Ste nts Are Not Enough: Statins

1. Stents Are Not Enough:Statins Keith Channon Department of Cardiovascular Medicine University of Oxford John Radcliffe Hospital, Oxford

4. 5.07 mm2 5.18 mm2 Plaque Remodelling in Angiographically Normal Artery Preservation of Lumen Area

5. Stable Plaque Unstable Plaque (Erosion, Rupture) Plaque Growth

6. Plaque Biology = Clinical Events “Vulnerable” plaque Lumen Lipid core area ofdetail – T lymphocyte Lumen – Macrophagefoam cell (tissue factor+) Lipid core – “Activated” intimal SMC (HLA-DR+) “Stable” plaque – Normal medial SMC

7. Cellular Mechanisms of Plaque Stability

8. IVUS Assessment of Plaque Stability Thick Fibrous Cap Thin Fibrous Cap

9. Acute vs. Chronic Coronary Syndromes: Plaque Composition Lipid Content >40% Macrophages (%) Smooth Muscle (%) Stable Unstable Stable Unstable Stable Unstable

10. Angiographic Stenosis in Infarct-Related Artery Most are not severely stenosed

11. Additional Unstable Plaques Beyond the Culprit Lesion 27 patients with ACS. Angio + 3 vessel IVUS

12. Plaque Biology, Stenosis and Risk: The Paradox for PCI

13. Plaque Biology, Stenosis and Risk Stents are Not Enough ? • Using current technology, Stenting alone cannot treat all high risk lesions • Stenting alone does nothing to alter disease biology or natural history …….Statins ?

14. LDL Cholesterol Lowering by Statins

15. VLDL LDL LDL LDL HMG CoA Reductase Cholesterol Metabolism – Regulation by HMG CoA Reductase Acetyl-CoA Cholesterol HMG-CoA Mevalonic Acid

16. VLDL LDL LDL LDL Cholesterol Metabolism – Regulation by HMG CoA Reductase Acetyl-CoA Cholesterol HMG-CoA Mevalonic Acid Statins

17. VLDL LDL LDL LDL LDL LDL LDL LDL LDL Cholesterol Metabolism – Regulation by HMG CoA Reductase Acetyl-CoA Cholesterol HMG-CoA Mevalonic Acid Statins

18. Modification of Cell Signalling Proteins Isoprenoid Derivatives Statins and Cholesterol Synthesis: Effects on Cell Signalling through Isoprenoids Acetyl CoA HMG CoA HMG CoA Reductase e.g. G-Proteins Rho, Rac Statins • ‘Pleiotrophic’ Effects on Vascular Cells: • Gene Regulation • Cell Proliferation • eNOS Expression • Inflammation • Apoptosis • Stem & Progenitor Cells Mevalonate Cholesterol

19. STATINS • CRP • Endothelial Function • Cytokines

21. Change in Plaque Vol (%) TVA 15.47 mm2 CRP (%) LDL-C (%) -1.0 1.0 2.0 3.0 0 Lumen 5.51 mm2 - 5 % - 25 % PRAVASTATIN 40 mg - 46 % - 36 % ATORVASTATIN 80 mg REVERSAL : Reductions in LDL, Plaque Volume and CRP 18 Months N=522 paired IVUS P=0.02 Plaque = 9.96 mm2

23. Heart Protection Study – Major Vascular Events

24. LIPS : Benefits of Statin Following PCI 80 mg

25. Statin Therapy and Outcome after PCI: Cleveland Clinic n=1552 n=5052 Circulation 2003; 107;1750-6 Circulation 2002; 105;691-6

26. AVERT : Atorvastatin Versus Revascularization Treatments Randomised to Atorvastatin 80 mg vs. PCI + Usual Care Pitt B et al. N Engl J Med 1999;341:170-6

27. AVERT : Time to First Ischaemic Event

28. AVERT : Major Exclusion Criteria

29. AVERT : Baseline Characteristics

30. AVERT : Ischaemic Events at 18 Months

31. Why are Stents not Enough ? Stents treat lesions that are selected on luminal stenosis Plaque events are determined more by plaque biology, rather than stenosis Coronary disease is diffuse and progressive PCI at discrete sites does not alter disease burden or progression

32. Why Statins ? Statins directly alter CAD natural history through lipid lowering and other direct cellular effects Effects on mortality and morbidity in very large studies in primary and secondary prevention, including PCI High Dose, more potent newer statins can achieve plaque regression and stabilisation Stenting symptomatic stenoses combined with high-dose statin therapy is currently best CAD management strategy