Role of statins in plaque stabilization


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Role of statins in plaque stabilization

  1. 1. PLAQUE STABILIZATION and REGRESSION A new Therapeutic Target The Role of Statins Alexandru Andritoiu Military Hospital, Craiova, Romania
  2. 2. Lower is better
  3. 3. TNT: Baseline and final LDL cholesterol levels LDL cholesterol level Mean baseline LDL cholesterol levels (mg/dL) Final LDL cholesterol levels (mg/dL) Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995) 98 97 101 77 LaRosa JC et al. - N Engl J Med 2005
  4. 4. TNT: Primary efficacy outcomes 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 LaRosa JC et al. N Engl J Med 2005
  5. 5. IDEAL The Incremental Decrease in End points through Agressive Lipid lowering 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. Pedersen TR et al - JAMA. 2005;294(19):2437-45.
  6. 6. 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
  7. 7. PROVE IT-TIMI 22 N Engl J Med. 2005;352:20-8
  8. 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 lipidlowering therapies.
  9. 9. 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
  10. 10. 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.
  11. 11. 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
  12. 12. High-Dose Lipid-Lowering Therapy and Long-Term Antithrombotic Therapy for Destabilized Plaques
  13. 13. 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.
  14. 14. 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
  15. 15. The extrinsic features that cause a vulnerable plaque to rupture • increased blood pressure • vasospasm
  16. 16. Plaque Stabilization: Can We Turn Theory into Evidence?
  17. 17. Atherosclerosis Regression, Vascular Remodeling, and Plaque Stabilization Lloyd W. Klein - J Am Coll Cardiol, 2007; 49:271-273
  18. 18. 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
  19. 19. 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 •
  20. 20. 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.
  21. 21. 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).
  22. 22. 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.
  23. 23. "Pathological vascular triad" implicated in acute coronary syndrome Ray, K. K. et al. - J Am Coll Cardiol 2005;46:1425-1433
  24. 24. Pleiotropic effects of statins on the vasculature Clin. Sci. (2003) 105, 251-266
  25. 25. 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 26week 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
  26. 26. REVERSAL Study - Results Nissen SE et al. N Engl J Med 2005;352(1):29-38
  27. 27. Imaging of the Vulnerable Plaque
  28. 28. 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)
  29. 29. 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
  30. 30. Invasive Techniques for Evaluation of the Atherosclerotic Vulnerable Plaques • • • • • • • Angiography Angioscopy Thermography IVUS (+CEUS) IVUS elastography Optical Coherence Tomography Infrared Spectrosopy
  31. 31. Plaque Volume and Necrotic Core Size Determine the Plaque Vulnerability Plaque Hemorrhage Is Associated With Neointimal Neovascularization and Vasa Vasorum Proliferation
  32. 32. 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 STATINS NEGATIVE REMODELING • moderate ATS • no increase in vessel size • the plaque approaches the lumen • associated with stable angina
  33. 33. TRUTH Treatment With Statin on Atheroma Regression Evaluated by Intravascular Ultrasound With Virtual Histology (TRUTH) Comparison of Arterial Remodeling and Changes in Plaque Composition Between Patients With Progression Versus Regression of Coronary Atherosclerosis During Statin Therapy 119 patients 2 groups: progessors vs regressors 8-month follow-up 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.
  34. 34. Neovascularization of Atherosclerotic Arteries
  35. 35. Role of Vessel Wall Neovascularization in Plaque Growth Doyle, B. et al. - J Am Coll Cardiol 2007;49:2073-2080
  36. 36. Relation between neovascularization and unstable plaque Matsumoto N 2010
  37. 37. Carotid plaque neovascularization Feinstein SB - JACC 2006
  38. 38. The plaque neovascularization and CV risk Staub D - Stroke 2010
  39. 39. The Prevalence of Carotid Plaques Pac. fara placa; 780; 60% Pacienti cu placa; 515; 40% N = 1295 subjects Age 40-90 yrs; M 720: F 575 Andritoiu A, nepubl.
  40. 40. The Carotid Plaques Prevalence in relation with Age Prevalenta % 100 81,25 80 60 40 20 43,8 57,14 28,35 13,79 0 40-49 50-59 60-69 70-79 80-89 Ani N =405; Age 40-90 yrs Andritoiu A 2009
  41. 41. Vulnerable Carotid Plaque • • • • Thin fibrous cap Ulcerated surface Lipidic core Hipo/anecogenicity
  42. 42. Vulnerable carotid plaque
  43. 43. Carotid ulcerated plaque
  44. 44. Statins and Stroke
  45. 45. Statins for Stroke Prevention Disappointment 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
  46. 46. 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
  47. 47. 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.
  48. 48. 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
  49. 49. 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 (nonstatin therapy, low-dose statin and highdose statin) affects cellular composition of carotid plaque over a short-term period of three months.
  50. 50. DD, M, 62yr- RICA stenosis (60%) • • • • • HBP (175/100 mmHg) Cholesterol 216 mg/dl LDL-Chol HDL-Chol 23 mg/dl TG 168 mg/dl Stenting + ACI inhibitor + Clopidogrel + Sortis 80 mg o.d
  51. 51. Plaque volume regression is real !
  52. 52. JAPAN-ACS Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome Pitavastatin 4 mg/d vs Atorvastatin 20 mg/d N = 307 pts with ACS + Hyper-Chol + coronary plaque OBJECTIVE: Plaque volum regression Method: IVUS volumetry 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. Takafumi Hiro et al. -JACC 2009;54:293-302
  53. 53. The plaque volume regression Atorvastatin 80 mg/d -3Mo Ainsworth CD - Stroke 2005
  54. 54. Message take home
  55. 55. Stabilizing the Destabilized Plaque • percutaneous intervention • long-term antithrombotic and anticoagulant approaches • high-dose lipid-lowering therapy
  56. 56. 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).
  57. 57. 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. • 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. Nicholls SJ et al. JACC 2007;49:263-270
  58. 58. Plaque stabilization in acute coronary syndromes
  59. 59. Ambrose JA - 2002