The SYNTAX-LE MANS Study Synergy Between PCI with TAXUS Express and Cardiac Surgery: Late (15-month) Left Main Angiographic Substudy A. Pieter Kappetein, MD, PhD Erasmus MC, Rotterdam, NL SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 1
Patient Profiling Local Heart team (surgeon & interventional cardiologist) assessed each patient in regards to:! Patient s operative risk (EuroSCORE & Parsonnet score)! Coronary lesion complexity (newly developed SYNTAX score)! Goal: SYNTAX score to provide guidance on optimal revascularization strategies for patients with high-risk lesions Sianos et al, EuroIntervention 25;1:219-227 Valgimigli et al, Am J Cardiol 27;99:172-181 Serruys et al, EuroIntervention 27;3:45-459 Calcification Thrombus Dominance Bifurcation Number & location of lesions SYNTAX score Tortuosity Left Main 3 Vessel Total Occlusion EuroInterv 25;1:219-227 BARI classification of coronary segments Leaman score, Circ 1981;63:285-299 Lesions classification ACC/AHA, Circ 21;13:319-341 Bifurcation classification, CCI 2;49:274-283 CTO classification, J Am Coll Cardiol 1997;3:649-656 SYNTAX Primary Endpoint Serruys TCT 14 October 28 Slide 2
There is 3-vessel disease and 3-vessel disease LCx 7-9% Patient 1 LM 99% Patient 2 LAD 99% LAD 7-9% LCx 1% SYNTAX SCORE 21 SYNTAX SCORE 55 Patient 1 Patient 2 RCA2 7-9% RCA3 7-9% RCA 1% SYNTAX Primary Endpoint Serruys TCT 14 October 28 Slide 3
SYNTAX Score Distribution by Cohort and Treatment Group 25 CABG RCT CABG Registry PCI RCT PCI Registry % of Patients 2 15 1 5 6 12 18 24 3 36 42 48 54 6 66 72 78 84 SYNTAX Score SYNTAX Primary Endpoint Serruys TCT 14 October 28 Slide 4
SYNTAX Trial Design 62 EU Sites + 23 US Sites CABG n=897 3VD 66.3% Heart Team (surgeon & interventionalist) All Pts with de novo 3VD and/or LM disease Total enrollment (n=4,337) N=375 Amenable for both Amenable for only one treatment options! Treatment preference (9.4%) treatment approach Randomized Arms! Referring LM MD and or Diabetes pts. refused LM and Diabetes informed consent (7.%)! Inclusion/exclusion (4.7%)! Withdrew before consent (4.3%) n=18 n= 1275! Other (1.8%) Randomized Arms LM 33.7% TAXUS * n=93! n=18 Medical treatment (1.2%) vs vs 3VD 65.4% Stratification: Stratification: 25 75 w/ f/u 71% enrolled (n=3,75) LM 34.6% 5 CABG n=177 5yr f/u n=649 Two Registry Arms Two Registry Arms no f/u n=428 PCI n=198 all captured w/ follow up * Taxus Express
Patient Characteristics Notable Differences CABG RCT + Registry CABG RCT N=897 CABG Reg N=644 Age, mean±sd (y) 65. ± 9.8 65.7 ± 9.4 Male, % 78.9 8.7 SYNTAX score, mean±sd 29.1 ± 11.4 37.8 ± 13.3 Diabetes, % 28.5 29.7 Hypertension, % 77. 73.5 Hyperlipidemia, % 77.2 76.4 Current smoker, % 22. 21.9 Prior MI, % 33.8 33.5 Unstable angina, % 28. 21.6 Add. EuroSCORE, mean±sd 3.8 ± 4.4 3.9 ± 2.7 Total Parsonnet score, mean±sd 8.4 ± 6.8 9. ± 7.1 * For descriptive purposes only; no statistical comparisons done
Overall MACCE to 12 Months CABG Registry Cumulative Event Rate (%) 3 2 8.8% 1 6 12 Months Since Allocation Event Rate ± 1.5 SE Per-protocol population
Patient Characteristics Notable Differences PCI RCT + Registry TAXUS RCT n=93 PCI Reg n=192 Age, mean±sd (y) 65.2 ± 9.7 71.2 ± 1 Male, % 76.4 7.3 SYNTAX score 28.4 ± 11.5 31.6 ± 12.3 Diabetes, % 28.2 35.4 Hyperlipidemia, % 78.7 67.5 Current smoker, % 18.5 11.2 Prior MI, % 31.9 4.4 Unstable angina, % 28.9 38. Add. EuroSCORE, mean±sd 3.8 ± 2.6 5.8 ± 3.1 Total Parsonnet score, mean ±SD 8.5 ± 7. 14.4 ± 9.5 * For descriptive purposes only; no statistical comparisons done
Overall MACCE to 12 Months PCI Registry Cumulative Event Rate (%) 3 2.4% 2 1 6 12 Months Since Allocation Event Rate ± 1.5 SE Per-protocol population
SYNTAX Trial Patient Distribution CABG registry (N=177) Enrolled SYNTAX trial patients (N=375) Randomized (N=18) PCI registry (N=198) PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 1
Patient Characteristics (II) Randomized Cohort Patient-based CABG N=897 TAXUS N=93 P value Total SYNTAX Score 29.1 ± 11.4 28.4 ± 11.5.19 Diffuse disease or small vessels, % 1.7 11.3.69 No. lesions, mean ± SD 4.4 ± 1.8 4.3 ± 1.8.44 3VD only, % 66.3 65.4.7 Left main, any, % 33.7 34.6.7 Left Main only 3.1 3.8.46 Left Main + 1 vessel 5.1 5.4.78 Left Main + 2 vessel 12. 11.5.72 Left Main + 3 vessel 13.5 13.9.78 Total occlusion, % 22.2 24.2.33 Bifurcation, % 73.3 72.4.67 Trifurcation, % 1.6 1.7.92 SYNTAX Primary Endpoint Serruys TCT 14 October 28 Slide 11
Procedural Characteristics TAXUS Randomized Cohort Patient-based TAXUS N=93 Staged procedure, % 14.1 Lesions treated/pt, mean ± SD 3.6 ± 1.6 No. stents implanted, mean ± SD 4.6 ± 2.3 Total length implanted, mm ± SD 86.1 ± 47.9 Range, mm 8 324 Long stenting (>1 mm), % 33.2 SYNTAX Primary Endpoint Serruys TCT 14 October 28 Slide 12
Death/CVA/MI to 12 Months CABG (N=897) TAXUS (N=93) Cumulative Event Rate (%) 2 1 P=.98 * 6 12 Months Since Allocation Event rate ± 1.5 SE. * Fisher exact test 7.7% 7.6% ITT population SYNTAX Primary Endpoint Serruys TCT 14 October 28 Slide 13
Combined Safety (Death/CVA/MI) to 12 months CABG TAXUS 12 month MACCE, % 15 1 5 P=.99 7,7 P=.39 7,6 8, 6,6 P=.29 9,2 7, P=.96 1,3 1,1 n=897 n=93 n=549 n=546 n=348 n=357 n=221 n=231 Overall 3VD LM Diabetes Medically Treated Diabetes SYNTAX Primary Endpoint Serruys TCT 14 October 28 Slide 14
SYNTAX Score Distribution by Cohort and Treatment Group % of Patients 25 2 15 1 Score Tertile Low Scores (-22) CABG RCT PCI RCT Score (23-32) Score Tertile High Scores ( 33) 5 6 12 18 24 3 36 42 48 54 6 66 72 78 84 SYNTAX Score SYNTAX Primary Endpoint Serruys TCT 14 October 28 Slide 15
MACCE to 12 Months by SYNTAX Score Tertile Low Scores (-22) CABG (N=274) TAXUS (N=299) Cumulative Event Rate (%) 3 2 1 P=.71 * 6 12 Months Since Allocation Event Rate ±1.5 SE, * Fisher exact test; raw SYNTAX score for illustrative purposes only 14.4% 13.5% RCT ITT pts; site-reported data PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 16
MACCE to 12 Months by SYNTAX Score Tertile Low Scores (-22) CABG (N=171) TAXUS (N=181) CABG (N=13) TAXUS (N=118) Cumulative Event Rate (%) 4 2 Mean baseline SYNTAX Score CABG 17.3 ± 3.7 TAXUS 17.3 ± 3.8 P=.66 * 3VD subset 17.3% 15.2% Cumulative Event Rate (%) 4 2 Mean baseline SYNTAX Score CABG 15.5 ± 4.3 TAXUS 15.7 ± 4.4 P=.19 * LM subset 13.% 7.7% 6 Months Since Allocation 12 12 6 12 Months Since Allocation Event rate ± 1.5 SE, * Fisher exact test Calculated by core laboratory; ITT population SYNTAX: Left Main Subset Serruys TCT 14 October 28 Slide 17
What does this mean for clinicians?! Patients with low SYNTAX Scores have comparable outcomes after revascularization with PCI or CABG! These patients have less complex anatomy! Treatment will depend on individual patient characteristics, patient preference and physician choice PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 18
MACCE to 12 Months by SYNTAX Score Tertile Intermediate Scores (23-32) CABG (N=3) TAXUS (N=31) Cumulative Event Rate (%) 3 P=.1 * 2 16.6% 1 11.7% 6 12 Months Since Allocation Event Rate ±1.5 SE, * Fisher exact test; raw SYNTAX score for illustrative purposes only RCT ITT pts; site-reported data PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 19
MACCE to 12 Months by SYNTAX Score Tertile Intermediate Scores (23-32) CABG (N=28) TAXUS (N=27) CABG (N=92) TAXUS (N=195) Cumulative Event Rate (%) 4 2 Mean baseline SYNTAX Score CABG 27.5 ± 2.7 TAXUS 27.4 ± 2.9 P=.2 * 3VD subset 18.6% 1.% Cumulative Event Rate (%) 4 2 Mean baseline SYNTAX Score CABG 27.2 ± 3. TAXUS 27. ± 2.7 P=.54 * LM subset 15.5% 12.6% 6 12 Months Since Allocation 6 12 Months Since Allocation Event Rate ± 1.5 SE, * Fisher exact test Calculated by core laboratory; ITT population SYNTAX: 3VD Mohr TCT 14 October 28 Slide 2
What does this mean for clinicians?! MACCE is slightly, but not significantly, increased in PCI patients with intermediate SYNTAX Scores! This suggests that PCI is still a valid option in patients with intermediate SYNTAX scores! Treatment will depend on the patients characteristics and comorbidity PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 21
MACCE to 12 Months by SYNTAX Score Tertile High Scores ( 33) CABG (N=316) TAXUS (N=29) Cumulative Event Rate (%) 3 P<.1 * 23.3% 2 1 1.7% 6 12 Months Since Allocation Event Rate ±1.5 SE, * Fisher exact test; raw SYNTAX score for illustrative purposes only RCT ITT pts; site-reported data PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 22
MACCE to 12 Months by SYNTAX Score Tertile High Scores ( 33) CABG (N=15) TAXUS (N=135) CABG (N=166) TAXUS (N=155) 4 Mean baseline SYNTAX Score CABG 41. ± 6.6 TAXUS 39.8 ± 6. 3VD subset 4 Mean baseline SYNTAX Score CABG 42.1 ± 7.6 TAXUS 43.8 ± 9.1 LM subset Cumulative Event Rate (%) 2 P=.2 * 21.5% 8.8% Cumulative Event Rate (%) 2 P=.8 * 25.3% 12.9% 6 12 Months Since Allocation 6 12 Months Since Allocation Event Rate ± 1.5 SE, * Fisher exact test Calculated by core laboratory; ITT population SYNTAX: 3VD Mohr TCT 14 October 28 Slide 23
What does this mean for clinicians?! MACCE rates in PCI patients with high SYNTAX Score were significantly higher than in CABG patients! These patients have very complex anatomy! This suggests that PCI is most likely not a viable option and these patients will remain surgical candidates PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 24
SYNTAX Trial Patient Distribution All Patients CABG registry (N=177) SYNTAX Scores 33 - SYNTAX Scores 23-32 All Patients +/- PCI registry (N=198) SYNTAX Scores -22 All Patients + PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 25
SYNTAX Trial Patient Distribution Left main CABG registry (N=177) SYNTAX Scores 33 - SYNTAX Scores 23-32 Left main +/- PCI registry (N=198) SYNTAX Scores -22 Left main + PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 26
SYNTAX Trial Patient Distribution 3VD PCI registry (N=198) CABG registry (N=177) SYNTAX Scores -22 SYNTAX Scores 33 3VD SYNTAX Scores 23-32 LM P=.2 3VD - - 3VD + PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 27
SYNTAX Trial Design 62 EU Sites + 23 US Sites Heart All Pts Team with (surgeon de novo & interventionalist) Total enrollment 3VD and/or LM disease (N=4,337) N=375 Amenable for both Amenable for only one treatment options! Treatment preference (9.4%) treatment approach Randomized Arms Stratification: Stratification: LM and Diabetes! Referring MD or pts. refused informed LM and consent Diabetes (7.%)! Inclusion/exclusion (4.7%)! Withdrew before consent (4.3%) N=18! Other (1.8%) N=1275 Randomized Arms Two Registry Arms! Medical treatment (1.2%) CABG n=18 TAXUS * CABG PCI vs 25 N=897 n=897 n=93 N=93 n=177 N=177 N=198 75 w/ f/u n=198 follow up Non LM DM vs 3VD DM NonDM 71% LM enrolled 5yr f/u no f/u (N=3,75) n=649 n=428 3VD DM 66.3% 28.5% 33.7% 71.5% 28.2% 65.4% 71.8% 34.6% 28 Two Registry Arms all captured w/ * TAXUS Express
Combined Safety (Death/CVA/MI) to 12 months in Diabetic Patients CABG TAXUS 12 Mo Death/CVA/MI, % P=.11 P=.71 P=.31 8/6 4/74 6/7 8/77 7/74 11/74 SYNTAX Primary Endpoint Serruys TCT 14 October 28 Slide 29
MACCE to 12 months in Diabetic Patients CABG TAXUS P=.78 P=.46 P=.3 MACCE, % 11/6 15/74 9/7 2/77 9/74 24/74 SYNTAX Primary Endpoint Serruys TCT 14 October 28 Slide 3
SYNTAX Trial Patient Distribution PCI registry (N=198) CABG registry (N=177) SYNTAX Scores -22 SYNTAX Scores 33 SYNTAX Scores 23-32 3VD + LM with DM LM w/o DM SYNTAX Primary Endpoint Serruys TCT 14 October 28 Slide 31
Post SYNTAX CABG 66% PCI only 6% CABG + 28% PCI Results of the SYNTAX trial suggest that 66 % of all patients are still best treated with CABG, however, for the remaining patients PCI is an excellent alternative to surgery at least for one year PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 32
Conclusions! Using as criteria, a non-significant difference in MACCE, we may state:! Results of the SYNTAX trial suggest that 66% of all patients are still best treated with CABG, however, for the remaining patients PCI (Syntax Score -22) is an excellent alternative to surgery in multivessel disease, in left main disease and in diabetic patients.! Left main disease, non-diabetic with score of 23-32 could also be treated by PCI. PCI Best Scenario Interpretation Serruys TCT 14 October 28 Slide 33
Background and Objectives! Angiographic patterns, hemodynamic consequences, and clinical symptoms of restenosis are not well defined in larger vessels such as the left main.! The SYNTAX-LE MANS study is a subprotocol of the SYNTAX trial, designed to prospectively compare late angiographic and clinical outcomes to better define long term vascular responses for both CABG and TAXUS Express PCI treatment arms in patients with left main disease.! Therefore, this analysis aims to:! Determine the late (15-month) patency and safety of stents and grafts in patients with left main disease! Assess the relationship of 15-month angiographic appearance to clinical outcome SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 34
Patient Population De novo disease Limited Exclusion Criteria Previous Coronary Intervention Acute MI with Creatine Kinase>2x Concomitant Cardiac Surgery Left Main Disease (isolated, +1, +2 or +3 vessels) 3 Vessel Disease (revasc all 3 vascular territories) LE MANS Substudy (patients provided separate informed consent) SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 35
Methods! Quantitative coronary angiography of left main territory at 15±1 months! Primary Endpoints:! TAXUS: Rate of long-term patency (<5% stenosis) of treated left main lesion(s) by QCA! CABG: Ratio of obstructed/occluded ( 5% stenosis) to placed grafts/anastomoses at 15 months! No formal statistical inferences between the two treatment groups were made due to the different primary endpoints for the TAXUS PCI and CABG treatment groups! Results presented separately for each group SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 36
SYNTAX-LE MANS Trial Design All RCT patients with LM 271 patients consented at 49 sites (13 US, 36 EU) CABG N=115 TAXUS N=156 3 pts died * 15 mo angio performed CABG N=115 TAXUS N=153 15 mo angio analyzed CABG N=114 TAXUS N=149 * 2 cardiac death: 1 cardiomyopathy and 1 sudden cardiac death SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 37
Baseline Demographics CABG (N=115) Variable TAXUS (N=156) 84% (97) Male 75% (117) 65±1 Age 65±1 21% (24) Medically-treated diabetes 15% (24) 15% (17) Isolated left main disease 12% (19) 19% (22) LM+1VD 17% (27) 28% (32) LM+2VD 33% (52) 38% (44) LM+3VD 37% (58) 3±2 Number of lesions 3±2 65% (75) Complete revascularization 67% (15) 32±13 Total SYNTAX Score 3±14 3.6±2.5 Additive euroscore 3.8±2.9 All data site-reported except SYNTAX Score which was determined by an angiographic core laboratory Values are percent (n) or mean±standard deviation SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 38
Principal Results CABG Cohort Primary Endpoint (Per graft): 5% to <1% =1% Per patient: 5% to <1% =1% Grafts (%) 2 1 16% 6% (15/262) 1% (26/262) Patients (%) 3 2 1 27% 9% (1/114) 18% (21/114) Obstruction/occlusion Ratio at 15 mo (per graft) Obstruction/occlusion Ratio at 15 mo* (per patient) Definitions: Occlusion Ratio: ratio of 5% obstructed or 1% occluded grafts/anastomoses (visual estimate) to the number of grafts/anastomoses placed *Proportion of patients with at least 1 obstructed/occluded graft SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 39
Secondary Results at 15 Months CABG Cohort Per Graft: 6 51% Per Patient: 6 54% Grafts (%) 4 2 34% 22% 15% Patients (%) 4 2 Baseline Complete Revasc: 65% 21/41 14/41 9/41 6/41 Ostium/ Distal Body of String Proximal Graft Sign Pattern & location of stenosis (QCA) per graft * 61/114 Complete Revascularization of the LM and LM territory at 15 mo Definitions: Complete Revascularization: revascularisation at follow-up is defined as unimpaired flow to all distal beds (vessels showing a significant lesion have been grafted and do not show significant graft lesions at follow up, nor new significant lesions in other vessels)..string Sign: diffuse narrowing with largest diameter <1 mm *Note that the presence of ostial/proximal occlusion would mask the detection of downstream stenosis. Patients may be counted in >1 category. SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 4
MACCE at 15 Months CABG Cohort 1 9% Patients (%) 8 6 4 2 MACCE 5% Death/ CVA/MI % Death (all-cause) 3% 3% 4% 1/114 6/114 3/114 3/114 5/114 CVA MI Revasc Analysis includes results from all lesions. SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 41
Graft Obstruction/Occlusion Not Associated With MACCE at 15 Mo CABG Cohort P=.85 1 8 6 4 2 <5% Graft Stenosis 5% Graft Stenosis 91% 9% 1 8 6 4 2 9% 1% 75/82 7/82 28/31 3/31 No MACCE MACCE No MACCE MACCE SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 42
Principal Results TAXUS Cohort Primary Endpoint: 1 92% 1 98% 9% 8 8 Patients (%) 6 4 Patients (%) 6 4 2 2 134/145 <5% stenosis at 15 mo 47/48 87/97 LM Non-distal LM Distal <5% stenosis at 15 mo Definitions: Diameter stenosis was assessed by QCA SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 43
Secondary Results at 15 months TAXUS Cohort 6 53% 1 Patients (%) 4 2 Baseline Complete Revasc: 67% Patients (%) 5 79/149 2/149 Complete revascularization Thrombus of LM and LM territory 1% % /149 Aneurysm Definitions: Diameter stenosis was assessed by QCA SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 44
Non-distal LM Angio Endpoints (QCA) TAXUS Cohort Vessel Size: Millimeters 5 4 3 2 1 1.7 3.4 3.1 Minimum Lumen Diameter 3.8 3.3 3.5 Reference Vessel Diameter Acute Gain/Late Loss: Millimeters 3 2 1 1.8mm Acute gain (in-stent).2mm Late loss (in-stent) Pre-procedure Post-procedure 15 Months SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 45
MACCE at 15 Months TAXUS Cohort Patients (%) 14 12 1 8 6 4 2 13% MACCE 6% Death/ CVA/MI 2% Death (allcause) 1% 4% 9% 2/156 1/156 3/156 2/156 6/156 14/156 CVA MI Revasc Analysis includes results from all lesions. SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 46
Stent Patency Significantly Associated With MACCE at 15 Months TAXUS Cohort P=.3 1 <5% Diameter Stenosis 5% Diameter Stenosis 91% 1 8 8 6 6 46% 55% 4 4 2 9% 12/134 MACCE 2 122/134 5/11 6/11 No MACCE MACCE No MACCE SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 47
Conclusions CABG Cohort! 1% of LM placed grafts/anastomoses were 1% occluded at 15 months post-procedure and an additional 6% were 5% obstructed! 54% of patients had complete revascularization * of LM & LM territory at 15 months (baseline 65%)! Graft obstruction/occlusion in grafts bypassing LM lesion(s) was not significantly associated with MACCE at 15 months * Note that definitions of complete revascularization differ between treatments and should not be compared. SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 48
Conclusions TAXUS Cohort! 92% of treated LM lesion(s) had <5% stent stenosis at 15 months post-procedure! Restenosis more common with LM distal lesions than with LM non-distal lesions! 53% complete revasc of LM & LM territory (baseline 67%) *, 1% thrombus, and % aneurysm at 15 months! Minimal Late Loss in non-distal LM lesions at 15 months! In-stent stenosis was significantly associated with MACCE at 15 months *Note that definitions of complete revascularization differ between treatments and should not be compared. SYNTAX-LE MANS Kappetein EuroPCR 19 May 29 Slide 49