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Aggressive Lipid Lowering Treatment

Aggressive Lipid Lowering Treatment. Richard CESKA Centre of Preventive Cardiology University Hospital, Prague, Czech Republic International Atherosclerosis Society Chair: Federation for EUROPE. Dyslipidemia Management. Part of the complex approach to decrease CV RISK.

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Aggressive Lipid Lowering Treatment

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  1. Aggressive Lipid Lowering Treatment Richard CESKA Centre of Preventive Cardiology University Hospital, Prague, Czech Republic International Atherosclerosis Society Chair: Federation for EUROPE

  2. Dyslipidemia Management Part of the complex approach to decrease CV RISK Influence all lipid parameters To lower MACROvascular risk LDL-C – The first target HDL-C,TGs, apoB… To lower MICROvascular risk To lower CV morbidity and mortality

  3. What does it mean? „Agressive Lipid Lowering“ . • LDL-C • Residual Risk (DLP risk)

  4. LDL-C • Killer No 1 • The most important risk factor for CVD • The first target for lipid lowering treatment

  5. What is an appropriate therapeutic target for LDL-C?

  6. The human evolutionWhat was the LDL-C of our ancestry?

  7. Hunter-Gatherer humans Newborn Primates Domestic animals Adult Euro/American (probable physiologic level) 1,3-1,9 50-75 0,8-1,8 30-70 1,0-2,1 40-80 > 2,1 >80 1,3-1,8 50-70 Desirable What is desirable LDL- C ?

  8. LDL-Receptor PathwaySREBP Pathway LDL-receptor Joseph GOLDSTEIN Michael BROWN Nobel Prize 1985 SREBP

  9. Familial hypercholesterolemia, positive family history, LDL-C 8,2mmol/l(W 27years)

  10. MERCURY: LDL-C 10R 10A 20A 20S 40P % change from baseline Rosuvastatin Atorvastatin Simvastatin Pravastatin p<0.0001 p<0.0001

  11. MERCURY: TG 10R 10A 20A 20S 40P % change from baseline Rosuvastatin Atorvastatin Simvastatin Pravastatin p=0.0682 (NS) p=0.6891 (NS) p=0.0011 p<0.0001

  12. Ezetimibe + statins LDL-C ezetimibe 10 mg + atorvastatin (n=255) ezetimibe 10 mg + simvastatin (n=274) ezetimibe 10 mg + pravastatin (n=204) ezetimibe 10 mg + lovastatin (n=192) ) ) l) 0 –10 –20 Střední hodnota % změny u vypočítaného LDL-C z výchozí hladiny po 12-ti týdnech –30 –39* –40* –40 –51* –50 –56* –60 *p<0,01 ezetimibe + sdružené dávky statinů vs. sdružené dávky statinů samotné Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Melani L et al Eur Heart J 2003;24:717–728,1381; Kerzner B et al Am J Cardiol 2003;91:418–424.

  13. Treatment of Hyperlipidemia LDL-C Therapeutic Lifestyle Change Drug Therapy Therapy of Choice: Statin Alternative/combo:Ezetimibe,resin or niacin Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

  14. The Lower = The Better • for LDL-C lowering • For clinical outcomes reduction

  15. Scandinavian Simvastatin Survival Study (4S) The Lancet, Vol 344, November 19, 1994

  16. Primary Endpoint: Overall Survival 30% risk reduction % Surviving p = 0.0003 Years since randomization The Lancet, Vol 344, November 19, 1994

  17. Coronary Mortality 42% Risk Reduction p<0.00001 Number of deaths The Lancet, Vol 344, November 19, 1994

  18. TNT Trial 10,003 patients with stable coronary heart disease Age 35-75 years, LDL between 130 and 250 mg/dL, triglyceride ≤ 600 mg/dL 19% female, mean age 60.3 years All received atorvastatin 10 mg during 8 week open-label run-in period Atorvastatin 80 mg n=4,995 Atorvastatin 10 mg n=5,006 Primary Endpoint:Major cardiovascular event defined as coronary heart death (CHD) , nonfatal M, resuscitated cardiac arrest, and fatal or nonfatal stroke at a mean follow-up of 4.9 years. Secondary Endpoint: Major coronary events, cerebrovascular events, hospitalization for congestive heart failure (CHF), all-cause mortality, peripheral artery disease, any cardiovascular event, any coronary event Presented at ACC 2005

  19. TNT: The Lower the Better -22% Intensive lipid-lowering therapy with atorvastatin 80 mg/day in patients with stable CHD provides significant clinical benefit beyond that provided by atorvastatin 10 mg/day J. C. LaRosa et al. Intensive Lipid Lowering with Atorvastatinin Patients with Stable Coronary Disease. // N Engl J Med 2005;352:1425-35.

  20. TNT pts after CABG n = 4,654MACE -27%

  21. IDEAL Trial: Study Design 8,888 patients ≤80 years with definite history of myocardial infarction and qualified for stain therapy at time of recruitment Randomized High-dose atorvastatin 80 mg/day If LDL was <40 mg/dL at 24 wks dose could be reduced to 40 mg/day n=4,439 Standard-dose simvastatin 20 mg/day If cholesterol >190 mg/dL at 24 wks dose could be increased to 40 mg/day n=4,449 Presented at AHA 2005

  22. IDEAL Trial: Primary Endpoint Primary Composite of major coronary event * (%) p = 0.07 • The primary composite endpoint of major coronary event occurred in 9.3% of the atorvastatin group and 10.4% of the simvastatin group. % * Major coronary event defined as coronary death, hospitalization for non-fatal acute MI or resuscitated cardiac arrest. Presented at AHA 2005

  23. IDEAL Trial: Secondary Endpoints Major cardiovascular events and any cardiovascular event (%) • Major cardiovascular events, defined as any primary event plus stroke, occurred less often in the atorvastatin group. • Any cardiovascular event, defined as major CV event plus hospitalization for CHF and peripheral artery disease, also occurred less often in the atorvastatin group. p<0.001 p=0.02 % Presented at AHA 2005

  24. UK Switching Study: Impact of Switching From Atorvastatin to Simvastatin 12 33% Increase in death or CV events with switch to Simvastatin (P=0.007) Patients Switched from Atorvastatin to Simvastatin (n=2511) 10 8 6 Death or CV Event (%) 4 Atorvastatin(n=9009) Primary end point: time to death or first major CV event (MI, stroke, and revascularization) 2 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Years after Index Date PHILLIPS B, et al. Poster accepted for presentation at the European Society of Cardiology Congress, Sep 1-5, 2007 PHILLIPS B, et al. Poster accepted for presentation at the European Society of Cardiology Congress, Sep 1-5, 2007

  25. LDL-C lowering with statins: reduced CHD events Secondary Prevention 4S-PL Primary Prevention 25 LIPID-PL 20 4S-Rx 15 CARE-PL CARE-Rx Events (%) WOSCOPS-PL 10 LIPID-Rx WOSCOPS-Rx 5 AFCAPS-Rx AFCAPS-PL 0 50 70 90 110 130 150 170 190 210 LDL Cholesterol (mg/dL) The Lower The Better

  26. Aggressive lipid-lowering therapy isas effective as angioplasty AVERT Treatment with atorvastatin, as compared with angioplasty, was associated with a significantly longer time to a first ischemic event and with a reduction in risk of 36% Pitt B.et al. AGGRESSIVE LIPID-LOWERING THERAPY COMPARED WITH ANGIOPLASTY IN STABLE CORONARY ARTERY DISEASE. // New Engl. J. Med. 1999;341:70-76.

  27. PROVE IT–TIMI 22(2-Year Trial) Pravastatin40 mg LogCHDRisk Atorvastatin80 mg 16% Reduction in CVD 60 100 LDL-C Level Cannon CP et al. N Engl J Med 2004;350:1495-1504.

  28. High dose atorvastatin after strokeor trasient ischemic attack (SPARCL) SPARCL -16% P. Amarenco et al. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack.// N Engl J Med 2006;355:549-59.

  29. 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 4S-S CHD Events (%) 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.

  30. Meta-Analysis of Intensive Statin Therapy All Endpoints Odds Ratio (95% CI) OR, 0.84 95% CI, 0.80-0.89 p<0.0001 OR, 0.84 95% CI, 0.77-0.91 p=0.00003 OR, 0.88 95% CI, 0.78-1.00 p=.054 OR, 1.03 95% CI, 0.88-1.20 p=0.73 OR, 0.94 95% CI, 0.85-1.04 P=0.20 OR 0.82 95% CI, 0.71-0.96 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.

  31. PROVE IT MI or UA IDEAL All MI 18% RRR P=0.04 Pravastatin 40 mg Simvastatin 20-40 mg 16% RRR P=0.005 Summary: 5 Years Of Follow-Up In IDEAL Is The Longest Period Of Follow-Up Of ACS Patients On Statin Therapy 60 50 40 Cardiac Event (%) 30 20 Atorvastatin 80 mg 10 0 0 30 months 5 years Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006

  32. PCSK9(proprotein convertase subtilisin/kexin type 9) Enzyme - associated with plasma levels of LDL –C (expressed in the liver, intestine and kidney) Overexpression of gene for PCSK9more PCSK9 enzyme LDL receptorsreduction (LDL-Receptor enable removal of LDL-C from the plasma) increase in circulating LDL-C High levels of PCSK9 = high LDL-C levels Conversely, lacking Pcsk9 leads to increased levels of hepatic LDL receptors,and they remove LDL from the plasma at an accelerated rate) Low levels of PCSK9 = low LDL- C levels 1.Brown, M.S.,Science, Vol 311, March 24, 2006 2. Cohen J.C. et al.,New England Journal of Medicine, Volume 354, 2006 Number 12

  33. Cohens et al. study The Longer The Better • Studied patients with lifelong low LDL-C levels, due to loss of- function mutations in the gene encoding PCSK9 = they have low level of PCSK9 = low level of LDL-C • Severe mutation: LDL-C was reduced by 1 mmol/l (38 mg/dl) prevalence of CHD declined by a remarkable 88%. • Less severe mut.:LDL-C was reduced by only 0,52 mmol/l (21 mg/dl) CHD incidence declined by 47%. Cohen et al., N Engl J Med 2006;354:1264-72. Brown, M.S.,Science, Vol 311, March 24, 2006

  34. Cohen et al. study The Longer The Better Why does lowering of LDL-C concentration by 40 mg/dl by a PCSK9 mutation reduce CHD incidence by 88%, whereas a 40-mg/dl lowering with a statin reduces CHD prevalence by only 23% on average ??? Cohen et al., N Engl J Med 2006;354:1264-72. Brown, M.S.,Science, Vol 311, March 24, 2006

  35. Cohens et al. study The Longer The Better The most likely answer is DURATION Cohen et al., N Engl J Med 2006;354:1264-72. Brown, M.S.,Science, Vol 311, March 24, 2006

  36. Cohens et al. study The Longer The Better • People with mutations in PCSK9 likely have maintained relatively low LDL levels throughout their lives. • People in statin trials have had their LDL levels lowered for only 5 years. • Atherosclerosis is a chronic disease that beginsin the teenage years Cohen et al., N Engl J Med 2006;354:1264-72. Brown, M.S.,Science, Vol 311, March 24, 2006

  37. Relationship between LDL-C and Progression Rate Recent Coronary IVUS Progression Trials 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

  38. ASTEROID: study design Patients CAD, undergoing coronary angiography Target coronary artery: ≤50% reduction in lumen diameter of ≥40 mm segment No cholesterol entry criteria ≥18 years Rosuvastatin 40 mg (n=349 evaluated serial IVUS examinations) 10 104 2 0 3 13 4 26 5 39 6 52 7 65 8 78 9 91 1 –6 Visit: Week: Eligibilityassessment Lipids IVUSLipidsTolerability LipidsTolerability Tolerability LipidsTolerability Tolerability Tolerability IVUSLipids CAD=coronary artery disease; PCI=percutaneous coronary intervention; IVUS=intravascular ultrasound

  39. IVUS Objem atero plátu EEM Area LumenArea (EEM area — Lumen Area) Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory Precise Planimetry of EEM and Lumen Bordersallows calculation of Atheroma Cross-sectional Area EEM = External Elastic Membrane

  40. ASTEROID Trial: Principal Findings Mean LDL level decrement and HDL level increment (mg/dL) • LDL Levels were reduced from 130.4 mg/dL at baseline to a mean of 60.8 mg/dL at 2 year follow-up (p<0.001), with 75% of patients achieving an LDL <70 mg/dL. • HDL levels were increased from 43.1 mg/dL at baseline to a mean of 49.0 mg/dL at follow-up (p<0.001). p<0.001 LDL/HDL mg/dL p<0.001 Presented at ACC 2006

  41. Median Atheroma Volume in the most diseased 10mm Median Normalised Total subsegment Atheroma Volume 0 -1 -2 -3 -4 Change from baseline (%) -5 -6 -7 - 6.8% -8 * -9 - 9.1% -10 * Endpoint analysis: Change in key IVUS parameters *p<0.001 for difference from baseline. Wilcoxon signed rank test Ref: Nissen S et al. JAMA 2006;295 (13):1556-1565.

  42. Regression of atherosclerosis in ASTEROID Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

  43. ACS Patients: Major Coronary Events MI + CHD Death + Resuscitated Cardiac Arrest 20 Simvastatin Atorvastatin 16 34% RRR 12 Cumulative Hazard (%) 8 4 HR = .66 (95% CI = 0.46, 0.95), P=.02 0 0 1 2 3 4 5 Years Since Randomization Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006

  44. 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

  45. Residual Cardiovascular Risk in Major Statin Trials: Standard Doses Patients Experiencing Major Coronary Events, % N 4444 9014 4159 20 536 6595 6605 LDL -35% -25% -28% -29% -26% -25% Secondary High Risk Primary Adapted from Libby PJ, et al. J Am Coll Cardiol, 2005:46:1225-1228.

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