Cardiovascular Disease in Cardiovascular Disease in Women: the Yentl Syndrome Women: the Yentl Syndrome

Gender-related Issues in MedicineGender-related Issues in MedicineUCLA December 11, 2012 UCLA December 11, 2012

C. Noel Bairey Merz, M.D., F.A.C.C, F.A.H.AWomen’s Guild Endowed Chair in Women’s Health

Barbra Streisand Women’s Heart CenterPreventive and Rehabilitative Cardiac Center

Cedars-Sinai Heart InstituteLos Angeles, California USA

merz@cshs.org

Bernadine P. Healy, M.D.

• EDITORIAL• The Yentl Syndrome• Bernadine Healy, M.D.• N ENGL J MED 1991; 325:274-276• Yentl, the 19th-century heroine of Isaac Bashevis Singer's

short story, had to disguise herself as a man to attend school and study the Talmud. Being "just like a man" has historically been a price women have had to pay for equality. Being different from men has meant being second-class and less than equal for most of recorded time and throughout most of the world. It may therefore be sad, but not surprising, that women have all too often been treated less than equally in social relations, political endeavors, business, education, research, and health care.

Problem: Adverse Mortality Gap Resulting in a New Female CVD Majority (National Center for Health Statistics and American Heart Association)

Current Strategies Not Working Optimally in Women

Disparities in CVD Treatment for Disparities in CVD Treatment for WomenWomen

• 35,835 pts with NSTEMI: 41% women35,835 pts with NSTEMI: 41% women

• Women had:Women had: DM, HTN, age; DM, HTN, age; CAD events CAD events Early ASA, heparin, GPIIb-IIIa, ACE-IEarly ASA, heparin, GPIIb-IIIa, ACE-I Revascularizations: CABG Revascularizations: CABG 41%41% Discharge ASA, beta blocker, ACE-I, Discharge ASA, beta blocker, ACE-I,

statins (Four Magic Pills)* statins (Four Magic Pills)* Death, MI, CHFDeath, MI, CHF

Blomkalns AL et al. CRUSADE NSTEMI database. Blomkalns AL et al. CRUSADE NSTEMI database. J Am Coll CardiolJ Am Coll Cardiol. 2005;45:832-837.. 2005;45:832-837.

* Associated with a 90% reduction in recurrent major adverse cardiac events

Sex and Gender Differences in CVD

Terminology:• Sex = biological sexual differentiation,

(e.g. women have ovaries, men have testes)

• Gender = socio-cultural attributes of the biological sex, e.g. women have complex social networks, men have wives

Sex and Gender Differences in CVD

More Terminology:• Sex genotype = XX chromosomal makeup, e.g.

XX dictates ovarian development of stromal cells in utero.

• Sex phenotype = genotype expression given the certain conditions, e.g. premenopausal women higher estrogen levels due to ovulation; postmenopausal women have lower estrogen levels due to no ovulation. Both are XX genotype but differ in phenotypic expression.

Sex and Gender Differences in CVD

• Sex differences in perception = women have greater perception (high frequency non-auditory brain testing). Gay men are intermediate between women (higher perception) and men (lower perception), suggesting that this may be genotypic1

• Sex differences in pain = women have lower thermal pain thresholds compared to men. Thresholds appear mediated by estrogen levels, with higher E2 levels associated with enhanced pain, suggesting that this may be phenotypic2

1Shaywitz et al, Nature 1995;373:607; 2 Fillingim et al, Pain Forum 1995;4:209

Sex and Gender Differences in CVD

• Gender differences in reporting = women are more comfortable discussing feelings with friends and reporting symptoms to physicians1, possibly due to gender-related acculturation

• Gender differences in physician response to symptoms = physicians are more likely to evaluate men compared to women and minorities2, possibly due to gender-related presentation styles, and/or cultural sexism/racism biases

1 Stoverink J Fam Pract 1996;43:567

Sex and Gender Difference in CVDConsequences of Sex and Gender Symptom Issues:• If women perceive chest pain sooner after the onset of

ischemia/MI, this will lead to “longer” estimated “ischemia onset” times in the ED, potentially leading to conclusions that “women delay seeking treatment”1, as well as making more women “ineligible” for thrombolytic therapy. These may contribute to more adverse outcomes.2

• If women report generally more symptoms suggestive of chest pain, it will be a less effective diagnostic tool, e.g. less specific for epicardial disease3. This may lead to physician lack of confidence in testing, and may also suggest that chest pain symptoms may be difficult to optimize as a diagnostic tool.

1 Meischke Ann Emerg Med 1993;22:1597; 2Vaccarino, Ann Int Med 2001;134:173; 3 Diamond NEJM 1979;300:1350

Potential Explanations for Potential Explanations for Disparities in CVD Treatment in Disparities in CVD Treatment in

WomenWomen• Blame the victim – women do not seek healthcare Blame the victim – women do not seek healthcare

for symptoms and/or delay seeking attentionfor symptoms and/or delay seeking attention• Ageism – women are older on average and older Ageism – women are older on average and older

patients are less aggressively treatedpatients are less aggressively treated• Sexism (medical judgment) – women are less likely Sexism (medical judgment) – women are less likely

to have and/or die from CAD to have and/or die from CAD • Biological sex differences in CVD – women more Biological sex differences in CVD – women more

often present with “female-pattern” disease, which often present with “female-pattern” disease, which is not recognized compared to “male-pattern” is not recognized compared to “male-pattern” diseasedisease

Potential Explanations for Potential Explanations for Disparities in CVD Treatment in Disparities in CVD Treatment in

WomenWomen

• Blame the victim – women do not seek healthcare Blame the victim – women do not seek healthcare for symptoms and/or delay seeking attentionfor symptoms and/or delay seeking attention

• Ageism – women are older on average and older Ageism – women are older on average and older patients are less aggressively treatedpatients are less aggressively treated

• Sexism (medical judgment) – women are less likely Sexism (medical judgment) – women are less likely to have and/or die from CAD to have and/or die from CAD

• Biological sex differences in CVD – women more Biological sex differences in CVD – women more often present with “female-pattern” disease, which often present with “female-pattern” disease, which is not recognized compared to “male-pattern” is not recognized compared to “male-pattern” diseasedisease

Gender Differences in Healthcare Seeking in the ED Gender Differences in Healthcare Seeking in the ED for CV Symptoms: for CV Symptoms: Women and men report CV Women and men report CV

symptoms with same frequencysymptoms with same frequency

McKinlay JFl, J Health and Social Behavior 1996;37:1

Gender Differences in ED Care for CV Symptoms: Gender Differences in ED Care for CV Symptoms: Women receive Women receive less assessment for CV symptomsless assessment for CV symptoms

McKinlay JFl, J Health and Social Behavior 1996;37:1

Potential Explanations for Potential Explanations for Disparities in CVD Treatment in Disparities in CVD Treatment in

WomenWomen

• Blame the victim – women do not seek healthcare Blame the victim – women do not seek healthcare for symptoms and/or delay seeking attentionfor symptoms and/or delay seeking attention

• Ageism – women are older on average and older Ageism – women are older on average and older patients are less aggressively treatedpatients are less aggressively treated

• Sexism (medical judgment) – women are less likely Sexism (medical judgment) – women are less likely to have and/or die from CAD to have and/or die from CAD

• Biological sex differences in CVD – women more Biological sex differences in CVD – women more often present with “female-pattern” disease, which often present with “female-pattern” disease, which is not recognized compared to “male-pattern” is not recognized compared to “male-pattern” diseasedisease

Sex and Myocardial Infarction (MI) Mortality: Sex and Myocardial Infarction (MI) Mortality: Largest Gaps in Young WomenLargest Gaps in Young Women

Vaccarino V et al. NRMI. Vaccarino V et al. NRMI. N Engl J MedN Engl J Med. 1999;341:217-225. . 1999;341:217-225.

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Age (years)Age (years)Age (years)Age (years)

WomenWomenWomenWomen

MenMenMenMen

MenMen WomenWomen

Potential Explanations for Potential Explanations for Disparities in CVD Treatment in Disparities in CVD Treatment in

WomenWomen

• Blame the victim – women do not seek healthcare Blame the victim – women do not seek healthcare for symptoms and/or delay seeking attentionfor symptoms and/or delay seeking attention

• Ageism – women are older on average and older Ageism – women are older on average and older patients are less aggressively treatedpatients are less aggressively treated

• Sexism (medical judgment) – women are less likely Sexism (medical judgment) – women are less likely to have and/or die from CADto have and/or die from CAD

• Biological sex differences in CVD – women more Biological sex differences in CVD – women more often present with “female-pattern” disease, which often present with “female-pattern” disease, which is not recognized compared to “male-pattern” is not recognized compared to “male-pattern” diseasedisease

Paradox: Pathophysiological Paradox: Pathophysiological Gender Differences: FRISC IIGender Differences: FRISC II

• 749 women and 1,708 men with unstable coronary artery 749 women and 1,708 men with unstable coronary artery diseasedisease

• Entry criteria = symptoms plus ischemia, defined as ECG Entry criteria = symptoms plus ischemia, defined as ECG change or + enzymes change or + enzymes

• Randomized to early invasive versus noninvasive strategyRandomized to early invasive versus noninvasive strategy• Women were Women were olderolder, had fewer prior MI, better LVEF and , had fewer prior MI, better LVEF and

lower troponin T levelslower troponin T levels

Lagerqvist et al, JACC 2001;38:41

Women are less likely to have obstructive Women are less likely to have obstructive CAD BUT equally/more likely to dieCAD BUT equally/more likely to die

EF EF 45%45% 12%*12%* 14%14%

No CADNo CAD 25%*25%* 10%10%

LM/3 VD/2 LM/3 VD/2 VD/2 prox LADVD/2 prox LAD

32%*32%* 43%43%

Noninvasive Noninvasive (Death/MI)(Death/MI)

11%11% 16%16%

Invasive Invasive (Death/MI)(Death/MI)

12%12% 11%**11%**

Women Men

Lagerqvist et al, JACC 2001;38:41*p<0.05 vs men; ** P = 0.001 vs noninvasive

Female Male

Potential Explanations for Potential Explanations for Disparities in CVD Treatment in Disparities in CVD Treatment in

WomenWomen• Blame the victim – women do not seek healthcare Blame the victim – women do not seek healthcare

for symptoms and/or delay seeking attentionfor symptoms and/or delay seeking attention• Ageism – women are older on average and older Ageism – women are older on average and older

patients are less aggressively treatedpatients are less aggressively treated• Sexism (medical judgment) – women are less likely Sexism (medical judgment) – women are less likely

to have and/or die from CAD to have and/or die from CAD • Biological sex differences in CVD – women more Biological sex differences in CVD – women more

often present with “female-pattern” disease, which often present with “female-pattern” disease, which is not recognized compared to “male-pattern” is not recognized compared to “male-pattern” diseasedisease

Bugiardini and Bairey Merz JAMA 2005;293:477-84

Paradox: Women have a two-fold increase in “normal” coronary arteries in the setting of ACS, nonSTE and STE AMI

Female-pattern Ischemic Heart DiseaseMicrovascular Coronary Disease (MCD)

Angina

Abnormal SPECT

No obstructive CAD

Abnormal coronary flow reserve and elevated LVEDP

Diffuse atherosclerosisby IVUS

NCDR estimate 3 million women in the US – a largerproblem than breast cancer.

Circulation. 1999;99:1774

Female-pattern IHD is Associated with Female-pattern IHD is Associated with Increased Risk of Major Adverse CV Increased Risk of Major Adverse CV

Events: NHLBI WISE StudyEvents: NHLBI WISE Study

0

5

10

15

20

25

30

0.58-<2.23

2.23-<2.70

> 2.70

CFR

% With Major Event

All Women, N=190,p(trend)=0.03

No CAD, N=153,p(trend)=0.03

_

Pepine JACC 2010

Challenges for Women With IHDChallenges for Women With IHD●●Delays in symptom recognition and Delays in symptom recognition and

treatmenttreatment●●MisdiagnosisMisdiagnosis●●Lower use of angiography, revascularization, aspirin, beta Lower use of angiography, revascularization, aspirin, beta

blockers, statins, agiotensin-converting enzyme inhibitors blockers, statins, agiotensin-converting enzyme inhibitors (ACE-I)(4 Magic Pills)*(ACE-I)(4 Magic Pills)*

●●Less counseling and risk factor controlLess counseling and risk factor control●●Fewer referrals to cardiac rehab; Fewer referrals to cardiac rehab;

more “drop-outs”more “drop-outs”●●Lower adherence to proven guidelines (ACC/AHA, NCEP, Lower adherence to proven guidelines (ACC/AHA, NCEP,

JNC VII, etc)JNC VII, etc)

↑ Mortality* Associated with a 90% reduction in recurrent major adverse cardiac events

The Yentl Syndromeis Alive and Well in 2011 Bairey Merz, EHJ 2011

→Men > women withwith recognized angina/ACS

The Yentl Syndromeis Alive and Well in 2011 Bairey Merz, EHJ 2011

→Men > women withwith recognized angina/ACS

→Men > women go to coronaryangiography

The Yentl Syndromeis Alive and Well

in 2011 Bairey Merz, EHJ 2011

→Men > women withwith recognized

angina/ACS

→Men > women go to

coronaryangiography

→Men > women receive

guidelines Rx

The Yentl Syndromeis Alive and Well in 2011 Bairey Merz, EHJ

2011

→Men > women withwith recognized

angina/ACS

→Men > women go to

coronaryangiography

→Men > women

receiveguidelines Rx

→Women > men death

What is the Answer?What is the Answer?

• What is the Problem?What is the Problem?• Lack of patient response to symptoms?Lack of patient response to symptoms?• Provider sexism (medical judgment)?Provider sexism (medical judgment)?• Ageism?Ageism?• Lack of knowledge and recognition of female-Lack of knowledge and recognition of female-

pattern ischemic heart disease resulting in pattern ischemic heart disease resulting in failure to use guidelines therapy?failure to use guidelines therapy?

What is the Answer?What is the Answer?

• What is the Problem?What is the Problem?• Lack of patient response to symptoms?Lack of patient response to symptoms?• Provide sexism (medical judgment)?Provide sexism (medical judgment)?• Ageism?Ageism?• Lack of knowledge and recognition of female-Lack of knowledge and recognition of female-

pattern ischemic heart disease resulting in pattern ischemic heart disease resulting in failure to use guidelines therapyfailure to use guidelines therapy

How to Get ResultsHow to Get Results• Re-name it “Ischemic Heart Disease (IHD) Re-name it “Ischemic Heart Disease (IHD)

rather than “Coronary Artery Disease (CAD)”rather than “Coronary Artery Disease (CAD)”

• Use a simplified approach to IHD Use a simplified approach to IHD management helps to increase adherence to management helps to increase adherence to guidelinesguidelines

• This can be achieved using an ABC format to This can be achieved using an ABC format to present important pharmacologic therapies present important pharmacologic therapies and lifestyle approachesand lifestyle approaches

Know Your ABCsKnow Your ABCs

• A A • Antiplatelets/anticoagulants*Antiplatelets/anticoagulants*• Angtiotensin-converting enzyme (ACE) Angtiotensin-converting enzyme (ACE)

inhibitors/angiotensin-receptor blockers inhibitors/angiotensin-receptor blockers (ARBs)*(ARBs)*

• AntianginalsAntianginals• BB

• Blood pressure controlBlood pressure control• Beta-blocker*Beta-blocker*

• CC• Cholesterol management (statin)*Cholesterol management (statin)*• Cigarette smoking cessationCigarette smoking cessation

* 4 Magic Pills

What About Women (and Men) with What About Women (and Men) with Female-Pattern Ischemic Heart Disease?Female-Pattern Ischemic Heart Disease?

• Remember, ACS/angina guidelines are Remember, ACS/angina guidelines are not “cath” based – treat evidence of not “cath” based – treat evidence of ischemia and angina, not the cathischemia and angina, not the cath

• Abundant evidence exists documenting Abundant evidence exists documenting lifesaving risk reduction of the 4 magic pills lifesaving risk reduction of the 4 magic pills (ASA, ACE, BB, statin)(ASA, ACE, BB, statin)

• The power of the prescription pen to The power of the prescription pen to implement guidelines therapy implement guidelines therapy preferentially saves women’s livespreferentially saves women’s lives

• This slide set was adapted from the following 2004-6 ACC/AHA guidelines:

• Cardiovascular Disease Prevention in Women 2004, 2007, 2010

• Management of Patients With ST-Elevation Myocardial Infarction

• Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction

• Preventing Heart Attack and Death in Patients with Atherosclerotic Cardiovascular Disease

• Management of Patients with Chronic Stable Angina

• Update for Coronary Artery Bypass Graft Surgery

• Evaluation and Management of Chronic Heart Failure in the Adult

• The full-text guidelines and executive summaries are also available on the

• ACC and AHA websites at www.acc.org and www.americanheart.org

Clinical Practice Guidelines

ACC=American College of Cardiology, AHA=American Heart Association

Impact of AHA Get With The Guidelines-CAD Impact of AHA Get With The Guidelines-CAD Program on Quality of CareProgram on Quality of Care

93

79

64 6757

95

83

6570 70

9787

6573 76

9687

6775 75

9791

6874

82

0102030405060708090

100

Aspirin Beta Blocker ACE Inhibitor Lipid Rx SmokingCessation

Baseline Q1 Q2 Q3 Q4

GWTG-CAD: 123 US Hospitals n=27,825Labresh, Fonarow et al. Circulation 2003;108:IV-722

GuidelineImplementation andACS and the Sex Survival Gap

Novak et al Am J Medicine 2008;121:602.

GuidelineImplementation andACS and the Sex Survival Gap

Following guidelineimplementation, mortality for womenimproves andthe sex gap narrows(RED)

Novak et al Am J Medicine 2008;121:602.

+

GuidelineImplementation andACS and the Sex Survival Gap

Following guidelineimplementation, mortality for womenimproves andthe sex gap narrows(RED)

Persistent sex gap (BLUE)suggests more workstill neededto understand sex-specific pathophysiologyto improve outcomesfor women and men

Novak et al Am J Medicine 2008;121:602.

+

1615PC Bairey-Merz/Slide #39

Women’s IschemiaSyndrome Evaluation

WISE

WISE-ISCHEMIA:WISE-ISCHEMIA:A Companion Trial to the A Companion Trial to the

NHLBI-sponsored ISCHEMIANHLBI-sponsored ISCHEMIANoel Bairey Merz MDNoel Bairey Merz MD

Carl Pepine MDCarl Pepine MDHarmony Reynolds MDHarmony Reynolds MD

Leslee Shaw PhDLeslee Shaw PhDEileen Handberg PhDEileen Handberg PhD

Rhonda Cooper-DeHoff PharmDRhonda Cooper-DeHoff PharmDJohn Spertus MDJohn Spertus MDDavid Maron MDDavid Maron MD

Judy Hochman MDJudy Hochman MD

International Study of Comparative Health Effectiveness with

Medical and Invasive ApproachesISCHEMIA

ISCHEMIAEnrolled patients

n=8650

ISCHEMIA - typePatients sent to

cath lab clinically(evidence of

ischemia)

Randomized in main trialn=8000

No obstructive CAD by ISCHEMIA CCTA

n ~ 250-400

No obstructive CAD by clinical invasive

coronary angiography n= 2200-2350

Obstructive CAD

WISE – ISCHEMIARandomized trial

n=2600

LM

no obstructive CAD(US/Canada)

ISCHEMIA

eligible

cons

ent

consent

no obstructive CAD

excluded

excluded

Figure 1. ISCHEMIA-WISE Companion Trial to ISCHEMIA

Current Strategies Not Working Optimally in Women

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Problem: Adverse Mortality Gap Resulting in a New Female CVD Majority (National Center for Health Statistics and American Heart Association)

NHLBI WISE Study And Guidelines Campaigns

Cardiovascular disease mortality trends for males and Cardiovascular disease mortality trends for males and females females (United States: 1979-2004).United States: 1979-2004). Source: NCHS and NHLBI

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79 80 85 90 95 00 04

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Problem: Adverse Mortality Gap Resulting in a New Female CVD Majority Solution: Clinical Translational Research and Guidelines

NHLBI WISE Study, NHLBI and AHA Red Dress Awarenessand Guidelines Campaigns

Summary: Women and Heart Summary: Women and Heart DiseaseDisease

• Women face a higher mortality from IHD Women face a higher mortality from IHD due to their relatively higher prevalence of due to their relatively higher prevalence of “female-pattern” ischemic heart disease“female-pattern” ischemic heart disease

• Application of guidelines therapy is improving outcomes in women with IHD.

• Ongoing work is evaluating mechanisms and interventions directed at sex differences in IHD.

• Questions, comments, referrals? Questions, comments, referrals? merz@cshs.orgmerz@cshs.org