Postmenopausal Hormone Use and Secondary Prevention of Coronary Events in the Nurses' Health Study: A Prospective, Observational Study

The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized clinical trial of postmenopausal hormone use in 2763 women (1). Unlike previous observational studies, it included only women with previous coronary heart disease, and hormone therapy was exclusively oral conjugated estrogen plus progestin. In HERS, overall rates of recurrent coronary heart disease did not differ between the treated and nontreated groups. However, in additional, unplanned analyses, the results of HERS were not uniformly null. A marked and statistically significant trend toward decreasing risk was observed with increasing duration of hormone use (1); in the first year, the rate of major coronary events was 52% higher in the treatment group. In the second year, rates were equal, but during the final fourth and fifth years, women assigned to hormone therapy had a 33% lower risk for coronary events. The overall results of HERS and the apparent changes in risk over time were both unexpected. Since no previous investigations have examined the relation between duration of hormone use or combined hormone treatment to secondary prevention of coronary heart disease events, it remains unclear whether the time trend was authentic and whether the observations in HERS are limited to that hormone regimen (2). In addition, we were interested in understanding how women's use of hormone therapy before their initial coronary disease event might affect the outcome of their hormone use after that event. In HERS, duration of hormone therapy before trial entry was necessarily disregarded (although 23% of participants had previously taken hormones); thus, it remains unknown how, or whether, to account for hormone use or duration of use before a patient's initial coronary event. To further examine the effects of duration of hormone therapy and to explore the effect of different hormone regimens, we investigated the relation between postmenopausal hormone use and secondary prevention of major coronary events in 2489 women with established coronary disease in the Nurses' Health Study, a large observational cohort. Methods The Nurses' Health Study Cohort The Nurses' Health Study began in 1976, when 121 700 female nurses 30 to 55 years of age completed a mailed questionnaire about postmenopausal hormone use and medical history, including cardiovascular disease and its risk factors. Every 2 years, we mail follow-up questionnaires to the original participants to update information on risk factors and to identify newly diagnosed cases of major illnesses. The total follow-up for the cohort to date exceeds 92%. Sample for Analysis For this analysis, we limited the cohort to postmenopausal women who reported a previous myocardial infarction or documented coronary atherosclerosis (coronary artery bypass graft surgery, percutaneous coronary revascularization, or angiographic evidence of 70% occlusion of one or more major coronary arteries). Such women were identified on the baseline questionnaire in 1976; postmenopausal women who reported one of these conditions on a subsequent follow-up questionnaire were added to the sample at that time. Women ranged in age from 34 to 73 years at entry into the sample for analysis; 60% of women had a natural menopause. These criteria closely parallel those used in HERS (1); however, in HERS, women with hysterectomy were excluded, occlusion was defined as at least 50%, and participants ranged in age from 44 to 79 years. We classified women as postmenopausal from the time of natural menopause or hysterectomy with bilateral oophorectomy. Women who underwent hysterectomy without bilateral oophorectomy were considered postmenopausal when they reached the age at which natural menopause had occurred in 90% of the cohort (54 years for smokers and 56 years for nonsmokers) (3). The women's reports of age at menopause and type of menopause were highly accurate (4). In HERS, women with a history of breast or endometrial cancers were excluded. In the current study, we excluded women who reported stroke or cancer (except nonmelanoma skin cancer) on the 1976 baseline questionnaire at the outset and excluded women from further follow-up if they reported these diseases on a subsequent biennial questionnaire. This was done to avoid potential bias, in which major diseases such as stroke or cancer may have caused women to alter their hormone use and may be related to risk for coronary heart disease. This type of bias could not have occurred in a randomized trial, such as HERS. Two hundred forty-eight postmenopausal women with coronary disease entered the analysis in 1976, and 2241 postmenopausal women were added during follow-up as they reported heart disease; thus, 17 239 person-years accrued during up to 20 years of follow-up from 1976 to 1996. Ascertainment of Hormone Use In 1976, women were asked about current and past use and duration of hormone therapy; this information was updated on each biennial questionnaire. Beginning in 1978 and on each subsequent questionnaire, we collected information on type of hormone used. For the period 19761978, we assigned women to the type of hormone reported on the 1978 questionnaire. If no data were available on hormone therapy for a given 2-year period, those women were assigned to a missing category for that period. In the HERS trial, women who had taken hormones in the 3 months before their screening visit were excluded (although 23% to 24% of the enrolled participants had previously used hormones). Because this study is observational, we could not impose a 3-month washout period; thus, we could not duplicate that aspect of the HERS protocol. We analyzed duration of hormone use in two different ways. In the main analysis, we performed a HERS replication and used a method similar to that in HERS to calculate duration of use. In HERS, duration of hormone therapy began to accrue at randomization (regardless of previous hormone use); randomization occurred sometime after the participant's initial coronary disease event. Therefore, in our main analysis, we began accruing duration of hormone use for each participant immediately after her initial coronary disease event (regardless of hormone use before this event). For example, if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986, her duration of use in 1990 would be 4 years. In an alternative analysis, we considered the women's full experience with hormone therapy (both before and after the initial coronary disease event). Thus, duration of hormone use accumulated continuously from start to termination of therapy. For example, if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986, her duration of use in 1990 would be 6 years. Similar to HERS participants, 29% of the nurses had taken hormones before their first coronary disease event. Identification of Second Coronary Disease Events Similar to HERS, in our study the category of recurrent major coronary heart disease included nonfatal myocardial infarction and fatal coronary disease that occurred between the return of the 1976 questionnaire and 1 June 1996. Nurses who reported a nonfatal infarction were asked for permission to review their medical records. Nonfatal myocardial infarctions were confirmed by hospital records if they met the World Health Organization criteria (5) (symptoms, plus either elevated cardiac enzyme levels or diagnostic electrocardiograms). Infarctions requiring hospitalization and corroborated by interview or letter, but for which medical records were unobtainable, were included as probable. Most deaths were reported by the participants' families. Every 2 years, we search the National Death Index (6) to identify deaths among nonrespondents; follow-up for death remains more than 98% complete to date. For all deaths possibly attributable to cardiovascular causes, we requested permission from relatives (subject to state regulations) to review the medical records. Deaths were considered due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infarction. Cases in which coronary disease was listed on the death certificate as the underlying cause of death and another, more plausible cause could not be discerned were included as probable cases, since the nurse was known to have had coronary disease before death. The investigators conducted all interviews and medical record reviews without knowledge of participants' hormone use status. In separate analyses, results for probable cases of coronary disease (20%) were almost identical to those for confirmed cases (80%); thus, we present data from analyses in which confirmed and probable cases are combined. Statistical Analysis For each participant, person-months were allocated to hormone categories according to the baseline data and were updated every 2 years according to information received on follow-up questionnaires. Examination of type of hormone therapy was limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate, as this was the most common hormone regimen. If information on hormone use was missing during a follow-up period, then person-time was assigned to a missing category for that time period. So that the study would be prospective, we established hormone status during each 2-year follow-up period from women's reports at the start of the time period; thus, we probably underestimate duration of use by an average of 1 year in both the main analysis and the alternate analysis. Follow-up for a participant ended with diagnosis of myocardial infarction, death, or 1 June 1996, whichever came first. The analysis is based on incidence rates, using person-months of follow-up as the denominator. We used relative risk as the measure of association, defined as the incidence of second major coronary events among women in various categories of hormone use divided by the rate among women who never used hormones.