A trend toward increased risk of peripheral arterial events with CEE was observed (hazard ratio [HR] 1.32, 95% CI 0.99-1.77). Carotid arterial events (HR 1.19, 95% CI 0.82-1.74), lower extremity arterial events (HR 1.41, 95% CI 0.86-2.32), and abdominal aortic aneurysm (HR 2.40, 95% CI 0.92-6.23) were more frequent, but not individually significant, in the CEE group. However, the composite of lower extremity arterial disease/abdominal aortic aneurysm was significantly more frequent among women assigned to CEE (HR 1.63, 95 % CI 1.05-2.51). In subgroup analyses, no clear pattern of risk with CEE was apparent by age or by time since menopause. Conclusions Unopposed CEE conferred no protection against peripheral arterial disease among generally healthy postmenopausal women; in fact, there was a suggestion of increased risk. (Am Heart J 2006;152:170 - 6.) The risks for both coronary heart disease (CHD) and death are increased in patients with peripheral arterial disease.1,2 In observational studies evaluating the relationship between postmenopausal hormone therapy and peripheral arterial disease, carotid atherosclerosis, assessed by ultrasound, was less frequent in women taking estrogen, either with or without progestin.3,4 In a randomized trial that evaluated an intermediate outcome, ultrasonographic progression of carotid intimamedia thickness, unopposed estradiol reduced progression of carotid disease over a 2-year treatment period.5 From the aDepartment of Medicine, George Washington University, Washington, DC, b Department of Family and Preventive Medicine, University of California at San Diego, San Diego, CA, cDepartment of Medicine, Wake Forest University, WinstonSalem, NC, dDivision of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, eFred Hutchinson Cancer Research Center, Seattle, WA, fDepartment of Epidemiology, University of Washington, Seattle, WA, g Division of General Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, hDepartments of Epidemiology and Medicine, College of Public Health, University of Iowa, Iowa City, IA, and iDepartment of Geriatric Medicine, University of Hawaii, Honolulu, HI. The National Heart, Lung, and Blood Institute funds the Women’s Health Initiative. Submitted August 1, 2005; accepted September 9, 2005. Reprint requests: Judith Hsia, MD, 2150 Pennsylvania Ave NW #4-414, Washington, DC 20037. E-mail: [email protected] 0002-8703/$ - see front matter n 2006, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2005.09.005

The impact of unopposed estrogen on clinical peripheral arterial events has not been previously evaluated in a randomized trial. In two trials of conjugated estrogens combined with daily medroxyprogesterone acetate, no effect on clinical peripheral arterial disease was identified either in healthy postmenopausal women 6 or those with CHD.2 In this analysis, we evaluated incident peripheral arterial disease in the Women’s Health Initiative randomized trial of unopposed conjugated equine estrogens (CEE).

Methods Study population This analysis includes 10 739 women, aged 50 to 79 years with prior hysterectomy at baseline, who were enrolled in a double-blind trial comparing 0.625 mg of oral CEE (Premarin, Wyeth) daily with placebo. The study population, recruitment methods, baseline data collection, randomization, and follow-up procedures for the Estrogen Alone trial have been previously reported.7-9 The protocol and consent forms were approved by institutional review boards of the participating institutions; all trial participants provided written informed consent. Peripheral arterial disease at baseline was defined as selfreported prior carotid or lower extremity revascularization. Coronary heart disease at baseline was defined as self-reported myocardial infarction or coronary revascularization.

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Table I. Baseline characteristics by treatment arm

Age (y) Ethnicity White Black Hispanic American Indian Asian/Pacific islander Unknown College degree or higher Hypertension Never treated Untreated Treated Diabetes mellitus treated with shots or pills High cholesterol requiring pills Current smoker CHD at baseline Peripheral arterial disease at baseline Statin use at baseline Aspirin use (> 81 mg/d) at baseline Nonsteroidal anti-inflammatory use at baseline

Table II. Incidence (annualized percentage) of peripheral arterial disease by randomization assignment

CEE (n = 5310)

Placebo (n = 5429)

63.6 (7.3)

63.6 (7.3)

4007 782 322 41 86 72 1216

(75.5) (14.7) (6.1) (0.8) (1.6) (1.4) (23.1)

4075 835 333 34 78 74 1327

(75.1) (15.4) (6.1) (0.6) (1.4) (1.4) (24.7)

2864 493 1460 410

(59.5) (10.2) (30.3) (7.7)

2989 500 1443 411

(59.9) (10.3) (29.8) (7.6)

.779

694 542 216 43

(14.5) (10.3) (4.1) (0.8)

766 571 225 41

(15.9) (10.6) (4.1) (0.8)

.505 .589 .842 .749

397 (7.5) 1087 (20.5)

430 (7.9) 1124 (20.7)

.388 .766

1837 (34.6)

1898 (35.0)

.691

P .863 .814

.060 .865

Values are expressed as mean (SD) or n (%). CHD at baseline, Self-reported prior myocardial infarction or coronary revascularization; Peripheral arterial disease at baseline, self-reported prior carotid or lower extremity revascularization.

Outcomes ascertainment Participants reported emergency department visits, overnight hospital stays, and outpatient coronary revascularization procedures semiannually. Medical records for every overnight hospitalization and outpatient coronary revascularization procedure were scrutinized for potential outcomes of interest. Centrally trained physician adjudicators classified outcomes on the basis of medical record review.10 Incident peripheral arterial disease was defined as overnight hospitalization with either symptoms or intervention and was categorized as carotid artery disease, abdominal aortic aneurysm, or lower extremity arterial disease. The first two conditions required physician diagnosis and confirmation by imaging study and/or revascularization procedure. Lower extremity arterial disease was confirmed by diagnostic testing, absence of pulses by Doppler, and/or revascularization procedure. Outpatient peripheral arterial diagnoses or revascularization procedures were not collected.

Statistical analysis Hazard ratios (HRs) with 95% CIs were calculated from Cox proportional hazards models stratified by age, prevalent peripheral arterial disease at baseline, and randomization status in the Dietary Modification trial.7 Kaplan-Meier plots show peripheral arterial disease event rates over time for the entire cohort as well as censoring for nonadherence. Sensitivity analyses were performed by censoring a participant 6 months after becoming nonadherent (consuming

CEE

Placebo

HR (95% CI)

Follow-up time (y) 7.1 (1.6) 7.1 (1.6) Entire cohort Total peripheral 104 (0.28) 81 (0.21) 1.32 (0.99-1.77) arterial disease Carotid 58 (0.15) 50 (0.13) 1.19 (0.82-1.74) Lower extremity 37 (0.10) 27 (0.07) 1.41 (0.86-2.32) Abdominal aortic 14 (0.04) 6 (0.02) 2.40 (0.92-6.23) aneurysm Excluding women with CHD or peripheral arterial disease at baseline Total peripheral 82 (0.23) 62 (0.17) 1.35 (0.97-1.88) arterial disease Carotid 47 (0.13) 40 (0.11) 1.20 (0.79-1.83) Lower extremity 27 (0.08) 20 (0.05) 1.38 (0.78-2.47) Abdominal aortic 12 (0.03) 4 (0.01) 3.06 (0.99-9.48) aneurysm Values are expressed as mean (SD) or n (annualized %). Cox proportional hazards models were stratified by age, prevalent peripheral arterial disease at baseline, and randomization status in the Dietary Modification trial.

b80% of study medication or beginning non-protocol hormone therapy). Peripheral arterial disease was not an outcome monitored by the Data and Safety Monitoring Board; consequently, adjustment for sequential monitoring was not performed. A wide range of clinical outcomes have been examined in this trial,9 increasing the probability that some nominal CIs may exclude 1 based on chance alone. However, peripheral arterial disease was a prespecified secondary outcome. For determination of HRs by year, tests of trends with time were performed using Cox proportional hazards analyses incorporating a linear time interaction term. Consistency of treatment effects among subgroups was assessed by formal tests of interaction; tests for linear trend were used where appropriate. Fourteen subgroups were evaluated; one would be expected to be significant at the .05 level by chance alone. All reported P values are 2-sided. Analyses were carried out using the SAS System for Windows v9 (SAS Institute, Cary, NC).

Results The Women’s Health Initiative Estrogen Alone trial randomized 5310 women to CEE and 5429 to placebo. Baseline characteristics of women in the two treatment arms were similar (Table I). Coronary heart disease at baseline was reported by 441 (4.1%) women and peripheral arterial disease by 84 (0.8%). At baseline, medication inventory revealed that hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) were used by 7.7%, aspirin by 20.6%, and nonsteroidal antiinflammatory agents (including aspirin) by 34.8%; no women took clopidogrel. There were 104 total peripheral arterial disease events among CEE recipients and 81 among placebo recipients. Among women without prevalent coronary

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Figure 1

Kaplan-Meier curves for total peripheral arterial disease in women assigned to CEE or to placebo. Peripheral arterial disease included abdominal aortic aneurysm, carotid artery disease, and lower extremity arterial disease. Hazard ratios and 95% CIs are from Cox proportional hazards regression analyses stratified by age, prevalent peripheral arterial disease, and randomization assignment in the Dietary Modification trial. The left panel shows intention-to-treat analysis; the right panel shows sensitivity analysis in which participants were censored 6 months after becoming nonadherent (defined as taking b80% of study medication or starting non-protocol hormone therapy).

Table III. CEE and the risk of peripheral arterial disease by year of follow-up Year 1 Total peripheral arterial disease CEE 15 (0.28) Placebo 12 (0.22) HR (95% CI) 1.28 (0.60-2.73) Carotid artery disease CEE 8 (0.15) Placebo 9 (0.17) HR (95% CI) 0.89 (0.35-2.32) Lower extremity arterial disease CEE 4 (0.08) Placebo 2 (0.04) HR (95% CI) 2.10 (0.38-11.51)

Year 2

Year 3

Year 4

Year 5

Year 6

_ 7 Year >

15 (0.29) 9 (0.17) 1.70 (0.74-3.88)

12 (0.23) 13 (0.25) 0.93 (0.43-2.05)

8 (0.16) 6 (0.12) 1.36 (0.47-3.93)

11 (0.22) 11 (0.21) 1.02 (0.44-2.35)

27 (0.55) 7 (0.14) 3.94 (1.72-9.05)

16 (0.23) 23 (0.31) 0.73 (0.39-1.38)

4 (0.08) 6 (0.11) 0.68 (0.19-2.42)

8 (0.16) 10 (0.19) 0.81 (0.32-2.05)

6 (0.12) 1 (0.02) 6.02 (0.73-50.00)

5 (0.10) 6 (0.12) 0.85 (0.26-2.77)

15 (0.31) 4 (0.08) 3.84 (1.27-11.57)

12 (0.17) 14 (0.19) 0.89 (0.41-1.93)

8 (0.15) 2 (0.04) 4.06 (0.86-19.10)

3 (0.06) 2 (0.04) 1.52 (0.26-9.12)

3 (0.06) 4 (0.08) 0.77 (0.17-3.46)

7 (0.14) 6 (0.12) 1.19 (0.40-3.54)

8 (0.16) 3 (0.06) 2.75 (0.73-10.36)

4 (0.06) 8 (0.11) 0.52 (0.16-1.72)

P for trend

.518

.498

.090

Values are expressed as number of cases (annualized percentage).

or peripheral arterial disease at baseline, incident carotid arterial events (0.12% per year), lower extremity arterial disease (0.06%), and abdominal aortic aneurysms (0.02% per year) were infrequent (Table II). Among women with prevalent coronary or peripheral arterial disease at baseline, the incidences of carotid

arterial events, lower extremity arterial disease, and abdominal aortic aneurysm were 0.63%, 0.51%, and 0.12% per year, respectively. Kaplan-Meier curves for peripheral arterial events in the two treatment groups are shown (Figure 1). For total peripheral arterial disease, which included carotid and

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Figure 2

CEE and the risk of peripheral arterial disease in various subgroups. Horizontal bars represent nominal 95% CIs. Cox proportional hazards models were stratified by age, prevalent peripheral arterial disease at baseline, and randomization status in the Dietary Modification trial. Because of missing data on some variables, the numbers of cases do not always add up to the total number of cases in the treatment group. NT, not tested.

lower extremity disease, as well as abdominal aortic aneurysm, a suggestion of greater risk with CEE was observed (HR 1.32, 95% CI 0.99-1.77). For carotid artery events, the HR was 1.19 (95% CI 0.82-1.74); for lower extremity arterial disease, the HR was 1.41 (95% CI 0.86-2.32). For the composite of lower extremity arterial disease/abdominal aortic aneurysm, the HR was 1.63 (95% CI 1.05-2.51). In sensitivity analysis, the HR for total peripheral arterial disease was 1.28 (95% CI 0.86-1.90), for carotid artery events 0.98 (95% CI 0.58-1.63), and for lower extremity arterial disease/ abdominal aortic aneurysm 2.02 (95% CI 1.10-3.72).

Hazard ratios for peripheral arterial disease are shown by year of follow-up (Table III). No early increase in HR was apparent for total peripheral arterial disease ( P for trend = .518), carotid artery events ( P for trend = .498), or for lower extremity arterial disease ( P for trend = .090). Subgroups were analyzed by baseline demographic and health characteristics including age, ethnicity, hypertension, diabetes, cigarette smoking, statin use, nonsteroidal anti-inflammatory use, body mass index, and prevalent coronary or peripheral arterial disease at baseline (Figure 2). No clear pattern of risk with CEE was

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apparent by age decade, although only 11% of peripheral arterial events occurred in women 50 to 59 years of age at baseline, limiting reliability of analyses by age. Ethnicity is included in the figure, but was not tested because of small numbers of events in some ethnic groups. Because onset of menopause may not be readily identified among women with hysterectomy, time since menopause was assessed three ways: as years since hysterectomy, years since hysterectomy without postmenopausal hormone therapy, and years since bilateral oophorectomy. Women with fewer years since hysterectomy appeared at higher risk with CEE ( P for interaction = .044), but no relationship between peripheral arterial disease risk with CEE and time since menopause was apparent for years since hysterectomy without postmenopausal hormone therapy or years since bilateral oophorectomy. Women without hypertension at baseline, either measured or physician-diagnosed, were at higher relative risk for peripheral arterial events with CEE ( P for interaction = .019). A suggestion of higher risk with CEE was also observed among women without physician-diagnosed diabetes mellitus at baseline ( P for interaction = .062). However, no interaction with CEE was apparent in other subgroups at lower atherosclerotic risk, such as nonsmokers, statin users, or women lacking CHD at baseline.

Discussion In this cohort of 10 759 postmenopausal women with prior hysterectomy, mean age 63.6 years at baseline, the HR for peripheral arterial events with CEE during 7.1 years of follow-up was 1.23 (95% CI 0.99-1.77). This increase in risk was predominantly due to a higher incidence of lower extremity arterial disease and abdominal aortic aneurysm with CEE. These results contrast with those of the companion Estrogen Plus Progestin trial6 and the Heart and Estrogen/progestin Replacement Study (HERS),2 both of which compared conjugated estrogens with daily medroxyprogesterone acetate to placebo. In those trials, the incidence of peripheral arterial events was similar in the active hormone and placebo groups. HERS defined peripheral arterial outcomes as revascularization procedures or amputation. Applying the HERS definition in the current analysis, we identified 46 carotid events in the CEE group and 37 in the placebo group (HR 1.27, 95% CI 0.83-1.96). Applying the HERS definition to lower extremity events, we identified 31 in the CEE group and 20 in the placebo group (HR 1.60, 95% CI 0.91-2.80). These HRs are very similar to those obtained with the Women’s Health Initiative outcomes definition, which also includes disease confirmed by imaging studies or physical examination.

Table IV. Hazard ratios (nominal 95% CI) for CHD, stroke, and peripheral arterial disease with unopposed CEE or conjugated estrogens with medroxyprogesterone acetate

CEE

Conjugated estrogens with medroxyprogesterone acetate

CHD 0.91 (0.75-1.12)16 Stroke 1.39 (1.10-1.77)9 Peripheral 1.32 (0.99-1.77) arterial disease

1.24 (1.00-1.54)12 1.31 (1.02-1.68)17 0.89 (0.63-1.25)6

The Estrogen Plus Progestin trial used the same definition of peripheral arterial outcomes as this analysis; the differing results of the Estrogen Alone and Estrogen Plus Progestin trials may be attributed to baseline characteristics of the cohorts, the hormone regimen, or chance. Peripheral arterial events were more frequent in the placebo group of the Estrogen Alone trial (0.21% per year) than in the placebo group of the Estrogen Plus Progestin trial (0.15% per year). Women in the Estrogen Alone trial had prior hysterectomy and higher prevalence of risk factors such as hypertension (36.3% vs 27.3% for CEE and estrogen plus progestin, respectively) and self-reported hypercholesterolemia (13.6% vs 11.5%). The question of whether hysterectomy per se increases cardiovascular risk was explored in the Women’s Health Initiative Observational Study; after multiple risk factor adjustment, hysterectomy was no longer an independent determinant of incident cardiovascular disease.11 It has been suggested that CEE may promote atherosclerotic events in a more atherogenic milieu,12 as in women with prior hysterectomy who have more prevalent risk factors. In fact, subgroup analyses from the present study suggest that CEE increased peripheral arterial disease risk among women at lower risk for atherosclerosis. We also cannot exclude the possibility that addition of progestin attenuates atherogenic properties of CEE, although this explanation is not consistent with the effects of these agents on CHD or stroke risk.9 During the first year of therapy, conjugated estrogens with medroxyprogesterone acetate increased the risk for CHD (HR 1.81)13; the HR for peripheral arterial events with combination therapy was 1.33.6 During the first year of therapy with unopposed CEE, the HR for CHD was 1.11; for peripheral arterial events, the HR was 1.28. Potential mechanisms underlying the early events include inflammatory effects, as both CEE and conjugated estrogens with medroxyprogesterone acetate increase C-reactive protein14 or hormone-induced increases in matrix metalloproteinases,15 which might destabilize atherosclerotic plaque. The effects of unopposed CEE and conjugated estrogens with medroxyprogesterone acetate on CHD and

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peripheral arterial disease risk appear to differ6,16,17 (Table IV). One interpretation of these findings is that both hormone regimens are neutral with regard to these end points, and the observed variation in HRs is due to chance. Another possible interpretation, which accounts for the consistent elevation in stroke risk, is that both hormone regimens increase thrombosis, a view supported by the increase in venous thromboembolism,9,18 and that thrombosis plays a greater role in stroke, whereas inflammatory and other mediators of atherosclerosis play a greater role in CHD and peripheral arterial disease.19-21 Susceptibility to postmenopausal hormone therapy may also differ between vascular beds.19,20,22,23 In a placebo-controlled trial, unopposed estradiol reduced progression of carotid intima-media thickness by 0.0053 mm/y (95% CI 0.0001-0.0105, P = .046).5 In the Estrogen Alone trial, the HR for clinical carotid arterial events was 1.19 (95% CI 0.82-1.74). One possible interpretation of these findings is that unopposed estrogen exerts a neutral effect on carotid risk, attributing the apparent protection with estradiol to chance. Alternative explanations include (1) differences in baseline characteristics of the cohorts and (2) choice of estrogen. Baseline characteristics of women in the estradiol trial suggest they were at lower atherosclerotic risk; however, subgroup analyses from the Estrogen Alone trial indicate that estrogen actually increased peripheral arterial disease risk in women at lower risk for atherosclerosis. Although we cannot exclude the possibility that estradiol and CEE affect carotid disease differently, in a secondary stroke prevention trial, estradiol did not reduce stroke risk (RR 1.1, 95% CI 0.8-1.6), increased the risk of fatal stroke (RR 2.9, 95% CI 0.9-9.0), and was associated with worse sequelae of nonfatal strokes.24 Unopposed CEE, like conjugated estrogens with medroxyprogesterone acetate, conferred no protection against peripheral arterial disease. In fact, CEE increased the risk of lower extremity arterial disease/abdominal aortic aneurysm. The 2004 guidelines for cardiovascular disease prevention in women25 categorized unopposed estrogen as a class III intervention based level C evidence (expert opinion, case studies, or standard of care). The categorization of CEE as bnot useful/effective and may be harmfulQ is supported by analyses of CHD, stroke, and peripheral arterial disease risk in the Women’s Health Initiative Estrogen Alone randomized trial.

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3. Jonas HA, Kronmal RA, Psaty BM, et al. Current estrogenprogestin and estrogen replacement therapy in elderly women: association with carotid atherosclerosis. CHD Collaborative Research Group. Cardiovascular Health Study. Ann Epidemiol 1996; 6:314 - 23. 4. Le Gal G, Gourlet V, Hogrel P, et al. Hormone replacement therapy use is associated with a lower occurrence of carotid atherosclerotic plaques but not with intima-media thickness progression among postmenopausal women: the vascular aging (EVA) study. Atherosclerosis 2003;166:163 - 70. 5. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939 - 53. 6. Hsia J, Criqui MH, Rodabough RJ, et al. Estrogen plus progestin and the risk of peripheral arterial disease. The Women’s Health Initiative. Circulation 2004;109:620 - 6. 7. The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative Clinical Trial and Observational Study. Control Clin Trials 1998;19:61 - 109. 8. Stefanick ML, Cochrane BB, Hsia J, et al. The Women’s Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol 2003;13(9 Suppl):S78 - 86. 9. The Women’s Health Initiative Steering Committee. Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy. The Women’s Health Initiative Randomized Controlled Trial. JAMA 2004;291:1701 - 12. 10. Curb JD, McTiernan A, Heckbert SR, et al. Outcomes ascertainment and adjudication methods in the Women’s Health Initiative. Ann Epidemiol 2003;13:S122 - 8. 11. Howard BV, Kuller L, Langer R, et al. Risk of cardiovascular disease by hysterectomy status, with and without oophorectomy. Women’s Health Initiative Observational Study. Circulation 2005;111:1462 - 70. 12. Mikkola TS, Clarkson TB, Notelovitz M. Postmenopausal hormone therapy before and after the Women’s Health Initiative study: what consequences? Ann Med 2004;36:402 - 13. 13. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and risk of coronary heart disease. N Engl J Med 2003;239:523 - 34. 14. Cushman M, Legault C, Barrett-Connor E, et al. Effect of postmenopausal hormones on inflammation-sensitive proteins. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation 1999;100:717 - 22. 15. Zanger D, Yang BK, Ardans J, et al. Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management. J Am Coll Cardiol 2000;36:1797 - 802. 16. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens alone and the risk of coronary heart disease. Arch Intern Med [in press]. 17. Wassertheil-Smoller S, Hendrix S, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003;289: 2673 - 84. 18. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004;292:1573 - 80. 19. Rosenberg RD, Aird WC. Vascular-bed–specific hemostasis and hypercoagulable states. N Engl J Med 1999;340:1555 - 64. 20. Muscari A, Martignani C, Bastagli L, et al. A comparison of acute phase proteins and traditional risk factors as markers of combined plaque and intima-media thickness and plaque density

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Appendix A Women’s Health Initiative Research Group Program Office: (National Heart, Lung, and Blood Institute, Bethesda, MD) Barbara Alving, Jacques Rossouw, Linda Pottern. Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Ross Prentice, Garnet Anderson, Andrea LaCroix, Charles L. Kooperberg, Ruth E. Patterson, Anne McTiernan; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker; (Medical Research Labs, Highland Heights, KY) Evan Stein; (University of California at San Francisco, San Francisco, CA) Steven Cummings. Clinical Centers: (Albert Einstein College of Medicine, Bronx, NY) Sylvia Wassertheil-Smoller; (Baylor College of Medicine, Houston, TX) Jennifer Hays; (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) JoAnn Manson; (Brown University, Providence, RI) Annlouise R. Assaf; (Emory University, Atlanta, GA) Lawrence Phillips; (Fred Hutchinson Cancer Research Center, Seattle, WA) Shirley Beresford; (George Washington University Medical Center, Washington, DC)

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Judith Hsia; (Harbor-UCLA Research and Education Institute, Torrance, CA) Rowan Chlebowski; (Kaiser Permanente Center for Health Research, Portland, OR) Evelyn Whitlock; (Kaiser Permanente Division of Research, Oakland, CA) Bette Caan; (Medical College of Wisconsin, Milwaukee, WI) Jane Morley Kotchen; (MedStar Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Northwestern University, Chicago/Evanston, IL) Linda Van Horn; (Rush-Presbyterian St. Luke’s Medical Center, Chicago, IL) Henry Black; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (State University of New York at Stony Brook, Stony Brook, NY) Dorothy Lane; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Alabama at Birmingham, Birmingham, AL) Cora E. Lewis; (University of Arizona, Tucson/Phoenix, AZ) Tamsen Bassford; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of California at Davis, Sacramento, CA) John Robbins; (University of California at Irvine, Orange, CA) Allan Hubbell; (University of California at Los Angeles, Los Angeles, CA) Howard Judd; (University of California at San Diego, LaJolla/Chula Vista, CA) Robert D. Langer; (University of Cincinnati, Cincinnati, OH) Margery Gass; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Hawaii, Honolulu, HI) David Curb; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Massachusetts/Fallon Clinic, Worcester, MA) Judith Ockene; (University of Medicine and Dentistry of New Jersey, Newark, NJ) Norman Lasser; (University of Miami, Miami, FL) Mary Jo O’Sullivan; (University of Minnesota, Minneapolis, MN) Karen Margolis; (University of Nevada, Reno, NV) Robert Brunner; (University of North Carolina, Chapel Hill, NC) Gerardo Heiss; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (University of Tennessee, Memphis, TN) Karen C. Johnson; (University of Texas Health Science Center, San Antonio, TX) Robert Brzyski; (University of Wisconsin, Madison, WI) Gloria E. Sarto; (Wake Forest University School of Medicine, Winston-Salem, NC) Denise Bonds; (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI) Susan Hendrix.