Drug eluting stents. Where are we now and what can we expect in 2003? Tony Gershlick Leicester

Transcription

1 Drug eluting stents Where are we now and what can we expect in 2003? Tony Gershlick Leicester

2 Trials Real World

3 What we need i. Prevent restenosis cost effective Either : - Treat all at equivalent cost 450) - Select those at higher risk - Treat those who develop ISR ii. Trials to reflect the patients undergoing PCI iii. Trials to continue to show benefit ( o late adverse events ) iv. N.I.C.E.

4 All or only in higher risk?

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6 68 yr non-insulin dependant diabetic

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8 Bifurcations?

9 Are the DES trials moving with the need? trial update trial evaluation what is new?

10 PACLITAXEL TLR 4.6% versus 12% (<0.05)

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13 Non polymer Guidant Achieve stent paclitaxel in ELUTES dose

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15 In segment BR TVF 20% % C treated C treated

16 GIUDANT / Cook paclitaxel

17 DES Trials and real life 1 Single Lesion < 25 mm Plus complicating factor DELIVER 2 Trial * CTO, Bifurcation, ISR 2 single lesions < 25 mm de novo or * 1 long lesion > 25 mm

18 PACLITAXEL DELIVER II Lesion characteristics(n = 500) Intended treatment One <25mm lesion with complicating factor * 47% Two <25mm lesions 26% One very long lesion (> 25 mm) 27% In-stent restenosis (25%) Bifurcations (28%) Chronic total/sub-total occlusions Death 3 (0.6%) TLR (PCI) 2 (0.4%) TLR (CABG) None Q-wave MI 3 (0.6%) Non Q-wave MI 7 (1.4%) Total 15 (3.0%) (19%)

19 TAXUS III In-Stent Restenosis Registry 28 out of 30 patients available for follow-up Preliminary Results 30-day 6 month MI (Q & non-q-wave) 3.6% 3.6% TVR (non-target lesion) 0% 0% TLR 0% 21.4% CABG 0% 3.6% Death 0% 0% Stent Thrombosis 0% 0% MACE 3.6% 28.6% Note: These results apply to this study only and are not necessarily representative. Caution: Investigational device: Limited by federal law to investigational use. Not available for sale in the US.

20 II

21 TAXUS IV To demonstrate safety and performance of TAXUS Express SR compared to uncoated express control TAXUS V Prospective randomised double blinded 80 U.S. Sites Anticipated Start Q Slow Release Formulation 6 Sites in US 1326 patients presenting with de novo lesions (10 to 28mm) De novo arm Randomisation was stratified by treated diabetes and vessel 1,000 diameter Patients In Stent Restenosis arm mm Lesion Lengths 500 Patients Primary endpoint - 9 months TVR rate TAXUS Stent versus Brachytherapy Stents: mm, Lengths: 8-32 mm Multiple Stents Allowed Recruitment complete currently in follow up phase. TAXUS V

22 TAXUS VI European Study designed evaluate safety and efficacy of TAXUS MR formulation (1mcg/mm2) De Novo lesions vessel diameter >2.5mm to <3.75mm Lesion Length >18mm and <40mm 448 patients randomised in 2 groups Primary endpoint TVR at 6 months Patients will be followed up for 5 years Enrollment commenced June 2002 will close Jan 2

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24 Non polymer dead in the water?? Lesion/patient risk & stent risk Await DELIVER 2? TAXUS to date some reflection of real life but on-going real test - % events in control group (poor stent, mix of risks) - overall (in-segment effect)

25 Mean lesion length 14.4mm SIROLIMUS

26 SIRUS how like real life was it?? Mean Lesion length Stented length CYPHER (%) (n=533) 14.4 ± ± 6.7 Control (%) (n=525) 14.4 ± ± 5.7 Diabetes Mellitus AHA/ACC A B B C

27 CYPHER (%) Control (%) Diameter > 2 stents Mean stents per patient (n) 1.4 ± ± 0.6 Patients with overlapping stents

28 SIRIUS - Diabetic sub-group Restenosis CYPHER n=131 Control n=148 In-stent < In-segment < TLR (%) < MACE (%) < P

29 SIRIUS: TLR Events Sirolimus Control P-value Overall Male Female Diabetes No Diabetes LAD Non-LAD Small Vessel (<2.75) Large Vessel Short Lesion Long Lesion (>13.5) Overlap No Overlap Hazards Ratio 95% CI CYPHER better

30 BIFURCATION Main Branch (N = 63) DES + DES Side Branch (N = 65) Main Branch (N = 22) DES + PTCA Side Branch (N = 22) Late Loss: In-lesion (mm) Binary Restenosis N/A in-stent % Binary Restenosis: In-lesion (%) % Pts with at least one Restenosis (MB or SB) Overall Stent Thrombosis rate was 3.6%

31 SIROLIMUS E-SIRIUS 250 patients De novo single vessel,15mm- 35mm long, mm diameter : reporting Q4/ACC RESOLVE ISR ISR VBT versus DES UK Europe FREEDOM trial: Diabetic MVD randomised - Cypher or CABG Cypher Registry real life cases Web based (2680) Start.. Spring 03

32 What else is happening??

33 Conor Stent: Drug delivery from large, discrete, non-deforming reservoirs Ductile Hinges Allow struts to open Without deformation

34 Cap Layer Drug Layer Barrier Layer The Conor Stent releases all of the stent contents in approximately 2 weeks invitro. The TAXUS stent releases about 10% of total loading in 10 days (about 10 ug), the remaining 90% remains on the stent permanently. Cumulative Percent 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Release of Paclitaxel Time (days)

35 Porcine Stent Injury Study PACLITAXEL 30 DAY QCA Late Loss mm Clear dose response All p<0.05 vs. metal d 0 METAL POLYMER 16 ug FR 64 ug FR 64 ug SR 180 ug SR 30d Proximal LAD metal Proximal LAD 16 ug

36 SCEPTER Study of Controlled Elution of Paclitaxel for The Elimination of Restenosis Spring two doses 15 ug and 75 ug cf bare metal Connor

37 Rapamycin analogues

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41 Why? I. Commercial 2. Alter potency.. Modifying affinity for binding proteins 3. Modify physical properties * Lipophilic, tissue penetration, residence time * Stability * Release kinetics 4. Alter metabolic elimination 5. Overcome edge effect 6. Higher risk populations

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43 Tacrolimus

44 Cyclosporin Tacrolimus Sirolimus Binding protein: Cyclophilin FKBP 12 Effector protein: Calcineurin TOR Actions: Blocks T-cell activation No effect on smooth muscle Toxic to kidneys Blocks T-cell proliferation (anti-inflammatory effect) Blocks SMC proliferation

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47 Sirolimus R=H Everolimus R= CH 2 CH 2 OH

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49 Everolimus and Guidant programme Biosensors Int FUTURE 1

50 Preliminary data 16 patients!! FUTURE 1 RAVEL TAXUS Late loss 0.08 mm mm 0.31 mm control 0.84 mm % Diameter stenosis 3% control 39% Binary restenosis 0% control 20% IVUS % intimal suppression 88% 95% 65% No edge effect

51 Everolimus Drug Eluting Stent - GUIDANT SS + EVAL Everolimus 2 Everolimus 3 Pig at 28 Days Everolimus 3 = Everolimus 2 =

52 % Stenosis Percent stenosis at 28 and 90 Days Following Everolimus-Eluting Stent Implanation in Pig Coronary Arteries % 18% control Everolimus days 90 days Everolimus mg +104 mg top coat Everolimus mg +169 mg top coat

53 Everolimus and Guidant programme VISION E studies SPIRIT 1 (etc etc) dosing, CE marking US pivotal n.b. no UK!!! (regulatory)

54 Similarities of ABT-578 and Rapamycin Structural Domains Binding to FKBP-12 and mtor H O 4 2 O O O Rapamycin O N H O O O O O O O H O N N N N 4 2 O O O ABT-578 O N H O O O O O O O H O FKBP Binding Domain mtor Effector Domain MEDTRONIC

55 % Inhibition In Vitro Inhibition of Human Coronary Artery Smooth Muscle Cell Proliferation 100 A ABT-578 Rapamycin Concentration (nm)

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57 A Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Coated Driver Coronary Stent in De Novo Native Coronary Artery Lesions Approx 70 Sites in Europe, Canada, Asian Pacific, Australia Approx 1100 subjects Double blind, two arm, randomized controlled trial of ABT-578 coated Driver stent vs. bare Driver stent Follow-up at 30 days, 6, 9, 12 months, yearly to 5 years First 400 (approx) subjects enrolled also participate in subset with angiographic follow-up at 8 months IVUS sub-study at selected centers, IVUS at index and 8 months Initial Enrolment: March 2003

58 Everolimus plus Sirolimus R=H Everolimus R= CH 2 CH 2 OH Everolimus plus R= CH 2 CH 2 R

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63 Future developments

64 (mm) Local Simvastatin Delivery After Vascular Injury * Neointimal P Thickness = 0.07 P<0.05 vs CON 14 days 28 days P = or more drugs Anti-restenotic Anti-thrombotic * * 20 0 Simvastatin Rapamycin Simvastatin Rapamycin Control

65 Paclitaxel Small vessels, edge effect 40ug /balloon. Vessel wall

66 Trials 2003 RAPAMYCIN ANALOGUES JOMED TACROLIMUS GUIDANT EVEROLIMUS MEDTRONIC ABT 578 TAXUS II +, SIRIUS, DELIVER 2 EVEROLIMUS PLUS MPA Real World

67 D.E.S. (current or improved ) are likely to impact on restenosis in the real world the Limus effect Lyticitis Qs. Can we afford them? Will N.I.C.E approve them?