3. Historical Perspective
! Surge of interest in the 1940s and 1950s with a focus on
middle-aged men
! Studies enrolled primarily men
Lee et al. JAMA. 2001;286:708-713
4. Women in Cardiology Trials
Trial % Women
BARI 26%
CAVEAT 18%
COMET 20%
VANQUISH 3%
BENESTENT 19%
4S 18%
CABRI 22%
HOPE 25%
TNT 19%
PAMI 25%
SIRIUS 28%
TAXUS 18%
COURAGE 15%
5. Enrollment of Women in NHLBI RCTs
Mean percent of women
enrolled in all trials
(27%) vs. mean percent
of all patients with CVD
Kim et al. J Am Coll Cardiol 2008;52:672-675 who were women (53%)
6. Mortality Trends
Cardiovascular Disease Mortality Trends
for Women and Men
United States: 1979-2004
520
500
Deaths in Thousands
480
460
440
420
400
0
380
79 80 85 90 95 00 04
Years
Males Females
Rosamond et al. Circulation 2007;115;e69-e171, Source: NCHS and NHLBI
8. AHA survey of women’s knowledge
ALL WOMEN 1997 2000 2003 2005
Identify heart disease as leading cause of death 30% 34% 46% 55%
Perceive heart disease as their greatest health threat 7% 8% 13% 21%
Perceive cancer as their greatest health threat 61% 62% 51% (38%)
Report heart health discussions initiated by their doctor 30% 38% 38% 46%
! Minority women face the highest risk of
dying from CVD, however they have a poor
awareness that heart disease is the leading killer
of women
-European-American: 68%
-African-American: 31%
-Hispanic-American: 29%
Mosca et al. J Women’s Health 2007;16:68-81
9. Cardiovascular Disease
! Leading cause of death among women in US
– 1 in 4 deaths attributable to CAD
– 1 in 2 deaths for all forms of CVD
! Heart disease:
! Second-leading cause of death for women 45 to 64 years
! Third-leading cause of death for women age 25 to 44 years
! Kills more than 500,000 women per year
! Kills 6 times as many women as breast cancer
! Kills almost twice as many women as all forms of cancer
combined
10. Sex Differences
! Women differ from men in terms of:
! Risk factor profiles
! Presentation
! Testing
! Treatment
! Outcomes
! Pathophysiology (?)
11. Heart Disease Risk Factors
! Age: women, " 55 yrs; men, " 45 yrs
! High LDL-cholesterol: " 160 mg/dl
! Low HDL-cholesterol: < 40 mg/dl*
– * < 50 mg/dl may be more appropriate cut-point for women
– Optimal, " 60 mg/dl (considered a “Negative Risk Factor”)
! Diabetes (fasting glucose " 126 mg/dl) = CHD equivalent
! High Blood Pressure: " 140/90 mm Hg
! Obesity
! Sedentary Lifestyle
! Cigarette Smoking
! Family History of premature CHD:
! 1st degree male relative (father, brother) < 55 yrs
! 1st degree female relative (mother, sister) < 65 yrs
12. Diabetes
! Having diabetes confers a greater relative risk of CVD events in
women compared with men
Barrett-Connor et al. Arch Int Med. 2004;164:934-942
13. Diabetes Trends from 1971 to 2000
! Mean BMI increased (for
all) Age-adjusted cardiovascular
! Average age of diagnosis disease mortality rates among men
decreased for women and women age 35 to 74 years
(mean age 51.6 to 48.7, 16.8 *Annual deaths per 1000 persons
p<0.05 )
! Men with diabetes 5.8
experienced a 43% relative
reduction in age-adjusted 8.1
all-cause mortality, but 7.1
women had no change
! The difference in all-cause
mortality between women
with and without diabetes
more than doubled
Gregg, E. W. et. al. Ann Intern Med 2007;147:149-155, NHANES data
14. Impaired Fasting Glucose
! Women with IFG have a significantly increased 4-year odds of
developing CHD or CVD compared to men
CHD CVD
Women Men Women Men
2003 Definition*
1.7 (p=0.048) 0.9 (p=0.55) 1.4 (p=0.16) 1.1 (p=0.56)
(FPG 100-125)
1997 Definition†
2.2 (p=0.02) 0.9 (p=0.67) 2.1 (p=0.01) 1.0 (p=0.98)
(FPG 110-125)
Diabetic*
2.5 (p=0.01) 2.6 (p<0.001) 2.3 (p=0.007) 2.8 (p<0.001)
(FPG !126 or on med)
* Referent group is FPG <100mg/dl CHD = MI, stable and unstable angina, a CHD death
† Referent group is FPG <110mg/dl CVD = any CHD event, CVA, TIA, claudication, CHF, or CVD death
Levitsky et al. J Am Coll Cardiol 2008;51:264-70
15. Prehypertension (120-139/80-89)
Cumulative hazard of cardiovascular
events by JNC7 blood pressure category
! Prehypertension is
independently associated with
an increased risk of MI, CVA,
HF, and CV death in post- WHI data, n=60K
menopausal women 39% had prehtn at baseline
Prehtn: HR 1.66 (1.44 to 1.92)
Htn: HR 2.89 (2.52 to 3.32)
*Adj by BMI, DM, hyperchol, tob use
Hsia et al. Circulation 2007;115:855-860
16. Lipids
! Low HDL and high triglycerides:
! Independent predictors of CVD mortality in women
! More powerful determinants of CAD risk in women than total
cholesterol and LDL levels.
Bass et al. Arch Int Med. 1993;153:2209-2216
17. Obesity and Physical Activity
! More adult women than men in the United States are obese
and sedentary
! Obesity and physical inactivity independently contribute to
the development of CHD in women
Li et al. Circulation. 2006;113:499-506
18. ?Other risk factors
! Maternal Placental Syndrome (gestational hypertension,
pre-eclampsia, placental abruption, placental infarction)
! Doubled risk of premature CVD, +/- simply reflection of pre-
pregnancy risks
Others:
• Gestational Diabetes
• Peripartum Vasc Dissection
• Low birth-weight children
• PCOS
• Hypothalamic hypoestrogenemia
• Weight gain during pregnancy
Ray et al. Lancet 2005;3666:1797-1803 (CHAMPS)
19. Class III Recommendations
}
! Menopausal Hormone Therapy
Not recommended for
! Antioxidants (Vitamin E, C, beta-carotene) primary or secondary
prevention
! Folic Acid
! Aspirin in women < 65 years for primary prevention of MI
Mosca et al. Circulation 2007;115:1481-1501
20. Menopausal Hormone Therapy
Are Hormone Effects on Clinical CVD
Different if Started Closer to Menopause?
! Secondary analysis of WHI E+P trial (2003)1
! Non-significant reduction of CHD risk in women less than 10 years
since menopause
! Secondary analysis of WHI CEE trial (2006)2
! Non-significant reduction of CHD risk in women age 50-59
! Significant reduction in revascularizations in women age 50-59
! Small numbers in subgroups may have obscured a real effect
! Both trials showed an increased risk of stroke not modified by
age or years since menopause
1. Manson et al. N Engl J Med 2003;349:523-534
2. Hsia et al. Arch Intern Med 2006
21. HT and CVD
! Combined WHI trials of CEE and CEE+MPA
! 27,347 postmenopausal women
! Main outcomes:
! CHD (nonfatal MI, silent MI, or CHD death)
! Stroke
! Other outcomes:
! Mortality (all-cause)
! Global Index (first occurrence of CHD, CVA, PE, breast CA,
colorectal CA, endometrial CA, hip fracture, or death from
other causes)
Rossouw et al. JAMA 2007;297:1465-1477
22. Events by Age Group at Baseline in
Combined Trials
50-59 years 60-69 years 70-79 years P for
Trend
N= 8,832 N= 12,362 N= 6,153
No. of HR No. of HR No. of HR
Cases Cases Cases
(95% CI) (95% CI) (95% CI)
CHD 120 0.93 352 0.98 294 1.26 0.16
(0.65-1.33) (0.79-1.21) (1.00-1.59)
81 1.13 258 1.50 237 1.21 0.97
Stroke
(0.73-1.76) (1.17-1.92) (0.93-1.58)
Death 164 0.70 465 1.05 445 1.14 0.06
(0.51-0.96) (0.87-1.26) (0.94-1.37)
Global 556 0.96 1378 1.08 1134 1.14 0.09
Index
(0.81-1.14) (0.97-1.20) (1.02-1.29)
Rossouw et al. JAMA 2007;297:1465-1477
23. Events by Years Since Menopause
in Combined Trials
<10 years 10-19 years >20 years P for
Trend
N= 7,137 N= 8,977 N= 8,293
No. of HR No. of HR No. of HR
Cases Cases Cases
(95% CI) (95% CI) (95% CI)
CHD 90 0.76 216 1.10 352 1.28 0.02
(0.50-1.16) (0.84-1.45) (1.03-1.58)
64 1.77 179 1.23 255 1.26 0.36
Stroke
(1.05-2.98) (0.92-1.66) (0.98-1.62)
Death 120 0.76 291 0.98 507 1.14 0.51
(0.53-1.09) (0.78-1.24) (0.96-1.36)
Global 425 1.05 922 1.12 1307 1.09 0.82
Index
(0.86-1.27) (0.98-1.27) (0.98-1.22)
Rossouw et al. JAMA 2007;297:1465-1477
24. Age and Years Since Menopause
! Short-term use of HT has no apparent benefit or
harm in CHD risk in younger women close to
menopause
! Increased risk of stroke (and breast CA) in
women closer to menopause
! Screen for and treat risk factors for CVA before starting HT
! Increased risk of CHD for older women "20
years from menopause, particularly those with
vasomotor symptoms
! Vasomotor sxs in older women may be a marker of increased
CHD risk
25. Conclusions on HT
! HT should not be initiated (or continued) for the
express purpose of preventing cardiovascular
disease in either younger or older
postmenopausal women
! The current recommendations are that hormone
therapy be limited to the treatment of
moderate-to-severe menopausal symptoms,
with the lowest effective dose used for the
shortest duration necessary
26. Symptoms
! Chest pain is most common symptom in men and women
! Men tend to report chest pain more often
! In women, it’s not always the first or most significant
symptom
! Women may experience more transient pain and may have
more subtle differences in their description
! heaviness
! pressure
! tightness
! squeezing
! sharp
! stabbing
27. Symptoms
! SOB
! Nausea/Vomiting
! Transient non-specific chest discomfort
! Women report a greater
number of less common ! Arm/shoulder pain, usually left-sided,
symptoms but more often right sided than men
! Abdominal pain
! Indigestion
! Men report more chest pain,
diaphoresis, belching, and ! Back pain or pain radiating to the back
hiccups
! Neck pain
! Although equally likely to have ! Jaw pain
exertional symptoms, more
likely to report pain at rest, ! Headache
during sleep, or with mental
stress ! Fatigue
! Symptoms may be worse ! Dizziness
during menstrual period ! Loss of appetite
! Palpitations
! Cough
28. Prodromal Symptoms
! 95% of women report prodromal symptoms
! Average 5 symptoms
! Most common are fatigue (71%), sleep disturbance (49%),
SOB (42%), indigestion (40%), and anxiety (36%)
! Only 30% report chest discomfort
! General occur for at least a month prior to event
29. Non-invasive Testing
! Exercise treadmill testing
! Lower specificity in women compared with men (higher false
positive rate), but slightly higher sensitivity
! Stress echocardiography and nuclear perfusion scan
! Sensitivity is similar to ETT (~80%), specificity better(~80%)
! CAC with EBCT or MDCT
! Sensitive, but not specific for significant CAD
! Radiation. Angio based on CAC alone not currently recommended
! Cardiac MRI
! Still not sufficient for coronaries, but may become more useful as a
non-invasive study of the coronary microcirculation
30. Coronary Artery Disease
! Trends apparent across stable angina, unstable
angina, NSTEMI, and STEMI
• older at presentation (~5-10 years)
• more comorbidities (hypertension, high cholesterol, diabetes)
• more likely to have depression before and after their diagnosis
• more likely to be in heart failure
• more likely to have a history of angina (and more severe)
• less likely to present with STEMI
• more likely to have NO obstructive disease
Daly et al. Circulation 2006;113:490-498
GUSTO IIb trial. Hochman et al. NEJM 1999;341:226-32
Gan et al. NEJM 2000;343:8-15
Fang et al. Am J Cardiol 2006;97:1722-1726
Anand et al. JACC. 2005;46:1845-51 (post-hoc analysis of the CURE trial)
31. Coronary Artery Disease
! Trends apparent across stable angina, unstable
angina, NSTEMI, and STEMI
• later to present, slower to receive treatment
• less likely to receive guideline-based medical therapy including
aspirin and statins
• less likely to have an angiogram or undergo revascularization
• significantly higher rates of moderate or severe bleeding
• more likely to have continued/recurrent angina after treatment
• less likely to be referred for cardiac rehab
• more death and MI at short- and long-term follow-up
Daly et al. Circulation 2006;113:490-498
GUSTO IIb trial. Hochman et al. NEJM 1999;341:226-32
Gan et al. NEJM 2000;343:8-15
Fang et al. Am J Cardiol 2006;97:1722-1726
Anand et al. JACC. 2005;46:1845-51 (post-hoc analysis of the CURE trial)
35. Angina
! 74 population samples of
13,331 angina cases in
199,494 women and 11,511
cases in 201,821 men from
31 countries, 5 countries
being English speaking
! Angina is more prevalent
among women than men
(pooled random-effects sex
ratio of 1.20 (95% CI 1.14 to
1.28, P<0.0001)).
! Ratio was 1.40 (95% CI 1.28
to 1.52) among Americans
(non-whites>whites)
Hemingway et al. Circulation 2008;117:1526-1536
37. Stable Angina: after visit to cardiologist
! Of patients having an angiogram, 63% of women and 87% of men had
significant CAD (p<0.001)
! Women had more single vessel disease (46% vs. 30%)
! Men had more double/triple vessel disease (32%/38% vs. 22%/32%)
! Among patients with proven CAD, women were less likely to be
revascularized (adjusted OR 0.70, 95% CI 0.52 to 0.94, p=0.019) or
to receive statins and antianginal drugs
38. Stable Angina: one year follow-up
Cumulative probability of death or MI
! Women with confirmed CAD
were
! more likely to have
continued angina (57% vs.
47%, p=0.007)
! Suffered more death and MI
39. USA & NSTEMI: Early Invasive vs. Conservative
! Three major
randomized, controlled
trials with sex data
! FRISC II
! RITA-3
! TACTICS-TIMI 18
Lagerqvist et al. J Am Coll Cardiol 2001;38:41-8
40. USA & NSTEMI: Early Invasive vs. Conservative
! Higher risk women benefit similarly to men from an early
invasive strategy, whereas lower risk women may have
excess events
MACE events at 180
days in higher risk
patients
Glaser et al. JAMA 2002;288:3124-3129 (TACTICS-TIMI 18)
41. STEMI
Men Women p-
Variable
n=740 n=308 value
Age (mean) 57.21 64.45 <0.01
Diabetes 18.78 25.65 0.01
History of Congestive Heart Failure 3.78 9.09 <0.01
Hypertension 53.78 68.83 <0.01
Cardiogenic Shock 8.11 18.83 <0.01
Outcomes
Mortality 3.11 7.47 <0.01
Re-infarction 0.95 1.62 0.35
Median Time to Treatment
Symptom Onset to Door (min) 84.0 97.0 0.02
Door to Balloon (min) 105.0 118.2 <0.01
PCI within 90 min 35% 26% 0.006
Moscucci et al. AHA abstract 2004
42. STEMI
! Later presentation, slower treatment
Characteristic Women (n = 68,108) Men (n = 70,848) p Value
Time to EKG – min 37.2 ± 50.0 33.5 ± 48.9 <0.001
Chest pain >6 hr before arrival 30.8% 27.6% <0.001
! Less thrombolysis, aspirin, and cath
! Less likely to be admitted to a hospital capable of
revascularization (45% vs. 52%, p<0.001)
! Less likely to undergo revascularization when admitted
to a capable hospital (54% vs. 60%, p<0.001)
! Higher adjusted short-term mortality
Gan et al. NEJM 2000;343:8-15
Fang et al. Am J Cardiol 2006;97:1722-1726
44. Symptoms and D2B-Case
! 62 yo Tongan woman arrives in ER at 0129
! PMHx: DM, htn, dyslipidemia, obesity, CRI
! Complains of 1-2 hours of constant, nonradiating
chest/epigastric pain, weakness, diaphoresis,
headache, SOB, N/V, palpitations, and light-headed.
No cough, fevers, or chills. BP 220/110.
46. Sequence of Events
! ASA at 0205, serial SLNTG
! STEMI call at 0211
! Interventional Fellow consenting at 0230
! Heparin bolus at 0239, Aggrastat at 0253
! Patient arrives cath lab at 0305
! Sheath in at 0313, left coronary images 0324
! Balloon inflated at 0336
! D2B = 127 minutes
47. Angiogram
Peak TnI 0.9, peak CKMB 5.6, peak total CK 256
48. Predictors of D2B Delay
40K patients who underwent
primary angioplasty for MI
Angeja et al. Am J Cardiol 2002;89:1156-1161, NRMI data
49. Delay with EMS
! Women are 50% more
likely to be delayed in
the EMS setting
Concannon et al. Circ Cardiovasc Qual Outcomes. 2009;2:9-15
50. Relative impact of delayed D2B time in women
! Delays in D2B time
have a greater impact
on late mortality in
women compared with
men
Brodie et al. JACC 2006;47:289-295
51. STEMI: Younger Women
! Younger women present later, have more diabetes, and are
sicker (higher Killip class, lower SBP)
! They have more complications such as hypotension, heart
failure, cardiogenic shock, and major bleeding, and are less
likely to undergo angiography and revascularization
OR for Death during Hospitalization for MI in Women vs. Men
Vaccarino et al. NEJM 1999;341:217-25
53. Depression after an MI
! Following an MI, the prevalence of major depression is higher in
women than men, with younger women have the highest prevalence
of depression (40%)
Prevalence of Depression
by Age and Sex
50
45
Patients with Depression, %
40
men
35
women
30
25
20
15
10
5
0
!60 >60
Age
Mallik, S. et al. Arch Intern Med 2006;166:876-883
54. PCI: NHLBI Dynamic Registry
! Shows improving outcomes (in-hospital mortality)
! 1985-1986: Adjusted OR 4.53, 95% CI 1.39-14.7
! 1997-1998: Adjusted OR 1.60, 95% CI 0.76-3.35
! Most recent analysis includes BMS and DES (2001-2004)
! Attempted lesions in women had a smaller reference
vessel diameter than those in men in both BMS and DES
! Men had more vein graft PCIs
! Otherwise, similar angiographic characteristics
Abbott et al. Am J Cardiol 2007;99:626-631
55. PCI: NHLBI Dynamic Registry
! No sex difference in death or MI in-hospital or at one year
! No sex difference in IIb/IIIa or antiplatelet therapy
! No sex difference in stent thrombosis rates
One-year
event rates
for repeat PCI
! Women have more vascular access site complications (p<0.001)
56. PCI Complications
! Bleeding complications more common in women (RPH, bleed
requiring transfusion, hematoma requiring repair or prolonged
hospital stay)
! Coronary vascular injury seen in younger women (intimal tear,
dissection, acute occlusion, or side branch closure)
Argulian et al. Am J Cardiol 2006;98:48-53
57. RPH — Independent Predictors
! Smaller body surface area (BSA <1.73m2)
! High puncture
! Being a woman (73% were ")
! Use of a IIb/IIIa inhibitor*
Farouque et al. JACC 2005;45:363-8 *Significant in Whitlow et al, CCI 2006
n=28,378
58. IIb/IIIa Inhibitors
! Women benefit from IIb/IIIa inhibitor use similar to men
! But women have higher rates of bleeding
p < 0.001 for both " and # p = 0.004 for major bleeding event
p < 0.001 for minor bleeding events
Cho et al. J Am Coll Cardiol 2000;36:381-6 (Pooled analysis of EPIC, EPILOG, and EPISTENT)
59. IIb/IIIa Inhibitors
! Women have more bleeding whether or not IIb/IIIa
inhibitors are used, however, 25% of the bleeding risk
in women is attributable to excess dosing
Alexander et al. Circulation 2006;114:1380-1387
60. Radial vs. Femoral Access
! 3261 consecutive
Women=black
interventional and/or Men=gray
diagnostic procedures
! Major bleeding (A)
! RPH or death
! Required surgical intervention
! Required blood transfusions
! Hg <4g/dl
! Hematoma >50% of the limb, associated
with pt. discomfort and prolonged
hospital stay
! Minor bleeding (B)
! All other puncture-related hemorrhages
Pristipino et al. Am J Cardiol 2007;99:1216-1221
*p=0.0008 vs. radial; **p=0.00001 vs. radial
61. Effect Most Pronounced in Women
! The protective effects of transradial interventions are
most pronounced in women
Rao et al. J Am Coll Cardiol Intv 2008;1:379-86
62. CABG: In-hospital Mortality
! Women have higher in-hospital mortality than men, as
well as higher rates of postoperative MI, neurologic
complications, and renal failure. This is particularly
true for younger women
Vaccarino et al. Circulation 2002;105:1176-1181
63. CABG: Outcomes
! The 30 day mortality after
CABG decreased
significantly from 1991-2004,
particularly in women
! Increased use of arterial
grafts
! After CABG, women are more likely to be readmitted than men,
typically for unstable angina and CHF rather than MI
! Overall, women have similar or better long-term survival than men,
but are more likely to have recurrent angina and lower QOL
Humphries et al. J Am Coll Cardiol 2007;49:1552-8
Guru et al. Circulation 2006;113:507-16
64. Pathophysiology: Non-obstructive CAD
Up to 20% of
symptomatic
patients presenting
for coronary
angiography will
have no significant
coronary artery
disease on
angiography
While ~60% are women, nearly 40%
are men
65. Pathophysiology
! Women presenting with symptoms suggestive of angina
are significantly less likely than men to have
angiographic evidence of obstructive CAD
! Women tend to get more diffuse atherosclerosis
! Women frequently have evidence of microvascular disease
! Women frequently have evidence of endothelial
dysfunction
!WISE Study (Women’s Ischemic
Syndrome Evaluation)
NOT A BENIGN PATHOLOGY
Associated with long-term CV !Sponsored by AHA/NHLBI
events and death !Four-center project, ~1000 women
(mean age 59±12 years) enrolled. Women
were presenting with suspected ischemia
and were referred for elective coronary
angiography.
67. Plaque Distribution
! A long, diffuse
lesion that is
moderately
narrowed can
cause a similar
reduction in distal
flow as a short,
focal lesion that
is severely
narrowed
68. Case
! 60 yo woman
! Movie Removed
! Hypertension
! Recent presentation to ER with
CP, ruled out
! Stress echo: mid-distal anterior
and apical ischemia
69. IVUS
! MLA 2.7mm2
! Movie Removed
! 24-26mm long
70. Post-stent
! 2.5 x 28mm Cypher stent
! Movie Removed
! Post-dilated with a 2.75mm
balloon.
74. Endothelial Dysfunction
All major cardiac risk factors
have been found to associated
with endothelial dysfunction in
a cumulative fashion.
Endothelial dysfunction is
at least partially
reversible through risk
factor modification.
75. Case
! 48 yo woman
! No significant risk factors except a 15-pack yr hx of tobacco
use 18 years ago
! Low stamina and excessive tachycardia with exercise for the
past year
! VO2 stress echo ! anterior ischemia
! Cath lab
! Normal appearing coronary arteries on angiography
! Only minimal plaque on IVUS
! Mild microvascular disease (IMR 23)
! Tested endothelial function
77. Example Patient
! Started Imdur 30 mg daily
! Decreased max. exertional heart rate from 180s to 160s
! Increased running distance from 0.5 to 2 miles
! Decreased running time from 14 min/ml to 11-12 min/ml
! More energy after work-outs
78. Sex Differences in Atheroma Burden and
Vascular Function Abnormalities
Han et al. Eur Heart J 2008;29:1359-1369
79. Summary
! Focus on exercise, weight reduction, avoidance of insulin
resistance/diabetes, hypertension, and ! triglycerides and " HDL
! Hormone Therapy: Smallest dose, shortest duration
! Aspirin for 1° prevention of MI or CV death if " 65
! Be attuned to “atypical” symptoms
! Women tend to be older, present later and sicker, have less
extensive CAD, have more complications (particularly bleeding),
and more recurrent/refractory symptoms
! Post-PCI/Post-MI/Post-CABG
! Standard medical care (ASA, b-blocker, statin, ACE inhibitor, Plavix)
! Continued aggressive risk factor modification
! Rehab (!)
! Depression/Stress
80. Summary
! Throughout care, treat a woman like a woman
(except when we know there’s a benefit to treating her like a man)
! New paradigm
! Key to ultimately changing outcomes
(and Monterey)
www.womensheart.stanfordhospital.com
