Evidence Based Management of Evidence Based Management of Cardiovascular Disease in Cardiovascular Disease in Women Women Karol E. Watson, MD, PhD, FACC Karol E. Watson, MD, PhD, FACC Co-director, UCLA Program in Preventive Co-director, UCLA Program in Preventive Cardiology Cardiology Associate Professor of Medicine/Cardiology Associate Professor of Medicine/Cardiology David Geffen School of Medicine at UCLA David Geffen School of Medicine at UCLA
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Evidence based management of cardiovascular disease in women
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Evidence Based Management of Evidence Based Management of Cardiovascular Disease in WomenCardiovascular Disease in Women
Karol E. Watson, MD, PhD, FACCKarol E. Watson, MD, PhD, FACC
Co-director, UCLA Program in Preventive CardiologyCo-director, UCLA Program in Preventive CardiologyAssociate Professor of Medicine/Cardiology Associate Professor of Medicine/Cardiology
David Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLA
Karol E. WatsonKarol E. Watson
Disclosure of Financial RelationshipsConsultant: Genentech, Genzyme
Clinical Trials Adjudication Committee: Merck
CV disease: Leading cause of death CV disease: Leading cause of death in Americansin Americans
0
100
200
300
400
500
A Total CVD*B Cancer D Chronic lower respiratory diseases
C Accidents
433,825
288,768
69,257 60,71334,301
493,623
268,503
64,10338,94841,877
Deaths(1000s)
*CHD, stroke, HF, hypertension, arterial diseasesData compiled for 2002
Men
Women
F Alzheimer’s Disease E Diabetes
CDC/NCHS and NHLBI.
A B C D E A B C F E
Cardiovascular Disease: Leading Cause of Cardiovascular Disease: Leading Cause of Death in WomenDeath in WomenCardiovascular Disease: Leading Cause of Cardiovascular Disease: Leading Cause of Death in WomenDeath in Women
2000 2000 Heart and Stroke Statistical UpdateHeart and Stroke Statistical Update , American Heart Association., American Heart Association.2000 2000 Heart and Stroke Statistical UpdateHeart and Stroke Statistical Update , American Heart Association., American Heart Association.
Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women--2011 Update: A Guideline
From the American Heart Association
L. Mosca et al. Circulation. 2011 Feb 16.
• Reducing atherosclerosis
• Preventing plaque rupture
• Limiting thrombosis
Prevention of CHD:Prevention of CHD:
Severe obstruction (angina, no rupture) vs Severe obstruction (angina, no rupture) vs mild obstruction (no angina, likely to rupture)mild obstruction (no angina, likely to rupture)
RevascularizationAnti-anginal Rx
Exertional angina• (+) ETT
Severe fibrotic plaque• Severe obstruction• No lipid• Fibrosis, Ca2+
Pharmacologic stabilizationEarly identification of high-risk?
Plaque rupture• Acute MI• Unstable angina• Sudden death
Vulnerable plaque•Minor obstruction•Large lipid pool•Thin fibrous cap
Courtesy of PH Stone, MD.
Typical Angina Atypical Angina
Age Women Men Women Men<40 13 21 4 4
40-49 20 42 7 15
50-59 32 60 12 31
60-69 42 72 18 38
70-79 53 77 31 48
>80 65 84 35 50
Women n=19,761Men n=23,868
ACC – NCDR: ACC – NCDR: CAD Prevalence in Diagnostic CatheterizationCAD Prevalence in Diagnostic Catheterization
WISE: Landmark study in womenWISE: Landmark study in women
Goals:• Improve diagnostic testing for ischemic heart
disease in women• Study pathophysiologic mechanisms for ischemia in
the absence of epicardial coronary artery stenoses• Evaluate the influence of menopausal status and
reproductive hormone levels on diagnostic testing results
Bairey Merz CN et al. J Am Coll Cardiol. 1999;33:1453-61.
Prospective cohort study conducted at 4 US sites
AA BB
CC
AA BB
CC
V3016V3016
Source: WISE – Unpublished data – S. Nissen
Negative Remodeling
Positive Remodeling
WISE: Persistent chest pain in WISE: Persistent chest pain in women predicts future CV eventswomen predicts future CV events
Johnson BD et al. Eur Heart J. 2006;27:1408-15.
With CADHR 1.17 (0.76–1.80)P = 0.49
Without CADHR 1.89 (1.06–3.39)P = 0.03
Event-freesurvival (%)
Years from PChP diagnosis (at one year)
0.7
0.6
1
0.9
0.8
0 1 2 3 4 5 6
Neither PChPNo CAD
No PChPCAD
Both
n = 673 WISE participants with chest pain at baseline
PChP = persistent chest pain
Plaque Erosion and Outward Plaque Erosion and Outward (Positive) Remodeling(Positive) Remodeling
• Plaque erosion and Plaque erosion and thrombus formation 2x thrombus formation 2x likely in women (men likely in women (men have more plaque have more plaque rupture)rupture)
• Outward (positive) Outward (positive) remodeling- remodeling- atherosclerotic lesion atherosclerotic lesion protrudes outward protrudes outward than impinging on the than impinging on the lumenlumen
Adapted from Bellasi et al, New insights into ischemic heart disease in women. cleveland clinic journal of medicine; 74: 585-594
Thrombus Formation
Lumen
Plaqueerosion
Women suffer more plaqueerosions (above) comparedto plaque explosions in men (below), leading to more acute coronary syndromes(unstable angina) and non-Q MI in women,making diagnosis more difficult and leading to delays in treatment.
Gender Differences in Atherosclerosis
NEJM 1999
Panting JR. New Engl J Med 2002; 346: 1948-53.
Con
trol
Syn
dro
me -X
Rest Stress
Perfusion CMR in Cardiac Syndrome-XPerfusion CMR in Cardiac Syndrome-X
• Women with chest pain suggestive of myocardial ischemia yet no or nonobstructive CAD (i.e., cardiac syndrome x) may have subendocardial ischemia as demonstrated using cardiac MR perfusion
• Reducing atherosclerosis
• Preventing plaque rupture / EROSION
• Limiting thrombosis
Prevention of CHD:Prevention of CHD:
• Tobacco Smoke
• High Blood Cholesterol
• High Blood Pressure
• Physical Inactivity
• Obesity and Overweight
• Diabetes Mellitus
• Age
Classic Cardiovascular Risk Factors
Diabetes and CV Risk in FraminghamAge 35-64 Years--30 Year Follow-up
High-Sensitivity C-Reactive Protein High-Sensitivity C-Reactive Protein (hsCRP)(hsCRP)
• hsCRP should not be used for routine screening of all women, but should be reserved for refining risk estimates in intermediate risk patients when there is uncertainty regarding the need to start drug therapy
• Consider statins in women over 60 years of age if, after lifestyle modification, hsCRP remains elevated above 2 mg/dL and no acute inflammatory process is present (Class IIb; Level of Evidence B)
Source: Mosca 2011, Ridker 2009
0 1 2 3 4 50
2
4
6
8C
-rea
ctiv
e P
rote
in (
mg
/L)
Number of Components of the Metabolic Syndrome
Ridker PM, et al. Circulation. 2003;107:391-397. (with permission)
Metabolic Syndrome and CRP Metabolic Syndrome and CRP LevelsLevels
• Increased body fat
• Smoking
• Low physical activity
• Poor aerobic fitness
• Low fruit and vegetable intake
• Low omega-3 fatty acid intake
Behavioral factors associated with elevated biomarkers of inflammation
Nicklas BJ, You T, Pahor M. Behavioral treatments for chronic systemic inflammation: effects of dietary weight loss and exercise training. Can Med Assoc J 2005; 172:1199-1209
Effect of antiplatelet treatment* on vascular events**
End points (mean, 10.1 yrs):● Combined end point of nonfatal MI, nonfatal stroke, or total cardiovascular death
● Incidence of total malignant neoplasms of epithelial cell origin
Women's Health Study: Women's Health Study: Low-Dose Aspirin in Primary Prevention TrialLow-Dose Aspirin in Primary Prevention Trial
Ridker PM. Presented at: 54th Annual Scientific Session of the American Collegeof Cardiology; March 7, 2005; Orlando, Fla. Ridker PM, et al. N Engl J Med. 2005;352.
Men ages 45-79Men ages 45-79Encourage aspirin use when potential CVD benefit (MIs prevented) outweighs potential harm of GI hemorrhage
Women ages 55-79 Encourage aspirin use when potential CVD benefit (strokes prevented) outweighs potential harm of GI hemorrhage.
10-year CHD risk 10-year stroke risk
Age 45-59 years ≥4% Age 55-59 years ≥3%
Age 60-69 years ≥9% Age 60-69 years ≥8%
Age 70-79 years ≥12% Age 70-79 years ≥11%
USPSTF: Risk level at which CVD events prevented (benefit) exceeds GI harms
Men Age <45 Years and Women Age <55 Years : Do not encourage aspirin use Men & Women Age ≥80 Years: No Recommendation (Insufficient Evidence) AHRQ Publication No. 09-05129-EF-3
Current as of March 2009
Women have strokes too Women have strokes too
0.6961 0.6218 - 2.0376 1.1256 3.4/3.0 55 - 64
0.0040 1.3205 - 4.3267 2.3903 2.5/1.0 45 - 54
0.6876 0.4715 - 3.1268 1.2142 1.2/1.0 35 - 44
P 95% CI OR Women/Men (%)
Age group (y)
NHANES data from 17,061 individuals older than 18 years between 1999 and 2004
• Weight maintenance/reduction– Maintain or lose weight through physical activity and appropriate
caloric intake to achieve appropriate body weight (BMI <25 kg/m2, waist size <35 inches) (Class I; LOE B).
• Omega-3 fatty acids– Consumption of omega-3 fatty acids in the form of fish or in
capsule form for women with hypertriglyceridemia or for primary or secondary prevention of CHD (Class IIb; LOE B).
Major Risk Factor InterventionsMajor Risk Factor Interventions
• Blood pressure management– Pharmacotherapy when blood pressure is ≥140/90 mm Hg
(≥130/80 mm Hg in the setting of chronic kidney disease and diabetes. (Class I; LOE B).
• Lipid Management– LDL-C–lowering drug therapy is recommended (along
with lifestyle) in women with CHD, other atherosclerotic CVD, diabetes mellitus or 10-year absolute risk >20% to achieve an LDL-C <100 mg/dL (Class I; LOE A)
– LDL-C–lowering with lifestyle therapy in all others, even if LDL > 190 mg/dL. (Class I LOE B).
Major Risk Factor Interventions Major Risk Factor Interventions (cont.)(cont.)
• Lipid Management (cont.)– In women >60 years of age and with an estimated CHD risk
>10%, statins could be considered if hsCRP >2 mg/dL after lifestyle modification and no acute inflammatory process is present (Class IIb; LOE B)
– Niacin or fibrate therapy can be useful when HDL-C is low (<50 mg/dL) or non–HDL-C is elevated (>130 mg/dL) in high-risk women after LDL-C goal is reached (Class IIb; LOE B)
• Diabetes Management– Lifestyle and/or pharmacotherapy to achieve HbA1C <7
(Class IIa LOE B).
Preventive Drug InterventionsPreventive Drug Interventions• Aspirin• Aspirin (75–325 mg/d) in women with CHD unless
contraindicated (Class I; LOE A).
• Aspirin (75–325 mg/d) is reasonable in women with diabetes (Class IIa; LOE B).
• Aspirin (81 mg daily or 100 mg every other day) can be useful in women ≥65 years of age, if … benefit for ischemic stroke and MI prevention is likely to outweigh risk of GI bleeding and hemorrhagic stroke (Class IIa; LOE B)
• Aspirin (81 mg daily or 100 mg every other day) may be reasonable for women <65 years of age for ischemic stroke prevention (Class IIb; LOE B).
Class III Interventions (Not Useful/Effective and May Be Harmful)
• Menopausal therapy– Hormone therapy … should not be used for the primary or
secondary prevention of CVD (Class III, LOA A).
• Antioxidant Supplements– Antioxidant vitamin supplements (eg, vitamins A, C, E) should
not be used for the primary or secondary prevention of CVD (Class III, LOA A).
• Folic Acid– Folic Acid, with or without B6 and B12, should not be used for the
primary or secondary prevention of CVD (Class III, LOA A).
• Aspirin for MI prevention in women <65– Routine use of aspirin in healthy women 65 years of age is not
11,324 patients with a recent MI randomized to Vitamin E (300 mg) or placebo for 3.5 years
*Includes freedom from death, nonfatal MI, and stroke
Bonna KH et al. NEJM 2006;354:1578-1588
Folic Acid and B-Vitamins: Secondary PreventionFolic Acid and B-Vitamins: Secondary Prevention
NORVIT: 3,749 patients with a NORVIT: 3,749 patients with a recent myocardial infarction recent myocardial infarction randomized to 4 treatment arms randomized to 4 treatment arms for 40 monthsfor 40 months
abdominal pain• Cold sweats or clammy skin• Dizziness
More common in women• Milder symptoms • Sudden onset of weakness,
shortness of breath, fatigue, body aches, or overall feeling of illness (without chest pain)
• Unusual feeling or mild discomfort in the back, chest, arm, neck, or jaw (without chest pain)
Source: AHA &: WISE data JACC 2006
Women’s Early Warning Signs of Heart Women’s Early Warning Signs of Heart AttackAttack
• Weeks before Heart Attack (95% of women)Weeks before Heart Attack (95% of women) Unusual fatigue (70.7%)Unusual fatigue (70.7%) Sleep disturbance (47.8%)Sleep disturbance (47.8%) Shortness of breath (42.1%)Shortness of breath (42.1%) Indigestion (39.4%)Indigestion (39.4%) Chest pain (29.7 %)Chest pain (29.7 %)
• At time of Heart AttackAt time of Heart Attack Shortness of breath (57.9%)Shortness of breath (57.9%) Weakness (54.8%)Weakness (54.8%) Fatigue (42.9%)Fatigue (42.9%) Chest pain (57%)Chest pain (57%)
McSweeney, JC et al. Circulation 2003; 2619-2623
Shaw LJ, et al. Coronary Artery Disease in Women.1999:327-350.
Limited Numbers of Women in Research on Noninvasive Testing
0102030405060708090
100
ECG ECHO MPI
Women
Men
% o
f P
atie
nts
Diagnostic Tests in WomenDiagnostic Tests in Women
Treadmill exercise electrocardiogram is often
inaccurate
~ 33% false positive rate
~ 25% false negative rate
Addition of nuclear imaging or exercise
echocardiogram increases predictive
accuracy to ~ 90%
SOURCE: Crouse. The Fourth Chicago Women & Heart Disease Conference, 1997.
AHA Consensus Statement – Algorithm AHA Consensus Statement – Algorithm for Evaluation of Symptomatic Women for Evaluation of Symptomatic Women
Using Cardiac ImagingUsing Cardiac Imaging
Source: Mieres Circulation 2005; 111:682–696
Intermediate-high likelihood women with atypical or typical chest pain symptomsIntermediate-high likelihood women with atypical or typical chest pain symptoms
Risk factormodification +/-anti-ischemic Rx
Good Ex toleranceGood Ex tolerance+ normal 12-L ECG+ normal 12-L ECG
Diabetes, abnormal 12-L ECG, orDiabetes, abnormal 12-L ECG, orquestionable Ex capacityquestionable Ex capacity
Ex or pharmacologic stress imagingEx or pharmacologic stress imagingExercise TM
test
Int riskInt riskTMTM
LowLowPost-ETTPost-ETT
LKLK
Able to ExAble to Ex Unable to ExUnable to Ex
Exercisestress
Pharmacologicstress
Normal or mildlyNormal or mildlyabnormal withabnormal with
normal LV functionnormal LV function
Moderate-severelyModerate-severelyabnormal orabnormal or
depressed EFdepressed EF
Cardiaccath
Cardiaccath
Ischemia in women may occur from mental Ischemia in women may occur from mental stress more often than physical stressstress more often than physical stress
• 160 men and 24 women with known CHD underwent exercise stress test and mental stress tests
• Women had more EKG documented ischemia during mental stress; men more ischemia during physical stress
Journal of Health Psychology January 2000; 5:75-85
• 170 men and 26 women with known CHD evaluated during daily activities, exercise, and mental stress • Women reported chest pain more often during daily activities (P =0.04) and during laboratory mental stressors (P =0.01); men reported chest pain more often during exercise
Sheps et al. Am Heart J. 2001 Nov;142(5):864-71
CONCLUSIONSCONCLUSIONS
• CHD is the leading cause of death in women
• Risk Factor Modification cornerstone of CV risk reduction
• Pathophysiology of Angina and ACS may differ
• Preventive Strategies may differ
• Evidence-based therapies should be utilized and therapies of no proven benefit should be avoided