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Hormone replacement therapy and cardiovascular disease
Stanley Zinberg, Associate
C
onflicting reports about the relationship between hormone replacement therapy and the prevention of cardiovascular disease in women have resulted in considerable confusion for obstetrician-gynecologists. The College has received so many requests from our members that we publish a position statement on this issue. The Committee on Gynecologic Practice determined at its recent meeting that there were insufficient data on which to draw any firm conclusions that could assist our membership on this important topic. There are, however, a number of powerful ongoing studies that have the potential to provide us with the answers. Unfortunately, because of the uncertainty of the recent reports, many physicians are withdrawing their patients from these crucial multicenter studies. We asked Robert A. Wild, MD, MPH, Professor of Obstetrics and Gynecology at the University at the Oklahoma Health Sciences Center to comment for us on this issue.
COMMENTSBY ROBERTA. WILD, MD, MPH ecent events have highlighted the eed to obtain definitive answers about the risks and benefits of hormone replacement therapy (HRT). On the issue of risks, the major focus remains on breast cancer. Taken together, the observational studies suggest that use of HRT for more than 5 years is associated with an increased risk of breast cancer of about 30%, compared with nonusers. However, individual observational studies continue to provide conflicting results. They have variously reported estrogen use to be associated with either increased risk or no risk, or an increased risk with estrogen and progestin given in cyclical but not continuous regimens. In at least two studies the risk appears to be concentrated in lobular
RJl
‘BZOOOby the American College of Obstetr oans and Gynecologists PublIshed by Elsewr Science Inc 1085-6862’00;$6 00
MD, MS Editor
rather than ductal tumors (lobular tumors are less common and are associated with a more favorable prognosis). Thus, whereas the studies have not suggested any increased risk with short-term use, the implications for long-term use remain uncertain. On the benefits side, few question that HRT protects against bone loss. However, the widely held assumption that HRT will protect women against heart disease is being questioned by the findings of four key studies: the Heart and Estrogen/progestin Replacement Study (HERS), the Nurses’ Health Study, the Estrogen Replacement and Atherosclerosis (ERA) trial, and the Women’s Health Initiative (WI-II). These studies have all found either lack of benefit or potential harm for heart disease during the first 2 to 3 years after commencing HRT. HERS, a clinical trial of Prempro versus placebo in women with heart disease, showed an almost 50% increase in coronary heart disease in the active treatment group during the first year, followed by no effect in the second year, and a trend toward benefit in subsequent years. One year following the publication of the HERS findings in 1998, the Nurses’ Health Study investigators reported a similar pattern of early harm and later benefit in the observational study data ofwomen with heart disease. This year, the ERA investigators reported no effect on Premarin or Prempro on coronary atherosclerosis in a 3-year angiographic trial. All of these studies involved women with existing disease, and the findings may have been dismissed as being of less relevance to healthy women. However, earlier this year the WI-II investigators alerted the more than 27,000 women in that study about a small increase in heart attacks, strokes, and blood clots over the first 2 years in the group on active treatment (either Premarin or Prempro) compared with placebo. The participant September/October
update and NHLBI press release noted that the excess events appear to diminish and may even disappear after 2 years. Taken together, these studies diminish expectations of benefit for cardiovascular disease, at least for the first year or two after commencing HRT. It remains possible that longer-term treatment will decrease risk for cardiovascular disease, as suggested by dozens of observational studies. The WHI trial and a similar trial in the United Kingdom is continuing, in the hope of providing more definitive data on this issue. Given the current uncertainties surrounding the use of long-term HRT, the time has come to put aside opinions and search for the facts. Reliable information can come only from large clinical trials such as WI-II, and ACOG members can help by supporting such trials. Disappointingly, WI-II investigators have found that the advice of the participants to start “real hormones” is the single most common reason for discontinuation of study medication. Dropouts from the study weaken the power of the study to find the answers. Now that the benefits of the “real hormones” are being questioned, it may be that enthusiasm for their use should be replaced by an equal enthusiasm to support studies that will find out what they really do. The most tangible way ACOG members can help the search for truth is by encouraging their patients to remain active participants in WHI. Alternatives to HRT exist for both cardiovascular protection and bone loss. Use of these alternatives may allow the patient to remain in the study, while prescription of HRT necessitates discontinuation of study medication. Individual clinical centers will be happy to work with physicians and their patients to find a solution that satisfies the best interest of all parties. 2000
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C
onflicting reports about the relationship between hormone replacement therapy and the prevention of cardiovascular disease in women have resulted in considerable confusion for obstetrician-gynecologists. The College has received so many requests from our members that we publish a position statement on this issue. The Committee on Gynecologic Practice determined at its recent meeting that there were insufficient data on which to draw any firm conclusions that could assist our membership on this important topic. There are, however, a number of powerful ongoing studies that have the potential to provide us with the answers. Unfortunately, because of the uncertainty of the recent reports, many physicians are withdrawing their patients from these crucial multicenter studies. We asked Robert A. Wild, MD, MPH, Professor of Obstetrics and Gynecology at the University at the Oklahoma Health Sciences Center to comment for us on this issue.
COMMENTSBY ROBERTA. WILD, MD, MPH ecent events have highlighted the eed to obtain definitive answers about the risks and benefits of hormone replacement therapy (HRT). On the issue of risks, the major focus remains on breast cancer. Taken together, the observational studies suggest that use of HRT for more than 5 years is associated with an increased risk of breast cancer of about 30%, compared with nonusers. However, individual observational studies continue to provide conflicting results. They have variously reported estrogen use to be associated with either increased risk or no risk, or an increased risk with estrogen and progestin given in cyclical but not continuous regimens. In at least two studies the risk appears to be concentrated in lobular
RJl
‘BZOOOby the American College of Obstetr oans and Gynecologists PublIshed by Elsewr Science Inc 1085-6862’00;$6 00
MD, MS Editor
rather than ductal tumors (lobular tumors are less common and are associated with a more favorable prognosis). Thus, whereas the studies have not suggested any increased risk with short-term use, the implications for long-term use remain uncertain. On the benefits side, few question that HRT protects against bone loss. However, the widely held assumption that HRT will protect women against heart disease is being questioned by the findings of four key studies: the Heart and Estrogen/progestin Replacement Study (HERS), the Nurses’ Health Study, the Estrogen Replacement and Atherosclerosis (ERA) trial, and the Women’s Health Initiative (WI-II). These studies have all found either lack of benefit or potential harm for heart disease during the first 2 to 3 years after commencing HRT. HERS, a clinical trial of Prempro versus placebo in women with heart disease, showed an almost 50% increase in coronary heart disease in the active treatment group during the first year, followed by no effect in the second year, and a trend toward benefit in subsequent years. One year following the publication of the HERS findings in 1998, the Nurses’ Health Study investigators reported a similar pattern of early harm and later benefit in the observational study data ofwomen with heart disease. This year, the ERA investigators reported no effect on Premarin or Prempro on coronary atherosclerosis in a 3-year angiographic trial. All of these studies involved women with existing disease, and the findings may have been dismissed as being of less relevance to healthy women. However, earlier this year the WI-II investigators alerted the more than 27,000 women in that study about a small increase in heart attacks, strokes, and blood clots over the first 2 years in the group on active treatment (either Premarin or Prempro) compared with placebo. The participant September/October
update and NHLBI press release noted that the excess events appear to diminish and may even disappear after 2 years. Taken together, these studies diminish expectations of benefit for cardiovascular disease, at least for the first year or two after commencing HRT. It remains possible that longer-term treatment will decrease risk for cardiovascular disease, as suggested by dozens of observational studies. The WHI trial and a similar trial in the United Kingdom is continuing, in the hope of providing more definitive data on this issue. Given the current uncertainties surrounding the use of long-term HRT, the time has come to put aside opinions and search for the facts. Reliable information can come only from large clinical trials such as WI-II, and ACOG members can help by supporting such trials. Disappointingly, WI-II investigators have found that the advice of the participants to start “real hormones” is the single most common reason for discontinuation of study medication. Dropouts from the study weaken the power of the study to find the answers. Now that the benefits of the “real hormones” are being questioned, it may be that enthusiasm for their use should be replaced by an equal enthusiasm to support studies that will find out what they really do. The most tangible way ACOG members can help the search for truth is by encouraging their patients to remain active participants in WHI. Alternatives to HRT exist for both cardiovascular protection and bone loss. Use of these alternatives may allow the patient to remain in the study, while prescription of HRT necessitates discontinuation of study medication. Individual clinical centers will be happy to work with physicians and their patients to find a solution that satisfies the best interest of all parties. 2000
l
ACOG
CLINICAL
REVIEW
l
11