Women And Coronary Artery Diseases

Women and Coronary Artery Diseases Rashed J. Al-Hamdan MD.

FRCP(C)

General Considerations

General Considerations • There are 2 important challenges for physicians specializing in cardiology and women’s health: (1) To educate women on the risk of CVD, and (2) To update the medical community on the true impact of CVD.

General Considerations • CVD is gaining recognition as a disease that does not discriminate based on sex. • By age 65, the number of deaths from CVD in women surpasses deaths in men by 11%.

General Considerations • Results of a recent AHA survey reveal that many women do not know their risk of CVD.

General Considerations • Among women surveyed, 61% in all age groups and 72% of those between the ages of 25 and 34 years responded that cancer was their primary health concern. • Although the women surveyed considered themselves to be well informed about heart disease, ≤10% considered CVD to be the greatest risk to their well-being.

General Considerations • Many people are familiar with the quoted “1-in-9” statistic for breast cancer. • This is misleading. It refers to the cumulative lifetime risk of developing breast cancer in a woman living past the age of 85. • In 50% of cases, the 1 woman in 9 who will be diagnosed with breast cancer will not develop the disease until 65 years of age.

“Breast Cancer is the REAL issue!” • What about the so called greatest fear for women, the women’s KILLER: BREAST CANCER and lung cancer • In a recent survey, 75% of women identified cancer as their leading cause of death…

Statistics • Heart Disease and Stroke – First and third leading causes of death in US – More women die every year from CVD than from any other cause – Accounts for more than 40% of all deaths

• About 95,000 Americans die of heart disease or stroke each year – Amounts to one death every 33 seconds

• Heart Disease is the leading cause of disability among working adults

Statistics

A Total CVD B Cancer C Accidents

D Chronic Lower Respiratory Diseases E Diabetes Mellitus F Influenza and Pneumonia

Statistics •

Leading Causes of Death for - White Males and Females US: 2000

A Total CVD B Cancer C Chronic Lower Respiratory Diseases

D E F G

Accidents Diabetes Mellitus Alzheimer’s Disease Influenza and Pneumonia

Statistics •

Prevalence of Cardiovascular Diseases in Americans Age 20 and Older by Age and Sex US: 1988-94

Leading causes of Death - USA 2000

General Considerations • Heart disease is far more age dependent in women than in men • Women with CVD are older and have more comorbidities. • Many effective pharmacological and non- pharmacological strategies are underutilized. • There is a lack of gender-specific data on numerous therapies.

General Considerations • Heart disease is on the decline in men but not women highlighting our failure.

Heart Disease is the #1 Killer of Women • Coronary heart disease is the single leading cause of death and a significant cause of morbidity among American women. • In 1997 CHD claimed the lives of 502,938 women (men had less deaths) • Since 1984, CVD has killed more American women than men each year.

In perspective: • 1 in 25 women will die of breast cancer. • 1 in 2 women will die of heart disease.

Economics • In 2001 the US Nationwide cost for all CVD was $300 billion • For heart disease, the cost was $105 billion and for stroke, $28 billion. • Lost productivity due to stroke and heart disease cost more than $129 billion

Are Women Different?

Are Women Different? • Differences between men and women in the circulatory system have been noted for a long time. These differences were attributed mostly to gonadal hormones. • Gonadal hormones alter many pathophysiological processes thought to be fundamental to the development of atherosclerosis, including thrombosis and inflammation

Are Women Different? • Estrogen receptors are present in cardiac myocytes of both males and females, a potential explanation for gender differences in gene regulation.

Are Women Different? • The differences between men and women in atherosclerosis are not limited to gonadal hormones. • Research has shown some major variation in the underlying mechanisms of disease. • In a study, a large population of MI survivors were examined for the presence of 71 single-nucleotide polymorphisms in candidate genes known to be relevant to the pathophysiology of atherosclerosis.

Are Women Different? • Two genes were found to be significantly more prevalent in men— connexin37 and p22phox. • Two different genes were relevant in women—plasminogen activator inhibitor 1 (PAI-1) and stromelysin-1 • The findings suggested that the genetic basis underlying coronary heart disease (CHD) varies by gender.

Are Women Different? • Such genetic differences are manifest in the physiology of atherosclerosis, including: ♦ Plaque components (more cellular and fibrous tissue in women), ♦ Endothelial function (estrogen-induced coronary vasodilation), ♦ Hemostasis (higher fibrinogen and factor VII levels in women).

Are Women Different? • Coronary thrombosis is the most likely cause of MI in both genders (only rarely are infarctions due to spasm or syndrome X). • However, women are twice as likely to have plaque erosion (37% in women vs. 18% in men), whereas men have plaque rupture as the underlying cause of the infarction (82% in men vs. 63% in women).

Are Women Different? • Once the cardiovascular disease is established, the two genders show 2 different compensatory mechanisms. • In increased afterload conditions, women tend to have more vigorous hypertrophy, with greater LV mass, and better preserved systolic function and contractile reserve than men.

Are Women Different? • In ischemic syndromes, animal studies suggest that females show less hypertrophy but also less pathological remodeling and dilation. • Apoptosis and myocyte necrosis in response to aging, injury, or stress are more pronounced in males than in females.

Are Women Different? • Because women are older and have a greater burden of risk factors and concomitant disease, they are more frail and less likely to recover fully from cardiovascular events. • Women, may underestimate the importance of atherosclerotic disease and fail to implement preventive strategies fully or even recognize and act on symptoms appropriately.

CAD in Women

Risk Factors • • • • • • •

DM Hypertension Dyslipidemias Smoking Menopause Obesity Psychosocial Factors

Risk Factors - DM • Diabetes is associated with a greater risk in women, completely eliminating the female gender advantage and increasing their risk by 5 to 7 folds. • The AHA awards double weight to DM in women when calculating CHD risk, similar to the weight given a systolic BP of ≥173 mm Hg, or a cholesterol level of ≥ 8.4 mmol/l or above.

Risk Factors - DM • More than in men, DM increases the mortality of MI in women.

Risk Factors - DM • Type 2 DM is associated with obesity, abdominal body fat distribution, hypertension, dyslipidemia, and insulin resistance, all of which have been associated with higher CHD risk. • This complex of abnormalities, termed "metabolic syndrome”. • It alters hepatic metabolism, lipoprotein levels, and circulating insulin levels

Risk Factors - DM • Obesity and body fat distribution appear to be independent CAD risk factors in women more than in men. • DM is also linked with endothelial dysfunction and platelet abnormalities. • Data from the Diabetes Control and Complications Trial suggest that intensive DM therapy reduces CVD complications in men and women younger than 40 years.

Risk Factors - Hypertension • More than 25 million American women have high BP. • Cardiovascular risk related to hypertension rises steeply with age in females. • Although women have fewer cardiovascular events, the population risk attributable to hypertension is higher for women than men because of the increased incidence with age and the longevity of women.

Risk Factors - Hypertension • Most trials have shown equal efficacy of blood BP lowering to prevent CVD events in men and women. • The JNC-VII includes a single set of guidelines for both men and women. • Although it is clear that hypertension in women should be treated as aggressively as in men, it is possible that the optimal choice of antihypertensive agent may differ.

Risk Factors - Hypertension • In the ALLHAT the superiority of diuretic therapy in the prespecified female cohort, as in the trial as a whole was evident. • The Second Australian National Blood Pressure Study Group found that ACE-I therapy decreased cardiovascular endpoints relative to HCTZ in men but not in women. • However, the numbers of women included in trials are often too small to draw conclusions.

Risk Factors - Lipids • The average lipid profile in women is affected by hormonal status and changes throughout life. • Young women have lower LDL levels and higher HDL levels than men of the same age. • As women age, HDL decreases, LDL increases, along with the risk of CHD.

Risk Factors - Lipids • However, elevated total cholesterol and LDL levels are only weakly associated with CHD in women and only in women ≤ 65 years old. • Instead, HDL is closely and inversely associated with CHD risk. • TGs are an independent predictor of CHD, particularly in older women.

Risk Factors - Lipids • Lipoprotein(a), a composite of LDL, apolipoprotein B-100, and apolipoprotein(a), is also associated with higher cardiac risk in women. • Initial modification of a high-risk lipoprotein profile is generally accomplished by the same life-style changes and medications in men and women, although dietary interventions may be less effective in women.

Risk Factors - Lipids • Multiple trials have demonstrated efficacy of statins, in both primary and secondary prevention of coronary events and death in women with both elevated and normal cholesterol, supporting the theory about the benefits of these agents independent of LDL-lowering effects.

Risk Factors - Lipids • However, women have generally not been included in trials of other classes of lipid-lowering agents. • Also, there are no data from large trials on the efficacy of lipid-lowering agents targeted more specifically at altering the HDL and TGs which appear more important in women.

Risk Factors - Smoking • Tobacco contributes to 17% of all female deaths in the US and results in more deaths from CHD and stroke than any other cause. • This results from a combination of accelerated atherosclerosis and propensity to thrombosis induced by smoking. • Cigarettes have an antiestrogenic effect and induce an unfavorable lipid profile, leading women to lose their "natural" protection.

Risk Factors - Smoking • As a result, there is a six- to nine-fold increased risk of MI among female smokers compared with nonsmokers. • Smoking yields a similar increase in stroke risk. • The combination of smoking and oral contraceptives appears to be particularly potent at increasing the risk of arterial thrombosis.

Risk Factors - Smoking • Currently available methods to assist with quitting may be less effective in women, perhaps because of a greater behavioral component and less nicotine addiction in women. • Environmental exposure to tobacco smoke increases the risk of CVD in women, and assessment of environmental exposure is an important part of risk assessment.

Risk Factors – Menopause • The presence of estrogen in the premenopausal female population is the presumed cause of the obvious protection this group enjoys against cardiovascular events. • The documentation of estrogen receptors in cardiomyocytes and vascular tissues in both men and women led to tremendous enthusiasm for use of postmenopausal hormone replacement therapy ( HRT )as a preventive measure.

Risk Factors – Menopause • The enthusiasm for HRT was further consolidated by multiple observational studies suggesting improved longevity and decreased CVD events in postmenopausals receiving HRT. • However, Multiple randomized controlled trials in the past few years have refuted this hypothesis and provided strong evidence of an increase in cardiovascular risk particularly in the first year after beginning HRT.

Risk Factors – Menopause • That increase in CVD risk was accompanied with increased risk of breast cancer, thromboembolic disease, and stroke, resulting in a withdrawal of prior recommendations.

Risk Factors – Menopause • The results of 2 large trials have left us with few answers and many more questions: ♦ Would alternative formulations of either estrogen or progesterone be of benefit? ♦ Does starting therapy immediately at menopause eliminate risk? ♦ Can genotype predict the risk-benefit profile of estrogen therapy? ♦ If the estrogen hypothesis is a fallacy, what is the underlying cause of the protection in the premenopausal female population?

Risk Factors – Obesity • Excess caloric intake and obesity are a growing epidemic worldwide, and more than 33% of American women are classified as obese. • The Nurses' Health Study revealed a sevenfold higher CVD mortality in the heaviest women. • The Framingham Offspring study demonstrated a dramatic rise in risk factors for cardiovascular disease at body mass indices above 20.

Risk Factors – Obesity The Nurses' Health Study 6

Rel5 ative Risk of 4 CHD Morta- 3 lity 2 1 0 <19

19.021.9

22.024.9

25.026.9

27.028.9

Body Mass Index (kg/m2)

29.031.9

>32.0

Risk Factors – Obesity

Risk Factors – Obesity • The combination of obesity and DM appears particularly deadly in women, as does the pattern of fat distribution. • Abdominal fat accumulation is an important predictor of type 2 DM, hypertriglyceridemia, high BP, and CHD. • Among women, a waist-to-hip ratio greater than 0.88 is predictive of a substantially increased risk of cardiovascular events, as is a waist circumference of more than 38 inches ( 97 cm ).

Risk Factors – Obesity • There is also some evidence linking obesity to myocardial structural and functional alterations related to insulin resistance and to LV volume overload. • These findings could be considered the very early stage of incipient obesity cardiomyopathy. ( Data pertaining to pts with extreme obesity, i.e. BMI of ≥ 40 ).

Risk Factors – Obesity • Physical inactivity is more prevalent among women than men. There is a strong inverse association between physical activity and coronary events in women. • Physical activity also has a strong effect on other cardiovascular risk factors, including hypertension, obesity, and DM. • The effect of regular exercise to increase HDL cholesterol and induce weight loss may be less in women than in men.

Risk Factors- Metabolic Syndrome RISK FACTOR

DEFINING LEVEL

Abdominal Obesity

Waist Circumference

Men Women TG’s HDL Men Women BP Fasting Glucose

>40 inches >35 inches >1.7 mmol/L <1.03 mmol/L <1.3 mmol/L >130/85 >5.55 mmol/L

Risks – Psychosocial Factors. • The interaction of psychosocial and behavioral factors and heart disease is complex and has not been rigorously studied. • Several CVD risk factors are related to behavior (obesity, smoking, exercise), yet modification may be more difficult for women than for men. • Perceived stress and lack of situational control have been found to increase CHD risk in both genders.

Summary of Risk Factors • • • • • • •

DM Hypertension Dyslipidemias Smoking Menopause Obesity Psychosocial Factors

CHD Mortality in Younger Women Women under 65 suffer the highest relative sex­specific CHD mortality 30 25.3 25

Death during Hospitalization (%)

Men 20

24.2

21.8 21.5

Women

18.4

19.1

16.6 15

13.4 11.1 9.5

10

5

2.9

10.7

8.2

7.4 6.1

14.4

5.7 4.1

0 < 50

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85-89

Figure 1. Rates of death during hospitalization for Myocardial Infarction among w omen and men, according to age. The interaction betw een sex and age w as significant (P<0.001).

Evaluation of Females with Suspected CAD

Evaluation of CAD in General • One has to standardize the approach to patients with suspected CAD. • A good understanding of the pathogenesis of CAD is mandatory for any physician who encounters the condition in order to address the underlying problem.

Evaluation of CAD in General • The progression of atherosclerosis is accelerated by three processes: ♦ Endothelial dysfunction, ♦ Inflammation, and ♦ Thrombosis.

• The advanced atherosclerotic lesion has a core of lipid and necrotic tissue surrounded by a fibrous cap. • This cap contains collagen, and its characteristics are related to the risk of plaque rupture, the most common cause of acute coronary syndromes.

Evaluation of CAD in General • Specifically, the thinner the cap, the more likely it is to rupture. • Shear stress at the edge or ‘‘shoulder’’ region of a plaque, inflammation at the endothelial surface of the cap, or internal degradation of the cap by enzymes known as metalloproteinases are other major determinants of the likelihood of plaque rupture. • A ruptured plaque leads very quickly to thrombus formation.

Evaluation of CAD in General

Evaluation of CAD in General • The complete occlusion of a coronary vessel by ruptured plaque manifests as an acute transmural or ST elevation myocardial infarction (ie, STEMI). • Non-occlusive thrombus can cause unstable angina or non–ST elevation MI (ie, NSTEMI). Non-occlusive thrombus may not cause symptoms but, instead, may change plaque geometry, leading to rapid plaque growth.

Evaluation of CAD in General • Typical or classic angina (defined as

exertional substernal discomfort relieved rapidly by rest or NTG) is commonly

due to atherosclerosis in women, particularly older women. • Atypical C/P (exertional substernal

discomfort with atypical radiation or not relieved rapidly by rest or NTG) is less

likely to be associated with angiographic CAD in women, particularly younger women, than in men.

Evaluation of CAD in General • Although equally likely to have effort angina, women with CHD are more likely than men to experience atypical symptoms, e.g. pain at rest, during sleep, or with mental stress. • Also, noncoronary chest pain syndromes are more common in women, further complicating clinical assessment of chest pain in females.

Evaluation of CAD in Women • Chest discomfort, although present in the majority of women when experiencing an MI, is not as predictive in less acute settings. • Noncardiac reasons for chest discomfort should be evaluated only after coronary disease has been ruled out.

Evaluation of CAD in Women • Abnormalities in the coronary circulation caused by microvascular disease, endothelial dysfunction, or abnormalities in coronary flow reserve are being identified as potential causes for symptoms in women but should not to be considered the primary initial focus of a disease evaluation strategy.

Evaluation of CAD in Women • Although most women have typical angiographic findings of atherosclerosis, women have higher prevalences of vasospastic angina, microvascular angina, and abnormal coronary vasodilator reserve. • These syndromes are associated with atypical chest pain, have distinct treatments, and have a more favorable prognosis than epicardial CAD.

Evaluation of CAD in Women • These differences make a genderbased approach essential in the recognition and assessment of acute and chronic ischemic syndromes. • Canto et al in JAMA in 2000 showed that up to 33% of pts with MI had no chest pain. These patients were more likely to be older, or females or diabetics.

Evaluation of CAD in Women • Women with undiagnosed chest pain have a better prognosis than men with chest pain because of a lower prevalence of atherosclerosis in women with chest pain. • However, when a diagnosis of atherosclerotic disease is made conclusively (e.g., by a history of MI), women are at equal and perhaps greater risk for adverse outcomes.

Evaluation of CAD in Women • In subjects older than 65 with exertional chest pain, women and men have the same relative risks of CHD death (2.7 versus 2.4). • Mortality after myocardial infarction is worse in women younger than 60 than that in men, indicating that once an atherosclerotic etiology for the C/P syndrome is identified, the prognosis is no different between the genders.

Evaluation of CAD in Women • The presence of elevated troponin in a woman with unstable angina predicts a worse outcome. • The positive serum troponin predicting a greater increase in risk of death or MI in women than in men.

Evaluation of CAD in Women • Women should be assessed for their overall level of risk for CAD and the severity and nature of symptoms. • Noninvasive testing is best applied to women at intermediate risk. • There are strengths and weaknesses for each of the available imaging modalities, but both nuclear scans and echocardiography have reasonable accuracy and reliability for detecting serious CAD in women.

Evaluation of CAD in Women

Milner Am J Cardiol 1999;84:396

Women have More atypical Symptoms of MI

Evaluation of CAD in Women • Low risk is considered <10% and High risk is considered >80%. • Anything in between is intermediate risk. • It is useless to apply a test to a subject with a pre-test probability of higher than 80% or lower than 10%. • Instead, tests should be for the intermediate risk group.

Evaluation of CAD in Women • One has to choose the best test modality that achieves the best diagnostic results at the lowest cost. • When it comes to women, tests which include a visualization modality like stress nuclear or stress echo are superior to regular stress ECG. • Stress ECG has a high negative predictive value.

Evaluation of CAD in Women • EST is associated with a higher falsepositive rate and a lower false-negative rate than in men (12% vs 40%), suggesting that routine testing reliably excludes the presence of CHD in women with negative tests. • Variables that may alter test accuracy are resting ST-T wave abnormalities, peak exercise HR, number of diseased vessels, age, drug use (digitalis, diazepam), hyperventilation, conduction abnormalities, LVH, MVP, vasospasm, and hormons.

Evaluation of CAD in Women • The addition of imaging to electrocardiographic stress testing markedly improves its accuracy in women, as noted by meta-analyses. • SPECT may not improve accuracy in women as much as it does in men. • Exercise echo improves diagnostic accuracy in women, even more so than in men.

Evaluation of CAD in Women Type of Study

Sensitivity

Specificity

Likelihood Ratio for Positive Test

Likelihood Ratio for Negative Test

Stress Nuclear

0.77 (0.69–

0.71 (0.69–

2.54 (1.95–

0.36 (0.28–

0.81)

0.78)

3.32)

0.46)

Stress Echo

0.82 (0.73–

0.60 (0.48–

2.06 (1.53–

0.29 (0.18–

0.89)

0.71)

2.77)

0.47)

Evaluation of CAD in Women • Women are more likely than men to experience vascular and renal complications from diagnostic angiography, possibly because of more advanced age, higher prevalence of diabetes, and smaller body size. • The incidences of myocardial infarction, stroke, and death complicating coronary angiography are similar in men and women.

Evaluation of CAD in Women • Because of atypical symptoms, women seek medical care later than men and are more likely to be misdiagnosed. • Women presenting with MI and CAD are more likely to be older, have a history of DM, HTN, Hyperlipids, CHF, and U/A than male counterparts. (JACC) • Because of comorbid conditions, there tends to be diagnostic confusion.

Evaluation of CAD in Women • Women were less likely to have an ECG or be admitted to the telemetry floors. • Women are under-diagnosed and can therefore get a false sense of security. • Less ASA, β-B, statins, cath, PTCA Antiarrhythmic Rx, CABG. • Women were less likely to enroll in cardiac rehabilitation after an MI or bypass surgery.

Evaluation of CAD in Women

Prevalence of angiographically significant CAD (70% or more luminal narrowing of one or more major epicardial arteries) CASS trial

Management of CAD in Women

Management of CAD in Women • Women have a different clinical presentation and hospital course following acute coronary syndromes and acute myocardial infarction and respond differently to medical and procedural therapies.

Management of CAD in Women • Women suffering from an ACS or MI are likely to be older; are more likely to have a history of hypertension, DM, unstable angina, hyperlipidemia, and congestive heart failure; and are less likely to be smokers than men. • They are also more likely to experience jaw, neck, and shoulder pain; abdominal pain; nausea; vomiting; palpitations; fatigue; and dyspnea in addition to chest pain and are less likely to report diaphoresis than men.

Management of CAD in Women • Although chest pain is the single most common presenting symptom of MI in women, women seem more susceptible to "silent" MI, particularly elderly women. • At least in part due to these atypical symptoms, women seek medical attention more slowly and even after hospital arrival may experience greater delays in receiving care.

Management of CAD in Women • Women with MI have higher risk initial presentations, with greater prevalences of tachycardia, rales, heart block, and a higher Killip class. • They are less likely to be admitted to a CCU or to be hospitalized in an institution in which catheterization is available.

Management of CAD in Women • Most studies, but not all, find that women with acute MI are less likely to undergo diagnostic catheterization during their hospital stay, even after controlling for age and a variety of clinical characteristics.

Management of CAD in Women • Women have higher rates of inhospital complications from infarction, including bleeding, stroke, shock, myocardial rupture, and recurrent chest pain, than do men, although most of these differences appear attributable to age and comorbidities.

Management of CAD in Women • Mortality in NSTEMI appears to be similar to that in men. • Women with unstable angina are less likely to have angiographic CHD, reinfarction, or death. • In STEMI, early or in-hospital mortality in women is greater than in men, and adjustment for age or clinical characteristics, or both, reduces but does not eliminate this difference.

Management of CAD in Women • This gap may be due to a higher rate of prehospital sudden death in men, but this cannot explain the twofold greater mortality in women younger than 50 years compared with similarly aged men. • Mortality 1 to 3 years after hospital discharge is also increased in younger women, although it is similar in postmenopausal women and men

Management of CAD in Women • Men and women show similar rates of coronary thrombosis on pretreatment angiography. • The efficacy of lysis is equivalent with similar infarct-related artery patency and preservation of LVEF. • Although mortality is similar, complication rates, particularly hemorrhagic stroke and recurrent myocardial infarction, appear to be higher in women.

Management of CAD in Women • Primary angioplasty is equally, if not more, effective in women, in part because of the greater reduction in hemorrhagic stroke. • Despite a greater risk profile in women, PCI is as safe and effective in women as it is in men.

Management of CAD in Women • There are physiological reasons to suspect that women may benefit from use of LMWH and clopidogrel, adequate trial data assessing efficacy in women are unavailable. • Use of GP IIb/IIIa inhibitors confers benefit in addition to that of aspirin in unstable coronary syndromes in women but not in men, provided there is evidence of injury. Women do not appear to benefit in the absence of positive biomarkers.

Management of CAD in Women • Data show the efficacy of stenting to be similar in men and women in both the short and long term. • The likelihood of angiographic success is similar in men and women in newer series, with lower success rates in women reported in older studies. However, the proportional risk of death from procedural complications remains greater in women.

Management of CAD in Women • The difference in outcome has been variously attributed to women's older age, smaller body size, greater severity of angina, more fragile vessels, and greater burden of comorbidity.

Management of CAD in Women • Gender differences in outcome following CABG are well established and, although decreasing, are persistant. • In-hospital mortality is 1.4 to 4.4 times higher, particularly for younger women (<60 years) and low- and medium-risk patients, with no difference in highest risk patients.

Management of CAD in Women • Women are less likely to receive IMA grafts or undergo complete revascularization and are more likely to experience the complications of heart failure, periop. MI, and hemorrhage. • Neurological complications of CABG, including stroke, TIA, and coma, are more frequent in women. • Rehospitalization rates for women are two times those for men in the first 2 months after CABG.

Management of CAD in Women • The causes of higher operative mortality and morbidity appear to be multiple, including technical factors such as smaller body size and coronary diameter, age, comorbidities such as diabetes and hypertension, and clinical factors such as the urgency of the procedure. • Controlling for these factors eliminates only a small portion of the excess risk, with about 70 percent of the risk unaccounted for.

Management of CAD in Women • Women with MI are more likely than men to be treated with nitrates, digoxin, and diuretics and less likely to receive thrombolytics, antiarrhythmics, antiplatelet agents, ACE-I, and BB’s despite evidence for similar benefit in women.

Management of CAD in Women • Although in the CASS, women treated medically had better 12-year survival with angiographically documented zero-, 1-, or 2-vessel disease than men with similar anatomy, other studies suggest that under treatment of women is related to a worse outcome.

Management of CAD in Women • Data from the Heart and Estrogen/progestin Replacement Study (HERS) are the most extensive and distressing. • At the start of the study, only 33% of patients were receiving beta blockers, 53% were receiving lipid-lowering drugs, and 83% were receiving ASA or other antiplatelet agents.

Management of CAD in Women • Women at greatest risk were less likely to be taking aspirin (p < 0.001) or lipid-lowering drugs (p = 0.006). • During the study period, the rate of ASA use by participants actually fell. • Lipid lowering is efficacious in women with atherosclerotic disease, with several statin trials showing reductions in cardiac events and death.

Management of CAD in Women • Diabetic, elderly, and symptomatic women appeared to benefit most, as did women with prior MI. • ASA and other antiplatelet agents also reduced vascular events in women. • Administration of a BB agent clearly provides substantial improvement in post MI survival in women equal to, if not greater than, that in men.

Management of CAD in Women • After hospital discharge, women are less likely to be scheduled for exercise tests or referred for cardiac rehabilitation, and recovery from infarction appears delayed with slower return to work and full resumption of all activities and more sleep disturbance and psychiatric and psychosomatic complaints.

Management of CAD in Women • Now we know that although women present somewhat differently from men who have CAD, they tend to benefit from the same lines of management. • We also know that women as a group, are underserved in the health care systems of almost all developed nations.

Management of CAD in Women • The question is whether there is a modality by which CAD could be prevented in women. • Physiologically, the best and clearest answer was HORMONES. • As it was seen in numerous observational studies, premenopausal women have less CAD.

Women and CAD - HRT • It is important to note that there is a substantial time lapse between study initiation and completion in observational studies, and then again before the data are fully analyzed and presented. A given study, therefore, usually reflects clinical practice of some 5 to 15 years before the date of publication. • It is impossible to eliminate all biases from observational studies. The results, therefore, should be interpreted cautiously.

Women and CAD - HRT • The use of hormonal replacement therapy (HRT) gained scientific approval as a result of multiple observational studies. • In all studies except one, HRT was found to be cardioprotective. • In several studies, the risk was significantly reduced.

Management of CAD - HRT • The general trend indicates more protection in the early studies and less in later trials. • The later studies included more exposure to combined HRT.

Women and CAD - HRT • In the later trials, the estrogen component of HRT was mostly 0.625 mg of conjugated estrogens or equivalent. In contrast, earlier studies reflected the use of higher doses of unopposed estrogen. • A meta-analysis of studies conducted from 1976-1996 showed that postmenopausal treatment with estrogen plus progestin was associated with a similar reduction in CVD risk (RR, 0.66; 95%; CI 0.53 to 0.84) as with ERT alone (RR, 0.70; 95% CI, 0.65 to 0.75).

Women and CAD - HRT • Some observational studies have been conducted in specific high risk patient subpopulations. • Sullivan et al. determined the risk of CVD events with ERT use in women with established CAD. Women who had undergone coronary angiograms were observed for 10 years for estrogen use and survival outcome.

Women and CAD - HRT • After 10 years, survival rates were >96% in women who had received ERT at some time during the 10-year period, regardless of the degree of CAD. • In contrast, in women who had never used ERT, survival rates decreased to around 90% in those with normal coronary arteries, and to 85% and 60% in those with moderate or severe CAD. • These results suggested that estrogen use provided benefit for survival in women with CAD, especially in women with more advanced disease.

Women and CAD - HRT • A drawback to this study was that, although the population initially enrolled was large (2,268 women), only 160 patients remained at the end of the follow-up period. • Non-HRT users were more likely to have CVD risk factors, such as DM, advanced age, and poorer health in general.

Women and CAD - HRT • Newton et al. conducted a retrospective analysis of 726 women (mean age, 66 years) who had survived a first MI, examining the risks of reinfarction and death in relation to ERT use. • The relative risk for both outcomes was lower in current ERT users versus past users, and in both groups versus women who had never used ERT.

Women and CAD - HRT • Adjustment such for factors as DM and CHF did not have a substantial effect on the results. • These findings were not significant, however: For current-user versus never-user subjects, the odds ratios were 0.64 (95% CI, 0.32 to 1.30) for reinfarction and 0.50 (95% confidence interval, 0.25 to 1.00) for death.

Women and CAD - HRT • 3 major prospective trial have examined the effects of HRT on CAD. • These are the: HERS (Heart and Estrogen/progestin Replacement Study), ERA ( Estrogen Replacement and Atherosclerosis) trial, and WHI (Women’s Health Initiative).

Women and CAD - HRT • The HERS trial tested only the effects of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) combination for the secondary prevention of heart diseases in older women. • The ERA trial investigated the effects of CEE or CEE plus MPA on the progression of atherosclerosis.

Women and CAD - HRT • The Women’s Health Initiative (WHI) is a primary prevention trial that is investigating the effects of CEE or CEE plus MPA on the incidence of coronary events.

Women and CAD - HERS • HERS was the first controlled trial to investigate the effect of HRT on the risk for subsequent cardiovascular events in postmenopausal women with established coronary disease. • The mean age of the 2,763 women enrolled was 66.7 years, with an average time since menopause of 18 years. This population was not representative of the typical woman considered for HRT.

Women and CAD - HERS • Subjects were randomized to receive placebo or CEE 0.625 mg/day plus MPA 2.5 mg/day. • A wide range of cardiovascular outcomes were assessed in HERS, including fatal and nonfatal MI, CABG, angioplasty, CHF, angina, stroke, and peripheral arterial disease.

Women and CAD - HERS • There were no significant differences between groups in any of the CVD outcomes. The data showed a null effect of HRT on overall CVD events.

Women and CAD - HERS • Treatment arm was associated with significant effects on the lipid profile, including lower LDL cholesterol and higher HDL cholesterol levels. It was also associated with significantly higher TGs levels (p < 0.001 vs placebo in all 3).

Women and CAD - HERS • A post-hoc analysis of the time trend of relative risks for second coronary events indicated that the risk was greater in the HRT group than in the placebo group in the first year of the trial, similar to placebo in the second year, and then lower than in the placebo group thereafter. This trend was significant (p <0.009).

Women and CAD - ERA • The ERA trial, was a randomized, controlled trial to test the effects of HRT on the progression of CAD. • The primary endpoint of the ERA trial was angiographic change rather than coronary events, to assess the effects of therapy on the underlying progression of atherosclerosis. • This trial was also designed to address the effect of unopposed estrogen. • In addition to the CEE/MPA and placebo groups, a third arm was included to examine the effect of unopposed CEE.

Women and CAD - ERA • The study population in the ERA trial (N 309) was similar to that in HERS: Women older than those typically considered for initiation of ERT/HRT today (average age, 65.8 years) and 2 decades after menopause (average time, 22 to 24 years after menopause), with established CVD.

Women and CAD - ERA • Levels of LDL cholesterol decreased and levels of HDL cholesterol and TGs increased with therapy. • However, at the average follow-up time of 3.2 ± 0.6 years, there was no effect on vessel diameter, or on the secondary outcomes of the percentage of women who developed new lesions or the incidence of cardiovascular events.

Women and CAD - ERA • These results demonstrate an agreement between angiographic markers in the ERA study and clinical outcome in the HERS trial. • Neither CEE 0.625 mg/day alone nor CEE 0.625 mg/day plus MPA 2.5 mg/day offered cardioprotection in this study of secondary prevention.

Women and CAD - ERA • Possible explanations for the lack of a cardioprotective effect are: (1) the older age of the study population, (2) the particular hormone combination that was used, or (3) simply that there was no benefit in terms of secondary prevention for HRT.

Women and CAD - ERA • As in HERS, the ERA trial results emphasize that dyslipidemia and the progression of atherosclerosis are not the only cardiovascular concerns. • Vasospasm, thrombosis, inflammation, and ulcerative effects on current lesions should also be taken into consideration.

Women and CAD - WHI • WHI is a large, complex study designed to examine the primary prevention of CAD breast cancer, fractures from osteoporosis, and bowel cancer among other common causes of mortality and morbidity in women. • There are 2 distinct populations in this study: (1) the observational cohort, which includes approximately 94,000 women, and (2) the clinical trial, which includes approximately 68,000 women enrolled in 3 overlapping components (low-fat diet, HRT, and calcium/vitamin D supplementation).

Women and CAD - WHI • The main aim of the observational study is to gather longitudinan infor-mation from a large cohort of women whose health habits and disease outcomes may reflect longterm trends in US women of similar age. • The observational study will: (1) serve as an external control for the clinical trial, (2) allow exploration of rare diseases, and (3) provide opportunities to examine novel and emerging risk factors for common diseases.

Women and CAD - WHI • The WHI was designed in 1991-1992 using cumulate data and knowledge up till then. • The WHI study enrolled 161,809 postmenopausal women who were 50 to 79 years of age at study entry. Only a small number of women in any WHI component had evidence of CVD when they entered the study.

Women and CAD - WHI • The WHI study includes postmenopausal women who were 50 to 79 years of age at study entry. Only a small number of women in any WHI component had evidence of CVD when they entered the study.

Women and CAD - WHI • Women were divided into those who had and those who had not have hysterectomy. • Women with hysterectomy were eligible for the unopposed estrogen arm, while those with intact uterus were randomized only in the combined estrogen/progesterone arm.

Women and CAD - WHI • 2. 3. 4. 5.

The women were enrolled in a set of trials including: Dietary habits, Vitamin D Supplementation, 2 sets of HRT, and An observational study in 40 centers in the US.

Women and CAD - WHI 16606 Randomized 18845 Provided consent & had no hysterectomy 373092 Women screened initially 8506 Received CEE + MPA

8102 Received Placebo

7968 Alive 307 Unknown 231 Dead

7608 Alive 276 Unknown 218 Dead

Women and CAD - WHI • The trial was stopped early at year 5.2 due to an excess rate of invasive breast cancer in the treatment arm group more than placebo with statistics of risk exceeding benefits.

Women and CAD - WHI

Women and CAD - WHI

Women and CAD - WHI • Blood levels of LDL, HDL and TGs changed in a similar manner as with the HERS. • Systolic blood pressure was 1mmHg higher in the treatment arm at year 1 increasing to 1.5mmHg in year 2. But, the diastolic blood pressure did not change.

Women and CAD - WHI • The overall rate of CVD was low. • The rate of CVD events was 29% higher in the HRT arm and this JUST reached statistical significance. • Most of the change was in the rate of nonfatal MI with n difference in the fatal ones nor in the revascularization rates. • Stroke rates and VTEs were also higher in the HRT arm.

Women and CAD - WHI • For every 10,000 women taking HRT for a year there will be: 7 more CHD events, 8 more invasive breast cancer cases, 8 more strokes, and 8 more pulmonary emboli 6 fewer colorectal cancers, and 5 fewer hip fractures

Women and CAD - WHI • Although the absolute risks for women’s health are small, the reality is that more women taking HRT will do more harm than good to their health. • Based on these results and untill further issues are addressed, we should refrain from prescribing HRT for long term use.

Women and CAD - WHI • Primum non nocere. • What about short term use? • The results suggest an increases absolute risks of CVD and VTE events with short term use ( ≤1 year ). • The possibilities of these short term results must be weighed against the benefits of alleviating menopausal or osteoperotic symptoms.

Women and CAD – Now What? • Women have their unique physiopathology when it comes to CAD. • They present differently, at different means of age than men and tend to be more vague in terms of their symptoms. • They usually require a different lines of diagnostic work-up.

Women and CAD – Now What? • Women also respond generally to the same treatment modalities like men with few exceptions. • The problem with women is us physicians. • As a group, they are underrepresented in clinical trials, underdiagnosed in the ERs, and undertreated in CCUs.

Women and CAD – Now What? • Prevention, prevention, prevention. • CAD is the No. 1 women killer despite them thinking otherwise. • Womn do much worse than men when they have the disease, it is thus more prudent to prevent them from getting it in the first place. • Prevention is the key. • HRT is a no no, until further notice.

Women and CAD – Now What? • Exercise for 30-45 mins of walking 5x’s/week reduces risk of MI in women by 50%. • It helps control BP, increases HDL, decreases body fat, DM risk, possibly prostate, breast and uterine cancers. • Life style modifications include smoking cessation, weight reduction, reduction of alcohol intake.

Women and CAD – Now What? • When you get a woman with a high risk score of CAD, be aggressive in the diagnosis as well as in the treatment. • Spend enough time with the patient. Your patient can help you a lot in taking care of his or her health if he/she knew what to do and what not to do.

Women and CAD – Now What? • An individualized approach based on cardiovascular risk• First-Assess and stratify women into high, intermediate, lower/optimal risk categories. • The aggressiveness of treatment should be linked with your risk of having a heart attack or event in the next 10 years- based on the Framingham Heart Study.

Framingham Risk Score • You get points for: • Age • Total Cholesterol • HDL Cholesterol • Smoking • Systolic Blood Pressure

• Add these numbers --you get a 10 yr CHD risk % (category):

Low Risk • A. Low Risk : 10% or less risk of having a heart attack or dying of heart disease in the next 10 years. • May include women with multiple risk factors, Metabolic Syndrome, or 1 or no risk factors.

Low Risk • Low Risk Women <10%: • Class I recommendations: Intervention is useful and effective: • Lifestyle Interventions” Smoking Cessation Physical Activity Heart Healthy Diet- DASH Diet Weight Reduction Treat Individual CVD risk factors

Intermediate Risk • Those with a 10-20% chance of a heart attack in the next 10 yrs. • Pts with the obesity, multiple risk factors, marked elevations of a single risk factor, first degree relative with CHD (male<55, female<65)

Intermediate Risk • Intermediate Risk Women (10-20%): Smoking Cessation Physical Activity Heart Healthy Diet- DASH Diet Weight Reduction Control BP and Lipids • Class Ila- most scientific evidence favors this type of therapy: ASA Rx-as long as BP is controlled (hemorrhagic stroke) and minimal risk of GI bleed

High Risk • 2. 3. 4. 5. 6.

You are automatically considered high risk if you have: PAD CRF AAA DM History of stroke

High Risk • High Risk Women (>20%): Class I Smoking Cessation Physical Activity/cardiac rehab Heart Healthy Diet- DASH Diet Weight Reduction Control BP and Lipids- statin ASA therapy β blocker therapy-esp in all s/p MI ACE-I or ARBS Glycemic control in DM

Women with Diastolic Heart Failure

Women and DHF • Most men with CAD have depressed heart function while most women have PRESERVED heart function. • In the Cardiovascular Health Study (CHS), a populationbased observational study of CVD risk in the elderly, CHF prevalence increased in women from 4.1% at age 70 years to 14.3% at age 85 years.

Women and DHF • During 6 years of follow-up, the incidence of CHF in CHS was 10.6/1000 personyears at age 65 and was 42.5/1000 person-years at age ≥80 years. • Women who develop HF,particularly those in the older age range, frequently have preserved LVEF, a syndrome commonly termed diastolic heart failure.

Women and DHF

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Prevalence of CHF vs. age in elderly men (dark bars) and women (light bars) in the Cardiovascular Health Study.

Women and DHF

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Numbers of patients in Olmsted County Minnesota hospitalized with CHF in 1991 vs. age with normal (dark bars) and reduced (light bars) LVEF.

Women and DHF • There is a remarkable sex-related difference in DHF. • In the cross-sectional analysis of CHS, 67% of elderly women with prevalent CHF had a normal EF, whereas this finding was present in only 42% of men.

Women and DHF • During the longitudinal analysis of 6year follow-up in CHS, over 90% of women who developed heart failure had normal systolic function. • Since women significantly outnumber men in the older population, the population-attributable risk of reduced systolic function was relatively small compared with those with normal systolic function.

Women and DHF • Other large population-based reports, including the Framingham Heart Study, the Strong Heart Study of American Indians, the Helsinki Ageing Study, and large Medicare studies, have found a similarly profound sex differential in this disorder.

Women and DHF • Thus, the typical person with heart failure living in the community is an older woman with normal LVEF and systolic hypertension. • This contrasts significantly with the typical patient seen in referral heart failure clinics, who is a middle-aged man with severely reduced LVEF and CAD.

Women and DHF • Relatively few data are available regarding the pathophysiology of DHF, and even fewer regarding women specifically. • Three large populationbased studies – Framingham, CHS, and HyperGEN (Hypertension Genetic Epidemiology Network) – have reported that Doppler LV diastolic filling velocities are significantly different in women compared with men, with increased early and atrial filling velocities in women.

Women and DHF • Women, particularly older women, tend to have higher LVEFs, independent of their smaller chamber size. • The female LV in mammals has a distinctly different response to pressure load, such as is typical of hypertension, compared with males.

Women and DHF • Evaluation of new-onset heart failure in an elderly patient should include an imaging test, usually an echo. • This will not only assess systolic function, but will also exclude unexpected but important diagnoses, such as AS, severe regurgitant lesions, HCM, …,etc. • However, a definitive noninvasive measure is not available for diastolic dysfunction.

Women and DHF

Diastolic indexes included: 1--transmitral early (E) and late (A) velocities and early deceleration time (DT); 2--pulmonary vein systolic (S), diastolic (D), and atrial reversal (AR) velocities; 3--systolic (Sa) and early (Ea) and late (Aa) diastolic mitral annular velocities measured from TDI of the septal annulus; 4--the velocity of propagation (Vp) of early filling (from mitral annulus to left ventricular apex) measured from the slope of the first aliasing velocity.

Women and DHF • The severity of exercise intolerance and the frequency of hospitalization appear to be similar in patients with SHF versus DHF. • This high rate of hospitalization is associated with poor quality of life and high health-care costs.

Women and DHF • The annual mortality rate for diastolic heart failure in the Framingham Study was 8.9% per year, a rate about half that reported for systolic heart failure (19.6%). Similar results were found in CHS. • However, in hospitalized patients, mortality is similar with DHF and SHF.

Women and DHF • The approach to the patient with heart failure and a normal EF should begin with a search for a primary etiology. • Most such patients will be found to have hypertension as their main underlying condition. • Of course, if one found an underlying cause like CAD or HCM, adequate control of this factor is of paramount importance.

Women and DHF • Control of hypertension may be the single most important treatment strategy for DHF. • Meta-analyses indicate that therapy of chronic, mild systolic hypertension in the elderly is a potent means of preventing the development of heart failure, and it is likely that a major proportion of cases prevented are due to DHF

Women and DHF • Management goals in women with DHF include relief of symptoms, improvement in functional capacity and quality of life, prevention of acute exacerbations and related hospital admissions, and prolongation of survival.

Women and DHF • Drug used are diuretics, digoxin, ACE-I, ARB, CCB. • Although BB are used in the treatment of hypertension, their role in DHF is still awaiting delineation because they impair early myocardial relaxation. • The use of aldosterone antagonists, although important in SHF, it is till not well established in DHF.

Women with Systolic Heart Failure and PPCMP

Women and SHF-PPCMP • More than half of all patients in the US with heart failure are women. • Among persons older than 70 years, the incidence of CHF in women is higher than in men, with the largest increase in prevalence occurring in the 65–74-yearold age group.

Women and SHF-PPCMP • The incidence of heart failure in women, however, has declined in the past 40 years, perhaps due to better BP control or perhaps due to a reduction in rheumatic heart disease. • The incidence in men during the same period has remained unchanged.

Women and SHF-PPCMP

Prevalence of congestive heart failure by sex and age according to National Health and Nutrition Examination Survey, 1999–2002.

Women and SHF-PPCMP • Hypertension is a stronger risk factor for the development of HF in women than in men. • Although the incidence of MI is lower in women, women who sustain an MI are more likely to develop CHF, (46%) compared with men (22%). • In addition, DM is a more potent risk factor in women than in men for the development of CHD, and diabetes increases the risk of death following an acute MI.

Women and SHF-PPCMP Differences in characteristics between women and men in several heart failure trials and in a specialty CHF clinic.

Women and SHF-PPCMP • In the early literature, there were conflicting data regarding the survival of women with CHF. • More recent data suggest that mortality has been is lower for women with heart failure in several large clinical trials following adjustment for differences in baseline variables.

Women and SHF-PPCMP • Treatment of CHF in women is the same as in men with some cautions. • Women tend to get more side effects out of the ACE-I and ARB is good for them. • Digoxin is good to reduce admissions and not to improve mortality. Serum levels should be kept below 1.0 ng/ml.

Women and SHF-PPCMP • PPCMP can be defined as an unexplained LV systolic dysfunction confirmed by echo and developing in the last month of pregnancy or within 5 months of delivery. • It requires that there be no other identifiable cause for the HF and that the LV systolic dysfunction be demonstrated echocardiographically.

Women and SHF-PPCMP • A consensus opinion was of an incidence of between 1 in 3000 and 1 in 4000, which gives an estimated 250–300 cases each year in the UK. • This would make it far more common than is generally realized. • The apparent rarity of PPCM in the developed world and the near certainty of serious under-reporting of it have made it difficult to study.

Women and SHF-PPCMP • Diagnostic Criteria: • Development of cardiac failure in the last month of pregnancy or within 5 months of delivery • Absence of another identifiable cause • Absence of identifiable heart disease before the last month of pregnancy • LV systolic dysfunction demonstrated by echocardiography • • EF less than 45% or • • M-mode FS less than 30% or both and • • EDD more than 2.7 cm/m2

Women and SHF-PPCMP • Etiology: Myocarditis? Autoimmunity? Infection?

Women and SHF-PPCMP • • • • •

Diagnosis: CHF Embolism Arrhythmias Chest pain

Women and SHF-PPCMP • Diagnosis Same as CHF

Women and SHF-PPCMP • Treatment: Same Anticoagulation!! Recurrence in future pregnancies ( as high as 21% ). Mortality is higher when LVEF is not fully recovered. Continue meds for 1 year after recovery! Future pregnancies and contraception.

Women and SHF-PPCMP

Women and SHF-PPCMP

Women and SHF-PPCMP

Women and SHF-PPCMP

Women and SHF-PPCMP

Women and SHF-PPCMP