Cardiovascular Risk Factor Overview and Management

1. Cardiovascular Risk Factor Overview and Management Nathan D. Wong, PhD, FACC Associate Professor and Director, Heart Disease Prevention Program, University of California, Irvine

2. Cardiovascular Disease: The Leading Cause of Death in US Women in 1995 Heart disease 375 Cerebrovascular disease 96.4 Lung cancer 60.6 COPD* 48.9 Pneumonia/Influenza 45.1 Breast cancer 43.8 Accidents 31.9 Diabetes 33.1 Ovarian cancer 9.9 0 50 100 150 200 250 300 350 400 Deaths (1,000) *COPD=chronic obstructive pulmonary disease. Adapted from Anderson RN et al. Monthly Vital Statistics Report.Vol 45(suppl 2):June 12, 1997.

3. CHD is the single largest killer of men and women ~13.9 million have history of MI and/or angina Each year 1.1 million people have MI 370,000 die of MI, 250,000 die within 1 hr By age 60, every 5th man and 17th woman develops CHD 1998 estimated direct and indirect costs of heart disease are $95.6 billion 53.3 million adults have elevated LDL-C and warrant intervention (1994 NHANES data) 22.3 million qualify for drug therapy, 5.5 million receive therapy CHD in the United States AHA. 1998 Heart and Stroke Statistical Update; 1997. National Center for Health Statistics. National Health and Nutrition Examination Survey (III);1994. (Data collected 1991-1994.)

4. CVD Mortality Trends for Males and Females* 520 500 480 Deaths inthousands 460 440 420 20 0 87 89 91 93 95 1979 81 83 85 1996 Years Males Females *United States: 1979-1996 mortality. AHA. 1999 Heart and Stroke Statistical Update; 1998.

5. 30 20 10 0 15-19 20-24 25-29 30-34 PDAY: Percentage of Right Coronary Artery Intimal Surface Affected With Early Atherosclerosis Raised lesions 30 30 Women Men Fatty streaks 20 20 10 10 0 0 Intimalsurface(%) 15-19 20-24 25-29 30-34 15-19 20-24 25-29 30-34 White White 30 20 10 0 15-19 20-24 25-29 30-34 Black Black Age (y) PDAY=Pathobiological Determinants of Atherosclerosis in Youth. Strong JP, et al. JAMA. 1999;281:727-735.

6. LipidsHTNDiabetes Behavioral HemostaticThrombotic Inflammatory Genetic Beyond Cholesterol: Predicting Cardiovascular Risk In the 21st Century Cardiovascular Risk

7. Continuum of Patients at Risk for a CHD Event Post MI/Angina Secondary Prevention Other Atherosclerotic Manifestations Subclinical Atherosclerosis PrimaryPrevention Multiple Risk Factors Low Risk Courtesy of CD Furberg.

8. Total Cholesterol Distribution: CHD vs Non-CHD Population Framingham Heart Study—26-Year Follow-up No CHD 35% of CHD Occurs in People with TC<200 mg/dL CHD 150 300 250 200 Total Cholesterol (mg/dL) Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9. 1996 Reprinted with permission from Elsevier Science.

9. Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal (Framingham) 12.50 11.91 11.91 14 9.05 10.7 11.24 12 6.6 10 5.53 3.83 6.56 8 14-y incidence rates (%) for CHD 4.85 6 4.67  260 2.06 4.15 3.77 4 2.78 230–259 2 200–229 Total-C (mg/dL) 0 < 200 < 40 40–49 50–59  60 HDL-C (mg/dL) Risk of CHD by HDL-C and Total-C levels; aged 48–83 y Castelli WP et al. JAMA 1986;256:2835–2838

10. CHD Incidence Related to HDL-C Levels in Various Trials CHD incidence Women Men 0 -2 % change in risk per 1 mg/dL increment in HDL-C -4 -6 -8 -10 LRCF FHS CPPT FHS LRCF MRFIT 95% confidence intervals (CIs) for adjusted proportional hazards regression coefficients. Gordon DJ et al. Circulation 1989;79:8–15

11. Clinical Benefits of Cholesterol Reduction • A recent meta-analysis of 38 trials demonstrated that for every 10% reduction in TC • CHD mortality decreased by 15% (P<0.001) • total mortality decreased by 11% (P<0.001) • Decreases were similar for all treatment modalities • Cholesterol reduction did not increase non-CHD mortality Gould AL et al. Circulation. 1998;97:946-952.

12. Positive risk factors Age male ³45 female ³55 Family Hx of CHD: 1st-degree relative with MI or sudden cardiac death - male relative: <age 55 female relative: <age 65 Current cigarette smoking Hypertension: BP ³140/90 mm Hg or on antihypertensive meds Low HDL-C: <40 mg/dL Diabetes IS A CHD QUIVALENT IDENTIFYING PT AS HIGH RISK Negative risk factor High HDL-C: 60 mg/dL Major CHD Risk Factors Other Than LDL-C According to NCEP ATP-III

13. Other Recognized Risk Factors • Obesity: traditionally determined by body mass index >30 kg/m2 with overweighted defined as 25-<30 kg/m 2. • Abdominal obesity involves waist circumference >40 in. in men, >35 in. in women • Physical inactivity: various definitions

14. JNC VI: Risk Stratification and Treatment* Group AGroup BGroup C Uncomplicated HTNHTN w/Risk FactorsTOD/ CCD/Diabetes High-normal Lifestyle Lifestyle Drug therapy‡(130-139/85-89) modification modification Stage 1 Lifestyle Lifestyle Drug therapy(140-159/90-99) modification modification† (up to 12 mo) (up to 6 mo) Stages 2 and 3 Drug therapy Drug therapy Drug therapy(160/ 100) JNC VI. November 1997:chapter 2. NIH publication 98-4080.

15. Probability of Death From CHD in Patients With NIDDM and in Nondiabetic Patients, With and Without Prior MI 100 80 60 Survival (%) 40 Nondiabetic subjects without prior MI Diabetic subjects without prior MI Nondiabetic subjects with prior MI Diabetic subjects with prior MI 20 0 5 6 3 4 7 2 8 0 1 Years Kaplan-Meier estimates Haffner SM et al. N Engl J Med 1998;339:229–234

16. Definitions of Diabetes and Impaired Fasting Glucose • New ADA definition (1998) defines fasting blood sugar of > 126 mg/dl as diabetes, casual blood glucose > 200 mg/dl. Impaired fasting glucose is 110-125 mg/dl • Diabetic control generally defined as HgbA1c <8%. • BP recommended <130/80 mmHg, LDL-C goal <100 mg/dl

17. Secondary CHD Prevention in Women: Results from the CARE Trial • CARE was a secondary prevention trial of pravastatin versus placebo treatment in 4159 men and women with average lipid levels over 5 years • 576 post-menopausal women were randomized; average age 61; 10% on HRT • Average baseline lipids: TC 215 mg/dL, LDL-C 140 mg/dL, HDL 45 mg/dL • 5 year treatment results: 46% reduction in all coronary events, 48% reduction in PTCA, 40% reduction in CABG, 56% reduction in stroke JACC 1998;32:140-146

18. Heart and Estrogen/Progestin Replacement Study (HERS): Secondary Prevention of CHD in Women • Randomized, placebo-controlled trial of E/P therapy vs. placebo in 2763 women with CHD; average age 67 years • Treatment was 0.625 mg CEE + 2.5 mg medroxyprogesterone daily for 4 years • Primary endpoint: nonfatal MI and CHD death • Secondary endpoints: CABG, PTCA, unstable angina, CHF, PVD, TIA JAMA 1998;280:605-613

19. HERS Results • Non-fatal MI HRT 116 Placebo 129CHD death HRT 71 Placebo 58 • End of Year 1 CHD events (HRT) 42.5/1000 women-years CHD events (Plac) 28/1000 women-years • Year 4-5: CHD events (HRT) 23/1000 women-years CHD events (Plac) 34.3/1000 women-years • DVT/PE HRT 6.3 vs. Plac 2.2 Cholelithiasis HRT 84 vs. Plac 62 JAMA 1998;280:605-613

20. HERS Results • No statistically significant difference between HRT and placebo in both primary and secondary endpoints after 4 years. • Within first year, greater incidence in CHD events in HRT group. In years 3 and 4, lower CHD events in HRT group compared to placebo. • HRT lowered LDL 11% and increased HDL 10% compared to placebo. • Approximately 50% of randomized women were on lipid-lowering drugs. • Higher incidence of VTE and cholelithiasis in HRT group. JAMA 1998;280:605-613

21. Is there clinical evidence that inflammatory markers predict future coronary events and provide additional predictive information beyond traditional risk factors?

22. hs-CRP and Risk of Future MI in Apparently Healthy Men P Trend <0.001 P < 0.001 P < 0.001 P = 0.03 Relative Risk of MI 1<0.055 20.056–0.114 30.115–0.210 4>0.211 Quartile of hs-CRP (range, mg/dL) Ridker PM et al. N Engl J Med 1997;336:973-979.

23. hs-CRP and Risk of Future Cardiovascular Events in Apparently Healthy Women P Trend <0.002 Any Event MI or Stroke Relative Risk 1<0.15 20.15–0.37 30.37–0.73 4>0.73 Quartile of hs-CRP (range, mg/dL) Ridker PM et al. Circulation 1998;98:731-733.

24. Lp(a) in Atherogenesis: Another Culprit? • Identical to LDL particle except for addition of apo(a) • Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies, although not all • Accumulates in atherosclerotic plaque • Binds apo B-containing lipoproteins and proteoglycans • Taken up by foam cell precursors • May interfere with thrombolysis Maher VMG et al. JAMA. 1995;274:1771-1774. Stein JH, Rosenson RS. Arch Intern Med. 1997;157:1170-1176.

25. Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring Cohort 10 5 3.6 2.7 2 1.9 1.8 1.8 1.2 1 RR 0.5 Lp(a) TC HDL-C HT GI Smoking 0.2 0.1 RR=relative risk; HT=hypertension; GI=glucose intolerance. Bostom AG et al. JAMA. 1996;276:544-548.

26. Homocysteine: Role in Atherogenesis • Linked to pathophysiology of arteriosclerosis in 1969 • CVD patients have elevated levels of plasma homocysteine • May cause vascular damage to intimal cells • Elevated levels linked to: • genetic defects • exposure to toxins • diet • Increased dietary intake of folate and vitamin B6 may reduce CVD morbidity and mortality

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