Advances in StentTherapy for Ischaemic Heart Disease

trix LO + + + + + + + BiodiYsio Matrix HI JoMed Sorin BionsensorsConor Medsytems Igaki-Tamai Mak Heart Pharmacologic Approaches Anti-inflammatory Immunomodulators Anti-proliferative Migration inhibitors ECM-modulators Promote healing and reendothelisation Dexamethasone M-prednisolone Interferon γ-=1b Leflunomide Sirolimus (& analogs) Tacrolimus Mycophenolic acid Mizoribine Cyclosporine Tranilast Biorest QP-2, Taxol Actinomycin Methothrexate Angiopeptin Vincristine Mitomycine Statins C-myc antisense Sirolimus (& analogs) RestenASE 2-chloro- deoxyadenosine PCNA Ribozyme Batimastat Prolyl hydroxylase inhibitors Halofuginone C-proteinase inhibitors Probucol BCP671 VEGF Estradiols NO donors EPC antibodies Biorest Advanced coatings Many agents have multiple actions Mak Heart SIRIUS Analysis 3-year Clinical Outcome Sirolimus Control P-value (n=533) (n=525) Death 3.9% (21) 2.9% (15) 0.4 All myocardial infarction 4.1% (22) 4.4% (23) 0.9 Q-wave 1.3% (7) 0.6% (3) 0.3 Non-Q-wave 2.8% (15) 3.8% (20) 0.4 TLR (all) 6.8% (36) 23.2% (122) <0.0001 TVR (all) 11.6% (62) 27.2% (143) <0.0001 TVR (non-TLR) 7.1% (38) 9.3% (49) 0.2 MACE 12.6% (67) 27.4% (144) <0.0001 TVF (1° endpoint) 15.6% (83) 30.1% (158) <0.0001 Mak Heart SIRIUS Analysis 3-year Clinical Outcome Sirolimus Control P-value (n=533) (n=525) Death 3.9% (21) 2.9% (15) 0.4 All myocardial infarction 4.1% (22) 4.4% (23) 0.9 Q-wave 1.3% (7) 0.6% (3) 0.3 Non-Q-wave 2.8% (15) 3.8% (20) 0.4 TLR (all) 6.8% (36) 23.2% (122) <0.0001 TVR (all) 11.6% (62) 27.2% (143) <0.0001 TVR (non-TLR) 7.1% (38) 9.3% (49) 0.2 MACE 12.6% (67) 27.4% (144) <0.0001 TVF (1° endpoint) 15.6% (83) 30.1% (158) <0.0001 Mak Heart SIRIUS Analysis 3-year Freedom from TLR 0 90 180 270 360 450 540 630 720 70 75 80 85 90 95 100 Control (n=525) Cypher (n=533) Days since index procedure Freedom from TLR 810 900 990 1080 92.9% 76.0% P<0.001∆16.9% Mak Heart TAXUS II, IV, V, VI Group Analysis Freedom from death to 2 years 0 100 200 300 400 500 600 700 800 70 75 80 85 90 95 100 Control (n=1727) TAXUS (n=1718) Days since index procedure Percentage 97.6% 97.7% P=0.73 Mak Heart TAXUS II, IV, V, VI Group Analysis Freedom from MI to 2 years 0 100 200 300 400 500 600 700 800 70 75 80 85 90 95 100 Control (n=1727) TAXUS (n=1718) Days since index procedure Percentage 94.2% 94.3% P=0.98 Mak Heart TAXUS II, IV, V, VI Group Analysis Freedom from TLR to 2 years 0 100 200 300 400 500 600 700 800 70 75 80 85 90 95 100 Control (n=1727) TAXUS (n=1718) Days since index procedure Percentage P<0.0001 92.2% 81.6% Mak Heart TAXUS II, IV, V, VI Group Analysis Freedom from TLR, 9 months to 2 years 0 100 200 300 400 500 600 700 800 70 75 80 85 90 95 100 Control (n=1727) TAXUS (n=1718) Days since index procedure Percentage 92.2% 81.6% 94.2% 85.2% -2.3% -3.6% P=0.0075 Mak Heart Primary Endpoint: 8-month Restenosis Rate 9.6 7.0 11.1 8.3 0 2 4 6 8 10 12 In Stent In Segment P=0.32 P=0.31 Sirolimus (n=684) Paclitaxel (n=699) R e s t e n o s i s R a t e ( % ) Mak Heart 10.4 5.04.74.8 1.8 9.2 11.5 5.4 4.6 5.5 1.2 10.6 0 2 4 6 8 10 12 14 MACE Death MI NQWMI TLR TVR 8-month Clinical Event Rate P=0.41 P=0.54 Sirolimus (n=684) Paclitaxel (n=699) R e s t e n o s i s R a t e ( % ) P=0.81 P=0.99 P=0.62 P=0.50 Mak Heart 9.2 0.09 -0.07 0.14 0.31 -0.01 -0.1 -0.05 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 8-month Late Loss (mm) Sirolimus (n=897) Paclitaxel (n=852) Proximal In-stent Distal P<0.001 P<0.001P<0.001 Mak Heart Endeavor II Analysis 9-month Clinical Outcome Endeavor Driver P-value (n=582) (n=585) Death 1.2% (7) 0.5% (15) ns All myocardial infarction 2.7% (16) 4.0% (23) ns Q-wave 0.3% (2) 0.9% (5) ns Non-Q-wave 2.4% (14) 3.1% (18) ns TLR (all) 4.6% (27) 12.1% (7) <0.0001 TVR (all) 5.7% (33) 12.8% (75) <0.0001 TVR (non-TLR) 1.1% (6) 0.7% (4) ns MACE 7,4% (43) 17.4% (102) <0.0001 TVF (1° endpoint) 8.1% (47) 15.4% (90) 0.0005 Mak Heart Let’s take a closer look! I’m not sure if he is seeing it! Mak Heart Sirolimus-eluting stents Late loss correlate poorly with TLR 7.5 4.6 4.7 7 5 3.0 0 1 2 3 4 5 6 7 8 9 10 Diabetes E Sirius SES Smart Sirius C Sirius Reality TLR (%) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 Late loss (mm) in-stent late loss in-segment late loss Mak Heart Paclitaxel-eluting stents Late loss correlate poorly with TLR 3.6 4.6 6.8 8.6 5.4 3.0 0 1 2 3 4 5 6 7 8 9 10 TAXUS I TAXUS II SR TAXUS IV TAXUS VI TAXUS V Reality TLR (%) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 Late loss (mm) in-stent late loss in-segment late loss Mak Heart Late Loss: Restenosis Late Loss (mm) 1.0 0.0 0.5 0.00 1.00 2.501.500.50 2.00 Late loss <0.6mm weak predictor of restenosis Late loss >0.6 mm increasing probability of restenosis Late loss of 1.2 mm associated with a 50% chance of binary restenosis P r o b a b i l i t y f o r R e s t e n o s i s P r o b a b i l i t y f o r P r o b a b i l i t y f o r R e s t e n o s i s R e s t e n o s i s Popma J . TAXUS IV Angiographic Results 2003. Mak Heart Late Loss: TLR Late loss <0.6 mm weak predictor of TLR Late Loss (mm) 1.0 0.0 0.5 0.00 1.00 2.501.500.50 2.00 Late loss >0.6mm increasing probability of TLR P r o b a b i l i t y f o r T L R P r o b a b i l i t y f o r T L R Popma J . TAXUS IV Angiographic Results 2003. Late loss of 1.6 mm associated with a 50% chance for TLR Mak Heart Late Loss in TAXUS Trials Consistent average late loss levels: 0.30mm to 0.39mm 0.0 1.0 2.51.50.5 2.0-1.5 -1.0 -0.5 100 0 50 Late Loss (mm) P r o b a b i l i t y f o r T L R ( % ) In-stent Late Loss* TAXUS I (SR) .36mm TAXUS II (SR) .31mm TAXUS II (MR) .30mm TAXUS IV (SR) .39mm TAXUS V (SR) .33mm TAXUS VI (MR).39mm .30 .39 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 In Segment Late Loss 0.67±0.58 0.31±0.49 P<0.0001Control TAXUS Mak Heart Late Loss and Healing Low But Positive Late Loss Allows a Level of Healing 100 0.0 1.0 2.51.50.5 2.0-1.5 -1.0 -0.5 0 50 P r o b a b i l i t y f o r T L R ( % ) Late Loss (mm) Mak Heart Late Loss and Healing Lumen Neointima • The Express2™ Stent strut thickness is 0.0052”, which converts to 0.13mm • This is well within the amount of late loss of a bare metal stent, suggesting complete stent strut coverage MLD follow up 0.50mm 0.13mm0.0052”= 0.13mm Mak Heart Late Loss and Healing Lumen Neointima • The Express2™ Stent strut thickness is 0.0052”, which converts to 0.13mm • Based on the TAXUS trials late loss values, neointima would be sufficient to completely cover the stent struts. MLD follow up 0.130mm0.0052”= 0.13mm 0.165- 0.195mm Mak Heart Late Loss: a Measure of Healing How much late loss is needed to cover a TAXUS™ Express2 stent strut Late loss = ~.3mm .15 mm .15 mm = 0.0052”= 0.13mm ~0.02mm covering stent strut TAXUSTM Express2 stent strut The TAXUSTM Express2 coronary stent system consistently provides ~0.15mm of neointima which may allow for coverage of the stent strut. Image courtesy of Dr. Robert Schwartz Mak Heart Late Loss and Healing Negative late loss indicates a lack of neointima to cover stent struts 100 0.0 1.0 2.51.50.5 2.0-1.5 -1.0 -0.5 0 50 P r o b a b i l i t y f o r T L R ( % ) Late Loss (mm) Mak Heart Late Loss Below a Certain Level May Not Be A Strong Predictor of TLR In-stent Late loss levels <0.6mm may not predict TLR Late Loss and TLR Mak Heart Late Stent Thrombosis 0 20 40 60 80 100 0 30 60 90 120 150 180 210 240 Follow-up (days) Culmulative percentage N=1191 Subacute stent thrombosis rate = 0.92% Late stent thrombosis rate = 0.76% mean time = 109 days (39-211 days) Bare Metal Stent Wang F et al. Cathet Cardiovasc Intervent 2002. Mak Heart Stent Thrombosis Bare Metal Stent Mak KH et al. J Am Coll Cardiol 1996. Mak Heart TAXUS II, IV, V, VI Group Analysis Stent Thrombosis 0 100 200 300 400 500 600 700 800 94 95 96 97 98 99 100 Control (n=1727) TAXUS (n=1718) Days since index procedure Percentage 99.3% 98.8% P=0.44 Mak Heart Stent Thrombosis 0.4 0.6 1.8 1.6 P=0.0723 P=0.0196 Sirolimus (n=684) Paclitaxel (n=699) P r o p o r t i o n o f p a t i e n t s ( % ) 0 1.0 2.0 0.2 0.4 0.6 0.8 1.2 1.4 1.6 1.8 Intention-to-treat Actually treated There is no late stent thrombosis in either group! 1 patient randomized to Sirolimus-eluting stent received a paclitaxel-eluting stent. Mak Heart Late Stent Thrombosis Endeavor II No late stent thrombosis in the either stent arm. Discharge – 30 DaysIn-Hospital 181 – 284 Days31 days – 180 Days P=NS 0.5% (n=3) Stent Thrombosis (%) Endeavor Stent (n=582) Driver (n=585) 30 Days 9 Months Total No Late Thrombosis0.3 0.2 0.3 0.9 (Late Thrombosis = 31 – 284 Days) 1.2% (n=7) Mak Heart Stent Thrombosis Drug Eluting Stent Stent thrombosis (n=15) Matched control (n=45) P value IVUS analyses Reference (most normal looking segment) Lumen CSA (mm2) 6.8±2.2 7.4±2.0 0.3 EEM CSA (mm2) 12.4±4.1 12.4±3.4 1.0 Reference (minimum lumen segment) Lumen CSA (mm2) 3.9±1.6 5.3±1.7 0.007 EEM CSA (mm2) 10.8±4.2 9.9±3.2 0.4 Plaque burden (%) 62±13 46±9 <0.001 Significant residual stensosis 10 (67%) 4 (9%) <0.001 Stent segment Minimum stent CSA (mm) 4.3±1.6 6.2±1.9 <0.001 Stent expansion 0.65±0.18 0.85±0.14 <0.001 Dissection 0 (0%) 3 (7%) 0.3 Malapposition 2 (13%) 7 (16%) 0.8 Plaque protrusion 0 (0%) 1 (2%) 0.6 Multiple variable analysis: stent expansion (p=0.03) and significant RD stenosis (p=0.02) Other variables: stent length, malapposition, MSA, dissection, protrusion Fujii K, et al. J Am Coll Cardiol 2005. Mak Heart Mechanisms of Late Stent Thrombosis •Compliance with long-term dual antiplatelet therapy •Resistance of antithrombotic therapy •Hypersensitivity reaction •Fever, breathing difficulties, rash, itch hives, BP changes •Metal, polymers, drugs, contaminants Mak Heart Mechanisms of Late Stent Thrombosis Across major branch High power view Farb A et al. Circulation 2003. Mak Heart Mechanisms of Late Stent Thrombosis Radiation Necrotic core Farb A et al. Circulation 2003. Mak Heart Conclusions •Sirolimus- and Paclitaxel-eluting stent have similar clinical efficacy •Differences in late loss may not be clinically significant •Although infrequent, late stent thrombosis remains a key concern • Innovations in material science, advances in cell replacement technology, genomic and proteomic medicine will further enhance the treatment of patients with ischaemic heart disease ._.