1. Update on Women and Cardiovascular Disease Amy Rawl Epps, M.D. Columbia Cardiology 2/5/09

2. Financial Relationships “As it pertains to CME, I have no relevant financial relationships with any commercial interest to disclose.”

3. Why is it so critical to recognize and diagnose CAD in women? Circulation 2005 Although US men have experienced a decline in CAD deaths, the number of coronary deaths in women, >240 000 annually, has increased CAD is a substantial cause of morbidity and disability for US women. Women, in particular young women (<55 years), have a worse prognosis from acute MI than their male counterparts, with a greater recurrence of MI and higher mortality. Up to 40% of initial cardiac events in women are fatal

4. * Number of deaths are rounded to the nearest thousand. COPD = chronic obstructive pulmonary disease. National Heart, Lung, and Blood Institute. The Healthy Heart Handbook for Women. 2003. Cause of Death Number of Deaths * 0 50,000 100,000 150,000 200,000 250,000 300,000 350,000 400,000 Heart Disease 366,000 Breast Cancer 42,000 COPD 62,000 Lung Cancer 65,000 Stroke 103,000 CHD mortality rate 10 X that from breast cancer 50% > all forms of cancer combined 38% one-year morality post-MI 46% six-year disability rate from CHF

5. Mortality Rates for Women United States 2001

6. CVD Mortality Trends for Males and Females: US 1979–2002 American Heart Association. Heart Disease and Stroke Statistics — 2005 Update. Dallas, Tex: American Heart Association; 2005. ©2005, American Heart Association. Years Males Females 400 440 480 520 0 1979 81 8385 87 89 91 93959799 0102 Deaths (thousands) NCEP I NCEP IINCEP III NCEP = National Cholesterol Education Program.

7. Compared with Men:  38% of women and 25% of men will die within one year of a first recognized heart attack.  35% of women and 18% of men heart attack survivors will have another heart attack within six years.  46% of women and 22% of men heart attack survivors will be disabled with heart failure within six years.  Women are almost twice as likely as men to die after bypass surgery.  Women are less likely than men to receive beta-blockers, ACE inhibitors or even aspirin after a heart attack.  More women than men die of heart disease each year, yet women receive only:  33% of angioplasties, stents and bypass surgeries  28% of inplantable defibrillators and  36% of open-heart surgeries  Women comprise only 25% of participants in all heart-related research studies.

8. Similar risk profile for men and women

10. Circulation. 2004;109:573-579

11. Why Women Don’t Women Take Action Against Heart Disease  Stereotype of only men getting heart disease  More concerned about ‘other’ diseases  Think they’re not old enough to be at risk  More accustomed to the role of caregiver  They don’t put their health as a top priority  Too busy to deal with it…do it later  Already feeling tired & stressed out

13. Risk Stratification: How much risk am I at?

14. Risk Stratification: Major Risk Factors:  Age > 55 years  Smoking  Hypertension (whether or not controlled with medication)  HDL cholesterol 130-160) (HDL cholesterol ≥ 60mg/dL is a negative risk factor)  Family history of premature CVD (Defined as CVD in a female first degree relative < 65 years old, or a first degree male relative < 55 years old)  Obesity/Sedentary Lifestyle ‘CHD equivalent’ (automatically places in “high-risk” category)  Diabetes  Established atherosclerotic disease (carotid, peripheral)  +/- kidney disease Source: Mosca 2004, ATP III 2002

15. Key Tests for Heart Disease Risk Risk Stratification  Blood pressure  Blood cholesterol  Fasting plasma glucose (diabetes test)  Body mass index (BMI) Testing  Electrocardiogram  Stress test  Other

16. Coronary Disease Mortality and Diabetes in Women Mortality (per 1000 women)

17. Relative Risk of Coronary Events for Smokers Compared to Non-Smokers Source: Adapted from Stampfer 2000 >

18. Obesity & Heart Disease <1.0

19. Body Weight & CHD Mortality Among Women P for trend < 0.001 ≥ Source: Adapted from Manson 1995

20. Noninvasive diagnostic and prognostic testing offers the potential to identify women at increased CAD risk and establish the basis for instituting preventive and therapeutic interventions.

21. PITFALLS in Diagnosing Heart Disease in Women Some diagnostic tests and procedures may not be as accurate in women, so physicians may avoid using them. (For example, the exercise stress test may be less accurate in women and giving a false positive result.) That means the disease process resulting in a heart attack or stroke may not be detected in women until later, with more serious consequences. More precise noninvasive and less invasive diagnostic tests tend to cost more. These include nuclear or echocardiographic stress tests and cardiac CT/MRI.

22. Evaluating for Ischemic Heart Disease is Difficult to do in Women  Symptoms are more likely to be atypical and therefore difficult to recognize  Higher rate of functional disability (due to co- morbidities)  Lower prevalence of obstructive CAD by coronary angiography as compared to men- therefore diagnostic accuracy of testing is variable and confusing

23. Questions to ask yourself before ordering a test……  What is the patient's pretest risk of disease?  How does the sensitivity and specificity of the alternative tests compare?  What are the costs and effects on health outcomes of each test?  Do special considerations make one test more suitable than another in a specific patient?

24. Benefits of the Stress ECG  Valuable prognostic information can be learned!!  Chronotropic and hemodynamic responses to exercise  Duke Treadmill Score can predict significant coronary stenosis  Women who exercise <5 metabolic equivalents (METs) are at increased risk of death

25. Prognostic value of functional capacity in asymptomatic (n = 8,715) and symptomatic (n = 8,214) women as synthesized from published reports

26. Disparity even after Stress Testing  Several researchers have found that a positive exercise test in women is often not followed up with subsequent testing. This finding has been cited as the reason for lower rates of catheterization and coronary bypass surgery in women and for the higher mortality of women after cardiac surgery. (Annals of Int Med 1990;112:561-7)  Other researchers have suggested that differences between the sexes in rates of treatment derive from the overtreatment of men at low risk of disease or death and an appropriately conservative level of care for women. (Annals of Int Med 1992;116: 791-7)  In men and women with a similar prevalence of abnormal results on initial stress tests for the diagnosis of coronary heart disease,additional studies were performed in only 38% of women, as compared with 62.3% of men. Follow-up revealed a higher incidence of coronary events in the women, regardless of initial stress-test results (1.6% for women with normal test results vs. 0.8 % for men; 14.3% for women with abnormal test results vs. 6.0% for men).

27. Cardiac CT Angiography

28. 3-D Volume Rendered Image

29. Coronary Angiography

30. SYMPTOMS OF A HEART ATTACK

31. JAMA. 2000;283:3223-3229

32. Atypical Warning Signs in Women

33. Early Warning Symptoms in Women Circulation. 2003;108:2619

34. Stable Angina  Women describe their angina using a more emotional presentation, calling the pain “hot-burning” or “tender” and rating it as more intense  More women than men suffer from chronic stable angina  The female stable angina patient is usually older than the male stable angina patient and female Syndrome X patients, and more often has diabetes and high hs-CRP levels  Compared with men, women with stable angina tend to receive fewer diagnostic tests, fewer prescriptions for recommended medications, and fewer interventional procedures  Women have a worse prognosis than men in terms of relief from angina pain after treatment  Clotting factors, BNP, and hs-CRP have been found to be predictive of adverse events after treatment for angina

35. Acute Coronary Syndrome/Unstable Angina  UA/NSTEMI is the most common cause of cardiac hospital admissions  Women presenting with UA/NSTEMI have worse clinical profiles, but less extensive CAD compared with men  Women with ACS are more likely to present with UA than MI  UA and NSTEMI are differentiated based on the presence of biomarkers of myocardial injury  Women with UA/NSTEMI are more likely to present with atypical symptoms than men

36. Acute Coronary Syndrome  The most common cause of UA/NSTEMI is the development of non-occlusive thrombus on a disrupted atherosclerotic plaque  All patients without contraindications should be given aspirin, nitroglycerin, beta blockers, and heparin  It is unclear whether female ACS patients managed medically benefit from the use of GP IIb/IIIa inhibitors  High-risk patients including women benefit from an early invasive strategy  It is unclear whether a routine invasive strategy is beneficial in women and/or lower-risk patients  The prognosis of women with UA/NSTEMI is as good as or better than that of men

37. Acute Myocardial Infarction  Female AMI patients are generally 5 to 10 years older and have more co-morbidities  Common acute symptoms of AMI in women include dyspnea, weakness, fatigue, nausea/vomiting, palpitations, and indigestion  Women <50 years old are more prone to coronary thrombosis due to plaque erosion than postmenopausal women  Younger female AMI patients have a higher in-hospital mortality than men of the same age and older female AMI patients  Women often have higher short-term mortality rates than men largely due to their older age and increased co- morbidities  Women are often under prescribed AMI discharge medications, including aspirin and beta blockers

39. Lifestyle Interventions Smoking cessation Physical activity (cardiac rehabilitation) Weight reduction/maintenance Heart healthy diet Omega 3 fatty acids Psychosocial factors Source: Mosca 2004

40. Women Receive Less Interventions to Prevent and Treat Heart Disease Less cholesterol screening Less lipid-lowering therapies Less use of heparin, beta-blockers and aspirin during myocardial infarction Fewer referrals to cardiac rehabilitation Source: Chandra 1998, Nohria 1998, Scott 2004, O’Meara 2004, Hendrix 2005

41. Lifestyle Approaches to Hypertension in Women Source: JNC VII 2004, Sacks 2001  Maintain ideal body weight  Weight loss of as little as 10 lbs reduces blood pressure   DASH eating plan  Even without weight loss, a diet rich in fruits, vegetables, and low fat dairy products can reduce blood pressure   Sodium restriction to 2400 mg/d  Further restriction to 1500 mg/d may be beneficial, especially in African American patients   Increase physical activity   Limit alcohol to one drink per day  Alcohol raises blood pressure  One drink = 12 oz beer, 5 oz wine, or 1.5 oz liquor

42. Guidelines at a Glance ParameterATP III + Update 1 Women 2. 1. ATP lll. JAMA. 2001;285:2486-2497. 2. Mosca L et al. Circulation. 2004;109:672-693. 3. American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S68-S71. 4. Grundy SM et al. Circulation. 2004;110:227-239. ADA Position 3 Optimal LDL-C<100 mg/dL Very high risk (2004 Update) 4 <70 mg/dL Optimal TG<150 mg/dL Optimal HDL-C<40 mg/dL*>50 mg/dL >40 mg/dL men >50 mg/dL women LDL-C goal for CHD or equivalents <100 mg/dL Non–HDL-C goal<130 mg/dL *Defined as high risk.

43. Framingham CHD Risk: HDL-C Predicts Risk at All LDL-C Levels * LDL-C (mg/dL) HDL-C (mg/dL) Adapted from Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A. RR for CHD After 4 y *Data represent men age 50-70 y from the Framingham Study. Patient 1: LDL-C: 100 mg/dL HDL-C: 25 mg/dL Patient 2: LDL-C: 220 mg/dL HDL-C: 45 mg/dL

44. Jupiter Trial Trial stopped early Looked at significance of elevated hsCRP levels in 15,000 low risk patients without CV disease and low or normal LDL Patients randomized to either Crestor 20mg or placebo Showed decreased cardiovascular morbidity and mortality in Crestor group

45. Abdominal obesity Glucose intolerance/ Insulin resistance Hypertension Atherogenic dyslipidemia Proinflammatory/ Prothrombotic state Characteristics of the Metabolic Syndrome: NCEP-ATP III National Cholesterol Educational Program (NCEP), Adult Treatment Panel (ATP) III; 2001. DiabetesDiabetes CVDCVD

46. Daily Aspirin High risk women 75-162 mg daily (clopidogrel if intolerant to aspirin) Unless contraindicated (bleeding, allergy) Intermediate risk women Consider aspirin therapy (75-162 mg) if benefit is likely to outweigh risk Lower risk women Many women, especially those >65 yo, may benefit from taking low-dose aspirin every other day to prevent MI or stroke The use of low dose aspirin should be balanced against the risk of increased internal bleeding

47. Hormone Replacement Therapy Risk vs. Benefit Benefits Vasomotor Symptoms Osteoporosis Vaginal Atrophy Colon Cancer Skin Preservation Depression Risks DVT/PE Gallbladder Disease Breast Cancer Breast/Bleeding Side Effects CHD Stroke Dementia Pancreatitis ?Ovarian Cancer Source: ACOG Task Force for Hormone Therapy 2004

48. Women’s Health Initiative: Estrogen Alone in Postmenopausal Women * * P <.05 * Favors Treatment Favors Placebo

49. Menopausal Hormone Therapy and CVD: Summary of Major Randomized Trials Use of estrogen plus progestin associated with a small but significant risk of CHD and stroke Use of estrogen without progestin associated with a small but significant risk of stroke Use of all hormone preparations should be limited to short term menopausal symptom relief Source: Hulley 1998, Rossouw 2002, Anderson 2004

50. Women’s Health Initiative Estrogen and Progestin Arm: Absolute Excess Risk  Excess CHD events: 7/10,000 woman-years  Excess stroke events : 8/10,000 woman-years  Excess pulmonary emboli: 8/10,000 woman-years  Excess invasive breast cancer: 8/10,000 woman-years Women’s Health Initiative Estrogen and Progestin Arm: Absolute Benefits  Fewer colorectal cancers: 6/10,000 woman-years  Fewer hip fractures: 5/10,000 woman-years

51. Antioxidants, etc. Antioxidants, Antibiotics, & Chelation Vitamins A, C, E, & homocysteine Antibiotics (azithromycin) Chelation therapy No cardiovascular benefit in randomized trials of primary and secondary prevention

52. Depression and CHD: Results from the Women’s Health Initiative Study Depression is an independent predictor of CHD death among women with no history of CHD Source: Wassertheil-Smoller 2004

53. CHD Risk Equivalents High Risk > 20% 10-yr risk for CHD events Established coronary artery disease Carotid artery stenosis Peripheral arterial disease Abdominal aortic aneurysm Diabetes Includes many patients with chronic renal disease, especially ESRD Source: Mosca 2004

54. Intermediate Risk 10-20% 10-yr risk for CHD events May include women with metabolic syndrome, especially women over the age of 60 or with individual factors that are markedly elevated or severe Often includes women with multiple risk factors, a single markedly elevated risk factor, or a 1 st degree relative with premature CVD May include women with subclinical cardiovascular disease (elevated coronary calcium score)- this is not included in Framingham risk calculations Source: Mosca 2004

55. Low Risk <10% 10-yr risk for CHD events women with one or more risk factors women with defined metabolic syndrome, if no individual factor is severe or markedly elevated women with no risk factors, but non-optimal lifestyle factors, such as lack of regular exercise or a high fat diet Optimal Risk <10% 10-yr risk for CHD events Optimal levels of risk factors Heart healthy lifestyle Source: Mosca 2004