Further Evidence of Gender-Based Differences Reported

Another study can be added to the growing arsenal of literature indicating treatment and outcome differences between women and men suffering myocardial infarction (MI), regardless of presentation symptoms.

In a letter to the editor in a recent issue of Archives of Internal Medicine, Mark Bing, MD, MPH, and associates discussed an investigation conducted by the Texas Medical Foundation in conjunction with the Cooperative Cardiovascular Project regarding gender-based differences in the treatment and outcome variances between male and female victims of myocardial infarction (Editor's Correspondence, Arch Intern Med, December 7/21, 1998;158:2513-2514). The Texas Medical Foundation is a peer-review organization established as part of the state's Health Care Quality Improvement Program.

First, the researchers established that differences in treatment between genders existed. Men were significantly more likely than women to receive aspirin in the hospital (OR, 1.24; P=.006) and at discharge (OR, 1.31; P=.001), as well as to have percutaneous transluminal coronary angioplasty while in the hospital (OR, 1.47; P=.02). They found no treatment differences between genders in the use of thrombolytic agents or the use of angiotensin-converting enzyme inhibitors and beta-adrenergic blocking agents.

Of considerable note, the researchers found that men were less likely than women to die from myocardial infarction, either in the hospital or within 30 days of discharge (OR, 0.86; P=.01 and OR, 0.86; and P=.004, respectively).

Second, the researchers sought to establish reasons for these treatment variances. Specifically, they investigated the possibility that women may report difference symptoms than do men, thus affecting their treatment.

Via chart study, they surmised the four most common complaints of MI patients. These were divided into categories including chest pain, syncope, arm pain, gastrointestinal symptoms (with or without respiratory symptoms), respiratory symptoms, and other. Patients were disqualified if their medical history was unknown.

Overall, significantly more women than men complained of symptoms other than chest pain (P=.01), however, most men and women suffering myocardial infarction (77.7 percent and 70.7 percent, respectively) presented to the hospital with chest pain, Bing et al. noted.

Given these data, why is there variability in treatment of women compared to men? In the opinion of these researchers, the presentation differences between men and women do not warrant the discrepancy in the treatment provided to them.

Women's Health Weekly: January 11, 1999 issue (excerpted with permission)

HRT Does Not Decrease Risk of Heart Attack In Some Women

A major clinical trial found that estrogen plus a progestin did not decrease the overall risk of heart attack and coronary death among post-menopausal women with previous heart disease.

The study, led by University of California San Francisco (UCSF) researchers and colleagues at 18 medical centers in the United States and published August 19, 1998, 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 by about 50 percent and then to decrease it after two years of treatment. In the fourth and fifth year of treatment, women taking the drug had about a 40 percent reduction in risk of heart attack. 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 post-menopausal 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 post-menopausal 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. The hormones consisted of 0.625 milligrams of conjugated estrogens and 2.5 mg 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. The effect of estrogen alone was not studied.

Progestins can reduce the beneficial effects of estrogen on blood cholesterol, but the estrogen plus progestin treatment used in the trial significantly improved cholesterol. Deborah Grady, MD, associate professor of epidemiology and medicine at UCSF and co-leader of the study, 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 post-menopausal 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 post-menopausal 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 initial increase was unexpected," noted Curt Furberg, MD, professor at Wake Forest University School of Medicine in North Carolina, 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 explained.

The change over time also could be due to chance. This is statistically unlikely, however, and recent findings from the Nurses' Health Study suggest that the change over time is real.

Most earlier observational studies 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 replacement therapy (HRT) are generally healthier and have lower risk for heart attack than women who do not take hormones. Also, observational studies usually are not able to detect the early effects of therapy.

It is important to note that HERS participants were older women with pre-existing 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.

The study was sponsored by Wyeth-Ayerst Laboratories.

In a comment issued by the American Heart Association (AHA), the group said the HERS results:

• should help guide physicians in their treatment of older women with heart disease;
  
  
• should not be generalized to women who are healthy (i.e., without heart disease);
  
  
• should stimulate more research about women in heart disease; and
  
  
• should reinforce the need for all women to talk with their physician about what they can do to reduce their risk for heart disease, which claims more women's lives than any other disease.

"This study indicates that care should be taken by doctors in their decisions about whether to initiate hormone replacement therapy in older women who already have advanced heart disease," said Rodman Starke, MD, AHA. "Women with heart disease who already are taking HRT should talk with their doctor about continuing the treatment. But, if they have been taking HRT for several years, they may be past the period of time when adverse events are more likely to occur according to the study."

"The follow-up time period in this study is too brief to make definitive answers," emphasized Valentin Fuster, MD, PhD, president of AHA. "The answers are still not in."

In an editorial accompanying the JAMA paper, Diana B. Petitti, MD, of Kaiser Permanente Southern California in Pasadena, commented on the different findings of the HERS study and previous observational studies. "These findings [Hulley et al.] are a sobering reminder of the limitations of observational research, the incompleteness of current understanding of the mechanisms of vascular disease, and the dangers of extrapolation," she said.

"There remains an impressive body of observation data on estrogen replacement therapy [ERT] and estrogen-progestin replacement therapy used for primary prevention. Women with coronary disease are likely to have unmodifiable risk factors, such as diabetes and obesity, that influence the tendency to thrombosis. If so, any procoagulant effect of hormones would be greatest in women with coronary disease. The HERS results should not be immediately extrapolated to ERT and HRT used for primary prevention," Petitti continued.

"The HERS results are important for women to consider in making decisions about hormone replacement. Physicians need to review carefully the HERS findings, but no woman, including those with coronary disease, should abruptly cease use of ERT or HRT because of the HERS results. Most women use hormones for reasons other than prevention of coronary heart disease. The beneficial effects of ERT and HRT on bone and menopausal symptoms have been established clearly in randomized trials. Discussions of the HERS findings between women and their physicians do not need to occur today, this week, or even this month. HERS identifies no new risks, and there is no emergency," Petitti concluded.

U.S. National Institutes of Health-sponsored research is underway to answer the question of whether HRT prevents heart disease in post-menopausal women who are healthy and without heart disease.

The American Heart Association's "Each One, Reach One" campaign provides information to help women reduce their risk for heart attack and stroke. For information, telephone 1-888-MY HEART or visit http://www.women.amhrt.org.

Women's Health Weekly: Women's Health Weekly: September 7, 1998 issue (excerpted with permission)

CWH Journal Watch: March 1999