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

4. 5.07 mm 2 5.18 mm 2 Plaque Remodelling in Angiographically Normal Artery Preservation of Lumen Area

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

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

7. Cellular Mechanisms of Plaque Stability

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

9. Acute vs. Chronic Coronary Syndromes: Plaque Composition Lipid Content >40%Macrophages (%)Smooth Muscle (%) 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. Acetyl-CoA HMG-CoA Mevalonic Acid Cholesterol VLDL LDL Cholesterol Metabolism – Regulation by HMG CoA Reductase HMG CoA Reductase

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

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

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

19. STATINS CRP Endothelial Function Cytokines

21. TVA 15.47 mm 2 Lumen 5.51 mm 2 Plaque = 9.96 mm 2 18 Months N=522 paired IVUS P=0.02 REVERSAL : Reductions in LDL, Plaque Volume and CRP PRAVASTATIN 40 mg ATORVASTATIN 80 mg LDL-C (%) - 25 % - 46 % CRP (%) - 5 % - 36 % Change in Plaque Vol (%) 0 1.02.03.0

23. Heart Protection Study – Major Vascular Events

24. 80 mg LIPS : Benefits of Statin Following PCI

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

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

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