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Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia

Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia. The ENHANCE trial ClinicalTrials.gov number: NCT00552097. John J.P. Kastelein, MD, PhD * Department of Vascular Medicine Academic Medical Center Amsterdam, The Netherlands. *On behalf of all ENHANCE investigators.

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Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia

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  1. Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia The ENHANCE trial ClinicalTrials.gov number: NCT00552097 John J.P. Kastelein, MD, PhD* Department of Vascular Medicine Academic Medical Center Amsterdam, The Netherlands *On behalf of all ENHANCE investigators ENHANCE Kastelein, et al, N Eng J Med 2008; In Press

  2. Presenter Disclosure Information John J.P. Kastelein, MD, PhD The following relationships exist related to this presentation: • Dr. Kastelein consults for Merck & Schering Plough • Dr. Kastelein is also a consultant for several other pharmaceutical companies with lipid-lowering agents. ENHANCE

  3. Although the authors allowed the sponsors to review the manuscript and the presentation, all data analyses and interpretation of the results are those of the academic investigators.

  4. Background Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of LDL-c when added to statin treatment. However, the effect of Ezetimibe on the progression of atherosclerosis is unknown ENHANCE

  5. ENHANCE logical next step after ASAP Timeline 1995 2000 2005 2010 ENHANCE LIPID (pediatric) ASAP Simvastatin 80 mg + Ezetimibe 10 mg Versus Simvastatin 80 mg Pravastatin 20-40 mg Versus Placebo Atorvastatin 80 mg Versus Simvastatin 40 mg Wiegman et al, Efficacy and Safety of Statin Therapy in Children With FH. JAMA 2004; 292(3):331-7 Smilde et al, Atorvastatin versus Simvastatin on Atherosclerotic Progression study. Lancet 2001;357:577-81 ENHANCE

  6. ENHANCE Study Design Pre-randomization Phase RANDOMI ZAT I ON FH: LDL-c ≥ 210 mg/dL Placebo Lead-In/ Drug Washout Screening and Fibrate Washout Simvastatin 80 mg Ezetimibe 10 mg-Simvastatin 80 mg IMT assessment -6 -10 to -7 0 21 24 3 18 15 6 9 12 Weeks Months

  7. ENHANCE Study Population Major inclusion criteria Major exclusion criteria • Age 30-75 years • HeFH: • Genotyping • Diagnostic criteria WHO • Untreated LDL-C levels > 210 mg/dL • (5.43 mmol/l) • Patients on lipid-lowering treatment • LDL-c after wash –out > 210 mg/dL • (5.43 mmol/l) • High-grade carotid stenosis • History carotid endarterectomy • Carotid stenting • Congestive heart failure III/IV ENHANCE

  8. ENHANCE cIMT Methodology Carotid Intima-Media thickness (cIMT) measurements • Measurements were made at a predefined angle of insonation • Only the far-walls of all segments were imaged • Images were stored in DICOM for offline image analyses ENHANCE de Groot E, et al. Circulation. (2004) 109[Suppl III]:III-33-III-38.

  9. Baseline characteristics

  10. Simva Eze-Simva LDL-cholesterol 10 0 -10 -20 P<0.01 -30 Percentage change from baseline -40 -16.5 % incremental reduction -50 -60 -70 0 6 24 18 12 Months ENHANCE

  11. Other Lipids and Apolipoproteins ENHANCE

  12. hsCRP Baseline24 months (mg/L)(mg/L) Simva 1.7(0.8-4.1) 1.2(0.6-2.4) Eze-Simva 1.7(0.8-3-9) 0.9(0.5-1.9) 10 0 p < 0.01 Simva -10 Eze-Simva -20 Median percent change from Baseline -30 -26 % incremental reduction -40 -50 -60 -70 -80 12 6 18 3 24 Months ENHANCE

  13. Primary Efficacy Outcome ENHANCE

  14. No significant changes in 1° or 2° endpoints consistent inferential results observed for non-parametric (median) and parametric (mean) analyses

  15. consistent inferential results observed for non-parametric (median) and parametric (mean) analyses

  16. Mean cIMT during 24 months of therapyLongitudinal, repeated measures analysis 0.80 Simva Eze-Simva 0.75 P=0.88 Mean IMT (mm) 0.70 0.65 0.60 12 18 6 24 Months ENHANCE

  17. No significant changes across any subgroup Progression Change cIMT (mm) Regression ENHANCE

  18. Discussion ENHANCE

  19. Possible explanations for the absence of an incremental reduction in cIMT • Measurement Technique • Technique not accurate enough to reflect changes in atherosclerotic burden? • The Compound • Ezetimibe lacks vascular benefit despite the observed LDL-c and hsCRP reduction • The Population • At too low a risk to detect changes, which would limit the ability to detect a differential response ENHANCE

  20. Quality of cIMT measurement Intraclass correlation coefficient at baseline: 0.93 Intraclass correlation coefficient at study endpoint: 0.95 Standard deviation between the paired measure at baseline: 0.053 mm Standard deviation between the paired measure at 24 months: 0.056 mm ENHANCE

  21. The CompoundEzetimibe no pleiotropic effects? Chronic heart failure patients (NYHA III), n=10 per group LDL-c reduction similar in both groups. Simvastatin: 15.6 % Ezetimibe: 15.4% P= n.s. P<0.01 12 12 9 9 Flow dependent dilation (percent change of diameter) Flow dependent dilation (percent change of diameter) 6 6 3 3 0 0 Baseline 4 weeks Baseline 4 weeks Simvastatin 10 mg group Ezetimibe 10 mg group ENHANCE Landmesser et al, Circulation 2005; 111(18): 2280-1

  22. Pleiotropic Effects of Statins:Benefit Beyond Cholesterol Reduction? ENHANCE Robinson et al, J Am Coll Cardiol 2005;46:1855-62

  23. The Population The treatment of patients with FH has witnessed profound changes ENHANCE

  24. Baseline cIMT in LIPID (pediatric), ASAP and ENHANCE ASAP ENHANCE LIPID (pediatric) Frequency 0.4 2.4 0.8 1.2 1.6 2.0 Mean CIMT (mm) ENHANCE

  25. Safety observations • Both regimens well tolerated, with overall safety profiles generally similar and consistent with product labels • One case of viral hepatitis A in the simvastatin-only arm • One case of myopathy (defined as CPK > 10 ULN, with associated muscle symptoms) in the simvastatin-only arm and 2 cases in the Ezetimibe-Simvastatin arm Subjects with 2 consecutive measurements for ALT and/or AST; a single last measurement ≥ 3 ULN; a measurement ≥ 3 X ULN followed by < 2 ULN that was taken more than 2 days after the last dose of study medication ENHANCE

  26. Conclusion The addition of Ezetimibe to Simvastatin did lead to expected changes in LDL-c and hsCRP, but did not reduce any cIMT parameter The reason(s) for this discrepancy currently remains unknown ENHANCE

  27. Acknowledgements John J.P. Kastelein MD PhD Fatima Akdim MD Erik S.G. Stroes MD PhD Aeilko H. Zwinderman PhD Michiel L. Bots MD PhD Anton F.H.. Stalenhoef MD PhD FRCP Frank L.J. Visseren MD PhD Eric J.G. Sijbrands MD PhD Mieke D. Trip MD PhD Evan A Stein MD PhD Daniel Gaudet MD PhD Raphael Duivenvoorden MD Enrico P. Veltri MD A. David Marais MD PhD Eric de Groot MD PhD ENHANCE

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