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Lipid Management Standard and Advanced Preview of ATP-IV Thomas G. Allison, PhD, MPH Mayo Clinic Rochester, MN USA.

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Presentation on theme: "Lipid Management Standard and Advanced Preview of ATP-IV Thomas G. Allison, PhD, MPH Mayo Clinic Rochester, MN USA."— Presentation transcript:

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2 Lipid Management Standard and Advanced Preview of ATP-IV Thomas G. Allison, PhD, MPH Mayo Clinic Rochester, MN USA

3 DISCLOSURE Relevant Financial Relationship(s) None Off Label Usage None

4 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285: Treatment Categories, LDL-C Goals and Cut-points: ATP-III Risk CategoryLDL-C Goal Consider Drug Therapy CHD or CHD risk equivalent<100 mg/dL 130 mg/dL* 2 Risk Factors 10-yr risk 10–20% 10-yr risk <10% <130 mg/dL 130 mg/dL 160 mg/dL <2 Risk Factors<160 mg/dL 190 mg/dL * 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy

5 Major ATP III Risk Factors Age Male 45 years Female 55 years Family History Male first degree relative < 55 years Female first degree relative < 65 years HDL-C < 40 mg/dL Hypertension Current Smoking

6 CAD Equivalents Coronary Artery Disease (CAD) Diabetes Mellitus Abdominal Aortic Aneurysm Carotid Artery Disease (>50% stenosis) Prior CVA or TIA Peripheral Arterial Disease Framingham Score >20% 10 yr Risk

7 CAD Risk Equivalents? Chronic Renal Insufficiency Abnormal Coronary Calcium Scores –Agatston score > 400

8 Goals for Therapy: 2004 Addendum NCEP ATP III guidelines for LDL Therapy LDL-C <160 for 1 or less risk factors LDL-C <130 for 2+ risk factors < 100 is a therapeutic option LDL-C <100 for CAD and CAD equivalents <70 is option for very high risk patients 1.CAD + multiple risk factors, especially diabetes 2.CAD + severe or poorly controlled risk factor(s) 3.CAD + metabolic syndrome 4.Acute coronary syndrome 5.CAD event despite baseline LDL-C < 100

9 LDL-C Therapy Lifestyle Change Statins Bile Acid Sequestrants Ezetimibe Niacin Plant Stanols, Sterols, Phytosterols

10 Residual Risk: Non-HDL-C ATP III: Non-HDL-C is a secondary target of drug therapy when TG 200mg/dL Represents all the triglyceride-rich lipoproteins – considered atherogenic Non-HDL-C = Total Cholesterol – HDL-C Valid even if patient is non-fasting Cost-Effective

11 Targets for Therapy after LDL-C Goal in Patients with TG 200 mg/dL Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285: Patient Category LDL-C target (mg/dL) Non-HDL-C target (mg/dL) CHD or CHD risk equivalent <100<130 No CHD, 2+ RF<130<160 No CHD, <2 RF<160<190

12 Potential Goal Modifying Factors Lp(a) High sensitivity CRP Metabolic Syndrome

13 Grundy, et al. Diagnosis and management of the metabolic syndrome: an AHA/NHLBI Scientific Statement. Circulation 2005;112: Risk FactorDefining Level Waist circumference (abdominal obesity)>40 in (>102 cm) in men >35 in (>88 cm) in women Triglyceride level>150 mg/dl HDL-C level<40 mg/dl in men <50 mg/dl in women Blood pressure>130/>85 mmHg Fasting glucose>100 mg/dl Definition of the Metabolic Syndrome Defined by presence of >3 risk factors

14 Dr. Allison Attempts to Call Forth the Contents of ATP-IV

15 Will ATP-IV Signal a New Wave of Lipid Management?

16 Sweeping Changes?

17 Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel IV) Expert Panel Membership Co-Chairs Alice H. Lichtenstein, D.Sc. Tufts University Boston, Massachusetts Neil Stone, M.D. Northwestern University School of Medicine Chicago, Illinois

18 C. Noel Bairey Merz, M.D. University of California, Los Angeles Conrad Blum, M.D. Columbia University Robert H. Eckel, M.D. University of Colorado, Denver Anne Carol Goldberg, M.D., FACP, FAHA Washington University Ronald M. Krauss, M.D. Children's Hospital Oakland Research Institute Donald M. Lloyd-Jones, M.D., Sc.M. Northwestern University Patrick McBride, M.D., M.P.H. University of Wisconsin Daniel Rader, M.D. University of Pennsylvania Jennifer Robinson, M.D, M.P.H. University of Iowa Frank M. Sacks, M.D. Harvard University School of Public Health J. Sanford Schwartz, M.D. University of Pennsylvania Sidney C. Smith, Jr. M.D. University of North Carolina Karol Watson, M.D., Ph.D. University of California at Los Angeles Peter W. F. Wilson, M.D. Emory University School of Medicine

19 Status Expected Availability for Public Review and Comment: Spring 2011 Expected Release Date: Fall 2011

20 Issues for ATP-IV 1.Should the goals for LDL-C in primary prevention be lowered? 2.What to do with CRP – routine use in risk stratification, secondary target? 3.What about secondary target? –Non-HDL-C, HDL-C, apo B, LDL Particle concentration? 4.Move from 10-year to lifetime risk?

21 Jupiter Trial To test the hypothesis that statin treatment will reduce CV events in patients without baseline CVD with normal LDL-C (< 130 mg/dL) and elevated hsCRP ( 2.0 mg/L) The most innovative and potentially important lipid-lowering trial since the 2004 ATP-II Addendum Ridker PM et al. NEJM 2008;359:

22 Jupiter Methods 17,802 subjects (38% women) –Men 50 years; women 60 years –Triglycerides < 500 mg/dL Randomized to Rosuvastatin 20 mg/day or placebo Planned 60 month follow-up Primary outcome was major CV event –Including elective revascularization

23 Jupiter Results Study terminated early on with median follow-up of 1.9 years Compliance at study termination was 75% 44% reduction in primary endpoint –0.77% versus 1.36% per year 20% reduction in total mortality –1.00% versus 1.25% per year

24 12-Month Laboratory Results (Medians) RosuvastatinPlacebo hs-CRP LDL-C55110 HDL-C5250 TG99119

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27 JUPITER Questions Would a lower-cost, generic statin show similar benefit? Is measurement of hsCRP necessary for risk stratification in primary prevention –Ridker conflict of interest issues Was the benefit due to LDL-C lowering or hsCRP lowering?

28 Risk Factors in Jupiter Subjects Average age = 66 years Current smokers = 16% Metabolic syndrome = 41% Family history of premature CAD = 11% 25% had fasting glucose > 102 mg/dL 25% had systolic BP > 145 mmHg

29 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

30 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) Rand.30 Days4 Mos. 8 Mos.16 Mos. Final Pravastatin 40mg Atorvastatin 80mg 49% 49% 21% 21% P<0.001 Median LDL-C (Q1, Q3) 95 (79, 113) 62 (50, 79) <24h

31 PROVE IT: Concomitant Therapies PCI for initial ACS pre-random. 69% Aspirin 93% Warfarin 8% Clopidogrel (initial) 72% (at F/U) 20% B-blockers 85% ACE 69% ARB 14% PCI for initial ACS pre-random. 69% Aspirin 93% Warfarin 8% Clopidogrel (initial) 72% (at F/U) 20% B-blockers 85% ACE 69% ARB 14%

32 All-Cause Death or Major CV Events in All Randomized Subjects % with Event Months of Follow-up Pravastatin 40mg (26.3%) Atorvastatin 80mg (22.4%) 16% relative risk reduction (p = 0.005) But absolute residual risk is 22%

33 Sources of Residual Risk Not providing appropriate medical therapy? Inadequate control of non-lipid risk factors? Not addressing emerging risk factors? –CRP, Lp(a) Inadequate control of lipids using LDL target only? –Non-HDL –HDL or apo A-1 –Apo B –LDL particle number –LDL particle size

34 Secondary Lipid Target In ATP-III, non-HDL-C was identified as the secondary lipid target –Sum of cholesterol in all atherogenic lipoproteins LDL-C, Lp(a)-C, VLDL-C, IDL-C No major trial since publication of ATP-III in 2001 that specifically treated non-HDL-C

35 Lowering non-HDL-C Increase the statin dose Add fibrate Add niacin High dose fish oil Exercise, CHO restriction, weight loss

36 FIELD Study Fenofibrate to Prevent Cardiovascular Events in Diabetics FIELD Study Investigators Lancet 2005; 366:

37 FIELD Mortality No significant benefit shown in ACCORD-Lipids for fenofibrate added to Simvastatin 40 mg/day. NEJM 2010, March 14.

38 LDL Particles Cause Atherosclerosis Low Density Lipoprotein particles (LDL) are the causal agents in atherosclerosis. 1 1 Fredrickson et al. NEJM 1967; 276: 148 The more LDL particles a person has, the higher the risk for plaque buildup that causes heart attacks, regardless of how much cholesterol those particles carry.

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40 This is LDL Cholesterol NONPOLAR LIPID CORE Cholesterol Ester Triglyceride POLAR SURFACE COAT Phospholipid Free cholesterol Apo B LDL-C is not LDL James Otvos 2007

41 EDTA sugars lipoproteins

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43 42% (n=603) Percent of Subjects 10% (n=141) 5 th 20 th 50 th 80 th percentile (nmol/L) 36% (n=509) 10% (n=150) 2% (n=22) LDL Particle Number Distribution in MESA LDL-C <100 mg/dL (n=1,425) LDL Size (nm) 21.3 (0.7) 20.5 (0.6) 20.1 (0.5) HDL-C (mg/dL) 58 (18) 47 (15) 41 (11) Triglycerides (mg/dL) 98 (60) 136 (71) 199 (75) AHA/ADA Metabolic Syndrome/Metabolic Risks meeting. San Francisco, May 3-5, 2006

44 (nmol/L) 4% (n=20) 33% (n=153) 46% (n=210) 17% (n=76) Percent of Subjects 0% (n=0) 24% (n=215) Percent of Subjects 1% (n=10) 5 th 20 th 50 th 80 th percentile MetSyn (-) (n=903) (nmol/L) 54% (n=484) 19% (n=168) 3% (n=26) MetSyn (+) (n=459) LDL Particle Number Distribution in MESA LDL-C = mg/dL 63%22% AHA/ADA Metabolic Syndrome/Metabolic Risks meeting. San Francisco, May 3-5, 2006

45 CHD Event Associations of NMR LDL Particle Number (LDL-P) versus LDL Cholesterol (LDL-C) Cromwell WC et al: J Clinical Lipidology 2007;1:

46 Brief Comments Apo B or Non-HDL versus LDL-P Apo B and non-HDL are likely better predictors of risk than LDL-C in patients with cardiometabolic syndrome Non-HDL costs nothing extra to measure Apo B measurement does not require unique, expensive technology

47 Apo B gives equal weight to each particle: LDL, Lp(a), VLDL, IDL –Not equal atherogenicity –Treatment strategies different for each particle Non-HDL similarly lumps particle types together Example 1 –TC=200, HDL=50, TG=200, non-HDL=150 Example 2 –TC=170, HDL=20, TG=500, non-HDL=150 Is risk equivalent for these 2 patients?

48 Prediction of Lifetime Risk for Cardiovascular Disease by Risk Factor Burden at 50 Years of Age Donald M. Lloyd-Jones et al Circulation 2006;113:

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51 Generic Prevention Drugs Drug Monthly Cost Statin $4.00 Beta blocker$4.00 Metformin$4.00 ACE-inhibitor ± HCTZ$4.00 Amlodipine$4.00 All national discount pharmacy chains –Lower price ($10) for 3 months supply Can potentially reduce cost further with a pill cutter

52 Living Under the Umbrella of Good Cardiovascular Health FBG <100 LDL-C <100 SBP <120

53 Predictions for ATP-IV 1.The goals for LDL-C in primary prevention will be lowered. 2.There will be a stronger statement on hsCRP, but routine use in risk stratification or use as secondary target will not be specifically endorsed. 3.Non-HDL-C will remain the secondary lipid target, but optional use of apo B or LDL-P will be endorsed. 4.A new risk calculator providing lifetime risk estimates will be provided.

54 Comments? Questions?


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