HERS II data: HRT does not lower cardiac risk

Results from two just-released studies of hormone replacement therapy (HRT) indicate that the drug regimen should not be initiated solely for purposes of preventing a second heart attack or death among women with heart disease.1,2

Initial results from the Heart and Estrogen/ Progestin Replacement Study (HERS), a randomized trial among postmenopausal women with pre-existing coronary heart disease (CHD), indicated that while HRT raised the risk of heart problems in the first year of treatment, it seemed to lower it during years three through five.3 (Contraceptive Technology Update reported on the data in the article "Update won’t stop Women’s Health Initiative" see the June 2000 issue, p. 68.)

The two new reports examined cardiovascular and noncardiovascular outcomes during 2.7 years of additional unblinded follow-up of women enrolled in HERS. They further clarify the initial findings. In the follow-up study, known as HERS II, researchers found that the lower rates of CHD events in the hormone therapy group observed during years three to five of HERS did not persist during additional follow-up.1 In addition, during all 6.8 years of follow-up, rates of venous thromboembolism and biliary tract surgery were increased significantly in the HRT group compared with the placebo group.2 Differences in cancer and fracture risk and total mortality were not statistically significant.

The follow-up study found no reduction in risk of heart attacks or death for women with heart disease during up to seven years of hormone therapy. Not only was there no cardiovascular benefit, there were adverse affects, including blood clots and gallbladder disease, states Deborah Grady, MD, MPH, professor of epidemiology and medicine at the University of California San Francisco and co-principal investigator on the studies.

"It is my opinion that hormone [HRT and estrogen replacement therapy] use for prevention of coronary disease in women who already have established coronary disease is no longer an option and should not be pursued," states Diana Petitti, MD, director of research at Kaiser Permanente Southern California in Pasadena. Petitti authored an accompanying editorial to the HERS II reports.4

Look at the research

The HERS II study was a 2.7-year follow-up of the 4.1-year HERS study, the first randomized, blinded, placebo-controlled trial large enough to detect the effects of hormone therapy on disease outcomes. Participants in HERS were assigned randomly to receive either 0.625 mg/d conjugated estrogen plus 2.5 mg medroxyprogesterone acetate, or a placebo that was identical in appearance. The women in the study group were nearly 20 years postmenopause; the study did not address the cardioprotective benefits for younger, healthier menopausal women.

Researchers found there were no significant decreases in rates of primary CHD events or secondary cardiovascular events among women assigned to the hormone group compared with the placebo group in HERS, HERS II, or overall.1 In the review of noncardiovascular disease outcomes, scientists concluded that treatment for 6.8 years with estrogen plus progestin in older women with coronary disease increased the rates of venous thromboembolism and biliary tract surgery.2 Trends in other disease outcomes were not favorable and should be assessed in larger trials and in broader populations, researchers noted.

Results of the HERS II data fall in line with a 2001 scientific advisory issued by the Dallas-based American Heart Association, which recommended that HRT should not be initiated for the prevention of future coronary events in women with cardiovascular disease.5 (CTU reported the recommendation in October 2001, p. 115: "Advisory issued on HRT and heart disease.")

The pattern of early increase and later decrease in risk seen in HERS led to the researchers’ initial recommendation that women with CHD should not start HRT, but that those who already were taking hormones for other indications could continue. The question of whether a benefit with regard to CHD events might be seen with longer follow-up was left unanswered.

With the HERS II data now in hand, consensus is being reached that HRT should not be used to reduce risk for CHD events in women with CHD.

References

1. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study Follow-Up (HERS II). JAMA 2002; 288:49-57.

2. Hulley S, Furberg C, Barrett-Connor E, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replace-ment Study Follow-Up (HERS II). JAMA 2002; 288:58-66.

3. Hulley S, Grady D, Bush T, et al, for the HERS Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998; 280:605-613.

4. Petitti DB. Hormone replacement therapy for prevention: More evidence, more pessimism. JAMA 2002; 288:99-101.

5. Mosca L, Collins P, Herrington DM, et al. Hormone replacement therapy and cardiovascular disease: A statement for health care professionals from the American Heart Association. Circulation 2001; 104:499-503.