Stents Are Not Enough:

Statins

Keith Channon

Department of Cardiovascular MedicineUniversity of Oxford

John Radcliffe Hospital, Oxford

5.07 mm2

5.18 mm2

Plaque Remodelling in Angiographically Normal ArteryPreservation of Lumen Area

Stable Plaque

Unstable Plaque(Erosion, Rupture)

Plaque Growth

Plaque Biology = Clinical Events

– T lymphocyte

– Macrophagefoam cell (tissue factor+)

– “Activated” intimal SMC (HLA-DR+)

– Normal medial SMC“Stable” plaque

“Vulnerable” plaque

Lumen

area ofdetail

Lumen

Lipidcore

Lipidcore

Cellular Mechanisms of Plaque Stability

IVUS Assessment of Plaque Stability

Thick Fibrous Cap Thin Fibrous Cap

Acute vs. Chronic Coronary Syndromes:Plaque Composition

Lipid Content >40% Macrophages (%) Smooth Muscle (%)

Stable Unstable Stable Unstable Stable Unstable

Angiographic Stenosis in Infarct-Related ArteryMost are not severely stenosed

Additional Unstable Plaques Beyond the Culprit Lesion

27 patients with ACS. Angio + 3 vessel IVUS

Plaque Biology, Stenosis and Risk:The Paradox for PCI

Plaque Biology, Stenosis and RiskStents 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 ?

LDL Cholesterol Lowering by Statins

Acetyl-CoA

HMG-CoA

Mevalonic Acid

Cholesterol

VLDLLDL LDL

LDL

Cholesterol Metabolism – Regulation by HMG CoA Reductase

HMG CoA Reductase

Acetyl-CoA

HMG-CoA

Mevalonic Acid

Cholesterol

VLDLLDL LDL

LDL

Cholesterol Metabolism – Regulation by HMG CoA Reductase

Statins

LDL

Acetyl-CoA

HMG-CoA

Mevalonic Acid

VLDLLDL

LDL

Cholesterol Metabolism – Regulation by HMG CoA Reductase

Statins

Cholesterol

LDL

LDL

LDL

LDLLDL

Statins and Cholesterol Synthesis: Effects on Cell Signalling through Isoprenoids

Acetyl CoA

HMG CoA

Mevalonate

Cholesterol

HMG CoA Reductase

IsoprenoidDerivatives

Modification ofCell 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

STATINS

• CRP

• Endothelial Function

• Cytokines

TVA 15.47 mm2

Lumen5.51 mm2

Plaque = 9.96 mm2

18 Months N=522 paired IVUS

P=0.02

REVERSAL : Reductions in LDL, Plaque Volume and CRP

PRAVASTATIN40 mg

ATORVASTATIN80 mg

LDL-C (%)

- 25 %

- 46 %

CRP (%)

- 5 %

- 36 %

Change in Plaque Vol (%)

-1.0 0 1.0 2.0 3.0

Heart Protection Study – Major Vascular Events

80 mg

LIPS : Benefits of Statin Following PCI

Statin Therapy and Outcome after PCI: Cleveland Clinic

n=1552

Circulation 2003; 107;1750-6

n=5052

Circulation 2002; 105;691-6

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

AVERT : Time to First Ischaemic Event

AVERT : Major Exclusion Criteria

AVERT : Baseline Characteristics

AVERT : Ischaemic Events at 18 Months

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

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