Transcript Ischemic Heart Disease in Women

Examining the Treatment and Management
of Ischemic Heart Disease in Women
John E. Clark, PharmD, MS, FASHP.
Clinical Consultant
Clinical Pharmacare Solutions, LLC
Learning Objectives





Review the prevalence of ischemic heart disease
(IHD) in the US
Discuss economic impact of suboptimal diagnosis
and management of IHD
Examine gender differences in clinical presentation
and diagnosis of IHD
Identify limitations to the diagnosis and
management of IHD
Review current and proposed IHD management
strategies according to individual patient
presentation
‡
Since 1984, Women Are the Majority
Impacted by Cardiovascular Disease
Deaths in Thousands
550
500
450
450
350
79
80
85
Males
90
Years
95
00
06
Females
CVD mortality trends for males and females (United States: 1979-2006). Source: NCHS. The overall comparability
for CVD between the ICD/9 (1979-1998) and ICD/10 (1999-2006). No comparability rations were applied.
Lloyd-Jones et al. Circulation. 2010;121:e46-215 ..
‡
Coronary Artery Disease
in Men and Women
Total men
N (%)
Total women
N (%)
P-value
Normal coronaries
1437 (9.8)
2154 (23.6)
<0.01
Mild CAD
1677 (11.5)
1466 (16.1)
<0.01
1-vessel disease
4092 (27.9)
2010 (22.1)
<0.01
2-vessel disease
(with prox LAD)
722 (4.9)
293 (3.2)
<0.01
All other 2-vessel
disease
1553 (10.6)
640 (7.0)
<0.01
3-vessel disease
3291 (22.5)
1176 (12.9)
<0.01
Left main disease
519 (3.6)
235 (2.6)
<0.01
Low risk CAD
7873 (63.5)
5941 (77.7)
<0.01
Severe CAD*
4532 (36.5)
1704 (22.3)
<0.01
*Severe CAD includes left main stenosis 50%, three-vessel disease with 70% stenosis or two-vessel disease
including proximal left anterior descending stenosis of 70%.
Kreatsoulas et al. J Intern Med. 2010;268:66-74.
Angina Increases the Cost of
CAD Care
CAD Without Angina
CAD With Angina
Health Care Costs for Patients
With Angina Are Twice as High
Patients With Angina Were More
Likely to Visit Emergency Room &
Be Hospitalized
Average Annual Cost
per Patient, US$
$22,004
20000
15000
$11,530
10000
5000
0
Proportion of Patients During the
Year Following Diagnosis, %
25000
50
43%
40
27%
30
20
12%
10%
10
0
Emergency
Hospitalizations
Room Visits
This claims-based analysis consisted of 140,001 managed-care patients with CAD and 25,535 patients
with a diagnosis of angina and multiple prescriptions of antianginal medications between 2001 and 2004.
5
CAD = coronary artery disease.
Kempf J, et al. Circulation. 2006;113:e810. Abstract P114.
Ischemic Heart Disease in Women
Is Associated with
Significant US Healthcare Costs

Five year CV death or
MI rates (P<0.0001)
 Non-obstructive
CAD: 4%
 3 Vessel CAD: 38%
Five year rates of
hospitalization for
angina (P<0.0001)
 Non-obstructive
CAD: 20%
 3 Vessel CAD: 55%
Shaw LJ, et al. Circulation. 2006; 114:894-904
Five-Year Cardiovascular Costs
Observed Direct Cost in 2003 $

$60,000
$48,000
$50,000
$40,000
$51,000
$53,398
$32,239
$30,000
$20,000
$10,000
$0
Nonobstructive 1 Vessel CAD 2 Vessel CAD 3 Vessel CAD
CAD
Women Have More Adverse Outcomes
Compared to Men
Angina
~2x  morbidity/mortality1
MI
~1.5x  1-year mortality1
CAD
Heart failure
~2x  incidence1
1Pepine.
J Am Coll Cardiol. 2004;43:1727-1730.
et al. Circulation. 2002;105:1176-1181.
2Vaccarino
CABG
~2x  morbidity/mortality2
Women with Ischemic Heart Disease

Women are more likely than men to have non chest pain
symptoms of ischemic heart disease (IHD)

Angina is the predominant initial and subsequent presentation
of IHD in women (versus MI, sudden death in men)

When presenting with initial MI, women are more likely than
men to have had antecedent stable angina

Compared to men, women presenting with IHD
 Older
  Hypertension, diabetes, heart failure
  Likelihood prior MI, myocardial revascularization

Population-based studies: comparable prevalence of stable
angina in both women and men
Wenger. Curr Cardiol Report. 2010;12(4):307-314.
Chronic Stable Angina
Chronic Angina Overview

Classic angina is characterized by discomfort or
pain in the chest, jaw, shoulder, back, or arm

Anginal symptoms typically occur with exertion or
psychological stress and are relieved by rest or
nitroglycerin

There is increasing awareness that symptoms of
ischemia frequently manifest differently in women,
the elderly, and in patients with diabetes
10
Alexander KP, et al. J Am Coll Cardiol. 1998;32:1657-1664; Ellis K, et al. Manual of Cardiovascular Medicine. 2nd ed. 2004;
Gibbons RJ, et al. J Am Coll Cardiol. 2003;1-126; McSweeney JC, et al. Circulation. 2003;108:2619-2623.
Burden of Chronic Angina in the U.S.

More than 10 million Americans have chronic angina1
 500,000 new cases diagnosed per year
•
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213 per 100,000 annual incidence in > 30 year-age group2
~50% experience angina as the initial sign of CAD2
~50% of patients diagnosed with MI have prior angina2
Angina post-revascularization is not uncommon2
 At 5 year follow-up point, > 25% of patients
experience angina despite PCI and optimal medical
therapy for CAD & angina3
W, et al. Heart Disease and Stroke Statistics – 2009 Update. Circulation. 2009;117:e1-e161.
RJ, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable
angina. P5. Available at: http://acc.org/qualityandscience/clinical/guidelines/stable/stable_clean.pdf
3 Boden WE, et al. Optimal Medical Therapy with or without PCI for Stable Coronary Disease. N Engl J Med.
2007;356:1510.
1 Rosamond
2 Gibbons
11
Symptoms of Chronic Angina
Affect Patient Activity
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Patients with angina may curtail activity to avoid
anginal episodes
 Physical exertion & emotional stress trigger
angina
 Many patients consider angina a warning to slow
down
Patients with CAD and anginal symptoms score
lower on the angina pectoris QOL questionnaire than
those without symptoms
Sedentary patients may have significant CAD but
may not report anginal symptoms because of their
lack of activity
CAD = coronary artery disease; QOL = quality of life.
Chestnut LG, et al. Med Decis Making. 1996;16:65-77; Maddox TM, et al. Arch Intern Med. 2008;168:1310-1316;
Marquis P, et al. Eur Heart J. 1995;16:1554-1560.
12
Symptoms Other Than Classic Anginal Chest
Pain Are Common in
Stable Ischemic Heart Disease
• In addition to chest pain or discomfort, other symptoms
of ischemia on exertion are common, including:
•Shortness of breath
•Fatigue, weakness
•Lightheadedness
•Diaphoresis
•Nausea, indigestion
• Symptoms of ischemia other than chest pain are
referred to as anginal equivalents
• Women, the elderly, and patients with diabetes are more
likely to present with non-pain symptoms
132004;
Alexander KP, et al. J Am Coll Cardiol. 1998;32:1657-1664; Ellis K, et al. Manual of Cardiovascular Medicine. 2nd ed.
Gibbons RJ, et al. J Am Coll Cardiol. 2003;1-126; McSweeney JC, et al. Circulation. 2003;108:2619-2623.
Pain Symptoms Occur at the
End of the Ischemic Cascade
Magnitude of Ischemia
Pain/Angina
0
ECG 
 Diastolic
ST alterations
Filling
 Contraction
 Relaxation
Biochemical
Alterations
Systolic
Dysfunction
Diastolic
Dysfunction
Stress Duration (sec)
ECG = electrocardiogram.
Adapted from Kern MJ. In: Braunwald’s Heart Disease. 7th ed. 2005.
30
14
Myocardial Ischemia:
Unbalanced Oxygen Supply and Demand
Coronary
Blood Flow
Contractility
Oxygen
Supply
Oxygen
Demand
Heart Rate
LV Wall Tension
Coronary Perfusion
Pressure
Systolic Volume
Pressure Overload
Coronary
Vascular
Resistance
External
Compression
Intrinsic
Regulation
Ischemia
LV = left ventricular.
Kern MJ. In: Braunwald’s Heart Disease. 7th ed. 2005. Naik H, et al. In: Lilly L, ed.
Pathophysiology of Heart Disease. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins;
2007:141-167.
15
Angina Disease Severity Classification
Angina Classification:
The Canadian Cardiovascular Society Grading System
www.ccs.ca. Accessed 5/8/11.
Frequency of CCS Class Angina
Symptoms According to Sex and Age
Women with severe CAD (by angiography) were more likely to have
CCS Class IV angina (56.7%) compared to men (47.8%), p<0.01
Severe CAD
Total patients
Male
Female
All
female
<60
years
60
years
<60
years
60
years
N = 13 933
N = 8621
N = 1326
N = 3066
N = 332
N = 1319
CCS Class 0-II
angina
31.2%
29.3%
23.0%
23.8%
18.7%
17.7%
CCS Class III
angina
24.8%
27.8%
27.9%
29.0%
26.8%
25.1%
CCS Class IV
angina
44.0%
42.9%
49.1%
47.2%
54.5%
57.2%
All male
CCS Angina
class
Kreatsoulas et al. J Int Med. 2010;268(1):66-74.
Angina, Health Status, and 2-Year Survival
Observational study of 5558 CAD patients to evaluate the prognostic utility of
the Seattle Angina Questionnaire (SAQ)
2-Year Kaplan-Meier Survival Curves by
Range of SAQ Physical Limitation Score
Survival, %
100
95
90
Severe
Moderate
Mild
Minimal
85
p < 0.0001
80
0
6
12
18
Time (Months)
24
SAQ scores were predictive of time to death throughout the 2-year follow-up period
SAQ = Seattle Angina Questionnaire.
Spertus JA, et al. Circulation. 2002;106:43-49.
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Diagnosis
Diagnosis of Stable Ischemic Heart Disease May
Be More Challenging in Women Than in Men


Women describe symptoms of exercise-induced
ischemia differently than men
In an analysis of 132 patients with evidence of
ischemia on myocardial perfusion imaging, women
reported more non–pain symptoms than men
Men
n = 94
Women
n = 38
Shortness of breath
67%
76%
Fatigue
52%
66%
Tightness in chest
45%
55%
Palpitations
26%
50%
Weakness
23%
40%
Most Common Non-pain
Symptoms Reported by Women
21
D’Antono B, et al. Am Heart J. 2006;151:813-819.
Hypothetical New Understanding of
Ischemic Heart Disease in Women
Shaw et al. J Am Coll Cardiol. 2009;54:1561-1575.
Diagnostic Accuracy in Women
of Non-Invasive Testing in Obstructive CAD
Diagnostic Test
N (% Women)
Sensitivity
Specificity
9567 (38.9%)
61%
70%
Stress
Echocardiogram2
991 (100%)
81%
84%
MPI with SPECT3
130 (100%)
91%
86%
MPI with PET4
877 (31.6%)
90%
89%
CAC/ CT4
1650 (27.6%)
83%
92%
Exercise ECG1
1Kwok
et al. Am J Cardiol. 1999;83:660-666.
et al. J Am Coll Cardiol. 2003;42:954-970.
3Amanullah et al. Am J Cardiol. 1997;80:132-137.
4Di Carli et al. Circulation. 2007:115:1464-1480.
2Cheitlin
‡
Typical Angina Is Less Accurate and Precise At
Indicating Coronary Artery Disease in Women*
Age
Nonanginal
Chest Pain
Atypical
Angina
Typical Angina
Year
Men
Women
Men
Women
Men
Women
30-39
5.20.8
0.80.3
21.82.4
4.21.3
69.73.2
25.86.6
40-49
14.11.3
2.80.7
46.11.8
13.32.9
87.31.0
55.26.5
50-59
21.51.7
8.41.2
58.91.5
32.43.0
92.00.6
79.42.4
60-69
28.11.9
18.61.9
67.11.3
54.42.4
94.30.4
90.61.0
* Each value represent the percent  standard error of the per cent, calculated from the prevalence of angiographic
coronary-artery disease in symptomatic patients and the prevalence of coronary-artery stenosis at autopsy.
Diamond and Forrester. New Engl J Med. 1979;300:1350-1358.
Assessment of Myocardial Ischemia and
Obstructive Coronary Disease in Women

Utility of the Exercise ECG in Women
 Up to 50% women cannot achieve >5 mets of exercise
 Exercise ECG variables include – exertional chest pain,
ST segment duration and treadmill time
•
Exercise capacity in an independent predictor of death in
asymptomatic women
Author, Year (Ref.)
Exercise
Electrocardiography
Stress
Echocardiography
Stress SPECT
Sensitivity Specificity Sensitivity Specificity Sensitivity Specificity
(%)
(%)
(%)
(%)
(%)
(%)
Fleischmann et al.,
1998 (143)
–
–
85
77
87
64
Kwok et al., 1999 (146)
61
70
86
79
78
64
Beattie et al., 2003 (143)
–
–
81
73
77
69
Average
61
70
84
76
81
66
Makaryus AN et al. Cardiology in Rieview 2007;15:279-287
In press . Leuzzi C. Nutr Metab Cardiovasc Dis 2010 .
Outcomes
Women Ischemic Syndrome Evaluation
(WISE) Study
Objective
Evaluate status and prognosis of women referred for coronary
angiography
Design
NIH-NHLBI-sponsored, four center, observational study
Population
673 women with chest pain undergoing angiography for suspected
ischemia
Data
Collected
Demographic and clinical data, symptom and psychosocial
variables, coronary angiographic and ventriculographic data,
brachial artery reactivity testing, resting/ambulatory
electrocardiographic monitoring and a variety of blood
determinations
Observation
Period
One year or more of follow-up
27
CAD = coronary artery disease; NHLBI = National Heart, Lung and Blood Institute; NIH = Nationals Institutes of Health.
Johnson BD, et al. Eur Heart J. 2006;27:1408-1415; Reis SE, et al. Am Heart J. 2001;141:735-741.
WISE: Persistent Chest Pain in Women
Predicts Future CV Events
Event-Free Survival, %
1
N = 673 women with chest pain at baseline
0.9
Without CAD
HR 1.89 (1.06–3.39)
p = 0.03
0.8
0.7
0.6
0
1
2
3
4
5
Years From PChP Diagnosis (at 1 y)
Neither
PChP
No CAD
No PChP
CAD
6
With CAD
HR 1.17 (0.76–1.80)
p = 0.49
PChP
CAD
Women with no evidence of epicardial obstructive disease by angiography and
persistent chest pain were at higher risk for future cardiovascular events
28
HR = hazard ratio; PChP = persistent chest pain; WISE = Women Ischemic Syndrome Evaluation. Johnson BD, et al.
Eur Heart J. 2006;27:1408-1415.
‡
Five Year Rates of Cardiovascular Outcomes:
Asymptomatic Women versus Symptomatic Women
Symptomatic Women (WISE)
Asymptomatic
Women (WTH)
(n=1000)
Normal Coronary
Arteries (n=318)
(0% stenosis)
Nonobstructive CAD
(n=222)
(1-49% stenosis)
Adjusted
P Valuea
Adjusted
P Valuec,b
MI, %
0.7
0.9
3.9
.07
.31
Hospitalization for CHF, %
0.3
3.3
5.6
<.001
.002
Stroke, %
1.0
2.4
5.2
.002
.004
Death due to CV, %
0.6
1.5
4.4
.11
.82
All-cause mortality, %
2.1
3.0
8.2
.04
.74
Primary composite end
point, %c
2.4
7.9
16.0
<.001
.002
Secondary composite end
point, %d
3.9
9.1
19.1
<.001
.008
CAD, coronary artery disease; CHF, congestive heart failure; CV, cardiovascular causes; MI, myocardial infarction; WISE, Women’s
Ischemia Syndrome Evaluation: WTH, St James Women Take Heart Program
aAdjusted
for age, race, body mass index, systolic blood pressure, diabetes mellitus, education, employment, family history of CAD,
smoking history, and the metabolic syndrome.
bCompares the WTH cohort with the WISE cohort who had normal coronary arteries.
cConsists of MI, hospitalization for heart failure, stroke, or cardiovascular death.
dConsists of MI, hospitalization for heart failure, stroke, or death due to any cause.
Gulati et al. Arch Intern Med. 2009;169(9):843-850.
Management Strategies
Treating Chronic Angina:
What are the Goals?
…the goal of treatment should be complete, or nearly
complete, elimination of anginal chest pain and return
to normal activities and a functional capacity of CCS
class I angina … with minimal side effects of therapy.
Gibbons RJ, et al. ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina.
Management of Chronic Stable Angina
Lifestyle
Intervention
Prevent Death
& MI
Revascularization
Pharmacotherapy
Reduce
Symptoms
CAD = coronary artery disease.
Evidence-based Therapies
for Risk Reduction
Gibbons RJ, et al. J Am Coll Cardiol. 2003:1-126.
32
Anti-ischemic Strategies for
Managing Angina
Initial Therapy
Pharmacotherapy
PCI
CABG
Persistent or Recurrent
Ischemia
 Antianginal Drug Therapy
(up-titrate/add additional agents)
Repeat Revascularization
(if possible)
CABG = coronary artery bypass graft; PCI = percutaneous coronary intervention.
Gibbons RJ, et al. J Am Coll Cardiol. 2003;41:159-168.
33
Pharmacotherapy for
Chronic Stable Angina

Disease-Modifying Therapies to Prevent MI and Death





Aspirin
Statins
ACE inhibitors/ARBs
Beta-blockers*
To Relieve Angina and Reduce Ischemia



Beta-blockers
Calcium channel blockers
Nitrates
•*For patients with previous MI and/or LV dysfunction
Smith SC Jr, et al. Circulation. 2006:113;2326-2372.
Gibbons RJ, et al. ACC/AHA 2002 guidelines. www.acc.org/qualityandscience/clinical/guidelines/stable/stable_clean.pdf.
Classes of Antianginal Drugs
Therapeutic Class
Proposed Mechanism of Action
Beta-blockers
Decreases myocardial oxygen demand by blocking ionotropic
and chronotropic effects of catecholamines, and by
decreasing blood pressure
Calcium channel
blockers*
Vasodilation; decrease myocardial oxygen demand, increase
oxygen supply
Long-acting
nitrates
Vasodilation; decrease myocardial oxygen demand, increase
oxygen supply
Proposed Mechanism of Action
Other
Late sodium current inhibition
ATP-sensitive potassium channel (KATP) opener
Sinus node inhibition
*Actions of the individual drugs in this class vary.
Naik H, et al. In: Lilly L, ed. Pathophysiology of Heart Disease. 4th ed. Baltimore, MD: Lippincott, Williams
& Wilkins;2007:141-167; Vadnais DS, Wenger NK. Clinical Medicine: Therapeutics. 2009;1:871-887.
35
Physiologic Effects
of Antianginal Treatments
O2 Supply
Therapy
Coronary
blood flow
O2 Demand
Heart
rate
Arterial
pressure
Venous
return
Myocardial
contractility
Beta-blockers
1
DHP CCBs
Non-DHP CCBs
Long-acting nitrates
/
Revascularization
2
1Less
2
2
/
2
reflex tachycardia with amlodipine. 2Specific data not available. CCB = calcium channel blocker; DHP = dihydropyridine
Bagger JP, et al. Cardiovasc Drugs Ther. 1997;11(3):479-484. Gibbons RJ, et al. ACC/AHA 2002 Chronic Angina Guidelines. 2003;41:159-168.36Kerins
DM, et al. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: The
McGraw-Hill Companies; 2001:843-870. Lilly L, ed. Pathophysiology of Heart Disease. 4th ed. Baltimore, MD: Lippincott, Williams & Wilkins;
2007:141-167.
‡
Gender Differences in Clinical
Management of Angina
Men
Women
P Value
Incidence of Obstructive CAD
87%
63%
<0.001
Referral for angiogram after
positive ECG
65%
56%
<0.001
Referral for revascularization
29%
13%
<0.001
Antiplatelet therapy
84%
76%
<0.001
Aspirin
81%
73%
<0.001
Lipid Lowering Drugs
53%
47%
<0.001
Beta Blockers
67%
65%
Daly et al. Circulation. 2006;113:490-498.
NS
Gender Differences in
Clinical Management of Angina

Despite evidence and guidelines supporting risk
reduction, women with obstructive CAD receive
suboptimal treatment

Revascularization, and/or medical therapies

30% of women with chest pain, normal angiogram,
and endothelial dysfunction develop obstructive CAD
during 10 year follow up2

In addition to routine diagnostic testing, identification
of compromised functional capacity and evidence of
ischemia as markers of an adverse prognosis are
also needed3
1Bugiardini
et al. Curr Vasc Pharmacol 2010;8:276-284.
et al. Circulation. 2004;109:2518-2523.
3Shaw et al. J Am Coll Cardiol. 2009;54:1561-1575.
2Bugiardini
Under-diagnosis and Less Aggressive
Treatment of Angina by Gender
Clinical Management of Angina
Pectoris by Gender
60
54
Men (n=610)
Women (n=552)
50
Patients (%)
42
38
40
30
37
28
25
22
20
12
10
0
Received
Exercise ECG
Testing
Received PCI
or CABG or
Both
Wenger NK, et al. Clin Pharmacol Ther. 2008; 83:37-51
Crilly M, et al. BMC Health Services Res. 2007;7:142
Beta-blocker
Use
Received
Angiography
Summary




Despite decreased prevalence of obstructive CAD,
women are at greater risk of IHD than men
Women more commonly present with non chest pain
symptoms of IHD
Differences in gender outcome and symptoms could
be related to underlying pathology
Women are under-diagnosed with IHD and are more
likely to receive suboptimal care