PREVENTION OF CARDIOVASCULAR DISEASE IN WOMEN

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1 1980 to 2000: Death rate fell from: to per 100K men to per 100K women 341,745 fewer deaths from CHD in 2000 Ford ES, NEJM, % from CHD treatments, 44% from risk factor modification Reductions in cholesterol: 24% Ford ES, NEJM, 2007

Placebo-Controlled Statin Trials simva 20-40 mg prava 40 mg prava 40 mg simva 40 mg prava 40 mg lova 80 mg Placebo-Controlled Statin Trials Celebrating Successes but Forgetting the Majority?

2 Placebo-Controlled Statin Trials simva mg prava 40 mg prava 40 mg simva 40 mg prava 40 mg lova 80 mg Placebo-Controlled Statin Trials Celebrating Successes but Forgetting the Majority? simva mg prava 40 mg prava 40 mg simva 40 mg prava 40 mg lova 80 mg Cardiovascular Disease in Women! One death per minute in US Over 400,000 deaths per year; more than cancer, COPD, Alzheimer s, accidents combined Rates in black women greater than in whites (286 vs 205/100,000 women) Lifetime risk one out of two

3 Prevention Of CVD in Women! Overwhelming majority of recommendations are the same for men and for women Aspirin use is a notable exception But there may be gender differences in the magnitude of the relative and absolute potential benefits A RISK-BASED APPROACH! Risk reduction $$ Harm The benefit from any given intervention is a function of:!!1) The relative risk reduction conferred by the!!!intervention, and!!2) The native risk of the patient! A 50 year women, in good health. Total cholesterol is 220. Which of the following is the most effective intervention for primary prevention of CVD?! 1. Aspirin 2. Folic acid 3. Estrogen 4. Vitamin E, C and beta carotene 5. Oily fish twice per week 6. All are effective 7. None are effective

4 Ineffective Interventions in Women: Class III! Hormone therapy should not be used for the primary or secondary prevention of CVD (Evidence A). Antioxidant vitamin supplements (eg, vitamin E, C, and beta carotene) should not be used for the primary or secondary prevention of CVD (Evidence A). Folic Acid, with or without B6 and B12 supplementation, should not be used for the primary or secondary prevention of CVD (Evidence A). Routine use of aspirin in healthy women <65 years of age is not recommended to prevent MI (Evidence B) A 50 year women, in good health. Total cholesterol is 220. Which of the following is the most effective intervention for primary prevention of CVD?! 1. Aspirin 2. Folic acid 3. Estrogen 4. Vitamin E, C and beta carotene 5. Oily fish twice per week 6. All are effective 7. None are effective CVD Risk in Women: High Risk! High risk (Any one or more): Clinically manifest CHD Clinically manifest cerebrovascular disease Clinically manifest peripheral arterial disease Abdominal aortic aneurysm End-stage or chronic kidney disease Diabetes mellitus 10-y predicted CVD risk 10%

5 CVD Risk in Women: At risk Any one or more! Cigarette smoking SBP 120 mm Hg, DBP 80 mm Hg, or treated hypertension Total cholesterol 200 mg/dl, HDL-C <50 mg/dl, or treated for dyslipidemia Obesity, particularly central adiposity Poor diet or physical inactivity Family history of premature CVD occurring in firstdegree relatives in men <55 y of age or in women <65 y of age CVD Risk in Women: At risk (Cont) Any one or more! Metabolic syndrome Evidence of advanced subclinical atherosclerosis (eg, coronary calcification, carotid plaque, or thickened IMT) Poor exercise capacity on treadmill test and/or abnormal heart rate recovery after stopping exercise Systemic autoimmune collagen-vascular disease (eg, lupus or rheumatoid arthritis) History of preeclampsia, gestational diabetes, or pregnancy-induced hypertension CVD Risk in Women: Ideal All of These! Total cholesterol <200 mg/dl (untreated) BP <120/<80 mm Hg (untreated) Fasting blood glucose <100 mg/dl (untreated) Body mass index <25 kg/m2 Abstinence from smoking Physical activity at goal for adults >20 y of age: 150 min/ wk moderate intensity, 75 min/wk vigorous intensity, or combination Healthy (DASH-like) diet

6 High Risk 19% At risk 5.5% Optimal 2.2% Rates of MI, CHD, Stroke (10 year) Classification and Levels of Evidence! Class I: Intervention useful and effective Class IIa: Evidence in favor of efficacy Class IIb: Efficacy less well established Class III: Intervention not helpful, no proven benefit Evidence Level A: Multiple RCTs Evidence Level B: Limited evidence from single RCT or other nonrandomized studies Evidence Level C: Expert opinion, case studies, standard of care Prevention of CVD Risk in Women: Cigarettes! Advise to not smoke and to avoid environmental tobacco smoke. Provide counseling at each encounter, nicotine replacement, and other pharmacotherapy as indicated in conjunction with a behavioral program or formal smoking cessation program (Evidence B).

7 Prevention of CVD Risk in Women: Physical Activity! At least 150 min/wk of moderate exercise, 75 min/wk of vigorous exercise, or an equivalent combination of moderate- and vigorous-intensity aerobic physical activity. (Evidence B). Additional CV benefits by increasing moderate-intensity aerobic physical activity to 5 h (300 min)/wk, or 2 1/2 h/ wk of vigorous-intensity physical activity, (Evidence B). Prevention of CVD Risk in Women: Physical Activity! Muscle-strengthening activities that involve all major muscle groups 2 d/wk (Evidence B). To lose weight or sustain weight loss 60 to 90 min of at least moderate-intensity physical activity (eg, brisk walking) on most, and preferably all, days of the week (Evidence B). Prevention of CVD Risk in Women: Dietary Intake! Consume a diet rich in fruits and vegetables; to choose whole-grain, high-fiber foods; to consume fish, especially oily fish, at least twice a week; to limit intake of saturated fat, cholesterol, alcohol, sodium, and sugar; and avoid trans-fatty acids. (Level of Evidence B). Maintain or achieve an appropriate body weight (eg, BMI <25 kg/m 2 in US women), waist size (eg, <35 in), or other target metric of obesity. (Level of Evidence B).

8 Prevention of CVD Risk in Women: Dietary Intake! Omega-3 fatty acids in fish or capsule (eg, EPA 1800 mg/ d) may be considered in women with hypercholesterolemia and/or hypertriglyceridemia (Class IIb; Level of Evidence B). Note: Pregnant women should avoid fish with the highest potential for mercury contamination (swordfish, mackerel, tile fish, etc) Note: Fish oil dietary supplements may have widely variable amounts of EPA and DHA 48 RCTs of 36,913 participants; 41 cohort trials No significant effect of omega 3 fats on mortality, CV events, or cancer Analysis of diet only trials: also no benefit No reason to advise people to stop rich sources of omega 3 fats, but better trials needed Cochrane Library, 2009 Prevention of CVD Risk in Women: Blood Pressure! BP <120/80 mm Hg encouraged through lifestyle approaches such as weight control, increased physical activity, alcohol moderation, sodium restriction, and increased consumption of fruits, vegetables, and low-fat dairy products (Level of Evidence B). Pharmacotherapy is indicated when blood pressure is 140/90 mm Hg ( 130/80 mm Hg in the setting of chronic kidney disease and diabetes mellitus).

9 Prevention of CVD Risk in Women: Blood Pressure! Thiazide diuretics should be part of the drug regimen for most patients (Evidence A). In ACS/MI use beta blockers and/or ACE inhibitors/arbs (Evidence A) Note: ACE inhibitors are contraindicated in pregnancy and used with caution in women who may become pregnant. Bonow RO, NEJM 2009 Prevention of CVD Risk in Women: Lipids! Goals with lifestyle: LDL-C <100 mg/dl, HDL-C >50 mg/ dl, TG <150 mg/dl, and non HDL-C (total cholesterol minus HDL) <130 mg/dl (Evidence B). Drug therapy with CHD to achieve an LDL-C <100 mg/dl (Evidence A) and with other CVD or diabetes or 10-year absolute risk >20% (Evidence B). A reduction to <70 mg/dl is reasonable in very-highrisk women (Class IIa; Level of Evidence B). RCT of 10,001 patients with stable CHD; yr LDL <130 mg/dl Atorvastatin 10 vs atorvastain 80 Followed for 4.9 years Research question: safety and efficacy of lowering LDL below 100 mg/dl Larosa NEJM, 2005

10 LDL Event % Death % LFTs % Atorv Atorv p value < Prevention of CVD Risk in Women: Lipids! Medications: If LDL-C level is 130 mg/dl, multiple risk factors, and the 10-y absolute CHD risk is 10% to 20% (Evidence B). If LDL-C level is 160 mg/dl and multiple risk factors even if 10-y absolute CHD risk is <10% (Evidence B). If LDL 190 mg/dl regardless of the presence or absence of other risk factors or CVD (Evidence B). Prevention of CVD Risk in Women: Aspirin! Aspirin ( mg/d) in women with CHD unless contraindicated (Evidence A). Aspirin in women 65 y of age (81 mg daily) if benefit for ischemic stroke and MI prevention is likely to outweigh risk of GI bleed and hemorrhagic stroke (Class IIa; Evidence B) Aspirin may be reasonable for women <65 y of age for ischemic stroke prevention (Class IIb; Level of Evidence B).

11 63 yo woman; s/p MI. On atorvastatin 80. LDL 95 HDL 40 TG 200 The best next step in lipid management is:! 1. Continue current therapy 2. Switch to rosuvastatin 3. Add fenofibrate 4. Add fish oil 5. Add niacin 6. Add ezetimibe RCT of 5518 patients with type 2 DM Fenofibrate Placebo p CV events: Death No difference in any secondary outcome Results do not support routine use of combination therapy in DM ACCORD, NEJM 2010

12 RCT of 3,414 patients with established CVD Simvastatin (or simvastatin + ezetimibe) to keep LDL at mg/dl (mean 71). HDL 35 mg/dl, TG 161 mg/dl Randomized to receive sustained-release niacin or placebo NEJM, 2011 Results: Study stopped early No reduction in cardiovascular events, MI and stroke Increase risk in ischemic stroke (28 vs 12) NEJM, 2011 RCT of 208 patients with CHD or CHD riskequivalent on statin at goal LDL Niacin 2000 vs Ezetimibe 10 Outcome: carotid intima-media thickness (IMT) Results: Niacin better Reduction in IMT Major cardiovascular events, 1% vs 5% Taylor NEJM, 2009

13 The best next step in lipid management is:! 1. Continue current therapy 2. Switch to rosuvastatin 3. Add fenofibrate 4. Add fish oil 5. Add niacin 6. Add ezetimibe 63 yo woman, no risks LDL 155 HDL 55 TG 160 SBP 120 Nonsmoker The best next step in lipid management is:! 1. Continue current therapy 2. Begin a statin 3. Begin fenofibrate 4. Begin a statin plus ezetimibe 5. Begin niacin

14 Truth About CVD Risk Prevention! Health professionals are not good at judging CV risk Counting risk factors is a blunt instrument and often leads to misclassification Calculate 10-year risk of hard CHD events (CHD death or non-fatal MI) using the Framingham Risk Score Framingham Risk -Limitations Not accurate in patients under 30 or over 75 Provide risk over 4-12 years only Relatively few patients with diabetes; no family history BUT Good discrimination for future CHD events Validated in several populations and found to be relatively transportable for risk ordering but calibration varies Examples of Proposed Novel Risk Markers C-reactive protein Fibrinogen vwf Factor VII Homocysteine Lipoprotein a LDL sub-fractions ST segment depression Heart rate variability Carotid Doppler Ankle-brachial index EBCT for coronary calcium Platelet activity

15 CRP AND Risk! CRP does not change overall predictive ability of Framingham However, CRP (plus family history) may reclassify some patients (especially intermediate risk patients) C-reactive protein (CRP)! Hard to directly integrate into the Framingham risk. Rough calculations: CRP in top third increases risk by!!factor of ! Risk in top tertile = 1.3x Average risk = x Risk in middle tertile = x Risk in middle tertile = 0.7x Coronary Calcium (CAC) and CV Prevention! Broad population-based strategy not warranted CAC may reclassify intermediate risk patients Unknown if findings lead to improved outcomes Bonow RO, NEJM 2009

16 63 yo woman, no risks LDL 155 HDL 55 TG 160 SBP 120 Nonsmoker 10 yr risk: 2% Therefore no medication recommended The best next step in lipid management is:! 1. Continue current therapy 2. Begin a statin 3. Begin fenofibrate 4. Begin a statin plus ezetimibe 5. Begin niacin (sustained release) Patients with CHD or CHD equivalent: Treat aggressively with statin independent of LDL level (to LDL <70 in most cases) Treat other risk factors aggressively as well, especially easy ones (HTN, Aspirin use) Treat elevated non-hdl cholesterol and low HDL Patients at high risk are undertreated

17 Patients without CHD: Assess lifetime CV risk with risk factors and 10-year CHD risk with Framingham Risk Score Novel markers (hscrp, coronary calcium score) may be useful for further discrimination among those with intermediate risk High hscrp may identify additional patients who are candidates for statins Do a better job with what we have: HTN, smoking, weight, exercise, diet Engage patient in shared decision making, especially if risk <10% Patients without CHD: Use medications at thresholds based on risk: LDL goal LDL drug treatment threshold High Risk (>20%) <100 (<70 optional) 100 Mod high risk (10-20%) < Moderate risk (<10%) < Low risk (no risk factors) < Patients without CHD: Use medications at thresholds based on risk: ASA STATIN High Risk (>20%) YES YES Mod high risk (10-20%) YES YES Moderate risk (<10%) NO Occasional YES Low risk (no risk factors) NO Usually NO

PREVENTION OF CARDIOVASCULAR DISEASE IN WOMEN

PREVENTION OF CARDIOVASCULAR DISEASE IN WOMEN Robert B. Baron MD MS Professor and Associate Dean UCSF School of Medicine Declaration of full disclosure: No conflict of interest EXPLAINING THE DECREASE