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Lipid Management Standard and Advanced Preview of ATP-IV

Lipid Management Standard and Advanced Preview of ATP-IV. Thomas G. Allison, PhD, MPH Mayo Clinic Rochester, MN USA. DISCLOSURE. Relevant Financial Relationship(s) None Off Label Usage None. Treatment Categories, LDL-C Goals and Cut-points: ATP-III.

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Lipid Management Standard and Advanced Preview of ATP-IV

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

  2. DISCLOSURE Relevant Financial Relationship(s) None Off Label Usage None

  3. Treatment Categories, LDL-C Goals and Cut-points: ATP-III * 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

  4. 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

  5. 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

  6. CAD Risk Equivalents? • Chronic Renal Insufficiency • Abnormal Coronary Calcium Scores • Agatston score > 400

  7. 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 • CAD + multiple risk factors, especially diabetes • CAD + severe or poorly controlled risk factor(s) • CAD + metabolic syndrome • Acute coronary syndrome • CAD event despite baseline LDL-C < 100

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

  9. 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

  10. 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;285:2486-2497.

  11. Potential Goal Modifying Factors • Lp(a) • High sensitivity CRP • Metabolic Syndrome

  12. Definition of the Metabolic Syndrome Defined by presence of >3 risk factors Grundy, et al. Diagnosis and management of the metabolic syndrome: an AHA/NHLBI Scientific Statement. Circulation 2005;112:2735-2752.

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

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

  15. Sweeping Changes?

  16. 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 UniversityBoston, MassachusettsNeil Stone, M.D.Northwestern University School of MedicineChicago, Illinois

  17. 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 CarolinaKarol Watson, M.D., Ph.D.University of California at Los AngelesPeter W. F. Wilson, M.D.Emory University School of Medicine C. Noel Bairey Merz, M.D.University of California, Los AngelesConrad Blum, M.D.Columbia UniversityRobert H. Eckel, M.D.University of Colorado, DenverAnne Carol Goldberg, M.D., FACP, FAHAWashington UniversityRonald M. Krauss, M.D.Children's Hospital Oakland Research InstituteDonald M. Lloyd-Jones, M.D., Sc.M.Northwestern University Patrick McBride, M.D., M.P.H.University of Wisconsin

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

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

  20. 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;359:2195-2207

  21. 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

  22. Jupiter Results • Study terminated early on 3-30-08 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

  23. 12-Month Laboratory Results (Medians)

  24. 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?

  25. 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

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

  27. Changes from (Post-ACS) Baseline in Median LDL-C LDL-C (mg/dL) Median LDL-C (Q1, Q3) 95 (79, 113) 62 (50, 79) 120 100 Pravastatin 40mg 21% 80 60 Atorvastatin 80mg 49%  40 P<0.001 20 <24h Rand. 30 Days 4 Mos. Final 8 Mos. 16 Mos. • Note: Changes in LDL-C may differ from prior trials: • 25% of patients on statins prior to ACS event • ACS response lowers LDL-C from true baseline

  28. 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%

  29. 0 30 3 6 9 12 15 18 21 24 27 All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40mg (26.3%) 25 20 % with Event Atorvastatin 80mg (22.4%) 15 16% relative risk reduction (p = 0.005) 10 5 But absolute residual risk is 22% 0 Months of Follow-up

  30. 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

  31. 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

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

  33. FIELD StudyFenofibrate to Prevent Cardiovascular Events in Diabetics FIELD Study Investigators Lancet 2005; 366:1849-1861

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

  35. LDL Particles Cause Atherosclerosis Low Density Lipoprotein particles (LDL) are the causal agents in atherosclerosis.1 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. 1 Fredrickson et al. NEJM 1967; 276: 148

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

  37. lipoproteins EDTA sugars

  38. LDL Particle Number Distribution in MESA LDL-C <100 mg/dL (n=1,425) 5th 20th 50th 80th percentile 10% (n=141) 42% (n=603) 36% (n=509) 10% (n=150) 2% (n=22) Percent of Subjects 700 1000 1300 1600 (nmol/L) 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

  39. 22% 63% LDL Particle Number Distribution in MESA LDL-C = 100-118 mg/dL 5th 20th 50th 80th percentile 1% (n=10) 24% (n=215) 54% (n=484) 19% (n=168) 3% (n=26) MetSyn (-) (n=903) Percent of Subjects 700 1000 1300 1600 (nmol/L) 0% (n=0) 4% (n=20) 33% (n=153) 46% (n=210) 17% (n=76) MetSyn (+) (n=459) Percent of Subjects 700 1000 1300 1600 (nmol/L) AHA/ADA “Metabolic Syndrome/Metabolic Risks” meeting. San Francisco, May 3-5, 2006

  40. CHD Event Associations of NMR LDL Particle Number (LDL-P) versus LDL Cholesterol (LDL-C) Cromwell WC et al: J Clinical Lipidology 2007;1:583-592

  41. Brief CommentsApo 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

  42. 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?

  43. Prediction of Lifetime Risk for Cardiovascular Disease by Risk Factor Burden at 50 Years of Age Donald M. Lloyd-Jones et al Circulation 2006;113:791-798

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