Risk Factors and Secondary Prevention in Women with Heart Disease: The Heart and Estrogen/progestin Replacement Study

Context Risk factors for recurrent events among women with known coronary disease and whether these women commonly receive secondary prevention treatments are mostly unknown. Contribution This large cohort study showed that 11 different factors, including several previous infarctions, renal dysfunction, diabetes, angina, heart failure, and uncontrolled hypertension, predicted up to a sixfold increased rate of coronary disease events in postmenopausal women with preexisting coronary disblockers, angiotensin-converting enzyme inhibitors, or cholesterol-lowering drugs. Implications Clinicians can identify women who have high risks for recurrent coronary events and should promote greater use of secondary prevention treatments for them. The Editors Coronary heart disease (CHD) is the leading cause of death in women. The major independent risk factors that predict CHD onset in healthy women are similar to those identified by epidemiologic studies of healthy men (1-7). A recent report described six independent risk factorsage, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, high blood pressure, diabetes mellitus, and smokingthat were strongly associated with risk for a first CHD event in both men and women (8). However, the strength of the association of certain risk factors with CHD events may vary by sex (9) as well as age. Diabetes may be a stronger risk factor in women than in men (7); among older women, HDL cholesterol level may be a relatively strong risk factor and LDL cholesterol level a relatively weak one (6). In the period immediately after myocardial infarction (MI), studies of mostly male samples have found that persistent ischemia, impaired left ventricular systolic function, and ventricular arrhythmias are the major determinants of subsequent MI and death (10-13). In the Coronary Drug Project study of men with a history of heart attack, electrocardiographic abnormalities and heart failure were stronger predictors than the atherosclerosis risk factors identified in primary prevention settings (14). However, the risk factors for coronary events among women with recognized but stable coronary disease are mostly unknown. Better understanding of these factors could improve secondary prevention in this large and high-risk group. The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized clinical trial of estrogen plus progestin for prevention of CHD events in women with coronary disease (15). Overall, no significant differences were noted between the hormone and placebo groups in CHD events; trends of more CHD events with therapy in year 1 were offset by fewer such outcomes during years 4 and 5. The trial collected extensive data on CHD risk factors and medication use and performed exhaustive outcome ascertainment procedures, with complete mortality follow-up. Therefore, HERS offers a unique opportunity to assess the long-term effect of coronary risk factors and use of recommended treatments in women with established coronary disease. Methods Participants Participants in HERS were postmenopausal women who were younger than 80 years of age, had not had a hysterectomy, and had known coronary artery disease (MI, coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, or angiographic evidence of 50% narrowing of one or more major coronary arteries). Women were excluded if they had had a coronary event within the 6 months before randomization, had a serum triglyceride level greater than 3.39 mmol/L (300 mg/dL), had used hormones within 3 months, or had a history of conditions that would contraindicate estrogen therapy (16). Participants in HERS were randomly assigned within clinical centers to 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate in one tablet daily (n = 1380) or a placebo of identical appearance (n = 1383). The institutional review boards at the coordinating center and each of the 20 HERS clinical centers approved the protocol, and all participants provided written informed consent. Predictors In the baseline interview, information was obtained by self-report on demographic characteristics, behavioral risk factors, and medical history. Among women who reported ever having smoked at least 100 cigarettes, years of smoking, average cigarettes per day, and current smoking were ascertained. Alcohol use in the past 30 days was assessed for frequency and usual numbers of drinks per occasion. Exercise was measured as participation in a regular exercise program such as cardiac rehabilitation or aerobics or walking at least occasionally for exercise more than 10 minutes at a time. Use of aspirin, -blockers, lipid-lowering medications (statins, niacin, fibrates, bile acidbinding resins, and probucol), angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, and folate or vitamin B was assessed by self-report. In the baseline physical examination, blood pressure, waist-to-hip ratio, and body mass index were measured. A physician assessed history and symptoms of heart failure (jugular venous distention, third heart sound, significant murmurs, pulmonary rales, and peripheral edema). High blood pressure was defined as systolic blood pressure greater than or equal to 140 mm Hg or diastolic blood pressure greater than or equal to 90 mm Hg, according to the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (17). Angina was defined as self-report of chest discomfort in the previous 4 weeks during exercise, emotion, or sexual activity. Serum specimens were obtained, and a centralized laboratory measured fasting levels of LDL cholesterol, HDL cholesterol, lipoprotein(a), triglycerides, glucose, and creatinine (15, 16). Creatinine clearance was estimated by using the CockcroftGault equation (18, 19). Outcomes The primary HERS outcome was CHD events, defined as nonfatal MI or CHD death. Suspected outcome events were reported within 24 hours to the coordinating center and were systematically assessed every 4 months at the follow-up contacts. An independent morbidity and mortality subcommittee that was blinded to treatment assignment adjudicated all deaths and suspected outcome events. Nonfatal MI was diagnosed by using an algorithm based on ischemic symptoms, electrocardiographic abnormalities, and elevated cardiac enzyme levels (16). Death from CHD included fatal documented MI, sudden death within 1 hour of symptom onset, unobserved death that occurred out of the hospital in the absence of other known causes, or death due to a coronary revascularization procedure or congestive heart failure. The date of each event was determined from the documentation obtained by the clinical centers. The total number of events reported here is slightly larger than that published in the primary HERS results (15) because of subsequent adjudications (20). Statistical Analyses We used multivariable Cox proportional-hazards models to assess the associations between risk factors and CHD events. These models were stratified by clinical center to account for potential clustering. Waist-to-hip ratio and LDL and HDL cholesterol levels were modeled as continuous variables, but lipoprotein(a) level was dichotomized at the median and creatinine clearance was dichotomized at 0.66 mL/s (40 mL/min) to reflect the nonlinear responses we have reported elsewhere (19, 21). We used an indicator for any alcohol use, since almost all of the 39% of HERS women who reported alcohol use were light or moderate drinkers. Exercise was modeled by an indicator for participation in an exercise program or walking for exercise for more than 10 minutes. The multivariable model includes previously identified risk factors that were significant (P 0.20) in unadjusted models and were not judged redundant on substantive grounds. Body mass index was excluded because it was clearly nonsignificant after adjustment (P > 0.2) and was also highly correlated with waist-to-hip ratio, which was the stronger predictor in unadjusted analysis. Similarly, triglyceride levels were excluded because of their strong negative correlation with HDL cholesterol levels, which in our judgment were more likely to be causal. We also controlled for use of aspirin, statins, other lipid-lowering medications, diuretics, -blockers, ACE inhibitors, calcium antagonists, and folate or vitamin B. The effect of assignment to hormone therapy was modeled separately for each year of follow-up, as in the post hoc analysis of HERS (15). Interactions between risk factors and relevant treatments were also examined. Specifically, we compared hazard rates among patients with diagnosed diabetes who reported use of insulin or oral hypoglycemic agents with rates in the combined group of diabetic persons not using these medications and women with fasting glucose levels greater than 6.94 mmol/L (>125 mg/dL) but no history of diabetes diagnosis. Likewise, we compared estimates for LDL and HDL cholesterol levels stratified by use of any lipid-lowering medication or assignment to hormone therapy; for lipoprotein(a) level, stratified by assignment to hormone therapy; for high blood pressure on examination, stratified by use of at least one antihypertensive medication; for heart failure and creatinine clearance less than or equal to 0.66 mL/s ( 40 mL/min), stratified by use of ACE inhibitors; and for more than one previous MI and angina, stratified by use of any indicated medications. The final model includes interactions that were significant at a P value less than or equal to 0.2. We used residuals to assess overall model fit, validity of the proportional hazards assumption, and linearity of associations with continuous predictors. The study lacked power to examine interactions between clinical center and potential risk factors. We tested the assumption of noninformative censoring by considering the two extremes of the possible outcomes for