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(Circulation. 2004;109:620-626.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Estrogen Plus Progestin and the Risk of Peripheral Arterial Disease

The Women’s Health Initiative

Judith Hsia, MD; Michael H. Criqui, MD, MPH; Rebecca J. Rodabough, MS; Robert D. Langer, MD, MPH; Helaine E. Resnick, PhD, MPH; Lawrence S. Phillips, MD; Matthew Allison, MD, MPH; Denise E. Bonds, MD, MPH; Kamal Masaki, MD; Panagiota Caralis, MD, JD; Jane M. Kotchen, MD, MPH, for the Women’s Health Initiative Investigators

From the Department of Medicine, George Washington University, Washington, DC (J.H.); Department of Family and Preventive Medicine, University of California at San Diego (M.H.C., R.D.L., M.A.); Fred Hutchinson Cancer Research Center, Seattle, Wash (R.J.R.); Department of Epidemiology, MedStar Research Institute, Hyattsville, Md (H.E.R.); Department of Medicine, Emory University, Atlanta, Ga (L.S.P.); Departments of Public Health Sciences and Internal Medicine, Wake Forest University, Winston-Salem, NC (D.E.B.); Department of Geriatric Medicine, University of Hawaii, Honolulu, Hawaii (K.M.); University of Miami School of Medicine and Miami Veterans Administration Medical Center, Miami, Fla (P.C.); and the Health Policy Institute, Medical College of Wisconsin, Milwaukee, Wis (J.M.K.).

Correspondence to Dr Judith Hsia, MD, 2150 Pennsylvania Ave NW, Washington, DC 20037. E-mail jhsia{at}mfa.gwu.edu

Received December 2, 2003; revision received December 2, 2003; accepted December 16, 2003.

	Abstract

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Background— Observational studies have reported less frequent carotid atherosclerosis in healthy women taking postmenopausal hormone therapy. Estrogen with progestin did not reduce peripheral arterial events among women with preexisting coronary heart disease. This analysis evaluates clinical peripheral arterial disease among generally healthy women in the Women’s Health Initiative randomized trial of estrogen plus progestin.

Methods and Results— The Estrogen Plus Progestin trial assigned 16 608 postmenopausal women, mean age 63.3±7.1 years, to daily conjugated estrogens (0.625 mg) with medroxyprogesterone acetate (2.5 mg) or placebo and documented health outcomes over an average of 5.6 years of follow-up. Hospitalization for peripheral arterial disease was infrequent, with annualized rates of 0.08%, 0.06%, and 0.02% for carotid disease, lower extremity arterial disease, and abdominal aortic aneurysm, respectively. The incidence of peripheral arterial events did not differ between treatment groups (hazard ratio [HR] 0.89, 95% confidence interval 0.63, 1.25). The risk was slightly greater among women assigned to active estrogen with progestin in years 1 (HR 1.33) and 2 (HR 1.27), and was slightly lower in later years (HR 0.85 and 0.87 in years 5 and 6). Among adherent participants, the hazard ratio for peripheral arterial events was 1.23 (95% confidence interval 0.79, 1.91) over the 5.6 years of follow up. Subgroup analysis identified no significant interactions between estrogen with progestin and baseline characteristics with regard to peripheral arterial disease risk.

Conclusions— Among generally healthy postmenopausal women, conjugated estrogens with progestin did not confer protection against peripheral arterial disease.

Key Words: peripheral vascular disease • hormones • women

	Introduction

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Peripheral arterial disease, like coronary heart disease, is a clinical manifestation of atherosclerosis and is associated with increased mortality.¹ Observational studies have reported less frequent carotid atherosclerosis, assessed by ultrasound, in women taking postmenopausal hormone therapy.^2–4 Randomized trials have provided variable results. Trials using conjugated estrogens with medroxyprogesterone acetate,⁵ estradiol with gestodene,^6,7 and estradiol with norgestrel⁸ found no effect on carotid or femoral artery intima-media thickness. In contrast, unopposed estradiol did reduce progression of ultrasonographic carotid disease.⁹

The Heart and Estrogen/progestin Replacement Study (HERS), a randomized trial in women with known coronary heart disease, found no effect of combination hormone therapy on clinical peripheral arterial events (revascularization and amputation).¹⁰ Whether postmenopausal hormone therapy confers protection in healthy women is uncertain. In this analysis, we evaluate incident peripheral arterial disease, a pre-specified secondary outcome, in the Women’s Health Initiative randomized trial of estrogen plus progestin.

	Methods

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Study Population
The study population, recruitment methods, baseline data collection, and randomization and follow-up procedures for the Estrogen Plus Progestin trial have been previously reported.^11,12 The protocol and consent forms were approved by the institutional review boards of participating institutions and written informed consent was obtained from all participants. This analysis includes 16 608 women, age 50 to 79 years, with intact uteri at baseline who were enrolled in the double-blind trial comparing 0.625 mg of oral conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate (Prempro, Wyeth) daily with a matching placebo.

Peripheral arterial disease at baseline was defined as self-reported prior carotid or lower extremity revascularization. Coronary heart disease at baseline was defined as self-reported myocardial infarction or coronary revascularization. Women using hydroxymethylglutaryl coenzyme A reductase inhibitors for at least 2 weeks at the baseline medication inventory were classified as statin users.

Outcomes Ascertainment
Participants reported overnight hospitalizations, emergency room visits, and outpatient coronary revascularization procedures on medical update forms collected 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.¹³

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. Classification as carotid disease or abdominal aortic aneurysm required physician diagnosis and confirmation by imaging study and/or revascularization procedure. Lower extremity arterial disease was confirmed by non-invasive testing, absence of pulses, and/or revascularization procedure.

Statistical Analysis
We compared baseline characteristics between treatment groups with unpaired 2-tailed t tests for continuous variables and ² tests for categorical variables. Subsequent comparisons between randomized treatment assignments used time-to-event methods and the intention-to-treat principle. Hazard ratios, 95% confidence intervals, and Wald probability values are reported from Cox proportional hazards analyses stratified by age, prevalent peripheral arterial disease, and randomization status in the Dietary Modification trial. Sensitivity analyses were performed using Cox proportional hazards analyses, censoring a participant 6 months after becoming non-adherent (consuming less than 80% 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 and behavioral outcomes have been examined in this trial,^12,14–17 increasing the probability that some nominal confidence intervals may exclude 1 based on chance alone.

For determination of hazard ratios by year, tests of trends with time were performed using Cox proportional hazards analyses incorporating a linear time interaction term. Kaplan-Meier plots show peripheral arterial disease event rates over time for the entire cohort and for adherent women.

Interactions between baseline characteristics and randomization assignment were assessed in Cox proportional hazards regression models that included both the risk factor (where applicable as a continuous variable for computing the test statistic and probability value) and randomization assignment as main effects. Probability values for assessing possible interactions were computed from likelihood ratio tests by comparing models with and without the interaction term. Eight subgroup comparisons were tested; less than one would be expected to be significant at the 0.05 level by chance alone. Analyses were carried out using the SAS System for Windows v9 (SAS Institute).

	Results

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The Women’s Health Initiative Estrogen Plus Progestin trial randomized 8506 postmenopausal women to conjugated estrogens with daily medroxyprogesterone and 8102 to placebo. The imbalance in size of the treatment groups is attributable to 331 women with intact uteri who were switched to the estrogen with progestin group from their original randomization to unopposed estrogen.¹² Baseline characteristics were similar for women in the 2 treatment arms (Table 1). Coronary heart disease at baseline was reported by 2.4% and peripheral arterial disease at baseline was reported by 0.5%. No women reported clopidogrel use at baseline.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics by Treatment Arm

Carotid arterial events (0.08% per year), lower extremity arterial disease (0.06% per year), and abdominal aortic aneurysm (0.02% per year) were infrequent. Incidence was similar among women assigned to placebo and to active estrogen with progestin for the entire cohort, as well as for the subset of women without prevalent coronary heart disease or peripheral arterial disease at baseline (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Incidence (Annualized Percentage) of Peripheral Arterial Disease by Randomization Assignment

Cumulative hazard rates for peripheral arterial events in the 2 treatment groups are provided in Figure 1. A slightly elevated risk of peripheral arterial disease in the estrogen plus progestin group is apparent in the years immediately after randomization, but it does not persist. Cumulative hazard ratio [HR] for the entire cohort was 0.89 (95% confidence interval 0.63, 1.25); HR for women who took at least 80% of their study medication was 1.23 (95% confidence interval 0.79, 1.91).

View larger version (21K): [in this window] [in a new window]   Figure 1. Kaplan-Meier curves for total peripheral arterial disease in women assigned to estrogen plus progestin or to placebo. Peripheral arterial disease included abdominal aortic aneurysm, carotid artery disease, and lower extremity arterial disease. Hazard ratios (HR) and 95% confidence intervals (CI) are from Cox proportional hazards regression analyses stratified by age, prevalent peripheral arterial disease (PAD), and randomization assignment in the Dietary Modification trial. Left panel shows intention-to-treat analysis. Right panel shows sensitivity analysis where participants were censored 6 months after becoming non-adherent (defined as taking <80% of study medication or starting non-protocol hormone therapy). E+P indicated estrogen with progestin.

Hazard ratios for peripheral arterial disease are shown by year of follow-up in Table 3. Peripheral arterial events were slightly increased in the active treatment group in year 1 (HR 1.33), in which the excess of peripheral arterial events was predominantly due to lower extremity disease. The increased event rate persisted in year 2 (HR 1.27), and dissipated thereafter with slight benefit in later years (HR 0.85 in year 5, HR 0.87 in years 6); probability value for test of trend by year of follow up was 0.39 for all peripheral arterial events. For lower extremity disease only, P for trend was 0.045.

View this table: [in this window] [in a new window]   TABLE 3. Estrogen Plus Progestin and the Risk of Peripheral Arterial Disease by Year of Follow-Up

Subgroups were analyzed by baseline demographic and health characteristics including age, ethnicity, hypertension, diabetes, cigarette smoking, statin use, body mass index, and prevalent coronary heart disease or peripheral arterial disease (Figure 2). Although race/ethnicity was not tested because of small numbers of events in some ethnic groups, it is included in the figure. In each subgroup, the risk of incident peripheral arterial disease was no different for women assigned to placebo or to estrogen with progestin. No significant interactions were identified between treatment assignment and the subgroup characteristics with regard to risk of peripheral arterial events.

View larger version (25K): [in this window] [in a new window]   Figure 2. Estrogen plus progestin and peripheral arterial disease risk (PAD) in various subgroups. PAD includes carotid artery disease, lower extremity arterial disease, and abdominal aortic aneurysm requiring hospitalization. Horizontal bars represent nominal 95% confidence intervals. 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. E+P indicates estrogen with progestin; NT, not tested; and CHD, coronary heart disease.

	Discussion

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In our cohort of 16 608 women 50 to 79 years of age, combination hormone therapy with continuous conjugated estrogens and medroxyprogesterone acetate neither favorably nor unfavorably affected risk of peripheral arterial events over an average of 5.6 years of follow-up. A slight increase in risk of peripheral arterial events was observed in the active hormone group during each of the first 2 years after randomization, consistent with prior reports of increased coronary risk after initiation of estrogen with progestin treatment,^14,18 and a slight decrease in peripheral arterial disease risk was observed in the later years. The incidence of peripheral arterial events was 0.14% per year, less than half the coronary event (myocardial infarction or coronary death) rate of 0.36% per year.¹⁴ Among women without known coronary heart or peripheral arterial disease at baseline, about 1 peripheral arterial event was reported per 1000 woman-years; among women with coronary or peripheral arterial disease at baseline, there were about 13 events per 1000 woman-years.

We compared the peripheral arterial event rate among women assigned to placebo in our trial with the women assigned to placebo in HERS, in which all women had documented coronary heart disease at baseline. The carotid and lower extremity event rates in HERS were 1.17% per year and 1.04% per year, respectively.¹⁰ Applying the HERS definition of peripheral arterial events to the subset of women in the Women’s Health Initiative Estrogen Plus Progestin trial without prevalent coronary or peripheral arterial disease at baseline, carotid and lower extremity event rates were 0.07% and 0.03%, respectively. Thus, the risk for carotid disease was 17 times greater and for lower extremity events 35 times greater in HERS women compared with Women’s Health Initiative Estrogen Plus Progestin trial participants. This difference reflects the increased risk for peripheral arterial disease conferred by prevalent coronary heart disease,¹⁹ as well as the fact that HERS women were on average 4 years older.

For this analysis, classification of peripheral arterial events required overnight hospitalization, a definition which omits both asymptomatic and symptomatic peripheral arterial disease of which individuals may be unaware or which does not require hospitalization. Prevalence of lower extremity atherosclerosis identified by ankle-brachial index screening in individuals at least 65 years of age is about 18% in the United States.²⁰ Whether postmenopausal estrogen with progestin therapy might affect subclinical peripheral arterial disease or symptomatic disease not leading to hospitalization is not addressed by this analysis.

The prevalence of conventional atherosclerotic risk factors in the Women’s Health Initiative Estrogen Plus Progestin trial participants was consistent with a generally healthy population. For example, 30% reported hypertension at baseline, compared with prevalence in the National Health and Nutrition Examination Survey (NHANES), 1999 to 2000, of 30% among individuals age 40 to 59 years, and 65% among those aged 60 or older.²¹ Diabetes was reported by 4% in the Women’s Health Initiative Estrogen Plus Progestin trial, compared with a prevalence of 8% for women age 40 to 74 years in NHANES III,²² although self-report in our trial may underestimate the actual prevalence. Current cigarette smoking was reported by 10.5%, compared with the Behavioral Risk Factor Surveillance System rate of 20% for adults 55 to 64 years of age and 13% for those 65 to 74 years of age.²³ The Women’s Health Initiative is not a random sample; thus, the so-called healthy volunteer effect²⁴ may lead to lower peripheral arterial disease event rates than might be expected in the general population.

Intermediate outcomes such as coronary angiographic progression for coronary heart disease^25–27 and carotid or femoral intima-media thickness for peripheral arterial disease^5–8 demonstrated no benefit from combination hormone therapy. Randomized trials with clinical end points demonstrated no benefit and a suggestion of early harm for both primary and secondary coronary prevention.^14,18 With HERS¹⁰ and the Women’s Health Initiative Estrogen Plus Progestin trial, we now have data for women both with and without prior coronary disease demonstrating no protection against peripheral arterial disease by combination hormone therapy.

Unopposed estrogen remains a viable candidate for modulation of peripheral arterial disease risk. In a randomized trial of estradiol, progression of intima-media thickening was slower in the active treatment group.⁹ The impact of unopposed estrogen on coronary heart disease, stroke, and peripheral arterial disease is being determined in the ongoing Women’s Health Initiative Estrogen Alone trial. In the meantime, the current analysis confirms in yet another vascular bed that postmenopausal estrogen with progestin therapy has no role in atherosclerotic prevention in generally healthy women in this age range.

	Appendix

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Women’s Health Initiative Investigators
Program Office
National Heart, Lung, and Blood Institute, Bethesda, Md: Barbara Alving, Jacques Rossouw, Linda Pottern, Shari Ludlam, Joan McGowan.

Clinical Coordinating Center
Fred Hutchinson Cancer Research Center, Seattle, Wash: Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth Patterson, Anne McTiernan, Barbara Cochrane, Julie Hunt, Lesley Tinker, Charles Kooperberg, Martin McIntosh, C.Y. Wang, Chu Chen, Deborah Bowen, Alan Kristal, Janet Stanford, Nicole Urban, Noel Weiss, Emily White; Wake Forest University School of Medicine, Winston-Salem, NC: Sally Shumaker, Pentti Rautaharju, Ronald Prineas, Michelle Naughton; Medical Research Labs, Highland Heights, KY: Evan Stein, Peter Laskarzewski; University of California at San Francisco, San Francisco, Calif: Steven Cummings, Michael Nevitt, Maurice Dockrell; University of Minnesota, Minneapolis, Minn: Lisa Harnack; McKesson BioServices, Rockville, Md: Frank Cammarata, Steve Lindenfelser; University of Washington, Seattle, Wash: Bruce Psaty, Susan Heckbert.

Clinical Centers
Albert Einstein College of Medicine, Bronx, NY: Sylvia Wassertheil-Smoller, William Frishman, Judith Wylie-Rosett, David Barad, Ruth Freeman; Baylor College of Medicine, Houston, Tex: Jennifer Hays, Ronald Young, Jill Anderson, Sandy Lithgow, Paul Bray; Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass: JoAnn Manson, Julie Buring, J. Michael Gaziano, Kathryn Rexrode, Claudia Chae; Brown University, Providence, RI: Annlouise R. Assaf, Richard Carleton (deceased), Carol Wheeler, Charles Eaton, Michelle Cyr; Emory University, Atlanta, Ga: Lawrence Phillips, Margaret Pedersen, Ora Strickland, Margaret Huber, Vivian Porter; Fred Hutchinson Cancer Research Center, Seattle, Wash: Shirley A.A. Beresford, Vicky M. Taylor, Nancy F. Woods, Maureen Henderson, Mark Kestin; George Washington University, Washington, DC: Judith Hsia, Nancy Gaba, Joao Ascensao, Somchia Laowattana; Harbor-UCLA Research and Education Institute, Torrance, Calif: Rowan Chlebowski, Robert Detrano, Anita Nelson, James Heiner, John Marshall; Kaiser Permanente Center for Health Research, Portland, Ore: Cheryl Ritenbaugh, Barbara Valanis, Patricia Elmer, Victor Stevens, Njeri Karanja; Kaiser Permanente Division of Research, Oakland, Calif: Bette Caan, Stephen Sidney, Geri Bailey Jane Hirata; Medical College of Wisconsin, Milwaukee, Wis: Jane Morley Kotchen, Vanessa Barnabei, Theodore A. Kotchen, Mary Ann C. Gilligan, Joan Neuner; MedStar Research Institute/Howard University, Washington, DC: Barbara V. Howard, Lucile Adams-Campbell, Maureen Passaro, Monique Rainford, Tanya Agurs-Collins; Northwestern University, Chicago/Evanston, Ill: Linda Van Horn, Philip Greenland, Janardan Khandekar, Kiang Liu, Carol Rosenberg; Rush-Presbyterian St. Luke’s Medical Center, Chicago, Ill: Henry Black, Lynda Powell, Ellen Mason; Stanford Center for Research in Disease Prevention, Stanford University, Stanford, Calif: Marcia L. Stefanick, Mark A. Hlatky, Bertha Chen, Randall S. Stafford, Linda C. Giudice; State University of New York at Stony Brook, Stony Brook, NY: Dorothy Lane, Iris Granek, William Lawson, Gabriel San Roman, Catherine Messina; The Ohio State University, Columbus, Ohio: Rebecca Jackson, Randall Harris, Electra Paskett, W. Jerry Mysiw, Michael Blumenfeld; University of Alabama at Birmingham, Birmingham, Ala: Cora E. Lewis, Albert Oberman, Mona N. Fouad, James M. Shikany, Delia Smith West; University of Arizona, Tucson/Phoenix, Ariz: Tamsen Bassford, John Mattox, Marcia Ko, Timothy Lohman; University at Buffalo, Buffalo, NY: Maurizio Trevisan, Jean Wactawski-Wende, Susan Graham, June Chang, Ellen Smit; University of California at Davis, Sacramento, Calif: John Robbins, S. Yasmeen, Karen Lindfors, Judith Stern; University of California at Irvine, Orange, Calif: Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, Bradley Monk; University of California at Los Angeles, Los Angeles, Calif: Howard Judd, David Heber, Robert Elashoff; University of California at San Diego, LaJolla/Chula Vista, Calif: Robert D. Langer, Michael H. Criqui, Gregory T. Talavera, Cedric F. Garland, R. Elaine Hanson; University of Cincinnati, Cincinnati, Ohio: Margery Gass, Suzanne Wernke, Nelson Watts; University of Florida, Gainesville/Jacksonville, Fla: Marian Limacher, Michael Perri, Andrew Kaunitz, R. Stan Williams, Yvonne Brinson; University of Hawaii, Honolulu, Hawaii: David Curb, Helen Petrovitch, Beatriz Rodriguez, Kamal Masaki, Santosh Sharma; University of Iowa, Iowa City/Davenport, Iowa: Robert Wallace, James Torner, Susan Johnson, Linda Snetselaar, Bradley VanVoorhis; University of Massachusetts/Fallon Clinic, Worcester, Mass: Judith Ockene, Milagros Rosal, Ira Ockene, Robert Yood, Patricia Aronson; University of Medicine and Dentistry of New Jersey, Newark, NJ: Norman Lasser, Bali Singh, Vera Lasser, Monika Safford John Kostis; University of Miami, Miami, Fla: Mary Jo O’Sullivan, Linda Parker, R. Estape, Diann Fernandez; University of Minnesota, Minneapolis, Minn: Karen L, Margolis, Richard H. Grimm, Donald B. Hunninghake, June LaValleur, Kathleen M. Hall; University of Nevada, Reno, Nev: Robert Brunner, Sachiko St. Jeor, William Graettinger, Vicki Oujevolk; University of North Carolina, Chapel Hill, NC: Gerardo Heiss, Pamela Haines, David Ontjes, Carla Sueta, Ellen Wells; University of Pittsburgh, Pittsburgh, Pa: Lewis Kuller, Arlene Caggiula, Jane Cauley, Sarah Berga, N. Carole Milas; University of Tennessee, Memphis, Tenn: Karen C. Johnson, Suzanne Satterfield, Raymond W. Ke, Jere Vile, Fran Tylavsky; University of Texas Health Science Center, San Antonio, Tex: Robert Brzyski, Robert Schenken, Jose Trabal, Mercedes Rodriguez-Sifuentes, Charles Mouton; University of Wisconsin, Madison, Wis: Catherine Allen (deceased), Douglas Laube, Patrick McBride, Julie Mares-Perlman, Barbara Loevinger; Wake Forest University School of Medicine, Winston-Salem, NC: Greg Burke, Robin Crouse, Lynne Parsons, Mara Vitolins; Wayne State University School of Medicine/Hutzel Hospital, Detroit, Mich: Susan Hendrix, Michael Simon, Gene McNeeley, Pamela Gordon, Paul Makela.

	Acknowledgments

 
This work was supported by the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the Department of Health and Human Services.

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