CORONARY ARTERY DISEASE IN WOMEN
From the University of Miami Miller School of Medicine’s Internal Medicine Update 2006
| WHAT’S DIFFERENT ABOUT WOMEN: LESSONS FOR CLINICIANS AND PATIENTS —Maureen
H. Lowery, MD, Professor of Medicine, Division of Cardiology, Department of Medicine, University of Miami
Miller School of Medicine, and Medical Director, Cardiovascular Outpatient Center and Non-Invasive
Diagnostic Laboratories at University of Miami Hospital and Clinics/ Sylvester Comprehensive Cancer Center,
Miami
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| “Go red”: red dress American Heart Association logo for 5-yr campaign to deliver message that heart disease
“number 1 killer in women”; disease behavior and treatment different in women
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| Disease prevalence: leading cause of death in both men and women; exceeds deaths from all cancers combined;
who gets coronary artery disease (CAD)—middle aged men, old men, and old women; mortality
trend—decreasing in men but not in women; new therapies benefiting men but not women; although
prevalence higher in men, more women die of CAD
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| Issue not new: featured on cover of May 1993 Consumer Reports, calling heart disease “number 1 killer in
women”; April 2003 Time magazine announced 1 of 3 women die of heart disease, more than from cancer
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| Facts about mortality: <10% of women recognize heart disease main cause of death; 8 million women in
United States living with heart disease; 38% of women vs 25% of men die within 1 yr of myocardial infarction
(MI); 1 in 5 women now have heart disease; lifetime risk of developing heart disease 32%, breast
cancer 13%; 1 in 30 women die from breast cancer vs 1 in 3 from heart disease
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| Impact of difference: physicians often unaware of problems and fail to follow up abnormal responses to
noninvasive testing; women “not treated equally,” eg, not given β-blockers, angiotensin-converting enzyme
(ACE) inhibitors, aspirin; age dependency as risk factor—greater in women; sharp spike in mortality begins at
65 yr of age; in middle age, 1 in 7 women have some form of heart disease, at ≥65 yr of age, 1 in 3
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| Diabetes: while 66% of men and women die from CAD, diabetes increases risk of CAD 3- to 7-fold in women
vs 2- to 3-fold in men; diabetes or glucose intolerance negates any advantage conferred by sex in premenopausal
women; diabetes raises risk as much as MI; Framingham and Nurses Health Study (NHS) demonstrate
increased risk from diabetes; new cholesterol treatment panel regards risk of diabetes and CAD as equal (goal
of lipid therapy same for both, ie, low density lipoprotein [LDL] cholesterol level <100 mg/dL])
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 | Lipids: high LDL predicts risk in men; low high-density lipoprotein (HDL) predicts risk in women (especially
if triglycerides elevated)
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| Role of menopause: Framingham data showed risk of CAD more closely related to ovarian function than
age; >33% of women’s lives spent in menopause
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| Clinical presentation: influenced by age dependency and menopause; women present with first symptom
10 yr after men and with first MI 20 yr after men
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| Studies misleading: Framingham and catheterization studies found differences in MI and angina; angina
first presenting symptom in 55% of women and 39% of men; men more often presented with MI, and MI
in men more often preceded by angina; by contrast, MI occurred less often in women and less often preceded
by angina; women more likely to have unrecognized (not “silent”) MI; more women with CAD
die; catheterization results—fewer women with angina had obstructive CAD (ie, >70% obstruction in 1
artery); resulting misperception—“that coronary artery disease (angina) is not such a big thing in
women”; consequently, fewer women with angina referred for stress testing
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| Atypical symptoms on presentation: atypical symptoms in men may be typical in women; both sexes
present with—eg, pain and pressure in chest; pain radiating to neck, back, shoulder or jaw; heartburn,
nausea, vomiting, and abdominal pain; cold sweats; typical in women—milder symptoms (without chest
pain); sudden onset of weakness, shortness of breath, fatigue, body aches, or overall feeling of illness
(without chest pain); unusual feeling or mild discomfort in back, chest, arm, neck, or jaw (without chest
pain); symptoms unrecognized—by physicians; do not lead women to visit doctor; women in age group
most likely to have MI not socialized to see doctor because of vague symptoms, so mere fact that
woman presents indicates real problem; electrocardiography (ECG)—findings different in women; QT
interval longer; more nonspecific ST-T wave changes; more poor R wave progression; higher incidence
of incorrect lead placement, resulting in difficult-to-interpret tracings
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| Differences in management: women less likely to be referred for catheterization and revascularization
procedures; less likely to receive medical treatment after MI, eg, aspirin, β-blockers, statins, angiotensin-
converting enzyme (ACE) inhibitors; calcium channel blockers overutilized in women
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| Experience with hormone replacement therapy (HRT): observational studies—found 50% reduction in
cardiac events in menopausal women on estrogen, 80% reduction in women with CAD or post-MI; consequently,
physicians began prescribing estrogen to prevent heart disease (although approved only for
perimenopausal symptoms and osteoporosis); presumed protective mechanism—decrease in LDL and increase
in HDL cholesterol (countering menopause’s negative effect on lipids); clinical trials—designed to overcome
weakness in observational studies in which women less likely to smoke or to be overweight, and more likely
to exercise and visit physician (practices recommended for primary prevention); Heart and Estrogen-progestin
Replacement Study (HERS) looked at older women with heart disease and uterus; Women’s Health Initiative
(WHI) looked at healthy women taking estrogen for perimenopausal symptoms and preventing osteoporosis;
results of HERS-I—reduction in LDL, rise in HDL, and rise in triglycerides; no difference in rate of MI or in
overall mortality; trend toward higher rate of CAD events and deaths in treatment group during first 2 yr; increased
venous thromboembolic events in first 2 yr; HERS-II—follow-up study; also found no overall reduction
in cardiac events; conclusion—do not start or continue HRT to treat or prevent CAD
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| Further thinking on HRT: differences in NHS and WHI—women in NHS younger (30-55 yr of age; perimenopausal);
women in WHI older (63 yr mean age on entry; postmenopausal for >5 yr); more smokers
in WHI (49.9%) than NHS (6.9%); fewer used aspirin in WHI (19.1%) than NHS (43.9%); more overweight
in WHI; suggestive findings on atherogenesis—in nonhuman primates, arteries similar to humans;
animals on high-fat diet underwent surgical menopause; estrogen introduced immediately, and plaque reduced
by 70% in one group; in other group, introduction of estrogen delayed 2 yr, and plaque unchanged;
definition of primary prevention—for vascular biologist, preventing fatty streak from becoming
complicated plaque; for cardiologist, preventing complicated plaque from rupturing; relevant research
findings—estrogen protective in early stages of atherogenesis (decreases LDL oxidation) but prothrombotic
in later stages (enhances endothelial dysfunction and plaque rupture); possible implications of study
results —-introducing estrogen later (in older women) in HERS and WHI may have accelerated plaque
rupture; CAD takes years to develop; effectiveness of HRT may depend on early initiation (as in observational
studies and NHS); suggests “our thinking was correct but our timing was off”
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| Recommendations on therapy: calculate Framingham Global Risk Score for individual women (same
predictive power as calcium score from high-resolution computed tomography [CT]); calculations based
on age, HDL and total cholesterol levels, resting systolic blood pressure, and present smoking status;
provides estimate of 10-yr risk; patient can be classified as high-, low-, or intermediate-risk; guidelines
for therapy based on risk; example—aspirin recommended for high-risk group but not for intermediate-
or low-risk groups; HRT guidelines—exclude use of estrogen with or without progestin to treat or prevent
heart disease; if patients refuse to discontinue estrogen, “tell them it’s okay; just follow them closely”
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| ADVICE ON DIAGNOSIS AND THERAPY —James J. Ferguson, MD, Assistant Professor of Medicine,
Baylor College of Medicine, and Associate Director, Cardiology Research, Texas Heart Institute, St.
Luke’s Episcopal Hospital, Houston; Dr. Lowery
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| Current status of HRT: Dr. Lowery—observational studies under way, including speaker’s trial of estrogen
in young women; guidelines fail to resolve therapeutic issues facing physicians (indications for therapy;
proper dosage; duration of therapy; screening tests before initiating therapy); recommendations
based on existing trial results, ie, no evidence of benefit for CAD and early increased risk; for symptom
relief, lowest dose of estrogen for shortest time recommended, but these parameters not defined
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| Statins in acute coronary syndrome: Dr. Ferguson—lowering LDL cholesterol not focus of therapy in
acute setting at speaker’s institution; high-dose atorvastatin (Lipitor) favored as first-line therapy for lipid
lowering
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| Antiplatelet therapy: Dr. Ferguson—women respond differently (aspirin prevents stroke but not MI in
women; aspirin prevents MI but not stroke in men); trial results suggest antiplatelet drugs may be less effective
in women; effects of dosing differ with clopidogrel [Plavix] and aspirin; with aspirin, no dose effect,
ie, increasing aspirin dose ineffective (antiplatelet effect of 4 g about same as 80-mg dose); with thienopyridines,
dose effect present (antiplatelet effect increases with dose); 75-mg dose of clopidogrel designed to
have same antiplatelet effect as 250-mg bid dose of ticlopidine; raising clopidogrel dose may increase antiplatelet
effect (bedside platelet function testing inadequate for dosing decisions); different dosing needs in
women based on underlying biology, not body weight
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| Stress testing in women: Dr. Lowery—prefers stress echocardiography (with dobutamine if possible; allows
inspection of valves); guidelines specify conventional stress ECG for women ≥65 yr age with normal
ST-T wave on resting ECG or right bundle branch block; financial reimbursement for stress testing in
women requires presence of CAD symptom; Dr. Ferguson—stress testing required if glucose intolerance
suspected
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Educational Objectives
| The goal of this program is to educate the listener about coronary artery disease (CAD) in women. After
hearing and assimilating this program, the clinician will be better able to:
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| 1. Explain the goals of the American Heart Association campaign to increase awareness of heart disease in
women.
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| 2. Recognize symptoms of CAD in women and order diagnostic testing.
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| 3. Prescribe effective drug therapy for CAD in women.
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| 4. Evaluate lessons from studies of hormone replacement therapy.
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| 5. Manage antiplatelet therapy in women.
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Suggested Reading
Alexander KP et al: Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment
elevation acute coronary syndromes. JAMA 294:3108, 2005; Clarkson TB et al: A comparison of tibolone
and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of
postmenopausal monkeys. J Clin Endocrinol Metab 86:5396, 2001; Gierach GL et al: Hypertension, menopause,
and coronary artery disease risk in the Women's Ischemia Syndrome Evaluation (WISE) Study. J Am
Coll Cardiol 47:S50, 2006; Grady D et al: Cardiovascular disease outcomes during 6.8 years of hormone
therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 288:49, 2002; Grodstein
F et al: A prospective, observational study of postmenopausal hormone therapy and primary prevention
of cardiovascular disease. Ann Intern Med 133:933, 2000; Henrikson CA et al: Female sex: a protective
role in suspected myocardial ischemia. Coron Artery Dis 17:153, 2006; Koh KK et al: Controversies regarding
hormone therapy: Insights from inflammation and hemostasis. Cardiovasc Res 2006, 2006; Kyker KA et
al: Gender differences in the presentation and symptoms of coronary artery disease. Curr Womens Health Rep
2:115, 2002; Lanz JR et al: Metabolic syndrome and coronary artery disease: Is there a gender specific effect?.
Int J Cardiol 107:317, 2006; Lemaitre RN et al: Hormone replacement therapy and associated risk of
stroke in postmenopausal women. Arch Intern Med 162:1954, 2002; Lowery MH et al: Noncompaction of
the ventricular myocardium: the use of contrast-enhanced echocardiography in diagnosis. J Am Soc Echocardiogr
16:94, 2003; Macchi L et al: Aspirin resistance: definitions, mechanisms, prevalence, and clinical significance.
Curr Pharm Des12:251, 2006; Quyyumi AA: Women and ischemic heart disease:
pathophysiologic implications from the Women's Ischemia Syndrome Evaluation (WISE) Study and future
research steps. J Am Coll Cardiol 47:S66, 2006; Quyyumi AA: Women and ischemic heart disease: pathophysiologic
implications from the Women's Ischemia Syndrome Evaluation (WISE) Study and future research
steps. J Am Coll Cardiol 47:S66, 2006; Saltiki K et al: Severity of cardiovascular disease in women:
Relation with exposure to endogenous estrogen. Maturitas Feb 4, 2006; Stafford RS: Aspirin use is low
among United States outpatients with coronary artery disease. Circulation 101:1097, 2000; Welty FK: Cardiovascular
disease and dyslipidemia in women. Arch Intern Med 161:514, 2001.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any
significant financial relationship with the manufacturer or provider of any commercial product or service
discussed. The following has been disclosed: Dr. Ferguson—Bristol Myers-Squibb (consulting, honoraria;
speakers bureau); Datascope (research grants; consulting, honoraria); Eli Lily and Company (consulting,
honoraria); Eisai Pharmaceuticals (consulting, honoraria); ESP Pharma/EPL (consulting,
honoraria); Guidant(research grants; consulting, honoraria); Johnson & Johnson (consulting, honoraria);
Sanofi-Aventi (research grants; consulting, honoraria; speakers bureau); Schering-Plough (consulting,
honoraria); The Medicines Company (consulting, honoraria); Therox (consulting, honoraria); Vitatron/
Medtronic (research grants)
Drs. Lowery and Ferguson were recorded at Internal Medicine Update 2006, sponsored by the University of
Miami Miller School of Medicine, January 22-27, 2006, in Key Biscyane, Florida. The Audio-Digest
Foundation thanks the speakers and the sponsor for their cooperation in the production of this program.
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