Evidence Based Management of Cardiovascular Disease in Women       Karol E. Watson, MD, PhD, FACCCo-director, UCLA Program...
Karol E. Watson Disclosure of Financial Relationships   Consultant: Genentech, GenzymeClinical Trials Adjudication Committ...
CV disease: Leading cause of death               in Americans                                                             ...
Cardiovascular Disease: Leading Cause ofDeath in Women                                        United States: 1997 Mortalit...
Effectiveness-Based Guidelines for thePrevention of Cardiovascular Disease in Women--2011 Update: A GuidelineFrom the Amer...
Prevention of CHD:• Reducing atherosclerosis• Preventing plaque rupture• Limiting thrombosis
Severe obstruction (angina, no rupture) vs    mild obstruction (no angina, likely to rupture)Severe fibrotic plaque       ...
ACC – NCDR:   CAD Prevalence in Diagnostic CatheterizationWomen n=19,761    Typical Angina    Atypical AnginaMen n=23,868A...
WISE: Landmark study in womenProspective cohort study conducted at 4 US sitesGoals:• Improve diagnostic testing for ischem...
V3016          V3016                          A                                         A        B                        ...
N e g a t iv e R e m o d e lin gP o s it iv e R e m o d e lin g
WISE: Persistent chest pain in          women predicts future CV eventsn = 673 WISE participants with chest pain at baseli...
Plaque Erosion and Outward                 (Positive) Remodeling                                             • Plaque eros...
Gender Differencesin Atherosclerosis Women suffer more plaque erosions (above) compared to plaque explosions in men (below...
Perfusion CMR in Cardiac Syndrome-X             Res t   S tre s sC o ntr                                 • Women with ches...
Prevention of CHD:• Reducing atherosclerosis• Preventing plaque rupture / EROSION• Limiting thrombosis
Classic Cardiovascular Risk Factors    •   Tobacco Smoke    •   High Blood Cholesterol    •   High Blood Pressure    •   P...
Diabetes and CV Risk in Framingham                             Age 35-64 Years--30 Year Follow-up             10          ...
The Metabolic Syndrome                         Diagnosis is established                     when ≥ 3 of risk factors are p...
Metabolic Syndrome and CV Mortality• European cohort studies (6156 men and 5356  women):• Modified WHO definition of Metab...
Elevated Triglycerides Increase CHD Risk                                    Framingham Heart Study      Relative Risk for ...
Prevention of CHD:• Reducing atherosclerosis• Preventing plaque rupture / EROSION• Limiting thrombosis
Inflammatory Pathways in                       Atherogenesis                                   Pro-inflammatory Risk      ...
Hs-CRP and Risk of Future Cardiovascular              Events in Apparently Healthy Women                 7                ...
Risk Factors for Future Cardiovascular         Events: Women’s Health Study      Lipoprotein(a)      Homocysteine      IL-...
High-Sensitivity C-Reactive Protein                      (hsCRP)• hsCRP should not be used for routine screening of all  w...
Metabolic Syndrome and CRP                                              Levels       C-reactive Protein (mg/L)    8       ...
Behavioral factors associated with elevated         biomarkers of inflammation• Increased body fat• Smoking• Low physical ...
Prevention of CHD:• Reducing atherosclerosis• Preventing plaque rupture / EROSION• Limiting thrombosis• Recognizing Presen...
Aspirin Evidence: Secondary Prevention                    Effect of antiplatelet treatment* on vascular events**         A...
Womens Health Study:Low-Dose Aspirin in Primary Prevention Trial               39,876 initially healthy† women, aged ≥45 y...
Aspirin : Primary Prevention in Women                                             Womens’ Health Study (WHS)     39,876 wo...
Womens’ Health Study (WHS)                                          Aspirin   Placebo   RR     95% CI       PPrimary endpo...
Womens’ Health Study (WHS)                                         Aspirin   Placebo   RR     95% CI      PSmoking status ...
USPSTF: Risk level at which CVD events          prevented (benefit) exceeds GI harms Men ages 45-79                       ...
Women have strokes tooAge group (y)    Women/Men       OR           95% CI           P                    (%)   35 - 44   ...
Stroke StatisticsU.S. Statistics• The risk stroke doubles each decade after the age  of 55.  – ~25% of strokes occur in pe...
Effectiveness-Based Guidelines for thePrevention of Cardiovascular Disease in Women--2011 Update: A GuidelineFrom the Amer...
Lifestyle Interventions• Cigarette smoking DON’T! (Class I; LOE B )• Physical activity  – 150 min/wk of moderate exercise ...
Lifestyle Interventions (cont.)• Weight maintenance/reduction  – Maintain or lose weight through physical activity    and ...
Major Risk Factor Interventions• Blood pressure management  – Pharmacotherapy when blood pressure is ≥140/90    mm Hg (≥13...
Major Risk Factor Interventions (cont.)• Lipid Management (cont.)  – In women >60 years of age and with an estimated    CH...
Preventive Drug Interventions• Aspirin• Aspirin (75–325 mg/d) in women with CHD unless  contraindicated (Class I; LOE A).•...
Class III Interventions (Not Useful/Effective and                 May Be Harmful)• Menopausal therapy  – Hormone therapy …...
WHI E+P Trial Findings, July 2002 (avg 5.2 y)       Risks                                                         Benefits...
WHI E Alone Trial Findings, 2004 (avg 6.8 y)                               Neutral for CHD       Risks               Neutr...
Vitamin E: Secondary Prevention                                                 (GISSI)-Prevenzione Trial  11,324 patients...
Folic Acid and B-Vitamins: Secondary Prevention                                          NORVIT: 3,749 patients with a    ...
Prevention of CHD:• Reducing atherosclerosis• Preventing plaque rupture / EROSION• Limiting thrombosis• Recognizing Presen...
Clinical Recognition of CAD : Gender      Differences in Heart Attack SymptomsTypical in both sexes              More comm...
Women’s Early Warning Signs of Heart                     Attack• Weeks before Heart Attack (95% of women)   Unusual fatig...
Limited Numbers of Women in Research on                          Noninvasive Testing                100                 90...
Diagnostic Tests in Women Treadmill exercise electrocardiogram is    often inaccurate           ~ 33% false positive rate...
AHA Consensus Statement –   Algorithm for Evaluation ofSymptomatic Women Using Cardiac            Imaging     Intermediate...
Ischemia in women may occur from mental  stress more often than physical stress• 160 men and 24 women with known CHD under...
CONCLUSIONS• CHD is the leading cause of death in women• Risk Factor Modification cornerstone of CV risk  reduction• Patho...
Evidence based management of cardiovascular disease in women
Evidence based management of cardiovascular disease in women
Evidence based management of cardiovascular disease in women
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Evidence based management of cardiovascular disease in women

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  • Total cardiovascular (CV) disease, including diseases of the heart, cerebrovascular disease, and arterial disorders, remains the leading cause of death in the United States. 1 Data compiled from death certificates by the National Center for Health Statistics for 2002 indicate that CV disease claimed 927,448 American lives in 2002, including 433,825 men and 493,623 women. 1 Overall, CV disease claims about as many Americans each year as the next 5 leading causes of death combined. 1. CDC/NCHS and NHLBI. In: Heart Disease and Stroke Statistics–2005 Update . Dallas, Tex: American Heart Association; 2005.
  • Stenotic lesions are a major cause of stable angina; resistance vessel dysfunction is another cause. Infrequently, stenotic lesions may undergo erosion, triggering a thromboembolic event (myocardial infarction or unstable angina). A more common cause of these events is plaque rupture. Plaques vulnerable to rupture tend to be associated with only mild obstruction on the angiogram. Severe obstruction (angina, no rupture) vs mild obstruction (no angina, likely to rupture)
  • The Women’s Ischemia Syndrome Evaluation (WISE) study is a prospective cohort study conducted at 4 sites in the US. WISE was intended to address deficiencies in understanding of ischemic heart disease in women. WISE: Landmark study in women
  • Johnson et al studied 673 participants in the WISE study. These women underwent coronary angiography for suspected myocardial ischemia. At baseline and 1 year follow-up, participants were asked, “In the last 12 months have you had pain or discomfort above the waist?” Persistent chest pain was defined as a positive response to this question at the 1 year follow-up. Descriptors such as shortness of breath or pain/discomfort in the shoulder region were considered positive responses. In the subgroup of women without obstructive CAD at baseline, self-reported persistent chest pain was associated with a higher risk of future CV events. WISE: Persistent chest pain in women predicts future CV events
  • Key Point 1: In this meta-analysis of 17 prospective studies, we once again can see a clear CHD risk in patients with elevated TGs. Key Point 2: For every increase in TG level of 89 mg/dl the risk of CHD is increased 30 percent in men and 69 percent in women . Key Point 3: Elevated TG levels are a clear threat to men and serious health risk for women. Reference: Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A. Hokanson JE. Curr. Cardiol. Rep. 2002;4:488-493.
  • SLIDE INFORMATION SOURCES: Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, Newby LK, Piña IL, Roger VL, Shaw LJ, Zhao D, Beckie TM, Bushnell C, D'Armiento J, Kris-Etherton PM, Fang J, Ganiats TG, Gomes AS, Gracia CR, Haan CR, Jackson EA, Judelson DR, Kelepouris E, Lavie CJ, Moore A, Nussmeier NA, Ofili E, Oparil S, Ouyang P, Pinn VW, Sherif K, Smith SC, Sopko G, Chandra-Strobos N, Urbina EM, Vaccarino V, Wenger NK. (2011). Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 Update: A Guideline From the American Heart Association. Circulation , 123, 1243-1262. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, Macfadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Trial Study Group. (2009). Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: A prospective study of the JUPITER trial. Lancet , 373(9670), 1175-82. The role that novel CVD risk biomarkers (e.g., hsCRP or advanced lipid testing) and imaging technologies (e.g., coronary calcium scoring assessment) should play in risk assessment and in delineation of appropriate preventive interventions is not yet well-defined. It should be noted that JUPITER did not test a strategy of routine screening with hsCRP to determine benefit of statin therapy, because those with lower hsCRP levels were not studied (2). These approaches should not be used for routine screening of all women. Instead, the American Heart Association and other national groups have recommended that the use of these novel modalities should be reserved for refining risk estimates in intermediate risk patients (defined either as 10% to 20% or 6% to 20% 10-year risk) when there is uncertainty regarding the need to start drug therapy. 04/03/12
  • This data was taken from the collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, MI, and stroke in high risk patients. Absolute reductions in the risk of having a serious vascular event were 36 ± 5 per 1,000 treated for 2 years among patients with previous MI; 38 ± 5 per 1,000 patients treated for 1 month among patients with acute MI; 36 ± 6 per 1000 treated for 2 years among those with previous stroke or TIA; 9 ± 3 per 1000 treated for 3 weeks among those with acute stroke; and 22 ± 3 per 1000 treated for 2 years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. Clopidogrel reduced serious vascular events by 10 ± 4% compared with aspirin, which was similar to the 12 ± 7% reduction observed with its analogue ticlopidine. The addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone.
  • The Women's Health Study was a randomized, double-blind, placebo-controlled trial designed to determine whether primary prevention with low dose aspirin (100 mg every other day) was associated with a reduction in CV events (nonfatal MI, nonfatal stroke, or death from a cardiovascular cause). The trial included 39,876 healthy women > 45 years of age, with a mean follow-up of 10 years. Aspirin use was associated with a 17% reduction in the risk of stroke (RR 0.83; 0.69-0.99; P=0.04), a 24% reduction in the risk of ischemic stroke (RR 0.76; 0.63-0.93; P=0.009), and a nonsignificant increase in the risk of hemorrhagic stroke (RR 1.24; 0.82-1.87; P=0.31). Aspirin had no effect on the risk of fatal or nonfatal myocardial infarction (RR 1.02; 0.84-1.25; P=0.83) or death from CV causes (RR 0.95; 0.74-1.22; P=0.68). Among women > 65 years of age, however, aspirin use was associated with a reduction of major cardiovascular events (RR 0.74; 0.59-0.92; P=0.008) and risk of ischemic stroke (RR 0.70; 0.49-1.00; P=0.05). GI bleeding requiring transfusion was more frequent in the aspirin group (RR 1.40; 1.07-1.83; P=0.02). Overall: The routine use of aspirin in low risk women (<10% 10 year risk of a CHD event) should generally be avoided. Aspirin use in women > 65 reduced the risk of cardiovascular events.
  • Vitamin E has not been shown to lower cardiovascular disease event rates in large clinical trials.
  • The Norwegian Vitamin (NORVIT) trial sought to evaluate the effects of B vitamin and folic acid supplementation in patients with a recent myocardial infarction. A total of 3,749 patients were randomized to one of four treatment arms: (a) vitamin B6 (40 mg), vitamin B12 (0.4 mg), and folic acid (0.8 mg), (b) vitamin B12 (0.4 mg) and folic acid (0.8 mg), (c) vitamin B6 (40 mg), or (d) placebo. The primary endpoint was a composite of myocardial infarction, stroke, and sudden death attributed to coronary heart disease. Homocysteine levels decreased by an average of 27 percent in patients given folic acid plus vitamin B12 as compared to placebo. This, however, did not translate into a reduction in the primary end point (RR 1.14; 95% CI 0.98 to 1.32; P=0.09). There was a trend towards increased risk in the group given folic acid, vitamin B12, and vitamin B6 (RR, 1.22; 95% CI 1.00 to 1.50; P=0.05).
  • Evidence based management of cardiovascular disease in women

    1. 1. Evidence Based Management of Cardiovascular Disease in Women Karol E. Watson, MD, PhD, FACCCo-director, UCLA Program in Preventive Cardiology Associate Professor of Medicine/Cardiology David Geffen School of Medicine at UCLA
    2. 2. Karol E. Watson Disclosure of Financial Relationships Consultant: Genentech, GenzymeClinical Trials Adjudication Committee: Merck
    3. 3. CV disease: Leading cause of death in Americans 493,623 500 433,825 400 Men 288,768 Women 300 268,503 Deaths (1000s) 200 100 69,257 60,713 64,103 34,301 41,877 38,948 0 A C D E C B A B F E A Total CVD* C Accidents E Diabetes B Cancer D Chronic lower respiratory diseases F Alzheimer’s Disease*CHD, stroke, HF, hypertension, arterial diseasesData compiled for 2002 CDC/NCHS and NHLBI.
    4. 4. Cardiovascular Disease: Leading Cause ofDeath in Women United States: 1997 Mortality 600 502,938 500 Deaths in 400 Breast cancer 41,943 Thousands 300 258,467 200 100 53,045 47,165 34,449 0 Total CVD Cancer Chronic Pneumonia Diabetes Obstructive and Influenza Mellitus Pulmonary Disease2000 Heart and Stroke Statistical Update, American Heart Association.
    5. 5. Effectiveness-Based Guidelines for thePrevention of Cardiovascular Disease in Women--2011 Update: A GuidelineFrom the American Heart Association L. Mosca et al. Circulation. 2011 Feb 16.
    6. 6. Prevention of CHD:• Reducing atherosclerosis• Preventing plaque rupture• Limiting thrombosis
    7. 7. Severe obstruction (angina, no rupture) vs mild obstruction (no angina, likely to rupture)Severe fibrotic plaque Vulnerable plaque• Severe obstruction •Minor obstruction• No lipid •Large lipid pool• Fibrosis, Ca2+ •Thin fibrous cap Plaque rupture Exertional angina • Acute MI • (+) ETT • Unstable angina Revascularization • Sudden death Anti-anginal Rx Pharmacologic stabilization Courtesy of PH Stone, MD. Early identification of high-risk?
    8. 8. ACC – NCDR: CAD Prevalence in Diagnostic CatheterizationWomen n=19,761 Typical Angina Atypical AnginaMen n=23,868Age Women Men Women Men<40 13 21 4 440-49 20 42 7 1550-59 32 60 12 3160-69 42 72 18 3870-79 53 77 31 48>80 65 84 35 50
    9. 9. WISE: Landmark study in womenProspective cohort study conducted at 4 US sitesGoals:• Improve diagnostic testing for ischemic heart disease in women• Study pathophysiologic mechanisms for ischemia in the absence of epicardial coronary artery stenoses• Evaluate the influence of menopausal status and reproductive hormone levels on diagnostic testing results Bairey Merz CN et al. J Am Coll Cardiol. 1999;33:1453-61.
    10. 10. V3016 V3016 A A B B AB AB C C C CSource: WISE – Unpublished data – S. Nissen
    11. 11. N e g a t iv e R e m o d e lin gP o s it iv e R e m o d e lin g
    12. 12. WISE: Persistent chest pain in women predicts future CV eventsn = 673 WISE participants with chest pain at baseline 1 0.9 Event-free Without CAD HR 1.89 (1.06–3.39)survival (%) 0.8 P = 0.03 0.7 With CAD HR 1.17 (0.76–1.80) 0.6 P = 0.49 0 1 2 3 4 5 6 Years from PChP diagnosis (at one year) Neither PChP No PChP Both No CAD CADPChP = persistent chest pain Johnson BD et al. Eur Heart J. 2006;27:1408-15.
    13. 13. Plaque Erosion and Outward (Positive) Remodeling • Plaque erosion and Lumen thrombus formation 2x likely in women Plaque (men have more erosion plaque rupture) • Outward (positive) remodeling- atherosclerotic lesion protrudes outwardThrombusFormation than impinging on the lumen Adapted from Bellasi et al, New insights into ischemic heart disease in women. cleveland clinic journal of medicine; 74: 585-594
    14. 14. Gender Differencesin Atherosclerosis Women suffer more plaque erosions (above) compared to plaque explosions in men (below), leading to more acute coronary syndromes (unstable angina) and non-Q MI in women, making diagnosis more difficult and leading to delays in treatment.NEJM 1999
    15. 15. Perfusion CMR in Cardiac Syndrome-X Res t S tre s sC o ntr • Women with chest pain ol suggestive of myocardial ischemia yet no or nonobstructive CAD (i.e., cardiac syndrome x) may have subendocardial m e -XS yn d r o ischemia as demonstrated using cardiac MR perfusion Panting JR. New Engl J Med 2002; 346: 1948-53.
    16. 16. Prevention of CHD:• Reducing atherosclerosis• Preventing plaque rupture / EROSION• Limiting thrombosis
    17. 17. Classic Cardiovascular Risk Factors • Tobacco Smoke • High Blood Cholesterol • High Blood Pressure • Physical Inactivity • Obesity and Overweight • Diabetes Mellitus • Age
    18. 18. Diabetes and CV Risk in Framingham Age 35-64 Years--30 Year Follow-up 10 P<0.001 P<0.001 8 Men WomenRisk Ratio 6 P<0.001 P<0.001 P<0.001 4 P<0.001 P<0.001 P<0.001 P<0.05 2 0 CHD Stroke Claudication Heart Total Failure CVDWilson Am J Kidney Dis 1998
    19. 19. The Metabolic Syndrome Diagnosis is established when ≥ 3 of risk factors are present Risk Factor Defining Level Abdominal obesity ( W a is t c ir c u m f e r e n c e ) >10 2 c m Men ( >4 0 in ) Wo me n >8 8 c m TG ≥15 05 ( >3 mn ) /d l i g HDL-C Men <4 0 m g /d l Wo me n <5 0 m g /d l ≥13 0 /≥8 5 m m Blood pressure Hg Fasting glucose ≥110 m g /d lS o u r c e : Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JA M A 2001;285:2486-2497.
    20. 20. Metabolic Syndrome and CV Mortality• European cohort studies (6156 men and 5356 women):• Modified WHO definition of Metabolic Syndrome• CV mortality –2.26 [1.61-3.17] in men – 2.78 [1.57-4.94] in women Hu et al. Arch Intern Med 2004; 164: 1066-76
    21. 21. Elevated Triglycerides Increase CHD Risk Framingham Heart Study Relative Risk for CHD 2.5 2.0 1.5 1.0 0.5 Women 0.0 50 100 150 200 250 300 350 400 MenMeta-Analysis of 17 For every increase in serum TG level of 89Prospective Studies mg/dL, risk of CHD increases 30% in men and 69% in women
    22. 22. Prevention of CHD:• Reducing atherosclerosis• Preventing plaque rupture / EROSION• Limiting thrombosis
    23. 23. Inflammatory Pathways in Atherogenesis Pro-inflammatory Risk Factors Primary Pro-Inflammatory Cytokines (eg, IL-1, TNF-α) IL-6 “Messenger” Cytokine ICAM-1 CRP Selectins, HSPs, etc. SAA Endothelium and other cells LiverAdapted from Libby P et al.Circulation. 1999;100:1148–1150. Circulation
    24. 24. Hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women 7 P Trend <0.002 6 Any Event 5 MI or Stroke Relative Risk 4 3 2 1 0 1 2 3 4 <0.15 0.15–0.37 0.37–0.73 >0.73 Quartile of hs-CRP (range, mg/dL)S o u r c e : Ridker PM et al. C irculation 1998;98:731-733.
    25. 25. Risk Factors for Future Cardiovascular Events: Women’s Health Study Lipoprotein(a) Homocysteine IL-6 TC LDL-C sICAM-1 SAA Apo B TC: HDL-C hs-CRP hs-CRP + TC: HDL-C 0 1.0 2.0 4.0 6.0IL, interleukin; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; sICAM, serum intercellular adhesionmolecule; SAA, serum amyloid A; ApoB, Apolipoprotein B; HDL-C, high-density lipo-protein cholesterol; hs-CRP, high-sensitivity C-reactive protein.Ridker PM, et al. N Engl J Med. 2000;342:836-843.
    26. 26. High-Sensitivity C-Reactive Protein (hsCRP)• hsCRP should not be used for routine screening of all women, but should be reserved for refining risk estimates in intermediate risk patients when there is uncertainty regarding the need to start drug therapy• Consider statins in women over 60 years of age if, after lifestyle modification, hsCRP remains elevated above 2 mg/dL and no acute inflammatory process is present (Class IIb; Level of Evidence B) Source: Mosca 2011, Ridker 2009
    27. 27. Metabolic Syndrome and CRP Levels C-reactive Protein (mg/L) 8 6 4 2 0 0 1 2 3 4 5 Number of Components of the Metabolic SyndromeRidker PM, et al. Circulation. 2003;107:391-397. (with permission)
    28. 28. Behavioral factors associated with elevated biomarkers of inflammation• Increased body fat• Smoking• Low physical activity• Poor aerobic fitness• Low fruit and vegetable intake• Low omega-3 fatty acid intake Nicklas BJ, You T, Pahor M. Behavioral treatments for chronic systemic inflammation: effects of dietary weight loss and exercise training. Can Med Assoc J 2005; 172:1199-1209
    29. 29. Prevention of CHD:• Reducing atherosclerosis• Preventing plaque rupture / EROSION• Limiting thrombosis• Recognizing Presence of CHD in women
    30. 30. Aspirin Evidence: Secondary Prevention Effect of antiplatelet treatment* on vascular events** Acute MI Acute CVA Prior MI Prior CVA/TIA Other high risk CVD(e.g. unstable angina, heart failure) PAD(e.g. intermittent claudication) High risk of embolism (e.g. Afib) Other (e.g. DM) All trials 0.0 0.5 1.0 1.5 2.0 Antiplatelet better Control betterAntithrombotic Trialist Collaboration. BMJ 2002;324:71–86
    31. 31. Womens Health Study:Low-Dose Aspirin in Primary Prevention Trial 39,876 initially healthy† women, aged ≥45 yrs Randomized, blinded, factorial Low-Dose Aspirin Placebo 100 mg on alternate days n=19,934 n=19,942 End points (mean, 10.1 yrs): ● Combined end point of nonfatal MI, nonfatal stroke, or total cardiovascular death ● Incidence of total malignant neoplasms of epithelial cell originRidker PM. Presented at: 54th Annual Scientific Session of the American Collegeof Cardiology; March 7, 2005; Orlando, Fla. Ridker PM, et al. N Engl J Med. 2005;352.
    32. 32. Aspirin : Primary Prevention in Women Womens’ Health Study (WHS) 39,876 women randomized to aspirin (100 mg every other day) or placebo for an average of 10 years 0.02 Aspirin Placebo Incidence of MI Cumulative 0.01 P=0.83 0.00 0 2 4 6 8 10 Years Aspirin does not reduce the risk of MI in low risk women But…Ridker P et al. NEJM 2005;352:1293-304
    33. 33. Womens’ Health Study (WHS) Aspirin Placebo RR 95% CI PPrimary endpoint: Major cardiovascular event* 477 522 0.91 0.80-1.31 .13Secondary endpoints: Stroke 221 206 0.83 0.69-0.99 .04 Ischemic 170 221 0.76 0.63-0.93 .009 Hemorrhagic 51 41 1.24 0.82-1.87 .31 Transient ischemic attack 186 238 0.78 0.64-0.94 .01 Myocardial infarction (MI) 198 193 1.02 0.84-1.25 .83 revascularization 389 374 1.04 0.90-1.20 .61 Cardiovascular death 120 129 0.95 0.74-1.22 .68 All-cause mortality 609 642 0.95 0.85-1.06 .32 Ridker P et al. NEJM 2005;352:1293-304
    34. 34. Womens’ Health Study (WHS) Aspirin Placebo RR 95% CI PSmoking status Current (n = 5235) 157 127 1.30 1.03-1.64 .03 Past/never (n = 34,605) 319 392 0.80 0.69-0.93 .003Age (yrs) 45-54 (n = 24,025) 163 161 1.01 0.81-1.26 .92 55-64 (n = 11,754) 183 186 0.98 0.80-1.20 .84 65+ (n = 4097) 131 175 0.74 0.59-0.92 .008Ridker P et al. NEJM 2005;352:1293-304
    35. 35. USPSTF: Risk level at which CVD events prevented (benefit) exceeds GI harms Men ages 45-79 Women ages 55-79 Encourage aspirin use Encourage aspirin use when potential CVD when potential CVD benefit (strokes prevented) benefit (MIs prevented) outweighs potential outweighs potential harm of GI hemorrhage. harm of GI hemorrhage 10-year CHD risk 10-year stroke risk Age 45-59 years ≥4% Age 55-59 years ≥3% Age 60-69 years ≥9% Age 60-69 years ≥8% Age 70-79 years ≥12% Age 70-79 years ≥11%Men Age <45 Years and Women Age <55 Years : Do not encourage aspirin use Men &Women Age ≥80 Years: No Recommendation (Insufficient Evidence) AHRQ Publication No. 09-05129-EF-3 Current as of March 2009
    36. 36. Women have strokes tooAge group (y) Women/Men OR 95% CI P (%) 35 - 44 1.2/1.0 1.2142 0.4715 - 3.1268 0.6876 45 - 54 2.5/1.0 2.3903 1.3205 - 4.3267 0.0040 55 - 64 3.4/3.0 1.1256 0.6218 - 2.0376 0.6961 NHANES data from 17,061 individuals older than 18 years between 1999 and 2004
    37. 37. Stroke StatisticsU.S. Statistics• The risk stroke doubles each decade after the age of 55. – ~25% of strokes occur in people < 65 years of age.• Stroke death rates are higher for African Americans than for whites, even at younger ages.• Each year, about 55,000 more women than men have a stroke.• The risk of ischemic stroke in current smokers is about double that of nonsmokers• High blood pressure is the most important risk factor for stroke. U.S. Centers for Disease Control and Prevention and the Heart Disease and Stroke Statistics - 2010 Update
    38. 38. Effectiveness-Based Guidelines for thePrevention of Cardiovascular Disease in Women--2011 Update: A GuidelineFrom the American Heart Association L. Mosca et al. Circulation. 2011 Feb 16.
    39. 39. Lifestyle Interventions• Cigarette smoking DON’T! (Class I; LOE B )• Physical activity – 150 min/wk of moderate exercise or 75 min/wk of vigorous exercise, performed in episodes of at least 10 min, (Class I; LOE B) – Muscle strengthening activities on ≥2 d per week (Class I; LOE B)• Cardiac rehabilitation YES (Class I; LOE B)• Dietary intake – Diet rich in fruits, vegetables, and whole grains. Limit saturated fat, cholesterol, alcohol, salt, and sugar. Avoid trans-fatty acids (Class I LOE B)
    40. 40. Lifestyle Interventions (cont.)• Weight maintenance/reduction – Maintain or lose weight through physical activity and appropriate caloric intake to achieve appropriate body weight (BMI <25 kg/m2, waist size <35 inches) (Class I; LOE B).• Omega-3 fatty acids – Consumption of omega-3 fatty acids in the form of fish or in capsule form for women with hypertriglyceridemia or for primary or secondary prevention of CHD (Class IIb; LOE B).
    41. 41. Major Risk Factor Interventions• Blood pressure management – Pharmacotherapy when blood pressure is ≥140/90 mm Hg (≥130/80 mm Hg in the setting of chronic kidney disease and diabetes. (Class I; LOE B).• Lipid Management – LDL-C–lowering drug therapy is recommended (along with lifestyle) in women with CHD, other atherosclerotic CVD, diabetes mellitus or 10-year absolute risk >20% to achieve an LDL-C <100 mg/dL (Class I; LOE A) – LDL-C–lowering with lifestyle therapy in all others, even if LDL > 190 mg/dL. (Class I LOE B).
    42. 42. Major Risk Factor Interventions (cont.)• Lipid Management (cont.) – In women >60 years of age and with an estimated CHD risk >10%, statins could be considered if hsCRP >2 mg/dL after lifestyle modification and no acute inflammatory process is present (Class IIb; LOE B) – Niacin or fibrate therapy can be useful when HDL-C is low (<50 mg/dL) or non–HDL-C is elevated (>130 mg/dL) in high-risk women after LDL-C goal is reached (Class IIb; LOE B)• Diabetes Management – Lifestyle and/or pharmacotherapy to achieve HbA1C <7 (Class IIa LOE B).
    43. 43. Preventive Drug Interventions• Aspirin• Aspirin (75–325 mg/d) in women with CHD unless contraindicated (Class I; LOE A).• Aspirin (75–325 mg/d) is reasonable in women with diabetes (Class IIa; LOE B).• Aspirin (81 mg daily or 100 mg every other day) can be useful in women ≥65 years of age, if … benefit for ischemic stroke and MI prevention is likely to outweigh risk of GI bleeding and hemorrhagic stroke (Class IIa; LOE B)• Aspirin (81 mg daily or 100 mg every other day) may be reasonable for women <65 years of age for ischemic stroke prevention (Class IIb; LOE B).
    44. 44. Class III Interventions (Not Useful/Effective and May Be Harmful)• Menopausal therapy – Hormone therapy … should not be used for the primary or secondary prevention of CVD (Class III, LOA A).• Antioxidant Supplements – Antioxidant vitamin supplements (eg, vitamins A, C, E) should not be used for the primary or secondary prevention of CVD (Class III, LOA A).• Folic Acid – Folic Acid, with or without B6 and B12, should not be used for the primary or secondary prevention of CVD (Class III, LOA A).• Aspirin for MI prevention in women <65 – Routine use of aspirin in healthy women 65 years of age is not recommended to prevent MI (Class III, LOA B).
    45. 45. WHI E+P Trial Findings, July 2002 (avg 5.2 y) Risks Benefits 105% Increase Dementia Fracture Reduction (Hip 23%) 24% Increase CHD 39% Reduction 31% Increase Colorectal Cancer Stroke 111% Increase Pulmonary Emboli 24% Increase Breast CancerSTOPPED Early, Clear Harm Stopped 3.3 yrs earlyAlso: DVTs JAMA. 2002;288:321-333
    46. 46. WHI E Alone Trial Findings, 2004 (avg 6.8 y) Neutral for CHD Risks Neutral for breast cancer 49% Increase Dementia Benefits 39% Increase Stroke 34% Increase Pulmonary Fracture Reduction (Hip 39%) Emboli STOPPED Early,suggestion of harm Stopped 1.7 yrs early Also: DVTs JAMA 2004;291:2947-58
    47. 47. Vitamin E: Secondary Prevention (GISSI)-Prevenzione Trial 11,324 patients with a recent MI randomized to Vitamin E (300 mg) % Surviving (free of MI, stroke, death) for 3.5 years or placebo 100 Primary End Point (%)* 95 90 Vitamin E Placebo 85 80 75 RR 0.95, P=0.293 70 0 6 12 18 24 30 36 42 48 Months Months*Includes freedom from death, nonfatal MI, and strokeGISSI-Prevenzione Investigators. Lancet 1999;354:447-55
    48. 48. Folic Acid and B-Vitamins: Secondary Prevention NORVIT: 3,749 patients with a recent myocardial infarction randomized to 4 treatment arms for 40 months • Vitamin B6 (40 mg), Vitamin B12 (0.4 mg), and Folic acid (0.8 mg)† • Vitamin B12 (0.4 mg) and Folic acid (0.8 mg)‡ • Vitamin B6 (40 mg)^ • Placebo † HR=1.22, P=0.05 compared to placebo ‡ HR=1.08, P=0.31 compared to placebo ^HR=1.14, P=0.09 compared to placeboBonna KH et al. NEJM 2006;354:1578-1588
    49. 49. Prevention of CHD:• Reducing atherosclerosis• Preventing plaque rupture / EROSION• Limiting thrombosis• Recognizing Presence of CHD in women
    50. 50. Clinical Recognition of CAD : Gender Differences in Heart Attack SymptomsTypical in both sexes More common in women• Pain, pressure, squeezing, or • Milder symptoms stabbing pain in the chest • Sudden onset of weakness,• Pain radiating to neck, shoulder, shortness of breath, fatigue, back, arm, or jaw body aches, or overall feeling of• Pounding heart illness (without chest pain)• Difficulty breathing • Unusual feeling or mild• Heartburn, nausea, vomiting, discomfort in the back, chest, arm, neck, or jaw (without chest abdominal pain pain)• Cold sweats or clammy skin• Dizziness Source: AHA &: WISE data JACC 2006
    51. 51. Women’s Early Warning Signs of Heart Attack• Weeks before Heart Attack (95% of women) Unusual fatigue (70.7%) Sleep disturbance (47.8%) Shortness of breath (42.1%) Indigestion (39.4%) Chest pain (29.7 %)• At time of Heart Attack Shortness of breath (57.9%) Weakness (54.8%) Fatigue (42.9%) Chest pain (57%) McSweeney, JC et al. Circulation 2003; 2619-2623
    52. 52. Limited Numbers of Women in Research on Noninvasive Testing 100 90 80% of Patients 70 60 Women 50 40 Men 30 20 10 0 ECG ECHO MPI Shaw LJ, et al. Coronary Artery Disease in Women.1999:327-350.
    53. 53. Diagnostic Tests in Women Treadmill exercise electrocardiogram is often inaccurate ~ 33% false positive rate ~ 25% false negative rate Addition of nuclear imaging or exercise echocardiogram increases predictive accuracy to ~ 90%SOURCE: Crouse. The Fourth Chicago Women & Heart Disease Conference, 1997.
    54. 54. AHA Consensus Statement – Algorithm for Evaluation ofSymptomatic Women Using Cardiac Imaging Intermediate-high likelihood women with atypical or typical chest pain symptoms Good Ex tolerance Diabetes, abnormal 12-L ECG, or + normal 12-L ECG questionable Ex capacity Risk factor modification +/- Ex or pharmacologic stress imaging anti-ischemic Rx Exercise TM test Low Able to Ex Unable to Ex Int risk Post-ETT TM LK Exercise Pharmacologic stress stress Normal or mildly Moderate-severely abnormal with abnormal or Cardiac normal LV function depressed EF cathSource: Mieres Circulation 2005; 111:682–696
    55. 55. Ischemia in women may occur from mental stress more often than physical stress• 160 men and 24 women with known CHD underwent exercise stress test and mental stress tests• Women had more EKG documented ischemia during mental stress; men more ischemia during physical stress Journal of Health Psychology January 2000; 5:75-85• 170 men and 26 women with known CHD evaluatedduring daily activities, exercise, and mental stress• Women reported chest pain more often during dailyactivities (P =0.04) and during laboratory mentalstressors (P =0.01); men reported chest pain more oftenduring exercise Sheps et al. Am Heart J. 2001 Nov;142(5):864-71
    56. 56. CONCLUSIONS• CHD is the leading cause of death in women• Risk Factor Modification cornerstone of CV risk reduction• Pathophysiology of Angina and ACS may differ• Preventive Strategies may differ• Evidence-based therapies should be utilized and therapies of no proven benefit should be avoided• As always…evidence continues to evolve

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