Myocardial Infarction and the Use of Estrogen and Estrogen-Progestogen in Postmenopausal Women

Studies that report on the risk for coronary heart disease in women who use estrogen replacement therapy alone are numerous, and information on this topic has been summarized in four published quantitative overviews or meta-analyses [1-4]. Although these overviews conclude that the risk for coronary heart disease is lower in estrogen users, the lack of experimental studies of estrogen use limits the ability to draw definitive conclusions about cause and effect. Fewer studies have examined the association between estrogen-progestogen therapy and coronary heart disease [5-10]. Several ongoing large randomized trials are now examining the relation of estrogen and estrogen-progestogen with coronary heart disease, but the results of these studies may not be available for several years. Until publication of the results of randomized trials examining the relation between hormone use and myocardial infarction, data from nonexperimental studies will be useful in guiding clinical policy. The primary goal of this casecontrol study was to estimate the odds ratio for incident acute myocardial infarction in relation to current use of estrogen and estrogen-progestogen in a population with a high prevalence of estrogen and estrogen-progestogen use. We used the exposure odds ratio to estimate the degree of risk. The secondary goals of this study were to estimate the odds ratios for incident myocardial infarction in 1) current users of estrogen or estrogen-progestogen in relation to the duration of current use and 2) past users of estrogen or estrogen-progestogen. These topics have not been examined closely in previous studies. We also estimated the odds ratio for incident myocardial infarction in current users of estrogen or estrogen-progestogen, considering many potentially confounding variables. Methods All case-patients were women 45 to 74 years of age who were hospitalized for myocardial infarction in any of 10 medical centers of the Kaiser Permanente Medical Care Program (KPMCP), Northern California region, between November 1991 and November 1994. Start and finish dates differed by facility so that the number of months of case ascertainment was different at each facility (mean, 33.4 months). Sources used to identify case-patients included daily admission logs containing admitting diagnoses and information about visits to KPMCP emergency departments. We also regularly reviewed the discharge diagnoses from a computerized database of all overnight hospitalizations in KPMCP, Northern California, centers. The medical records of all case-patients were abstracted by medical abstracters and reviewed by the medically trained project coordinators (one was a registered nurse who had research experience in cardiovascular disease studies; the other was a physician), who consulted with one of the physician-investigators as needed. Case-patients who had a history of coronary heart disease before the date of symptom onset, as ascertained by medical record review done before the study interview, were excluded in an attempt to limit the study to persons with incident coronary heart disease. This was done because the presence of coronary heart disease might influence clinical decision making with regard to the use of estrogen or estrogen-progestogen. In addition, a personal history of coronary heart disease was obtained from all interviewed participants (case-patients and controls) and was included as an adjustment variable in the analysis. Diagnostic criteria for myocardial infarction were adapted from those of the American Heart Association Council on Epidemiology [11]. These criteria use presence or absence of chest pain, results of cardiac enzyme tests, and electrocardiograms to classify events as definite myocardial infarction, probable myocardial infarction, suspected myocardial infarction, or not myocardial infarction. Like investigators in other epidemiologic studies of myocardial infarction defined by using these criteria, we included events categorized as definite or probable cases of myocardial infarction. According to these criteria, the presence of cardiac pain and abnormal enzyme test results are sufficient to categorize an event as a definite or probable myocardial infarction, making it unnecessary to have the electrocardiogram examined by an independent expert. For women who could not be categorized as having definite or probable myocardial infarction on the basis of the presence of chest pain and abnormal enzyme test results, electrocardiograms were sent for coding to the Minnesota ECG Coding Center at the University of Minnesota. This information was used to categorize events as definite myocardial infarction, probable myocardial infarction, suspected myocardial infarction, or not myocardial infarction. For each case-patient, an attempt was made to interview one control, matched for year of birth and facility of usual care. To do this, three potential controls were selected at random from among all female members of the KPMCP. If the first potential control could not be located, declined to participate, or did not speak English or Spanish, an attempt was made to enroll the second potential control, and, if necessary, the third, in order to obtain one interviewed control per case-patient. Controls were identified for 98.2% of confirmed case-patients, and 79.6% of controls were the first of the three potential candidates. Eligible case-patients and controls were interviewed in person by trained interviewers who used a standardized instrument. All participants were interviewed as soon as possible after the events in the case-patient occurred. The mean interval between the index date and the interview date was 71.8 days for case-patients and 78.5 days for controls. If a case-patient died or was unable to communicate verbally, an attempt was made to interview a proxy. Interview information from proxies and the corresponding controls was excluded from this analysis because 1) the prevalence of both current and past hormone replacement therapy ascertained by proxy interview was much lower than that ascertained in direct interviews and 2) a comparison of proxy responses with medical records showed substantial underreporting of documented hormone use. We did not use information from medical records for the analysis because use on a particular date and long-term past use could not be reliably ascertained from these records. All interview questions were asked in relation to an index date, which was the date of symptom onset for each case-patient and the same date for each matched control. Information about the lifetime use of estrogen and estrogen-progestogen preparations was obtained by using the calendar method, in which information on use of hormone replacement therapy is gathered by structuring questions in relation to significant life events. Visual aids, consisting of actual pills for commonly used preparations and a color chart with pictures of all hormone replacement preparations ever marketed in the United States, was used to facilitate recall of the formulation of hormone replacement preparations used currently and in the past. A study participant was defined as having hypertension, diabetes, or a high cholesterol level if she answered yes to questions about whether she was taking medication for these risk factors (she was also defined as having a high cholesterol level if she reported that a physician had told her that she had high cholesterol levels). A participant was defined as a nonsmoker if she answered no to the question, Have you ever smoked cigarettes? If she answered yes to this question, she was categorized as a current regular, occasional, or former smoker on the basis of her answer to the question, On [index date], were you still smoking regularly? (Regularly was defined as at least 5 cigarettes per week almost every week.) Body mass index (kg/m2) was determined by using participant-reported height and weight. A participant was defined as having a previous self-reported history of coronary heart disease if she stated that a physician had told her that she had had a heart attack or angina. The analysis was restricted to postmenopausal women. A study participant was categorized as postmenopausal if she had undergone bilateral oophorectomy or if she had not had a hysterectomy and reported that she had ceased having menstrual periods. Women who have undergone both hysterectomy and unilateral oophorectomy do not know whether they are pre- or postmenopausal on the basis of menstrual function; thus, we excluded such women if they were younger than 55 years of age because they could not be classified with certainty as postmenopausal. These exclusions were applied to both case-patients and controls. Among women who used replacement therapy, most who had had hysterectomy used estrogen (50.6% used estrogen; 1.2% used estrogen-progestogen) and most women who had not had hysterectomy used estrogen-progestogen (18.4% used estrogen-progestogen; 3.0% used estrogen). For this reason, estimates of the odds ratios for myocardial infarction in users of estrogen who did not have hysterectomy and the odds ratios for myocardial infarction in users of estrogen-progestogen who had had hysterectomy were highly unstable statistically. Thus, we excluded from this analysis women who had had hysterectomy and used estrogen-progestogen, women who had not had hysterectomy and used estrogen, and women of unknown hysterectomy status (n = 3) who used either estrogen-progestogen or estrogen. Women who used only progestogen were also excluded as both case-patients and controls because there were few women in this group and valid estimates of risk in relation to exposure to progestogen only could not be derived. These exclusion criteria were applied to both case-patients and controls. Conditional logistic regression was used in the main analyses. For these analyses, we defined an exposure variable-current hormone use-as yes for women who had had hy