The Women's Health Initiative (WHI) Trials Resurrected
A new perspective on not so new data
The Women’s Health Initiative is one of the largest randomized trials focusing on women’s health in the US, beginning in 1993 and enrolling 161,808 women ages 50-79 with the goal being to inform clinical practice about the role of hormone therapy in preventing chronic diseases such as cardiovascular disease, cancer, and hip fractures. Many “sub-studies” emerged from this massive data collection, some still ongoing today.
This trial rocked the media headlines in 2002 when investigators terminated the estrogen/progestin arm of the trial due to what they interpreted as a statistically significant increase in breast cancer incidence found in the treatment group compared to the placebo group to the extent that risks of continuing the study outweighed any potential benefits. This led to a media firestorm leaving providers and patients fearful of prescribing and using hormone therapy to manage menopausal symptoms. Sadly, millions of women suffering from debilitating symptoms have gone untreated resulting in $1.8 billion in lost productivity every year according to a study from the Mayo Clinic.
Over the last 22 years since the discontinuation of this arm of the study, the debate still rages on. However, numerous studies have emerged lending more clarity to the nature and magnitude of risk and a clearer delineation of subgroups who may experience greater benefit or risk.
In May 2024, a group of WHI trials was reviewed in The Journal of the American Medical Association (JAMA) focusing on the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern. Here, we will review the pertinent points of the review with some editorial commentary to follow.
The Women’s Health Initiative Randomized Trials and Clinical Practice - A Review
Manson JE, Crandall CJ, Rossouw JE, et al.
JAMA May 2024 online doi:10.1001/jama.2024.6542
GOAL: Review of the findings and conclusions of the WHI trials investigating the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern
METHODS: The review focused on the findings of the 4 WHI study arms below. :
CEE + MPA (estrogen plus progestin) vs placebo (Uterus intact)- 16,608 participants; main outcome measure: Coronary heart disease (CHD)
CEE (estrogen alone) vs placebo (After hysterectomy) - 10,739 participants; main outcome measure: CHD
Calcium and Vitamin D supplementation vs placebo - 36,282 participants; main outcome measure: Hip fracture.
Low-Fat Dietary Modification Trial: 20% reduction in dietary fat, increased fruits, vegetables, and grains vs usual diet - 48,835 participants; main outcome measure: invasive breast and colorectal cancer.
CEE: Conjugated equine estrogens, MPA: Medroxyprogesterone acetate
Rates of invasive breast cancer were monitored in the two hormonal trials as a safety measure. The intended length of the CEE alone and CEE + MPA trials was 9 years.
FINDINGS
CEE + MPA vs Placebo:
After 6 years the data safety monitoring board recommended discontinuing this arm of the study because they concluded that the risks of continuing the trial outweighed the benefits. They specifically cite a greater incidence of invasive breast cancer, CHD, stroke, and pulmonary embolism at 5.6 years. However, when analyzing the group ages 50-59 alone, the trends toward these risks appeared to be less. The death rate from breast cancer increased after 11-year follow-up, however, after 20 years, the differences were no longer significant.
Secondary outcome findings:
There was an initial reduction in colorectal cancer however was no longer significant after long-term follow-up
A reduction in the incidence of endometrial cancer was observed initially and through long-term follow-up.
There was a significant reduction in the rate of hip fracture that persisted through long-term follow-up
A decreased risk of diabetes and an increased risk of gallbladder disease was observed.
There was a “Probable” increase in dementia risk
A “Composite index” was defined as the risk of CHD, pulmonary embolism, stroke, breast cancer, colorectal and endometrial cancer, or death from other causes. In the treatment group, there were 20 excess cases per 10,000 women per year (12 excess cases ages 50-59) in the short term, however after a 13-year follow-up the differences were no longer significant.
CEE Alone vs Placebo
The trial was stopped 1 year early by the National Institutes of Health (NIH) due to an increased risk of stroke and no statistically significant benefit for the prevention of CHD.
Secondary outcome findings
In the entire cohort, there was no effect of CEE alone on the Composite Index defined above. However, when stratified by age group, more favorable trends were seen in ages 50-59 with 19/10,000 fewer composite index cases, as compared to ages 70-79 where 51/10,000 excess events. After 13 years, these age differences persisted.
The CEE group had a 14% lower risk of type 2 diabetes and 55% higher rates of gallbladder disease.
In the study participants aged 65 and older receiving CEE alone showed a trend toward increased risk of dementia by in-person cognitive testing. A follow-up study of women aged 50-55 performed 7 years after the trial ended showed no difference in dementia risk.
Authors’ Conclusions from the CEE and CEE + MPA Trials
Results from the WHI do not support either CEE plus MPA or CEE alone for preventing CHD, stroke, dementia, or other chronic diseases in postmenopausal women.
Younger menopausal women (< age 60, within 10 years of the onset of menopause) have low absolute risk of many of these chronic diseases and low HT-related risk. These women may derive significant quality-of-life benefits from symptom relief achieved with HT.
Differences in breast cancer outcome risk between CEE alone and CEE + MPA have clinical implications with risk increasing with longer duration of therapy and with CEE + MPA therapy.
The findings from these trials cannot be extrapolated to women < age 45 experiencing premature menopause.
Calcium and Vitamin D Supplementation Trial
The WHI calcium and vitamin D supplementation trial investigated whether calcium plus vitamin D supplementation, compared with placebo, lowered the risk of hip fracture, (primary endpoint), total fractures, and colorectal cancer (secondary endpoints) in postmenopausal women at average risk of fracture.
36,282 women were randomly assigned to 1000 mg/d of elemental calcium carbonate with 400 IU/d of vitamin D3 or placebo.
Primary and Secondary outcomes
During the 7-year trial period, Calcium and vitamin D supplementation did not significantly impact hip fracture rates in the entire study cohort.
A reduction in hip fractures was seen in the cohort aged 60 and older, and an increase in fracture risk was seen in younger women.
*** These findings included women who were compliant AND non-compliant with therapy. In women who were compliant with therapy, a reduction in hip fracture risk was seen across the entire cohort (all ages).
Women receiving calcium plus vitamin D supplementation had greater preservation of total hip BMD than women assigned to placebo but no statistically significant differences in bone density.
Over the 11-year follow-up, there was no statistically significant effect of vitamin D and calcium supplementation on hip fracture risk, however in individuals compliant with therapy, there was a significant difference in the risk of hip fracture.
During the 7-year intervention and over the 11-year follow-up period, Calcium and vitamin D supplementation did not impact the incidence of invasive colorectal cancer. This finding persisted when the analysis only included women compliant with the supplementation regimen.
Compared with placebo, calcium plus vitamin D supplementation had no statistically significant effect on total mortality during the intervention period or 11-year follow-up.
There was no statistically significant effect on cardiovascular events during the intervention period or cumulative follow-up.
There was no significant effect on coronary artery calcium (CAC) scores during the intervention period or cumulative follow-up.
Calcium plus vitamin D supplementation had no effect on invasive breast cancer risk.
Compared with the placebo group, Calcium and vitamin D supplementation significantly increased the risk of kidney stones.
Authors’ Conclusions from the Calcium and Vitamin D Supplementation Trial
Compared with placebo, calcium plus vitamin D supplementation had no effect on lower arm or wrist fracture, total fracture, colorectal cancer, CVD, or total mortality.
In the overall study cohort, calcium plus vitamin D supplementation did not significantly reduce hip fractures in postmenopausal women compared with placebo.
Greater preservation of total hip BMD and reduction in hip fractures was seen among women aged 60 years or older and among women adherent with study medications.
The results of this trial do not support routine calcium plus vitamin D supplementation for postmenopausal women at typical risk of fracture.
Dietary Modification Trial
This trial investigated whether a low-fat diet (compared to a usual diet) rich in fruits, vegetables, and grains reduced the risk of invasive breast cancer or colorectal cancer (primary endpoints), and CHD (secondary endpoint).
The dietary program aimed to reduce fat consumption to 20% of total energy intake, increase vegetable and fruit intake to 5 or more servings per day, and increase grain intake to at least 6 servings per day.
Neither total caloric intake nor physical activity levels were considered in this study
The intervention period was a median 8.5- year behavioral intervention, delivered primarily by registered dietitians in small-group sessions.
Primary and secondary outcomes
Compared with usual diet, the low-fat diet high in fruits and vegetables did not significantly reduce breast or colorectal cancer, however, all-cause mortality after a breast cancer diagnosis was decreased in the low-fat diet group. At 20-year follow-up, a reduction in breast cancer mortality was observed in the low-fat diet group.
Coronary heart disease, defined as nonfatal myocardial infarction plus coronary death, was not significantly reduced by the low-fat dietary pattern. The author’s note that a differential rate of statin use in the comparison group as compared to the dietary intervention group may have skewed these findings.
The low-fat dietary intervention did not significantly reduce endometrial, ovarian, or total cancer compared with the usual diet.
The dietary intervention also did not significantly reduce stroke or total CVD outcomes compared with usual diet
Author’s Conclusions from the Dietary Modification Trial
A low-fat diet with increased fruits, vegetables, and grains has no impact on preventing breast or colorectal cancer, however, the potential role of a low-fat dietary pattern in reducing breast cancer mortality warrants further study.
In My Humble Opinion….
When I first read this study, my thought was that there was really nothing new pertaining to the hormone therapy trials. But to be fair, although the data itself is not new, the fresh perspective and interpretation that the authors put forth raise some points and nuances that may not have been appreciated when the data was initially released more than 20 years ago.
Regarding the hormone studies (CEE along, CEE + MPA), the debate over whether this data is relevant given that the HT preparations used in the study are different from what is typically used today is ongoing. While this is true, the intial findings raised these questions and led to investigations that have provided important information about how different formulations impact the clinical experience. Some examples include:
There is evidence that the use of transdermal estrogen preparations is less thrombogenic (lower risk of blood clots) than oral preparations.
Breast cancer risk may be impacted by the type of progestongen used in HT formuations with bioidentical micronized progesterone showing more favorable results.
The main observation that has stood the test of time and has appeared in every Menopause Society position statement from 2012 is the difference in risk of INITIATION of HT in women >age 60/>10 years since menopause onset and those <age 60, < 10 years since menopause onset. The findings surrounding the timing of HT start initially discovered in the WHI trials, still holds true today even across the use of different formuations. So I would humbly submit, that although there are critical differences in practice today, there is still much to appreciate about these original findings.
The other key finding that has emerged from further study of the use of HT in younger vs older women is that there does not need to be an arbitrary stopping point for the use of HT at any age if the individual’s benefits of using HT outweigh the risk. This is new as of the 2022 Menopause Society Hormone Therapy Position Statement and results from years of follow-up study from the initial observations of the WHI trials.
So, although there has been valid criticism of the messaging, results interpretation, and statistical analysis of the initial studies, some good came out of these initial findings and attempts to answer the criticisms from the studies that followed.
I found the Calcium and Vitamin D study interesting because of the multiple references to “the study population that was adherent to the supplementation regimen”. It puzzles me why subjects that were NOT compliant with the supplementation were included in the study. Those that were compliant with supplementation appreciated a lower fracture risk, particularly in the older population at greater fracture risk according to this study.
So at the end of the day after considering this data and the many studies that followed, my personal practice is to only recommend Calcium supplementation to those women at high risk of fracture by DEXA BMD, dietary calcium intake, prior medical history, family history, and physical activity patterns. I am not opposed to universal Vitamin D supplementation given the minimal apparent risk and reduced GI absorption of Vitamin D often seen in menopausal women.
The Dietary Modification Trial was equally puzzling, as many of the major risk factors for the primary and secondary outcomes were not considered. Physical activity level, BMI, and weight loss (study participants lost an average of 1.9kg, <5lbs) were not specifically addressed in the trial, nor was it mentioned by the authors of this review. In my opinion, the fact that few differences in the primary and secondary outcomes were seen between the study cohort (modified diet) and the controls (usual diet) may be because these other factors are indeed important. Had the study considered a more holistic approach to health habits rather than simply focusing on nutrition metrics, the study may have yielded different results.
Conclusion
I applaud the author’s for providing a renewed perspective on this very important and at times, controversial study. They did a very good job of clearly and concisely delineating the study methods, primary, and secondary outcome measures. As studies continue to emerge through the years, it will continue to shape the lens through which we see the original data and hopefully, yield additional insight and inspire continued study of these issues so critical for the health and well-being of women.