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 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 Women • 35,835 pts with NSTEMI: 41% women • Women had: DM, HTN, age; CAD events Early ASA, heparin, GPIIb-IIIa, ACE-I Revascularizations: CABG 41% Discharge ASA, beta blocker, ACE-I, statins (Four Magic Pills)* • Death, MI, CHF • • • • * Associated with a 90% reduction in recurrent major adverse cardiac events Blomkalns AL et al. CRUSADE NSTEMI database. J Am Coll Cardiol. 2005;45:832-837. 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 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 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 Disparities in CVD Treatment in Women • Blame 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 treated • Sexism (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” disease Potential Explanations for Disparities in CVD Treatment in Women • Blame 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 treated • Sexism (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” disease 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 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 Potential Explanations for Disparities in CVD Treatment in Women • Blame 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 treated • Sexism (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” disease Sex and Myocardial Infarction (MI) Mortality: Largest Gaps in Young Women Hospital Mortality (%) 30 25 20 15 Women 10 Men 5 0 Men Men Women Women Overall <50 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 Age (years) Vaccarino V et al. NRMI. N Engl J Med. 1999;341:217-225. Potential Explanations for Disparities in CVD Treatment in Women • Blame 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 treated • Sexism (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” disease Paradox: Pathophysiological Gender Differences: FRISC II • 749 women and 1,708 men with unstable coronary artery disease • Entry criteria = symptoms plus ischemia, defined as ECG change or + enzymes • Randomized to early invasive versus noninvasive strategy • Women were older, had fewer prior MI, better LVEF and lower troponin T levels Lagerqvist et al, JACC 2001;38:41 Women are less likely to have obstructive CAD BUT equally/more likely to die FemaleWomen Male Men EF 45% 12%* 14% No CAD 25%* 10% LM/3 VD/2 VD/2 prox LAD Noninvasive (Death/MI) Invasive (Death/MI) 32%* 43% 11% 16% 12% 11%** *p<0.05 vs men; ** P = 0.001 vs noninvasive Lagerqvist et al, JACC 2001;38:41 Potential Explanations for Disparities in CVD Treatment in Women • Blame 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 treated • Sexism (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” disease Paradox: Women have a two-fold increase in “normal” coronary arteries in the setting of ACS, nonSTE and STE AMI Bugiardini and Bairey Merz JAMA 2005;293:477-84 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 Female-pattern IHD is Associated with Increased Risk of Major Adverse CV Events: NHLBI WISE Study 30 25 20 A ll Wo m e n, N =19 0 , p( t re nd) =0 .0 3 % Wit h M a jo r 15 E v e nt N o C A D , N =15 3 , p( t re nd) =0 .0 3 10 5 0 0 .5 8 <2 .2 3 Pepine JACC 2010 2 .2 3 <2 .7 0 CFR _ > 2 .7 0 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 The Yentl Syndrome is Alive and Well in 2011 Bairey Merz, EHJ 2011 → Men > women with with recognized angina/ACS 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 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 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 What is the Answer? • What is the Problem? • • • • Lack of patient response to symptoms? Provider sexism (medical judgment)? Ageism? Lack of knowledge and recognition of femalepattern ischemic heart disease resulting in failure to use guidelines therapy? What is the Answer? • What is the Problem? • • • • Lack of patient response to symptoms? Provide sexism (medical judgment)? Ageism? Lack of knowledge and recognition of femalepattern ischemic heart disease resulting in failure to use guidelines therapy How to Get Results • 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 guidelines • This can be achieved using an ABC format to present important pharmacologic therapies and lifestyle approaches Know Your ABCs • A • Antiplatelets/anticoagulants* • Angtiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor blockers (ARBs)* • Antianginals • B • Blood pressure control • Beta-blocker* • C • Cholesterol management (statin)* • Cigarette smoking cessation * 4 Magic Pills 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 cath • 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 lives Clinical Practice Guidelines • 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 ACC=American College of Cardiology, AHA=American Heart Association Impact of AHA Get With The Guidelines-CAD Program on Quality of Care Q1 Baseline 100 90 80 70 60 50 40 30 20 10 0 97 97 9395 96 83 79 8787 Q4 91 64656567 Aspirin Q3 Q2 68 737574 70 67 Beta Blocker ACE Inhibitor GWTG-CAD: 123 US Hospitals n=27,825 Labresh, Fonarow et al. Circulation 2003;108:IV-722 70 7675 82 57 Lipid Rx Smoking Cessation Guideline Implementation and ACS and the Sex Survival Gap Novak et al Am J Medicine 2008;121:602. 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. 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 sexspecific pathophysiology to improve outcomes for women and men + Novak et al Am J Medicine 2008;121:602. 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 Women’s Ischemia Syndrome Evaluation WISE International Study of Comparative Health Effectiveness with Medical and Invasive Approaches 1615PC Bairey-Merz/Slide39# Figure 1. ISCHEMIA-WISE Companion Trial to ISCHEMIA ISCHEMIA Enrolled patients n=8650 C C T A LM no obstructive CAD (US/Canada) ISCHEMIA - type Patients sent to cath lab clinically (evidence of ischemia) C A T H Randomized in main trial n=8000 no obstructive CAD excluded No obstructive CAD by ISCHEMIA CCTA n ~ 250-400 WISE – ISCHEMIA Randomized trial n=2600 No obstructive CAD by clinical invasive coronary angiography n= 2200-2350 Obstructive CAD excluded Atherothombotic Strategy Atorvastatin 40-80 mg daily Aspirin 81-325mg daily Hypertension / Angina Strategy Step 1 • Metoprolol 50400mg or Verapamil SR 240-480mg if metoprolol intolerant daily Continued Angina Strategy Step 1 • Isosorbide mononitrate 30-120mg daily Step 2 Step 2 • Add ramipril 2.5-20mg daily or losartan 50-100mg daily for ramipril intolerant Step 3 • Add HCTZ 12.5-25mg daily • Add ranolazine 500-1000mg twice daily Problem: Adverse Mortality Gap Resulting in a New Female CVD Majority (National Center for Health Statistics and American Heart Association) Deaths in Thousands 520 500 480 460 NHLBI WISE Study And Guidelines Campaigns 440 420 400 3800 79 80 85 90 95 Years Males Females 00 04 Problem: Adverse Mortality Gap Resulting in a New Female CVD Majority Solution: Clinical Translational Research and Guidelines Deaths in Thousands 520 500 480 460 440 420 400 3800 79 80 85 90 95 Years Males Females NHLBI WISE Study, NHLBI and AHA Red Dress Awareness and Guidelines Campaigns 00 04 Summary: Women and Heart Disease • Women 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.org