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The commentaries of Drs. Salim Yusuf, Sonia Anand and Dr. Anna Day are also included. CMAJ 2002; 164(4) 357-59, 361-62.

Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women

Principal Results From the Women's Health Initiative Randomized Controlled Trial

Writing Group for the Women's Health Initiative Investigators

Context Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.

Objective To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.

Design Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.

Interventions Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).

Main Outcomes Measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

Results On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.

Conclusions Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

JAMA. 2002;288:321-333

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Hormone replacement therapy: a time for pause

Salim Yusuf and Sonia Anand

Dr. Yusuf is Professor of Medicine, Heart and Stroke Foundation of Ontario Chair in Cardiovascular Research, Senior Scientist of the Canadian Institutes of Health Research, McMaster University, Hamilton, Ont. Dr. Sonia Anand is Assistant Professor of Medicine, Eli Lilly Canada-May Cohen Chair in Women's Health, Clinician Scientist of the Canadian Institutes of Health Research, McMaster University, Hamilton, Ont.

Correspondence to: Dr. Salim Yusuf, McMaster Clinic, 2nd floor, Rm. 252, Population Health Research Institute, 237 Barton St. E, Hamilton ON L8L 2X2; fax 905 521-1166; yusufs@mcmaster.ca

Oh, what a tangled web we weave, When first we practice to deceive!

— Sir Walter Scott, Marmion

A pill that prevents the ills of aging — fewer heart attacks, stronger bones and better quality of life — how can women be denied this wonder pill? Thus, some physicians have been prescribing various hormone preparations (estrogens with or without progestins) since the mid-1970s, and women in Western societies have been willingly taking them. Some "minor" side effects were known — clots in the legs and gallstones — but most believed that the benefits outweighed the inconveniences. All this has to be rethought with the early termination of one of the trial arms of the Women's Health Initiative (WHI) that was evaluating hormone replacement therapy (HRT).1

Menopause heralds the end of reproductive life for women, but why most species continue to have reproductive cycles into old age and humans do not has long perplexed anthropologists.2 Some postulate that menopause frees up women from reproductive responsibilities and allows them to devote their energies to helping their offspring flourish.3 Despite nature's designs, the process of menopause has become "medicalized" in Western society, such that many consider HRT to be physiologic.

In the first place, how good was the evidence in favour of the use of HRT? Women were prescribed HRT for several reasons: relief of hot flashes accompanying menopause, prevention of heart disease and osteoporosis, and a host of other supposed benefits such as improvement in quality of life.

There is strong evidence from randomized trials that HRT relieves hot flashes and that women who have severe symptoms experience immediate benefits.4 But is there a need for the average postmenopausal woman to use HRT? The answer to this question has been far from clear. Although hot flashes and night sweats occur in about half of postmenopausal women, they are severe in only a quarter, with the symptoms generally subsiding over the next year or 2 after menopause.5 It was also assumed that the prevention of heart disease and osteoporosis would outweigh any adverse effects — such as an increase in venous thromboembolism or breast cancer.

It was precisely to address the balance of benefit versus risks of long-term use that the WHI was established. This massive study involves a total of about 160 000 postmenopausal women between the ages of 50 and 79 years, of whom about 100 000 are included in an observational study and about 55 000 in various interventional trials, using a partial 2 2 2 factorial design. The first component is the evaluation of low-fat diet in preventing breast cancer; the second component evaluates 2 HRT regimens (among women with a uterus, evaluation of conjugated equine estrogen at a dose of 0.625 mg/d in combination with 2.5 mg of medroxyprogesterone acetate v. placebo; and among women who have had a hysterectomy, evaluation of estrogen alone v. placebo). The third component of the trial evaluates the efficacy of calcium and vitamin D in preventing fractures.6

On May 31, 2002, after a mean of 5.2 years of follow-up, the trial arm evaluating estrogen plus progestin versus placebo was stopped because of an excessive number of cases of breast cancer (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.00–1.59; weighted z score –3.19) and major cardiovascular events (coronary heart disease [CHD]: HR 1.29, 95% CI 1.02–1.63; stroke: HR 1.41, 95% CI 1.07–1.85; pulmonary embolism: HR 2.13, 95% CI 1.39–3.25). Although there were fewer hip fractures (HR 0.66, 95% CI 0.45–0.98) and colorectal cancers (HR 0.63, 95% CI 0.43–0.92), a "global index" that incorporated several prespecified outcomes (heart disease, breast cancers, hip fractures, colorectal cancers) was significantly adverse (HR 1.15, 95% CI 1.03–1.28). Add to this the significant 40% excess in strokes and doubling in the risk of pulmonary embolism and it is clear that the hazards of HRT are much larger than the benefits.

Perhaps the trial results may be surprising to some, given that the findings of excess numbers of cases of CHD are in sharp contrast to the results of observational studies that claimed large reductions (by about a half) in the risk of CHD with prolonged use of HRT.7 The potential biases and confounders (e.g., HRT users may have healthier lifestyles and are wealthier) that cannot be fully "adjusted" for by statistical manipulation in observational data are well known, and their potential for misleading results is recognized. Yet, the seductiveness of such promising effects with HRT from observational data and the extrapolation from a selective emphasis of the favourable effects on surrogate outcomes (vascular reactivity, impact on lipids) have had a profound impact.8 Theoretical calculations, using decision analysis methodology, suggested that the potential reductions in CHD would be much larger than any adverse impact on breast cancers and led to recommendations for the widespread use of HRT.9 The increased risk of deep venous thrombosis has been recognized in previous studies, but the WHI is the first to report an excess number of cases of pulmonary embolism, which is a more serious complication. The results of previous randomized studies of HRTs had indicated a lack of benefit regarding CHD. For example, an increased risk of CHD and death was reported with 2 regimens of estrogens as early as in the 1970s in patients who had previously had an infarction,10,11 but because the study was done in men, the applicability of the results to women was questioned. A meta-analysis of several small studies,12 a recent study of secondary prevention,13 a study of progression of atherosclerosis14 and one in stroke patients15 all showed no benefit for HRTs. Therefore, the lack of reduction in CHD in WHI should come as no surprise, and most reasonable and objective individuals would be hard pressed to now believe that HRT can reduce CHD. The excess numbers of cases of myocardial infarction, stroke and venous thromboembolism suggest a prothrombotic tendency affecting the venous bed and multiple arterial territories. Therefore, the collective data from randomized trials are conclusive that HRT increases the risk of vascular thrombosis.

When clinical trial results contradict observational and mechanistic studies, potential explanations for the lack of benefit or harm are often put forward. In the case of HRT, concerns regarding compliance, dose and route of administration have been raised and force us to ask if qualitatively different (i.e., beneficial) results could be obtained with other preparations of HRT? There are no data at present to address this question reliably, but the current verdict has to be "unlikely." Note that in the Coronary Drug Project (albeit in men), 2 doses of estrogens increased CHD risk;10,11 in women, tamoxifen16 and raloxifene17 (2 selective estrogen receptor modulators) increase the risk of venous thromboembolism. The WHI is continuing a parallel study of estrogen alone compared with placebo in women who have undergone hysterectomy, a similar study is ongoing in the United Kingdom and there is a major study evaluating raloxifene. Given that different "directional" effects with similar agents or variations in dose are rare, one cannot assume that these alternative agents or preparations are safe or effective; and until proven otherwise, the use of other preparations cannot be advocated.18

Whereas the excess numbers of thrombotic events in the WHI trial emerged early and persisted throughout the study, the excess number of cases of breast cancer emerged after about 3–4 years with increasing risk with more prolonged exposure. Indeed, the risks of breast cancer were higher for individuals who had previously used HRT, which is consistent with epidemiologic data19 and with the hypothesis that prolonged exposure to carcinogens is needed to cause cancers. A nominal decrease in colorectal cancers has been observed, but there was no time trend, with differences becoming apparent even in the first year. This rapidity of effect is surprising and may be an artifact. The reduction in fractures, including hip fractures, is noteworthy and consistent with data suggesting a decrease in the rate of osteoporosis.

The high rate of cessation of therapy in 42% of the subjects in the active group and use of HRT in 10.7% of the placebo group over 5 years (i.e., about a 50% contrast) in the trial would tend to underestimate any differences. This implies that had all women adhered to their initial treatment allocation (i.e., 100% contrast), the net hazards would probably have been substantially larger. Because the trial included women between the ages of 50 and 79 years, it could be asked whether the impact of HRT among women within the first few years after menopause had been evaluated. Subgroup analysis by age indicates no heterogeneity of results in different age categories (5522 trial subjects were aged between 50 and 59 years, which is a greater number of women than in all previous trials of HRT), suggesting that there is no reason to believe that the results would be different for women in the early years post menopause.

One of the important reasons why HRT is prescribed is to alleviate hot flashes after menopause. The WHI does not challenge its value in this situation. Severe hot flashes affect about a quarter of postmenopausal women, but usually become less severe in a few years. Contrary to popular belief, HRT does not improve the quality of life in all postmenopausal women, but only in the 20%–25% of women who suffer from severe hot flashes.20 Although alternatives to HRT for the treatment of hot flashes, including selective serotonin reuptake inhibitors,21 clonidine22 or diets high in phytoestrogens,23 have been suggested, these have not been evaluated in long-term studies such as the WHI, so that their risks and benefits during 2–4 years of therapy are uncertain. Since the publication of the WHI results, many physicians will likely consider that the risks do not justify using HRT in most postmenopausal women, and women may accept that some symptoms of menopause are inevitable; physicians should emphasize to patients the benefits of altering their lifestyle and that they should only resort to HRT if hot flashes are severe. Furthermore, patients should clearly understand the increased risks of vascular disease, even if HRTs are used for short periods, and of cancer if used long term. Even in these circumstances, it would be advisable to use HRT for as short a period as possible and gradually taper it. (Note that the increased risk of cardiovascular events is seen within the first year; CHD: HR 1.78, venous thromboembolism: HR 3.60.) Women who are currently taking HRT with the expectation of a health benefit should be advised to stop gradually, perhaps by "dose tapering" or "day tapering" to minimize the symptoms of withdrawal.24

For the prevention of cardiovascular disease, there are alternatives available, such as smoking cessation, maintenance of an ideal body weight, exercise, a healthy diet and, in those at high risk, aspirin, lipid lowering with statins, blood pressure lowering, angiotensin converting enzyme inhibitors and beta-blockers.25 Collectively, these measures could lower the risk of future vascular disease by over 80%. For the prevention of osteoporosis, there are alternatives including exercise, perhaps calcium and vitamin D, and, in high-risk women, bisphophonates (e.g., alendronate).

The results of the WHI may be viewed as "unwelcome news" by some, but for vast numbers of physicians and their patients, the information simplifies what has been a confusing past decade. We should not use HRT for its purported preventive effects, because it causes more harm than good. Instead, women, with the support of their physicians, should focus on adopting preventive strategies that are clearly proven to be helpful. The WHI also confirms the importance of well-designed, large randomized trials as the only reliable method to evaluate most common interventions. The direct and indirect costs related to the use of HRT probably run into a few billion dollars worldwide each year, with the cumulative costs over the last 2 decades probably in excess of a $100 billion. Had studies such as the WHI been conducted earlier, a significant proportion of this waste could have been avoided, not to mention the avoidance of adverse effects in several million women. The costs of conducting even "relatively expensive" trials pale in comparison to the economic costs saved and human suffering avoided. Other approaches to research have clearly been misleading in this and several other instances, and this should challenge our governments and health research funding bodies to consider whether their allocation of funds for clinical trials is inadequate.

In conclusion, the WHI is a large, well-designed and carefully conducted study that will have a tremendous impact on the health of women. The message for healthy women without severe symptoms of menopause is now clear: to avoid as far as possible HRT, which on balance does more harm than good.

The web of our life is of a mingled yarn, good and ill together.

— William Shakespeare, All's Well That Ends Well

Footnotes

Contributors: Both authors were involved in the ideas and in the drafting of this document.

Acknowledgements: We thank Dr. John Collins for his helpful suggestions and Judy Lindeman for administrative support.

Competing interests: None declared.

References

Lessons from the Women's Health Initiative: primary prevention and gender health

Anna Day

Dr. Anna Day is Associate Professor, Departments of Medicine and Health Policy, Management and Evaluation, University of Toronto, Toronto, Ont.

Correspondence to: Dr. Anna Day, Sunnybrook and Women's College Health Sciences Centre, Women's College Campus, 76 Grenville St., Toronto ON M5S 1B2; fax 416 323-7550; a.day@utoronto.ca

The Women's Health Initiative (WHI) was designed to assess the risks and benefits of a number of primary prevention strategies in healthy postmenopausal women, including the use of hormone replacement therapy, calcium and vitamin D supplementation and a low-fat diet.1 The outcome of the study of combined estrogen and progestin replacement, with risks exceeding benefits, is not surprising in 2002, although it was not expected when the study was designed in 1991–1992. The evidence for an increased risk of breast cancer with hormone replacement therapy has been steadily accumulating for the past 10 years.2 We have become better informed about the increased risk of thromboembolic events, including stroke, deep vein thrombosis and pulmonary embolism.3 Results of the HERS4 studies suggested that hormone replacement therapy is associated with an increased risk of cardiovascular events, although this increased risk was not noted in healthy women in the Nurses Health Study.3 On the other hand, there has been consistent evidence that hormone replacement therapy at menopause delays osteoporosis and decreases the incidence of hip fractures and a suggestion that it protects against colorectal cancer.

With the release of the WHI findings, the evidence is now unequivocal. There is more potential for harm than good in healthy postmenopausal women taking a combination of estrogen and progesterone to prevent chronic disease. The early termination of the portion of the WHI on combination hormone replacement therapy provides us with some important lessons on primary prevention, research and gender health.

As more of the population reaches old age with expectations of a significantly longer, healthier lifespan, there is an increasing focus on primary prevention strategies. Most randomized controlled trials are carried out to demonstrate the efficacy of a therapy for a single medical condition or the ability of a therapy to prevent a disease in people considered to be at increased risk for that condition. These studies are often funded by the pharmaceutical industry and are geared to end points that will allow licensing of new therapies or new uses of an existing product. Long-term studies that evaluate broader health effects are rarely funded by industry. The WHI, which is publicly funded by the US National Institutes of Health, demonstrates that the large, long-term, complex and costly studies that are needed to assess the efficacy of primary prevention interventions require the resources and support of the public sector.

The results of the WHI should make us evaluate whether we are targeting and funding primary prevention efforts appropriately. If the risks of hormone replacement therapy outweigh the benefits, what are the options for women who hope to avoid the fractures associated with osteoporosis? Recent studies demonstrate that the risk of osteoporosis is related to the peak bone mass achieved in the teens and twenties.5 Primary prevention of osteoporosis could therefore consist of ensuring that teenagers and young adults maximize their bone mass with appropriate exercise and diet. Primary prevention of cardiovascular disease could consist of dealing with the societal tensions and marketing campaigns that drive young people to begin smoking, develop poor eating habits and choose a sedentary lifestyle. These types of nonpharmacologic interventions targeted at adolescents and young adults have barely been incorporated into our primary prevention strategies, and in many Canadian provinces there are no or minimal resources allocated to such interventions for any age group.

The results of this portion of the WHI also elegantly demonstrate that the scientific validity of ideas that appear to be intuitively correct must be proven through well- designed studies. Because women seem to be protected from coronary artery disease before menopause and have an accelerated risk of developing the disease in the 10 years after menopause, it seemed intuitively correct to hypothesize that hormone replacement therapy in postmenopausal women should provide them with protection from coronary artery disease. Good research demonstrated that our intuition was wrong.

Research panels and key opinion leaders fund research that is consistent with their perception of what is important. It is largely accepted that the WHI took place because of the leadership of people like Bernadine Healy, former Director of the National Institutes of Health, and Vivian Pinn, Associate Director for Research on Women's Health at the NIH. These women created a mandate to develop a research agenda to identify and address gaps in our knowledge of women's health. They had the power necessary to push this research agenda forward in the face of considerable scientific opposition and the wisdom to recognize that a project on the scale of the mammoth, very expensive WHI was required.

Both men and women should be involved in making decisions about the allocation of funding for research and they should represent an appropriate balance of ethnic backgrounds and experience. For example, female researchers may ask different questions and propose different research methodologies than do male researchers, because of differences in their life experiences, perceptions of priorities and styles of interactions with peers. We must continually assess whether we are incorporating sufficient diversity into the processes that determine the direction and priorities of our research enterprise.

The WHI was carried out because of the vision and new-found power of women in the United States. Because women are different and more physiologically complex than men, there has been a tendency to exclude them from studies or to not carry out studies that are of importance to women. Of even more concern has been the tendency to extrapolate findings from studies of men to women. Some of the gaps in our knowledge of women's health, such as in the area of cardiovascular disease, are now being addressed. However, major issues in women's health remain unexplored, including the increased morbidity for women with asthma6 and the lack of any evidence on the utility of annual chest x-ray screening for female smokers.7 We are fortunate in Canada that as the Medical Research Council evolved into the Canadian Institutes of Health Research its directors recognized the importance of research relating to the differing health issues for women and men and established an Institute of Gender and Health to carry out this work.

The results of the WHI should also remind us that women seem to be particularly targeted to receive therapies to prevent future disease or to enhance or maintain their physical appearance. There is an increasing demand for breast implants, liposuction, facelifts and injections of botulinum toxin, despite the lack of adequate studies of their risks and benefits. Physicians and their female patients are willing to undertake even high-risk therapy if it is presented as primary prevention. Medications that produce anorexia, although known to be associated with a significant risk of pulmonary hypertension, were felt to be an acceptable therapy because obese women have an increased risk of coronary artery disease and diabetes.8 Women of all ages are increasingly being prescribed medications for the treatment of depression and anxiety with little knowledge about the long-term effects of these drugs, although suggestions are emerging that users of selective serotonin reuptake inhibitors may be at a higher risk for suicide.9

The lessons learned so far from the WHI are important for both men and women. The norms and values of the society in which an individual and their physician reside often influence patient care. On the basis of a belief that hormones are associated with youth and health, hormone replacement therapy for women was believed to be good. In a similar fashion, we are now witnessing the discovery of andropause and the initiation of androgen therapy for men with the belief that it will lead to better overall health. The WHI has clearly demonstrated that it is imperative that trials assessing the overall risk and benefit of primary prevention interventions for both men and women be conductedbefore such therapies are broadly instituted. We must ensure that we understand the values and paradigms that drive our hypotheses and we must be willing to fund the research necessary to validate the effectiveness of our interventions. The WHI demonstrates the potential for doing harm ... we cannot continue to do so.

ß See related articles pages 357, 363, 377 and 387

Footnotes

Competing interests: None declared.

References

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