- Email: [email protected]
Commentary on the Women's Health Initiative
Maturitas 34 (2000) 109 – 112 www.elsevier.com/locate/maturitas
Commentary on the Women’s Health Initiative Joan A. McGowan a,*, Linda Pottern b a
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIAMS/NIH, Natcher Building, Room 5AS-43E Bethesda, MD 20892 -6500, USA b National Heart Lung and Blood Institute, Bethesda, MD, USA Received 20 August 1999; accepted 15 November 1999
Abstract The Women’s Health Initiative (WHI), established by the National Institutes of Health in 1991, is a long-term national health study that focuses on strategies for preventing heart disease, breast and colorectal cancer and osteoporosis in postmenopausal women. These chronic diseases are the major causes of death, disability and frailty in older women of all races and socioeconomic backgrounds. The WHI a 15-year multi-million dollar endeavor, and one of the largest U.S. prevention studies of its kind. The study involves over 161 000 women aged 50 – 79, and is one of the most definitive, far reaching clinical trials of women’s health ever undertaken in the U.S. The WHI Clinical Trial and Observational Study will attempt to address many of the inequities in women’s health research and provide practical information to women and their physicians about hormone replacement therapy, dietary patterns and calcium/vitamin D supplements, and their effects on the prevention of heart disease, cancer and osteoporosis. Emerging information from the NIH Women’s Health Initiative and other studies of women’s health begun in the 1990’s should be changing the landscape of options for older women in the years to come. Published by Elsevier Science Ireland Ltd. All rights reserved. Keywords: Women’s Health Initiative; Postmenopausal women; Heart disease; Cancer; Osteoporosis
In 1993 the National Institutes of Health (NIH) launched the women’s health initiative (WHI), the largest prevention study of it’s kind, to address some of the major causes of death and disability in older women. The project involves a combination of three nested clinical trials and an observational study to investigate preventive strategies for cardiovascular disease, breast and colon cancer and osteoporosis. * Corresponding author. Tel.: +1-301-5945055; fax: +1301-4804543. E-mail address: joan – [email protected] (J.A. McGowan)
The driving force for starting the WHI was a confluence of public interest in women’s health, political will to provide the resources, and, most particularly, the scientific need to provide answers to some major public health questions [1]. The public support and political will came from a growing recognition that some aspects of women’s health had been neglected and that women were represented less frequently in clinical trials supported by the NIH. Many studies were launched in the 1990s by the NIH, and elsewhere, to address significant questions in women’s health. But it was recognized that some of the most important
0378-5122/00/$ - see front matter Published by Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 9 9 ) 0 0 1 0 9 - 7
J.A. McGowan, L. Pottern / Maturitas 34 (2000) 109–112
110
questions for postmenopausal women would require a very large coordinated study and, consequently, a large commitment of fiscal, scientific and clinical resources. The questions posed by the randomized clinical trials that constitute the women’s health initiative are simple yet extraordinarily relevant to the lives of postmenopausal women. The scientific background for the conduct of the study and the details of the experimental design are described elsewhere [2,3]. Table 1 describes the interventions and primary outcomes. What are the risks and benefits of postmenopausal hormone replacement therapy (HRT)? The three outcomes of major interest — cardiovascular disease, osteoporotic fractures, and breast cancer — had unfortunately never been tested in randomized clinical trials in healthy postmenopausal women, despite the millions of women world-wide using hormones. Many physicians, scientists and women have already made up their minds about the health benefits of HRT. Although the evidence from observational studies appears compelling, even in the best designed observational studies the contribution of selection bias is difficult to determine. Women who self-select or are advised by their doctors to start HRT are healthier when they make the choice and may continue in a more healthy lifestyle. Matthews et al. [4] have reported that the cardiovascular risk factors of women choosing hormone replacement were more favorable at the time of the choice than the risk factors of women who decide not to take estrogen. These differences based on preference Table 1 The women’s health initiative clinical trials interventions and outcomes Trial
HRT
Intervention
(a) Premarin (b) Premarin+MPA Dietary Modifica- 20% Calories from tion fat Fruits, vegetables, cereals Calcium+Vitamin 1000 mg Ca+400 D IU D3
Primary Outcomes CVD Breast cancer Colorectal cancer Hip fractures
are extremely difficult to completely adjust for in observational studies. The only way to counter the impact of these both known and unknown biases is to conduct randomized trials. The recent publication of the results of the heart and estrogen replacement study (HERS) [5], a randomized placebo controlled trial of estrogen plus medroxyprogesterone in women with existing heart disease to test the efficacy of hormone replacement in secondary prevention of heart disease, has stimulated an important new dialog and scientific scrutiny of hormone replacement therapy. The unanticipated lack of overall cardiovascular benefit in this trial of women with heart disease may or may not be relevant to healthy women but certainly encourages further studies. Breast cancer is a major concern of women and the contribution of diet to the risk of breast cancer has been supported by animal studies and suggested by the differential distribution of the disease incidence throughout the world. The WHI asks whether a low fat dietary regimen will reduce the risk of breast and colorectal cancer in healthy postmenopausal women? Women whose current intake of calories from dietary fat is above 32% are enrolled in this part of the study. They undergo training and education with a goal to change the composition of their diet to 20% of calories from fat with an increased consumption of fruits, vegetables and grains. This dietary change pattern is not easy to adopt in the context of American dietary habits. It is, however, appealing to women as a natural way to reduce cancer risk — if it works. Osteoporotic fractures are a major cause of morbidity in older women. A hip fracture often means the end of independent living and has great social and psychological, as well as, medical cost. Can calcium and vitamin D supplements prevent hip fractures? Numerous reports have recommended adequate calcium intake to build and maintain bone mass. But do normal women profit from years of supplements? The randomized clinical trial of supplements will be the first to adequately test whether supplements can prevent hip fractures in a diverse group of initially healthy postmenopausal women. Calcium and Vitamin D supplementation did dramatically reduce the inci-
J.A. McGowan, L. Pottern / Maturitas 34 (2000) 109–112 Table 2 WHI Enrollment HRT Dietary Modification (DM) Calcium/Vitamin D* Clinical Trials total** Observational Study WHI Total
27 348 48 837 32 234 68 135 93 726 161 861
* The calcium/D trial is still randomizing women already in the HRT or DM trials. ** The total number of women in CT reflects the overlap of women in both HRT and DM.
dence of hip fractures in a group of elderly, vitamin D deficient women [6]. An important part of the WHI study of supplements will be the identification of other risk groups who profit from supplementation. The women recruited, at 40 clinical centers around the US, were given the opportunity to choose to participate in either the HRT or the dietary modification trial or both. About 12% of the women are in both studies. At the first annual visit the women already participating are invited to join the Calcium/Vitamin D arm of the trial. Those who were unwilling or not eligible to join one of the intervention trials were invited to be in the observational study. That part of the WHI will follow over 90 000 women with a follow-up visit at three years and questionnaires at 6 and 9 years. The observational study is designed to ascertain new predictors and biological markers of disease. In addition to cardiovascular, cancer and fracture outcomes, the WHI is collecting a full set of information on psychosocial and quality of life issues. These will be assessed both as outcomes of the interventions and as predictors of clinical outcomes. Overall recruitment was completed in late 1998. See Table 2 for the enrollment numbers. Postmenopausal women between 50 and 79 years of age were enrolled into the trials with few exclusion criteria. The eligibility and exclusion criteria were designed to be broad in order to increase the generalizability of the results. However, due to the rigors of participation in this long-term trial — pill taking, diet modification and clinic visits — those who agree to participate may not be completely representative of post-
111
menopausal women in the US. They may be healthier, at least at the early stages of the trial, and more interested in health than the general population. This selection bias is common to all clinical trials and is anticipated to have minimal impact on the generalizability of the observed treatment effects. A great effort was made to recruit women from the major minority groups in the US and that effort has yielded a sample of minority women resembling the composition of the US in that age group. There are unique difficulties in monitoring a study with a variety of outcomes. The WHI data and safety monitoring board has developed a plan to monitor the study after scrutinizing scenarios of what could happen in the trial [7]. The greatest difficulty in monitoring is balancing and evaluating the emerging risks and benefits on multiple organ systems and disease outcomes. While difficult, this does mirror the real life of women after menopause. At the onset of this project several major practical questions were posed: 1. Would women enroll in a randomized set of trials of common interventions that are already in practice? 2. Would women agree to be randomized to HRT or haven’t most women decided for or against hormone replacement? The large number of women who have shown that they are willing to participate in a long-term health study of this nature, has answered the question about the willingness of healthy women to participate in a prevention trial. Maintaining participation and adherence to the interventions over a long period of follow-up is a major challenge being addressed in this study. With the end of recruitment the focus of the WHI investigators is now on adherence and retention. The success of this effort will provide a major clue to the efficacy of long term interventions in the general population. What is a woman (and her doctor) to do while she waits for the answers on HRT, low fat diets, and calcium and vitamin D supplementation? Obviously, it is not possible to suspend judgment on all of these issues until the results of the WHI are available. Trial results for all components will be available after the trial closes in 2005 and before 2007. Newly menopausal women now come to physicians with a set of ideas about hormones and
112
J.A. McGowan, L. Pottern / Maturitas 34 (2000) 109–112
individual decisions need to be made based on available evidence of risks and benefits. But there is much more to menopausal health than hormones. Alternative non-hormonal treatments for osteoporosis exist. Currently physicians treating women do not make sufficient use of known effective treatments for hypertension and hypercholesterolemia. Physicians can recommend, without reservation, adequate dietary calcium, fruits and vegetables, and physical activity to healthy postmenopausal women. A woman (and her doctor) should see menopause as an opportune time to take stock of her health-related habits and make positive changes. The emerging information from the Women’s Health Initiative and all the other studies begun in the 1990s should make the next decade one of exciting progress in women’s health.
[2]
[3]
[4]
[5]
[6]
[7]
References [1] Rossouw JE, Finnegan LP, Harlan WR, Pinn VW, Clifford C, McGowan JA. The evolution of the women’s
.
health initiative: perspectives from the NIH. J Am Med Womens Assoc 1995;50(2):50 – 5. The Women’s Health Initiative Study Group. Design of the women’s health initiative clinical trial and observational study. Control Clin Trials 1998;19(1):61 – 109. Matthews KA, Shumaker SA, Bowen DJ, Langer RD, Hunt JR, Kaplan RM, Klesges RC, Ritenbaugh C. Women’s health initiative: why now? What is it? What’s new? Am Psychol 1997;52(2):101– 16. Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol 1996;143(10):971– 8. Heart and Estrogen/progestinre Placement Study (HERS) Research Group, Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280(7):605– 13. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992;327(23):1637– 42. Freedman L, Anderson G, Kipnis V, Prentice R, Wang CY, Rossouw J, Wittes J, DeMets D. Approaches to monitoring the results of long-term disease prevention trials: examples from the Women’s Health Initiative. Control Clin Trials 1996;17(6):509– 25.
Commentary on the Women’s Health Initiative Joan A. McGowan a,*, Linda Pottern b a
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIAMS/NIH, Natcher Building, Room 5AS-43E Bethesda, MD 20892 -6500, USA b National Heart Lung and Blood Institute, Bethesda, MD, USA Received 20 August 1999; accepted 15 November 1999
Abstract The Women’s Health Initiative (WHI), established by the National Institutes of Health in 1991, is a long-term national health study that focuses on strategies for preventing heart disease, breast and colorectal cancer and osteoporosis in postmenopausal women. These chronic diseases are the major causes of death, disability and frailty in older women of all races and socioeconomic backgrounds. The WHI a 15-year multi-million dollar endeavor, and one of the largest U.S. prevention studies of its kind. The study involves over 161 000 women aged 50 – 79, and is one of the most definitive, far reaching clinical trials of women’s health ever undertaken in the U.S. The WHI Clinical Trial and Observational Study will attempt to address many of the inequities in women’s health research and provide practical information to women and their physicians about hormone replacement therapy, dietary patterns and calcium/vitamin D supplements, and their effects on the prevention of heart disease, cancer and osteoporosis. Emerging information from the NIH Women’s Health Initiative and other studies of women’s health begun in the 1990’s should be changing the landscape of options for older women in the years to come. Published by Elsevier Science Ireland Ltd. All rights reserved. Keywords: Women’s Health Initiative; Postmenopausal women; Heart disease; Cancer; Osteoporosis
In 1993 the National Institutes of Health (NIH) launched the women’s health initiative (WHI), the largest prevention study of it’s kind, to address some of the major causes of death and disability in older women. The project involves a combination of three nested clinical trials and an observational study to investigate preventive strategies for cardiovascular disease, breast and colon cancer and osteoporosis. * Corresponding author. Tel.: +1-301-5945055; fax: +1301-4804543. E-mail address: joan – [email protected] (J.A. McGowan)
The driving force for starting the WHI was a confluence of public interest in women’s health, political will to provide the resources, and, most particularly, the scientific need to provide answers to some major public health questions [1]. The public support and political will came from a growing recognition that some aspects of women’s health had been neglected and that women were represented less frequently in clinical trials supported by the NIH. Many studies were launched in the 1990s by the NIH, and elsewhere, to address significant questions in women’s health. But it was recognized that some of the most important
0378-5122/00/$ - see front matter Published by Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 9 9 ) 0 0 1 0 9 - 7
J.A. McGowan, L. Pottern / Maturitas 34 (2000) 109–112
110
questions for postmenopausal women would require a very large coordinated study and, consequently, a large commitment of fiscal, scientific and clinical resources. The questions posed by the randomized clinical trials that constitute the women’s health initiative are simple yet extraordinarily relevant to the lives of postmenopausal women. The scientific background for the conduct of the study and the details of the experimental design are described elsewhere [2,3]. Table 1 describes the interventions and primary outcomes. What are the risks and benefits of postmenopausal hormone replacement therapy (HRT)? The three outcomes of major interest — cardiovascular disease, osteoporotic fractures, and breast cancer — had unfortunately never been tested in randomized clinical trials in healthy postmenopausal women, despite the millions of women world-wide using hormones. Many physicians, scientists and women have already made up their minds about the health benefits of HRT. Although the evidence from observational studies appears compelling, even in the best designed observational studies the contribution of selection bias is difficult to determine. Women who self-select or are advised by their doctors to start HRT are healthier when they make the choice and may continue in a more healthy lifestyle. Matthews et al. [4] have reported that the cardiovascular risk factors of women choosing hormone replacement were more favorable at the time of the choice than the risk factors of women who decide not to take estrogen. These differences based on preference Table 1 The women’s health initiative clinical trials interventions and outcomes Trial
HRT
Intervention
(a) Premarin (b) Premarin+MPA Dietary Modifica- 20% Calories from tion fat Fruits, vegetables, cereals Calcium+Vitamin 1000 mg Ca+400 D IU D3
Primary Outcomes CVD Breast cancer Colorectal cancer Hip fractures
are extremely difficult to completely adjust for in observational studies. The only way to counter the impact of these both known and unknown biases is to conduct randomized trials. The recent publication of the results of the heart and estrogen replacement study (HERS) [5], a randomized placebo controlled trial of estrogen plus medroxyprogesterone in women with existing heart disease to test the efficacy of hormone replacement in secondary prevention of heart disease, has stimulated an important new dialog and scientific scrutiny of hormone replacement therapy. The unanticipated lack of overall cardiovascular benefit in this trial of women with heart disease may or may not be relevant to healthy women but certainly encourages further studies. Breast cancer is a major concern of women and the contribution of diet to the risk of breast cancer has been supported by animal studies and suggested by the differential distribution of the disease incidence throughout the world. The WHI asks whether a low fat dietary regimen will reduce the risk of breast and colorectal cancer in healthy postmenopausal women? Women whose current intake of calories from dietary fat is above 32% are enrolled in this part of the study. They undergo training and education with a goal to change the composition of their diet to 20% of calories from fat with an increased consumption of fruits, vegetables and grains. This dietary change pattern is not easy to adopt in the context of American dietary habits. It is, however, appealing to women as a natural way to reduce cancer risk — if it works. Osteoporotic fractures are a major cause of morbidity in older women. A hip fracture often means the end of independent living and has great social and psychological, as well as, medical cost. Can calcium and vitamin D supplements prevent hip fractures? Numerous reports have recommended adequate calcium intake to build and maintain bone mass. But do normal women profit from years of supplements? The randomized clinical trial of supplements will be the first to adequately test whether supplements can prevent hip fractures in a diverse group of initially healthy postmenopausal women. Calcium and Vitamin D supplementation did dramatically reduce the inci-
J.A. McGowan, L. Pottern / Maturitas 34 (2000) 109–112 Table 2 WHI Enrollment HRT Dietary Modification (DM) Calcium/Vitamin D* Clinical Trials total** Observational Study WHI Total
27 348 48 837 32 234 68 135 93 726 161 861
* The calcium/D trial is still randomizing women already in the HRT or DM trials. ** The total number of women in CT reflects the overlap of women in both HRT and DM.
dence of hip fractures in a group of elderly, vitamin D deficient women [6]. An important part of the WHI study of supplements will be the identification of other risk groups who profit from supplementation. The women recruited, at 40 clinical centers around the US, were given the opportunity to choose to participate in either the HRT or the dietary modification trial or both. About 12% of the women are in both studies. At the first annual visit the women already participating are invited to join the Calcium/Vitamin D arm of the trial. Those who were unwilling or not eligible to join one of the intervention trials were invited to be in the observational study. That part of the WHI will follow over 90 000 women with a follow-up visit at three years and questionnaires at 6 and 9 years. The observational study is designed to ascertain new predictors and biological markers of disease. In addition to cardiovascular, cancer and fracture outcomes, the WHI is collecting a full set of information on psychosocial and quality of life issues. These will be assessed both as outcomes of the interventions and as predictors of clinical outcomes. Overall recruitment was completed in late 1998. See Table 2 for the enrollment numbers. Postmenopausal women between 50 and 79 years of age were enrolled into the trials with few exclusion criteria. The eligibility and exclusion criteria were designed to be broad in order to increase the generalizability of the results. However, due to the rigors of participation in this long-term trial — pill taking, diet modification and clinic visits — those who agree to participate may not be completely representative of post-
111
menopausal women in the US. They may be healthier, at least at the early stages of the trial, and more interested in health than the general population. This selection bias is common to all clinical trials and is anticipated to have minimal impact on the generalizability of the observed treatment effects. A great effort was made to recruit women from the major minority groups in the US and that effort has yielded a sample of minority women resembling the composition of the US in that age group. There are unique difficulties in monitoring a study with a variety of outcomes. The WHI data and safety monitoring board has developed a plan to monitor the study after scrutinizing scenarios of what could happen in the trial [7]. The greatest difficulty in monitoring is balancing and evaluating the emerging risks and benefits on multiple organ systems and disease outcomes. While difficult, this does mirror the real life of women after menopause. At the onset of this project several major practical questions were posed: 1. Would women enroll in a randomized set of trials of common interventions that are already in practice? 2. Would women agree to be randomized to HRT or haven’t most women decided for or against hormone replacement? The large number of women who have shown that they are willing to participate in a long-term health study of this nature, has answered the question about the willingness of healthy women to participate in a prevention trial. Maintaining participation and adherence to the interventions over a long period of follow-up is a major challenge being addressed in this study. With the end of recruitment the focus of the WHI investigators is now on adherence and retention. The success of this effort will provide a major clue to the efficacy of long term interventions in the general population. What is a woman (and her doctor) to do while she waits for the answers on HRT, low fat diets, and calcium and vitamin D supplementation? Obviously, it is not possible to suspend judgment on all of these issues until the results of the WHI are available. Trial results for all components will be available after the trial closes in 2005 and before 2007. Newly menopausal women now come to physicians with a set of ideas about hormones and
112
J.A. McGowan, L. Pottern / Maturitas 34 (2000) 109–112
individual decisions need to be made based on available evidence of risks and benefits. But there is much more to menopausal health than hormones. Alternative non-hormonal treatments for osteoporosis exist. Currently physicians treating women do not make sufficient use of known effective treatments for hypertension and hypercholesterolemia. Physicians can recommend, without reservation, adequate dietary calcium, fruits and vegetables, and physical activity to healthy postmenopausal women. A woman (and her doctor) should see menopause as an opportune time to take stock of her health-related habits and make positive changes. The emerging information from the Women’s Health Initiative and all the other studies begun in the 1990s should make the next decade one of exciting progress in women’s health.
[2]
[3]
[4]
[5]
[6]
[7]
References [1] Rossouw JE, Finnegan LP, Harlan WR, Pinn VW, Clifford C, McGowan JA. The evolution of the women’s
.
health initiative: perspectives from the NIH. J Am Med Womens Assoc 1995;50(2):50 – 5. The Women’s Health Initiative Study Group. Design of the women’s health initiative clinical trial and observational study. Control Clin Trials 1998;19(1):61 – 109. Matthews KA, Shumaker SA, Bowen DJ, Langer RD, Hunt JR, Kaplan RM, Klesges RC, Ritenbaugh C. Women’s health initiative: why now? What is it? What’s new? Am Psychol 1997;52(2):101– 16. Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol 1996;143(10):971– 8. Heart and Estrogen/progestinre Placement Study (HERS) Research Group, Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280(7):605– 13. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992;327(23):1637– 42. Freedman L, Anderson G, Kipnis V, Prentice R, Wang CY, Rossouw J, Wittes J, DeMets D. Approaches to monitoring the results of long-term disease prevention trials: examples from the Women’s Health Initiative. Control Clin Trials 1996;17(6):509– 25.