1. Cardiovascular Disease in Women: the Yentl Syndrome Gender-related Issues in Medicine UCLA December 11, 2012 C. Noel Bairey Merz, M.D., F.A.C.C, F.A.H.A Women’s Guild Endowed Chair in Women’s Health Barbra Streisand Women’s Heart Center Preventive and Rehabilitative Cardiac Center Cedars-Sinai Heart Institute Los Angeles, California USA merz@cshs.org

2. Bernadine P. Healy, M.D.

3. 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.

4. 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

5. Disparities in CVD Treatment for Women 35,835 pts with NSTEMI: 41% women35,835 pts with NSTEMI: 41% women Women had:Women had:  DM, HTN, age;  CAD events  DM, HTN, age;  CAD events  Early ASA, heparin, GPIIb-IIIa, ACE-I  Early ASA, heparin, GPIIb-IIIa, ACE-I  Revascularizations: CABG  41%  Revascularizations: CABG  41%  Discharge ASA, beta blocker, ACE-I, statins (Four Magic Pills)*  Discharge ASA, beta blocker, ACE-I, statins (Four Magic Pills)*  Death, MI, CHF  Death, MI, CHF Blomkalns AL et al. CRUSADE NSTEMI database. J Am Coll Cardiol. 2005;45:832-837. * Associated with a 90% reduction in recurrent major adverse cardiac events

6. 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

7. 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.

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

9. Sex and Gender Differences in CVD Gender differences in reporting = women are more comfortable discussing feelings with friends and reporting symptoms to physicians 1, possibly due to gender-related acculturation Gender differences in physician response to symptoms = physicians are more likely to evaluate men compared to women and minorities 2, possibly due to gender-related presentation styles, and/or cultural sexism/racism biases 1 Stoverink J Fam Pract 1996;43:567

10. Sex and Gender Difference in CVD Consequences 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 disease 3. 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; 2 Vaccarino, Ann Int Med 2001;134:173; 3 Diamond NEJM 1979;300:1350

11. Potential Explanations for Disparities in CVD Treatment in Women Blame the victim – women do not seek healthcare for symptoms and/or delay seeking attentionBlame the victim – women do not seek healthcare for symptoms and/or delay seeking attention Ageism – women are older on average and older patients are less aggressively treatedAgeism – women are older on average and older patients are less aggressively treated Sexism (medical judgment) – women are less likely to have and/or die from CADSexism (medical judgment) – women are less likely to have and/or die from CAD Biological sex differences in CVD – women more often present with “female-pattern” disease, which is not recognized compared to “male-pattern” diseaseBiological sex differences in CVD – women more often present with “female-pattern” disease, which is not recognized compared to “male-pattern” disease

12. Potential Explanations for Disparities in CVD Treatment in Women Blame the victim – women do not seek healthcare for symptoms and/or delay seeking attentionBlame the victim – women do not seek healthcare for symptoms and/or delay seeking attention Ageism – women are older on average and older patients are less aggressively treatedAgeism – women are older on average and older patients are less aggressively treated Sexism (medical judgment) – women are less likely to have and/or die from CADSexism (medical judgment) – women are less likely to have and/or die from CAD Biological sex differences in CVD – women more often present with “female-pattern” disease, which is not recognized compared to “male-pattern” diseaseBiological sex differences in CVD – women more often present with “female-pattern” disease, which is not recognized compared to “male-pattern” disease

13. Gender Differences in Healthcare Seeking in the ED for CV Symptoms: Women and men report CV symptoms with same frequency McKinlay JFl, J Health and Social Behavior 1996;37:1

14. Gender Differences in ED Care for CV Symptoms: Women receive less assessment for CV symptoms McKinlay JFl, J Health and Social Behavior 1996;37:1

15. Potential Explanations for Disparities in CVD Treatment in Women Blame the victim – women do not seek healthcare for symptoms and/or delay seeking attentionBlame the victim – women do not seek healthcare for symptoms and/or delay seeking attention Ageism – women are older on average and older patients are less aggressively treatedAgeism – women are older on average and older patients are less aggressively treated Sexism (medical judgment) – women are less likely to have and/or die from CADSexism (medical judgment) – women are less likely to have and/or die from CAD Biological sex differences in CVD – women more often present with “female-pattern” disease, which is not recognized compared to “male-pattern” diseaseBiological sex differences in CVD – women more often present with “female-pattern” disease, which is not recognized compared to “male-pattern” disease

16. Sex and Myocardial Infarction (MI) Mortality: Largest Gaps in Young Women Vaccarino V et al. NRMI. N Engl J Med. 1999;341:217-225. Hospital Mortality (%) OverallOverall 302520151050 <5050-5455-5960-6465-6970-7475-7980-8485-89 Age (years) WomenWomen MenMen MenWomen

17. Potential Explanations for Disparities in CVD Treatment in Women Blame the victim – women do not seek healthcare for symptoms and/or delay seeking attentionBlame the victim – women do not seek healthcare for symptoms and/or delay seeking attention Ageism – women are older on average and older patients are less aggressively treatedAgeism – women are older on average and older patients are less aggressively treated Sexism (medical judgment) – women are less likely to have and/or die from CADSexism (medical judgment) – women are less likely to have and/or die from CAD Biological sex differences in CVD – women more often present with “female-pattern” disease, which is not recognized compared to “male-pattern” diseaseBiological sex differences in CVD – women more often present with “female-pattern” disease, which is not recognized compared to “male-pattern” disease

18. Paradox: Pathophysiological Gender Differences: FRISC II 749 women and 1,708 men with unstable coronary artery disease749 women and 1,708 men with unstable coronary artery disease Entry criteria = symptoms plus ischemia, defined as ECG change or + enzymesEntry criteria = symptoms plus ischemia, defined as ECG change or + enzymes Randomized to early invasive versus noninvasive strategyRandomized to early invasive versus noninvasive strategy Women were older, had fewer prior MI, better LVEF and lower troponin T levelsWomen were older, had fewer prior MI, better LVEF and lower troponin T levels Lagerqvist et al, JACC 2001;38:41

19. Women are less likely to have obstructive CAD BUT equally/more likely to die EF  45% 12%*14% No CAD 25%*10% LM/3 VD/2 VD/2 prox LAD 32%*43% Noninvasive (Death/MI) 11%16% Invasive (Death/MI) 12%11%** WomenMen Lagerqvist et al, JACC 2001;38:41 *p<0.05 vs men; ** P = 0.001 vs noninvasive FemaleMale

20. Potential Explanations for Disparities in CVD Treatment in Women Blame the victim – women do not seek healthcare for symptoms and/or delay seeking attentionBlame the victim – women do not seek healthcare for symptoms and/or delay seeking attention Ageism – women are older on average and older patients are less aggressively treatedAgeism – women are older on average and older patients are less aggressively treated Sexism (medical judgment) – women are less likely to have and/or die from CADSexism (medical judgment) – women are less likely to have and/or die from CAD Biological sex differences in CVD – women more often present with “female-pattern” disease, which is not recognized compared to “male-pattern” diseaseBiological sex differences in CVD – women more often present with “female-pattern” disease, which is not recognized compared to “male-pattern” disease

21. 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

22. Female-pattern Ischemic Heart Disease Microvascular Coronary Disease (MCD) Angina Abnormal SPECT No obstructive CAD Abnormal coronary flow reserve and elevated LVEDP Diffuse atherosclerosis by IVUS NCDR estimate 3 million women in the US – a larger problem than breast cancer. Circulation. 1999;99:1774

23. Female-pattern IHD is Associated with Increased Risk of Major Adverse CV Events: NHLBI WISE Study _ Pepine JACC 2010

24. Challenges for Women With IHD ● Delays in symptom recognition and treatment ● Misdiagnosis ● Lower use of angiography, revascularization, aspirin, beta blockers, statins, agiotensin-converting enzyme inhibitors (ACE-I)(4 Magic Pills)* ● Less counseling and risk factor control ● Fewer referrals to cardiac rehab; more “drop-outs” ● Lower adherence to proven guidelines (ACC/AHA, NCEP, JNC VII, etc) ↑ Mortality * Associated with a 90% reduction in recurrent major adverse cardiac events

25. The Yentl Syndrome is Alive and Well in 2011 Bairey Merz, EHJ 2011 → Men > women with with recognized angina/ACS

26. The Yentl Syndrome is Alive and Well in 2011 Bairey Merz, EHJ 2011 → Men > women with with recognized angina/ACS → Men > women go to coronary angiography

27. The Yentl Syndrome is Alive and Well in 2011 Bairey Merz, EHJ 2011 → Men > women with with recognized angina/ACS → Men > women go to coronary angiography → Men > women receive guidelines Rx

28. The Yentl Syndrome is Alive and Well in 2011 Bairey Merz, EHJ 2011 → Men > women with with recognized angina/ACS → Men > women go to coronary angiography → Men > women receive guidelines Rx → Women > men death

29. 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- pattern ischemic heart disease resulting in failure to use guidelines therapy?Lack of knowledge and recognition of female- pattern ischemic heart disease resulting in failure to use guidelines therapy?

30. 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- pattern ischemic heart disease resulting in failure to use guidelines therapyLack of knowledge and recognition of female- pattern ischemic heart disease resulting in failure to use guidelines therapy

31. How to Get Results Re-name it “Ischemic Heart Disease (IHD) rather than “Coronary Artery Disease (CAD)”Re-name it “Ischemic Heart Disease (IHD) rather than “Coronary Artery Disease (CAD)” Use a simplified approach to IHD management helps to increase adherence to guidelinesUse a simplified approach to IHD management helps to increase adherence to guidelines This can be achieved using an ABC format to present important pharmacologic therapies and lifestyle approachesThis can be achieved using an ABC format to present important pharmacologic therapies and lifestyle approaches

32. Know Your ABCs A Antiplatelets/anticoagulants*Antiplatelets/anticoagulants* Angtiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor blockers (ARBs)*Angtiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor blockers (ARBs)* AntianginalsAntianginals B Blood pressure controlBlood pressure control Beta-blocker*Beta-blocker* C Cholesterol management (statin)*Cholesterol management (statin)* Cigarette smoking cessationCigarette smoking cessation * 4 Magic Pills

33. What About Women (and Men) with Female-Pattern Ischemic Heart Disease? Remember, ACS/angina guidelines are not “cath” based – treat evidence of ischemia and angina, not the cathRemember, ACS/angina guidelines are not “cath” based – treat evidence of ischemia and angina, not the cath Abundant evidence exists documenting lifesaving risk reduction of the 4 magic pills (ASA, ACE, BB, statin)Abundant evidence exists documenting lifesaving risk reduction of the 4 magic pills (ASA, ACE, BB, statin) The power of the prescription pen to implement guidelines therapy preferentially saves women’s livesThe power of the prescription pen to implement guidelines therapy preferentially saves women’s lives

34. 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

35. Impact of AHA Get With The Guidelines-CAD Program on Quality of Care GWTG-CAD: 123 US Hospitals n=27,825 Labresh, Fonarow et al. Circulation 2003;108:IV-722

36. Guideline Implementation and ACS and the Sex Survival Gap Novak et al Am J Medicine 2008;121:602.

37. Guideline Implementation and ACS and the Sex Survival Gap Following guideline implementation, mortality for women improves and the sex gap narrows (RED) Novak et al Am J Medicine 2008;121:602. +

38. Guideline Implementation and ACS and the Sex Survival Gap Following guideline implementation, mortality for women improves and the sex gap narrows (RED) Persistent sex gap (BLUE) suggests more work still needed to understand sex- specific pathophysiology to improve outcomes for women and men Novak et al Am J Medicine 2008;121:602. +

39. 1615PC Bairey-Merz/Slide #39 Women’s Ischemia Syndrome Evaluation WISE WISE-ISCHEMIA: A Companion Trial to the NHLBI-sponsored ISCHEMIA Noel Bairey Merz MD Carl Pepine MD Harmony Reynolds MD Leslee Shaw PhD Eileen Handberg PhD Rhonda Cooper-DeHoff PharmD John Spertus MD David Maron MD Judy Hochman MD International Study of Comparative Health Effectiveness with Medical and Invasive Approaches ISCHEMIA

40. Enrolled patients n=8650 ISCHEMIA - type Patients sent to cath lab clinically (evidence of ischemia) Randomized in main trial n=8000 No obstructive CAD by ISCHEMIA CCTA n ~ 250-400 No obstructive CAD by clinical invasive coronary angiography n= 2200-2350 Obstructive CAD WISE – ISCHEMIA Randomized trial n=2600 LM no obstructive CAD (US/Canada) ISCHEMIA eligible consent no obstructive CAD excluded Figure 1. ISCHEMIA-WISE Companion Trial to ISCHEMIA

41. Atherothombotic Strategy Atorvastatin 40-80 mg daily Aspirin 81-325mg daily Hypertension / Angina Strategy Step 1 Metoprolol 50- 400mg or Verapamil SR 240-480mg if metoprolol intolerant daily Step 2 Add ramipril 2.5-20mg daily or losartan 50-100mg daily for ramipril intolerant Step 3 Add HCTZ 12.5-25mg daily Continued Angina Strategy Step 1 Isosorbide mononitrate 30-120mg daily Step 2 Add ranolazine 500-1000mg twice daily

42. Current Strategies Not Working Optimally in Women 0 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

43. Cardiovascular disease mortality trends for males and females United States: 1979-2004). Cardiovascular disease mortality trends for males and females (United States: 1979-2004). Source: NCHS and NHLBI 0 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 Awareness and Guidelines Campaigns

44. Summary: Women and Heart Disease Women face a higher mortality from IHD due to their relatively higher prevalence of “female-pattern” ischemic heart diseaseWomen face a higher mortality from IHD due to their relatively higher prevalence of “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? merz@cshs.orgQuestions, comments, referrals? merz@cshs.org