Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial
Andrea Z LaCroix, Rowan T Chlebowski, JoAnn E Manson, Aaron K Aragaki, Karen C Johnson, Lisa Martin, Karen L Margolis, Marcia L Stefanick, Robert Brzyski, J David Curb, Barbara V Howard, Cora E Lewis, Jean Wactawski-Wende, WHI Investigators, Jacques Rossouw, Shari Ludlam, Joan McGowan, Nancy Geller, Leslie Ford, 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, Evan Stein, Peter Laskarzewski, Steven R Cummings, Michael Nevitt, Lisa Palermo, Lisa Harnack, Frank Cammarata, Steve Lindenfelser, Bruce Psaty, Susan Heckbert, Sylvia Wassertheil-Smoller, William Frishman, Judith Wylie-Rosett, David Barad, Ruth Freeman, Aleksandar Rajkovic, Jennifer Hays, Ronald Young, Haleh Sangi-Haghpeykar, JoAnn E Manson, Kathryn M Rexrode, Brian Walsh, J Michael Gaziano, Maria Bueche, Charles B Eaton, Michele Cyr, Gretchen Sloane, Annlouise Assaf, Lawrence S Phillips, Vicki Butler, Vivian Porter, Shirley A A Beresford, Vicky M Taylor, Nancy F Woods, Maureen Henderson, Robyn Andersen, Lisa Martin, Judith Hsia, Nancy Gaba, Richard Katz, Rowan Chlebowski, Robert Detrano, Anita Nelson, Michele Geller, Erin LeBlanc, Yvonne Michael, Evelyn Whitlock, Victor Stevens, Njeri Karanja, Bette Caan, Stephen Sidney, Geri Bailey, Jane Hirata, Jane Morley Kotchen, Vanessa Barnabei, Theodore A Kotchen, Mary Ann C Gilligan, Joan Neuner, Barbara V Howard, Lucile Adams-Campbell, Lawrence Lessin, Cheryl Iglesia, Linda K Mickel, Linda Van Horn, Philip Greenland, Janardan Khandekar, Liviu Klein, Carol Rosenberg, Henry Black, Lynda Powell, Ellen Mason, Martha Gulati, Marcia L Stefanick, Mark A Hlatky, Bertha Chen, Randall S Stafford, Sally Mackey, Dorothy Lane, Iris Granek, William Lawson, Catherine Messina, Gabriel San Roman, Rebecca Jackson, Randall Harris, Electra Paskett, W Jerry Mysiw, Michael Blumenfeld, Cora E Lewis, Albert Oberman, James M Shikany, Monika Safford, Cynthia A Thomson, Tamsen Bassford, Cheryl Ritenbaugh, Zhao Chen, Marcia Ko, Jean Wactawski-Wende, Maurizio Trevisan, Ellen Smit, Amy Millen, Michael LaMonte, John Robbins, S Yasmeen, Lihong Qi, F Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, Bradley Monk, Lauren Nathan, David Heber, Robert Elashoff, Simin Liu, Robert D Langer, Michael H Criqui, Gregory T Talavera, Cedric F Garland, Matthew A Allison, Margery Gass, Nelson Watts, Marian Limacher, Michael Perri, Andrew Kaunitz, R Stan Williams, Yvonne Brinson, J David Curb, Helen Petrovitch, Beatriz Rodriguez, Kamal Masaki, Patricia Blanchette, Robert Wallace, James Torner, Susan Johnson, Linda Snetselaar, Jennifer Robinson, Judith Ockene, Milagros Rosal, Ira Ockene, Robert Yood, Patricia Aronson, Norman Lasser, Baljinder Singh, Vera Lasser, John Kostis, Peter McGovern, Mary Jo O'Sullivan, Linda Parker, JoNell Potter, Diann Fernandez, Pat Caralis, Karen L Margolis, Richard H Grimm, Mary F Perron, Julia A Levin, Robert Brunner, William Graettinger, Vicki Oujevolk, Michael Bloch, Gerardo Heiss, Pamela Haines, David Ontjes, Carla Sueta, Ellen Wells, Lewis Kuller, Jane Cauley, N Carole Milas, Karen C Johnson, Suzanne Satterfield, Rongling Li, Stephanie Connelly, Fran Tylavsky, Robert Brzyski, Robert Schenken, Allison Rodgers, Nicole Budrys, Gloria E Sarto, Douglas Laube, Patrick McBride, Julie Mares, Barbara Loevinger, Mara Vitolins, Greg Burke, Robin Crouse, Scott Washburn, Michael S Simon, Sally Shumaker, Stephen Rapp, Claudine Legault, Mark Espeland, Laura Coker, Michelle Naughton, Aleksandar Rajkovic, Jennifer Cousins, Jennifer Hays, John Foreyt, Annlouise R Assaf, Dallas Hall, Sally McNagny, Maureen Henderson, Ruth Patterson, Valery Miller, Yvonne Michael, Evelyn Whitlock, Barbara Valanis, Robert Hiatt, Carolyn Clifford, Linda Pottern, Philip Greenland, Henry Black, William Elliott, Electra Paskett, Maurizio Trevisan, Albert Oberman, Tamsen Bassford, Tom Moon, Cheryl Ritenbaugh, Frank Meyskens Jr, Howard Judd, Margery Gass, James Liu, Nelson Watts, Marianna Baum, Richard Grimm, Sandra Daugherty, David Sheps, Barbara Hulka, William Applegate, Robert Schenken, Catherine Allen, Denise Bonds, Greg Burke, Susan Hendrix, Andrea Z LaCroix, Rowan T Chlebowski, JoAnn E Manson, Aaron K Aragaki, Karen C Johnson, Lisa Martin, Karen L Margolis, Marcia L Stefanick, Robert Brzyski, J David Curb, Barbara V Howard, Cora E Lewis, Jean Wactawski-Wende, WHI Investigators, Jacques Rossouw, Shari Ludlam, Joan McGowan, Nancy Geller, Leslie Ford, 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, Evan Stein, Peter Laskarzewski, Steven R Cummings, Michael Nevitt, Lisa Palermo, Lisa Harnack, Frank Cammarata, Steve Lindenfelser, Bruce Psaty, Susan Heckbert, Sylvia Wassertheil-Smoller, William Frishman, Judith Wylie-Rosett, David Barad, Ruth Freeman, Aleksandar Rajkovic, Jennifer Hays, Ronald Young, Haleh Sangi-Haghpeykar, JoAnn E Manson, Kathryn M Rexrode, Brian Walsh, J Michael Gaziano, Maria Bueche, Charles B Eaton, Michele Cyr, Gretchen Sloane, Annlouise Assaf, Lawrence S Phillips, Vicki Butler, Vivian Porter, Shirley A A Beresford, Vicky M Taylor, Nancy F Woods, Maureen Henderson, Robyn Andersen, Lisa Martin, Judith Hsia, Nancy Gaba, Richard Katz, Rowan Chlebowski, Robert Detrano, Anita Nelson, Michele Geller, Erin LeBlanc, Yvonne Michael, Evelyn Whitlock, Victor Stevens, Njeri Karanja, Bette Caan, Stephen Sidney, Geri Bailey, Jane Hirata, Jane Morley Kotchen, Vanessa Barnabei, Theodore A Kotchen, Mary Ann C Gilligan, Joan Neuner, Barbara V Howard, Lucile Adams-Campbell, Lawrence Lessin, Cheryl Iglesia, Linda K Mickel, Linda Van Horn, Philip Greenland, Janardan Khandekar, Liviu Klein, Carol Rosenberg, Henry Black, Lynda Powell, Ellen Mason, Martha Gulati, Marcia L Stefanick, Mark A Hlatky, Bertha Chen, Randall S Stafford, Sally Mackey, Dorothy Lane, Iris Granek, William Lawson, Catherine Messina, Gabriel San Roman, Rebecca Jackson, Randall Harris, Electra Paskett, W Jerry Mysiw, Michael Blumenfeld, Cora E Lewis, Albert Oberman, James M Shikany, Monika Safford, Cynthia A Thomson, Tamsen Bassford, Cheryl Ritenbaugh, Zhao Chen, Marcia Ko, Jean Wactawski-Wende, Maurizio Trevisan, Ellen Smit, Amy Millen, Michael LaMonte, John Robbins, S Yasmeen, Lihong Qi, F Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, Bradley Monk, Lauren Nathan, David Heber, Robert Elashoff, Simin Liu, Robert D Langer, Michael H Criqui, Gregory T Talavera, Cedric F Garland, Matthew A Allison, Margery Gass, Nelson Watts, Marian Limacher, Michael Perri, Andrew Kaunitz, R Stan Williams, Yvonne Brinson, J David Curb, Helen Petrovitch, Beatriz Rodriguez, Kamal Masaki, Patricia Blanchette, Robert Wallace, James Torner, Susan Johnson, Linda Snetselaar, Jennifer Robinson, Judith Ockene, Milagros Rosal, Ira Ockene, Robert Yood, Patricia Aronson, Norman Lasser, Baljinder Singh, Vera Lasser, John Kostis, Peter McGovern, Mary Jo O'Sullivan, Linda Parker, JoNell Potter, Diann Fernandez, Pat Caralis, Karen L Margolis, Richard H Grimm, Mary F Perron, Julia A Levin, Robert Brunner, William Graettinger, Vicki Oujevolk, Michael Bloch, Gerardo Heiss, Pamela Haines, David Ontjes, Carla Sueta, Ellen Wells, Lewis Kuller, Jane Cauley, N Carole Milas, Karen C Johnson, Suzanne Satterfield, Rongling Li, Stephanie Connelly, Fran Tylavsky, Robert Brzyski, Robert Schenken, Allison Rodgers, Nicole Budrys, Gloria E Sarto, Douglas Laube, Patrick McBride, Julie Mares, Barbara Loevinger, Mara Vitolins, Greg Burke, Robin Crouse, Scott Washburn, Michael S Simon, Sally Shumaker, Stephen Rapp, Claudine Legault, Mark Espeland, Laura Coker, Michelle Naughton, Aleksandar Rajkovic, Jennifer Cousins, Jennifer Hays, John Foreyt, Annlouise R Assaf, Dallas Hall, Sally McNagny, Maureen Henderson, Ruth Patterson, Valery Miller, Yvonne Michael, Evelyn Whitlock, Barbara Valanis, Robert Hiatt, Carolyn Clifford, Linda Pottern, Philip Greenland, Henry Black, William Elliott, Electra Paskett, Maurizio Trevisan, Albert Oberman, Tamsen Bassford, Tom Moon, Cheryl Ritenbaugh, Frank Meyskens Jr, Howard Judd, Margery Gass, James Liu, Nelson Watts, Marianna Baum, Richard Grimm, Sandra Daugherty, David Sheps, Barbara Hulka, William Applegate, Robert Schenken, Catherine Allen, Denise Bonds, Greg Burke, Susan Hendrix
Abstract
Context: The Women's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.
Objective: To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009.
Design, setting, and participants: The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10,739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent.
Main outcome measures: The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death.
Results: The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction).
Conclusions: Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.
Trial registration: clinicaltrials.gov Identifier: NCT00000611.
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Source: PubMed