WHI trial of estrogen plus progestin stopped as health risks outweigh benefits

Susan Jeffrey

July 09, 2002

Chicago, IL - A trial comparing estrogen plus progestin with placebo as a primary prevention strategy for healthy postmenopausal womenpart of the Women's Health Initiative (WHI)has been stopped because of apparent increased risks of invasive breast cancer, coronary heart disease events, stroke, and pulmonary embolism among treated women[1]. Using a global index, the risks were judged to outweigh some benefit seen with HRT in reduced fractures and colorectal cancers.

The trial was suspended on May 31, 2002, after 5.2 of a projected 8.5 years of follow-up, because of the safety concerns. Full results are published in the July 17, 2002 issue of the Journal of the American Medical Association but are being released before publication on July 9, 2002 on its website, , "because of the importance of the researchers' findings," a JAMA press release notes.

"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," Dr Jacques E Roussow (National Heart, Lung, and Blood Institute), Dr Garnet L Anderson (Fred Hutchinson Cancer Research Center, Seattle), and the WHI investigators conclude in their report.

Too high a price

"The study found that these hormones increase the risk of both cardiovascular disease and breast cancer, which is too high a price to pay to prevent hip fractures," WHI Steering Committee member Dr JoAnn Manson (Brigham and Women's Hospital, Harvard Medical School) told heartwire . For an individual woman, the increased risk of these outcomes is small, she noted, "but nationwide, we are talking about tens of thousands of extra cases of these serious health events."

 

Women worldwide have been seeking these answers for decades, and this study will help women make more informed choices about their health.

 

"Women worldwide have been seeking these answers for decades, and this study will help women make more informed choices about their health," Manson said.

Other clinical trials being conducted under the auspices of the WHI, including 1 comparing estrogen alone versus placebo in women who have had a hysterectomy, are continuing. The planned end of the combined equine estrogen (CEE)/placebo comparison is March 2005, when the average follow-up will be about 8.5 years.

"When the estrogen-only trial is completed, a comparison of the results of these 2 trials may provide a better idea of the roles of estrogen, compared with estrogen plus progestin, in health and disease," Dr Marcia Stefanick (Stanford University, Palo Alto, CA), chair of the WHI Steering Committee, is quoted in a statement from the NHLBI.

The WHI investigators add, however, that their findings do not necessarily apply to short-term use of estrogen plus progestin for the treatment of menopausal symptoms such as hot flashes, which was not specifically addressed by their study, and where the risk-benefit ratio may still be favorable.

Women taking the hormone combination for this purpose should discuss with their physicians whether to continue, Manson said. "This will depend on their overall health status and their duration of hormone use."

CHD the primary end point

This WHI trial was a randomized, controlled primary prevention trial, comparing CEE in a dose of 0.625 mg/day plus 2.5 mg/day of medroxyprogesterone acetate (MPA) with placebo among 16 608 postmenopausal women with an intact uterus. The women, aged 50 to 79 years at baseline, were recruited at 40 participating US centers between 1993 and 1998.

Follow-up was planned for an average of 8.5 years. The primary outcome was coronary heart disease (nonfatal MI and CHD death), and invasive breast cancer was the primary adverse outcome. A global index summarizing the balance of risk and benefits included these 2 outcomes, as well as stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

The data and safety monitoring board recommended stopping the trial on May 31, 2002, after a mean of 5.2 years of follow-up, when the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported an excess of risk over benefit, the investigators note. Their report includes data on events recorded through April 30, 2002.

HRT vs placebo in the Women's Health Initiative: Hazard ratios for major clinical outcomes

Outcome

Cases

Hazard ratio

95% CI

 CHD 286 1.29 1.02-1.63
 Breast cancer 290 1.26 1.00-1.59
 Stroke 212 1.41 1.07-1.85
 Pulmonary embolism 101 2.13 1.39-3.25
 Colorectal cancer 112 0.63 0.43-0.92
 Endometrial cancer 47 0.83 0.47-1.47
 Hip fracture 106 0.66 0.45-0.98
 Death due to other causes 331 0.92 0.74-1.14

  HRT vs placebo in the Women's Health Initiative: Hazard ratios for composite outcomes

Composite outcome

Hazard ratio

95% CI

 Total CVD 1.22 1.09-1.36
 Total cancers 1.03 0.90-1.17
 Combined fractures 0.76 0.69-0.85
 Total mortality 0.98 0.82-1.18
 Global index 1.15 1.03-1.28

 "Absolute excess risks per 10 000 person-years attributable to the combination therapy 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 authors point out. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.

"The trial results indicate that treatment for up to 5.2 years is not beneficial overall and that there is early harm for CHD, continuing harm for stroke and VTE (blood clots), and increasing harm for breast cancer with increasing duration of treatment," the WHI investigators write.

Roussow et al point out that on the basis of the Heart and Estrogen/Progestin Study (HERS), which showed an increased risk of CHD events with this same combination among older postmenopausal women with established heart disease, the American Heart Association had recommended against starting HRT for secondary prevention but had made no firm recommendation on primary prevention pending findings from this study.

"Results from WHI indicate that the combined postmenopausal hormones CEE, 0.625 mg/day, plus MPA, 2.5 mg/day, should not be initiated or continued for the primary prevention of CHD. In addition, the substantial risks for cardiovascular disease and breast cancer must be weighed against the benefit for fracture in selecting from the available agents to prevent osteoporosis," the authors conclude.

Primum non nocere

In an editorial accompanying the publication[2], Drs Suzanne W Fletcher and Graham A Colditz (Harvard Medical School) point out that 38% of postmenopausal women in the United States use HRT. In 2000, 46 million prescriptions were written for Premarin® (CEE)(Wyeth), making it the second most frequently prescribed medication in the US and accounting for $1 billion in sales, and 22.3 million prescriptions were written for Prempro®(Wyeth), the combination CEE and MPA. While FDA-approved indications include the relief of menopausal symptoms and prevention of osteoporosis, long-term use has been "in vogue" to prevent chronic disease, especially heart disease, they point out.

"How should practicing clinicians and the millions of women taking an estrogen/progestin combination react to the unexpected and disquieting results of this study?" they write.

The editorialists note that the absolute risks to the individual woman reported by the WHI investigators are very small, but that over the 5.2 year follow-up, the excess number of events with active treatment was 100 per 10 000, or 1 in 100 women. "This is still a small risk, but it demonstrates that risks from the drug add up over time."

However, the "whole purpose of healthy women taking long-term estrogen/progestin therapy is to preserve health and prevent disease," Fletcher and Colditz write. "The results of this study provide strong evidence that the opposite is happening for important aspects of women's health, even if the absolute risk is low.

"Given these results, we recommend that clinicians stop prescribing this combination for long-term use. Primum non nocere applies especially to preventive health care."

 
The WHI provides an important health answer for generations of healthy postmenopausal women to come—do not use estrogen/progestin to prevent chronic disease.
 

For women with osteoporosis, they point out that there are alternative preventive strategies, "at least one of which also prevents breast cancer (although the cardiovascular effects are not yet clear)."

While prevention trials are expensive and difficult, they point out, studies such as the WHI, the Breast Cancer Prevention Trial, and the Multiple Outcomes of Raloxifene Evaluation (MORE) study have produced important results for healthcare. "The WHI provides an important health answer for generations of healthy postmenopausal women to comedo not use estrogen/progestin to prevent chronic disease."

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