Download VU University Medical Center, Amsterdam, the Netherlands

ONLINE APPENDIX
Explore Trial Organization
Steering Committee
Jose P. S. Henriques, Principal investigator, Academic Medical Center of the
University of Amsterdam, Amsterdam, the Netherlands
Rene van der Schaaf, Co-Principal investigator, Onze Lieve Vrouwe Gasthuis,
Amsterdam, the Netherlands
Jan G. P. Tijssen, biostatistician, Academic Medical Center of the University of
Amsterdam, Amsterdam, the Netherlands
And all international investigators
Data and Safety Monitoring Board
Felix Zijlstra, Thorax Center, Erasmus University Medical Center, Rotterdam, the
Netherlands
Menko-Jan de Boer, Radboud University Medical Center Nijmegen, Nijmegen, the
Netherlands
Clinical Event Committee
Rolf Michels, Catharina Hospital, Eindhoven, the Netherlands
Martijn Meuwissen, Amphia Hospital, Breda, the Netherlands
Database Management
Med-base, Zwolle, the Netherlands
Angiographic Clinical Event Committee/Angiographic Corelab
Pierfrancesco Agostoni, University Medical Center Utrecht, Utrecht, the Netherlands
K. Gert van Houwelingen, Thoraxcentrum Twente, Medisch Spectrum Twente,
Enschede, the Netherlands
Syntax Score Adjudication Corelab
Cardialysis, Rotterdam, the Netherlands
Independent Monitor
Cordinamo, Wezep, the Netherlands
Nuclear Medicine Corelab
Hein J. Verberne, Academic Medical Center of the University of Amsterdam,
Amsterdam, the Netherlands
Echocardiography Corelab
Alexander Hirsch, Academic Medical Center of the University of Amsterdam,
Amsterdam, the Netherlands
MRI Corelab
ClinFact, Leiden, the Netherlands
Explore trial investigators
Academic Medical Center of the University of Amsterdam, Amsterdam, the
Netherlands
José P. S. Henriques
Jan J. Piek
Robbert J. de Winter
Karel T. Koch
Marije M. Vis
Jan Baan
Joanna Wykrzykowska
Sahlgrenska University Hospital, Gothenburg, Sweden
Truls Råmunddal
Dan Ioanes
North Estonia Medical Center, Tallinn, Estonia
Peep Laanmets
Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands
René J. van der Schaaf
Ton Slagboom
Giovanni Amoroso
Haukeland University Hospital, Bergen, Norway
Erlend Eriksen
Vegard Tuseth
Haga Teaching Hospital, The Hague, the Netherlands
Matthijs Bax
Carl E. Schotborgh
Sint Antonius Ziekenhuis, Nieuwegein, the Netherlands
Maarten J. Suttorp
Sunnybrook Health Sciences Centre, Toronto, Canada
Bradley H. Strauss
Onze Lieve Vrouwe Ziekenhuis, Aalst, Belgium
Emanuele Barbato
VU University Medical Center, Amsterdam, the Netherlands
Koen M. Marques
Quebec Heart-Lung Institute, Quebec, Canada
Olivier Bertrand
Amphia Hospital, Breda, the Netherlands
Martijn Meuwissen
Maasstad Ziekenhuis, Rotterdam, the Netherlands
Martin van der Ent
Catharina Hospital, Eindhoven, the Netherlands
Jacques Koolen
Appendix A
Inclusion criteria
Patients with a non–infarct-related chronic total occlusion undergoing successful
primary PCI for STEMI (within 12 hours of onset of symptoms) are screened for
entry into this trial. For the purpose of this trial, a primary PCI is “successful” when
the residual stenosis of the culprit lesion <30% and the TIMI flow is ≥2.
STEMI is diagnosed when both of the following apply:

Typical chest pain

Electrocardiographic new or presumed new ST-segment elevation at the J
point in two or more contiguous leads with the cutoff points ≥0.2 mV in leads
V1, V2, or V3 and ≥0.1 mV in other leads
Patients are suitable for inclusion in this trial if coronary angiography preceding
the primary PCI reveals at least 1 chronic total occlusion with all of the following
characteristics:
1. Located in a non–infarct-related coronary artery:
a. In the left coronary system if the right coronary artery (RCA) is the
culprit lesion
b. In the RCA or left circumflex artery (LCX) if the left anterior
descending artery (LAD) is culprit lesion;
c. In the RCA or LAD if the LCX is the culprit lesion.
2. A 100% luminal narrowing without antegrade flow or with antegrade or
retrograde filling through collateral vessels
3. Amenable to PCI treatment, as assessed by the local heart team and dedicated
CTO operators
4. A reference diameter of ≥2.5 millimeters by visual estimation
Appendix B
Exclusion criteria
1. Older than 80 years of age
2. Persistent or permanent atrial fibrillation
3. Known renal insufficiency (e.g. serum creatinine level of more than 265
μmol/L [i.e., more than 3.5 mg/L])
4. More than 48 hours of hemodynamic instability after primary PCI, defined as
pre-shock (heart rate >100/min and or systolic blood pressure <100 mm Hg)
or shock (sustained systolic blood pressure ≤80 mm Hg despite fluid hydration
with ≥2 low-dose or 1 high-dose vasopressor or inotropic drug[s] or a cardiac
index of ≤2.2 liters per minute per square meter of body surface area and a
pulmonary capillary wedge pressure of at least 15 mm Hg if known)
5. Cardiac events between primary PCI and randomization:
a. Extended myocardial infarction, as evidenced by a new episode of
chest pain with new ST-segment elevations and a new CK/CK-MB
peak
b. Acute stent thrombosis
c. Ventricular arrhythmias (i.e., sustained ventricular tachycardia [VT] or
ventricular fibrillation [VF] more than 48 hours after primary PCI [i.e.,
late ventricular arrhythmia])
6. Significant left main stenosis (diameter stenosis ≥50%)
7. Indication for coronary artery bypass grafting (CABG)
8. Severe valvular heart disease requiring cardiac operation within 4 months
9. Indication for implantable cardioverter-defibrillator (ICD) within 4 months
10. Inability to schedule the index procedure within 7 days after primary PCI
11. Unsatisfactory baseline investigations (i.e., MRI not suitable for endpoint
assessment)
12. Any contraindication to MRI:
a. Pacemaker
b. Cerebrovascular clips
c. Claustrophobia
13. Serious known concomitant disease with a life expectancy of less than 1 year
14. Circumstances that prevent follow-up (e.g., no permanent home or address,
transience)
15. Previous participation in this trial
16. Current participation in another trial
Appendix C
Power calculation considerations:
The power calculation for the EXPLORE trial resulted from a process in which all
evidence available at the time of the inception of the trial (2006) was weighed. It
would have been impossible to provide an entirely accurate power calculation because
EXPLORE is the first trial of its kind. However, in our own cohort of patients
receiving successful CTO PCI we had found a mean LVEF of approximately 40%.
Moreover, a meta-analysis performed at that time (which was eventually published in
an updated form in 2015) showed a mean difference of 4.81% in LVEF in favor of
patients receiving CTO PCI compared with patients not receiving CTO PCI (Chung et
al., Danchin et al., Dzavik et al., Engelstein et al., Ermis et al., Fang et al., Gottschall
et al., Heyder et al., Ivanhoe et al., Jin et al., Kux et al., Melchior et al., Mori et al.,
Piscione et al. 2005, Schacherer et al., Sirned et al., Werner et al.). This was rounded
off to a 5% expected difference of LVEF. Because we estimated a success rate of
80%, this resulted in an absolute difference of 4% (leading to the expected LVEF of
36% in the conservative-treatment group).
Regarding the power calculation for LVEDV, the calculations were based on
all available data available in 2006 (Danchin et al., Fang et al., Piscione et al., Baks et
al.). In these studies, a mean difference in LVEDV index of -6.5 ml/m2 was found
after CTO PCI. In EXPLORE absolute LVEDV values were used instead of LVEDV
index; assuming a mean body surface area of 1.9 m2 in men, this resulted in an
absolute reduction of 12.35 ml. This number was rounded to 15 ml and used this for
the calculation. As mean baseline LVEDV we used the values of patients with an
ejection fraction around 40% (which was 200 ml).
Online Table 1
Table detailing participating sites in the EXPLORE trial and the number of patients
enrolled in each site
Center
Total inclusion
Academic Medical Center, the
Netherlands
Number of included patients
304
78
Sahlgrenska University Hospital, Sweden
61
North-Estonia Medical Center, Estonia
41
OLVG, the Netherlands
30
Haukeland University Hospital, Norway
29
Haga Ziekenhuis, the Netherlands
17
Sint Antonius Ziekenhuis, the
Netherlands
11
OLVZ, Belgium
9
Sunnybrook Health Sciences Centre,
Canada
9
VU Medical Center, the Netherlands
8
Quebec Heart-Lung Institute, Canada
4
Amphia ziekenhuis, the Netherlands
4
Maasstad Ziekenhuis, the Netherlands
2
Catharina Ziekenhuis, the Netherlands
1
TIMI flow post–CTO PCI per treatment group:
TIMI flow post–CTO
PCI
0
1
2
3
Successful CTO PCI
(n=106)
0
0
2 (1.9%)
104 (98.1%)
Not successful CTO PCI
(n= 41)
32 (78%)
6 (14.6%)
3 (7.3%)
0
Frequency All J-CTO total scores per treatment group, and in the total group (core-lab
adjudicated on pPCI angiography):
J-CTO
0
1
2
3
4
5
CTO PCI (n =
148)
11 (7.4%)
37 (25%)
45 (30.4%)
39 (26.4%)
16 (10.8%)
-
No CTO PCI (n =
154)
5 (3.2%)
33 (21.4%)
50 (32.5%)
41 (26.6%)
24 (15.6%)
1 (0.6%)
Total (n = 302)
16 (5.3%)
70 (23.2%)
95 (31.5%)
80 (26.5%)
40 (13.2%)
1 (0.3%)
Segment of the CTO per treatment group, and in the total group (core-lab
adjudicated):
CTO segment
1 RCA-prox
2 RCA-mid
3 RCA-dist
4 RDP
5 LM
6 LAD-prox
7 LAD-mid
8 LAD-dist
9 D1
10 D2
11 RCx-prox
12 OM1/IM
13 RCx-dist
14 OM2
15 LDP
16 RPL
CTO PCI (n =
148)
18 (12.2%)
38 (25.7%)
8 (5.4%)
0
0
4 (2.7%)
30 (20.3%)
0
2 (1.4%)
0
15 (10.1%)
8 (5.4%)
19 (12.8%)
6 (4.1%)
0
0
No CTO PCI (n =
154)
20 (13%)
45 (29.2%)
12 (7.8)
1 (0.6%)
0
14 (9.1%)
17 (11%)
4 (2.6%)
4 (2.6%)
0
8 (5.2%)
7 (4.5%)
18 (11.7%)
4 (2.6%)
0
0
Total (n = 302)
38 (12.6%)
83 (27.5%)
20 (6.6%)
1 (0.3%)
0
18 (6.0%)
47 (15.6%)
4 (1.3%)
6 (2.0%)
0
23 (7.6%)
15 (5.0%)
37 (12.3%)
10 (3.3%)
0
0