Women's Health Initiative: What the Hormone Therapy Trial Found

Stopped after 5.2 years of a planned 8.5

On 31 May 2002, the trial's data and safety monitoring board recommended that the estrogen-plus-progestin arm be shut down.

Two things triggered it. The test statistic for invasive breast cancer had crossed the stopping boundary set for that adverse outcome. And a summary measure the trial called the global index — combining the main benefits and harms into one number — showed risks running ahead of benefits.

What the primary outcome actually was

It is often described as a breast cancer trial. That is not quite what it was designed as.

The primary outcome was coronary heart disease: non-fatal heart attack and death from heart disease. Invasive breast cancer was named in advance as the primary adverse outcome — the harm the trial was watching for most closely. The global index folded in both of those plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death from other causes.

The reason for that design is that combined hormone therapy was being given to healthy women to prevent chronic disease, on the strength of observational data suggesting it protected the heart.

Who took part, and what they took

Field	Detail
Trial	Women's Health Initiative, estrogen plus progestin component
Identifier	NCT00000611
Design	Randomised controlled primary prevention trial
Participants	16,608 postmenopausal women aged 50 to 79 with an intact uterus, recruited at 40 US centres between 1993 and 1998
Comparator	One daily tablet combining conjugated equine estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg (8,506), against placebo (8,102)
Primary outcome	Coronary heart disease, with invasive breast cancer as the primary adverse outcome

Planned duration was 8.5 years. Data reported here run through 30 April 2002, after a mean of 5.2 years of follow-up.

The harms

Hazard ratios with nominal 95% confidence intervals, and the number of cases each is based on:

• Coronary heart disease 1.29 (1.02 to 1.63), 286 cases
• Invasive breast cancer 1.26 (1.00 to 1.59), 290 cases
• Stroke 1.41 (1.07 to 1.85), 212 cases
• Pulmonary embolism 2.13 (1.39 to 3.25), 101 cases

The breast cancer interval touches 1.00 exactly. That result sat right at the edge of significance, and it is worth knowing when the finding is quoted as settled.

The benefits

• Colorectal cancer 0.63 (0.43 to 0.92), 112 cases
• Hip fracture 0.66 (0.45 to 0.98), 106 cases
• Combined fractures 0.76 (0.69 to 0.85)
• Endometrial cancer 0.83 (0.47 to 1.47), 47 cases — no clear effect

Total cancer of all kinds was 1.03 (0.90 to 1.17): no overall increase. Total mortality was 0.98 (0.82 to 1.18): unchanged.

Adding it up: 19 extra events per 10,000 person-years

JAMA reports the absolute figures per 10,000 person-years — that is, per 10,000 women followed for one year, or 5,000 followed for two, and so on.

Attributable to estrogen plus progestin: 7 more coronary heart disease events, 8 more strokes, 8 more pulmonary embolisms, and 8 more invasive breast cancers. Against those: 6 fewer colorectal cancers and 5 fewer hip fractures.

The net excess for everything in the global index was 19 events per 10,000 person-years. That is the number the monitoring board acted on. It is also small enough per woman per year to explain why the harm went unnoticed for decades outside a randomised trial.

What this does not mean

• It does not apply to every hormone formulation. This was one specific combination, at one dose, in women whose average age was in the sixties. Estrogen alone, other preparations, lower doses and women starting at menopause were not what this arm tested.
• It does not mean hormones shorten life. Total mortality was unchanged.
• It does not mean the breast cancer result is beyond dispute. Its confidence interval ran from 1.00 to 1.59.
• It does not settle the treatment of menopausal symptoms. This was a trial of preventing chronic disease in healthy women, and the authors' conclusion was specifically that this regimen should not be started or continued for the primary prevention of coronary heart disease.

Questions about hormone therapy

• Which preparation and dose are we discussing, and is it the one tested here?
• How old am I relative to menopause, and does that change the balance?
• What is the goal — symptom relief, or prevention of something?

Sources

This article was written from the sources below, which were checked on the source-check date shown above.

• JAMA: Risks and Benefits of Estrogen Plus Progestin (WHI, 2002) (primary)
• PubMed record for the same JAMA report (primary)

How this article was prepared

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