Double Jeopardy: Hormone Therapy on Trial Again

--------------------~~--------------------DOUBLE JEOPARDY: HORMONE THERAPY ON TRIAL AGAIN Robert L. Reid, MD, FRCSC Professor of Obstetrics and Gynaecology; Head, Division of Reproductive Endocrinology and Infertility, Queen's University, Kingston ON

In April 2004, the first results from the estrogen-only arm of the Women's Health Initiative (WHI-ET) were reported in JAMA.1 Like the conjugated equine estrogen/medroxyprogesterone acetate (CEE/MPA) arm of the WHI (WHI-EPT), which has been widely reported in the medical and lay press over the past 2 years, the WHI-ET was a double-blind, randomized, placebo-controlled trial evaluating the potential disease prevention benefits and concomitant risks of hormone therapy in a largely asymptomatic population of women aged 50 to 79 at enrollment. At its 14th interim safety analysis in November 2003, the Data and Safety Monitoring Board noted that the increased risk of stroke in the CEE arm crossed a predefined adverse effect monitoring boundary, yet could not reach a consensus about whether the trial should be continued until its planned termination 1 year later. Since available data indicated that no cardiovascular benefit would be demonstrable after 1 further year of follow-up, and since there appeared to be a small but real risk for stroke with continuing use, the National Institutes of Health, after additional outside consultation, elected to terminate the trial on March 1, 2004. 1 To understand information from this arm of the WHI, we need to ask: What are the principal findings? Do they make biological sense? Are they clinically significant? To incorporate this understanding into our clinical practice, we need to ask: Is it appropriate to extrapolate these findings to my patient population? How should I communicate the risks and benefits of estrogen-only hormone therapy? The recent report from the WHI-ET arm reported that the use of CEE alone in women with prior hysterectomy neither affords any long-term benefit/protection nor confers any shortor long-term risk for coronary heart disease (CHD) (hazard ratio [HR] 0.91; nominal 95% confidence interval [nCI], 0.75-1.12). While cautioning that subgroup analysis, by

KeyWords Hormone replacement therapy, estrogen replacement therapy, coronary heart disease, breast cancer, venous thromboembolism, fracture, colon cancer

reducing subject numbers, may reduce the power to detect important differences in outcomes, the authors report that for women 50 to 59 years of age, the HR for CHD among CEE users was decreased to 0.66 (nCI, 0.80-1.03), an effect that was not significant since the 95% CI overlapped 1.0. For non-fatal stroke, the HR for CEE users overall was 1.39 (nCI, 1.05-1.84), indicating 12 additional cases of non-fatal stroke for every 10 000 users each year. No increased risk of stroke was seen in women 50 to 59 years of age. Deep vein thrombosis (DVT) was increased in CEE users (HR 1.47; nCI, 1.04-2.08), with overall venous thromboembolism (DVT and PE) accounting for 7 additional cases in 10 000 CEE users per year. This effect appeared equally in all age groups. Reduced rates of both hip fractures (HR 0.61; nCI, 0.41-0.91) and vertebral fractures (HR 0.62; nCI, 0.42-0.93) were observed, for an overall reduction in fractures of 56 per 10 000 CEE users per year. The result that surprised many was the decrease in detection of breast cancers among CEE users (HR 0.77; nCI, 0.59-1.01). This decrease in breast cancer rate among CEE users failed to meet strict criteria for statistical significance (since the 95% CI just overlapped 1.0), and as such has been discounted by some as the result of chance. Unlike the WHI-EPT arm, no difference was observed in rates of colorectal cancer among women using hormone versus placebo (HR 1.08; nCI, 0.75-1.55). There was no difference in deaths rates between CEE and placebo users. Although many of the questions about long-term hormone use that led to the development of the WHI were unanswered when this trial was launched, most of the findings should not be surprising in light of publications that have appeared in the past 5 years. Clarkson's data in the non-human primate predicted that early initiation of estrogen therapy prior to development of atherosclerotic plaque might afford long-term protection, whereas starting estrogen after plaque formation might actually lead to plaque destabilization and precipitate acute coronary events. 2 The Heart and Estrogen/progestin Replacement Study (HERS) trial showed an increase in early cardiovascular events

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in women with established coronary disease who initiated hormone therapy, 3 and in the Estrogen Replacement and Atherosclerosis (ERA) trial, the progression of angiographically demonstrable coronary atherosclerosis was unaltered by use of hormones (either estrogen alone or combined estrogen progestin therapy).4 An evaluation of cardiovascular event rates in the first year of2 randomized placebo-controlled trials involving early postmenopausal women (many more than were enrolled in the WHI) revealed no increase in rates of stroke or heart attack in hormone users 5; and the Estrogen in the Prevention of Atherosclerosis Trial (EPAT) showed that early introduction ofhormone therapy in women at risk for atherosclerosis could retard the rate of thickening of the carotid intima-media layer, an established forerunner of carotid atherosclerosis. 6 Accordingly, one might have expected potential cardiovascular disease (CVD) benefits in newly menopausal women (which would only be demonstrable with larger numbers and longer follow-up) and potential immediate harm (stroke or heart attack) in some older women with pre-established coronary artery disease. The increase in DVT is biologically plausible and expected. The dramatic overall decrease in osteoporotic fractures is not surprising, although the author's focus on hip fractures may be minimizing the importance of all fractures to both morbidity and quality of life.? The decreased risk of osteoporotic fractures in this study is particularly noteworthy since it occurred in a population of women with reduced risk for fracture, because a full 30% were under age 60 and many were overweight, which on its own affords significant protection from fragility fractures. The "trend toward reduced breast cancer diagnosis" in women on CEE seems to lack biological plausibility and therefore demands careful consideration abour possible explanations. Li et al. 8 recently reported that even long-term use of estrogen alone (up to 25 years) was not associated with an increase in the risk for breast cancer. Postmenopausal obesity confers increased risk of breast cancer, and an adverse effect of exogenous hormones has only been observed in thin women in some past studies. 9 It is possible that genetic factors, body weight, and local estrogen production within the breast (an effect of aromatase activity in breast tissue) were more important determinants of breast cancer risk in this obese population.IO,l! However, other explanations also need to be considered. Since almost half of all women who have had a hysterectomy who were enrolled in the WHI-ET arm had previously used hormone therapy, I it is possible that the common practice of prescribing estrogen to women following hysterectomy might have already eliminated women with hormone-sensitive tumours from the population of women volunteering for the WHI-ET study. Further analysis of the breast cancer data may shed additional light on this reassuring finding. The WHI-ET study is one of the largest prospective studies JOGC

to have examined the benefits and risks of estrogen-only therapy in postmenopausal women who have had a hysterectomy. As such, the reassuring findings are important. 3 The World Health Organization's Council for International Organizations of Medical Sciences (CIOMS) task force developed a scale to categorize frequency of adverse events, which is a useful adjunct to counselling. 12 Adverse events occurring at a frequency ofless than 1 per 1000 are considered rare, and those occurring in less than 1 per 10 000 are deemed to be very rare. The increased risk for stroke of 12 per 10 000 women per year at all ages and the lack of an increase in women between 50 and 59 years of age indicate that this is a rare risk overall and a clinically insignificant risk for newly menopausal women. Can the findings of the WHI-ET study be extrapolated to Canadian women seeking advice on hormone therapy to control menopausal symptoms? First and foremost, it is important to compare the WHI-ET study subjects to our patient population. Certainly, the ages of women being recruited into the WHI represent a much older and broader population than would typically be seeking hormone therapy. Seventy percent of women enrolled in this trial were over 60 years of age, at least 6.8 years before the study was closed. Indeed, close to 50% of the women were 70 years of age or older when the study was terminated. The editorial accompanying the WHI-ET report notes that baseline risks for diseases evaluated in the WHI-ET trial increase dramatically with age so that the absolute impact of a specific percentage increase or decrease is greater in older women and smaller in younger women. 13 According to the authors, "Women in their 50s have half the risk of women in their 60s and one-quarter of the risk of women in their 70s." Accordingly, when absolute risks are computed for the entire WHI-ET population, we need to remember that these numbers reflect a significant overestimate of the absolute risks for newly menopausal women seeking relief from symptoms in the menopausal transition. Women in the WHI also differed from Canadian postmenopausal women in that only 20.5% of women in the WHI-ET had a BMI less than 25, whereas twice as many postmenopausal Canadian women have a BMI below this cut-off (43.9% of women aged 55-64 in 1999). In the WHI-ET, 79% of women had a BMI greater than 25, whereas many fewer Canadian postmenopausal women fall into this category (54.4% of women aged 55-64 in 1999).1 4 Clearly, the postmenopausal women enrolled in the WHI-ET were considerably heavier than their Canadian counterparts. The US National Institutes of Health (NIH) guidelines on overweight and obesityl5 indicate that adults who have a BMI of 25 or more are considered at risk for premature death and disability. These health risks increase even more as the severity of an individual's obesity increases. Postmenopausal obesity is directly related to both the incidencel6 and mortalityl? of breast cancer, an effect observed primarily in women not using hormone JUNE 2004

therapy. Compared to women with a BMI of less than 21, ischemic stroke risk is 75% higher in women with a BMI greater than 27 and 137% higher in women with a BMI greater than 32.18 The Nurses Health Study, after controlling for other variables known to affect CVD risk, found that women with a BMI greater than 29 had a 300% increase in risk for CVD compared to women with a BMI less than 21. 19 Women with a BMI greater than 29 kg/m2 are twice as likely to get colon cancer compared to women with a BMI less than 21. 20 Clinicians are left to translate the WHI results into meaningful information that will help women understand both potential benefits and potential risks of the best studied therapy for distressing vasomotor symptoms. The exaggerated risks that have dominated media coverage of the WHI have, for the most part, failed to consider demographics of the WHI population and have assumed that one "average" risk estimate for that entire older population applies equally to women of all ages. It seems clear that for newly menopausal women with distressing vasomotor symptoms, low-dose systemic hormone therapy remains a relatively safe and highly effective therapy. As clinicians, we need to redouble our efforts to educate the public about the adverse effects of obesity, smoking, excessive alcohol ingestion, and lack of exercise, which far outweigh those of short-term hormone therapy. Clinician scientists will undoubtedly contrast the results of the WHI's EPT and ET arms and search for new and potentially safer therapeutic avenues for control of menopausal symptoms.

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