18 Years of WHI follow-up data on menopausal HT and all-cause mortality provide reassurance
JoAnn E. Manson, MD, DrPH, NCMP
A new analysis from the Women's Health Initiative (WHI) randomized trials examined all-cause and cause-specific mortality during the intervention and postintervention follow-up periods.1 We followed more than 27,000 postmenopausal women aged 50 to 79 (mean age, 63) who were recruited to 2 randomized WHI trials of HT between 1993 and 1998. The trials continued until 2002 for the estrogen-progestin trial and to 2004 for the estrogen-alone trial. The trials ran for 5 to 7 years' duration, with post-stopping follow-up for an additional 10 to 12 years (total cumulative follow-up of 18 years).
The participants were randomly assigned to receive active treatment or placebo. The interventions were conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) versus placebo for women with an intact uterus and CEE alone versus placebo for women who had a hysterectomy.
All-cause mortality did not increase with HT use
The primary outcome measure was all-cause mortality in the 2 pooled trials and in each trial individually. We found that there was no link between HT and all-cause mortality in the overall study population (ages 50-79) in either trial. However, there was a trend toward lower all-cause mortality among the younger women in both trials. In women aged 50 to 59, there was a statistically significant 31% lower risk of mortality in the pooled trials among women taking active HT compared with those taking placebo, but no reduction in mortality with HT among older women (P for trend by age = .01).
Notably, all-cause mortality provides a critically important summary measure for interventions such as HT that have a complex matrix of benefits and risks. We know that HT has a number of benefits in menopausal women. It reduces hot flashes and other menopausal symptoms. It lowers the risk of hip fracture, other types of bone fractures, and type 2 diabetes. However, HT increases the risk of venous thrombosis, stroke, and some forms of cancer.
A summary measure that assesses the net effect of a medication on serious and life-threatening health outcomes is very important. As such, all-cause mortality is the ultimate bottom line for the balance of benefits and risks. This speaks to why we conducted the mortality analysis--WHI is the largest randomized trial of HT with long-term follow-up, allowing detailed analyses by age group. Although there have been previous reports on individual health outcomes in the WHI trials, no previous report had specifically focused on all-cause and cause-specific mortality with HT, stratified by age group, over long-term follow-up.
Hopefully the results of this study will alleviate some of the anxiety associated with HT because, as mentioned, there was no increase in overall total mortality or specific major causes of death. In addition, the younger women had a trend toward benefit for all-cause mortality.
We think that these findings support the recommendations from The North American Menopause Society and other professional societies that endorse the use of HT for managing bothersome menopausal symptoms, especially when started in early menopause. These results should be reassuring that there is no increase in mortality with HT use. Although these findings do not support prescribing HT for the express purpose of trying to prevent cardiovascular disease, dementia, or other chronic diseases (due to some potential risks), they do support an important role of HT for management of bothersome hot flashes, especially in early menopause.
Cause-specific mortality
Regarding cause-specific mortality and HT use, we looked in detail at deaths from cardiovascular causes, cancer, dementia, and other major illness. Overall, we observed no increase or decrease in cardiovascular or cancer deaths. In the estrogen-alone trial, there was a surprising finding of a 26% reduction in dementia deaths. In the estrogen-progestin trial, the results were neutral for dementia deaths.
Overall, the cause-specific mortality results were neutral. This is surprising because even for total cancer deaths there was no increase or decrease, despite a great deal of anxiety about cancer risk with HT. It appears that for cancer, HT has complex effects: it increases some types of cancer, such as breast cancer, and decreases others, such as endometrial cancer (in the estrogen-progestin group), and possibly colorectal cancer. Moreover, CEE alone was associated with a reduction in breast cancer mortality, but it remains unclear if this applies to other formulations. HT's net effect on total cancer mortality was neutral in both trials, that is, no increase or decrease.
Cautions and takeaways
We need to keep in mind that in current clinical practice, lower doses and different formulations and routes of administration of HT are now often used, including transdermal estradiol patches, gels, sprays, and micronized progesterone. These formulations, and the lower doses, may have an even more favorable benefit-risk profile. We need additional research on the long-term benefits and risks of these newer formulations and lower dosages.
Generally, these findings from the WHI trials indicate that for women who have significant hot flashes, night sweats, or other bothersome menopausal symptoms, it's important to discuss their symptoms with their health care provider and understand that hormone therapy may be an option for them. If it's not an option, many other treatments are available, including nonhormonal prescription medications, nonprescription medications, and behavioral approaches.
These findings should alleviate some fear about HT use, especially in younger women who have an overall favorable trend in terms of all-cause mortality with treatment, plus a much lower absolute risk of adverse events than older women. In a woman in early menopause who has bothersome hot flashes or other symptoms that disrupt her sleep or impair her quality of life, it's likely that the benefits of HT will outweigh the risks.
Reference
- Manson JE, Aragaki AK, Rossouw JE, et al; for the WHI Investigators. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women's Health Initiative randomized trials. JAMA. 2017;318(10):927-938.