Roxana Mehran, MD, Mt. Sinai - Cardiac Safety

Women’s Health and PCI:
What are the issues 2012?
Roxana Mehran, MD
Professor of Medicine (Cardiology), and Health Policy
Mount Sinai School of Medicine

Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial
interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship Company
• Grant/Research Support
• Consulting Fees/Honoraria
• Sanofi/BMS, TMC, Lilly/DSI-
Significant
• Astra Zeneca, Regado
Biosciences, Merck, Janssen

The Vasculatory of Women v. Men With IHD
Structural findings of Macrovessels and microvessels
Smaller size
Increased stiffness (fibrosis, remodeling)
More diffuse disease, erosion>rupture
Microemboli, rarefaction (drop out), disarray
Functional findings
Endothelial dysfunction
Microvascular disease
Smooth muscle dysfunction (Raynaud’s, migrane, CAS)
Inflammation
Plasma markers (↑CRP ↑BNP)
Vasculitis (Takayasu’s, rheumatoid, SLE, CNSV, giant cells)
JACC 2006; 47:305-355

Mechanism of MI May be Different
in Women
• Atherosclerotic: plaque erosion: women > men;
plaque rupture: men > women
• Spontaneous coronary dissection: women > men
• Takotsubo (high circulating levels of catecholamines):
women > men
• Spasm (migranes, Raynauds): women > men
• Non-STEMI: women > men (subendocardial ischemia
due to LVH, microvascular disease, endothelial
dysfunction)

Women Prone to ‘Broken Heart’Syndrome
• National Huso database with 6837 patients with
discharge dx of Takotsubo
(MI with normal coronaries, suspected excessive catecholamines)
• Women 9x more likely to develop takotsubo MI than
men
• Women older than 55 were 4.6 times more likely to
develop the the condition than younger women
• Sharp divide at the age of 55 for women
(Hormonal influence?);
no difference in TTC rate in men related to age
Deshmukh, 2011 AHA Orlando

Challenges with PCI in Women
• Later diagnosis → elderly with more comorbidities
• More diabetes → restenosis
• Smaller coronaries → restenosis
• Coronary tortuosity → difficulty tracking
equipment, dissections, rigid stents
straighten vessels and may fracture
• Hemodynamics: low cardiac output despite
normal EF → unable to tolerate coronary
occlusion
• Bleeding and Vascular complications
• Unknowns; late and unusual presentations in
AMI

Women Have Higher Rate of
Vascular Complications After PCI
Circ 2005;III;940-953

6 independent RF for non-CABG bleeding
(n=17421, from HORIZONS and ACUITY)
1.female sex
2. advanced age
3. elevated serum creatinine
4. white blood cell count
5. anemia
6. non-ST-segment elevation MI or STsegment
elevation MI
JACC 2010;55:2556-66.

Bivalirudin Reduces (but does not eliminate)
PCI Related Bleeding Differences
Between Men and Women
(Non-CABG) Major Bleeding %
14.00%
12.00%
10.00%
8.00%
6.00%
4.00%
2.00%
0.00%
11.80%
(p

Radial Approach is still Associated
with More Bleeding in Women
• 1348 ACS patients pretreated with ASA, clopidogrel
→ radial PCI using 70 u/kg uFH and abciximab
(EASY trial of early discharge)
Sheath size – 5F
– 6F
Women Men p value
57%
43%
44%
55%
0.0003
Hb drop 1.7% 0.4% 0.059
Hematoma 22% 5.8% 0.001
Final ACT (sec) 322 308 0.003
AHJ 2009; 157:740

Possible Mechanism for
Increased Mortality in Women with AMI
• Lower hemoglobin – less 0 2 carrying capacity
• More bleeding
• More vasospasm, microvascular disease
• Differences in vascular resistance
� Greater exercise-induced ↑ BP
� Increased catecholamine release during stress
• Diastolic dysfunction – more pulmonary edema
• 10-20% less LV mass after adjusting for BSA – lower baseline cardiac
output
• Less cardiac reserve
� Exercise EF lower, LV dilates in response to exercise
• ? Differences in collaterals

Gender Differences in CAD Significance
ACS % with Significant CAD
90
80
70
60
50
40
30
20
10
0
after Diagnostic Cath for ACS
P

Sex Differences in Outcomes After Cardiac
Catheterization: APPROACH Registry
King KM et al. JAMA 2004;291:1220-5
Male
(N=26,202)
Female (N=11,199) P
Male vs Female
Age 62 ± 3 65 ± 3

%
10
8
6
4
2
0
4.6
Sex Differences in Outcomes
After Cardiac Catheterization:
APPROACH Registry
One Year Mortality
P

Dilemma
• Women have atypical symptoms → physicians need
high level of suspicion and aggressive diagnostic
testing, however . . . . .
• Women have higher rates of normal coronaries at the
time of cath
• How can one avoid over-utilization of cath, but at the
same time avoid misdiagnosis in women?
� Noninvasive testing
� Determine pre-test probability of CAD
� CT angiography (avoid radiation exposure in younger
women)

Gender Differences in Response
to Anticoagulants
• Among drug applications submitted to FDA
between 1994 and 2000, 20% had gender
differences in pharmacokinetics
- gender differences in gastric emptying
- more hepatic cytochrome CYP3A in women
- more dietary supplements taken by women
- more accumulation in fat
- less renal excretion
• Three fold increase in HIT in women compared
to men (Blood 2006;108:2937-410)

How much gender-specific data do
we have? NOT MUCH!
Low Rate of Gender-Specific Results
Reporting in Cardiovascular Trials
Source: Mayo Clinic Proceedings, Feb. 2007
24% Sex-specific
results reported

Women in Clinical Trials
Courtesy: S. Priori

PCI Group Medical Therapy
(N=1149) (N=1138)
Male gender 979 (85%) 965 (85%)
Female gender 169 (15%) 169 (15%)
male patients

Aspirin for Primary Prevention
of Cardiovascular Disease
Ridker et al. NEJM 2005;352:1293

Revascularization
Overall population
Revascularization
Proven CAD
Adjusted for age and RF
Effect of Gender on
Revascularization
Daly C et al. Circulation 2006;113:490-8
Revascularization During Follow-up
Hazard Ratio & 95% CI
0.25 1.0 4.0
Favors Men
Favors Women
P
0.38
(0.31-0.46)

Death or MI
Death or MI
adjusted for age, DM,
LVEF, CAD
Death or MI
adjusted for age, statin,
Antiplatelet Rx
Death or MI
adjusted for age, DM,
LVEF, CAD
Effect of Gender on Risk of Death or MI in Patients
With Angiographically Proven CAD
Daly C et al. Circulation 2006;113:490-8
0.25
Death or MI @ One Year
Hazard Ratio & 95% CI
Favors Women
1.0
Favors Men
2.07
(1.16-3.72)
2.09
(1.14-3.85)
2.07
(1.14-3.74)
2.20
(1.22-3.98)
4.0
P
0.01
0.02
0.02
0.009

What about surgical revascularisation?

XIENCE V
SPIRIT WOMEN
2,000 Female CAD
Patients, treated
per the IFU
XIENCE V SPIRIT Women
Trial Design
Randomized
Sub-Study
N = 450
Up to 35 sites CYPHER Select Plus
N = 150
Non-Randomized
Registry
N = 1,550
Up to 95 sites
2
:
1
XIENCE V
N = 300
• PI: Marie-Claude Morice, MD Stephan
Windecker
• Primary end points:
-Randomized: In-Stent LL at 9M
-Registry: MACE at One Year
• Select Female Variables Studied:
-Hormone levels
-Menopausal and hysterectomy status
-Use of contraceptives and weak estrogens

BASELINE DEMOGRAPHICS
Unstable Angina 37%
Prior Cardiac Intervention 17%
Current Smoker 14%
Prior MI 26%
Braunwald Class lll 16%
Hypertension 78% IDDM 11%
Hypercholesterolemia 64%
Prior Oophorectomy 9%
Age 67 Years
‘Real World’
N=1572
General Obesity 27%
Post Menopausal 94%
Multi Vessel Disease 36%
Diabetes 34%
Family History CAD 36%
Prior Hysterectomy 20%
Central Obesity* 71%
*Waist circumference >88 cm

1 YEAR ARC DEFINED
CLINICAL RESULTS
Non-Hierarchical N=1550
All Death (%)
Cardiac Death
All ARC Defined MI* (%)
ARC Defined Peri-procedural MI
ARC Defined TV MI**
1.6
0.8
9.2
7.1 #
ARC Defined Q-Wave TV MI 0.1
ARC Defined Non Q-Wave TV MI 8.6
TLR (%) 2.4
by PCI 2.1
by CABG 0.3
TVR including TLR (%) 3.0
by PCI 2.7
by CABG
# 111 out of 1572 patients (7.1%) had an ARC Defined Peri-procedural MI
8.7
0.3
All revascularizations are considered clinically indicated

Why Do We Need Sex Specific
Research?
• Gestational diabetes or HTN increased risk of CV
disease later in life
• Diabetes in women – higher risk than men of
developing CAD, stroke, death
• TZD’s (Avandia, Actos) for diabetes – doubles risk
of fractures in women, but not men
• Afib – women have higher risk of stroke (age
adjusted) drug-induced proarrhythmia and
anticoagulant related bleeding

Many Cardiovascular Devices Approved
by FDA Without Sex-Specific Data
• Premarket approval (PMA)
applications for high-risk
cardiovascular devices submitted to
the FDA from 2000 through 2007
• Only 26% reported differences in
safety or efficacy between men and
women.
Circ CV Qual Outcomes 2011;4:165-171

Barriers for Women to Participate in
Cardiovascular Trials
• Fifty-four percent of women surveyed
indicated they would not participate in
clinical research
• Reasons for declining participation
included personal illness (24.8%),
transportation issues (17.9%), reluctance to
increase medication (15.2%), and concern
about adverse effects (13.1%).
A Cheung, et al. J Obstet Gynaecol Can 2008;30:332-337

Under Representation of Women in
Clinical Trials: What Can Be Done?
• Women only randomized controlled trials
• Liberalize inclusion criteria
� No upper age limit
� Allow women of child bearing age
• “Sell” the value of research participation to women
• Provide flexible visits, visiting nurses,
transportation, financial incentives

Gender Data Forum
Thursday, December 8, 2011
Washington, DC
Outcomes of Women After ACS

Gender Data Forum
• Initiative of Women in Innovations (WIN),
ACC, and SCAI
• Rare opportunity to gather clinical trialists
from around the world to discuss and analyze
the data from their trials specifically as it
relates to women.
• This effort is an attempt to answer some of
the lingering questions related to the gender
disparities in cardiovascular outcomes.

Gender-based Outcomes: ACS
• Gender Gaps in ACS:
� Prevalence of ACS presentation is lower
in women compared to men- Is this why
we have less women in the trials?
� Recommendations for new
drugs/interventions in ACS have not
been different in men v. women
� Yet only 25% of pivotal trials include
women
� Safety and efficacy of pharmacologic
therapies have not been evaluated in
large prospective multi-center trials in
women

Goals
• Explore the gender differences in ACS
• Evaluate safety and efficacy of pharmacologic
treatments from large prospective multi-center clinical
trials in women
• Provide possible solutions and next steps in further
understanding for closing the gap for women with ACS
• White paper document with full synopsis of our
findings and recommendations
• standardized data tables/fields should be established
for comparable data analysis across the trials
• Use of existing databases for comparative
effectiveness: NCDR, Claims data, Medicare

We Must Overcome these
Obvious Challenges:
� Validity and applicability of trial data to
women
� Reduced accuracy and power of subgroup
analyses
� Usually no subgroup analyses on safety data,
given these are often secondary endpoints
• In this context – review what there is and
attempt to extrapolate some conclusions…
This must go away and SAFE PCI is leading
the way!!