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Anthony N. DeMaria Judith and Jack White Chair in Cardiology Founding Director, Sulpizio Cardiovascular Center UCSD School of Medicine Judith and Jack.

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Presentation on theme: "Anthony N. DeMaria Judith and Jack White Chair in Cardiology Founding Director, Sulpizio Cardiovascular Center UCSD School of Medicine Judith and Jack."— Presentation transcript:

1 Anthony N. DeMaria Judith and Jack White Chair in Cardiology Founding Director, Sulpizio Cardiovascular Center UCSD School of Medicine Judith and Jack White Chair in Cardiology Founding Director, Sulpizio Cardiovascular Center UCSD School of Medicine

2 (Adapted from Glagov et al.) Coronary Remodeling NormalvesselMinimalCAD Progression Compensatory expansion maintains constant lumen Expansion overcome: lumen narrows SevereCADModerateCAD Glagov et al, N Engl J Med, 1987.

3 Plaque Composition and Risk Stable Vulnerable Eroded Ruptured

4 Implications of Coronary Remodelling Plaque and obstruction are not the same Plaque and obstruction are not the same Luminology (angiography) has limitations. Luminology (angiography) has limitations. Plaque and obstruction are not the same Plaque and obstruction are not the same Luminology (angiography) has limitations. Luminology (angiography) has limitations.

5 An Apparently Successful Angioplasty PreinterventionPreintervention PostinterventionPostintervention

6 Coronary Heart Disease Risk Markers ModifiableNot l Elevated LDL-C l Low HDL-C l Elevated blood pressure l Elevated triglycerides Pyorala K, et al. Eur Heart J. 1994;15:1300-1331. l Male gender l Family history of CHD l Age l Personal history of CHD l Thrombogenic factors – PAI-1 – Fibrinogen – C-reactive protein l Diet l Tobacco smoking l Excess alcohol consumption l Physical inactivity l Obesity

7 Metabolic Syndrome (3 components) Abdominal obesity Abdominal obesity High trigycerides High trigycerides Low HDL (good cholesterol) Low HDL (good cholesterol) High blood pressure High blood pressure Elevated glucose Elevated glucose Abdominal obesity Abdominal obesity High trigycerides High trigycerides Low HDL (good cholesterol) Low HDL (good cholesterol) High blood pressure High blood pressure Elevated glucose Elevated glucose

8 Prevalence of ATP III Metabolic Syndrome Components: NHANES III Ford ES, et al. JAMA. 2002;287:356-359. % of Population

9 JAMA 1999;282:16, JAMA 2001;286:10. Obesity Trends* Among U.S. Adults: BRFSS 1985

10 Obesity Trends* Among U.S. Adults: BRFSS 1986 JAMA 1999;282:16, JAMA 2001;286:10.

11 Obesity Trends* Among U.S. Adults: BRFSS 1987 JAMA 1999;282:16, JAMA 2001;286:10.

12 Obesity Trends* Among U.S. Adults: BRFSS 1988 JAMA 1999;282:16, JAMA 2001;286:10.

13 Obesity Trends* Among U.S. Adults: BRFSS 1989 JAMA 1999;282:16, JAMA 2001;286:10.

14 Obesity Trends* Among U.S. Adults: BRFSS 1990 JAMA 1999;282:16, JAMA 2001;286:10.

15 Obesity Trends* Among U.S. Adults: BRFSS 1991 JAMA 1999;282:16, JAMA 2001;286:10.

16 Obesity Trends* Among U.S. Adults: BRFSS 1992 JAMA 1999;282:16, JAMA 2001;286:10.

17 Obesity Trends* Among U.S. Adults: BRFSS 1993 JAMA 1999;282:16, JAMA 2001;286:10.

18 Obesity Trends* Among U.S. Adults: BRFSS 1994 JAMA 1999;282:16, JAMA 2001;286:10.

19 Obesity Trends* Among U.S. Adults: BRFSS 1995 JAMA 1999;282:16, JAMA 2001;286:10.

20 Obesity Trends* Among U.S. Adults: BRFSS 1996 JAMA 1999;282:16, JAMA 2001;286:10.

21 Obesity Trends* Among U.S. Adults: BRFSS 1997 JAMA 1999;282:16, JAMA 2001;286:10.

22 Obesity Trends* Among U.S. Adults: BRFSS 1998 JAMA 1999;282:16, JAMA 2001;286:10.

23 Obesity Trends* Among U.S. Adults: BRFSS 1999 JAMA 1999;282:16, JAMA 2001;286:10.

24 Obesity Trends* Among U.S. Adults: BRFSS 2000 JAMA 1999;282:16, JAMA 2001;286:10.

25 Obesity Trends* Among U.S. Adults: BRFSS 2001 JAMA 1999;282:16, JAMA 2001;286:10.

26 Obesity Trends* Among U.S. Adults: BRFSS 2002 http://www.cdc.gov/brfss/#interactive

27 Obesity and Physical Inactivity in Children: A Call to Arms US Children US Children –15% are overweight –Type 2 DM now exceeds type 1 2/3 have  1 component of the Metabolic Syndrome 2/3 have  1 component of the Metabolic Syndrome –10% have Metabolic Syndrome Pediatrics. August 2003 De Ferranti et al. Circulation 2004; 110: 2494-2497

28 Hardee's "Monster Thickburger 2 1/3-pound slabs of Angus beef 4 strips of bacon 3 slices of cheese Mayonnaise Buttered sesame seed bun 1420 Calories 107 g Fat Portion Distortion

29 Meal and Desert in One: Fried Ice Cream Burger

30 Beware the Fried Twinkie

31 Deep Fried Butter Balls

32 Physical inactivity: A call to arms

33 Visceral Adiposity: The Heart of the Problem Viseral AdiposityNormal Dyslipidemia Inflammation Adipocytokine Production Impaired Glucose Metabolism Prothrombosis Endothelial Dysfunction

34 NCEP ATP III LDL-C Treatment Goals Based on Risk Category (2001) Risk Category LDL-C Goal (mg/dL) High Risk: CHD and CHD equivalents <100 Intermediate Risk: (multiple RFs) <130 Lower Risk: (0-1 RF) <160 RF = risk factor. NCEP ATP III, Expert Panel. JAMA. 2001;285:2486. NCEP ATP III, Expert Panel. Circulation. 2002;106:3143.

35

36 Coronary Imaging

37 Angiography: Significant Limitations in Atheroma Assessment Angiography reflects a planar, 2-dimensional silhouette of the lumen Angiography reflects a planar, 2-dimensional silhouette of the lumen Remodeling Remodeling –Because angiography does not visualize the vessel wall, it cannot account for positive or negative remodeling Composition Composition –Because angiography does not assess plaque composition, it cannot differentiate lipid-rich, more vulnerable plaques Postprocedure Postprocedure –Due to plaque fissuring, angiography overestimates the degree of postintervention lumen expansion Angiography reflects a planar, 2-dimensional silhouette of the lumen Angiography reflects a planar, 2-dimensional silhouette of the lumen Remodeling Remodeling –Because angiography does not visualize the vessel wall, it cannot account for positive or negative remodeling Composition Composition –Because angiography does not assess plaque composition, it cannot differentiate lipid-rich, more vulnerable plaques Postprocedure Postprocedure –Due to plaque fissuring, angiography overestimates the degree of postintervention lumen expansion Nissen SE et al in Restenosis After Intervention With New Mechanical Devices, 1992; Yamashita T et al, Progress in Cardiovascular Diseases, 1999; Topol EJ et al, Circulation, 1995.

38 Mortality According to Blood Pressure in Men Age 50 to 69 Society of Actuaries. Blood Pressure Study, 1939. Ratio (%) of actual to expected mortality Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) www.hypertensiononline.org

39 Relative risk of CHD mortality He J, et at. Am Heart J. 1999;138:211-219. Copyright 1999, Mosby Inc. <112 <71 Risk of CHD Death According to SBP and DBP in MRFIT 123456789 10 Decile 112- 71- 118- 76- 121- 79- 125- 81- 129- 84- 132- 86- 137- 89- 142- 92- >151 >98 (lowest 10%)(highest 10%) SBP (mmHg) DBP (mmHg) Systolic blood pressure (SBP) Diastolic blood pressure (DBP) www.hypertensiononline.org CHD=coronary heart disease

40 Relative risk of stroke death <112 <71 Risk of Stroke Death According to SBP and DBP in MRFIT 123456789 10 Decile 112- 71- 118- 76- 121- 79- 125- 81- 129- 84- 132- 86- 137- 89- 142- 92- >151 >98 (lowest 10%)(highest 10%) SBP (mmHg) DBP (mmHg) www.hypertensiononline.org Systolic blood pressure (SBP) Diastolic blood pressure (DBP) He J, et at. Am Heart J. 1999;138:211-219. Copyright 1999, Mosby Inc.

41 CathSAP II image provided by the American College of Cardiology Intravascular Ultrasound

42

43 Angiographically Silent Atherosclerosis

44

45 Precision Cross-Sectional Planimetry Lumen 5.51 mm 2 Direct and Calculated Atheroma Measurements EEM — 15.47 mm 2 Atheroma Area — 9.96 mm 2 Area Reduction — 64.4%

46 (Adapted from Glagov et al.) Coronary Remodeling NormalvesselMinimalCAD Progression Compensatory expansion maintains constant lumen Expansion overcome: lumen narrows SevereCADModerateCAD Glagov et al, N Engl J Med, 1987.

47 3.1 mm Angiography Cannot Account for Coronary Remodeling

48 Atheroma Morphology by Ultrasound “Soft” Lipid-Laden Plaque “Hard” Fibrous Plaque

49 Thin Cap With Lipid Core Thick Stable Fibrotic Cap Same Lumen Size: Different Atheromas

50 Atheroma Morphology by Ultrasound Moderate Calcification Severe Calcification

51 Angiography Has Major Limitations in Assessing Complicated Lesions.

52 LAORAO Angiography Masks Complicated Lesions

53 An Apparently Successful Angioplasty PreinterventionPreintervention PostinterventionPostintervention

54 AA CC B D

55 Angiography Underestimates Diffuse Disease.

56

57 What Is the Culprit Lesion? 58-year-old male with chronic stable angina Positive stress test with small reversible ischemic defect on nuclear scintigraphy Medical Rx, but 6 weeks later… 3-day history of unstable angina, including 30 minutes of rest pain Medically “cooled off” followed by angiography 58-year-old male with chronic stable angina Positive stress test with small reversible ischemic defect on nuclear scintigraphy Medical Rx, but 6 weeks later… 3-day history of unstable angina, including 30 minutes of rest pain Medically “cooled off” followed by angiography Case provided by the McLaren Heart and Vascular Center, Flint, Michigan; used with permission.

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59 Absence of Correlation Between Angiographic Results and Clinical Outcomes (Adapted from Brown et al.) (Adapted from Brown et al.) Brown BG et al, Circulation, 1993.

60 Assessing Volumetric Atheroma Changes Trial performed at Kobe General Hospital (Kobe, Japan) Trial performed at Kobe General Hospital (Kobe, Japan) Hypothesis: patients with angiographically normal arteries receiving statin therapy will show reduced progression of coronary plaque as measured by IVUS Hypothesis: patients with angiographically normal arteries receiving statin therapy will show reduced progression of coronary plaque as measured by IVUS Trial performed at Kobe General Hospital (Kobe, Japan) Trial performed at Kobe General Hospital (Kobe, Japan) Hypothesis: patients with angiographically normal arteries receiving statin therapy will show reduced progression of coronary plaque as measured by IVUS Hypothesis: patients with angiographically normal arteries receiving statin therapy will show reduced progression of coronary plaque as measured by IVUS Takagi T et al, Am J Cardiol, 1997.

61 IVUS: Changes in Atheroma Volume Results for 25 patients (13 in the pravastatin group, 12 in the control group) who completed the study. These patients were similar at baseline with regard to dyslipidemia (LDL-C 200-260 mg/dL) and IVUS. Mean plaque index at baseline was 41.2%. Qualifying arteries had not undergone a procedure and were angiographically normal (<25% lumen reduction). (Adapted from Takagi et al.) Statin reduced TC and LDL-C; no change in HDL-C or TG Statin reduced TC and LDL-C; no change in HDL-C or TG Takagi T et al, Am J Cardiol, 1997.

62 REVERSAL: Study Design International, prospective, randomized, multicenter, double-blind International, prospective, randomized, multicenter, double-blind Projected completion: 2002 Projected completion: 2002 International, prospective, randomized, multicenter, double-blind International, prospective, randomized, multicenter, double-blind Projected completion: 2002 Projected completion: 2002 Data on file, Pfizer Inc., New York, NY.

63 Interventions Beyond Lipid Reduction Lichtlen PR et al, Lancet, 1990; Waters D et al, Circulation, 1990; Borhani NO et al, JAMA, 1996.

64 Carotid Disease: A Reliable Predictor of Coronary Risk Carotid atherosclerosis, even when very mild, is associated with MI and sudden cardiac death Carotid atherosclerosis, even when very mild, is associated with MI and sudden cardiac death Ultrasound-derived carotid intimal-medial thickness (IMT) has been shown to predict the risk of MI Ultrasound-derived carotid intimal-medial thickness (IMT) has been shown to predict the risk of MI The same risk factors predispose patients to atherosclerosis in both the coronary and carotid arterial systems The same risk factors predispose patients to atherosclerosis in both the coronary and carotid arterial systems Carotid atherosclerosis, even when very mild, is associated with MI and sudden cardiac death Carotid atherosclerosis, even when very mild, is associated with MI and sudden cardiac death Ultrasound-derived carotid intimal-medial thickness (IMT) has been shown to predict the risk of MI Ultrasound-derived carotid intimal-medial thickness (IMT) has been shown to predict the risk of MI The same risk factors predispose patients to atherosclerosis in both the coronary and carotid arterial systems The same risk factors predispose patients to atherosclerosis in both the coronary and carotid arterial systems Salonen R in Risk Factors for Ultrasonographically Assessed Common Carotid Atherosclerosis, 1991; O’Leary DH et al, N Engl J Med, 1999; Androulakis AE et al, Eur Heart J, 2000.

65 Emerging Risk Factors Increased serum homocysteine Increased serum homocysteine Increased lipoprotein (a) (Lp[a]) Increased lipoprotein (a) (Lp[a]) Increased C-reactive protein (CRP) Increased C-reactive protein (CRP) Chlamydia pneumoniae infection Chlamydia pneumoniae infection Estrogen deficiency Estrogen deficiency Coagulation factor abnormalities Coagulation factor abnormalities –Plasma fibrinogen –Factor VII –Endogenous tissue plasminogen activator –Plasminogen-activator inhibitor type I –D -Dimer Increased serum homocysteine Increased serum homocysteine Increased lipoprotein (a) (Lp[a]) Increased lipoprotein (a) (Lp[a]) Increased C-reactive protein (CRP) Increased C-reactive protein (CRP) Chlamydia pneumoniae infection Chlamydia pneumoniae infection Estrogen deficiency Estrogen deficiency Coagulation factor abnormalities Coagulation factor abnormalities –Plasma fibrinogen –Factor VII –Endogenous tissue plasminogen activator –Plasminogen-activator inhibitor type I –D -Dimer Braunwald E, N Engl J Med, 1997.

66 Multiple Risk Factors: Additive Risk Grundy SM et al, J Am Coll Cardiol, 1999; Data on file, Pfizer Inc., New York, NY. Risk of developing CAD over 10 years according to specified BP levels and other risk factors. Calculations are based on a Framingham Heart Study computer program, which includes variables for systolic BP, diastolic BP, TC, HDL-C, LVH by ECG, cigarette smoking, and glucose intolerance. The following remained constant unless otherwise indicated: male, age 45 years, TC 180 mg/dL, HDL 45, and nonsmoker. Elevated LDL-C estimated based on TC 250 mg/dL with triglycerides 200 mg/dL. (Data on file, Pfizer Inc.)

67 (Adapted from Glagov et al.) Coronary Remodeling NormalvesselMinimalCAD Progression Compensatory expansion maintains constant lumen Expansion overcome: lumen narrows SevereCADModerateCAD Glagov et al, N Engl J Med, 1987.

68 Article Options Abstract PDF VIDEO SUPPLEMENT Send to a Friend Related articles in this issue Similar articles in this journal Literature Track Add to File Drawer Download to Citation Manager PubMed citation Articles in PubMed by Nissen SE DeMaria AN DeMaria AN Articles that cite this article ISI Web of Science (1) Contact me when this article is cited Featured Link Featured Link E-mail Alerts E-mail AlertsE-mail AlertsE-mail Alerts JAMA. 2004;291:1071-1080. JAMA. 2004;291:1071-1080. Effect of Intensive Compared With Moderate Lipid- Lowering Therapy on Progression of Coronary Atherosclerosis; A Randomized Controlled Trial Effect of Intensive Compared With Moderate Lipid- Lowering Therapy on Progression of Coronary Atherosclerosis; A Randomized Controlled Trial Steven E. Nissen, MD; E. Murat Tuzcu, MD; Paul Schoenhagen, MD; B. Steven E. Nissen, MD; E. Murat Tuzcu, MD; Paul Schoenhagen, MD; B. Greg Brown, MD; Peter Ganz, MD; Robert A. Vogel, MD; Tim Crowe, BS; Gail Howard, MS; Christopher J. Cooper, MD; Bruce Brodie, MD; Cindy L. Grines, MD; Anthony N. DeMaria, MD; for the REVERSAL Investigators

69 Statin Trials Utilizing IVUS: REVERSAL Primary hypothesis A large (vs moderate) reduction in LDL-C will cause a greater decrease in the total atherosclerotic burden in patients with established CAD measured by IVUS A large (vs moderate) reduction in LDL-C will cause a greater decrease in the total atherosclerotic burden in patients with established CAD measured by IVUS Secondary hypothesis The reduction in plaque burden as assessed by IVUS will be evident despite the absence of any angiographically apparent improvement The reduction in plaque burden as assessed by IVUS will be evident despite the absence of any angiographically apparent improvement Primary hypothesis A large (vs moderate) reduction in LDL-C will cause a greater decrease in the total atherosclerotic burden in patients with established CAD measured by IVUS A large (vs moderate) reduction in LDL-C will cause a greater decrease in the total atherosclerotic burden in patients with established CAD measured by IVUS Secondary hypothesis The reduction in plaque burden as assessed by IVUS will be evident despite the absence of any angiographically apparent improvement The reduction in plaque burden as assessed by IVUS will be evident despite the absence of any angiographically apparent improvement Data on file, Pfizer Inc., New York, NY.

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71 Aggressive lipid lowering strategy  Atorvastatin (80 mg)  n=253 Aggressive lipid lowering strategy  Atorvastatin (80 mg)  n=253 Endpoints (follow-up 18 months):  Primary – Percent change in atheroma volume on IVUS between baseline and 18 month follow-up  Secondary – Absolute change in atheroma volume; change in the percent obstructive volume Endpoints (follow-up 18 months):  Primary – Percent change in atheroma volume on IVUS between baseline and 18 month follow-up  Secondary – Absolute change in atheroma volume; change in the percent obstructive volume REVERSAL Trial AHA 2003, Orlando, FL 502 symptomatic coronary artery disease patients with elevated LDL Randomized, double-blind, multicenter 502 symptomatic coronary artery disease patients with elevated LDL Randomized, double-blind, multicenter Moderate lipid-lowering strategy  Pravastatin (40 mg)  n=249 Moderate lipid-lowering strategy  Pravastatin (40 mg)  n=249

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74 REVERSAL Trial LDL at follow-up p<0.001 AHA 2003, Orlando, FL mg/dL Total-cholesterol at follow-up p<0.001 mg/dL HDL at follow-up p=0.06 mg/dL

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76 REVERSAL Trial Change in atheroma volume p=0.02 for change between atorvastatin vs pravastatin Change in percent obstruction volume p=0.0002 for change between atorvastatin vs pravastatin AHA 2003, Orlando, FL

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78

79 REVERSAL Trial Percent Reduction in CRP p<0.001 AHA 2003, Orlando, FL

80 Relation of Change: LDL to Atheroma Volume

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82 REVERSAL Trial Among patients with symptomatic CAD and elevated LDL, use of an aggressive lipid-lowering strategy through treatment with 80- mg atorvastatin was associated with a reduction in percent change in atheroma volume compared with a more moderate lipid-lowering strategy through treatment with 40-mg pravastatin Among patients with symptomatic CAD and elevated LDL, use of an aggressive lipid-lowering strategy through treatment with 80- mg atorvastatin was associated with a reduction in percent change in atheroma volume compared with a more moderate lipid-lowering strategy through treatment with 40-mg pravastatin Primary endpoint used an IVUS endpoint and the trial was not designed to assess mortality or clinical events, and a much larger trial would be needed to assess superiority of one statin over another for these endpoints Primary endpoint used an IVUS endpoint and the trial was not designed to assess mortality or clinical events, and a much larger trial would be needed to assess superiority of one statin over another for these endpoints Among patients with symptomatic CAD and elevated LDL, use of an aggressive lipid-lowering strategy through treatment with 80- mg atorvastatin was associated with a reduction in percent change in atheroma volume compared with a more moderate lipid-lowering strategy through treatment with 40-mg pravastatin Among patients with symptomatic CAD and elevated LDL, use of an aggressive lipid-lowering strategy through treatment with 80- mg atorvastatin was associated with a reduction in percent change in atheroma volume compared with a more moderate lipid-lowering strategy through treatment with 40-mg pravastatin Primary endpoint used an IVUS endpoint and the trial was not designed to assess mortality or clinical events, and a much larger trial would be needed to assess superiority of one statin over another for these endpoints Primary endpoint used an IVUS endpoint and the trial was not designed to assess mortality or clinical events, and a much larger trial would be needed to assess superiority of one statin over another for these endpoints

83 PRavastatin Or atorVastatin Evaluation and Infection Therapy (TIMI 22)

84 BackgroundBackground Statin therapy is highly effective vs. placebo in long-term treatment of CHD Statin therapy is highly effective vs. placebo in long-term treatment of CHD – Are statins effective in reducing events in patients with an acute coronary syndrome (ACS)? – Does “intensive” LDL-C lowering to an average of 65 mg/dL achieve a greater reduction in clinical events than “standard” LDL-C lowering to an average of 95 mg/dL?

85 4,162 patients with an Acute Coronary Syndrome < 10 days ASA + Standard Medical Therapy “Standard Therapy” Pravastatin 40 mg “Intensive Therapy” Atorvastatin 80 mg Duration: Mean 2 year follow-up (>925 events) Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke PROVE IT - TIMI 22: Study Design 2x2 Factorial: Gatifloxacin vs. placebo Double-blind

86 Baseline Characteristics Atorvastatin 80mgPravastatin 40mg (2099)(2063) Mean Age (years)5858 Male/Female (%)78 / 2278 / 22 History of HTN (%)5149 Current Smoker (%)3637 History of Diabetes (%)1918 History of CHD (%)3739 STEMI / NSTEMI / UA (%)36 / 36 / 2933 / 37 / 30 Prior Statin Use (%)2625 Atorvastatin 80mgPravastatin 40mg (2099)(2063) Mean Age (years)5858 Male/Female (%)78 / 2278 / 22 History of HTN (%)5149 Current Smoker (%)3637 History of Diabetes (%)1918 History of CHD (%)3739 STEMI / NSTEMI / UA (%)36 / 36 / 2933 / 37 / 30 Prior Statin Use (%)2625

87 Concomitant Therapies PCI for initial ACS pre-Rand 69% Aspirin 93% Warfarin 8% Clopidogrel (initial) 72% (at F/U) 20% B-blockers 85% ACE 69% ARB 14% PCI for initial ACS pre-Rand 69% Aspirin 93% Warfarin 8% Clopidogrel (initial) 72% (at F/U) 20% B-blockers 85% ACE 69% ARB 14%

88 Changes from (Post-ACS) Baseline in Median LDL-C Note: Changes in LDL-C may differ from prior trials: 25% of patients on statins prior to ACS event 25% of patients on statins prior to ACS event ACS response lowers LDL-C from true baseline ACS response lowers LDL-C from true baseline LDL-C (mg/dL) 20 40 60 80 100 120 Rand.30 Days4 Mos.8 Mos.16 Mos.Final Pravastatin 40mg Atorvastatin 80mg 49%  21%  P<0.001 Median LDL-C (Q1, Q3) 95 (79, 113) 62 (50, 79) <24h

89 All-Cause Death or Major CV Events in All Randomized Subjects031821242730691215 % with Event Months of Follow-up Pravastatin 40mg (26.3%) Atorvastatin 80mg (22.4%) 16% RR (P = 0.005) 30 25 20 15 10 5 0

90 Events Rates RR Atorva 80 Prava 40 17%1.9% 2.2% 18%6.3% 7.7% 14%12.2% 14.1% 16%22.4%* 26.3%* 30 Days 90 Days 180 Days End of Follow-up Primary Endpoint Over Time Atorvastatin 80mg Better 0.5 0.75 1.0 1.25 Pravastatin 40mg Better *2-year event rates

91 Reductions in Major Cardiac Endpoints 2 Year Event Rates RR Atorva 80 Prava 40 28% 2.2% 3.2% 30% 1.1% 1.4% 13% 6.6% 7.4% 18% 8.3% 10.0% 14% 16.3% 18.8% 29% 3.8% 5.1% 25% 12.9% 16.7% 0.51.01.5 All-Cause Mortality Death or MI Death/MI/Urg.Revasc MI Revasc > 30 d UA Req Hosp 0.751.25 Atorvastatin 80 mg BetterPravastatin 40 mg Better CHD Death

92 Benefits of Very Low LDL in PROVE IT Wiviott et al; JACC, 2006

93 SummarySummary In patients recently hospitalized within 10 days for an acute coronary syndrome: In patients recently hospitalized within 10 days for an acute coronary syndrome:  “Intensive” high-dose LDL-C lowering (median LDL-C 62 mg/dL) compared to “moderate” standard-dose lipid- lowering therapy (median LDL-C 95 mg/dL) reduced the risk of all cause mortality or major cardiac events by 16% (p=0.005)  Benefits emerged within 30 days post ACS with continued benefit observed throughout the 2.5 years of follow-up  Benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups In patients recently hospitalized within 10 days for an acute coronary syndrome: In patients recently hospitalized within 10 days for an acute coronary syndrome:  “Intensive” high-dose LDL-C lowering (median LDL-C 62 mg/dL) compared to “moderate” standard-dose lipid- lowering therapy (median LDL-C 95 mg/dL) reduced the risk of all cause mortality or major cardiac events by 16% (p=0.005)  Benefits emerged within 30 days post ACS with continued benefit observed throughout the 2.5 years of follow-up  Benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups

94 Lipid Lowering In TNT

95

96 LDL Lowering to 60: Asteroid Trial

97 LDL Lowering and Atheroma Volume

98 FOCUS ISSUE: PROVE IT-TIMI 22 Can Low-Density Lipoprotein Be Too Low? The Safety and Efficacy of Achieving Very Low Low-Density Lipoprotein With Intensive Statin Therapy A PROVE IT-TIMI 22 Substudy Stephen D. Wiviott, MD *, Christopher P. Cannon, MD, FACC *,, David A. Morrow, MD, MPH, FACC *,, Kausik K. Ray, MD, Marc A. Pfeffer, MD, PhD, FACC *, Eugene Braunwald, MD, MACC *, for the PROVE IT-TIMI 22 Investigators * Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts The TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts

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100

101 Relation of LDL to Lumen Diameter O’Keefe et al; JACC, 2004

102 Relation of LDL to Event Rate O’Keefe et al; JACC, 2004

103 Relation of LDL to Event Rate O’Keefe et al; JACC, 2004

104 Relation of LDL to Event Rate O’Keefe et al; JACC, 2004

105 Comparative Cholesterol Levels

106 HDL: The Next Frontier

107

108 “Be There”: Making San Diego County a Heart Attack and Stroke-Free Zone Anthony DeMaria, MD Judith and Jack White Chair in Cardiology University of California, San Diego Chair, San Diego Right Care-Be There Campaign Anthony DeMaria, MD Judith and Jack White Chair in Cardiology University of California, San Diego Chair, San Diego Right Care-Be There Campaign 108 GR MH Tony 1 st subm TJ edits 9Feb2012

109 BackgroundBackground Cardiovascular disease (CVD) remains the leading cause of death in the United States Cardiovascular disease (CVD) remains the leading cause of death in the United States San Diego and CVD San Diego and CVD –Heart disease and stroke together are the leading cause of death Nearly 5,000 deaths annually from heart disease (rate 112)Nearly 5,000 deaths annually from heart disease (rate 112) Quick comparison of rates to those nationwideQuick comparison of rates to those nationwide Risk factors have been identified for which effective interventions exist (ABCS) Risk factors have been identified for which effective interventions exist (ABCS) Cardiovascular disease (CVD) remains the leading cause of death in the United States Cardiovascular disease (CVD) remains the leading cause of death in the United States San Diego and CVD San Diego and CVD –Heart disease and stroke together are the leading cause of death Nearly 5,000 deaths annually from heart disease (rate 112)Nearly 5,000 deaths annually from heart disease (rate 112) Quick comparison of rates to those nationwideQuick comparison of rates to those nationwide Risk factors have been identified for which effective interventions exist (ABCS) Risk factors have been identified for which effective interventions exist (ABCS) 109

110 San Diego County Health and Human Services: Stakeholders in CVD Prevention Live Well San Diego Live Well San Diego 110 http://www.sdcounty.ca.gov/hhsa/programs/sd/health_strategy_agenda/index.html  Communities Putting Prevention to Work (CDC grant)  Reduce chronic disease by physical activity, nutrition, and school environments  Community Transformation Grant (CDC grant)  Tobacco free, active living, healthy eating, reduce hypertension and high cholesterol  Beacon Grant (NIH)  Awarded across the country to serve as pilots for wide-scale use of health information technology through the Beacon Community program

111 How It All Started Coordinated effort to improve quality – –State Department of Managed Health Care – –Medical groups beyond managed care organizations – –UC Berkeley School of Public Health – –Rand Health (GO Grant) Goal: Achieve national HEDIS 90% percentile targets – –Blood pressure, lipids, blood sugar University of Best Practices meetings – –Monthly meetings – –Physicians, nurses, administrators, pharmacist – –Discuss successful strategies – –Now sharing data among group participants Coordinated effort to improve quality – –State Department of Managed Health Care – –Medical groups beyond managed care organizations – –UC Berkeley School of Public Health – –Rand Health (GO Grant) Goal: Achieve national HEDIS 90% percentile targets – –Blood pressure, lipids, blood sugar University of Best Practices meetings – –Monthly meetings – –Physicians, nurses, administrators, pharmacist – –Discuss successful strategies – –Now sharing data among group participants 111 HEDIS, Healthcare Effectiveness Data and Information Set

112 Be There Campaign Concept: “Heart Attack and Stroke-free Zone” Concept: “Heart Attack and Stroke-free Zone” –Audacious goal to capture attention –Extends the risk reduction efforts to all citizens –Actively engages persons in their own health (care) –Conveys ownership to population –Taps in to community pride Aim: Achieve both screening for risk factors and compliance with interventions Aim: Achieve both screening for risk factors and compliance with interventions Funding: $650,000; philanthropy Funding: $650,000; philanthropy Steering Committee: Private-public partnership Steering Committee: Private-public partnership Concept: “Heart Attack and Stroke-free Zone” Concept: “Heart Attack and Stroke-free Zone” –Audacious goal to capture attention –Extends the risk reduction efforts to all citizens –Actively engages persons in their own health (care) –Conveys ownership to population –Taps in to community pride Aim: Achieve both screening for risk factors and compliance with interventions Aim: Achieve both screening for risk factors and compliance with interventions Funding: $650,000; philanthropy Funding: $650,000; philanthropy Steering Committee: Private-public partnership Steering Committee: Private-public partnership 112

113 San Diego Demonstration Project Going Emotional!  Emotional “tug” is critical for commitment to change one’s behavior  Benefit to those we love can be a bigger driver than benefit to oneself  Caring for one’s own health makes it possible to “be there” for those we love! for those we love!  Emotional “tug” is critical for commitment to change one’s behavior  Benefit to those we love can be a bigger driver than benefit to oneself  Caring for one’s own health makes it possible to “be there” for those we love! for those we love! 113 “When something is missing in your life, it usually turns out to be someone”. Robert Brault

114 Be There Campaign Steering Committee Anthony N. DeMaria, MD Judith and Jack White Chair in Cardiology, Professor of Medicine, University of California, San Diego, Editor-in- Chief, Journal of the American College of Cardiology, Chair, San Diego Right Care-Be There Campaign Anthony N. DeMaria, MD Judith and Jack White Chair in Cardiology, Professor of Medicine, University of California, San Diego, Editor-in- Chief, Journal of the American College of Cardiology, Chair, San Diego Right Care-Be There Campaign Daniel Dworski, MD, Medical Director, Scripps Medical Group Daniel Dworski, MD, Medical Director, Scripps Medical Group Jim Dudl, MD, Vice-Chair, Steering Committee, Clinical Lead, Kaiser Care Management Institute Jim Dudl, MD, Vice-Chair, Steering Committee, Clinical Lead, Kaiser Care Management Institute James Dunford, MD, FACEP, City of San Diego Medical Director of Emergency Medical Services. President,San Diego American Heart Association James Dunford, MD, FACEP, City of San Diego Medical Director of Emergency Medical Services. President,San Diego American Heart Association Nora Faine, MD, MPH, Medical Director, Sharp Health Plan Nora Faine, MD, MPH, Medical Director, Sharp Health Plan Scott Flinn, MD, Medical Director, Arch Medical Group Scott Flinn, MD, Medical Director, Arch Medical Group Lawrence Friedman, MD, Medical Director, Managed Care, Ambulatory Care and Medical Group Quality and Safety, University of California, San Diego Lawrence Friedman, MD, Medical Director, Managed Care, Ambulatory Care and Medical Group Quality and Safety, University of California, San Diego Anthony N. DeMaria, MD Judith and Jack White Chair in Cardiology, Professor of Medicine, University of California, San Diego, Editor-in- Chief, Journal of the American College of Cardiology, Chair, San Diego Right Care-Be There Campaign Anthony N. DeMaria, MD Judith and Jack White Chair in Cardiology, Professor of Medicine, University of California, San Diego, Editor-in- Chief, Journal of the American College of Cardiology, Chair, San Diego Right Care-Be There Campaign Daniel Dworski, MD, Medical Director, Scripps Medical Group Daniel Dworski, MD, Medical Director, Scripps Medical Group Jim Dudl, MD, Vice-Chair, Steering Committee, Clinical Lead, Kaiser Care Management Institute Jim Dudl, MD, Vice-Chair, Steering Committee, Clinical Lead, Kaiser Care Management Institute James Dunford, MD, FACEP, City of San Diego Medical Director of Emergency Medical Services. President,San Diego American Heart Association James Dunford, MD, FACEP, City of San Diego Medical Director of Emergency Medical Services. President,San Diego American Heart Association Nora Faine, MD, MPH, Medical Director, Sharp Health Plan Nora Faine, MD, MPH, Medical Director, Sharp Health Plan Scott Flinn, MD, Medical Director, Arch Medical Group Scott Flinn, MD, Medical Director, Arch Medical Group Lawrence Friedman, MD, Medical Director, Managed Care, Ambulatory Care and Medical Group Quality and Safety, University of California, San Diego Lawrence Friedman, MD, Medical Director, Managed Care, Ambulatory Care and Medical Group Quality and Safety, University of California, San Diego Lisa Gleason, MD CMIO, Cardiology Department Head, Naval Medical Center San Diego Lisa Gleason, MD CMIO, Cardiology Department Head, Naval Medical Center San Diego Hattie Rees Hanley, MPP, Right Care Initiative Project Director and Special Advisor to the Dean for Outcomes Improvement and Innovation, UC Berkeley School of Public Health and Department of Managed Health Care Hattie Rees Hanley, MPP, Right Care Initiative Project Director and Special Advisor to the Dean for Outcomes Improvement and Innovation, UC Berkeley School of Public Health and Department of Managed Health Care Elizabeth Helms, Executive Director, CA Chronic Care Coalition and Right Care San Diego Coordinator Elizabeth Helms, Executive Director, CA Chronic Care Coalition and Right Care San Diego Coordinator Susan Kaweski, MD, President, San Diego County Medical Society Susan Kaweski, MD, President, San Diego County Medical Society Jerry Penso, MD, Medical Director, Continuum of Care, Sharp Rees-Stealy Medical Group, Chair: University of Best Practices Jerry Penso, MD, Medical Director, Continuum of Care, Sharp Rees-Stealy Medical Group, Chair: University of Best Practices James Schultz MD, Council of Community Clinics James Schultz MD, Council of Community Clinics Robert Smith, MD, Chief Medical Officer, Veteran’s Administration San Diego Medical Center Robert Smith, MD, Chief Medical Officer, Veteran’s Administration San Diego Medical Center Melissa J. Wilimas, Executive Director, American Heart Association Melissa J. Wilimas, Executive Director, American Heart Association Nick Yphantides, MD, MPH, Executive Medical Consultant, San Diego County Public Health and Human Services Nick Yphantides, MD, MPH, Executive Medical Consultant, San Diego County Public Health and Human Services 114

115 Wireless Heart Monitors  Technology Integration  Important differentiating component of the Campaign  Incorporation of innovative medical and health related technological advancements to enhance target user groups’ interest, adherence, and participation in the program Wireless monitors to track exercise regime Smart Phones to track and report vitals 115 Be There Campaign Pill bottles that monitor medication adherence

116 Selected Implementation Activities Detailed implementation tactics have been developed but as an overview, here is a summary of some of the patient engagement strategies that will be used by the “Be There San Diego” campaign  Recruit physicians using University of Best Practices  Screening events  Shopping malls, pharmacies, schools, faith based groups  “Be There San Diego”  Pins worn by pharmacists and medical office staff  Bus to implement screening across county  Multimedia advertising campaign across all media platforms  Social media viral campaign to connect with community 116

117 117 Be There Campaign

118 118

119 Be There Campaign 119

120 Be There Campaign 120

121 Way Forward  In response to a call to action to eliminate CV disease from San Diego:  The entire medical community has organized  Philanthropy has been received  A patient activation campaign has been developed  A strong integration with San Diego County health programs has been established  Our goal is to create a program that can be exported to cities throughout the country 121

122 Be There Campaign 122

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125 Important Low HDL-C Facts: Independent Risk Factor for CHD 70% of all infarctions occur in patients with low HDL-C (<45 mg/dl) based on the Framingham 70% of all infarctions occur in patients with low HDL-C (<45 mg/dl) based on the Framingham A 1 mg/dl increase in HDL-C reduces MI risk by 3- 4%, based on Framingham A 1 mg/dl increase in HDL-C reduces MI risk by 3- 4%, based on Framingham Low HDL-C is identified as an independent CHD risk factor in the NCEP guidelines Low HDL-C is identified as an independent CHD risk factor in the NCEP guidelines Low HDL-C was the second most important risk factor in 4S Low HDL-C was the second most important risk factor in 4S 70% of all infarctions occur in patients with low HDL-C (<45 mg/dl) based on the Framingham 70% of all infarctions occur in patients with low HDL-C (<45 mg/dl) based on the Framingham A 1 mg/dl increase in HDL-C reduces MI risk by 3- 4%, based on Framingham A 1 mg/dl increase in HDL-C reduces MI risk by 3- 4%, based on Framingham Low HDL-C is identified as an independent CHD risk factor in the NCEP guidelines Low HDL-C is identified as an independent CHD risk factor in the NCEP guidelines Low HDL-C was the second most important risk factor in 4S Low HDL-C was the second most important risk factor in 4S

126 HDL is a major Predictor of CAD 0 20 40 60 80 100 120 <3535 - 55>55 HDL-cholesterol (mg/dL ) Incidence of CHD (per 1000 in 6 years) n=4,407 Assmann G, et al. Atherosclerosis 1996;124(suppl):S11-S20.

127 Increased HDL and Reduced CHD Incidence Framingham Study Relative Risk of CHD HDL (mg/dl) Kannel WB, Carter BL. Am Heart J 118 1989

128 100160220 Risk of CHD Low HDL-C is an Independent Predictor of CHD Risk Even When LDL-C is Low HDL-C (mg/dL ) LDL-C (mg/dL) 25 Gordon T et al. Am J Med 1977;62:707-714. 45 65 85

129 Torcetrapib: a novel CETP Inhibitor Effects on HDL N Engl J Med 2004; 350:1505- 1515

130 Apo AI- Milano Nissen S. Jama 2004

131 Role of HDL for Regression Nichols et al; JAMA, 2007

132 Apo-A1 Milano; Plaque “Drano”

133 Ezetimibe in Enhance Study Kastelein et al; NEJM, 2008

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136 Hunter/GathererHunter/Gatherer ANDAND


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