March 5, 2008 — Women who took estrogen plus progestin in the Women's Health Initiative (WHI) trial of hormone replacement therapy (HRT) remain at higher risk of breast cancer three years after the trial was stopped, compared with those who took placebo [1]. Higher risks of cardiovascular events seen in those taking the active preparation abated in the follow-up period, however, as did the beneficial effects of HRT on bone strength.

Dr Gerardo Heiss (University of North Carolina, Chapel Hill) and colleagues report their findings in the March 5, 2008 issue of the Journal of the American Medical Association. "We had the opportunity to examine the persistence of effects following the long-term use of estrogen plus progestin after the intervention was stopped, but the rest of the protocol continued under controlled conditions. This gave us the chance to examine the changes in benefits and risks associated with these preparations," Heiss told heartwire .

"As anticipated, we found that some of the risks subsided very quickly—namely, cardiovascular ones such as heart attack and blood clots. And the benefits in terms of bone health unfortunately regressed back toward the null, but again this was anticipated. What was not anticipated was the greater risk of malignancies overall, attributed in particular to the persistence of the risk of breast cancer in women who were assigned to HRT vs placebo," he added.

Hormone's effects on breast cancer "appear to linger"

The WHI trial of estrogen plus progestin included 16,608 postmenopausal women and set out to examine whether conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) prevented cardiovascular disease and fractures and to examine any associated change in the risk of breast cancer. The trial was stopped prematurely in 2002 when data indicated an increased risk of breast cancer and unexpected, higher risks of stroke, MI, and venous thromboembolism. There was a lower risk of fracture and colorectal cancer among those who took HRT compared with placebo recipients.

In the new analysis, Heiss and colleagues examined the risk/benefit balance of 15,730 of the participants after the trial was stopped in July 2002 out to March 2005. This was performed at a planned point of three years after the HRT arm was stopped to better understand the changes in hormone-relevant health conditions, Heiss said, with the average follow-up being 2.4 years. Women continued to have annual mammograms.

The annualized event rates for the outcome "all cancers" was higher during the postintervention follow-up for the HRT group (1.56% per year) compared with the placebo group (1.26% per year). This was primarily due to a greater risk of invasive breast cancer: 79 women who took HRT developed breast cancer in the postintervention phase compared with 60 who got placebo. Heiss et al do note, however, that further follow-up is needed to better characterize the risk of breast cancer in this WHI population. The rates of colorectal cancer did not differ significantly between the two groups, and rates of endometrial cancer were lower in the HRT group.

"The hormones' effects on breast cancer appear to linger," says Dr Leslie Ford (National Cancer Institute, Bethesda, MD), "These findings reinforce the importance of women getting regular breast exams and mammograms."

All-cause mortality during the trial did not differ between the active and placebo arms, but a slightly higher mortality was seen in the HRT arm after the intervention, although it was not significant (233 deaths in HRT group vs 196 in the placebo arm). Heiss and colleagues say this was most likely due to a higher number of deaths from lung cancer in the hormone group and that there is some evidence that HRT is associated with decreased survival in women with lung cancer.

Clinical outcomes in WHI trial and its three-year postintervention follow-up

HRT: Not to be used long-term to prevent chronic diseases

The follow-up data on heart disease are encouraging, says Dr Elizabeth G Nabel (director, National Heart, Lung, and Blood Institute, Bethesda, MD). "The good news is that after women stop taking combination hormone therapy, their risk of heart disease appears to decrease," she notes. In the postintervention phase, there were 343 cardiovascular events overall among those who received HRT vs 323 among those who did not.

But Nabel warns, "These findings also indicate that women who take estrogen plus progestin continue to be at increased risk of breast cancer, even years after stopping therapy. Today's report confirms the study's primary conclusion that combination hormone therapy should not be used to prevent disease in healthy, postmenopausal women."

Heiss agrees: "The balance of the benefits and risks of estrogen plus progestin therapy continues to be unfavorable after stopping therapy," he explained to heartwire . "As such, these findings confirm the results of the WHI study as originally published—this is not a preparation that ought to be used over long periods to prevent chronic disease. That's it in a nutshell."

Continued vigilance necessary

Asked by heartwire whether women who had taken HRT could be reassured that after they stopped therapy, their risks of particular chronic diseases would diminish after a certain period of time, Heiss said this was a difficult question to answer.

"Overall, the summary of benefits and risks appears to be unfavorable," Heiss reiterates, "and this suggests that vigilance is required after the use of these preparations. Women should take care of their health and lifestyle and make sure they undergo screening for every preventable chronic condition."

However, Heiss said this does not preclude the use of HRT for brief periods for menopausal symptoms. "I think the current guidelines are quite appropriate regarding the use of these preparations, which should be for the shortest time possible and at the smallest effective doses. I believe our OB/GYN colleagues are adhering to this."

The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services. Four of the study authors have disclosed various financial relationships and honoraria with Merck, the Egg Nutrition Council, Pfizer, Schering-Plough, Lilly, Organon, Procter & Gamble Pharmaceuticals, Roche, Wyeth Pharmaceuticals (maker of MPA used in the study), Aventis, Esprit Pharma, GlaxoSmithKline, Novartis, and Upsher-Smith Laboratories Inc. Three of the study authors have obtained funding. The remaining study authors have disclosed no relevant financial relationships. Dr. Heiss has disclosed no financial relationships.

Source

1. Heiss G, Wallace R, Anderson GL, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299:1036-1045.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Clinical Context

Study Highlights

• Women eligible for participation in the study were between the ages of 50 and 79 years. They were assigned to receive CEE 0.625 mg plus MPA (Prempro; Wyeth Ayerst) 2.5 mg daily or matching placebo.
• The main study outcomes of cardiovascular disease, fractures, and cancer were verified in the medical record. The study was stopped prematurely at a mean of 5.6 years of follow-up because of an increased risk for breast cancer associated with CEE/MPA vs placebo.
• The postintervention phase lasted from 2002 to 2005, with a mean follow-up of 2.4 years.
• 8506 and 8102 women were originally randomized to receive CEE/MPA or placebo, respectively. The average age at baseline was 63 years, and 84% of subjects were white. Baseline characteristics were similar in the CEE/MPA and placebo groups.
• 95% of women in the original study cohort were followed up through the postintervention period.
• The risks for cardiovascular disease, deep vein thrombosis, and pulmonary embolism normalized to a point of no significant difference between the CEE/MPA and placebo groups in the postintervention period.
• The rate of all-incident cancer was 1.56% per year in the CEE/MPA group and 1.26% per year in the placebo group, a significant difference (hazard ratio, 1.24). This difference was mostly because of a nonsignificant increase in the risk for incident breast cancer and lung cancer in the active treatment group. Rates of colorectal cancer were similar between groups during the postintervention period.
• The risk for fracture was similar in the CEE/MPA and placebo cohorts during the postintervention period.
• The risk for mortality was similar between treatment groups during the active phase of the WHI trial. However, the risk for all-cause mortality in the postintervention period was 15% higher in the CEE/MPA vs the placebo group, and this difference was largely explained by higher rates of cancer-related mortality.
• The global index of risk continued to favor the placebo vs the CEE/MPA group during the postintervention period.
• A sensitivity analysis examining only women who had been very compliant with study treatment or continued hormone therapy during the postintervention period, or both, failed to significantly alter the current study's main results, although there was a higher relative risk for death associated with CEE/MPA in this analysis.

Pearls for Practice

• At the conclusion of the active phase of the WHI trial, postmenopausal HRT reduced the risks for fracture and colorectal cancer vs placebo but increased the risks for myocardial infarction, stroke, deep venous thrombosis, and breast cancer.
• The current study demonstrates that cessation of CEE/MPA can reduce its attendant cardiovascular risk, but the increased risk for cancer associated with CEE/MPA may be present for years after stopping this medication.

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