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Dyslipidémies Approche 2006 André Roussin MD, labo vasc HND

Dyslipidémies Approche 2006 André Roussin MD, labo vasc HND. Notion de risque CV Diète Pharmacothérapie Conclusion. .org. André Roussin MD Disclosures. AstraZeneca Bristol-Myers Squibb Boeringher-Ingelheim Glaxo SmithKline Leo Pharma. Merck Frosst Pfizer Roche Diagnostics

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Dyslipidémies Approche 2006 André Roussin MD, labo vasc HND

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  1. DyslipidémiesApproche 2006André Roussin MD, labo vasc HND • Notion de risque CV • Diète • Pharmacothérapie • Conclusion .org

  2. André Roussin MDDisclosures AstraZeneca Bristol-Myers Squibb Boeringher-Ingelheim Glaxo SmithKline Leo Pharma Merck Frosst Pfizer Roche Diagnostics Schering-Plough sanofi aventis I have been on advisory boards or received honorarium as consultant or speaker or received research funds from the following companies:

  3. Notion de risque vasculaireConsensus Canadien 2006 sur les DyslipidémiesCalcul du risque de coronaropathie à 10 ans • ASO présente • Coronaropathie (MCAS) • Maladie artérielle périphérique • Maladie vasculaire cérébrale • Insuffisance rénale chronique (<30 ml/min) • Patients > 40 ans avec Diabète sucré • Dyslipidémie sévère • Hypercholestérolémie familiale (LDL) • Hypoalphalipoprotéinémie familiale (HDL) • Tous les autres • Préciser le risque avec les tables de Framingham Risque Élevé

  4. Recommendations for the Management of Dyslipidemia and the Prevention of Cardiovascular Disease: 2006 Update Diagnosis of Asymptomatic Atherosclerosis Class IIa, Level of evidence C Class IIa, Level of evidence C Class IIa, Level of evidence C Class IIb, Level of evidence C • Possibly useful in subjects at MODERATE risk • Ankle-brachial index • Carotid ultrasonography • Graded exercise testing • Electrocardiogram • Lab measurements possibly useful • Apo B, hsCRP, Lp(a), HbA1c (if FPG↑) McPherson R & al. Can J Cardiol 2006. 22(11):913-927

  5. Recommendations for the Management of Dyslipidemia and the Prevention of Cardiovascular Disease: 2006 Update Diagnosis of Asymptomatic Atherosclerosis • Not currently recommended based on available evidence • Flow-mediated vasodilatation • Plethysmography • Arterial compliance • MRI scanning • Intravascular ultrasonography • Electron beam CT scanning (Good emerging data) McPherson R & al. Can J Cardiol 2006. 22(11):913-927

  6. CCS position statement 2006Treatment of dyslipidemia and prevention of CVD Adapté de: Can J Cardiol 2006; 22 (11): 913-927

  7. Cholesterol Treatment Trialists’ (CTT) Collaboration:Relative Risk in Major Vascular Events versus mean LDL-C difference 14 statin trials 60% 50% 22% reduction per 1 mmol/L lower LDL cholesterol 40% Relative risk reduction 30% 20% 10% 0% 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 -10% LDL cholesterol difference (mmol/L) -20% Baigent C. Lancet 2005; 366:1267-78

  8. Pourcentage de manifestations coronariennes Essais marquants portant sur les statines en prévention primaireTaux de C-LDL vs manifestations coronariennes 10 9 8 7 WOSCOPS-P WOSCOPS-S 6 5 AFCAPS-S AFCAPS-P Prévention primaire 4 Pravastatine 3 ASCOT-P Lovastatine 2 Atorvastatine ASCOT-S 1 0 2,8 (110) 3,9 (150) 4,4 (170) 2,3 (90) 3,4 (130) 5,4 (210) 4,9 (190) C-LDL, en mmol/L (mg/dL) S = traitement par une statine; P = placebo Modified from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1):S17-S21

  9. Réduction du C-LDL Effet sur le risque de coronaropathie POSCH-PL Primary prevention trials 4S-PL 25 Secondary prevention trials POSCH-Rx 20 CARE-PL 4S-Rx HPS 15 LIPID-PL Statin trials % Patients with CHD Event TNT-10A HPS-PL CARE-Rx WOSCOPS-PL 10 LIPID-Rx non statin trials TNT-80A WOSCOPS-Rx HPS-Rx LRC-PL 5 ASCOT-PL LRC-Rx ASCOT-Rx AFCAPS-PL AFCAPS-Rx 0 50 170 190 210 (mg/dL) 1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L)

  10. Lipid Tx: meta-analysis BMJ 2006Major coronary events in Primary prevention trials Mean F-up 4.5 yrs 23% RRR Costa J et al. BMJ 2006; 332: 1115-1124

  11. Lipid Tx: meta-analysis BMJ 2006Major coronary events in Secondary prevention trials Mean F-up 4.5 yrs 23% RRR Costa J et al. BMJ 2006; 332: 1115-1124

  12. DyslipidémiesMédication simplifiée disponible au Canada en 2006 • LDL : Statines (et ézétimibe si objectifs non atteints) • TG : Fibrates • Acide Nicotinique • Huiles de poissons si TG difficiles à abaisser • HDL : Acide nicotinique • Prescrire les doses utilisées dans les études • Doses minimales équivalentes à simvastatine (Zocor™) 40mg • Combinaisons utiles mais risquées • Fenofibrate (Lipidil™) si statine ou ezetimibe utilisées

  13. Dyslipidémies: diète simplifiée pour votre patientCholestérol et Triglycérides • CHOL⇒ gras saturés • TG⇒ poids + alcool

  14. Dyslipidémies: diète simplifiée pour votre patientCHOL-HDL abaissé: que faire ? • Cesser le tabagisme • Faire de l’exercice • Huiles mono-insaturées (olive, canola) • Ne pas déconseiller l’alcool (1-2 onces OD)

  15. Dyslipidémies: diète simplifiée pour votre patientAnti-oxydants / vitamines • Vitamines et anti-oxydants • Origine alimentaire • Encourager +++ • Suppléments inutiles • Interférence avec les statines

  16. Dyslipidémies: diète simplifiée pour votre patientAcides gras « trans » : à éviter • Ces gras résultent de l’hydrogénation incomplète des acides gras mono ou poly-insaturés vers leurs formes saturées. • Ce processus « intermédiare » transforme les gras cis en gras trans, athérogéniques et pires pour le CHOL-LDL que les gras saturés!

  17. Dyslipidémies: diète simplifiée pour votre patientAcides gras poly-insaturésOméga-3 Sources • Poissons gras • Source d’DHA et de EPA • 22 et 20 carbones • Efficaces en soi ( TG et mort.) • Végétaux : lin, canola, noix, algues... • Source d’ALA • 18 carbones • Élongation partielle in vivo en DHA et EPA • Efficaces après conversion

  18. Étude HPSNotion de patient à risque plutôt que de lipides anormaux CHD n=13,379 (65%) Hypertension n=8,455 (41%) with MI 8,510 (41%) no MI 4,869 (24%) with CHD 5,595 (27%) no CHD 2,860 (14%) CVD n=3,280 (16%) PVD n=6,748 (33%) Diabetes n=5,963 (29%) with CHD 1,458 (7%) no CHD 1,822 (9%) with CHD 4,042 (20%) no CHD 2,706 (13%) with CHD 1,978 (10%) no CHD 3,985 (19%) 20,536 patients Lancet 2002; 360: 7-22

  19. Simvastatine - Heart Protection Study:Thérapie évaluée • Simvastatin vs Placebo(40 mg daily) • Vitamins vs Placebo(600 mg E, 250 mg C & 20 mg beta-carotene) Durée: Moyenne de 5.5 années ET Lancet 2002; 360: 7-22

  20. HPSÉvènements vasculaires majeurs Vascular event Statin (n=10,269) Placebo (n=10,267) Risk ratio and 95% CI 914 1,234 Total CHD 456 613 Total stroke Revascularisation 926 1,185 2,042 2,606 24%SE 2.6 reduction ANY OF ABOVE (2P<0.00001) (19.9%) (25.4%) 0.4 0.6 0.8 1.0 1.2 1.4 Statin better Statin worse Lancet 2002; 360: 7-22

  21. HPSÉvènements selon le critère d’entrée Baseline feature Statin (n=10,269) Placebo (n=10,267) Risk ratio and 95% CI Previous MI 1,007 1,255 Other CHD (not MI) 452 597 No prior CHD CVD 182 215 PVD 332 427 Diabetes 279 369 ALL PATIENTS 2,042 2,606 24%SE 2.6reduction (19.9%) (25.4%) (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Statin better Statin worse Lancet 2002; 360: 7-22

  22. HPSÉvènements selon l’âge et le sexe c 2 Het = 4.4 3 c 2 Het = 0.4 1 Baseline feature Statin (n=10,269) Placebo (n=10,267) Risk ratio and 95% CI Age group (years) < 65 838 1,093 65 - 69 516 677 70-74 550 628 75 138 208 Sex Male 1,676 2,148 Female 366 458 ALL PATIENTS 2,042 2,606 24%SE 2.6reduction (19.9%) (25.4%) (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Statin better Statin worse Lancet 2002; 360: 7-22

  23. HPSÉvènements selon le taux de LDL à l’entrée c 2 Het = 0.8 3 Baseline feature Statin (n=10,269) Placebo (n=10,267) Risk ratio and 95% CI LDL (mmol/L) < 2.6 (100 mg/dL)  2.6 < 3.4  3.4 (130 mg/dL) ALL PATIENTS 285 360 670 881 1,087 1,365 2,042 2,606 24%SE 2.6 reduction (19.9%) (25.4%) (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Statin better Statin worse Lancet 2002; 360: 7-22

  24. REVERSALThe Reversing Atherosclerosis with Aggressive Lipid Lowering Study Schéma de l’étude • Population : • Présence de coronaropathie sympto. • Critères angiographiques : • rétrécissement  20 % de lalumière d’une ou de plusieursartères coronaires • rétrécissement > 50 % de la lumière du tronc coronaire gauche •  1 artère coronaire sténosée à ≤ 50 % • C-LDL 3.2 à 5.4 mmol/L Période à double insu Atorvastatine, 80 mg/jour 654 patients Pravastatine, 40 mg/jour Suivi de 18 mois avec EIV (évaluation de la vasodilatation réactionnelle de l’artère brachiale après 3 mois) Paramètre primaire : Variations en pourcentage du volume total des plaques Nissen SE et al. JAMA 2004; 291:1071-1080.

  25. REVERSALThe Reversing Atherosclerosis with Aggressive Lipid Lowering Study Nissen SE et al. JAMA 2004; 291:1071-1080.

  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 Cannon et al. NEJM 2004; 350: 1495-504

  27. Changes from (Post-ACS) Baseline in Median LDL-CPROVE IT - TIMI 22 120 100 Pravastatin 40mg 21% 80 LDL-C (mg/dL) 60 Atorvastatin 80mg 49%  40 P<0.001 20 <24h Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final Cannon et al. NEJM 2004; 350: 1495-504

  28. All-Cause Death or Major CV Events PROVE IT - TIMI 22 0 30 3 6 9 12 15 18 21 24 27 30 Pravastatin 40mg (26.3%) 25 20 % with Event Atorvastatin 80mg (22.4%) 15 10 16% RR (P = 0.005) 5 0 Months of Follow-up Cannon et al. NEJM 2004; 350: 1495-504

  29. Primary Efficacy Outcome Measure:Major Cardiovascular Events* Relative risk reduction = 22% 0 1 2 3 4 5 6 Time (years) 0.15 HR = 0.78 (95% CI 0.69, 0.89) P=0.0002 Atorvastatin 10 mg Atorvastatin 80 mg 0.10 Proportion of patients experiencing major cardiovascular event 0.05 0 *CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke LaRosa JC, et al. N Eng J Med. 2005;352

  30. Lower Is Better 4S-P 4S-S LIPID-P CARE-P LIPID-S HPS-P CARE-S HPS-S TNT: Atorvastatin 10 mg TNT: Atorvastatin 80 mg S = statin treated P = placebo treated (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2)

  31. Results: primary outcome Placebo Fenofibrate CHD events (CHD death + nonfatal MI) HR = 0.89 95% CI = 0.75–1.05 P=0.16 Diabétiques Keech A. Lancet. 2005 366(9500):1849-61

  32. ASTEROID Trial - Rosuvastatin 40 mgDual Primary IVUS Efficacy Parameters Median Change in PercentAtheroma Volume Median Change in Most Diseased Subsegment Change InPercentAtheroma Volume (%) Change InAtheroma Volume (mm3) Regressionp<0.001* Regressionp<0.001* *Wilcoxon signed rank test for comparison with baseline Nissen SE. JAMA. 2006 Mar 13; [Epub ahead of print]

  33. 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 SE. JAMA. 2006 Mar 13

  34. Elevations in CK and LDL-C Reduction Cerivastatin (0.2, 0.3, 0.4, 0.8 mg) Atorvastatin (10, 20, 40, 80 mg) 3.0 Pravastatin (20, 40 mg) Rosuvastatin (10, 20, 40 mg) 2.5 Simvastatin(40, 80 mg) 2.0 1.5 CK >10 × ULN (%) 1.0 0.5 0.0 20 25 30 35 40 45 50 55 60 65 70 LDL-C Reduction (%) Brewer. Am J Cardiol. 2003;92(suppl)23K-29K.

  35. Statines : Incidence des transaminases élevées Brewer, B. Am J Cardiol 2003;92(suppl):23K-29K

  36. Patients Not at LDL-C Goal: CALIPSO Study (n = 3,721) 72.8% 27.2% At Goal Not at Goal Patients not at LDL-C goal: • 91% at high risk for CHD • 65% required at least 10% additional LDL- C reduction • 36% already taking high-dose statin • 27% “perceived” as being at goal • 24% up-titrated at study visit • 67% had no change in treatment at study visit • ALL PATIENTS: Mean baseline LDL-C: 4.31 mmol/L • Mean achieved LDL-C: 2.52 mmol/L Bourgault C et al. Can J Cardiol 2005; 21(13): 1187-1193

  37. CALIPSO FindingsBased on NCEP III 90 80 70 60 50 40 30 20 10 0 All patients High-risk patients 81% 57% % of Patients Not at Goal 36% 27% % Not at Goal (High-risk target: 2.5 mmol/L) % Not at Goal (High-risk target: 1.8 mmol/L) Bourgault C et al. Can J Cardiol 2005; 21(13): 1187-1193

  38. Cholesterol Absorption Inhibition For Broader Lipid Control VLDL IDL LDL Statins synthesis 2/3 BILIARY SECRETION Absorption Cholesterol Absorption Inhibition INTESTINE 1/3 Excretion DIETARY CHOLESTEROL

  39. Ezetimibe and a Statin: Complimentary Mechanisms of Action X Ezetimibe LDLapoB100 Statin Duodenum Liver Jejunum Ileum CM RemnantapoB48 CM apoB48 Colon

  40. Ezetimibe et statines : rationale de la combinaison Chez le chien avec diète normale Clader J W. Am J Med Chemistry 2004; vol 47 no 1

  41. Development of TachyphylaxisAmong Patients Taking Stratins Cromwell WC and Ziajka PE. Am J Cardiol 2000;86:1123–112

  42. 4S: Efficacy Accordingto Cholesterol Absorption Placebo (n=434) Simvastatin 20-40 mg (n=434) % Major Coronary events 1 2 3 4 Quartiles of cholesterol absorption 4S = Scandinavian Simvastatin Survival Study. Miettinen et al. BMJ. 1998;316:1127.

  43. Individual LDL-C Response to Ezetimibe 10mg Hegele R et al. Lipids in Health and Disease 2005, 4:16

  44. Diabetics Patients Have An Increase In Absorption of Biliary Cholesterol and Possibly of Newly Synthesized Cholesterol in the Intestine In type 2 diabetes it would appear that the increase in NPC1L1 and decrease in ABCG5 and ABCG8 leads to the increase in chylomicron cholesterol. Lally S et al. Diabetologia (2006) 49: 1008–1016

  45. Individual LDL-C, TG and LDL-C/HDL-C % Response to Atorvastatin 10mg/day Pedro-Botet J et al. Atherosclerosis 158 (2001) 183-193

  46. Ezetimibe Monotherapy(Pooled Phase III Studies) Mean % changes from baseline to week 12 LDL-C Triglyceride HDL-C 5 + 1.0* +0.3 +3.5 0 - 1.6 -5 - 4.2* -10 -15 -17.4* -20 Placebo (n=409) Ezetimibe 10 mg (n=1234) * P< 0.01 vs. placebo Knopp RH et al. Atherosclerosis 2001; 2 (Suppl 2): 38: Abstract.

  47. EZE + Simva 10 mg vs. Simva alone Simvastatin EZE +Simvastatin 10 mg(n=67) 10 mg(n=70) 20 mg(n=61) 40 mg(n=65) 80 mg(n=67) P<0.01

  48. EZE + Atorva 10 mg vs Atorva alone Atorvastatin EZE +Atorvastatin 10 mg(n=65) 10 mg(n=60) 20 mg(n=60) 40 mg(n=66) 80 mg(n=62) P<0.01

  49. Ezetimibe — Triglycerides and HDL-C with Atorvastatin or Simvastatin HDL-C (mean) TG (median) † Atorvastatin (n=248) (n=255) Simvastatin (n=263) (n=274) Atorvastatin (n=248) (n=255) Simvastatin (n=263) (n=274) %ChangeFromUntreatedBaseline Atorvastatin Simvastatin Ezetimibe + Statin All data are pooled across doses. *P0.01 for ZETIA + statin vs statin alone. †P0.05 for ZETIA + statin vs statin alone.

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