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High dose statins in plaque stabilization


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statins, atherosclerotic plaque

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High dose statins in plaque stabilization

  1. 1. PLAQUEPLAQUE STABILIZATION and REGRESSIONSTABILIZATION and REGRESSION A new Therapeutic TargetA new Therapeutic Target Role of High-Dose Statins RegimenRole of High-Dose Statins Regimen Alexandru Andritoiu Military Hospital, Craiova, Romania
  2. 2. 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.
  3. 3. 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
  4. 4. 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
  5. 5. The extrinsic features that cause a vulnerable plaque to rupture • increased blood pressure • vasospasm
  6. 6. 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.
  7. 7. Atherosclerosis Regression, Vascular Remodeling, and Plaque Stabilization Lloyd W. Klein - J Am Coll Cardiol, 2007; 49:271-273
  8. 8. 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
  9. 9. 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
  10. 10. 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.
  11. 11. Pleiotropic effects of statins on the vasculaturePleiotropic effects of statins on the vasculature Clin. Sci. (2003) 105, 251-266Clin. Sci. (2003) 105, 251-266
  12. 12. CAD/ACS • Culprit lesions • Vulnerable plaque • Unstable plaque • Complicated plaque • Calcium score • %stenosis • Occlusion
  13. 13. Ray, K. K. et al. - J Am Coll Cardiol 2005;46:1425-1433 "Pathological vascular triad" implicated in acute coronary syndrome
  14. 14. Plaque Volume and Necrotic Core Size Determine the Plaque Vulnerability Plaque Hemorrhage Is Associated With Neointimal Neovascularization and Vasa Vasorum Proliferation
  15. 15. Plaque stabilization in acute coronary syndromes
  16. 16. Imaging of the Vulnerable Plaque
  17. 17. Invasive Techniques for Evaluation of the Atherosclerotic Vulnerable Plaques • Angiography • Angioscopy • Thermography • IVUS (+CEUS) • IVUS elastography • Optical Coherence Tomography • Infrared Spectrosopy
  18. 18. 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)
  19. 19. Culprit lesion/Plaque rupture in ACS Okaki Y et al. Eur Heart J 2011;32:2814-2823
  20. 20. Culprit lesion/Stable plaque images in Stable angina Okaki Y et al. Eur Heart J 2011;32:2814-2823
  21. 21. 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.
  22. 22. High-Dose Lipid-Lowering Therapy and Long-Term Antithrombotic Therapy for Destabilized Plaques
  23. 23. 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
  24. 24. 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.
  25. 25. IVUS in REVERSAL • 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.
  26. 26. 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).
  27. 27. Rosuvastatin 40 mg (n =694) Atorvastatin 80 mg (n=691) Safety Safety Lipids Safety IVUS Lipids Safety Lipids Safety Safety Safety Visit: Week: 1 –4 3 0 4 13 5 26 6 39 7 52 8 65 9 78 10 91 11 104 Screening Period 2 –2 Rosuva 20 mg Atorva 40 mg IVUS Lipids Lipids Randomization Period Lipids Safety Safety 1385 patients with symptomatic CAD (angiographic stenosis >20%) LDL-C with (>80 mg/dL) or without (>100 mg/dL) statin use last 4 weeks Study DesignStudy Design
  28. 28. Primary IVUS Efficacy Parameter Change Percent Atheroma Volume -1.22 -0.99 P=0.17† P<0.001* P<0.001* Median Change Percent Atheroma Volume † comparison between groups. * comparison from baseline
  29. 29. JAPAN-ACS Japan 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.
  30. 30. 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. 8-month follow-up
  31. 31. Carotid plaque
  32. 32. 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.
  33. 33. The Carotid Plaques Prevalence in relationship with Age decades 13,79 28,35 43,8 57,14 81,25 0 20 40 60 80 100 40-49 50-59 60-69 70-79 80-89 Ani Prevalenta% N =405; Age 40-90 yrs Andritoiu A, 2009
  34. 34. Carotid atherosclerosis and CVRF Fabris F et al. Stroke. 1994;25:1133-1140
  35. 35. Carotid atherosclerosis and CVRF Fabris F et al. Stroke. 1994;25:1133-1140
  36. 36. Carotid plaque
  37. 37. Carotid US plaque Nodular plaque Parietale plaque
  38. 38. Vulnerable Carotid Plaque • Thin fibrous cap • Ulcerated surface • Lipidic core • Hipo/anecogenicity
  39. 39. Vulnerable carotid plaque
  40. 40. Carotid ulcerated plaque
  41. 41. AJNR 2010 31: 1395-1402
  42. 42. 15 6 stenoza ocluzie Prevalenta stenozei si ocluziei carotidiene 1.15/1000 0.46/1000 Andritoiu A, 2009 N = 1295 subiecti; 40-90 ani; B 720: F 575
  43. 43. DD, M, 62yr- RICA stenosis (60%) ACI inhibitor+AAS+Clopidogrel+Sortis 40 (80) mg o.d Stenting vs Endarterectomy? • HBP (175/100 mmHg) • Cholesterol 216 mg/dl • LDL-Chol 130 mg/dL • HDL-Chol 23 mg/dl • TG 168 mg/dl
  44. 44. • In the United States, 90% of carotid intervention (endarterectomy and stenting) is now for asymptomatic carotid stenosis. • Until a modern randomized trial comparing stenting, endarterectomy and best medical therapy is carried out, widespread endarterectomy or stenting of asymptomatic carotid stenosis for unselected patients with asymptomatic carotid stenosis should be regarded as malpractice.
  45. 45. J. David Spence Professor of Neurology and Clinical Pharmacology, Director, Stroke Prevention & Atherosclerosis Research Centre (SPARC)-ROBARTS Research Institute The father of carotid plaque Plaque area or plaque volume vs. CIMT Spence J.D., Hackam D.G. Treating Arteries Instead of Risk Factors. A Paradigm Change in Management of Atherosclerosis. Stroke 2010;41:1193-1199. 20102010 Stroke Innovation AwardStroke Innovation Award
  46. 46. Plaque area
  47. 47. Plaque volume 3D-Reconstruction
  48. 48. RT- elastography of carotid plaque
  49. 49. Neovascularization of Atherosclerotic Arteries
  50. 50. Doyle, B. et al. - J Am Coll Cardiol 2007;49:2073-2080 Role of Vessel Wall Neovascularization in Plaque Growth
  51. 51. Contribution of Neovascularization to Plaque Growth
  52. 52. Relation between neovascularization and unstable plaque Matsumoto N 2010
  53. 53. The plaque neovascularization and CV risk Staub D - Stroke 2010
  54. 54. CEUS-plaque neovascularization Staub D - Stroke 2010
  55. 55. The plaque neovascularization and CV risk Staub D - Stroke 2010
  56. 56. Carotid plaque stabilization and regression
  57. 57. 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
  58. 58. 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. University of Padua Each group received: atorvastatin 10 mg/day, atorvastatin 80 mg/day, or cholestyramine 8 g/day plus sitosterol 2.5 g/day
  59. 59. Ainsworth CD - Stroke 2005 The plaque volume regression Atorvastatin 80 mg/d -3Mo Plaque volume regression is real !
  60. 60. 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
  61. 61. The answer is: Yes!!!
  62. 62. Plaque Stabilization: Can We Turn Theory into Evidence?
  63. 63. Stabilizing the Destabilized Plaque • percutaneous intervention • long-term antithrombotic and anticoagulant approaches • high-dose lipid-lowering therapy