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

• Grant/Research Support

• Consulting Fees/Honoraria

• Sanofi/BMS, TMC, Lilly/DSI- Significant

• Astra Zeneca, Regado

Biosciences, Merck, Janssen

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

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 co-

morbidities • 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 ST-

segment elevation MI

JACC 2010;55:2556-66.

Bivalirudin Reduces (but does not eliminate) PCI Related Bleeding Differences

Between Men and Women

11.80%

4.90%6.30%

2.50%

0.00%

2.00%4.00%

6.00%8.00%

10.00%12.00%

14.00%

Women Men

(Non

-CA

BG

) Maj

or B

leed

ing

%

UFH+GPIIb/IIIaBivalirudin

(n=1401) (n=3779)

(p<0.001)

(p<0.0001)

Lancet 2007;369:;907

AJC 2009;103:1197

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) Women Men p value Sheath size – 5F – 6F

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 02 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 after Diagnostic Cath for ACS

0

10

20

30

40

50

60

70

80

90

Black Hispanic N. Amer. Asian Caucasian

ACS

% w

ith S

igni

fican

t CAD

WomenMen

P<0.0001

N = 23,382 8,708 1,596 3,725 412,918

% Female

50.2 39.1 37.6 39.4 38

Circ 2008;117:1792 ACC/NCDR database

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 <0.001 HTN 59 49 <0.001 Diabetes 18 21 <0.001 Smoking 28 23 <0.001 Cholesterol 47 45 <0.001 Previous MI 52 40 <0.001 Previous CABG 9 4 <0.001 Coronary anatomy <0.001

High risk 44 28 Low risk 56 72 No revascularization 44 60 <0.001

PCI 34 27 <0.001 CABG 23 14 <0.001

Sex Differences in Outcomes After Cardiac Catheterization:

APPROACH Registry

5%

10%

15%

4.65.6

0

2

4

6

8

10

Male (N=26,202)Female (N=11,199)

King KM et al. JAMA 2004;291:1220-5

P<0.001

% One Year Mortality

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!

24% Sex-specific results reported

Low Rate of Gender-Specific Results Reporting in Cardiovascular Trials

Source: Mayo Clinic Proceedings, Feb. 2007

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

Effect of Gender on Revascularization

Daly C et al. Circulation 2006;113:490-8

Hazard Ratio & 95% CI

Favors Men

P

Revascularization Overall population

0.38 (0.31-0.46) <0.001

0.25 1.0 4.0

Revascularization During Follow-up

Favors Women

Revascularization Proven CAD

Adjusted for age and RF

0.70 (0.52-0.94) 0.019

Effect of Gender on Risk of Death or MI in Patients With Angiographically Proven CAD

Daly C et al. Circulation 2006;113:490-8

Hazard Ratio & 95% CI

Favors Women

P

Death or MI 2.07 (1.16-3.72) 0.01

0.25 1.0 4.0

Death or MI @ One Year

Favors Men

Death or MI adjusted for age, DM,

LVEF, CAD 2.09

(1.14-3.85) 0.02

Death or MI adjusted for age, statin,

Antiplatelet Rx

2.07 (1.14-3.74)

0.02

Death or MI adjusted for age, DM,

LVEF, CAD

2.20 (1.22-3.98)

0.009

What about surgical revascularisation?

XIENCE V SPIRIT Women Trial Design

2,000 Female CAD Patients, treated

per the IFU Non-Randomized

Registry N = 1,550

Up to 95 sites

Randomized Sub-Study

N = 450 Up to 35 sites CYPHER Select™ Plus

N = 150

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

XIENCE V SPIRIT WOMEN

2 : 1

BASELINE DEMOGRAPHICS

Prior MI 26%

Unstable Angina 37%

Braunwald Class lll 16%

Hypertension 78% IDDM 11%

Post Menopausal 94%

Current Smoker 14%

Family History CAD 36%

Prior Cardiac Intervention 17%

Hypercholesterolemia 64%

Diabetes 34% ‘Real World’

N=1572

Prior Hysterectomy 20% Prior Oophorectomy 9%

Central Obesity* 71% General Obesity 27%

Multi Vessel Disease 36%

*Waist circumference >88 cm

Age 67 Years

1 YEAR ARC DEFINED CLINICAL RESULTS

Non-Hierarchical N=1550

All Death (%)

Cardiac Death

1.6

0.8

All ARC Defined MI* (%)

ARC Defined Peri-procedural MI

ARC Defined TV MI**

9.2

7.1#

8.7

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

0.3

#111 out of 1572 patients (7.1%) had an ARC Defined Peri-procedural MI 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!!