DUKE CLINICAL RESEARCH INSTITUTE

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Surgical Treatment for Ischemic Heart Failure
(STICH) Trial CABG versus CABG SVR LORENZO
A. MENICANTI Irccs Policlinico San Donato
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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
  OConnor, Robert Michler, Jae Oh
• DSMB chair Sidney Goldstein
• Policy and Publication Committee chair James
  Hill
• Clinical Endpoints Committee chair Peter Carson

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

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Baseline Clinical Characteristics
Characteristic CABG N 499 CABG SVR N 501

Age, median 25th, 75th, years 62 (54, 66) 62 (56, 69)
Female 78 (16) 69 (14)
White 90 92
Diabetes 35 34
Creatinine, gt0.5 mg/dL 8 9
Prior stroke 6 6
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Mitral Regurgitation by Treatment in 1,000
Hypothesis 2 Patients
Mitral Regurgitation Severity CABG N 499 CABG SVR N 501

None or trace 173 (35) 190 (38)

Mild (2) 233 (47) 216 (44)

Moderate (3) 72 (15) 70 (14)

Severe (4) 16 (3) 20 (4)

Not assessed 5 (4) 5 (3)
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Site Reported Left Ventricular Function for
1,000 Hypothesis 2 Patients by Treatment
LV Function CABG N 499 CABG SVR N 501
Site Qualifying Study
Echocardiogram () 66 63
Contrast ventriculogram 13 18
CMR 11 9
Gated SPECT 10 10

LVEF, median (25th, 75th) .28 (.23, .31) .28 (.24, .31)

ESVI, median (25th, 75th), mL/m2 82 (65, 102) 82 (66, 105)

anterior wall with akinesia/ dyskinesia, median (25th, 75th) 56 (40, 60) 50 (40, 60)
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Coronary Anatomy by Treatment for 1,000
Hypothesis 2 Patients
Major Coronary Arteries with Stenosis Stenosis CABG N 499 CABG SVR N 501
One 50 7 10
LM stenosis 50-74 14 12
One 75 17 20
Two 75 41 42
Three 75 41 36
Proximal LAD 75 78 74
LM stenosis 75 6 7
Duke coronary disease index Median (25th, 75th) 65 (43, 91) 65 (39, 91)
0 coronary angiogram shows no coronary
disease, 100 95 LM stenosis
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Medication at Baseline
Medication CABG N 499 CABG SVR N 501

Beta blocker 85 87
ACE inhibitor or angiotensin receptor blocker 87 89
ACE inhibitor 80 82
Digoxin 17 14
Diuretic 69 66
Aspirin 77 77
Aspirin or warfarin 81 83
Statin 79 75
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Operative Conduct by Operation Received in 979
Hypothesis 2 Patients
Variable CABG N 490 CABG SVR N 489 P
Status at Operation
Elective operation 84 83 0.54
Urgent 13 13
Emergency 3 4

Bypass Grafts 0.34
1 or more arterial grafts 93 89
2 or less total grafts 27 30
3 or more total grafts 73 70

Mitral surgery 17 19 0.50
SVR patch 59
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Efficiency of Operative Care in 979 Hypothesis 2
Patients
Duration of Operation Duration of Operation CABG N 490 CABG SVR N 489 P
Total time in operating room (median, 25th, 75th), hours Total time in operating room (median, 25th, 75th), hours 4.9 (4.1, 6.0) 5.5 (4.7, 6.6) lt0.001
Cardiopulmonary bypass time (median, 25th, 75th), minutes Cardiopulmonary bypass time (median, 25th, 75th), minutes 99 (73, 125) 124 (99, 158) lt0.001
Aortic occlusion (median, 25th, 75th), minutes Aortic occlusion (median, 25th, 75th), minutes 62 (45, 84) 80 (62, 106) lt0.001
Requirements for Postoperative Care Requirements for Postoperative Care Requirements for Postoperative Care
Endotracheal intubation (median, 25th, 75th), hours 15.1 (10.9, 22.1) 15.1 (10.9, 22.1) 16.6 (12.0, 25.2) 0.002
Acute care (median, 25th, 75th), hours 49.8 (28.8, 95.5) 49.8 (28.8, 95.5) 69.5 (42, 137) lt0.001
Hospitalization gt30 days 22 (5) 22 (5) 31 (6) 0.20
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Baseline and Four Month End-Systolic Volume Index
(ESVI) in 373 Hypothesis 2 Patients With
Quantitative Echocardiogram at Both Intervals
ESVI
82 ml/m2
77 ml/m2
83 ml/m2
67 ml/m2
Plt0.001
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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 (P0.84).
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New York Heart Association Heart Failure Class in
Hypothesis 2 Patients at Baseline and Latest
Follow-up
CABGNYHA HF Class
CABGSVRNYHA 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)
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Baseline and Four Month 6-Minute Walk in 693
Hypothesis 2 Patients with Baseline Assessment
Patients
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30-Day Mortality
Outcome Outcome CABG N 499 CABG SVR N 501 P

Death Within 30 Days After Randomization Death Within 30 Days After Randomization Death Within 30 Days After Randomization
All patients by intention to treat All patients by intention to treat 22/499 (4.4) 30/501 (6.0) 0.26

Death During or Within 30 Days of Operation Death During or Within 30 Days of Operation Death During or Within 30 Days of Operation
Operated patients by intention to treat 25/490 (5.1) 25/490 (5.1) 26/489 (5.3) 0.88
Operated patients by operation received 23/498 (4.6) 23/498 (4.6) 28/481 (5.8) 0.40

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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
499
319
270
220
99
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CABG
501
319
275
216
11
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CABGSVR
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Death or Cardiac
Hospitalization Kaplan-Meier
Estimates of Primary Endpoint
0.7
HR 0.99 (95 CI 0.84, 1.17), P0.90
0.6
0.5
0.4
Event Rate
0.3
292 events
0.2
CABG
289 events
CABGSVR
0.1
0
0
1
2
3
4
5
Years from Randomization
No. at Risk
499
319
270
220
99
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CABG
501
319
275
216
11
23
CABGSVR
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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
499
434
417
363
201
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CABG
501
429
404
352
193
53
CABGSVR
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Mortality (All-Cause)
Kaplan-Meier Estimates
0.7
HR 1.00 (95 CI 0.79, 1.26), P0.98
0.6
0.5
0.4
Mortality Rate
0.3
0.2
141 deaths 138 deaths
CABG
0.1
CABGSVR
0
0
1
2
3
4
5
Years from Randomization
No. at Risk
499
434
417
363
201
59
CABG
501
429
404
352
193
53
CABGSVR
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Summary of Outcomes in STICH H2
Outcomes CABG N 499 CABG SVR N 501 Hazard Ratio 95 CI P

Death or cardiac hospitalization 292 (59) 289 (58) 0.99 (0.84, 1.17) 0.90

Death 141 (28) 138 (28) 1.00 (0.79, 1.26) 0.98

Hospitalization (cardiac) 211 (42) 204 (41) 0.97 (0.80, 1.18) 0.73

Hospitalization (all cause) 272 (55) 268 (53) 0.98 (0.83, 1.16) 0.82

Acute MI 22 (4) 20 (4) 1.01 (0.54, 1.87) 0.96

Stroke 31 (6) 23 (5) 0.77 (0.45, 1.32) 0.35
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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) lt 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)
CABGSVRBetter
CABGBetter
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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) gt 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)
CABGSVRBetter
CABGBetter
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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)
CABGSVRBetter
CABGBetter
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Jones R et al. N Engl J Med 200910.1056/NEJMoa090
0559
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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.

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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

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• 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 lt 35
• LO STUDIO PERDE LA SUA CARATTERISTICA PRINCIPALE
  DI STUDIO SU MALATI SCOMPENSATI PER DIVENIRE UNO
  STUDIO SU PAZIENTI ISCHEMICI

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• 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.

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

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• LINTERVENTO 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.

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• 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.

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• VIENE RIPORTATA UNA RIDUZIONE VOLUMETRICA DEL 5
  NEI PAZIENTI SOTTOPOSTI A CABG E DEL 20 IN
  QUELLI OPERATI SVR, SI PUò ARGUIRE CHE
  LINTERVENTO DI SVR DIMINUISCE IL VOLUME DEL 15

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

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Average ESV reduction following CABG plus SVR


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

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• 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

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• 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.

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NYHA Functional Class changes following
CABGSVR San Donato Experience
9
84
75
120
75
18
N213
N170
Baseline EFlt/35
STICH NEJM 2009
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ESVI Changes following CABG SVR
Baseline EF lt/35

STICH Patients (n161) San Donato
Patients (n110)
(Unpublished data)
(NEJM March 2009)
83 ml/m2
67ml/m2
- 35
-19
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EDVI
ESVI Changes following CABG SVR (San Donato
Experience)
Baseline EF lt/35
0.0001
126 ml/m2
93 ml/m2
22
EF
0.001
- 26
36
28
Baseline
8 months
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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 EFlt/35
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Pre and Post-operative NYHA functional class
distribution
10
42
41
Milano
44
49
5
14
39
45
STICH
45
56
10
Baseline EFlt/35
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Hemodynamic Changes following CABG plus SVR in
STICH-like patients (Baseline vs FUP)
N110
22
9
-26
-35
Average FUP 1 year