This document provides an overview and update on gender differences in the treatment of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI). Some key points summarized: 1) Women have historically experienced later referrals for treatment of ACS, resulting in more advanced coronary artery disease and worse outcomes. However, outcomes after PCI have improved over time for both men and women. 2) Women continue to be underrepresented in clinical trials of PCI due to barriers like later presentation and higher risk profiles making them ineligible. 3) While early data showed gender was an independent predictor of mortality after PCI, more recent studies have found no differences in death or re-intervention rates between men and women after adjusting for

1. ACS & AMI Update
WIN Program - SCAI 2010
Kimberly A. Skelding MD FSCAI FACC FAHA
Associate Interventional Cardiology
Geisinger Health System
Danville, Pennsylvania

2. Disclosure Information
ACS & AMI Update
WIN Program - SCAI 2010
Kimberly A. Skelding. MD, FSCAI, FAHA, FACC
Nothing to Disclose

3. Gender Differences in Treatment
• Late referrals
- more advanced CAD
- more urgent/emergent procedures
- longer DTB times in STEMI cases
• Lower rates of IMA grafts in women even after
adjustment for age, extent of disease and urgent
surgery
• Similar benefits from GP IIb/IIIa agents and stents
• Improved PCI mortality over time in both men and
women
ClinCardiol 2007;30:491-5

4. Percutaneous Coronary Intervention
• Only 33% of PCI are performed in women annually
• Delayed treatment with PCI in women is common
– Often >24 hours after presentation
• Women continue to be underrepresented in clinical
trials of percutaneous coronary intervention
– They don’t meet inclusion criteria!!!
• Get there late
• More risk factors: older, worse renal function
• Sicker on presentation
Blomkalns AL et al. J Am Coll Cardiol 2005;45:832-37, Lee et al. JAMA.
2001;286:708-713, Harris DJ et al. N Engl J Med 2000;343(7):475-480, Simon V. Science 2005;308(5728):1517.

5. Outcomes following PCI
• Early data (1978-81) reported gender
was independently predictive of
mortality
• Later data (1985-6), corrected for risk
factors, decreased but did not remove
the gender gap
• More recent data suggests no
difference in death, MI, and emergent
CABG but continued increased risk of
morbidity, particularly bleeding
Cowley MJ et al. Circulation 1985;71(1):90-7, Kelsey SF. Circulation 1993;87(3):720-7, Argulian E et al. Am J
Cardiol 2006;96:48-53, Abbott JD et al. Am J Cardiol 2007;99:626-631, Thompson CA et al Catheter Cardiovasc
Interv 2006;67(1):25-31, Blomkalns AL et al. J Am Coll Cardiol 2005;45:832-37, Lansky AJ et al. Circulation
2005;111:940-953

6. Outcomes following PCI
• Contemporary subacute or late thrombosis rates
are similar between genders, 1.3% vs 1.2%, p=NS
• Women are 61% more likely to present with in-
stent restenosis following drug eluting stents,
particularly diffuse in-stent restenosis
– Harder to treat
– Worse prognosis
• 1.9x more women will return to the ER within 30
days of their intervention  even after
successful interventions
Abbott JD et al. Am J Cardiol 2007;99:626-631, Trabattoni D et al. Ital Heart J 2005;6:138-142, Hubbard BL et al.
Am J Cardiol 2007;99:197-201.

7. Differences Between Men and Women
Undergoing PTCA
Clinical
Observations Anatomy Explanation
↑ unstable angina Less MV disease Spasm
Lower hemoglobin
↑ angina at f/u Similar rates of Higher heart rate
incomplete revasc. Higher BP
Fewer repeat PTCAs Similar restenosis rates Gender bias
↑ CHF Better EF Diastolic dysfunction

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

9. Vascular Complications are
Decreasing
JInvCardiol 2007;369:372

10. 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 57% 44% 0.0003
– 6F 43% 55%
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

11. 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
• Nine fold increase in HIT in women compared
to men (Blood 2006;108:2937-410)

13. Bivalirudin Reduces (but does not eliminate)
PCI Related Bleeding Differences
Between Men and Women
(p<0.001)
UFH+GPIIb/IIIa
Bivalirudin
(Non-CABG) Major Bleeding %
14.00%
11.80%
12.00%
10.00% (p<0.0001)
8.00% 6.30%
6.00% 4.90%
4.00% 2.50%
2.00%
0.00%
(n=1401) (n=3779) Lancet 2007;369:;907
Women Men AJC 2009;103:1197

14. Are we still
discriminating against
women, or are we
using good clinical
judgment?

15. 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 overutilization 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)

16. Gender differences in CAD significance
after diagnostic cath for ACS
P<0.0001
90
Women
ACS % with Significant CAD
80 Men
70
60
50
40
30
20
10
0
Black Hispanic N. Amer. Asian Caucasian
N= 23,382 8,708 1,596 3,725 412,918
% 50.2 39.1 37.6 39.4 38
Female
Circ 2008;117:1792
ACC/NCDR database

17. Differences in ACS Management
• CURE trial data: 4,836 women and 7,726 men
with ACS
– Women older, more diabetes, more
hypertension and hyperlipidemia.
– Men more smoking, MI history, PAD and CVA.
• Women had fewer invasive procedures with
ACS, 47.6% vs 60.5%, p=0.0001, regardless of
risk
• No difference in CV death, MI or CVA if they
presented with ACS.
• Women more likely to develop refractory angina
and be re-hospitalized, (16.6% vs 13.9%,
p=0.0001) after their first episode of ACS
Anand SS et al J Am Coll Cardiol 2005

18. Treatment of Women with
Acute Coronary Syndrome
• Less likely to have an ECG done within 10 minutes of
presentation
• Less likely to be cared for by a cardiologist during their
inpatient admission
• Less likely to acutely be given appropriate pharmacotherapy
such as heparin, aspirin, statins, ACE-I
LESS OFTEN RECEIVE GUIDELINE RECOMMENDED
THERAPY BUT WOULD SIGNIFICANTLY BENEFIT FROM
AN EARLY AGGRESSIVE INVASIVE STRATEGY
Blomkalns AL et al. J Am Coll Cardiol 2005;45:832-37, Lansky AJ et al. Circulation
2005;111:940-953, Braunwald E et al. J Am Coll Cardiol 2002;40:1366-1374

19. Outcome Following Treatment of
Acute Coronary Syndrome
• Young women, <55 years old, have >2 times the risk of
having a dissection or artery occlusion during their procedure
• All women have increased bleeding and vascular access site
complications, those <55 years old have >5 times the risk
compared to men
• Following PCI, women with ACS have a 37% higher risk of
death, MI or rehospitalization than men with ACS
• Women <65 years old are at 46% higher risk of death, MI or
rehospitalization
Glaser R et al. Am J Cardiol 2006;98:1446-1450, Abbott JD et al. Am J Cardiol
2007;99:626-631, Chauhan MS et al. Am J Cardiol 2005;95:101-104, Argulian E et al
Am J Cardiol 2006;98:48-53, Lansky AJ et al. Circulation 2005;111:940-953,
Anand SS et al. J Am Coll Cardiol 2005;46:1845-51.

21. Meta-Analysis of Invasive vs
Conservative Rx for ACS
• Eight trials (3075 women and 7075 men)
• Women older, more comorbidites, but more likely to have insignificant (<50%)
CAD at cath (24 vs 8% p<0.001)
JAMA 2008;300:71

22. Conclusions of ACS Meta-Analysis
• Men - Both high and low risk benefit from invasive
strategy
• Women - High risk ACS women benefit from
invasive approach
- Low risk women may be treated
conservatively (but invasive approach
not harmful)
JAMA 2008;300:71

23. Gender Differences in
Atherosclerosis
• Plaque erosion as the
etiology of coronary
thrombosis and AMI
A B
occurs at a higher frequency
in women than in men
• In an autopsy study of 291
patients who died of AMI and
had coronary thrombosis,
C
the prevalence of plaque D
erosions was 37%
in women and 18% in men
Arbustini. Heart. 1999;82:269-272.

24. Gender Differences in AMI Management Persist:
Get with the Guidelines Database 2001-2006
Measure/Treatment Men (n=47 556) Women (n=30 698) P value
Early medical therapy
Aspirin within <24 h 93.3 91.0 <0.0001
β-Blockers within <24 h 87.2 84.7 <0.0001
Invasive procedures
Cardiac catheterization 56.2 45.6 <0.0001
PCI 52.3 36.1 <0.0001
CABG 9.2 5.4 <0.0001
Revascularization 60.2 40.9 <0.0001
Any reperfusion therapy* 73.0 56.3 <0.0001
Primary PCI 61.1 47.3 <0.0001
Fibrinolytic Therapy 6.2 5.1
Fibrinolytic therapy + PCI 5.8 3.9
Timeliness of reperfusion*
DTN time median (25th-75th) min 39.0 47.0 <0.0001
DTB time median (25th – 75th) min 95.0 103.0 <0.0001
Circ 2008;118:2803
*STEMI subpopulation (28.2% women, 35.1% men, p<0.0001)

25. Mechanism of MI May be Different
in 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)

26. Treatment of Acute Myocardial Infarction
• Women have longer door-to-balloon times
• Women are less likely to undergo invasive
evaluation on the index admission regardless
of age
• Contemporary in-hospital and late mortality
rates are similar across genders when
treated in randomized controlled trials ~
treated irrespective of gender
Zahn R et al. Heart 2005;91(8):1041-6, Lansky AJ et al. Circulation 2005;111:940-953, Antman EM et al.
Circulation. 2008 Jan 15;117(2):296-329, Reynolds HR et al. Arch Intern Med 2007;
167:2054-2060, Milcent C et al. Circulation 2007;115:833-839.

27. AMI in Women:
Later Presentation and Delay in Treatment
- CADILLAC Primary PCI Trial-
P
Men Women Value
N 1520 562 -
Chest pain to ER (hrs) 2.6 ± 2.5 3.0 ± 2.6 < 0.001
ER to procedure (hrs) 1.9 ± 2.2 2.1 ± 2.3 < 0.001
Stent use 57% 57% NS
Abciximab use 54% 51% NS

28. Outcomes Following 1st Myocardial
Infarction
• 38% of women will die within one year versus 25%
of men
• Within 6 years 35% of women will have another MI
vs 18% of men
• More than twice as many women will be disabled
with heart failure within 6 years of their first MI
• Women are 55% less likely to participate in cardiac
rehabilitation
• Women experience more depressive symptoms
following AMI, particularly those <60 years old
Rosamond W et al. Circulation 2008;117:e25-146. Witt BJ et al. J Am Coll Cardiol 2004;44:988-
996, Mallik S et al Arch Inern Med 2006;166:876-883.

29. Primary PCI is Superior to Lytics in Women
Meta-Analysis - 23 Randomized Trials (PCAT-2)
16 Lytic
14.4
14 Primary PCI
30-Day Mortality
12
9.6
10 8.5
7.7
8 7.1
6 5.3 4.9
3.5
4
2
0
≤ 2 hrs > 2 hrs ≤ 2 hrs > 2 hrs
Women Men

30. What if we Treat Irrespective
of Gender?

31. CAD in Women: Conclusions
• The risk factor profile in women presenting with ACS
and AMI is distinctive compared to men. Women are
older, have more HTN, DM, but less extensive CAD
and better preserved LVEF.
• Despite having less extensive CAD, prognosis is
worse than in men
• Symptoms may be atypical – even in the midst of
AMI! Have a high level of suspicion
• In ACS and AMI women benefit from early invasive
strategy and enoxaparin therapy.

32. Treat With Parity
• Use clinical judgement
• Be an advocate for women in your
institution
• Look at your own local data
• Improve outcomes, improve your
practice, improve enrollment in clinical
trials