A major clinical trial led by University of California San Francisco researchers and colleagues at 18 medical centers in the United States found that estrogen plus a progestin did not decrease the overall risk of heart attack and coronary death among postmenopausal women with previous heart disease.
The study, published August 19 in the Journal of the American Medical Association (JAMA), reported that the hormone therapy appeared to increase the risk of heart attack in the first year of treatment and then to decrease it after two years of treatment. The two effects balanced out, so that the number of women who had heart attacks or coronary death over the whole four years was similar in women who took hormones and in women who did not.
"Based on these findings, we don't recommend starting estrogen plus progestin for the purpose of preventing heart attacks in postmenopausal women with existing heart disease," said Stephen B. Hulley, MD, professor and chair of epidemiology and biostatistics at UCSF, and the leader of the Heart and Estrogen/progestin Replacement Study (HERS). "There was no overall benefit during the four years of the trial, and the risk of heart attacks seemed to increase soon after starting hormones. But women who are already taking estrogen plus progestin could decide to continue, given the apparent decrease in risk of heart attack after several years.
The first clinical trial large enough to examine the effects of postmenopausal estrogen plus progestin on cardiac disease outcomes, HERS also found that hormone therapy increased the risk of blood clots in the legs or lungs, and the risk of gallbladder disease. Previous observational data have reported similar findings.
HERS was a randomized trial that included 2,763 women. At the beginning of the study, all of the women already had some form of coronary heart disease, including previous heart attack, bypass surgery, angioplasty or coronary artery narrowing. All of the women had gone through menopause. Their average age was 67 at the start of the study.
Half of the women in HERS were randomly assigned to treatment with hormones and the other half took a placebo -- an inactive pill that was identical in appearance. The hormones consisted of 0.625 milligrams of conjugated estrogens and 2.5 milligrams of medroxyprogesterone acetate taken once daily. The participants were followed for 4.1 years to determine who had a heart attack or died of heart disease.
"Women in the HERS trial took estrogen with progestin," noted Deborah Grady, MD, associate professor of epidemiology and medicine at UCSF and co-leader of the study, "so we don't have any information on the effect of estrogen taken alone." Progestins can reduce the beneficial effects of estrogen on blood cholesterol, but the estrogen plus progestin treatment used in the trial significantly improved cholesterol. Grady noted that there was an 11 percent decrease in LDL cholesterol, the bad cholesterol, and a 10 percent increase in HDL cholesterol, the good cholesterol.
"HERS studied women with known heart disease," Hulley said, "so we don't know if our findings apply to postmenopausal women who don't have heart disease. We need the results of other clinical trials to answer that question." A large trial that includes healthy postmenopausal women and women taking estrogen alone is part of the Women's Health Initiative that is scheduled for completion in 2005, and several other trials are in progress.
The HERS trial found that estrogen plus progestin increased the risk of heart attack about 50 percent in the first year of the trial. In the fourth and fifth year of treatment, women taking the drug had about a 40 percent reduction in risk of heart attack. It's not clear what might cause such a change over time.
"The initial increase was unexpected," noted Curt Furberg, MD, professor at Wake Forest University School of Medicine and chair of the HERS steering committee of investigators. "Perhaps estrogen plus progestin had a bad effect at the outset, such as increased clotting, that was later outweighed by a good effect on cholesterol. It often takes one to two years for drugs that reduce cholesterol to lower the risk of heart attacks," Furberg said.
The change over time could also be due to chance. However, this is statistically unlikely, and recent findings from the Nurses' Health Study suggest that the change over time is real. A preliminary report from this observational study at the Third International Symposium on Women's Health and Menopause in Florence, Italy, June 13-16, 1998, revealed a pattern similar to the HERS trial results among women with prior cardiovascular disease.
Most prior observational studies have reported that estrogen plus progestin substantially reduces the risk of heart attack. According to Grady, evidence from observational studies might be misleading because women who choose to take hormone therapy are generally healthier and have lower risk for heart attack than women who do not take hormones. Also, observational studies are usually not able to detect the early effects of therapy.
"While the results of this investigation did not demonstrate the prevention of heart attacks during the four-year study, HERS is a significant contribution to understanding how hormone treatment acts on the coronary system of cardiac-compromised older women," said Philip J. de Vane, MD, vice-president of clinical affairs and North American medical director of Wyeth-Ayerst Laboratories, which sponsored the study. It is important to note that HERS participants were older women with preexisting heart disease. Typical hormone users do not have existing heart disease and start therapy at a younger age - at the outset of menopause - for the treatment of menopausal symptoms and the prevention of osteoporosis.
Funding for HERS was provided by Wyeth-Ayerst Research, an affiliate of American Home Products Corp. (NYSE:AHP)
HERS Principal Investigators at Clinical Centers
William Applegate, MD, University of Tennessee, Memphis, TN
Elizabeth Barrett-Connor, MD, University of California San Diego, CA
Trudy L. Bush, PhD, MHS, The Johns Hopkins University, Baltimore, MD
Robert Califf, MD, Duke University Medical Center, Durham, NC
Jane Cauley, DrPH, University of Pittsburgh, Pittsburgh, PA
Michael Davidson, MD, Chicago Center for Clinical Research, Chicago, IL
William Haskell, PhD, Stanford Center for Research in Disease Prevention, Palo Alto,CA
Alan Herd, MD, Baylor College of Medicine, Houston, TX
David Herrington, MD, Wake Forest University School of Medicine, Winston-Salem, NC
Judith Hsia, MD, George Washington University, Washington, DC
Donald Hunninghake, MD, University of Minnesota, Heart Disease Prevention Clinic, Minneapolis, MN
Steven Khan, MD, Cedars-Sinai Medical Center, Los Angeles, CA
Robert Knopp, MD, Northwest Lipid Research Clinic, Seattle, WA
Maureen Lowery, MD, University of Miami School of Medicine, Miami, FL
William Rogers, MD, University of Alabama, Birmingham, AL
Helmut Schrott, MD, University of Iowa, Iowa City, IA
David Waters, MD, Hartford Hospital, Hartford, CT
Nanette Wenger, MD, Emory University, Atlanta, GA
HERS Principal Investigators at Other Sites
Curt Furberg, MD, Chairman HERS Steering Committee, Wake Forest University
School of Medicine, Winston-Salem, NC
Paul Bachorik, PhD, Lipid Laboratory, The Johns Hopkins University, Baltimore, MD
Deborah Grady, MD, Coordinating Center Co-Principal Investigator, University of California San Francisco, CA
Stephen Hulley, MD, MPH, Coordinating Center Principle Investigator, University of California San Francisco, CA
Pentti Rautaharju, MD, ECG Center, EPICARE, Winston-Salem, NC