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BMJ No 7115 Volume 315 Education and debate Saturday 25 October 1997 Coronary heart disease: an older woman's major health risk Nanette K Wenger Summary points Coronary heart disease is the major cause of death in postmenopausal women in many industrialised countries and will become epidemic in elderly women as the population ages unless preventive interventions across the lifespan are undertaken Risk factors for coronary heart disease in older women must be evaluated and preventive measures instituted throughout a woman's lifetime Mortality and morbidity after myocardial infarction and coronary revascularisation procedures are greater in women than in men. Characteristics and treatments likely to be associated with better outcomes in older women must be identified Results from studies of the current earlier and more intensive evaluation of chest pain in women must be evaluated, and the role of postmenopausal hormone treatment in improving the long term outcomes of women with coronary heart disease must be assessed Only when prospectively derived, contemporary, gender specific information becomes available will doctors be able to identify the diagnostic, treatment, and prognostic features specific to the coronary care of older women Coronary heart disease has traditionally been considered a problem which predominantly affects men - its extent and poor prognosis in women have only recently been identified. As shown in the Framingham study,(1) women are more likely than men to die after myocardial infarction; this is now also evident after coronary artery bypass graft surgery and coronary angioplasty. However, the prognosis is currently also influenced by access to coronary diagnostic procedures and treatments, which may in turn be affected by factors such as women's and their doctors' decisions about diagnostic procedures and treatments, by the allocation of health care resources, and by society's perceptions of the importance of coronary heart disease in women. Epidemiology Coronary heart disease is more dependent on age in women than in men: women are usually 10 years older than men when any coronary manifestations first appear, and myocardial infarction occurs as much as 20 years later.(1) One in 8 or 9 American women aged 45-64 years has clinical evidence of coronary heart disease and this increases to 1 in 3 in women older than 65 years (fig 1). Coronary heart disease is the leading cause of death in women in the United States; it is responsible for over 250,000 deaths annually (fig 2).(2) With the aging of the population, more women than men now die of coronary heart disease each year in the United States. A white postmenopausal woman in the United States is 10 times more likely to die of heart disease than of breast cancer.(3) But most women do not understand the coronary threat. Studies show that women do not usually list heart disease among the health problems they consider most important.(4-5) Morbidity from coronary heart disease in older women is also considerable; 36% of American women aged 55-64 years and 55% of those over 75 years with coronary disease are disabled by symptoms of their illness.(1)(6-7) Mortality from coronary heart disease in women varies considerably between countries but generally parallels the mortality for men in any one country (fig 3). In many industrialised nations, it is now the major cause of death in postmenopausal women and a principal contributor to hospital admissions and consultations with doctors. Coronary risk factors and their modification in older women Coronary heart disease will probably become epidemic in older women as the population ages unless women take preventive measures throughout their lives.(8) The prevalence of risk factors is high in women of all racial and ethnic groups in the United States(6-7) - only a third of all American women do not have at least one major coronary risk factor, and this proportion decreases in older women. American women aged over 65 pay less attention to exercise and diet and use fewer other preventive health services than younger women.(9) Risk factors are more prevalent in socioeconomically and educationally disadvantaged women; in the United States almost twice as many women as men aged 65 years or older are at the poverty level. Fig 1: Incidence of chronic diseases in relation to age in women Fig 2: Leading causes of death in women, United States, 1993 Fig 3: Mortality from ischaemic heart disease (age standardised to the European standard population) in men and women from various industrialised nations, 1991-3 Data for American women aged 20-74 years in 1991 showed that more than a third had hypertension; more than a quarter each had hypercholesterolaemia, were cigarette smokers, or were overweight; and two thirds had a sedentary lifestyle. The only risk factor less pronounced in older than younger women was smoking. Some risk factors for men and women cross over with aging. Hypertension and hypercholesterolaemia are more prevalent in younger men than women, but at older ages they become more prevalent in women than men.(7)(10) Cholesterol Cholesterol concentrations continue to predict coronary risk in older women. Lowering cholesterol after myocardial infarction in the Scandinavian simvastatin survival study (4S) reduced major coronary events by a third in women and men, and the benefit was maintained at older ages.(11) In the cholesterol and recurrent events (CARE) trial, lowering cholesterol after myocardial infarction in patients with average cholesterol values reduced death or subsequent infarction by 46% in women and 26% in men.(12) All the women in the heart and estrogen/progestin replacement study (HERS) had coronary heart disease, and almost half were taking a lipid lowering drug at enrolment; however, most had concentrations of low density lipoprotein cholesterol that exceeded the treatment goals of the national cholesterol education program.(13) Hypertension In people aged 60 or more in the systolic hypertension in the elderly program (SHEP), control of isolated systolic hypertension reduced strokes, deaths from cardiovascular events, and the number of non-fatal cardiovascular events in both women and men.(14) Smoking Cigarette smoking triples the risk for myocardial infarction, with the greatest risk in women with other coronary risk factors and older age women. Nevertheless, within two years of stopping smoking, middle aged women in the nurses' health study (NHS) lowered their risk of cardiovascular mortality by 24%, regardless of the amount or duration of cigarette smoking or the age at which they stopped smoking.(15) Data from the coronary artery surgery study (CASS) registry suggest that the benefit of stopping smoking does not lessen with older age.(16) Diabetes mellitus Diabetes is a far greater risk factor for women than men.(17) Women over 45 years are twice as likely as men to develop diabetes. Diabetes has an adverse effect on the in-hospital and long term prognoses after myocardial infarction, and this is much worse for women than men. More women than men who undergo myocardial revascularisation procedures are diabetic, which probably contributes to the less favourable outcomes in women. Physical inactivity Physical inactivity is a highly prevalent and independent risk factor in women, although data are limited for elderly women. In epidemiological studies, exercise reduced coronary risk, even at older ages.(18) Moderate leisuretime activity (30-45 minutes' walking three times weekly) reduced the risk of myocardial infarction by half.(18) Despite these benefits, fewer women, and particularly elderly women, are referred for exercise rehabilitation after a coronary event.(19) Postmenopausal hormone therapy Interest in postmenopausal hormone treatment to reduce coronary heart disease is encouraged by the benefits suggested for oestrogen, which include favourable effects on the lipid profile and on fibrinogen concentrations.(20) Oestrogen also favourably affects coronary vasodilation. Data from many observational studies suggest consistently that the coronary risk is 35-50% lower in women who take oral oestrogen. In the nurses' health study, mortality was reduced in women at high coronary risk who were currently taking hormone treatment.(21) The benefit fell with longer term treatment, however, because of an increase in mortality from breast cancer. The likelihood of selection bias is an inherent weakness of these observational data, in that oestrogen is typically prescribed in healthy women. However, postmenopausal hormone use by elderly women was associated with both a more favourable cardiovascular risk profile and more favourable preclinical cardiovascular characteristics.(22) Oestrogen alone and several combinations of oestrogen and progestin improved the coronary risk profile of subjects in the postmenopausal estrogen/progestin interventions (PEPI) trial.(23) However, a third of the women who had not had a hysterectomy and who took oestrogen unopposed, developed adenomatous or atypical endometrial hyperplasia within three years, which placed them at risk for endometrial cancer. Oestrogen plus a progestin is indicated for these women, while unopposed oestrogen remains appropriate for women after hysterectomy. Decisions about postmenopausal hormone therapy are also influenced by the fact that it reduces osteoporosis and menopausal symptoms and may lessen the risk of Alzheimer's disease.(24) Adverse effects include the increased risks of breast cancer and of venous thromboembolism. In the nurses' health study, the relative risks for breast cancer were greatest in women more than 60 years (1.71 at age 60-64) and in women who had used hormone therapy for more than five years (1.45) - features characteristic of women who use hormone treatment to prevent coronary heart disease and osteoporosis.(25) Data from randomised clinical trials which are in progress may clarify the relative benefits and risks of postmenopausal hormone treatment and give better information to guide this treatment in older women. Aspirin Randomised controlled trial data are also needed to define in women the risks and benefits of taking aspirin as a preventive measure. The increased risk of haemorrhagic stroke associated with taking aspirin is of concern. In women this risk is potentially greater than the benefit from a reduction in the risk of myocardial infarction.(26) Clinical characteristics of coronary heart disease: sex differences Angina pectoris Angina pectoris is the main initial and subsequent presenting symptom of coronary heart disease in women, while myocardial infarction and sudden death are the predominant presentations in men.(27) Women with angina are likely to be older than men and to have hypertension, diabetes, and heart failure more commonly. They are also less likely than men to have had either a prior myocardial infarction or a myocardial revascularisation procedure.(28) Investigating chest pain in older women The best non-invasive method of evaluating chest pain to identify coronary heart disease is uncertain in women.(29) Because coronary heart disease is a more likely reason for chest pain in older than in younger women, they have fewer false positive results for exercise tests than at younger ages. However, because of poor physical condition or other illnesses, older women are less likely to perform an exercise test of sufficient intensity and usually require pharmacological radionuclide or echocardiographic imaging. The newer diagnostic procedures - positron emission tomography, magnetic resonance imaging and angiography, and electron beam computed tomography - have not been adequately explored in women of all ages and fewer data are available for elderly women.(29) Risk stratification More women than men have stable angina before their first myocardial infarction. It must be determined whether early risk stratification procedures for women with stable angina might identify a high risk group who could be treated more aggressively, and this might prevent subsequent myocardial infarction.(30) In people aged over 65 with chest pain on exertion the risk of coronary death is not affected by gender (relative risk 2.7 for men and 2.4 for women), and the association is independent of other coronary risk factors.(31) Invasive testing after non-invasive testing In the past decade, knowledge of the adverse outcomes of coronary heart disease in women has increased, and doctors in the United States now carry out objective testing in women with chest pain more promptly than than they used to.(32) However, specific information is lacking for elderly women. In one study of non-invasive testing, the benefit of subsequent myocardial revascularisation was comparable in women and men, but in patients who had not undergone revascularisation procedures, the outcome was poorer in women.(33) A recent evaluation of emergency department care of patients with new onset chest pain showed that in women and men with similar symptoms, women were diagnosed and treated less aggressively.(34) Coronary arteriography seems to be the most important determinant of access to myocardial revascularisation procedures.(35) Differences in performing myocardial revascularisation procedures in men and women in the United States were related only to the underlying severity of coronary obstruction seen at arteriography, which is typically less severe in women.(36) Where coronary angiography showed similar obstruction, revascularisation rates were comparable in women and men, and no sex differences were seen in the rates of coronary events during follow up.(37) Myocardial infarction Hospital mortality from myocardial infarction is higher in women than in men.(38) A recent study showed hospital mortality of 16% for women and 11% for men.(39-40) Although the presentations of myocardial infarction were indistinguishable in women and men, women were not treated as aggressively; they were half as likely to receive acute catheterisation, coronary angioplasty, thrombolysis, or coronary artery bypass surgery. Women who survived had earlier and more frequent recurrence of myocardial infarction, and their mortality at one year was also greater.(39-40) Although sex differences lessen when older age and comorbidity in women are controlled for, they do not disappear. Women who present with myocardial infarction are more likely to have a higher Killip class, tachycardia, atrioventricular block, pulmonary rales, shock, heart failure, recurrent chest pain, and cardiac rupture than are men.(41-43) Coronary thrombolysis In the GUSTO I trial, the survival benefit from thrombolytic treatment for acute myocardial infarction was similar in women and men, even though women had more bleeding as a complication of thrombolytic treatment, particularly intracerebral bleeding and resultant stroke.(44) Nonetheless, the mortality difference between sexes persisted - unadjusted mortality at 30 days was 13% for women and 4.8% for men. The risk of non-fatal complications including shock, heart failure, and reinfarction was also greater in women.(44-45) Women (and particularly older women) commonly present with atypical symptoms of myocardial infarction, and this may partly explain why they receive coronary thrombolysis less often. A more important explanation is that after myocardial infarction they tend to arrive at hospital too late to benefit from thrombolysis. Patients who have had thrombolytic treatment seem more likely to undergo risk stratification subsequently than those who have not. The underutilisation of coronary thrombolysis in women may therefore have a cascade effect. Primary angioplasty Because women have an increased risk of intracranial bleeding with coronary thrombolysis, primary angioplasty is an exciting alternative. In one trial this was associated with less intracranial bleeding and better survival than was coronary thrombolysis.(46) Furthermore, the hospital outcomes of primary coronary angioplasty were equally good in women and men. Drug treatment A recent study of drug treatment for suspected acute myocardial infarction also showed consistently lower use of thrombolytic agents, |gb blocking drugs, and aspirin in women than men, and in elderly patients than younger ones.(47) Although treatment with |gb blocking drugs seems to provide comparable if not better survival after myocardial infarction in women than in men, specific data in elderly women are not available. Risk stratification Whether the current lower rate of risk stratification after myocardial infarction in women is appropriate or not is uncertain. This is particularly so in elderly women, since comorbidity and other features not documented in the available datasets may make them less suitable candidates for myocardial revascularisation. Nor do we know whether more women than men, and particularly more elderly women, refuse these procedures when they are recommended. The thrombolysis in myocardial ischaemia (TIMI III) registry study showed that elderly patients of both sexes had more severe disease shown by angiography, were more likely to be treated medically, and had substantially worse outcomes; the representation of women in an elderly population is disproportionately high. Women had less severe coronary disease than the men and were treated less intensively, but their outcome was comparable; with less severe disease, women should have been expected to have a better outcome.(48) Psychosocial complications Psychosocial complications of myocardial infarction, particularly anxiety, depression, and guilt about illness, are more common in women.(49) Although women resume moderate to heavy housework early in their recovery, they are less likely than men to return to paid work and those who return to work take longer to do so. Myocardial revascularisation procedures Women who have coronary artery bypass graft surgery are generally older than their male counterparts, describe greater impairment of function, are more likely to have severe and unstable angina, and thus are more likely to have urgent or emergency surgery.(50-51) The mortality for this procedure is twice as high in women.(52) Women also have lower rates of graft patency, are less likely to receive an internal mammary artery graft, obtain less relief of symptoms from coronary artery bypass graft surgery, more commonly have infarction and heart failure perioperatively, and are more likely to require reoperation within five years of the initial surgery.(53) As with myocardial infarction, women are more likely to have adverse psychosocial outcomes; however, 15 years after coronary bypass surgery, survival is comparable in women and men.(53) Women referred for percutaneous transluminal coronary angioplasty are older, more often have a history of heart failure and unstable angina, and are more likely to have associated hypertension, hypercholesterolaemia, and diabetes.(54-55) However, the success and safety of the procedure are comparable in women and men.(55-56) Despite the initial good results, relief of symptoms and long term survival are poorer in women, but the latter finding mostly reflects their older age. The newer transcatheter revascularisation procedures have lower success rates and higher complication rates in women, mainly because the devices used are large in relation to the size of the coronary arteries in women. Whether there are sex differences in the rates of restenosis after coronary intravascular procedures is unknown. During the past decade the rates of coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, and other transcatheter revascularisation procedures in women have almost tripled in the United Sates. This is partly related to doubling of coronary arteriography in women and partly to the greater use of revascularisation procedures in elderly people. Conclusion Whether the current more intensive and aggressive evaluation of chest pain syndromes in women in the United States will improve their long term outcomes is unknown. In addition, current assessment of the role of postmenopausal hormone treatment, a risk intervention unique to women, will probably help to guide the management of half of all coronary patients in clinical practice - women - most of whom are elderly. Only as prospectively derived, contemporary information specific to women becomes available can we discover which components of the traditional middle aged male model of coronary disease apply to older women. We can then identify the diagnostic procedures, treatments, and prognoses that apply to their coronary care, which should allow us to improve the outcome for coronary disease in older women. (Accepted 10 September 1997) Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30303, USA Nanette K Wenger, professor of medicine Correspondence to: Professor Wenger nwenger@emory.edu References 1 Wenger N K, Speroff L, Packard B. Cardiovascular health and disease in women. 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