This Article  • Full text  • PDF  • JAMA News Video  • Correction  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (209)  • Contact me when this article is cited  Related Content  • Related letters  • Similar articles in JAMA  Topic Collections  • Women's Health  • Menopause  • Women's Health, Other  • Cardiovascular Disease/ Myocardial Infarction  • Alert me on articles by topic  Social Bookmarking   What's this?

Jacques E. Rossouw, MD; Ross L. Prentice, PhD; JoAnn E. Manson, MD, DrPH; LieLing Wu, MSc; David Barad, MD; Vanessa M. Barnabei, MD, PhD; Marcia Ko, MD; Andrea Z. LaCroix, PhD; Karen L. Margolis, MD; Marcia L. Stefanick, PhD

JAMA. 2007;297:1465-1477.

Context  The timing of initiation of hormone therapy may influence its effect on cardiovascular disease.

Objective  To explore whether the effects of hormone therapy on risk of cardiovascular disease vary by age or years since menopause began.

Design, Setting, and Participants  Secondary analysis of the Women's Health Initiative (WHI) randomized controlled trials of hormone therapy in which 10 739 postmenopausal women who had undergone a hysterectomy were randomized to conjugated equine estrogens (CEE) or placebo and 16 608 postmenopausal women who had not had a hysterectomy were randomized to CEE plus medroxyprogesterone acetate (CEE + MPA) or placebo. Women aged 50 to 79 years were recruited to the study from 40 US clinical centers between September 1993 and October 1998.

Main Outcome Measures  Statistical test for trend of the effect of hormone therapy on coronary heart disease (CHD) and stroke across categories of age and years since menopause in the combined trials.

Results  In the combined trials, there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 379 cases of CHD and 239 cases of stroke in the placebo group. For women with less than 10 years since menopause began, the hazard ratio (HR) for CHD was 0.76 (95% confidence interval [CI], 0.50-1.16); 10 to 19 years, 1.10 (95% CI, 0.84-1.45); and 20 or more years, 1.28 (95% CI, 1.03-1.58) (P for trend = .02). The estimated absolute excess risk for CHD for women within 10 years of menopause was –6 per 10 000 person-years; for women 10 to 19 years since menopause began, 4 per 10 000 person-years; and for women 20 or more years from menopause onset, 17 per 10 000 person-years. For the age group of 50 to 59 years, the HR for CHD was 0.93 (95% CI, 0.65-1.33) and the absolute excess risk was –2 per 10 000 person-years; 60 to 69 years, 0.98 (95% CI, 0.79-1.21) and –1 per 10 000 person-years; and 70 to 79 years, 1.26 (95% CI, 1.00-1.59) and 19 per 10 000 person-years (P for trend = .16). Hormone therapy increased the risk of stroke (HR, 1.32; 95% CI, 1.12-1.56). Risk did not vary significantly by age or time since menopause. There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women (HR of 0.70 for 50-59 years; 1.05 for 60-69 years, and 1.14 for 70-79 years; P for trend = .06).

Conclusions  Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion for statistical significance. A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since menopause. These data should be considered in regard to the short-term treatment of menopausal symptoms.

Trial Registration  clinicaltrials.gov Identifier: NCT00000611

Author Affiliations: National Heart, Lung, and Blood Institute, Bethesda, Md (Dr Rossouw); Fred Hutchinson Cancer Research Center, Seattle, Wash (Drs Prentice and LaCroix and Ms Wu); Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (Dr Manson); Departments of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, New York, NY (Dr Barad); Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee (Dr Barnabei); Division of Women's Health Internal Medicine, Mayo Clinic, Scottsdale, Ariz (Dr Ko); Berman Center for Clinical Research, University of Minnesota, Minneapolis (Dr Margolis); Department of Medicine, Stanford University, Palo Alto, Calif (Dr Stefanick).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati     What's this?

RELATED LETTERS

Hormone Therapy and Cardiovascular Risk
Samuel Shapiro
JAMA. 2007;298(6):623.
EXTRACT | FULL TEXT  

Hormone Therapy and Cardiovascular Risk
Lynn E. T. Shaffer and Carl A. Krantz
JAMA. 2007;298(6):623-624.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Invited Commentary: Hormone Therapy Risks and Benefits--The Women's Health Initiative Findings and the Postmenopausal Estrogen Timing Hypothesis
Banks and Canfell
Am J Epidemiol 2009;170:24-28.
ABSTRACT | FULL TEXT  

Benefits and Risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause
Prentice et al.
Am J Epidemiol 2009;170:12-23.
ABSTRACT | FULL TEXT  

Postmenopausal Hormone Treatment
Hulley and Grady
JAMA 2009;301:2493-2495.
FULL TEXT  

Hormone replacement therapy and cardiovascular disease revisited
Stevenson
Menopause Int 2009;15:55-57.
ABSTRACT | FULL TEXT  

Effects of the menopause transition and hormone use on cognitive performance in midlife women
Greendale et al.
Neurology 2009;72:1850-1857.
ABSTRACT | FULL TEXT  

Hormone therapy and cognitive function
Maki and Sundermann
Hum Reprod Update 2009;0:dmp022v1-dmp022.
ABSTRACT | FULL TEXT  

Effect of hormone replacement therapy on vasomotor function of the coronary microcirculation in post-menopausal women with medically treated cardiovascular risk factors
Schindler et al.
Eur Heart J 2009;30:978-986.
ABSTRACT | FULL TEXT  

Interference of Progestins With Endothelial Actions of Estrogens: A Matter of Glucocorticoid Action or Deprivation?
Arnal et al.
Arterioscler. Thromb. Vasc. Bio. 2009;29:441-443.
FULL TEXT  

Age at Natural Menopause and Risk of Ischemic Stroke: The Framingham Heart Study
Lisabeth et al.
Stroke 2009;40:1044-1049.
ABSTRACT | FULL TEXT  

RE: "ESTROGEN PLUS PROGESTIN THERAPY AND BREAST CANCER IN RECENTLY POSTMENOPAUSAL WOMEN"
Langer
Am J Epidemiol 2009;169:784-785.
FULL TEXT  

Cost-effectiveness of hormone replacement therapy for menopausal symptoms in the UK
Lekander et al.
Menopause Int 2009;15:19-25.
ABSTRACT | FULL TEXT  

Prevention, Diagnosis, and Management of Osteoporosis-Related Fracture
Fakih
JAOA: Journal of the American Osteopathic Association 2009;109:191-193.
FULL TEXT  

Estrogen and Mechanisms of Vascular Protection
Xing et al.
Arterioscler. Thromb. Vasc. Bio. 2009;29:289-295.
ABSTRACT | FULL TEXT  

On Looking at Subgroups
Wittes
Circulation 2009;119:912-915.
FULL TEXT  

Effects of the Selective Estrogen Receptor Modulator Raloxifene on Coronary Outcomes in The Raloxifene Use for the Heart Trial: Results of Subgroup Analyses by Age and Other Factors
Collins et al.
Circulation 2009;119:922-930.
ABSTRACT | FULL TEXT  

The transactivating function 1 of estrogen receptor {alpha} is dispensable for the vasculoprotective actions of 17{beta}-estradiol
Billon-Gales et al.
Proc. Natl. Acad. Sci. USA 2009;106:2053-2058.
ABSTRACT | FULL TEXT  

Review: postmenopausal hormone therapy increases risk of stroke and venous thromboembolism but not coronary heart disease events
Cheung
Evid. Based Med. 2009;14:18-18.
FULL TEXT  

A Select Combination of Clinically Relevant Phytoestrogens Enhances Estrogen Receptor {beta}-Binding Selectivity and Neuroprotective Activities in Vitro and in Vivo
Zhao et al.
Endocrinology 2009;150:770-783.
ABSTRACT | FULL TEXT  

Sex Hormones Save Our Skin: The Vascular Networking of Estrogen
Werner and Nickenig
Circ. Res. 2009;104:135-137.
FULL TEXT  

Use of primary care electronic medical record database in drug efficacy research on cardiovascular outcomes: comparison of database and randomised controlled trial findings
Tannen et al.
BMJ 2009;338:b81-b81.
ABSTRACT | FULL TEXT  

Meta-analysis of Risk Reduction Estimates Associated With Risk-Reducing Salpingo-oophorectomy in BRCA1 or BRCA2 Mutation Carriers
Rebbeck et al.
JNCI J Natl Cancer Inst 2009;101:80-87.
ABSTRACT | FULL TEXT  

Herbal medicines for menopausal symptoms
DTB 2009;47:2-6.
ABSTRACT | FULL TEXT  

Reassessing Benefits and Risks of Hormone Therapy
Gass et al.
AMERICAN JOURNAL OF LIFESTYLE MEDICINE 2009;3:29-43.
ABSTRACT  

Approach to the Patient with Menopausal Symptoms
Martin and Manson
J. Clin. Endocrinol. Metab. 2008;93:4567-4575.
ABSTRACT | FULL TEXT  

Commentary: The Year in Basic Science: Update of Estrogen Plus Progestin Therapy for Menopausal Hormone Replacement Implicating Stem Cells in the Increased Breast Cancer Risk
Horwitz
Mol. Endocrinol. 2008;22:2743-2750.
ABSTRACT | FULL TEXT  

Hypercoagulable States in Cardiovascular Disease
Chan et al.
Circulation 2008;118:2286-2297.
FULL TEXT  

Inflammatory, Lipid, Thrombotic, and Genetic Markers of Coronary Heart Disease Risk in the Women's Health Initiative Trials of Hormone Therapy
Rossouw et al.
Arch Intern Med 2008;168:2245-2253.
ABSTRACT | FULL TEXT  

Research Resource: Rapid Recruitment of Temporally Distinct Vascular Gene Sets by Estrogen
Schnoes et al.
Mol. Endocrinol. 2008;22:2544-2556.
ABSTRACT | FULL TEXT  

Review: Prevention of coronary heart disease in women
Rohit Seth Loomba and Arora
Ther Adv Cardiovasc Dis 2008;2:321-327.
ABSTRACT  

Hot Flashes and Subclinical Cardiovascular Disease: Findings From the Study of Women's Health Across the Nation Heart Study
Thurston et al.
Circulation 2008;118:1234-1240.
ABSTRACT | FULL TEXT  

Prophylactic oophorectomy in premenopausal women and long-term health
Shuster et al.
Menopause Int 2008;14:111-116.
ABSTRACT | FULL TEXT  

Sex Differences in Autoimmune Disease from a Pathological Perspective
Fairweather et al.
Am. J. Pathol. 2008;173:600-609.
ABSTRACT | FULL TEXT  

Tibolone and the Promise of Ideal Hormone-Replacement Therapy
El-Hajj Fuleihan
NEJM 2008;359:753-755.
FULL TEXT  

Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis
Sare et al.
Eur Heart J 2008;29:2031-2041.
ABSTRACT | FULL TEXT  

Update on Hormone Therapy: Evidence-Based Approaches
JWatch Women's Health 2008;2008:1-1.
FULL TEXT  

Update in Female Reproduction: A Life-Cycle Approach
Barbieri
J. Clin. Endocrinol. Metab. 2008;93:2439-2446.
ABSTRACT | FULL TEXT  

Newly Appreciated Pathophysiology of Ischemic Heart Disease in Women Mandates Changes in Perioperative Management: A Core Review
Matyal
Anesth. Analg. 2008;107:37-50.
ABSTRACT | FULL TEXT  

Cardiovascular Consequences of Subclinical Thyroid Dysfunction: More Smoke but No Fire
Ladenson
ANN INTERN MED 2008;148:880-881.
FULL TEXT  

A 10-year follow-up of the effect of continuous-combined hormone replacement therapy and its discontinuation on bone in postmenopausal women
Heikkinen et al.
Menopause Int 2008;14:70-77.
ABSTRACT | FULL TEXT  

Hormone therapy and the rise and perhaps fall of US breast cancer incidence rates: critical reflections
Krieger
Int J Epidemiol 2008;37:627-637.
ABSTRACT | FULL TEXT  

Vascular Actions of Estrogens: Functional Implications
Miller and Duckles
Pharmacol. Rev. 2008;60:210-241.
ABSTRACT | FULL TEXT  

Menopausal Complaints Are Associated With Cardiovascular Risk Factors
Gast et al.
Hypertension 2008;51:1492-1498.
ABSTRACT | FULL TEXT  

A Comparison of the Short-Term Effects of Oral Conjugated Equine Estrogens Versus Transdermal Estradiol on C-Reactive Protein, Other Serum Markers of Inflammation, and Other Hepatic Proteins in Naturally Menopausal Women
Shifren et al.
J. Clin. Endocrinol. Metab. 2008;93:1702-1710.
ABSTRACT | FULL TEXT  

Effects in Postmenopausal Women of Estradiol and Medroxyprogesterone Alone and Combined on Resistance Artery Function and Endothelial Morphology and Movement
Kublickiene et al.
J. Clin. Endocrinol. Metab. 2008;93:1874-1883.
ABSTRACT | FULL TEXT  

Persistent Hot Flushes in Older Postmenopausal Women
Huang et al.
Arch Intern Med 2008;168:840-846.
ABSTRACT | FULL TEXT  

Prolonged Ovarian Hormone Deprivation Impairs the Protective Vascular Actions of Estrogen Receptor {alpha}Agonists
Pinna et al.
Hypertension 2008;51:1210-1217.
ABSTRACT | FULL TEXT  

Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin
Heiss et al.
JAMA 2008;299:1036-1045.
ABSTRACT | FULL TEXT  

Cardiovascular disease in women
Stevenson
Menopause Int 2008;14:5-5.
FULL TEXT  

Management of Parkinson's disease in older women
Price and Shulman
Menopause Int 2008;14:38-39.
ABSTRACT | FULL TEXT  

Primary prevention of coronary heart disease in women
Rees et al.
Menopause Int 2008;14:40-45.
ABSTRACT | FULL TEXT  

Estrogen Plus Progestin and Breast Cancer Detection by Means of Mammography and Breast Biopsy
Chlebowski et al.
Arch Intern Med 2008;168:370-377.
ABSTRACT | FULL TEXT  

Evidence-based common sense?
Sherman
cfp 2008;54:166-168.
FULL TEXT  

Bon sens fonde sur des donnees probantes?
Sherman
cfp 2008;54:169-171.
FULL TEXT  

Insulin Secretion and Clearance after Subacute Estradiol Administration in Postmenopausal Women
Van Pelt et al.
J. Clin. Endocrinol. Metab. 2008;93:484-490.
ABSTRACT | FULL TEXT  

Time Since Menopause Influences the Acute and Chronic Effect of Estrogens on Endothelial Function
Vitale et al.
Arterioscler. Thromb. Vasc. Bio. 2008;28:348-352.
ABSTRACT | FULL TEXT  

Effect of ovariectomy on cardiac gene expression: inflammation and changes in SOCS gene expression
Hamilton et al.
Physiol. Genomics 2008;32:254-263.
ABSTRACT | FULL TEXT  

Perimenopausal Depression
Parry
Am. J. Psychiatry 2008;165:23-27.
FULL TEXT  

Selective Estrogen Receptor- Agonists Repress Transcription of Proinflammatory Genes
Cvoro et al.
J. Immunol. 2008;180:630-636.
ABSTRACT | FULL TEXT  

THE AUTHORS REPLY
Manson and Bassuk
Am J Epidemiol 2007;166:1481-1482.
FULL TEXT  

The Effects of Biological Sex and Diet on the Development of Heart Failure
Konhilas and Leinwand
Circulation 2007;116:2747-2759.
FULL TEXT  

New findings from non-linear longitudinal modelling of menopausal hormone changes
Dennerstein et al.
Hum Reprod Update 2007;13:551-557.
ABSTRACT | FULL TEXT  

Hormone therapy for younger women may not increase CHD risk during 5 7 years follow-up, but stroke risk was increased independent of age
Reid
Evid. Based Med. 2007;12:137-137.
FULL TEXT  

Can Computerized Decision Support Help Patients Make Complex Treatment Decisions? A Randomized Controlled Trial of an Individualized Menopause Decision Aid
Col et al.
Med Decis Making 2007;27:585-598.
ABSTRACT  

Estrogen Therapy and Coronary-Artery Calcification
Hodis et al.
NEJM 2007;357:1252-1254.
FULL TEXT  

Invited Commentary: Hormone Therapy and Risk of Coronary Heart Disease Why Renew the Focus on the Early Years of Menopause?
Manson and Bassuk
Am J Epidemiol 2007;166:511-517.
ABSTRACT | FULL TEXT  

Hormone Therapy and Cardiovascular Risk
Shapiro
JAMA 2007;298:623-623.
FULL TEXT  

Hormone Therapy and Cardiovascular Risk
Shaffer and Krantz
JAMA 2007;298:623-624.
FULL TEXT  

Hormone replacement therapy comes full circle
Roberts
BMJ 2007;335:219-220.
FULL TEXT  

Management of cardiovascular risk in the peri-menopausal woman: a consensus statement of European cardiologists and gynaecologists
Collins et al.
Eur Heart J 2007;28:2028-2040.
ABSTRACT | FULL TEXT  

HRT and the Young at Heart
Mendelsohn and Karas
NEJM 2007;356:2639-2641.
FULL TEXT  

Women Need Tailored CHD Prevention
Beckley
DOC News 2007;4:5-5.
FULL TEXT  

Hormone Therapy and the Heart: Timing Matters
JWatch Women's Health 2007;2007:3-3.
FULL TEXT  

Review Article: Vascular and Metabolic Effects of Sex Steroids: New Insights Into Clinical Trials
Wierman and Kohrt
Reproductive Sciences 2007;14:300-314.
ABSTRACT  

Postmenopausal hormone therapy
Grady and Barrett-Connor
BMJ 2007;334:860-861.
FULL TEXT  

HRT and CHD, Revisited
Journal Watch Cardiology 2007;2007:1-1.
FULL TEXT  

Hormone Therapy, Age, and Risk for Heart Disease
JWatch General 2007;2007:1-1.
FULL TEXT