1. SMILE
TRIAL
Featured Clinical Research II
Impact of one Stage compared with Multistaged percutaneous complete coronary revascularIzation on cLinical outcome in multivessel NSTEMI patiEnts.
(NCT )
On behalf of SMILE TRIAL investigators
GENNARO SARDELLA MD, FACC ,FESC
O.U. of Interventional Cardiology
Dept. of Cardiovascular and Pulmonary Sciences
Policlinico Umberto I
“Sapienza “ University of ROME

2. Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship
Company
Grant/Research Support
Consulting Fees/Honoraria
Major Stock Shareholder/Equity
Royalty Income
Ownership/Founder
Intellectual Property Rights
Other Financial Benefit
None
Boston Scientific, Astra Zeneca,Alvimedica,Biosensors,Terumo

3. Multi-vessel Disease in the setting of ACS
SMILE
TRIAL
30-40% in the setting of STEMI
Muller DW, et al Multivessel coronary artery disease: a key predictor of short-term prognosis after reperfusion therapy for acute myocardial infarction. Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group. Am Heart J 1991;121:1042-9
Toma M,, et al. Non-culprit coronary artery percutaneous coronary intervention during acute ST-segment elevation myocardial infarction: insights from the APEX-AMI trial. European Heart Journal 2010;31:1701-7
44-60% in the setting of NSTEMI
Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB Trial. Thrombolysis in Myocardial Ischemia. Circulation
1994;89:1545–1556.
Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators.
Lancet 1999;354:708–715.

4. Multi-vessel Disease in the setting of ACS
SMILE
TRIAL
Multi-vessel Disease in the setting of ACS
Culptit lesion uncertain and misleading

5. Guidelines and Multi-Vessels NSTEMI Patients
No suggestions
No References
The strategy of multivessel stenting for suitable significant stenoses rather than stenting the culprit lesion only has not been evaluated appropriately in a randomized fashion

6. Impact of one Stage compared with Multistaged
percutaneous complete coronary revascularIzation on cLinical outcome in
multivessel NSTEMI patiEnts.
HYPOTHESIS:
Complete coronary revascularization, in multivessel NSTEMI patients, is superior to ad hoc culprit lesion PCI
OBJECTIVE: The aim of our study is to compare one stage (S-PCI) vs multi-staged (MS-PCI) complete coronary revascularization during the index hospitalization in NSTEMI patients with > 1 vessel > 70% angiographically.

7. Statistical Analysis
On the basis of a two-sided test size of 5% and a power of 80%, it was calculated that a minimum of 247 patients would need to be recruited in each group to detect a difference in the incidence of MACCE at one year of 9%. .
Expected MACCE at 1 year * **
Multi-staged = 9%
One Staged = 18%
Applying the Pocock group sequential design for a trial with two planned analyses (the first after half the number of patients were recruited) would assume P<0.029 as a stopping rule at each analysis for a treatment difference.
*Shishehbor MH, et al. J Am Coll Cardiol 2007;49:849–854.
**Kornowski R, Mehran R, Dangas G, et al. JACC 2011; 58 (7):

8. Study Design 500 NSTEMI pts
DESIGN: Prospective, randomized, open label,double-arm, multi-center study
Primary Endpoint: Incidence of major adverse cardiac and cerebrovascular events (MACCE) defined as cardiac or non-cardiac death, re-infarction, re-hospitalization for acute coronary syndrome,repeat coronary revascularization and stroke 1 year.
Secondary endpoint : Incidence of Bleedings at 30 days, 6 months and 1 year
500 NSTEMI pts
Early Invasive Strategy (within 24 hrs)
Angio
> 1 vessel with > 70% DS
1:1 Randomization
SINGLE stage PCI revascularization
n= 253
Multi- stage PCI revascularization
n= 247
Clinical Follow-Up ( Months)

9. P.I. : Gennaro Sardella MD Steering Committe: M.Mancone,R.Garbo
S.Giovanni Bosco Hospital
Turin
P.I. : Gennaro Sardella MD
Steering Committe: M.Mancone,R.Garbo
L.Lucisano, M.Pennacchi
Safety Committee: U.Fabrizio,G.Boccuzzi
R.Garbo MD
F.Ugo MD
G.Boccuzzi MD
G.Sardella MD
M.Mancone MD
M.Pennacchi MD
L.Lucisano MD
Policlinico
Umberto I
Rome

10. METHODS Exclusion Criteria Inclusion Criteria age ≥ 18 years,
diagnosis of NSTEMI according to current guidelines
MV disease at angio (> 1 vessel with
> 70% stenosis)
The unculprit vessel should be a major (>2mm) epicardial coronary artery or branch (>2mm) and be suitable for stent implantation.
signed informed consent.
cardiogenic shock or any condition
requesting an Urgent Invasive Strategy
(< 2hrs)
left main coronary artery disease,
CTO
Syntax Score > 32
previous coronary artery bypass grafting surgery,
candidate to by-pass surgery,
severe valvular heart disease
kidney impairment 10

11. FLOW-Chart 476 pts excluded : 143 pts suitable for EIS (< 2hrs)
30 pts previous coronary artery
bypass grafting surgery
303 pts with a single lesion
Between September 2011 and August pts with diagnosed NSTEMI
were scheduled.
615 Multivessel pts
(56,3%)
73 pts excluded :
5 pts left main coronary artery disease,
55 Syntax Score >32 and/or indication to CABG revascularization
3 pts severe valvular heart disease
10 refused consent
542 pts randomized
27 unsuccessful complete coronary revascularization
15 pts were lost to the follow-up
SINGLE stage PCI revascularization n= 253
MACCE at 12 months analyzed
Multi- stage PCI revascularization n= 247
MACCE at 12 months analyzed

12. Baseline Characteristics
SINGLE Staged (tot. = 253)
MULTI Staged (tot. =247)
p value
Mean Age - yr
69.48 ± 11.36
69.95 ± 11.79
0.64
Sex – no. (%)
Male
Female
200 (79.05)
53 (20.94)
198 (80.16)
49 (19.84)
0.82
Medical History – no. (%)
Diabetes NID
Diabetes ID
Hypertension
Hypercholesterolemia
Smoking Status
Family History
Prior MI
Prior PCI
Prior CABG
87 (34.38)
6 (2.37)
190 (75.09)
147 (58.10)
118 (46.64)
134 (52.96)
71 (28.06)
39 (15.41)
21 (8.30)
91 (36.84)
9 (3.64)
171 (69.23)
139 (56.28)
101 (40.89)
131 (53.04)
58 (23.48)
40 (16.19)
20 (8.10)
0.57
0.44
0.16
0.71
0.20
1.00
0.26
0.90
Mean Serum Creatinine – mg/dL
1.02 ± 0.32
1.03 ± 0.43
0.76
Troponin - ng/ml
0.55±1.40
0.45±1.31
0.41
Mean GRACE Death in Hospital score
± 30.63
± 31.41
0.87
Mean CRUSADE score
23.60 ± 10.49
23.45 ± 11.94
Mean Systolic Blood Pressure - mmHg
± 10.66
± 16.51
0.80
Mean Heart rate - bpm
79.88 ± 12.17
77.98 ± 12.36
0.07
Mean Left ventricle Ejection Fraction - %
47.26 ± 9.44
46.81 ± 10.57
0.61
Killip class – no. (%)
III IV
6 (2.43)
2 (0.81)
1 (0.40)
7 (2.83)
0.12
0.17

13. Anti-aggregation therapy at Hospitalization
SINGLE Staged (tot. = 253)
MULTI Staged (tot. = 247)
p value
Thienopyridines pre-randomization
Clopidogrel 75 mg
Clopidogrel 300 mg
Clopidogrel 600 mg
Prasugrel 60 mg
Prasugrel 5 mg
Ticagrelor 90 mg
Ticagrelor 180 mg
42 (16.66)
49 (19.36)
53 (20.94)
2 (0.79)
106(41.89)
1 (0.39)
21 (8.50)
55 (22.26)
60 (24.29)
4 (1.62)
2 (0.81)
102 (41.29)
3 (1.21)
0.64
Gp IIb/IIIa Inhibitors – no. (%)
None
Abciximab
Tirofiban
Eptifibatide
219 (86.56)
10 (3.95)
12 (4.74)
214 (86.64)
9 (3.64)
13 (5.26)
11 (4.45)
0.47
Thienopyridines post-procedure
Prasugrel 10 mg
109 (43.08)
140 (55.33)
105 (42.51)
136 (55.06)
0.71

14. Artery access site (A) p value A vs. B A vs. C Characteristics
SINGLE Staged (tot. =253)
(A)
MULTI Staged (tot. =247)
First procedure (B)
p value
A vs. B
Second procedure (C)
A vs. C
Access site – no. (%)
Right femoral
Left femoral
Right radial
Left radial
43 (16.99)
1 (0.39)
7 (2.76)
202 (79.84)
29 (11.74)
6 (2.43)
15 (6.07)
197 (89.75)
0.09
0.06
0.08
1.00
75 (30.36)
2 (0.81)
41 (16.60)
129 (52.23)
0.0005
1.0
<0.0001

15. Procedural characteristics
SINGLE Staged (tot. =253)
MULTI Staged (tot. =247)
P value
Target vessel – n. (%)
Left anterior descending
Right coronary artery
Left circumflex
Left main
225 (36.88)
152 (24.92)
209 (34.26)
24 (3.93)
223 (36.67)
157 (25.82)
201 (33.05)
13 (2.13)
0.61
Mean number of treated vessels
2.41 ± 0.37
2.46 ± 0.67
0.30
Lesion Type – n. (%) A B1 B2 C
87 (11.90)
199 (27.22)
185 (25.31)
260 (35.57)
76 (10.55)
180 (25.00)
189 (26.25)
275 (38.19)
0.37
Baseline angiographic analysis
Mean DVR – mm
Mean Lesion Length – mm
Mean MLD – mm
Diameter stenosis - %
FFR/IVUS utilization %
2.91 ± 0.42
22.75 ± 12.72
0.84 ± 0.52
84.48 ±
10,6
2.87 ± 0.39
23.43 ± 16.40
0.81 ± 0.62
86.06 ± 12.25
18,6
0.26
0.60
0.55
0.18
0. 32
Mean Syntax Score
15.77 ± 3.96
15.26 ± 7.73
0.34
Mean TIMI flow pre-procedure
2.70 ± 0.71
2.79 ± 0.69
0.15
Stents per patient
3.07 ± 1.37
3.14 ± 1.44
0.58
Stent type – no. (%)
Bare Metal
Biolimus
Zotarolimus
Everolimus
POBA
135 (17.26)
297 (37.97)
38 (4.85)
306 (39.13)
6 (0.76)
139 (17.93)
295 (38.06)
40 (5.16)
294 (37.93)
7 (0.90)
0.65
Mean Minimum stent diameter - mm
2.95 ± 0.41
2.90 ± 0.63
0.28
Mean cumulative stent length – mm
23.04 ± 15.50
24.46 ± 20.60
0.38

16. Myocardial Enzymes p<0.001 p=ns p=ns Post Procedure Characteristics
SINGLE Staged (tot. =253)
MULTI Staged (tot. =247)
First procedure
Second procedure
P value
Single vs Multi 1st procedure
Single vs Multi 2nd
procedure
CK-MB Pre
9.58±13.34
10.66±11.82
0.33
Troponin Pre
0.55±1.40
0.45±1.31
0.41
Myoglobin pre
111.09±250.06
91.02±82.56
0.4337
Post Procedure
CK-MB Post
9.82±24.64
10.61±12.72
10.91±11.66
0.6545
0.5300
Troponin Post
0.54±0.96
0.95±1.28
0.60±0.83
˂0.0001
0.4578
Myoglobin post
79.31±129.73
80.19±58.86
59.81±34.88
0.9227
0.0230
p<0.001
p=ns
p=ns

17. In-Hospital Clinical Events
Characteristics
SINGLE Staged (tot. =253)
MULTI Staged (tot. =247)
P value
MACCE – no. (%)
Death – no. (%)
Cardiac Death – no. (%)
Stroke – no.(%)
Myocardial Infarction *
Q – no. (%)
non-Q – no. (%)
UA needing Hospitalization
TVR – no. (%)
1 (0.39)
3 (1.21)
2 (0.80)
1 (0.40)
0.36
0.45
0.68
1.00
Definite Stent thrombosis
1.0
Bleedings – no. (%)
Minimal
Minor
Major
6 (2.42)
0.01
* Excluded peri-procedural MI

18. 1 month Clinical Events *According to BARC Criteria
Characteristics
SINGLE Staged (tot. =253)
MULTI Staged (tot. =247)
P value
MACCE – no. (%)
Death – no. (%)
Cardiac Death – no. (%)
Stroke – no.(%)
Myocardial Infarction
Q – no. (%)
non-Q – no. (%)
UA needing Hospitalization
TVR – no. (%)
6 (2.37)
5 (1.97)
4 (1.58)
1 (0.39)
2 (0.78)
3 (1.21)
2 (0.88)
1 (0.40)
4 (1.61)
0.50
0.45
0.68
1.00
Definite Stent thrombosis
1.0
Bleedings – no. (%) *
7 (2.82)
0.01
*According to BARC Criteria
* Mehran R, Circulation. 2011;123:

19. 6 months Clinical Events
Characteristics
SINGLE Staged (tot. =253)
MULTI Staged (tot. =247)
P value
MACCE – no. (%)
Death – no. (%)
Cardiac Death – no. (%)
Stroke – no.(%)
Myocardial Infarction
Q – no. (%)
non-Q – no. (%)
UA needing Hospitalization
TVR – no. (%)
13 (5.13)
8 (3.16)
6 (2.37)
4 (1.58)
5 (1.97)
9 (3.55)
27 (10.93)
19 (7.69)
10 (4.04)
7 (2.83)
2 (0.80)
5 (2.02)
4 (1.61)
13 (5.26)
0.02
0.31
1.00
0.37
0.24
0.74
0.51
Definite Stent thrombosis
1 (0.39)
1 (0.40)
Bleedings – no. (%)
8 (3.22)
0.01

20. 12 months Clinical Events
Characteristics
SINGLE Staged (tot. =253)
MULTI Staged (tot. =247)
P value
MACCE – no. (%)
Death – no. (%)
Cardiac Death – no. (%)
Stroke – no.(%)
Myocardial Infarction
Q – no. (%)
non-Q – no. (%)
UA needing Hospitalization
TVR – no. (%)
33 (13.04)
14 (5.53)
9 (3.55)
1 (0.39)
7 (2.76)
2 (0.78)
5 (1.98)
11 (4.34)
22 (8.69)
57 (23.07)
28 (11.33%)
13 (5.26%)
9 (3.64)
3 (1.21)
6 (2.42)
13 (5.26)
36 (14.57%)
0.0036
0.02
0.38 1
0.61
0.68
0.76
0.67
0.05
Definite Stent thrombosis
1 (0.40)
1.00
Bleedings – no. (%)
4 (1.56)
12(4.85)
0.03

21. 12 months follow-up Survival Analysis MACCE One-stage rev.
Multi-stage rev.
Cum MACCE
p log rank =0.004
Time (days)

22. 12 months follow-up Survival Analysis Non- Cardiac Death
One-stage rev.
Multi-stage rev.
Cum Non-Cardiac Death
p log rank =0.021
Time (days)

23. Target Vessel Revascularization
12 months follow-up
Survival Analysis
Target Vessel Revascularization
One-stage rev.
Multi-stage rev.
Cum TVR
p log rank =0.045
Time (days)

24. 12 months follow-up Survival Analysis Cardiac Death One-stage rev.
Multi-stage rev.
Cum Cardiac Death
p log rank =0.361
Time (days)

25. MACCE (cardiac death only)
12 months follow-up
Survival Analysis
MACCE (cardiac death only)
One-stage rev.
Multi-stage rev.
Cardiac death
p log rank =0.060
Time (days)

26. Conclusions
One staged complete coronary revascularization is associated:
to less minor bleeding
a rapid decrease of myocardial enzymes in particular troponin
to minor incidence of MACCE
The superiority of one staged complete coronary revascularization in terms of MACCE is mainly due to the unexplained higher incidence of non cardiac death.
One staged revascularization is associated to a lower TVR rate.

27. Positive Features of SMILE TRIAL Limitations of SMILE TRIAL
Trial completed
Strict definition of recurrent MI
All lesions angio > 70%
Contemporary trial
(high % radial/ and 2nd generation of DES)
High percent of pts completed
Follow-up (92.3%)
Small study
Primary Combined end point
Not Powered for secondary
end-points
Open label study
Low rate of FFR /IVUS for severity

28. Thank you

29. 12 months follow-up: Survival Analysis non-Q MI
One-stage population
Multi-stage population
Cum non-Q MI
p log rank =0.734
Time (days)

30. 12 months follow-up Survival Analysis Q MI One-stage population
Multi-stage population
Cum Q MI
p log rank =0.636
Time (days)

31. 12 months follow-up Survival Analysis STROKE One-stage population
Multi-stage population
Cum STROKE
p log rank =0.550
Time (days)