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Welcome Ask The ExpertsMarch 24-27

Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary ... Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary ...

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Welcome Ask The ExpertsMarch 24-27

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  1. Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

  2. Christopher P. Cannon, MDSenior Investigator, TIMI Study GroupCardiovascular DivisionBrigham and Women's HospitalAssociate Professor of MedicineHarvard Medical SchoolBoston, MA LDL or HDL: Which is More Important?

  3. LDL or HDL: Which is More Important? Christopher Cannon, M.D. Senior Investigator, TIMI Study Group Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA

  4. The Case for LDL

  5. A2Z 20 A2Z 80 TNT 10 IDEAL S20/40 TNT 80 IDEAL A80 CHD Event Rates in Secondary Prevention and ACS Trials 30 y = 0.1629x · 4.6776R² = 0.9029p < 0.0001 4S-P 25 20 HPS-P LIPID-P CHD Events (%) 4S-S 15 HPS-S CARE-P LIPID-S 10 PROVE-IT-AT CARE-S PROVE-IT-PR 5 0 30 50 70 90 110 130 150 170 190 210 LDL Cholesterol (mg/dl) Updated from - O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

  6. TNT IDEAL Cholesterol Trialist CollaborationMeta-Analysis of Dyslipidemia Trials Major Vascular Events 50% 40% 30% Proportional Reduction in Event Rate (SE) 20% 10% 0% 0.5 1.0 1.5 2.0 -10% Reduction in LDL Cholesterol (mmol/L) Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78

  7. Meta-Analysis of Intensive Statin Therapy Coronary Death or MI Odds Ratio (95% CI) PROVE IT-TIMI 22 A-to-Z TNT IDEAL OR, 0.84 95% CI, 0.77-0.91 p=0.00003 Total 0.658451 1 1.51872 High-dose better High-dose worse Cannon CP, et al. Cannon CP, et al.

  8. Meta-Analysis of Intensive Statin Therapy Odds Ratio (95% CI) OR, 0.84 p<0.000001 OR, 0.84 p=0.00003 OR, 0.88 p=.054 OR, 1.03 p=0.73 OR, 0.94 P=0.20 OR 0.82 p=0.012 0.5 1 2.5 High-dose statin better High-dose statin worse Cannon CP, et al. Cannon CP, et al. JACC 2006; 48: 438 - 445. slides available www.timi.org - TIMI Library

  9. Meta-Analysis of Intensive Statin Therapy CHF Study (n) Odds ratio (95% CI) Treatment Achieved LDL (mg/dl) Moderate Intensive TNT (10,001) 0.74 (0.58,0.94) Atorvastatin 80 77 Atorvastatin 10 101 A to Z (4497) 0.72 (0.52,0.98) Simvastatin 80 63 Simvastatin 20 77 PROVE-IT (4162) 0.54 (0.34,0.85) Atorvastatin 80 62 Pravastatin 40 95 IDEAL (8888) 0.80 (0.61,1.05) Atorvastatin 80 81 Simvastatin 20 104 Overall (95% CI) 0.73 (0.63,0.84), p<0.001 0.5 3.0 1 Moderate statin therapy better Intensive statin therapy better Odds ratio Scirica BM, et al. AHA 2005

  10. Meta-Analysis of Intensive Statin Therapy in ACS Any Cardiovascular Event HR (95% Cl) 1.02 (0.95-1.09) 0.84 (0.72-1.02) 0.76 (0.70-0.84) 0.80 (0.76-0.84) 0.81 (0.77-0.87) 0.84 (0.76-0.94) Hulten E, et al. Arch Intern Med. 2006;166:1814-1821

  11. Month 4 LDL and Long-Term Risk of Death or Major CV Event Hazard Ratio Referent >80 - 100 0.80 (0.59, 1.07) >60 - 80 0.67 (0.50, 0.92) > 40 - 60 0.61 (0.40, 0.91) <40 0 1 2 *Adjusted for age, gender, DM, prior MI, baseline LDL Lower Better Higher Better Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-1416. Wiviott SD, et al. JACC. 2005

  12. Major CV Events Across Quintiles of Achieved LDL P < 0.0001* P < 0.0001* % patients P < 0.05* P < 0.01* *P-value for trend across LDL-C LaRosa JC. AHA. 2005

  13. Nissen et al JAMA 2004

  14. Recent Coronary IVUS Progression Trials Relationship between LDL-C and Progression Rate 1.8 CAMELOT placebo REVERSAL pravastatin 1.2 Median Change In Percent AtheromaVolume (%) ACTIVATE placebo 0.6 REVERSAL atorvastatin A-Plus placebo 0 r2= 0.95 p<0.001 -0.6 ASTEROID rosuvastatin -1.2 50 60 70 80 90 100 110 120 Mean Low-Density Lipoprotein Cholesterol (mg/dL) Nissen S. JAMA 2006

  15. IMPROVE IT 66 52 The Statin Decade: For LDL: “Lower is Better” R² = 0.9029p < 0.0001 4S LIPID CHD Events (%) CARE HPS TNT PROVE IT –TIMI 22 30 50 70 90 110 130 150 170 190 210 LDL Cholesterol (mg/dl) Adapted and Updated from O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

  16. I I I IIa IIa IIa IIa IIb IIb IIb IIb III III III III I I I IIa IIa IIa IIa IIb IIb IIb IIb III III III III I I I IIa IIa IIa IIa IIb IIb IIb IIb III III III III Lipid Management Goal LDL-C should be less than 100 mg/dL Further reduction to LDL-C to < 70 mg/dL is reasonable If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL* *Non-HDL-C = total cholesterol minus HDL-C

  17. Subgroups: Reduction in All-Cause Mortality or Major CV Events 2 Year Events Atorva 80 Prava40 23.0% 26.2% 20.3% 27.0% 28.8% 34.6% 21.0% 24.6% 28.1% 29.5% 20.1% 25.0% 27.5% 28.9% 20.6% 25.5% 21.7% 26.7% 23.1% 26.0% 20.1% 28.2% 23.5% 25.6% % of Pts 78 22 18 82 30 70 25 75 44 56 27 73 Male Female Diabetes No Diabetes Age > 65 Age < 65 Prior Statin No Prior Statin HDL-C > 40 HDL-C < 40 LDL-C > 125 LDL-C < 125 All pinteraction = NS except as noted 0.5 0.75 1.0 1.25 1.5 Atorvastatin 80 mg Better Pravastatin 40 mg Better

  18. The Case for HDL

  19. Frequency of Low HDL-C in Men With Premature CHD Risk factor Controls Cases (n = 601) (n = 321) Cigarette smoking 29% 67%* HDL-C < 35 mg/dL 19% 57%* Hypertension 21% 41%* LDL-C ³ 160 mg/dL 26% 34%* Diabetes mellitus 1% 12%* *Significantly different from controls (P < 0.001) Genest JJ et al. Am J Cardiol 1991;67:1185–1189

  20. Low HDL-C is a Risk Factor for CHD Even When LDL-C Levels are Well Controlled Risk of CHD After 4 Yrs HDL (mg/dL) LDL (mg/dL) Am J Med 1977;62:707-714

  21. Low HDL-C is a Predictor of Coronary Events in Statin Treated Patients Statin Placebo 4S LIPID CARE HPS 35 30 25 20 Coronary Events (%) 15 10 5 0 HDL-C (mg/dl) mmol/L mg/dl  1.35 52  0.99 38  1.0 39  1.0 39  1.26 44  0.75 33  1.1 42 < 0.9 35 Adapted from Ballantyne CM et al. Circulation 1999;99:736-743.

  22. “On-treatment” HDL-C Predicts Cardiovascular Events: TNT Major Cardiovascular Events On treatmentHDL-C (mg/dL) % Mean LDL-C99 mg/dL Mean LDL-C73 mg/dL Barter et al. ACC 2006. Abstract 914-203.

  23. Coronary Drug Project • Long-term efficacy and safety of five lipid-influencing drugs • Niacin, clofibrate, dextrothyroxine, and two estrogen regimens • 8,341 men (aged 30–64 y) with previous MI • Initial study conducted between 1966 and 1975 (mean follow-up: 6.2 y) • At end of study, 6,008 survivors followed for additional mean 8.8 y Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255

  24. Coronary Drug Project Long-Term Mortality Benefit of Niacin in Post-MI Patients 100 90 80 70 Niacin 60 Survival (%) 50 Placebo 40 30 P = 0.0012 20 10 16 14 12 10 6 8 4 0 2 Years of follow-up Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255

  25. AIM-HIGHStudy Overview Simvastatin Atherogenic Dyslipidemia (HDL<40 or 50; TGL>149; LDL<160) CV Death NFMI Stroke ACS 3-5 yr Vascular Dz. Age >45 years Simvastatin + niaspan 2 year enrollment Hypothesis -30% event rate with Simva -23% event rate with simva-nia - 50% relative reduction based on ~46% placebo rate 3300 patients from 60 sites (U.S. and Canada LDL-C target <80 mg/dl both groups (may add ezetimibe if needed)

  26. Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis: Study Design 1455 patients from 4 trials (REVERSAL, CAMELOT, ACTIVATE, ASTEROID) with CAD undergoing serial intravascular ultrasonography while receiving statin treatment. Post-hoc analysis of raw data from the four prospective, randomized trials. Follow-up at 18 or 24 months. Exclusion criteria: Target segment selected was required to have no greater than 50% lumen narrowing for a length of at least 30 mm and target vessel required to have not previously undergone percutaneous coronary intervention. ASTEROID n=349 ACTIVATE n=364 CAMELOT n=240 REVERSAL n=502 18 or 24 mos. follow-up • Primary Endpoint: Relationship between changes in LDL-C and HDL-C levels and atheroma burden. Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508.

  27. Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis: Study Design Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508.

  28. The Case for HDL • Many patients have low HDL • Low HDL-C is a major predictor of CV events (even with low LDL-C) • Niacin worked in large outcomes trial

  29. Kaplan-Meier Estimates by TG Quintiles between 30 d and 2 yr follow-up Miller M AHA 2006

  30. Triple Goal: Hazard ofdeath, MI and recurrent ACS with number of goals achieved based on LDL-C (< 70 mg/dL), CRP (< 2 mg/L) & TG (< 150 mg/dL) Miller M AHA 2006

  31. 0.10 0.10 0.08 0.08 LDL >70 mg/dL, CRP <2 mg/L LDL <70 mg/dL, CRP >2 mg/L 0.06 0.06 Recurrent MI or Coronary Death (Percent) 0.04 0.04 LDL <70 mg/dL, CRP <2 mg/L LDL <70 mg/dL, CRP <1 mg/L 0.02 0.02 0.00 0.0 0.0 0.0 0.0 0.5 0.5 0.5 0.5 1.0 1.0 1.0 1.0 1.5 1.5 1.5 1.5 2.0 2.0 2.0 2.0 2.5 2.5 2.5 2.5 Follow-Up (Years) Clinical Relevance of Achieved LDL and CRP Post Statin TherapyTreatment LDL > 70 mg/dL, CRP >2 mg/L Ridker PM, et al. N Engl J Med. 2005;352:20-28.

  32. Achieved CRP and LDL vs. Outcomes Figure 4 Cumulative probability of death or MI (%) CRP ≥ 2 and LDL ≥ 70N = 1244 CRP ≥ 2 and LDL < 70N = 500 CRP <2 and LDL ≥ 70N = 1140 CRP < 2 and LDL< 70N = 659 Follow-up after Month 4 (days) Morrow JACC 2006

  33. Cardiomonitor: Trends in LDL Levels in Acute Coronary Syndrome Patients % US CVD Patients

  34. Cardiomonitor • 4,676 U.S. outpatients with CVD from 250 primary care physicians and 50 cardiologists

  35. Conclusion • In 2007: LDL > HDL • But • Both are important • (as well as Trig, and BP, gluc…) • We need to do better on implementation

  36. Question & Answer

  37. Thank You! Please make sure to hand in your evaluation and pick up a ClinicalTrialResults.org flash drive

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