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ADVANCE ANGIOPLASTY 2004 LONDON, Jan 15-16 2004 LATEST CLINICAL EVIDENCE WITH DEXAMET GERMANO DI SCIASCIO, MD, FACC, FE

ADVANCE ANGIOPLASTY 2004 LONDON, Jan 15-16 2004 LATEST CLINICAL EVIDENCE WITH DEXAMET GERMANO DI SCIASCIO, MD, FACC, FESC Professor and Chairman of Cardiology, Campus Bio-Medico University of Rome. Dexamet TM is the Bio divYsio PC coated stents preloaded with Dexamethasone.

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ADVANCE ANGIOPLASTY 2004 LONDON, Jan 15-16 2004 LATEST CLINICAL EVIDENCE WITH DEXAMET GERMANO DI SCIASCIO, MD, FACC, FE

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  1. ADVANCE ANGIOPLASTY 2004 LONDON, Jan 15-16 2004 LATEST CLINICAL EVIDENCE WITH DEXAMET GERMANO DI SCIASCIO, MD, FACC, FESC Professor and Chairman of Cardiology, Campus Bio-Medico University of Rome

  2. DexametTM is the BiodivYsio PC coated stents preloaded with Dexamethasone • BiodivYsio Interdependent cell design • Non-inflammatory PC coating • Non-thrombogenic PC coating • Long term implant history Arterial Side 0.5 µg/mm2 Dexamethasone PC coating 1 mm } Targeted drug delivery direct to arterial wall Stent Strut Stent strut cross-section Lumen Side

  3. Dexamethasone • is a potent anti-inflammatory agent that treats the first step of the neointima formation/restenosis process • has also anti-proliferative action by affecting the inflammation process • is non-cytotoxic and does not destroy healthy cells and does not reduce or slow down the re-endothelisation 1 S.H.Park and A.M.Lincoff, Semin. Interv. Cardiol., 1998, 3, 191-195

  4. Dexamethasone (II) • is delivered (when it’s most needed) early to target the inflammatory cells • has strong clinical experience in humans •  demonstrated clinical benefits preferably in unstable in STRIDE and SAFE 1 S.H.Park and A.M.Lincoff, Semin. Interv. Cardiol., 1998, 3, 191-195

  5. Dexamet’s first clinical trial :STRIDE Study of anti-restenosis with BiodivYsio Dexamethasone-Eluting stent - A pilot Phase II trial, multi-centre, prospective, non-randomised study. Dexamethasone dose 0.5 ug/mm2 - 71 patients in 8 centres in Belgium - PI: Ivan De Scheerder - Endpoints: - 30-day and 6-month MACE - In-stent restenosis 6 months - Clinical and QCA :Late loss, loss index,MLD

  6. STRIDE STudy of Anti-Restenosis with BIodivYsioDexamethasone-Eluting Stent 71 patients with 6-month angiographic follow-up Stent: BiodivYsio stent (dexamethasone 45 μg) Unstable angina Stable angina p=0.017 % in-stentstenosis MACE at 30 days = 1% (TLR =1%) MACE at 6 months = 3% (TLR=3%) MACE at 12 months: 3% (TLR=3%)

  7. PC coated stents without Dexamethasone BiodivYsio TrialsLate Loss Comparisons

  8. First registry of DexametTM : SAFE - A multi-centre registrywith DexametTM & Dexamet SV - PI: Dr Pieter Stella, Utrecht, Netherlands - 1000“Real-world” patients with no specific inclusion/exclusion criteria - patients must meet the indications specified in the Directions For Use - 66 centres over 16 countries in Europe, Middle-East, Africa and Asia-Pacific - Endpoints are in-hospital, 30-day and 6-month MACE - Results available at JIM 2004

  9. DEXAMETHASONE-ELUTING STENTS IMPROVE SIGNS OF INFLAMMATION IN PATIENTS WITH UNSTABLE CORONARY SYNDROMES UNDERGOING PERCUTANEOUS CORONARY INTERVENTION G. Patti, A. D’Ambrosio, A. Carcagni’, M. Cortes-Morichetti, P. Carminati, G. Di Sciascio CAMPUS BIOMEDICO UNIVERSITY OF ROME

  10. DEXAMETHASONE-ELUTING STENTS IN UNSTABLE CORONARY SYNDROMES Methods Study design: case-control study with prospective evaluation Population: 60 pts receiving dexamethasone-eluting stent (Dexamet, N=30) or Biodivysio phosphorylcholine-coated stent (N=30) Inclusion criteria: - unstable angina (IIB-IIIB) or angina post recent (< 1 mo) myocardial infarction - angiographic evidence of “complex” coronary lesions that could be covered by a single stent Plasma levels of CRP were measured at: - 3 to 6 hours before PCI - 6, 24, 48 hours and 7 days after PCI Follow-up assessment: occurrence of MACE (myocardial infarction, death, repeat revascularization)

  11. DEXAMETHASONE-ELUTING STENTS IN UNSTABLE CORONARY SYNDROMES 18 15 * P=0.041 vs non DES ** P=0.026 vs non DES 11.4 12 9.8 9 CRP mg/l 5.2 DexametTM 6 3.6 2.8 5.8 5.4 * 3.7** 3 3.2 Non DES 2.3 0 Pre 6 h post 24 h post 48 h post 7 days post

  12. DEXAMETHASONE-ELUTING STENTS IN UNSTABLE CORONARY SYNDROMES 400 396 326 350 300 P=0.03 250 P=0.01 CRP % increase from baseline Non DES 200 152 DexametTM 150 85 93 100 32 50 0 24 h 48 h 7 days

  13. DEXAMETHASONE-ELUTING STENTS IN UNSTABLE CORONARY SYNDROMES 199 P=0.009 200 Baseline CRP <3 mg/l (N=19) 160 121 CRP percent increase from baseline 96 120 69 80 40 Baseline CRP3 mg/l (N=11) 14 40 0 24 h 48 h 7 days

  14. DEXAMETHASONE-ELUTING STENTS IN UNSTABLE CORONARY SYNDROMES Event-free survival curves 100 80 P=0.06 60 % of patients Dexamet 40 Non DES 20 0 0 1 2 3 4 6 months after stenting

  15. CONCLUSIONS • Dexamethasone-eluting stents improve early inflammatory response after PCI; this effect is more evident in pts with higher baseline CRP status • The sustained attenuation of CRP values at 7 days may suggest early plaque stabilization with dexamethasone-eluting stents in pts with unstable coronary syndromes • Clinical follow-up at 6 months shows a trend towards favorable intermediate-term results • Will steroid-eluting stents be the treatment of choice for pts with unstable coronary syndromes?

  16. RESULTS Patti, Di Sciascio et al. – Am J Cardiol P = 0.09 27 30 25 20 16% MACE during the follow-up (%) 15 10 5 5 0 1 2 3 4 Pre-procedural CRP Quartiles

  17. From morphology ................ To plaque “biology”

  18. Distribution of CRP plasma levels P=0.046 P=0.07 ³1,20 P=0.66 0,80 CRP (mg/dl) 0,40 0 Controls N=12 Stable angina N=49 Unstable angina N=57 Patti, Di Sciascio et al. – IL-1Ra: a sensitive marker of instability in patients with coronary artery disease J Thromb Thrombol 2002; 14: 139

  19. Patti, Di Sciascio et al. Prognostic value of IL-1Ra in patients undergoing percutaneous coronary intervention– Am J Cardiol 2002; 89: 372 P = 0.008 33 MACE during the follow-up (%) 0 1 2 3 4 Pre-procedural IL-1Ra Quartiles

  20. Arterial Injury Dexamethasone reduces Inflammation: PC reduces thrombus formation Arterial injury - Neutrophils - Monocytes - Macrophage - Lymphocytes Growth Factors & cytokines Thrombus Inflammation Growth Factors & cytokines Reduced Receptor activation Smooth muscle cell (SMC) Smooth muscle cell SMC receptors Signal transduction S Signal transduction Cell cycle G0 G1 G2 cell cycle M SMC Proliferation Reduces SMC Proliferation Matrix secretion Migration Migration Matrix secretion Dual mechanism of action of: PC coating and Dexamethasone

  21. THERMOGRAPHY in ACUTE CORONARY SYNDROMES • Temperature of the plaque is inversely correlated to cap thickness (Casscells W, Lancet 1996) • Pts presenting with AMI and unstable angina have significantly more temperature heterogeneity in their coronary atherosclerotic plaques than pts with stable angina (Stefanadis C, Circulation 1999). • Temperature was found to be the most powerful predictor of outcome (Stefanadis C, Circulation 2000) and to have a significant correlation with CRP levels (Stefanadis C, J Mol Cell Cardiol 2000)

  22. Inflamed plaque

  23. 300 pts, 824 specimens Di Sciascio et al. – Am Heart J 1994; 128: 419-26 Di Sciascio, Patti – Cardiologia 1999; 44: 333-9

  24. 0.002°C sensitivity

  25. Liuzzo, Maseri et al. The prognostic value of CRP and serum amyloid A protein in severe unstable angina. N Engl J Med 1994; 331: 417 % UA and CRP <0.3 mg/dl UA and CRP >0.3 mg/dl In-hosp. MACE Recurrent ischemia

  26. IL-1Ra in ischemic syndromes P=0.038 ³500 P=0.99 400 P=0.002 300 IL1-Ra (pg/ml) 200 100 0 Controls N=12 Stable angina N=49 Unstable angina N=47 Patti, Di Sciascio et al. – IL-1Ra: a sensitive marker of instability in patients with coronary artery disease J Thromb Thrombol 2002; 14: 139

  27. MACE-free survival % 100 IL-1Ra (1st quart.) 80 IL-1Ra (4th quart.) 60 40 20 0 months 0 3 6 12 18 Patti, Di Sciascio et al. Prognostic value of IL-1Ra in patients undergoing percutaneous coronary intervention– Am J Cardiol 2002; 89: 372

  28. Drug Eluting Stent Trials Late Loss (mm) (stable AP) (unstable AP) (Non-drug)

  29. Pepine CJ et al. A controlled trial of corticosteroids to prevent restenosis after coronary angioplasty. M-HEART Group – Circulation 1990; 81: 1753 • 915 patients undergoing PTCA randomized to placebo or • 1 g methylprednisolone before the procedure • PTCA success rate 87% % Restenosis Placebo Steroids

  30. Oral prednisone therapy for 45 days in pts with elevated (>0.5 mg/dl) CRP levels 72 hours post PCI Versaci et al. Immunosuppressive therapy for the prevention of restenosis after coronary Artery stent implantation (IMPRESS study) – JACC 2002; 40: 1935

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