duke clinical research institute

Surgical Treatment for Ischemic
Heart Failure (STICH) Trial:
CABG versus CABG + SVR
LORENZO A. MENICANTI
Irccs Policlinico San Donato
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
Hypothesis 2 Enrollment by Country
 1000
patients
 96
clinical sites
 23
countries
 1231
days
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.
Baseline Clinical Characteristics
Characteristic
CABG
N = 499
CABG + SVR
N = 501
62 (54, 66)
62 (56, 69)
78 (16%)
69 (14%)
White
90%
92%
Diabetes
35%
34%
Creatinine, >0.5 mg/dL
8%
9%
Prior stroke
6%
6%
Age, median 25th, 75th, years
Female
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%)
18%
Site Reported Left Ventricular Function for
1,000 Hypothesis 2 Patients by Treatment
LV Function
CABG
N = 499
CABG + SVR
N = 501
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)
Site Qualifying Study
Coronary Anatomy by Treatment for
1,000 Hypothesis 2 Patients
Major Coronary
Arteries with
Stenosis
% Stenosis
CABG
N = 499
CABG + SVR
N = 501
≥50%
7%
10%
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%
Median
(25th, 75th)
65 (43, 91)
65 (39, 91)
One
LM stenosis
Duke coronary
disease index*
* 0 = coronary angiogram shows no coronary disease, 100 = ≥95% LM stenosis
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%
Operative Conduct by Operation Received
in 979 Hypothesis 2 Patients
Variable
CABG
N = 490
CABG + SVR
N = 489
P
Elective operation
84%
83%
0.54
Urgent
13%
13%
Emergency
3%
4%
Status at Operation
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%
17%
19%
Mitral surgery
SVR patch
59%
0.50
Efficiency of Operative Care
in 979 Hypothesis 2 Patients
Duration of Operation
CABG
N = 490
CABG + SVR
N = 489
P
Total time in operating room
(median, 25th, 75th), hours
4.9 (4.1, 6.0)
5.5 (4.7, 6.6)
<0.001
Cardiopulmonary bypass time
(median, 25th, 75th), minutes
99 (73, 125)
124 (99, 158)
<0.001
Aortic occlusion (median, 25th,
75th), minutes
62 (45, 84)
80 (62, 106)
<0.001
Requirements for Postoperative Care
Endotracheal intubation
(median, 25th, 75th), hours
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)
69.5 (42, 137)
<0.001
22 (5%)
31 (6%)
0.20
Hospitalization >30 days
Baseline and Four Month End-Systolic Volume
Index (ESVI) in 373 Hypothesis 2 Patients With
Quantitative Echocardiogram at Both Intervals
80
60
ESVI
40
82 ml/m2
77 ml/m2
83 ml/m2
67 ml/m2
20
0
P<0.001
Baseline
4 Months
CABG
(N = 212)
Baseline
4 Months
CABG+SVR
(N = 161)
Canadian Cardiovascular Society Angina Class in
Hypothesis 2 Patients at Baseline and Latest Follow-up
CABG
CCS Angina Class
CABG+SVR
CCS Angina Class
500
400
300
No Angina
121
No Angina
128
Class I-II
130
Class I-II
129
Patients
No Angina
339
No Angina
339
200
100
0
Class III-IV
248
Class III-IV
244
Class I-II
88
Baseline
(N = 499)
Class I-II
83
Class III-IV
8
Latest
Follow-up
(N = 435)
Baseline
(N = 501)
Angina symptoms improved by an average of 1.7 classes
in both cohorts (P=0.84).
Class III-IV
6
Latest
Follow-up
(N = 428)
New York Heart Association Heart Failure Class in
Hypothesis 2 Patients at Baseline and Latest Follow-up
CABG
NYHA HF Class
500
Class I 36
CABG+SVR
NYHA HF Class
Class I 50
400
300
Class II
222
Class I
165
Class II
207
Class I
179
Patients
200
100
0
Class III-IV
241
Class II
190
Class III-IV
244
Class III-IV
80
Baseline
(N = 499)
Latest
Follow-up
Follow-up
(N = 435)
436)
Class II
190
Class III-IV
80
Baseline
(N = 501)
Latest
Follow-up
Follow-up
(N = 429)
435)
Baseline and Four Month 6-Minute Walk in 693
Hypothesis 2 Patients with Baseline Assessment
Patients
30-Day Mortality
Outcome
CABG
N = 499
CABG + SVR
N = 501
P
30/501 (6.0%)
0.26
Death Within 30 Days After Randomization
All patients by intention
to treat
22/499 (4.4%)
Death During or Within 30 Days of Operation
Operated patients by
intention to treat
25/490 (5.1%)
26/489 (5.3%)
0.88
Operated patients by
operation received
23/498 (4.6%)
28/481 (5.8%)
0.40
Death or Cardiac Hospitalization
Kaplan-Meier Estimates of Primary Endpoint
0.7
Event Rate
0.6
0.5
0.4
0.3
0.2
CABG
0.1
0
0
1
No. at Risk
CABG
499
CABG+SVR 501
319
319
292 events
2
3
4
Years from Randomization
270
275
220
216
99
11
5
23
23
Death or Cardiac Hospitalization
Kaplan-Meier Estimates of Primary Endpoint
0.7
HR 0.99 (95% CI: 0.84, 1.17), P=0.90
Event Rate
0.6
0.5
0.4
0.3
0.2
CABG
292 events
0.1
CABG+SVR
289 events
0
0
1
No. at Risk
CABG
499
CABG+SVR 501
319
319
2
3
4
Years from Randomization
270
275
220
216
99
11
5
23
23
Mortality (All-Cause)
Kaplan-Meier Estimates
0.7
Mortality Rate
0.6
0.5
0.4
0.3
0.2
0.1
0
CABG
0
1
No. at Risk
CABG
499
CABG+SVR 501
434
429
141 deaths
2
3
4
Years from Randomization
417
404
363
352
201
193
5
59
53
Mortality (All-Cause)
Kaplan-Meier Estimates
0.7
HR 1.00 (95% CI: 0.79, 1.26), P=0.98
Mortality Rate
0.6
0.5
0.4
0.3
0.2
CABG
141 deaths
CABG+SVR 138 deaths
0.1
0
0
1
No. at Risk
CABG
499
CABG+SVR 501
434
429
2
3
4
Years from Randomization
417
404
363
352
201
193
5
59
53
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
Hazard Plots of Selected Baseline Characteristics
Subgroup
N
All Subjects
1000
Age
≥ 65
391
< 65
609
Gender
Male
853
Female
147
Race
Minority
124
Non-minority
876
Current NYHA HF class
I or II
515
III or IV
485
HR (95% CI)
0.99 (0.84, 1.17)
P Value
0.48
1.06 (0.83, 1.35)
0.94 (0.76, 1.17)
0.60
1.01 (0.84, 1.20)
0.90 (0.58, 1.39)
0.44
0.83 (0.51, 1.36)
1.01 (0.85, 1.20)
0.97
0.99 (0.78, 1.25)
0.99 (0.79, 1.24)
0.5
1.0
CABG+SVG
CABG+SVR
Better
Better
2.0
CABG
Better
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)
0.5
1.0
CABG+SVG
CABG+SVR
Better
Better
2.0
CABG
CABG
Better
Better
Hazard Plots of Selected Baseline Characteristics cont
Subgroup
Mitral regurgitation
None or trace
Mild (≤ 2+)
Mod. or severe
Stratum
B
C
Region
Poland
USA
Canada
West Europe
Other
N
HR (95% CI)
363
449
178
0.89 (0.68, 1.17)
1.12 (0.88, 1.43)
0.94 (0.65, 1.36)
P Value
0.44
0.44
141
859
1.15 (0.76, 1.76)
0.96 (0.81, 1.15)
0.41
288
200
154
164
194
1.02 (0.76, 1.37)
1.10 (0.79, 1.54)
0.77 (0.50, 1.18)
0.80 (0.53, 1.22)
1.24 (0.81, 1.91)
0.5
1.0
CABG+SVG
CABG+SVR
Better
Better
2.0
CABG
Better
Jones R et al. N Engl J Med 2009;10.1056/NEJMoa0900559
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 longterm 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.
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

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

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.

RANDOMIZZAZIONE COINVOLGE MENO
DEL 20% DEI PAZIENTI ELIGIBILI.

80% DEI PAZIENTI ELIGIBILI è STATO
SOTTOPOSTO A SVR PER EVIDENZA
DELLA SUPERIORITà DELLA PROCEDURA

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.

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.

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%

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
0
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-20
-30
-40
-50
-60
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Average % ESV reduction following CABG plus SVR

LA VARIABILITà GEOGRAFICA DEI
RISULTATI SEMBRA CONFERMARE I
DUBBI SULLA OMOGENEITà DEL
TRATTAMENTO CHIRURGICO.

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

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.
NYHA Functional Class changes following CABG+SVR
San Donato Experience
250
9
200
Class 1
84
150
75
Class 2
Class 3-4
100
120
75
50
18
0
Baseline
N=213
Baseline EF</=35%
Follow-Up
N=170
STICH NEJM 2009
ESVI Changes following CABG + SVR
Baseline EF </=35%
STICH Patients (n=161)
100
(NEJM March 2009)
San Donato Patients (n=110)
100
80
80
60
60
40
(Unpublished data)
93ml/m2
83 ml/m2
67ml/m2
40
20
20
0
0
4 months
Baseline
-19%
60 ml/m2
Baseline
- 35%
8 months
EDVI
ESVI Changes following CABG + SVR (San Donato Experience)
140
Baseline EF </=35%
120
0.0001
100
80
60
126 ml/m2
93 ml/m2
40
20
+22%
EF
0
0.001
40
Baseline
8 months
- 26%
35
30
25
20
15
36%
28%
10
5
0
Baseline
8 months
NYHA functional class changes (% distribution)
% pts
100
80
I
I
II
60
STICH
40
II
III-IV
20
100
I
III-IV
I
80
0
Baseline
II
Follow-Up
San Donato
60
% pts
II
40
III-IV
20
III-IV
Baseline EF</=35%
0
Baseline
Follow-Up
Pre and Post-operative NYHA functional class distribution
100
10%
90
80
70
41%
42%
Class 1
Class 2
60
50
44%
40
30
Class 3-4
Milano
49%
5%
20
14%
10
100
90
0
Baseline
Follow-Up
80
39%
45%
Class 1
70
STICH
Class 2
60
50
40
30
56%
45%
20
10%
10
Baseline EF</=35%
0
Baseline
Follow-Up
Class 3-4
Hemodynamic Changes following CABG plus SVR in
STICH-like patients (Baseline vs FUP)
30
N=110
20
+22%
10
+9%
0
-10
-26%
-35%
-20
-30
-40
EDVI
Average FUP= 1 year
ESVI
SVI
EF