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Microsoft PowerPoint - Cardiology Conference (Grube)

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Microsoft PowerPoint - Cardiology Conference (Grube)

  1. 1. Biosensors International Cardiology Conference August 3rd, 2005 The Evolution of Drug-Eluting Stents Eberhard Grube MD FACC, FSCAI Heart Center Siegburg, Siegburg, Germany Stanford University, School of Medicine, CA, USA Siegburg / Stanford
  2. 2. U.S. Penetration of DES 75% (2004) 87 83 77 28% (2003) 56 percent 47 41 19 0 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2003 2004 Cypher as of 4/03 and Taxus as of 3/04 Siegburg / Stanford
  3. 3. Market penetration of DES 03/04
  4. 4. Bare Metal Stents =
  5. 5. Drug-Eluting Stents =
  6. 6. Suppression of intimal proliferation Bare metal stent versus Drug Eluting Stent BMS DES Siegburg / Stanford
  7. 7. How to Assess Efficacy Intimal Hyperplasia Angiographic Surrogate Late Lumen Loss Clinical Surrogate Target Lesion Revascularization Siegburg / Stanford
  8. 8. SIRIUS Results TLR: Subset Summary # events prevented per Sirolimus Control P-value 1,000 patients Overall 4.1 16.6 0.0001 124 Male 4.4 16.6 0.0001 122 Female 3.4 16.5 0.0007 130 Diabetes 6.9 22.3 0.0006 154 No Diabetes 3.2 14.3 0.0001 111 LAD 5.1 19.8 0.0001 147 Non-LAD 3.4 14.3 0.0001 109 Small Vessel (<2.75) 6.3 18.7 0.0001 125 Large Vessel 1.9 14.8 0.0001 128 Short Lesion 3.2 16.1 0.0001 129 Long Lesion (>13.5) 5.2 17.4 0.0001 122 Overlap 4.5 17.7 0.0003 131 No Overlap 3.9 16.1 0.0001 121 Hazards Ratio 95% CI 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.9 0.8 0.7 Sirolimus better Siegburg / Stanford
  9. 9. TAXUS IV Results TLR: Subset Summary RR TAXUS Control P All 0.27 3.0 11.3 <0.0001 Non-diabetic 0.24 2.4 9.8 <0.0001 Diabetic, oral meds 0.28 4.8 17.4 0.004 Diabetic, insulin 0.45 5.9 13.0 0.32 LAD 0.25 3.4 13.4 <0.0001 Non-LAD 0.29 2.8 9.7 0.0001 RVD ≤2.5 mm 0.22 3.4 15.4 <0.0001 RVD >2.5-3.0 mm 0.28 3.1 11.2 0.0004 RVD >3.0 mm 0.38 2.5 6.7 0.57 Lsn length <10 mm 0.35 3.3 9.3 0.01 Lsn length 10-20 mm 0.27 2.8 10.5 0.0001 Lsn length >20 mm 0.18 3.3 18.6 0.0009 0 0.5 1.0 1.5 RR [95% CI] Siegburg / Stanford
  10. 10. The Winners Sirolimus Paclitaxel Ravel Sirius 1. 1. FIM (45) FIM (45) 22. SICTO (25) 2. Sirolimus PK (19) 22. SICTO (25) 2. Sirolimus PK (19) 23. 23. SVG-Feas (150) SVG-Feas (150) 3. 3. SECURE (252) SECURE (252) 24. DIRECT (220) 4. RAVEL (238) 24. DIRECT (220) 4. RAVEL (238) 25. 25. DECODE US (100) DECODE US (100) 5. 5. SIRIUS (1058) SIRIUS (1058) 26. DECODE (100) 6. China (41) 26. DECODE (100) 6. China (41) 27. 27. BRIDGE (1000) BRIDGE (1000) 7. 7. Taiwan (50) Taiwan (50) 28. PORTO II& II (300) 28. PORTO & II (300) 8. 8. 9. 9. Argentina (20) Argentina (20) BIF (86) BIF (86) 29. 29. SCORPIUS (190) SCORPIUS (190) TAXUS 30. 30. Cypher-SMART (256) Cypher-SMART (256) 10. 10. E-SIRIUS (353) E-SIRIUS (353) 31. EVASTENT (2000) 11. C-SIRIUS (100) 31. EVASTENT (2000) 11. C-SIRIUS (100) 32. 32. TYPHOON (700) TYPHOON (700) 12. 12. ISR-Feas (41) ISR-Feas (41) 33. DESSERT (250) 13. US ISR-Feas (8) 33. DESSERT (250) 13. US ISR-Feas (8) 34. 34. SVELTE (101) SVELTE (101) 14. 14. TROPICAL (160) TROPICAL (160) 35. REDOX (60) 15. SISR (400) 35. REDOX (60) 15. SISR (400) 36. 36. 3D (44) 3D (44) 16. 16. ISR-Barragan (23) ISR-Barragan (23) 37. SC US (tbd) 17. ARTS II (600) 37. SC US (tbd) 17. ARTS II (600) 38. 38. SC EU (tbd) SC EU (tbd) 18. 18. FREEDOM (2600) FREEDOM (2600) 39. SVS-Feas (45) 19. 2.25 mm (100) 39. SVS-Feas (45) 19. 2.25 mm (100) 40. 40. SIROCCO II(36) SIROCCO (36) 20. 20. 4.00 mm (100) 4.00 mm (100) 41. SIROCCO II (57) 21. ATLAS (100) 41. SIROCCO II (57) 21. ATLAS (100) 42. 42. GREAT (101) GREAT (101) Siegburg / Stanford
  11. 11. CYPHER Trials - Clinical Events All Events (to 9 months) Sirolimus (n=1204) Control (n=870) P<0.0001 P<0.0001 19,2% 17,1% % 80% 70% 5,7% 3,5% TLR TVR Siegburg / Stanford
  12. 12. TAXUS II + IV + VI Meta-analysis (n=2,289) 12 Month TLR and TVR Control TAXUS 12 Month Events (%) RR=0.31 [0.24,0.42], P<0.0001 RR=0.44 [0.34,0.55], P<0.0001 17.5% 15.6% 7.6% 4.9% N=1,148 N=1,141 N=1,148 N=1,141 TLR TVR Siegburg / Stanford
  13. 13. TAXUS metaanalysis TAXUS in diabetic patients Control TAXUS P<0.0001 P<0.0001 P<0.0001 18.6 16.9 14.8 TLR (%) 7.3 5.8 5.8 all patients Diabetics Insulin req Siegburg / Stanford
  14. 14. Recommendation DES I IIa IIb III Cypher™ TAXUS™ RAVEL TAXUS-I SIRIUS TAXUS-II E-SIRIUS TAXUS-IV C-SIRIUS TAXUS-VI De-Novo Läsionen RVD 2.5 – 3.75 mm, ≤30 mm in length Siegburg / Stanford
  15. 15. DES - 2005 Need for more Evidence ? Long Lesions Small vessels ISR lesions (esp. ultra-diffuse and s/p VBT) Bifurcations (esp. ostial sidebranch) LM disease (esp. distal bifurcation) SVGs CTOs AMI Multivessel Disease …
  16. 16. TAXUS VI Restenosis benefit independent of classic risk factors Control TAXUS MR P<0.0001 P<0.0001 P=0.0015 P<0.0001 Binary restenosis in-stent 50.0 45.5 40.4 40.5 (%) 82 % 86 % 80 % 89 % 7.3 7.0 8.1 4.8 23/57 4/55 17/34 3/43 17/42 3/37 25/55 3/62 Small vessels Long lesions Diabetics Overlapping <2.5mm ≥26mm stents Siegburg / Stanford
  17. 17. SES vs. Historical Gamma VBT TROPICAL Clinical Outcome at 180 Days Non- Hierarchical Event Rate (%) 30 TROPICAL 18.8 GAMMA I/II 25 20 n= 162 SES P<0.001 P<0.001 14 262 VBT 15 P=0.004 9.4 P=0.080 10 P=0.490 3.7 3.9 5 2.5 0.6 2.0 1.8 0.6 0 MACE Death MI Clinically Stent driven TLR thrombosis Neumann et al., PCR 2004 Siegburg / Stanford
  18. 18. CYPHER in CTO’s RESEARCH Registry Siegburg / Stanford
  19. 19. ISAR – DESIRE CYPHER vs. TAXUS Siegburg / Stanford
  20. 20. ISAR – DESIRE CYPHER vs. TAXUS Siegburg / Stanford
  21. 21. HORIZONS AMI Study - 3400 randomized patients undergoing primary PCI - Anti-thrombotic Hypothesis: Use of bivalirudin + bail-out therapy IIb/IIIa will reduce the composite rate of Randomize 1:1 death, reinfarction, TVR, disabling stroke and major bleeding at 30-days UFH + Bivalirudin IIb/IIIa + inhibitor bail-out IIb/IIIa Target vessel Hypothesis: Use of the TAXUS PTx- stenting eluting stent will safely reduce the 1-year Randomize 1:3 rate of ischemia-driven TVR Bare metal TAXUS Express™ stent stent PI: Gregg W. Stone Siegburg / Stanford
  22. 22. FREEDOM Trial Multivessel Sirolimus Stenting vs. CABG in Diabetics Eligibility: DM patients with MV-CAD eligible for stent or surgery Exclude: Patients with acute MI and/or cardiogenic shock 2300 pts Randomized 1:1 CABG MV-sirolimus stenting With or without CPB With abciximab All concomitant Meds shown to be beneficial are encouraged, including: Plavix, ACE inhibitors, b-blockers, statins, etc. 1o Endpoint: 5-year mortality 5-year MACE 2o Endpoint : MACE/stroke at 12 months
  23. 23. SYNTAX Studie TAXUS vs. CABG De novo disease acceptable for revascularization N=4500 Left main disease OR 3-vessel disease R TAXUS PCI CABG Primary endpoint – MACCE •All cause death •MI •Cerebrovascular events •Repeat revascularization Siegburg / Stanford
  24. 24. Need for Improvements? urse.... O f co
  25. 25. Safety Cost Efficacy Siegburg / Stanford
  26. 26. Drug Eluting Stents
  27. 27. Safety Cost Efficacy Siegburg / Stanford
  28. 28. DES - Animal Studies What do the “bad things” look like… • Excessive thrombus • Severe inflammatory • Incomplete endothelialization response • Persistent fibrin + • Medial necrosis inflammation • Malapposition
  29. 29. REALITY Stent Thrombosis (Acute + Subacute) CYPHER® TAXUS™ 2.5 P=0.0723 P=0.0196 1.8 2.0 1.6 % of 1.5 Patients 1.0 0.6 0.4 0.5 4 11 3 12 0.0 Intention-to-Treat Actually-Treated* Per protocol analysis: CYPHER® 0.4, TAXUS™ 1.7: P=0.033 TAXUS™ * 1 patient randomized to CYPHER® actually treated with a TAXUS™ stent TAXUS™ Siegburg / Stanford
  30. 30. Stent Thrombosis after DES 2229 patients after successful DES implantation SES PES 1062 pts 1167 pts 2272 stents 2223 stents SAT SAT P=0.5 4 (0.4%) 10 (0.9%) LST LST P=0.3 5 (0.5%) 10 (0.9%) 10.2 ± 4.4 m 9.3 ± 5.6 months 7.9 ± 3.6 m Total SES Total DES 29/2229 (1.3%) Total PES 9 (0.9%) P=0.09 20 (1.7%) Siegburg / Stanford
  31. 31. Acute stent thrombosis: Up to 30 days Range in each program Limus Paclitaxel MILESTONE SIRIUS II E-SIRIUS ARRIVE C-SIRIUS WISDOM SIRTAX SIRTAX REALITY REALITY RESEARCH TAXUS II SR /TSEARCH MILAN DES TAXUS IV ENDEAVOR TAXUS V II TAXUS VI Observed 2.0 0.2 0.2 1.6 Observed Range Range 4.0 2.0 0 2.0 4.0 Stent Thrombosis (%) Siegburg / Stanford
  32. 32. Single TLR in TAXUS-SR at Day 522 61 y.o. male with prior MI and hypercholesterolemia Baseline Post Stent Thrombosis 2 year • Mid RCA • RVD:4 mm • Pre-dilation Day 522 • LL: 4 mm • 1 SS: 3.5 x 15mm • Non Q-wave MI • % DS: 75% Day 738 • No complications • Thrombectomy, PTCA • 6mo FU • On ASA, off • Asymptomatic • Asymptomatic clopidogrel • No restenosis Siegburg / Stanford
  33. 33. Stent thrombosis Siegburg / Stanford
  34. 34. TAXUS IV Stent Thrombosis In-hospital Discharge - 30 days 31 days - 1 year* 1-2 years TAXUS 1.1% 0,3 0,3 0,5 (n=625) (n=7) Control 0.8% 0,3 0,3 0,2 (n=613) (n=5) P=0.77 0 0,5 1 1,5 Stent thrombosis, % * All within 1-6 months Siegburg / Stanford
  35. 35. Safety Cost Efficacy Siegburg / Stanford
  36. 36. Restenosis of ABT-578-eluting stent (OCT) 43.8% 53.8% 2.1 mm2 3.5 mm2 ENDEAVOR-II 8 mths follow-up 4.8 mm2 6.5 mm2 16.4% 25.5% 1.0 mm2 1.4 mm2 Stent A Lumen A LA / SA 6.1 mm2 5.5 mm2 Stent overlap area Siegburg / Stanford
  37. 37. TAXUS V 9-Month Angiography 2.25 mm Stent Subgroup (n=203) Control (n=85) TAXUS (n=93) p<0.0001 p=0.004 p=0.007 p=0.01 49,4 0.90 44,7 ±0.63 0.61 31,2 0.49 ±0.59 24,7 ±0.61 0.36 ±0.53 85 93 85 93 38/85 23/93 42/85 29/93 In-stent In-Segment In-stent In-Segment Late Loss Binary Restenosis Siegburg / Stanford
  38. 38. Various Approaches to Improve Drug Eluting Stents Better Stent design Better Better Pharmacologic Drug- Drug- Drug carrier agent vehicle Eluting Stent Siegburg / Stanford
  39. 39. BioMatrix™ Stent Components (Biosensors International Group) S-Stent™ (stainless steel) • Quadrature-link design; increased flexibility • Excellent scaffolding • Reduced turbulence and wall injury PLA Polymer • Uniform thickness; bioresorbable • Simultaneously releases drug and polymer Stent • Controlled biodegradability • High drug-carrying capacity • Minimizes polymer weight to minimize inflammation; polymer absorbed into tissue Biolimus A9™ (rapamycin derivative) • Powerful immunosuppressant, anti-inflammatory • Prevents smooth muscle cell proliferation • More lipophilic; faster cellular absorption Siegburg / Stanford
  40. 40. STEALTH I: Clinical Follow-up 120 Patients Control BMS S-Stent BioMatrix n = 40 n = 80 6-Month Follow-up: 95% (n=114) 12-Month Follow-up: 99.2% (n=119) Siegburg / Stanford
  41. 41. STEALTH I: Hierarchical MACE at 6 and12 Months Cumulative 6 Months 12 Months* RESULTS S-Stent BioMatrix S-Stent BioMatrix MACE 2.5% 3.8% 5.0% 6.3% Death** 0.0% 0.0% 2.5% 1.3% Q Wave MI 0.0% 1.3% 0.0% 1.3% Non-Q Wave MI 2.5% 1.3% 2.5% 1.3% TLR-CABG 0.0% 0.0% 0.0% 1.3% TLR-PTCA 0.0% 1.3% 0.0% 1.3% *Not adjudicated **Death events were noncardiac: 1 traffic accident (S-Stent); 1 acute leukemia (BioMatrix) Siegburg / Stanford
  42. 42. Biolimus-eluting stent STEALTH-1 12 mths follow-up Siegburg / Stanford
  43. 43. STEALTH I: Late Loss—Edge Results 0,80 P=0.23 P<0.001 P=0.73 P=0.004 0.74 65% 0,60 69% 20% Late Loss 50% 0,40 0.40 0.14 0,20 0.26 0.10 0.08 0.17 0.14 0.10 0,00 Proximal In-Stent Distal In- Segment Control BMS Biolimus A9 In-segment Siegburg / Stanford
  44. 44. Comparison of Neointimal Volume 35,0 30,0 25,0 Taxol family Limus family 20,0 No Polymer % 32,0 Polymer 15,0 10,0 16,7 Polymer 12,8 12,2 5,0 7,9 7,2 3,1 2,9 2,6 1,5 1,1 1,0 0,0 TA gh FU IUS TA IV I TA II II PE ow FU TE SV I L S ST E 1 S H VE BM S RE Hi S XU EL LT L XU R R XU RA CT TU TU SI CT EA PE AS AS Courtesy Shimada, Honda, Hassan, Fitzgerald Siegburg / Stanford
  45. 45. Conclusions DES are highly efficient in prevention of restenosis; this has been demonstrated by the largest body of evidence ever collected in the history of device evaluation More data are coming up soon, which will expand the official recommendations for DES use; however there is still need for further investigations in specific subgroups (SVG, etc) DES are safe, but continuing surveillance is recommended to monitor the unknown long-term effects of this young technology New DES will improve both safety and efficacy of this revolutionary treatment concept Siegburg / Stanford
  46. 46. Siegburg / Stanford
  47. 47. Thank you Siegburg / Stanford
  48. 48. Stent thrombosis in BMS Siegburg / Stanford
  49. 49. Stent thrombosis in BMS Siegburg / Stanford

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