Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women’s Health Initiative randomized trials

WHI Investigators

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146 Citations (Scopus)

Abstract

IMPORTANCE: Health outcomes from the Women’s Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. OBJECTIVE: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women’s Health Initiative hormone therapy trials. DESIGN, SETTING, AND PARTICIPANTS: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. INTERVENTIONS: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median). MAIN OUTCOMES AND MEASURES: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. RESULTS: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. CONCLUSIONS AND RELEVANCE: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

Original languageEnglish (US)
Pages (from-to)927-938
Number of pages12
JournalJAMA - Journal of the American Medical Association
Volume318
Issue number10
DOIs
StatePublished - Sep 12 2017

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Women's Health
Hormones
Mortality
Placebos
Therapeutics
Estrogens
Age Groups
Conjugated (USP) Estrogens
Neoplasms
Medroxyprogesterone Acetate
Progestins
Group Psychotherapy
Random Allocation
Cardiovascular Diseases
Randomized Controlled Trials
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{07ef71053c4e472baf21198ac834c382,
title = "Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women’s Health Initiative randomized trials",
abstract = "IMPORTANCE: Health outcomes from the Women’s Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. OBJECTIVE: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women’s Health Initiative hormone therapy trials. DESIGN, SETTING, AND PARTICIPANTS: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. INTERVENTIONS: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median). MAIN OUTCOMES AND MEASURES: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. RESULTS: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6{\%} white), mortality follow-up was available for more than 98{\%}. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1{\%} in the hormone therapy group vs 27.6{\%} in the placebo group (hazard ratio [HR], 0.99 [95{\%} CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95{\%} CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95{\%} CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95{\%} CI, 0.92-1.08 [8.9 {\%} with hormone therapy vs 9.0{\%} with placebo]); for total cancer mortality, the HR was 1.03 (95{\%} CI, 0.95-1.12 [8.2 {\%} with hormone therapy vs 8.0{\%} with placebo]); and for other causes, the HR was 0.95 (95{\%} CI, 0.88-1.02 [10.0{\%} with hormone therapy vs 10.7{\%} with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95{\%} CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95{\%} CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. CONCLUSIONS AND RELEVANCE: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.",
author = "{WHI Investigators} and Manson, {Jo Ann E.} and Aragaki, {Aaron K.} and Rossouw, {Jacques E.} and Anderson, {Garnet L.} and Prentice, {Ross L.} and LaCroix, {Andrea Z.} and Chlebowski, {Rowan T.} and Howard, {Barbara V.} and Cynthia Thomson and Margolis, {Karen L.} and Lewis, {Cora E.} and Stefanick, {Marcia L.} and Jackson, {Rebecca D.} and Johnson, {Karen C.} and Martin, {Lisa W.} and Shumaker, {Sally A.} and Espeland, {Mark A.} and Jean Wactawski-Wende",
year = "2017",
month = "9",
day = "12",
doi = "10.1001/jama.2017.11217",
language = "English (US)",
volume = "318",
pages = "927--938",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "10",

}

TY - JOUR

T1 - Menopausal hormone therapy and long-term all-cause and cause-specific mortality

T2 - The Women’s Health Initiative randomized trials

AU - WHI Investigators

AU - Manson, Jo Ann E.

AU - Aragaki, Aaron K.

AU - Rossouw, Jacques E.

AU - Anderson, Garnet L.

AU - Prentice, Ross L.

AU - LaCroix, Andrea Z.

AU - Chlebowski, Rowan T.

AU - Howard, Barbara V.

AU - Thomson, Cynthia

AU - Margolis, Karen L.

AU - Lewis, Cora E.

AU - Stefanick, Marcia L.

AU - Jackson, Rebecca D.

AU - Johnson, Karen C.

AU - Martin, Lisa W.

AU - Shumaker, Sally A.

AU - Espeland, Mark A.

AU - Wactawski-Wende, Jean

PY - 2017/9/12

Y1 - 2017/9/12

N2 - IMPORTANCE: Health outcomes from the Women’s Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. OBJECTIVE: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women’s Health Initiative hormone therapy trials. DESIGN, SETTING, AND PARTICIPANTS: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. INTERVENTIONS: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median). MAIN OUTCOMES AND MEASURES: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. RESULTS: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. CONCLUSIONS AND RELEVANCE: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

AB - IMPORTANCE: Health outcomes from the Women’s Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. OBJECTIVE: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women’s Health Initiative hormone therapy trials. DESIGN, SETTING, AND PARTICIPANTS: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. INTERVENTIONS: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median). MAIN OUTCOMES AND MEASURES: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. RESULTS: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. CONCLUSIONS AND RELEVANCE: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

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U2 - 10.1001/jama.2017.11217

DO - 10.1001/jama.2017.11217

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C2 - 28898378

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VL - 318

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JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 10

ER -