Surgical Treatment for Ischemic Heart Failure (STICH) Trial: CABG versus CABG + SVR

1. Surgical Treatment for Ischemic Heart Failure (STICH) Trial: CABG versus CABG + SVR LORENZO A. MENICANTI Irccs Policlinico San Donato

2. Core STICH Study Organization • Principal Investigator: Robert H. Jones • Co-Principal investigator: Eric Velazquez • DCC Principal Investigator: Kerry L. Lee • Study Chair: Jean L. Rouleau • Executive Committee: Robert H. Jones, Eric Velazquez, Kerry L. Lee, Jean L. Rouleau, Patrice Desvigne-Nickens, George Sopko, Christopher O’Connor, Robert Michler, Jae Oh • DSMB chair: Sidney Goldstein • Policy and Publication Committee chair: James Hill • Clinical Endpoints Committee chair: Peter Carson

4. Hypothesis 2 Enrollment by Country 1000 patients 96 clinical sites 23 countries 1231 days

6. Hypothesis 2 • Surgical ventricular reconstruction (SVR) combined with CABG and evidence-based medical therapy (MED) decreases death or cardiac hospitalization compared to CABG and MED without SVR. • 90% power for 20% reduction assuming ≥45% 3-year event rate allowing for 20% treatment crossovers. • 7% of CABG and 9% of CABG + SVR patients did not receive assigned operation. • Follow-up 99% complete over median of 48 months. • All outcomes reported by operation assigned by randomization. • Conduct of operation reported by procedure received.

7. Baseline Clinical Characteristics

8. Mitral Regurgitation by Treatment in 1,000 Hypothesis 2 Patients 18%

9. Site Reported Left Ventricular Function for 1,000 Hypothesis 2 Patients by Treatment

10. Coronary Anatomy by Treatment for 1,000 Hypothesis 2 Patients * 0 = coronary angiogram shows no coronary disease, 100 = ≥95% LM stenosis

11. Medication at Baseline

12. Operative Conduct by Operation Received in 979 Hypothesis 2 Patients

13. Efficiency of Operative Care in 979 Hypothesis 2 Patients

14. Baseline and Four Month End-Systolic Volume Index (ESVI) in 373 Hypothesis 2 Patients With Quantitative Echocardiogram at Both Intervals ESVI 82 ml/m2 83 ml/m2 77 ml/m2 67 ml/m2 P<0.001

15. Canadian Cardiovascular Society Angina Class in Hypothesis 2 Patients at Baseline and Latest Follow-up No Angina121 No Angina128 Class I-II130 Class I-II129 No Angina339 No Angina339 Patients Class III-IV248 Class III-IV244 Class I-II88 Class I-II83 Class III-IV8 Class III-IV6 Angina symptoms improved by an average of 1.7 classes in both cohorts (P=0.84).

16. New York Heart Association Heart Failure Class in Hypothesis 2 Patients at Baseline and Latest Follow-up CABGNYHA HF Class CABG+SVRNYHA HF Class Class I 36 Class I 50 Class I179 Class I165 Class II222 Class II207 Patients Class II190 Class II190 Class III-IV241 Class III-IV244 Class III-IV80 Class III-IV80 Baseline(N = 499) LatestFollow-up(N = 435) Baseline(N = 501) LatestFollow-up(N = 429)

17. Baseline and Four Month 6-Minute Walk in 693 Hypothesis 2 Patients with Baseline Assessment Patients

18. 30-Day Mortality

19. Death or Cardiac Hospitalization Kaplan-Meier Estimates of Primary Endpoint 0.7 0.6 0.5 0.4 Event Rate 0.3 0.2 292 events CABG 0.1 0 0 1 2 3 4 5 Years from Randomization No. at Risk CABG 499 319 270 220 99 23 CABG+SVR 501 319 275 216 11 23

20. Death or Cardiac Hospitalization Kaplan-Meier Estimates of Primary Endpoint 0.7 HR 0.99 (95% CI: 0.84, 1.17), P=0.90 0.6 0.5 0.4 Event Rate 0.3 292 events 0.2 CABG 289 events CABG+SVR 0.1 0 0 1 2 3 4 5 Years from Randomization No. at Risk CABG 499 319 270 220 99 23 CABG+SVR 501 319 275 216 11 23

21. Mortality (All-Cause) Kaplan-Meier Estimates 0.7 0.6 0.5 0.4 Mortality Rate 0.3 0.2 141 deaths 0.1 CABG 0 0 1 2 3 4 5 Years from Randomization No. at Risk CABG 499 434 417 363 201 59 CABG+SVR 501 429 404 352 193 53

22. Mortality (All-Cause) Kaplan-Meier Estimates 0.7 HR 1.00 (95% CI: 0.79, 1.26), P=0.98 0.6 0.5 0.4 Mortality Rate 0.3 0.2 141 deaths 138 deaths CABG 0.1 CABG+SVR 0 0 1 2 3 4 5 Years from Randomization No. at Risk CABG 499 434 417 363 201 59 CABG+SVR 501 429 404 352 193 53

23. Summary of Outcomes in STICH H2

24. Hazard Plots of Selected Baseline Characteristics Subgroup N HR (95% CI) P Value All Subjects 1000 0.99 (0.84, 1.17) Age 0.48 ≥ 65 391 1.06 (0.83, 1.35) < 65 609 0.94 (0.76, 1.17) Gender 0.60 Male 853 1.01 (0.84, 1.20) Female 147 0.90 (0.58, 1.39) Race 0.44 Minority 124 0.83 (0.51, 1.36) Non-minority 876 1.01 (0.85, 1.20) Current NYHA HF class 0.97 I or II 515 0.99 (0.78, 1.25) III or IV 485 0.99 (0.79, 1.24) CABG+SVRBetter CABGBetter

25. Hazard Plots of Selected Baseline Characteristics cont Subgroup N HR (95% CI) P Value CCS angina class 0.39 ≤ Class II 508 0.92 (0.73, 1.16) Class III or IV 492 1.06 (0.85, 1.34) Baseline diabetes 0.20 Yes 344 1.14 (0.87, 1.50) No 656 0.92 (0.75, 1.12) LVEF (site reported) 0.33 ≤ 28 534 1.07 (0.86, 1.31) > 28 466 0.90 (0.70, 1.17) # of diseased vessels ≥ 50% 0.21 1 or 2 362 0.87 (0.65, 1.13) 3 638 1.07 (0.87, 1.31) Left main ≥ 50% or proximal LAD ≥ 75% 0.53 No 179 0.89 (0.61, 1.30) Yes 821 1.02 (0.85, 1.22) CABG+SVRBetter CABGBetter

26. Hazard Plots of Selected Baseline Characteristics cont Subgroup N HR (95% CI) P Value Mitral regurgitation 0.44 None or trace 363 0.89 (0.68, 1.17) Mild (≤ 2+) 449 1.12 (0.88, 1.43) Mod. or severe 178 0.94 (0.65, 1.36) Stratum 0.44 B 141 1.15 (0.76, 1.76) C 859 0.96 (0.81, 1.15) Region 0.41 Poland 288 1.02 (0.76, 1.37) USA 200 1.10 (0.79, 1.54) Canada 154 0.77 (0.50, 1.18) West Europe 164 0.80 (0.53, 1.22) Other 194 1.24 (0.81, 1.91) CABG+SVRBetter CABGBetter

27. Jones R et al. N Engl J Med 2009;10.1056/NEJMoa0900559

28. Conclusions • The STICH trial definitively shows adding SVR to CABG provides no clinical benefit beyond that of CABG alone in the study population. • Both operative strategies provided similar short- and long-term relief of angina and HF and improvement in 6-minute walk test performance. • SVR added to CABG decreased LV size significantly more than CABG alone and confirms the anatomic change reported in prior SVR studies. • Further analyses of STICH Hypothesis 2 data may identify patient characteristics associated with benefit or harm from adding SVR to CABG.

29. MOTIVI DI DUBBIO • PUR AUMENTANDO LA COMPLESSITA’ DELLA PRUCEDURA CHIRURGICA LA MORTALITA’ NON CAMBIA • NONOSTANTE LA DIMINUZIONE DEL VOLUME DEL 20% NON VI E’ NESSUN BENEFICIO SULLA SOPRAVVIVENZA

30. SONO STATI CAMBIATI I CRITERI DI ARRUOLAMENTO DURANTE LO STUDIO, NELLA VERSIONE 2003 SCOMPARE IL SINTOMO SCOMPENSO • IL VOLUME NON E’ PIU’ UN CRITERIO DI ARRUOLAMENTO E PERMANE SOLAMENTE LA FE < 35% • LO STUDIO PERDE LA SUA CARATTERISTICA PRINCIPALE DI STUDIO SU MALATI SCOMPENSATI PER DIVENIRE UNO STUDIO SU PAZIENTI ISCHEMICI

31. LIMITI DI UNO STUDIO RANDOMIZZATO SU UNA PRATICA CHIRURGICA BEN CONOSCIUTA CON RISULTATI NOTI • NON ETICA LA RANDOMIZZAZIONE IN PAZIENTI IN CUI IL BENEFICIO ERA EVIDENTE • OFFRIRE IL MEGLIO DELLA TERAPIA MEDICA E CHIRURGICA CONOSCIUTA E DISPONIBILE IN BASE AL CONCETTO DI EQUIPOSE DI CIASUN CENTRO.

33. RANDOMIZZAZIONE COINVOLGE MENO DEL 20% DEI PAZIENTI ELIGIBILI. • 80% DEI PAZIENTI ELIGIBILI è STATO SOTTOPOSTO A SVR PER EVIDENZA DELLA SUPERIORITà DELLA PROCEDURA

34. L’INTERVENTO DI SVR è INDICATO COME PUBBLICATO OVUNQUE IN PRESENZA DI SINTOMI DI SCOMPENSO DETERMINATO DA UN INGRANDIMENTO DELLA CAVITà SINISTRA DOPO INFARTO TRANSMURALE,IN PRESENZA QUINDI DI TESSUTO CICATRIZIALE, NON QUANDO VI SIA TESSUTO VITALE.

35. LA TECNICA CHIRURGICA INFLUENZA PESANTEMENTE IL RISULTATO • SE LA RIDUZIONE VOLUMETRICA è TROPPO SPINTA VI è IL RISCHIO DI AVERE UNA DISFUNZIONE DIASTOLICA IMPORTANTE. • SE LA RIDUZIONE è LIMITATA NON VI è ALCUN BENEFICIO.

36. VIENE RIPORTATA UNA RIDUZIONE VOLUMETRICA DEL 5% NEI PAZIENTI SOTTOPOSTI A CABG E DEL 20% IN QUELLI OPERATI SVR, SI PUò ARGUIRE CHE L’INTERVENTO DI SVR DIMINUISCE IL VOLUME DEL 15%

37. E’ SUFFICIENTE UNA RIDUZIONE DEL 20% DEL VOLUME ? • GLI STUDI OSSERVAZIONALI PUBBLICATI RIPORTANO UNA DIMINUZIONE DEL VOLUME TRA IL 30% ED IL 50% • L’INTERVENTO DI SVR NON è UN INTERVENTO COSMETICO

38. Average % ESV reduction following CABG plus SVR %

39. LA VARIABILITà GEOGRAFICA DEI RISULTATI SEMBRA CONFERMARE I DUBBI SULLA OMOGENEITà DEL TRATTAMENTO CHIRURGICO.

40. MENO DEL 50% DEI PAZIENTI ERANO IN CLASSE III E IV • 13% DEI PAZIENTI NON AVEVANO STORIA DI INFARTO MIOCARDICO ACUTO • 25% DEI PAZIENTI NON PRESENTAVA LESIONE CRITICA DELA IVA

41. LO STICH TRIAL RAPPRESENTA UN VASO DI PANDORA SE I DATI PUBBLICATI CON UNA CERTA FRETTA SARANNO ANALIZZATI APPROFONDITAMENTE PROBABILMENTE DARANNO ALCUNE RISPOSTE CHE SI CERCAVANO, SE ALTRIMENTI CI SI FERMERà SOLAMENTE AGLI OUTCOME PRIMARI ALLORA SARà UN TRIAL NEUTRO CHE NON CONTRIBUISCE ALLA COMPRENSIONE DEL FENOMENO SCOMPENSO.

42. NYHA Functional Class changes following CABG+SVR San Donato Experience 9 84 75 120 75 18 N=213 N=170 Baseline EF</=35% STICH NEJM 2009

43. 93ml/m2 60 ml/m2 ESVI Changes following CABG + SVR Baseline EF </=35% STICH Patients (n=161) San Donato Patients (n=110) (Unpublished data) (NEJM March 2009) 83 ml/m2 67ml/m2 - 35% -19%

44. EDVI ESVI Changes following CABG + SVR (San Donato Experience) Baseline EF </=35% 0.0001 126 ml/m2 93 ml/m2 +22% EF 0.001 - 26% 36% 28% Baseline 8 months

45. NYHA functional class changes (% distribution) % pts I I II STICH II III-IV I III-IV I II San Donato % pts II III-IV III-IV Baseline EF</=35%

46. Pre and Post-operative NYHA functional class distribution 10% 42% 41% Milano 44% 49% 5% 14% 39% 45% STICH 45% 56% 10% Baseline EF</=35%

47. Hemodynamic Changes following CABG plus SVR in STICH-like patients (Baseline vs FUP) N=110 +22% +9% -26% -35% Average FUP= 1 year