PLAQUE STABILIZATIONand

REGRESSIONA new Therapeutic Target

The Role of Statins

Alexandru AndritoiuMilitary Hospital, Craiova, Romania

Lower is better

LaRosa JC et al. - N Engl J Med 2005

TNT: Baseline and final LDL cholesterol levels

LDL cholesterol level Atorvastatin 10 mg (n=5006)

Atorvastatin 80 mg (n=4995)

Mean baseline LDL cholesterol levels (mg/dL)

98 97

Final LDL cholesterol levels (mg/dL) 101 77

TNT: Primary efficacy outcomes

LaRosa JC et al. N Engl J Med 2005

Outcome Atorvastatin 10 mg

(n=5006)

Atorvastatin 80 mg

(n=4995)

Hazard ratio(95% CI)

p

Total major cardiovascular events (%)

10.9 8.7 0.78(0.69-0.89)

<0.001

•Death from coronary heart disease (%)

2.5 2.0 0.80(0.61-1.03)

0.09

•Nonfatal MI (%) 6.2 4.9 0.78(0.66-0.93)

0.004

•Resuscitation after cardiac arrest (%)

0.5 0.5 0.96(0.56-1.67)

0.89

•Fatal or nonfatal stroke (%)

3.1 2.3 0.75(0.59-0.96)

0.02

IDEAL The Incremental Decrease in End points through Agressive Lipid lowering

Pedersen TR et al - JAMA. 2005;294(19):2437-45.

High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL

study: a randomized controlled trial.

Results:

• In the IDEAL study, 68 CV events were prevented among 1000 patients managed with atorvastatin 80 mg compared with those receiving simvastatin 40 mg daily. • The mean LDL-C level in patients receiving simvastatin 40 mg was 2.7 mmol/L compared with that of 2.1 mmol/L in those receiving atorvastatin 80 mg.

PROVE IT-TIMI 22

• In 2005, an analysis of data from PROVE IT-TIMI 22 showed that intensive therapy using atorvastatin 80 mg was associated with a significant reduction in the composite clinical endpoint (MACE) as early as 30 days after the acute event compared with standard-dose pravastatin (40 mg).

• A trend in favor of intensive therapy was evident at 15 days after randomization.

J Am Coll Cardiol 2005;46:1405-10

N Engl J Med. 2005;352:20-8

PROVE IT-TIMI 22

N Engl J Med. 2005;352:20-8

Hypotheses

• The two dominant hypotheses to explain the discrepancy between the magnitude of the angiographic and clinical benefit of cholesterol reduction therapy are:

• plaque stabilization • improved endothelial function • One or both mechanisms may play a role

in the clinical benefit seen with the lipid-lowering therapies.

Concept

• The concept of plaque stabilization was first proposed in the 1990s in an attempt to explain the discrepancy between the small amount of plaque regression demonstrated angiographically in many randomized trials of lipid lowering and the large reduction in clinical events seen in these trials (Ambrose JA 2002)

• The concept of the vulnerable plaque should be expanded to include any plaque that is high-risk and prone to destabilization and thrombosis whether lipid-rich or proteoglycan-rich.

Ambrose JA - Circulation 2002; Muller JE-JACC 1994

Plaque-Specific Considerations

The destabilized (disrupted and/or thrombosed) culprit plaque in a patient with an acute coronary syndrome requires a different treatment philosophy and strategy than plaques that have not destabilized.

Characteristic of Vulnerable Plaque

increased lipid content increased macrophage content foam cell and T lymphocyte content a reduced collagen and smooth muscle cell content

• Rupture tends to occur at the margins or ‘shoulder region’ of plaques where the overlying fibrous cap is necrotic, very thin and extensively infiltrated by macrophages and adjacent to relatively normal tissue

• The ‘shoulder region’ is the site exposed to the greatest shear stress

High-Dose Lipid-Lowering Therapy and Long-Term Antithrombotic Therapy for

Destabilized Plaques

Stabilization of Vulnerable Plaques

• To reduce subsequent events, vulnerable plaques must remain stable and quiescent.

• Plaque stabilization may not only reduce the incidence of acute coronary syndromes but also prevent the evolution of plaques to more stenotic lesions.

ACS

• Acute coronary syndromes (unstable angina, acute myocardial infarction and sudden cardiac death) result from fissure, erosion or frank rupture of a vulnerable atherosclerotic plaque

• An acute coronary syndrome will occur only if coronary blood flow is reduced and collateral flow is inadequate

The extrinsic features that cause a vulnerable plaque to rupture

• increased blood pressure

• vasospasm

Plaque Stabilization: Can We Turn Theory into

Evidence?

Atherosclerosis Regression, Vascular Remodeling, and

Plaque Stabilization

Lloyd W. Klein - J Am Coll Cardiol, 2007; 49:271-273

What Degree of Plaque Regression Has Been Achieved by Pharmacotherapy?

• REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial , median atheroma volume decreased (regressed) 0.4% in the high-dose statin group versus progressed 2.7% in the moderate-dose group over an 18-month period.

• ASTEROID (A Study to Evaluate the Effect of ROsuvastatin on Intravascular Ultrasound Derived Coronary Atheroma Burden) study, 63.6% of patients experienced regression and mean total atheroma volume decreased 7%, with a 1% decrease in percent atheroma volume, after 24 months of treatment.

• Intravenous recombinant apolipoprotein A1 Milano administered in 5 weekly infusions showed a 4.1% decrease in total atheroma volume (p < 0.001).

Although the absolute amount of regression achieved is small, it may be sufficient to produce clinical benefit

Which Components of the Plaque Are Most Likely to be Targets of

Pharmacotherapy?

• The lipid pool is a highly accessible target for statin therapy By increasing cholesterol efflux, an imbalance between the deposition and

removal of vascular cholesterol after endothelial injury may be corrected.

• Fibrous tissue seem to be irreversible despite metabolic manipulation. However, statins have been shown to diminish smooth muscle cell accumulation and collagen deposition.

• Calcification seems to be a nonreversible change, but this has not been formally evaluated.

• Inflammatory reaction in the forms of cellular migration, humoral substance release, and edema are obviously potential targets.

• Statins decrease inflammation, an effect correlated with clinical benefit

Regression and Stabilization: Is There a Relationship?

• Decreasing endothelial injury, diminishing lipid content, and altering the cellular elements and inflammatory milieu in the subendothelial layer may ameliorate the susceptibility to plaque rupture.

• Treatment with statins is associated with constrictive remodeling

• The hyperechogenicity index (composed of dense fibrous or elastic tissue) increase in atorvastatin-treated patients, whereas calcification and hypoechogenic plaque (lipoid, and necrotic tissue) remained constant.

ESTABLISH Early Statin Treatment in Patients With Acute Coronary

Syndrome Trial

• Early statin treatment in patients with ACS resulted in regression of atherosclerotic lesions 6 months later.

• Plaque volume was reduced 13% from baseline in the atorvastatin-treated group, but increased 9% in the control group (p < 0.03).

REVERSAL – NORMALIZE Studies (IVUS)

• the more calcified atheromas were resistant to change, either progression or regression

• less calcification was a sign of potential for significant changes over time, either progression or regression

The findings suggest that the various components of atheroma respond differently to treatment with medical therapies, and can be used to target

plaques that are likely to respond.

Ray, K. K. et al. - J Am Coll Cardiol 2005;46:1425-1433

"Pathological vascular triad" implicated in acute coronary syndrome

Pleiotropic effects of statins on the vasculature Pleiotropic effects of statins on the vasculature

Clin. Sci. (2003) 105, 251-266 Clin. Sci. (2003) 105, 251-266

Comparative Atorvastatin Pleiotropic Effects (CAP)

• The primary objective of the study is to evaluate the efficacy of atorvastatin 80 mg daily as compared to atorvastatin 10 mg daily in reducing C-reactive protein levels over a 26-week treatment period in subjects with documented coronary artery disease.

Collaborators (67) Ma PT, Opgenorth A, Frohlich J, …

Cinteza M, Dimulescu D, Vintila M, Ahmedzhanov N, Lopatin Y, Dukat A, Filipova S, Murin J.

Bonnet J, Clin Ther 2008;30(12):2298-313

REVERSAL Study - Results

Nissen SE et al. N Engl J Med 2005;352(1):29-38

Imaging of the Vulnerable Plaque

Noninvasive Techniques for Evaluation of the Atherosclerotic

Vulnerable Plaques

• US (B mod, CDUS, Power-angio) -3D• Electron Beam Computed Tomography (EBCT)• Magnetic Resonance Imaging (MRI)

IVUS Elastography of Vulnerable Plaque

IVUS (A), elastogram (B), macrophage staining (C), and collagen staining (D). In the elastogram, a vulnerable plaque is indicated by a high strain on the surface. In the corresponding histology, a high amount of macrophages (C) is visible with a thin cap (D) and a lipid pool (LP).

Schaar JA et al. – Circulation 2003;108:2636-2641

Invasive Techniques for Evaluation of the Atherosclerotic Vulnerable

Plaques

• Angiography

• Angioscopy

• Thermography

• IVUS (+CEUS)

• IVUS elastography

• Optical Coherence Tomography

• Infrared Spectrosopy

Plaque Volume and Necrotic Core Size Determine the Plaque

Vulnerability

Plaque Hemorrhage Is Associated With Neointimal Neovascularization and Vasa

Vasorum Proliferation

REMODELIG

POSITIVE REMODELING• early phase of ATS• luminal size is not

affected by plaque growth• enlargement of vessel

size• inflamation, calcification,

medial thinning• associated with unstable

angina

NEGATIVE REMODELING• moderate ATS• no increase in vessel size• the plaque approaches

the lumen• associated with stable

angina

STATINS

TRUTH

Comparison of Arterial Remodeling and Changes in Plaque Composition Between Patients With Progression Versus Regression of Coronary Atherosclerosis During

Statin Therapy

Treatment With Statin on Atheroma Regression Evaluated by Intravascular Ultrasound With Virtual

Histology (TRUTH)

119 patients 2 groups: progessors vs regressors

CONCLUSION:• Coronary arteries showed negative remodeling during statin-induced plaque regression. • The difference in plaque composition between patients with progression and those with regression of coronary atherosclerosis during statin therapy arose from the difference in the change in fibrous component.

Nozue T et al - Am J Cardiol 2012;109:1247-1253

8-month follow-up

Neovascularization of Atherosclerotic Arteries

Doyle, B. et al. - J Am Coll Cardiol 2007;49:2073-2080

Role of Vessel Wall Neovascularization in Plaque Growth

Relation between neovascularization and unstable plaque

Matsumoto N 2010

Carotid plaque neovascularization

Feinstein SB - JACC 2006

The plaque neovascularization and CV risk

Staub D - Stroke 2010

The Prevalence of Carotid Plaques

Pacienti cu placa;

515; 40%Pac. fara

placa; 780; 60%

N = 1295 subjects Age 40-90 yrs; M 720: F 575

Andritoiu A, nepubl.

The Carotid Plaques Prevalence in relation with Age

13,7928,35

43,857,14

81,25

0

20

40

60

80

100

40-49 50-59 60-69 70-79 80-89

Ani

Pre

vale

nta

%

N =405; Age 40-90 yrsAndritoiu A 2009

Vulnerable Carotid Plaque

• Thin fibrous cap• Ulcerated surface • Lipidic core• Hipo/anecogenicity

Vulnerable carotid plaque

Carotid ulcerated plaque

Statins and Stroke

Statins for Stroke PreventionDisappointment and Hope

• lack of association between cholesterol levels and stroke in most epidemiological and observational studies.

• cholesterol as a risk factor for stroke is controversial

• the relatively modest effects on stroke (compared with other stroke prevention strategies) were obtained primarily in patients with established CHD, not in ischemic stroke patients without CHD. The latter constitute the majority of stroke patients.

Amarenco P – Circulation 2004;109:44-49

Statins in Carotid Atherosclerosis

• Statins may have a direct effect on atherosclerotic plaques in the carotid arteries.

• Studies have shown that statins reduce the progression of carotid stenosis in patients without previous cardiac or cerebrovascular events and may reduce carotid intima-media thickness in patients with hypercholesterolemia or CHD.

• More aggressive cholesterol reduction may have a greater effect on carotid atherosclerosis.

MacMahon S - Circulation 1998; Smilde TJ - Lancet 2001

Risk of Hemorrhagic Stroke?

• One concern from observational cohort data is the possibility of an increased risk of hemorrhagic stroke with cholesterol-lowering therapy.

• However, an increase in hemorrhagic stroke was not observed in the long-term statin secondary prevention trials that examined hemorrhagic stroke as a secondary end point.

• The incidence of hemorrhagic stroke was ≤0.5% in both the placebo and statin-assigned groups.

SPARCL Stroke Prevention by Agressive Reduction in Cholesterol Levels

• intense lipid lowering with atorvastatin 80 mg/day reduced the risk of cerebro- and cardiovascular events in patients with and without carotid stenosis

• The carotid stenosis group may have greater benefit

• In the group with carotid artery stenosis, treatment with atorvastatin 80 mg/day was associated with a 33% reduction in the risk of any stroke

Sillesen H,et al - Stroke 2008

The Multicenter Atorvastatin Plaque Stabilization (MAPS) Study

Inclusion Criteria

• Symptomatic carotid stenosis > 70% (NASCET criteria)• Eligibility for carotid endarterectomy• Total cholesterol level between 5.83 and 7.64 mmol/L• Never treated with lipid lowering drugs

Purpose

how different lipid-lowering strategies (non-statin therapy, low-dose statin and high-dose statin) affects cellular composition of carotid plaque over a short-term period of three months.

DD, M, 62yr- RICA stenosis (60%)

Stenting + ACI inhibitor + Clopidogrel + Sortis 80 mg o.d

• HBP (175/100 mmHg)• Cholesterol 216 mg/dl• LDL-Chol • HDL-Chol 23 mg/dl• TG 168 mg/dl

Plaque volume regression is real !

JAPAN-ACSJapan Assessment of Pitavastatin and Atorvastatin in

Acute Coronary Syndrome

Pitavastatin 4 mg/d vs Atorvastatin 20 mg/d

OBJECTIVE:Plaque volum regression Method: IVUS volumetry

N = 307 pts with ACS + Hyper-Chol + coronary plaque

Takafumi Hiro et al. -JACC 2009;54:293-302

Follow-up: 8-12 months

There were significant correlations between the change in plaque volume and the change in external elastic membrane (EEM) volume (A), whereas no significant correlation was observed between the change in plaque volume and the change in lumen volume (B). The regression of plaque volume was associated with negative vessel remodeling.

Ainsworth CD - Stroke 2005

The plaque volume regressionAtorvastatin 80 mg/d -3Mo

Message take home

Stabilizing the Destabilized Plaque

• percutaneous intervention

• long-term antithrombotic and anticoagulant approaches

• high-dose lipid-lowering therapy

ESTABLISH Early Statin Treatment in Patients With

Acute Coronary Syndrome trial

• Early statin treatment (Atorvastatin 20 mg) in patients with ACS resulted in regression of atherosclerotic lesions 6 months later.

• Plaque volume was reduced 13% from baseline in the atorvastatin-treated group, but increased 9% in the control group

(p < 0.03).

IVUS in REVERSAL and NORMALIZE studies

• the more calcified atheromas were resistant to change, either progression or regression.

• less calcification was a sign of potential for significant changes over time, either progression or regression.

Nicholls SJ et al. JACC 2007;49:263-270

• The findings suggest that the various components of atheroma respond differently to treatment with medical therapies, and can be used to target plaques that are likely to respond.

Plaque stabilization in acute coronary syndromes

Ambrose JA - 2002