Mise à Jour sur le traitement du Pluritronculaire Philippe Généreux, MD

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1 Mise à Jour sur le traitement du Pluritronculaire Philippe Généreux, MD Columbia University Medical Center and The Cardiovascular Research Foundation, New York, USA Hôpital du Sacré-Coeur de Montréal, Montréal, Canada

2 Disclosures Philippe Généreux, MD None

3 Agenda Left Main Diabetic Patients SYNTAX Score II

4 Update Left Main

5 Published by Elsevier Inc. doi:1.116/j.jacc Interventional Cardiology Percutaneous Coronary Intervention Versus Coronary Artery Bypass Graft Surgery in Left Main Coronary Artery Disease A Meta-Analysis of Randomized Clinical Data Davide Capodanno, MD,* Gregg W. Stone, MD, Marie C. Morice, MD, Theodore A. Bass, MD, Corrado Tamburino, MD, PHD* Catania, Italy; New York, New York; Massy, France; and Jacksonville, Florida 211 Capodanno J Am Coll Cardiol

6 vs. for Left Main Disease Meta-analysis of 4 RCTs, 1,611 Patients Trial LEMANS SYNTAX LM Boudriot et al. PRECOMBAT Year N total Age, mean years Male 67% 74% 75% 77% Diabetes 18% 25% 36% 32% Distal LM involved 58% 61% 71% 65% +/1/2/3 VD, % /9/23/68 13/2/31/36 29/31/27/14 1/17/32/41 Syntax Score, mean Log Euroscore, mean LIMA-LAD 81% 97% 99% 94% Capodanno et al, JACC 211;58:

7 vs. for Left Main Disease Meta-analysis of 4 RCTs, 1,611 Patients 1-Year Death OR (95%CI) p-value LEMANS 1/52 4/53.24 ( ).21 OR (95%CI ) SYNTAX left main 15/355 15/ ( ).88 Boudriot et al. 2/1 5/11.39 (.7-2.7).27 PRECOMBAT 6/3 8/3.75 ( ).59 Fixed effects estimate 3.% 4.1%.74 ( ).29 (24/87) (32/79) Random effects estimate.74 ( ).29 I 2 =% Favors Favors Capodanno et al, JACC 211;58:

8 vs. for Left Main Disease Meta-analysis of 4 RCTs, 1,611 Patients 1-Year MI OR (95%CI) p-value LEMANS 1/52 3/53.33 ( ).34 OR (95%CI ) SYNTAX left main 15/355 14/ ( ).97 Boudriot et al. 3/1 3/ ( ).99 PRECOMBAT 4/3 3/ (.3-6.3).71 Fixed effects estiamate 2.8% 2.9%.98 ( ).95 (23/87) (23/79) Random effects estimate.98 ( ).95 I 2 =% Favors Favors Capodanno et al, JACC 211;58:

9 vs. for Left Main Disease Meta-analysis of 4 RCTs, 1,611 Patients 1-Year Stroke OR (95%CI) p-value LEMANS /52 2/53.2 (.1-4.9).3 OR (95%CI ) SYNTAX left main 1/355 8/ (.1-.93).4 Boudriot et al. PRECOMBAT /3 2/3.2 ( ).3 Fixed effects estiamate.1% 1.7%.15 (.3-.67).1 (1/77) (12/689) Random effects estimate.15 (.3-.67).1 I 2 =% Favors Favors Capodanno et al, JACC 211;58:

10 vs. in LMCA Disease: Stroke Meta-Analysis ULMCAD Budriot LE MANS SYNTAX LM Fixed effects (I-squared=.%) Random effects 3-day outcomes HR (95%CI) 5.5 (.24, 16.53) 5.1 (.24, 18.77) 9.34 (.5, ) 6.29 (1.11, 35.77) 6.29 (1.11, 35.77) 2/11 2/53 4/348 8/52 (1.6%) /1 /52 /357 /59 (%) Favors Favors Mid-term (~12 month) outcomes ULMCAD Budriot LE MANS PRECOMBAT SYNTAX LM Fixed effects (I-squared=.%) Random effects HR (95%CI) 5.5 (.24, 16.53) 5.1 (.24, 18.77) 5.3 (.24, 15.29) 9.34 (1.19, 75.) 6.58 (1.72, 25.16) 6.58 (1.72, 25.16) 2/11 2/53 2/3 9/348 15/82 (1.9%) /1 /52 /3 1/357 1/89 (.1%) Favors Favors Palmerini T et al. JACC 212;6:798-85

11 vs. for Left Main Disease Meta-analysis of 4 RCTs, 1,611 Patients 1-Year Repeat Revascularization OR (95%CI) p-value LEMANS 15/52 5/ ( ).2 OR (95%CI ) SYNTAX left main 45/355 22/ ( ).7 Boudriot et al. 14/1 6/ ( ).6 PRECOMBAT 18/3 1/ ( ).13 Fixed effects estiamate 11.4% 5.4% 2.25 ( ) <.1 (92/87) (43/79) Random effects estimate 2.25 ( ) <.1 I 2 =% Favors Favors Capodanno et al, JACC 211;58:

12 vs. for Left Main Disease Meta-analysis of 4 RCTs, 1,611 Patients 1-Year MACCE OR (95%CI) p-value LEMANS 16/52 13/ ( ).48 OR (95%CI ) SYNTAX left main 56/355 46/ ( ).44 Boudriot et al. 19/1 14/ ( ).33 PRECOMBAT 26/3 2/ ( ).36 Fixed effects estiamate 14.5% 11.8% 1.28 ( ).11 (117/87) (93/79) Random effects estimate 1.28 ( ).11 I 2 =% Favors Favors Capodanno et al, JACC 211;58:

13 SYNTAX: MACCE to 5 Years Left Main Subset (N=348) TAXUS (N=357) Cumulative Event Rate (%) 5 25 Before 1 year * 13.7% vs 15.8% P= years * 7.5% vs 1.3% P= years * 5.2% vs 5.7% P=.78 P= years * 6.4% vs 8.3% P= years * 5.9% vs 5.5% P= % 31.% Months Since Allocation SYNTAX 3VD 5-year Outcomes TCT 212 Serruys 23 October 212 Slide 13 Mohr FW et al. Lancet 213;381:629 38

14 Left Main Disease 5-year Outcomes (N=75) (n=348) TAXUS (n=357) P=.53 P=.1 P=.3 P<.1 P=.12 Patients (%) All Death MI CVA Revasc. MACCE SYNTAX 3VD 5-year Outcomes TCT 212 Serruys 23 October 212 Slide 14 Mohr FW et al. Lancet 213;381:629 38

15 MACCE to 5 Years by SYNTAX Score Tercile Low to Intermediate Scores (-32) (N=196) TAXUS (N=221) P value Cumulative Event Rate (%) 5 25 P=.74 LM Disease 32.1% 31.3% Death 15.1% 7.9%.2 CVA 3.9% 1.4%.11 MI 3.8% 6.1%.33 Death, CVA or MI 19.8% 14.8% Months Since Allocation Revasc. 18.6% 22.6%.36 SYNTAX 3VD 5-year Outcomes TCT 212 Serruys 23 October 212 Slide 15 Serruys PW et al. Lancet 213;381:629 38

16 MACCE to 5 Years by SYNTAX Score Tercile High Scores 33 (N=149) TAXUS (N=135) P value 5 P=.3 LM Disease 46.5% Death 14.1% 2.9%.11 CVA 4.9% 1.6%.13 MACCE (%) % MI 6.1% 11.7%.13 Death, CVA or MI 22.1% 26.1% Months Revasc. 11.6% 34.1% <.1 SYNTAX 3VD 5-year Outcomes TCT 212 Serruys 23 October 212 Slide 16 Serruys PW et al. Lancet 213;381:629 38

17 The SYNTAX Score Dogma?

18 Log HR SYNTAX Score II: Designed to Objectively Discriminate Between and Interactions Syntax score Age CrCl P int = All other interaction P values <.1 LVEF VD vs LM Gender COPD PVD P int = 1. Log HR VD LMS F M No Yes No Yes Farooq V et al. Lancet 213;381:639 5

19 SYNTAX Score I vs II: The SYNTAX Trial LM pts: Risk Predictions by Tertiles of the SYNTAX Score Log hazard Syntax score -22 Syntax score Syntax score % (2.7%) 38.3% (1.2%) 68.2% (19.2%) Favors Favors Favors Favors Favors Favors 62.8% (18.8%) 61.7% (9.2%) 31.8% (.7%) Log hazard favored Overall 62.8% >95%CI 18.8% favored Overall 61.7% >95%CI 9.2% favored Overall 31.8% >95%CI.7% Farooq V et al. Lancet 213;381:639 5

20 EXCEL Trial

21 EXCEL: Study Design 36 pts with unprotected le7 main disease SYNTAX score 32 Consensus agreement by heart team Yes (N=26) 165 internanonal sites No (N=1) Enrollment registry (Xience Prime) (N=13) (N=13) Clinical follow- up: 1 mo, 6 mo and yearly through 5 years

22 Why May win in EXCEL

23 What is Novel About EXCEL? The primary endpoint: Death, MI or stroke at 3 years

24 MACCE to 5 Years Left Main Subset (n=348) TAXUS (n=357) Event rate (%) P=.12 P=.53 P=.3 P=.1 P<.1 36,9 31, 26,7 14,6 12,8 15,5 8,2 4,3 1,5 4,8 MACCE Death CVA MI Revasc Cumulative KM Event Rate Log-rank P value Serruys PW et al. Lancet 213;381:629 38

25 What is Novel About EXCEL? Restriction of enrollment to Syntax Score 32

26 MACCE to 3 Years by SYNTAX Score Tercile LM Subset Low to Intermediate Scores (-32) 4 (N=196) TAXUS (N=221) Left Main Disease P value Death 9.% 3.7%.2 Cumulative Event Rate (%) P= % 2.5% CVA 3.3%.9%.9 MI 2.6% 4.6%.33 Death, CVA or MI 13.2% 8.7% Months Since Allocation 36 Revasc. 13.7% 15.7%.61 Cumulative KM Event Rate ± 1.5 SE; log-rank P value

27 What is Novel About EXCEL? Use of best in class DES

28 SYNTAX: Definite/Probable ARC Stent Thrombosis to 5 Years (Per Patient) ~4.5% ST in year 1 ~1.2% ST/yr in years (3/896) (23/893) (15/874) (11/85) (12/83) Acute 1d 2.6 Subacute 2-3d 1.7 Late d Very Late d 195d 146d Days Post-procedure.9 (1/83) (7/768) d (76/73) Total 5 year Rate was ~ same in the LM and 3VD cohorts, and roughly independent of Syntax Score Serruys PW. JACC 213:on-line

29 Network Meta-analysis: 77 RCTs, 57,138 pts 1-year definite stent thrombosis Control BMS (Ref) Sirolimus (Ref) Paclitaxel (Ref) Everolimus (Ref) Zotarolimus (Ref) Treatment Sirolimus Paclitaxel Everolimus Zotarolimus Zotarolimus-R Paclitaxel Everolimus Zotarolimus Zotarolimus-R Everolimus Zotarolimus Zotarolimus-R Zotarolimus Zotarolimus-R Favors Treatment OR (95% Crl) Favors Control OR [95% CrI].75 (.45, 1.2).81 (.51, 1.48).27 (.14,.55) 1.34 (.63, 3.21).41 (.41, 12.53) 1.1 (.66, 1.91).36 (.2,.7) 1.79 (.91, 4.4) 2.73 (.6, 16.87).34 (.18,.61) 1.7 (.76, 3.6) 2.52 (.51, 14.79) 5.16 (2.9, 12.31) 7.44 (1.88, 39.43) Zotarolimus-R 1.55 (.29, 9.83) Bangalore S et al. Circulation 212;125:

30 LEMAX: Propensity-matched Comparison of PES and EES in ULM ds matched pts in each group - Cardiac death TV-MI Clinically indicated TLR P=.6 2 P=.4 2 P= % 2.3% 1 9.9% 1 4.1% 5.8% 4.1% Months Months Months TLF Stent thrombosis (any) 2 P=.1 2 P=.2 PES EES % 1 7.6% 7.% 1.7% Months Months Moynagh A et al. EuroIntervention 213;9:452-62

31 Updates Diabetes

32 1 Endpoint: Death, Stroke, or MI FU: minimum 2 years, median 3.8 years Death, Stroke, MI, % st Gen DES 13.% 11.9% P = % 18.7% /DES Years Farkouh ME et al. NEJM 212

33 Death, Stroke, MI by Syntax Score Death, MI, Stroke (%) SYNTAX Score 22 (N=669) 1 st Gen DES (N=329) (N=34) Years 1 st Gen DES Death, MI, Stroke (%) % 17.2% Death, MI, Stroke (%) SYNTAX Score 33 (N=374) 1 st Gen DES (N=182) (N=192) SYNTAX Score (N=844) 1 st Gen DES (N=438) (N=46) Years Years 3.6% 22.8% P int = % 17.7% Farkouh ME et al. NEJM 212

34 Stroke Stroke, % 1 5 Severely Disabling Scale /DES NIH > 4 55% 27% Rankin >1 7% 6% /DES 5.2% 2.4% P =.3 /DES Years Farkouh ME et al. NEJM 212

35 Quality of Life Angina frequency, physical limitations, and quality-of-life domains of the SAQ assessed at baseline, at 1, 6, and 12 months, and annually thereafter. SAQ Angina Frequency SAQ Quality of Life SAQ Physical Limitations Adjusted: * P<.5 favoring *P<.5 favoring Abdallah MS et al. JAMA 213;on-line

36 SYNTAX: Death, CVA, MI to 5 Years Impact of Diabetes Diabetes TAXUS P int =.76 No diabetes Death, stroke or MI (%) 6% 5% 4% 3% 2% 1% No. at risk: Days % 231 HR[95%CI] = 1.27 [ ] P= % 19.1% Days Death, stroke or MI (%) 6% 5% 4% 3% 2% 1% % No. at risk: Days 672 HR[95%CI] = 1.27 [ ] P= % 15.9% Days Kappetein AP et al. EJCTS 213:on-line

37 Death, CVA, MI to 5 Years: Impact of Diabetes and Syntax Score Diabetes TAXUS No diabetes 5-Year death/stroke/mi (%) P=.79 P=.89 P= n=12 n=14 n=16 n=17 n=14 n=23 5-Year death/stroke/mi (%) P=.68 P=.38 P= n=27 n= n=35 n=36 n=39 n=53 Syntax score -22 (n=136) (n=156) 33 (n=157) Syntax score -22 (n=438) (n=454) 33 (n=448) Kappetein AP et al. EJCTS 213:on-line

38 Log HR SYNTAX Score II: Designed to Objectively Discriminate Between and Interactions Syntax score Age LVEF All other interaction P values >.1 CrCl P int = VD vs LM Gender COPD PVD P int = 1. Log HR VD LMS F M No Yes No Yes Farooq V et al. Lancet 213;381:639 5

39 SYNTAX Score I vs II: The SYNTAX Trial Interactions: Diabetes Log HR P interaction =.67 Diabetes was not an independent predictor of mortality or MACE in either the or arm, and had a negative interaction effect No Yes Farooq V et al. Lancet 213;381:639 5

40 Impact of Lesion Severity on DES Results in Diabetic vs. Non-diabectic pts Diabetes was present in 3,467 (18.8%) of 18,441 pts enrolled in 18 DES RCTs; 2 propensity matched groups of 3,167 pts created (6,334 pts total) TLR (%) No. at risk DM A/B1 No DM A/B1 DM B2/C No DM B2/C Diabetes mellitus with type A/B1 lesions No diabetes mellitus with type A/B1 lesions Diabetes mellitus with type B2/C lesions No diabetes mellitus with type B2/C lesions HR (B2/C vs. A/B1 in Non-DM):.93 [95% CI:.65, 1.32] HR (B2/C vs. A/B1 in DM): 1.75 [95% CI: 1.25, 2.43] HR (DM vs. Non-DM in B2/C subgroup): 1.8 [95% CI: 1.39, 2.33] HR (DM vs. Non-DM in A/B1 subgroup):.96 [95% CI:.64, 1.44] Months P int = P<.1 8.% 4.8% 4.6% 4.5% Kedhi E, Généreux, P, Stone, G. et al. JACC 214 in press

41 FREEDOM 5-Year KM Event-Free Estimated Insulin vs. Non-Insulin Dependent % % Treatmet%effect%[Δ%of%endpoint%rates%(% %)]% Stroke MI Death MACCE Stroke MI Death MACCE Non-ITDM 1.5 Hazard Ratio Dangas, G. TCT 213 ITDM

42 SYNTAX Score II

43 SYNTAX Score II SYNTAX Score Age (years) CrCl (ml/min) LVEF (%) Log HR SYNTAX Score AGE CrCl EF Left Main Gender COPD Diabetes PVD Log HR VD LMS F M COPD Diabetes PVD 3VD LMS F M No Yes No Yes EQUIPOISE Findings that FOR were LONG validated TERM MORTALITY in the multinational BETWEEN DELTA Registry AND

44 Central Hypotheses of SYNTAX Score II 1. That there are potentially low (or high) risk patients hidden in the conventional tertiles of the SYNTAX Score 2. Category based approach (low/interm/high) may be detrimental 3. Individualised approach, with addition of clinical & anatomical variables, may improve decision making between and

45 Recalculating SYNTAX Score by incorporating ischemiaproducing lesions as determined by FFR decreases the number of higher-risk patients and better discriminates risk for the adverse events in patients with multivessel disease undergoing.

46 Reclassifies Functional SYNTAX > 3% of Score Cases Nam et al. JACC Sep 211 Death/MI at 1Y, % Low SS Med SS High SS 5,4 6, 11,7 163 (32%) 167 (34%) 4,8 7,5 167 (34%) 15,8 Classic Syntax Score Functional Syntax Score P<.1 35 P<.1 P<.1 MACE at 1Y, % Low FSS Med FSS High FSS 2,9 1,2 8,4 9, Classic Syntax Score 11 (2%) 16 (21%) 11,3 29 (59%) 26,7 Functional Syntax Score

47 Upcoming trials

48 Upcoming Trials EXCEL SYNTAX trial-2 FAME 3

49 Conclusion: LM and Multivessel disease Physiologicaly based FFR guided Individualized based Avoiding the SYNTAX and FREEDOM Dogma SYNTAX score 2