Risk Factors for Coronary Artery Disease The Symphony of Life

1. Risk Factors for Coronary Artery DiseaseThe Symphony of Life Yehuda Adler, M.D, MHA. Medical Diretor Shfela Region, Leumit Health Fund, Cardiac Rehabilitation, Chaim Sheba Medical Center and Sackler Medical School, Tel Aviv University, Israel

2. 14.5.02

5. Your Chances of Dying From: • Aids: 1/1,000,000 • Murder: 1/10,000 • Car accident: 1/5,000 • Heart disease: 1/2* * So look at the person next to you!

6. Normal artery wall Endothelial cells Contractile VSMCs

8. Early atherosclerosis Lipid accumulates in the intimal space and is associated with abnormal endothelial cell function Lipid

9. Early atherosclerosis Activated endothelial cells express adhesion molecules and recruit inflammatory cells, predominantly monocytes Lipid

10. Early atherosclerosis Monocytes migrate into the intima, differentiate into macrophages and ingest lipid to form foam cells Lipid

11. Unstable coronary artery disease Thrombus forms and extends into the lumen and the plaque Thrombus Lipid core Adventitia

19. Nonmodifiable Factors Age Gender Family History Modifiable Factors Cigarette smoking Obesity Hypertension Physical inactivity Diabetes Elevated LDL-C Low HDL Established Cardiovascular Risk Factors

21. Total Cholesterol LDL-Cholesterol TG HDL-Cholesterol Lipoproteins

22. Epidemiologic Data – MRFITRelationship between Serum Cholesterol and CHD Death 18 16 14 12 Age-Adjusted CHD Death Rate/1000 Men/6 Years 10 8 6 4 2 0 140 180 220 260 300 160 200 240 280 Serum Cholesterol mg/dl MRFIT. Lancet. 1986;2:933.

23. Age-adjusted CHD death rate per 1,000 person-years in men with CHD Pekkanen, et al, N Engl. J Med.. 322(24) 1700-07 1990

24. NCEP ATP III Guidelines For LDL Cholesterol • Risk Factor StatusLDL-C Goal • No CHD and • < 2 CHD Risk Factors <160 mg/dL • No CHD and 2 or • more CHD Risk Factors <130 mg/dL • Established CHD* <100 mg/dL * Or 10-year risk for hard CAD>20%, PVD, abdominal aortic aneurysm, symptomatic carotid stenosis, diabetes JAMA 2001;285:2486-97

25. Primary Prevention Evidence with Statins

26. WOSCOPS Study Design Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia Males aged 45-64 years with total-C  252 mg/dland no prior MI Diet therapy x 4 weeks LDL-C  155 mg/dl on visits 2 and 3and  174  232 mg/dl on 1 of these visits Placebo(n = 3293) Pravastatin 40 mg QD(n = 3302) 5 years Shepherd et al. N Engl J Med. 1995;333:1301-7.

27. Early Benefit with Pravastatin in WOSCOPS Myocardial Infarction* 12 Placebo (n = 3293) 10 Pravastatin (n = 3302) 31% risk reduction 8 Percent P < 0.001 with 6 Event 4 2 0 1 2 3 4 5 6 Years Shepherd et al. N Engl J Med. 1995;333:1301-7. *Primary endpoint: Nonfatal MI and CHD death

28. Benefit with Pravastatin in WOSCOPS Total Mortality 6 Placebo (n = 3293) 22% risk reduction P = 0.051 5 Pravastatin (n = 3302) 4 Percent with 3 Event 2 1 0 1 2 3 4 5 6 Years Shepherd et al. N Engl J Med. 1995;333:1301-7.

29. 37% risk reduction P = 0.009 Benefit with Pravastatin in WOSCOPS PTCA/CABG 3.0 Placebo (n = 3293) 2.5 Pravastatin (n = 3302) 2.0 Percent withEvent 1.5 1.0 0.5 0.0 0 1 2 3 4 5 Years Shepherd et al. N Engl J Med. 1995;333:1301-7.

30. Air Force/Texas Coronary Atherosclerosis Prevention Study(AFCAPS/TexCAPS) Gotto AM, AHA Orlando, 1997 MS

31. AFCAPS TexCAPS Study Design 6605 Males & females aged 45-73 years with no clinical evidence of atherosclerotic CVD Diet + Placebo run-in Total C between 180 & 264 mg/dl; LDL between 130 & 190 mg/dl HDL < 50 mg/dl; Total-C/HDL ratio < 5 Lovastatin 20-40 mg QD (titrate to LDL < 110 mg/dl) Placebo 5 years Gotto A. AHA 1997.

32. AFCAPS/TexCAPS:Lipid Change from Baseline to Year 1 TC LDL-C TG % HDL-C Gotto AM, AHA Orlando, 1997 MS

33. AFCAPS/TexCAPS: Primary Endpoint First Acute Major Coronary Event/Mortality 3.5 Placebo (n = 3301) 3.0 Lovastatin (n = 3304) 36% risk reduction 2.5 p < 0.001 Percent 2.0 with 1.5 Event 1.0 0.5 0.0 0 1 2 3 4 5 6 Years Gotto AM, AHA Orlando, 1997 MS

34. The Heart Protection Study (HPS) Lancet 2002;360:7-22 Dr. Rory Collins Biggest-ever statin study will change practice worldwide...

35. The Heart Protection Study (HPS) 20,000 volunteers, ages 40 to 80 yrs, T. Chol > 135 mg/dl, who were at high risk of CAD Simva 40 mg QD vs placebo for 5.5 years with/without antioxidant vitamins E (600 mg), C (250 mg) and  carotene (20 mg) Baseline LDL: <116 (33%), 116-135 (25%), >135 (42%) Lancet 2002;360:7-22

36. HPS - All Cause Mortality % P<0.001

37. HPS - Tolerability Statin Placebo n=10269 n=10267 ALT>3xULN 0.8% 0.9% CPK>10xULN 0.09% 0.05% Lancet 2002;360:7-22

38. Secondary Prevention Evidence with Statins

39. 4S LIPID 20 1.00 Placebo Simvastatin 0.95 15 Placebo Proportion alive Fatal CHD/nonfatalMI (%) 0.90 10 Pravastatin 0.85 5 Risk reduction, 30%Log-rank p=0.0003 Risk reduction, 24%p<0.001 0.80 0.00 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 7 CARE 15 Fatal CHD/nonfatalMI (%) 10 Placebo Pravastatin 5 Risk reduction, 24%p=0.003 0 0 1 2 3 4 5 6 Years Early secondary prevention trials only focussed on long-term event reductions in stable patients 4S Study Group. Lancet 1994;344:1383–1389. Sacks FM et al. N Engl J Med 1996;335:1001–1009. LIPID study group. N Engl J Med 1998;339:1349–1357.

40. LIPID: Cardiovascular Event Reduction with Pravastatin Total Mortality CHD Death Stroke 0 19% P<0.001 10 Relative Risk Reduction (%) * 22% P=0.001 24% P<0.001 20 30 * 24% of the placebo group were receiving lipid lowering therapy at the end of the trial. 40 N Engl J Med. 1998;339:1349–1357.

41. Effect of Lowering Total Cholesterol Concentration on CHD Events 4S-PL 25 Primary prevention trials 20 LIPID-PL 4S-Rx Secondary prevention trials Percent with CHD Event 15 CARE-PL CARE-Rx WOSCOPS-PL LIPID-Rx 10 WOSCOPS-Rx 5 AFCAPS-Rx AFCAPS-PL 0 50 70 90 110 130 150 170 190 210 LDL cholesterol (mg/dl) The influence of LDL reduction on CHD events in primary and secondary prevention trials with simvastatin, pravastatin and lovastatin

42. CURVES Mean Percent Change in LDL-C at Starting Doses Atorvastatin Simvastatin Pravastatin Lovastatin Fluvastatin 0 -10 % Change -20 -17%* -24%* -30 -28%* -29%* -38% -40 10 mg 20 mg Dose *P<0.002 vs atorvastatin.

43. Potential mechanisms of benefit of statins Statins LDL-C reduction Reduction in chylomicron and VLDL remnants, IDL, LDL-C • Restore endothelial function • Maintain SMC function • Anti-inflammatory effects • Decreased thrombosis Macrophages Lumen Lipid core Smooth muscle cells

44. Serum Cholesterol and FMD    15   FMD (%) Simvastatin 10 mg/d 10   Pravastatin 20 mg/d  5  Pravastatin 40 mg/d CAD Patients 150 175 200 Serum Cholesterol Level (mg/dl) Vogel RA. Am J Med 1999;107:479-87

45. Cholesterol Lowering With Statin Drugs: Risk of Stroke, and Total Mortality Stroke Total Mortality CVD Deaths 29% 22% 28% % Herbert PR, et al. JAMA 1997;278:313-321

46. HMG CoA Reductase Inhibitors (Statins) Demonstrated Therapeutic Benefits • Reduce major coronary events • Reduce CHD mortality • Reduce coronary procedures (PTCA/CABG) • Reduce stroke • Reduce total mortality JAMA 2001;285:2486-97

47. Lessons from WOSCOPSNumber of 55-64 yrs Treated to Prevent One Event Isolated Hypertension - MRC Isolated Hypercholesterolemia Total WOSCOPS Cohort Hypertension WOSCOPS Family History Smoking or HDL < 42 mg/dL Pre-existing vascular disease Minor ECG Abnormality Number Treated to Prevent One Event

49. מה היא רמת סוכר תקינה בדם ? בצום mg/dl פחות מ- 110 110 - 125 mg/dl mg/dl מעל 125 קטגוריה תקין רמת סוכר מוגברת סוכרת גם לנבדקים עם רמת סוכר מוגברת שאינה מגיעה לטווח של סוכרת סיכון מוגבר לחלות בטרשת עורקים. חלק ניכר מהם לוקים גם בסוכרת של ממש תוך מספר שנים.

50. הכוונה היא למחלת לב כלילית מוקדמת ! קרוב משפחה מדרגה ראשונה שלקה במחלה מתחת לגיל 55 קרובת משפחה מדרגה ראשונה שלקתה במחלה מתחת לגיל 65 מה הוא סיפור משפחתי למחלת לב כלילית ?