Publications

CONTEXT

Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials.

OBJECTIVE

To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease.

DESIGN

Randomized, blinded, placebo-controlled secondary prevention trial.

SETTING

Outpatient and community settings at 20 US clinical centers.

PARTICIPANTS

A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years.

INTERVENTION

Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years.

MAIN OUTCOME MEASURES

The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered.

RESULTS

Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).

CONCLUSIONS

During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.

The development of monoclonal antibodies and the emergence of recombinant DNA technology has made it possible to identify and selectively inhibit distinct cell subsets, surface molecules and secreted products that contribute to normal and pathological immune responses. These advances have helped to clarify the mechanisms that promote autoimmune diseases. As a result, it is now possible to contemplate rational strategies for the treatment of these diseases. Some of these strategies are designed to influence the cell surface interactions that determine whether potentially autoreactive T cells become activated or tolerant following antigen stimulation. Other strategies are designed to augment or inhibit distinct cytokines that regulate autoimmunity. All of these strategies have shown promise in animal models for systemic lupus erythematosus, and they may soon be translated into effective new therapies for people.

The Heart and Estrogen/progestin Replacement Study (HERS) is a randomized, double-blind, placebo-controlled trial designed to test the efficacy and safety of estrogen plus progestin therapy for prevention of recurrent coronary heart disease (CHD) events in women. The participants are postmenopausal women with a uterus and with CHD as evidenced by prior myocardial infarction, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, or other mechanical revascularization or at least 50% occlusion of a major coronary artery. Between February 1993 and September 1994, 20 HERS centers recruited and randomized 2763 women. Participants ranged in age from 44 to 79 years, with a mean age of 66.7 (SD 6.7) years. Most participants were white (89%), married (57%), and had completed high school or some college (80%). As expected, the prevalence of coronary risk factors was high: 62% were past or current smokers, 59% had hypertension, 90% had serum LDL-cholesterol of 100 mg/dL or higher, and 23% had diabetes. Each woman was randomly assigned to receive one tablet containing 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate daily or an identical placebo. Participants will be evaluated every 4 months for an average of 4.2 years for the occurrence of CHD events (CHD death and nonfatal myocardial infarction). We will also assess other major CHD endpoints, including revascularization and hospitalization for unstable angina. The primary analysis will compare the rate of CHD events in women assigned to active treatment with the rate in those assigned to placebo. The trial was designed to have power greater than 90% to detect a 35% reduction in the incidence of CHD events, assuming a 50% lag in effect for 2 years and a 5% annual event rate in the placebo group. The design, analysis, and conduct of the study are controlled by the Steering Committee of Principal Investigators and coordinated at the University of California, San Francisco. HERS is the largest trial of any intervention to reduce the risk of recurrent CHD events in women with heart disease and is the first controlled trial to seek evidence of the efficacy and safety of postmenopausal hormone therapy to prevent recurrent CHD events.

BACKGROUND

Although bleeding lesions anywhere in the gastrointestinal tract can cause a positive reaction on guaiac-based fecal occult-blood tests, the relative frequency of upper gastrointestinal and colonic lesions is unknown.

METHODS

During a period of 30 months, we prospectively studied all patients with at least one stool specimen containing fecal occult blood who were referred for further evaluation. Fecal occult blood was detected by standard guaiac-based tests of stool specimens obtained as part of routine screening or of stool obtained by digital rectal examination. Patients with documented iron-deficiency anemia or active gastrointestinal bleeding were excluded from the study. All participants had a detailed history taken and underwent colonoscopy, followed by esophagogastroduodenoscopy.

RESULTS

Of the 409 patients with fecal occult blood who were referred, 310 were potentially eligible to participate, and 248 (mean age, 61 years; range, 40 to 89) were studied; 40 percent were women. We identified lesions consistent with occult bleeding in 119 patients (48 percent); in 71 bleeding lesions were found in the upper gastrointestinal tract, and in 54 they were identified in the colon. Six patients had abnormalities in both areas. The most common upper gastrointestinal lesions were esophagitis (23 patients), gastric ulcer (14), gastritis (12), and duodenal ulcer (10). Thirty patients with lesions in the upper gastrointestinal tract were long-term users of aspirin, ethanol, nonsteroidal antiinflammatory drugs, or a combination of these substances. The most common colonic lesions were adenomas more than 1.0 cm in diameter (29 patients), carcinoma (13), colitis (5), and vascular ectasia (5). Although the overall sensitivity of symptoms for the detection of gastrointestinal lesions was low, logistic-regression analysis demonstrated that the presence of symptoms in the upper gastrointestinal tract was associated with the detection of lesions in the upper gastrointestinal tract (odds ratio, 2.6; 95 percent confidence interval, 1.4 to 4.7). In both patients with symptoms and those without symptoms, the prevalence of lesions in the upper gastrointestinal tract was greater than or equal to that of colonic lesions.

CONCLUSIONS

In a group of patients with positive fecal occult-blood tests who were referred for further evaluation, from which those with iron-deficiency anemia and active bleeding had been excluded, upper gastrointestinal lesions were identified more frequently than colonic lesions.