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Procedural and Long-Term Outcomes of Percutaneous Coronary Intervention for In-Stent Chronic Total Occlusion
JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 10, NO. 9, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
ISSN 1936-8798/$36.00 http://dx.doi.org/10.1016/j.jcin.2017.01.047
Procedural and Long-Term Outcomes of Percutaneous Coronary Intervention for In-Stent Chronic Total Occlusion Lorenzo Azzalini, MD, PHD, MSC,a Rustem Dautov, MD, PHD,b,c Soledad Ojeda, MD, PHD,d Susanna Benincasa, MD,a Barbara Bellini, MD,a Francesco Giannini, MD,a Jorge Chavarría, MD,d Manuel Pan, MD, PHD,d Mauro Carlino, MD,a Antonio Colombo, MD,a Stéphane Rinfret, MD, SMb,c
ABSTRACT OBJECTIVES The study sought to investigate the long-term outcomes and predictors of adverse events of percutaneous coronary intervention (PCI) for in-stent chronic total occlusion (IS-CTO). BACKGROUND IS-CTO PCI has traditionally been associated with suboptimal success rates. METHODS We performed a multicenter registry of consecutive patients undergoing CTO PCI at 3 specialized centers. Patients were divided in IS-CTO and de novo CTO. The primary endpoint (major adverse cardiac events [MACE]) was a composite of cardiac death, target-vessel myocardial infarction, and ischemia-driven target-vessel revascularization (TVR) on follow-up. Independent predictors of MACE were sought with Cox regression. RESULTS We included 899 patients (n ¼ 111 IS-CTO, n ¼ 788 de novo CTO). Baseline clinical and angiographic characteristics were balanced between the 2 groups. Overall mean J-CTO (Japanese-Chronic Total Occlusion) score was 1.88 1.24 and mean PROGRESS-CTO (Prospective Global Registry for the Study of Chronic Total Occlusion InterventionCTO) score was 1.04 0.88. Antegrade wire escalation was used in 59.0% of IS-CTO and 48.1% of de novo CTO patients (p ¼ 0.08). Procedural success was achieved in 86.5% in both groups (p ¼ 0.99). After a median follow-up of 471 (interquartile range: 354 to 872) days, MACE were observed in 20.8% versus 13.9% in IS-CTO versus de novo CTO (p ¼ 0.07), driven by TVR (16.7% vs. 9.4%; p ¼ 0.03). IS-CTO was an independent predictor of MACE (hazard ratio: 2.16; 95% confidence interval: 1.18 to 3.95; p ¼ 0.01), together with prior surgical revascularization and renal function, CTO PCI indicated for acute coronary syndrome, number of diseased vessels, and PROGRESS-CTO score. CONCLUSIONS Procedural success was high and similar in patients with IS-CTO, as compared with de novo CTO. However, IS-CTO was independently associated with MACE (driven by TVR) on follow-up. (J Am Coll Cardiol Intv 2017;10:892–902) © 2017 by the American College of Cardiology Foundation.
C
hronic total occlusion (CTO) percutaneous
(IS-CTOs) have traditionally been associated with
coronary intervention (PCI) has witnessed a
suboptimal procedural success rates (63% to 71%)
remarkable improvement in success rates
(2–4), albeit these figures improved in the recent
(>90%) as well as procedural metrics and safety
report from the PROGRESS-CTO (Prospective Global
during the past few years (1).
Registry for the Study of Chronic Total Occlusion
However, specific patient and lesion subsets still
Intervention-CTO) registry (86%) (5). Additionally,
represent a challenge. In particular, in-stent CTOs
treatment of in-stent occlusive segments has been
From the aDivision of Interventional Cardiology, Cardio-Thoracic-Vascular Department, San Raffaele Scientific Institute, Milan, Italy; bDivision of Interventional Cardiology, McGill University Health Centre, Montreal, Canada; cDivision of Interventional Cardiology, Quebec Heart and Lung Institute and Laval University, Quebec City, Canada; and the dDivision of Interventional Cardiology, Reina Sofia Hospital, University of Córdoba, Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), Córdoba, Spain. Dr. Rinfret has served as a consultant for Boston Scientific and SoundBite medical; has received honoraria for proctorship and lectures for Boston Scientific, Abbott Vascular, and Terumo; and has received research funding from Medtronic and Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received October 7, 2016; revised manuscript received December 21, 2016, accepted January 27, 2017.
Azzalini et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 9, 2017 MAY 8, 2017:892–902
893
Outcomes of In-Stent CTO PCI
identified as an independent predictor of the need for
Specifically, the use of CrossBoss for IS-CTO
ABBREVIATIONS
revascularization after CTO PCI (6).
was considered a true-to-true crossing, if
AND ACRONYMS
Little data exist on the outcomes of this challenging
not followed by Stingray.
patient subgroup on follow-up. Similarly, predictors
Technical success was defined as a residual
of major adverse cardiac events (MACE) on follow-up
stenosis <30% with antegrade TIMI flow
are poorly characterized. The aim of the present
grade 3 in the CTO target vessel (5). Proce-
study is to address these important questions.
dural
SEE PAGE 903
METHODS PATIENT POPULATION. We queried the CTO PCI
database of the 3 participating centers (San Raffaele Hospital, Milan, Italy; Quebec Heart and Lung Institute, Quebec City, Canada; Reina Sofia Hospital, Córdoba, Spain) to identify all consecutive patients with and without IS-CTO who underwent CTO PCI. A total of 991 procedures were performed in 899 patients by experienced CTO PCI operators (>80% success rate) (7) between January 2009 and December 2015. Only the first procedure for each patient was considered for analyses. All procedures were indicated according to the presence of angina, ischemia or both, and were performed electively (ad hoc PCI was discouraged) (1). Baseline, procedural and hospitalization data were recorded. Follow-up was performed by means of phone interview, revision of hospital records or outpatient visit. The study was approved by the institutional review boards of the 3 participating hospitals. Figures 1 and 2 show 2 cases of IS-CTO PCI.
success
was
defined
as
technical
success plus the absence of in-hospital adverse events (all-cause death, Q-wave myocardial infarction [MI], stroke, recurrent angina requiring target vessel revascularization [TVR] with PCI or coronary artery bypass graft [CABG], tamponade requiring pericardiocentesis or surgery) (5).
BMS = bare-metal stent(s) CABG = coronary artery bypass graft
CTO = chronic total occlusion DES = drug-eluting stent(s) eGFR = estimated glomerular filtration rate
HR = hazard ratio IS-CTO = in-stent chronic total occlusion
IVUS = intravascular ultrasound
Major procedural complications included:
MACE = major adverse cardiac
procedure-related death, stroke, periproce-
event(s)
dural type 4a MI (10), major bleeding (bleeding
MI = myocardial infarction
requiring transfusion, vasopressors, surgery
PCI = percutaneous coronary
or
intervention
percutaneous
intervention),
coronary
perforation with cardiac tamponade requiring
TVR = target vessel
intervention
revascularization
(pericardiocentesis,
coiling,
covered stent implantation or surgery), and contrastinduced nephropathy (increase in serum creatinine >25% or >0.5 mg/dl at 48 h post-procedure). MACE on follow-up were defined as the composite of cardiac death, target-vessel MI (Q-wave and non–Q-wave MI) and ischemia-driven TVR, defined as any revascularization in the CTO vessel, including proximal segments or distal branches, driven
by
angina
or
ischemia
on
noninvasive
imaging tests.
DEFINITIONS. CTO was defined as an occlusive (100%
STATISTICAL ANALYSIS. Continuous variables are
stenosis) coronary lesion with antegrade Thrombol-
presented as mean SD and Student t test was used
ysis In Myocardial Infarction flow grade 0 for at least
for comparisons. Categorical variables are presented
3 months (5). A CTO was considered to be IS if the
as frequency (percentage) and were compared using a
occlusion was located within a previously deployed
chi-square test.
stent or within the 5 mm proximal and distal to it (5).
Predictors of MACE on follow-up were sought
The J-CTO (Japanese-Chronic Total Occlusion) score
using multivariate Cox regression. Variables showing
(8) and the PROGRESS-CTO score (9) were calculated
a p < 0.20 in univariate analysis or deemed to be
for each lesion.
associated with the outcome of interest according to
A dissection/re-entry crossing was defined by the
clinical judgment were used as candidate predictors
use of any wire-based (with knuckled or straight
for multivariate analysis. Variable selection was
wires) or CrossBoss-based (Boston Scientific, Marl-
performed by fitting a penalized Cox regression
borough, Massachusetts) access to the subintimal
model with LASSO (Least Absolute Shrinkage and
space, followed by a re-entry technique (either ante-
Selection Operator) penalty and a tuning parameter
grade or retrograde, contrast guided or non–contrast
selected by cross-validation (lambda ¼ 0.01237) (11).
guided, or involving the Stingray [Boston Scientific]
The candidate variables were: IS-CTO, center, age,
system). True-to-true crossing was considered the
diabetes, prior MI, prior CABG, estimated glomerular
most likely mechanism with the use of guidewire
filtration rate (eGFR), acute coronary syndrome
escalation (either retrograde or antegrade) or when
presentation, number of diseased vessels, J-CTO
the CrossBoss passed the occlusion reaching the true
score, PROGRESS-CTO score, use of dissection/
lumen (i.e., without Stingray-facilitated re-entry).
re-entry
techniques,
drug-eluting
stent
(DES)
894
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JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 9, 2017 MAY 8, 2017:892–902
Outcomes of In-Stent CTO PCI
eGFR,
F I G U R E 1 Left Anterior Descending IS-CTO Recanalized With the Retrograde
acute
coronary
syndrome
presentation,
number of diseased vessels, J-CTO score, PROGRESS-
Approach
CTO score, use of dissection/re-entry techniques. The results of this analysis are presented as hazard ratios (HRs) and 95% confidence intervals. Survival curves were plotted to ascertain if the presence of
IS-CTO
was
independently
associated
with
MACE and TVR on follow-up, after adjustment for the independent predictors of MACE previously identified. For all tests, a p < 0.05 was considered significant. Statistical analysis was performed using SPSS version 20 (IBM Corporation, Armonk, New York) and R 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria).
Penalized
Cox
regression
model
with
LASSO penalty was performed using the glmnet package for R (12).
RESULTS BASELINE CLINICAL CHARACTERISTICS. The study
population included 899 patients (n ¼ 111 with IS-CTO and n ¼ 788 with de novo CTO). The prevalence of IS-CTO PCI was therefore 12.3%. Clinical characteristics of the study population are shown in Table 1. There were no differences between IS-CTO and de novo CTO patients with regards to age, gender, prevalence of cardiovascular risk factors, renal function, ejection fraction and indication of CTO PCI. Subjects with IS-CTO had a higher prevalence of prior MI and prior PCI. BASELINE
ANGIOGRAPHIC
CHARACTERISTICS.
Baseline angiographic data are presented in Table 2. Compared to the de novo CTO group, IS-CTO patients had a lower burden of coronary artery disease. No differences were observed regarding the target CTO A 67-year-old man with ostial left anterior descending in-stent occlusion (A [dotted line]
vessel, J-CTO and PROGRESS-CTO scores, and the
and B). J-CTO (Japanese-Chronic Total Occlusion) score was 2 (blunt stump, length
amount of collateralization. The IS-CTO group had
>20 mm) and PROGRESS-CTO (Prospective Global Registry for the Study of Chronic Total
lower prevalence of moderate/severe calcifications
Occlusion Intervention-CTO) score was 1 (proximal cap ambiguity). Both ipsilateral and contralateral collaterals were observed; the distal cap was at the bifurcation with a
and bifurcation at the distal cap. However, IS-CTO
diagonal branch (A and B). A retrograde approach was chosen. (C) A Sion guidewire
also had a lower prevalence of adequate landing
(Asahi Intecc, Nagoya, Japan) was advanced through a Corsair microcatheter (Asahi
zone beyond the distal cap, as well as a higher prev-
Intecc) (arrow) from the right coronary artery. (D) The stent was penetrated
alence of occlusion length >20 mm and ostial
retrogradely with a Confianza guidewire (Asahi Intecc), supported by the microcatheter
location.
(arrow). The wire was externalized and standard chronic total occlusion percutaneous coronary intervention techniques followed. (E) The result after pre-dilatation; (F) the final result after implantation of 2 overlapping drug-eluting stents.
PROCEDURAL CHARACTERISTICS. Table 3 shows
procedural data. There was a trend toward lower use of radial access in IS-CTO patients, as compared with de novo CTO subjects. Antegrade wire escalation was implantation, procedural success, and major proce-
the most frequent successful crossing strategy (59.0%
dural complications. The final model obtained after
in IS-CTO vs. 48.1% in de novo CTO; p ¼ 0.08). The
penalization
variables
retrograde approach and dissection/re-entry tech-
(Online Figure 1): IS-CTO, diabetes, prior CABG,
niques were used less often in IS-CTO patients. The
included
the
following
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JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 9, 2017 MAY 8, 2017:892–902
Outcomes of In-Stent CTO PCI
F I G U R E 2 Right Coronary Artery IS-CTO Recanalized With a CrossBoss-Based Antegrade Approach
(A) A 65-year-old man with mid right coronary artery in-stent occlusion (dotted line). J-CTO (Japanese-Chronic Total Occlusion) score was 2 (blunt stump, length >20 mm) and PROGRESS-CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention-CTO) score was 0. (A) Contralateral epicardial collaterals were observed. (B) An antegrade approach was chosen. The CrossBoss (Boston Scientific, Marlborough, Massachusetts) was used to cross the in-stent segment (arrow). (C) A Confianza guidewire (Asahi Intecc, Nagoya, Japan) was subsequently used to reach the distal true lumen, using the CrossBoss (Boston Scientific, Marlborough, Massachusetts) as a support microcatheter (arrow). (D) The final result, after implantation of 2 overlapping drug-eluting stents.
use of CrossBoss was 4-fold higher in IS-CTO (26.1%
Technical (87.4% vs. 87.2%; p ¼ 0.95) and proce-
vs. 6.6%; p < 0.001). Second-generation DES were the
dural (86.5% vs. 86.5%; p ¼ 0.99) success rates
preferred stents in both cohorts, although bio-
were similar between the 2 groups. The incidence of
resorbable scaffolds were used more frequently in
major procedural complications was also similar
de novo CTO lesions. Despite the fact that dissection/
between groups (2.7% vs. 2.4%; p ¼ 0.84). In partic-
re-entry
of
ular, 1 perforation with tamponade, 1 case of major
IS-CTO patients, true-to-true crossing of the occlu-
bleeding, and 1 case of contrast-induced nephropathy
sion segment containing the restenosed stent was
were observed in the IS-CTO group. In patients treated
always possible in our experience, and in no case
for de novo CTO, we observed 8 cases of perforation
subintimal crushing of the previous stent was
with tamponade (2 of these patients subsequently
required. Total stent length tended to be longer in
died), 1 case of major bleeding, 4 cases of stroke (2 of
IS-CTO. Procedural metrics were similar between the
them
2 groups.
nephropathy, and 3 periprocedural MIs.
techniques
were
utilized
in
30%
later
died),
3
cases
of
contrast-induced
895
Azzalini et al.
896
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 9, 2017 MAY 8, 2017:892–902
Outcomes of In-Stent CTO PCI
CLINICAL OUTCOMES ON FOLLOW-UP
T A B L E 1 Baseline Clinical Characteristics
Age, yrs
Overall (N ¼ 899)
In-Stent CTO (n ¼ 111)
De Novo CTO (n ¼ 788)
p Value
65.1 10.7
65.1 10.3
65.1 10.8
0.98
Follow-up was available for 807 of 899 (89.8%) patients. Median follow-up was 471 (interquartile range: 354 to 872) days. Table 4 shows clinical outcomes on
Male
778 (86.5)
92 (82.9)
686 (87.1)
0.23
Body mass index, kg/m2
28.9 5.3
29.2 5.4
28.9 5.3
0.68
follow-up. IS-CTO patients tended to have a higher
Diabetes
335 (37.8)
45 (41.3)
290 (37.3)
0.42
incidence of MACE (20.8% vs. 13.9%; p ¼ 0.07) driven
Dyslipidemia
714 (80.4)
91 (85.0)
623 (79.8)
0.20
by TVR (16.7% vs. 9.4%; p ¼ 0.03). No differences
Hypertension
665 (74.9)
85 (79.4)
580 (74.3)
0.25
were observed regarding cardiac death and target-
Current smoker
193 (23.1)
22 (21.6)
171 (23.3)
0.69
424 (48.2)
76 (70.4)
348 (45.1)
<0.001
vessel MI.
Prior myocardial infarction Prior PCI
545 (60.7)
111 (100)
434 (55.1)
<0.001
Prior coronary artery bypass graft eGFR, ml/min/1.73 m2 eGFR <60 ml/min/1.73 m2
Table 5 shows univariate and multivariate predictors of MACE on follow-up. Treatment of IS-CTO
191 (21.3)
22 (19.8)
169 (21.5)
0.69
83.4 28.3
82.7 26.5
83.6 28.5
0.76
remained
83 (9.6)
11 (10.4)
72 (9.5)
0.78
(HR: 2.16; 95% confidence interval: 1.18 to 3.95;
independently
associated
with
MACE
16 (1.9)
3 (2.8)
13 (1.7)
0.43
p ¼ 0.01), in addition to post-CABG status (HR: 1.73;
53.0 11.4
52.1 11.5
53.1 11.4
0.39
p ¼ 0.05), eGFR (HR: 0.92; p ¼ 0.04), acute coro-
Symptoms
527 (59.1)
65 (59.1)
462 (59.2)
0.74
Silent ischemia
175 (19.6)
20 (18.2)
155 (19.8)
number of diseased vessels (HR: 1.44; p ¼ 0.03),
Acute coronary syndrome
163 (18.3)
20 (18.2)
143 (18.3)
26 (2.9)
5 (4.5)
21 (2.7)
eGFR <30 ml/min/1.73 m2 Left ventricular ejection fraction, %
nary syndrome presentation (HR: 1.92; p ¼ 0.008),
Indication of CTO PCI
Other
and the PROGRESS-CTO score (HR: 1.41; p ¼ 0.01). Figure
3
presents
adjusted
2-year
curves
of
survival free from MACE and TVR. Patients with IS-CTO had a >2-fold increase in the risk of adverse
Values are mean SD or n (%). CTO ¼ chronic total occlusion; eGFR ¼ estimated glomerular filtration rate; PCI ¼ percutaneous coronary intervention.
outcomes, with events accumulating throughout follow-up.
DISCUSSION
T A B L E 2 Baseline Angiographic Characteristics
Overall (N ¼ 899)
In-Stent CTO (n ¼ 111)
De Novo CTO (n ¼ 788)
p Value
The main findings of our study are as follows: 1)
1.83 0.81
1.66 0.75
1.86 0.82
0.02
IS-CTO PCI is performed in about 12% of consecu-
Left anterior descending
254 (28.4)
30 (27.0)
224 (28.6)
0.82
Circumflex
174 (19.4)
20 (18.0)
154 (19.6)
Number of diseased vessels
tive CTO interventions in large CTO PCI programs;
Target-vessel CTO
Right coronary artery
2)
these
patients
and
lesions
do
not
present
marked differences regarding clinical and proce-
467 (52.2)
61 (55.0)
406 (51.8)
Blunt stump
410 (46.0)
55 (49.5)
355 (45.5)
0.43
Moderate or severe calcifications
392 (43.8)
21 (19.1)
371 (47.2)
<0.001
>45 bending
274 (31.0)
35 (32.1)
239 (30.8)
0.78
Lesion length >20 mm
404 (45.7)
74 (68.5)
330 (42.5)
<0.001
Retry
211 (23.4)
26 (23.4)
185 (23.4)
1.00
independently associated with a 2-fold increase in
dural characteristics, and therefore success rates are high and similar to de novo CTO PCI in the hands of experienced operators using the hybrid algorithm;
3)
despite
this
observation,
IS-CTO
is
J-CTO score
1.88 1.24
1.90 1.21
1.88 1.24
0.84
the adjusted risk of MACE (driven by TVR) on
J-CTO score $2
534 (59.3)
72 (64.9)
462 (58.6)
0.21
follow-up.
Proximal cap ambiguity
379 (43.4)
42 (38.9)
337 (44.1)
0.31
Absence of interventional collaterals
181 (20.7)
25 (23.1)
156 (20.4)
0.51
Moderate or severe tortuosity
181 (20.6)
22 (20.2)
159 (20.7)
0.90
Circumflex CTO
174 (19.4)
20 (18.0)
154 (19.6)
0.69
1.04 0.88
1.01 0.79
1.05 0.89
0.65
traditionally been associated with suboptimal suc-
PROGRESS-CTO score $2
248 (28.4)
28 (25.9)
220 (28.8)
0.54
cess rates (2–4). Abbas et al. (2) studied the out-
Ostial CTO
135 (15.2)
31 (27.9)
104 (13.3)
<0.001
comes of a cohort of patients undergoing IS-CTO PCI
Distal cap at bifurcation
299 (34.3)
26 (24.3)
273 (35.7)
0.02
during the bare-metal stent (BMS) era (25% of the
Good distal landing zone
662 (75.9)
69 (64.5)
593 (77.5)
0.003
study population). Success rates were similar for IS-
CC0
57 (6.8)
5 (4.9)
52 (7.1)
0.44
CC1
455 (54.2)
63 (61.2)
392 (53.2)
CC2
328 (39.0)
35 (34.0)
293 (39.8)
PROGRESS-CTO score
Werner’s CC class
Prior to the development and widespread adoption of the hybrid algorithm (13) and dedicated devices (e.g., CrossBoss), PCI of IS-CTO lesions had
CTO versus de novo CTO (63% vs. 70%). Although inability to wire the occlusion was the primary mechanism of failure in both groups, inability to advance or fully dilate the balloon was more
Values are mean SD or n (%).
frequent in the IS-CTO group. Werner et al. (4) re-
CC ¼ collateral channel; CTO ¼ chronic total occlusion; J-CTO ¼ Japanese-CTO; PROGRESS-CTO ¼ Prospective Global Registry for the Study of Chronic Total Occlusion Intervention-CTO.
ported that only 5% of all CTO treated at their institution were IS-CTO. Success rate was 70%, lower
Azzalini et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 9, 2017 MAY 8, 2017:892–902
897
Outcomes of In-Stent CTO PCI
T A B L E 3 Procedural Characteristics
Overall (N ¼ 899)
In-Stent CTO (n ¼ 111)
De Novo CTO (n ¼ 788)
p Value
374 (41.6)
38 (34.2)
336 (42.7)
0.09
Antegrade wire escalation
392 (49.5)
59 (59.0)
333 (48.1)
0.08
Antegrade dissection/re-entry
139 (17.6)
16 (16.0)
123 (17.8)
Radial access* Successful crossing technique
Retrograde wire escalation Retrograde dissection/re-entry
77 (9.7)
11 (11.0)
66 (9.5)
184 (23.2)
14 (14.0)
170 (24.6)
Successful crossing technique: retrograde approach
261 (33.0)
25 (25.0)
236 (34.1)
0.07
Successful crossing technique: dissection/re-entry
323 (40.8)
30 (30.0)
293 (42.3)
0.02
80 (9.0)
29 (26.1)
51 (6.6)
<0.001 0.03
Use of CrossBoss Type of stent Bare-metal stents
14 (1.8)
0 (0)
14 (2.0)
Bioresorbable scaffolds
72 (9.1)
2 (2.1)
70 (10.0)
708 (89.1)
93 (97.9)
615 (87.9)
57 (8.1)
4 (4.3)
53 (8.6)
651 (91.9)
89 (95.7)
562 (91.4)
DES First-generation DES Second-generation DES
0.15
Number of stents implanted
2.21 1.27
2.34 1.31
2.20 1.27
0.29
Total stent length, mm
70.1 42.0
77.3 49.7
69.1 40.7
0.07
Use of intravascular ultrasound
116 (12.9)
11 (9.9)
105 (13.3)
0.39
Contrast volume, ml
328 137
302 134
332 137
0.06
Fluoroscopy time, min
55 34
51 37
55 33
0.24
Total procedure time, min
127 70
115 75
128 69
0.10
Major procedural complications
22 (2.4)
3 (2.7)
19 (2.4)
0.84
Technical success
784 (87.2)
97 (87.4)
687 (87.2)
0.95
Procedural success
778 (86.5)
96 (86.5)
682 (86.5)
0.99
Values are n (%) or mean SD. *Cases with dual radial access or cases with a single access, being radial. CTO ¼ chronic total occlusion; DES ¼ drug-eluting stent(s).
than for de novo CTO (85%), despite the availability of retrograde techniques. In the small series by
T A B L E 5 Predictors of Major Adverse Cardiac Events on Follow-Up
Abdel-Karim et al. (3) success rate was 71%. Failure was due to inability to cross the occlusion in all cases. de la Torre et al. (14) recently reported a procedural success rate of 82% in a single-arm study on 233 patients with IS-CTO. However, patient in-
In-stent CTO
Univariate HR (95% CI)
p Value
Adjusted HR (95% CI)
p Value
1.44 (0.88–2.35)
0.15
2.16 (1.18–3.95)
0.01
1.10 (0.69–1.75)
0.70
Center
0.09
Center 2 vs. Center 1
1.53 (0.94–2.50)
0.09
Center 3 vs. Center 1
0.98 (0.58–1.64)
0.93
clusion spread across a decade, and this study is
Age (per 10-yr increment)
1.17 (0.98–1.40)
0.08
therefore not representative of a modern approach
Diabetes
1.61 (1.12–2.33)
0.01
to IS-CTO PCI.
Prior myocardial infarction
1.55 (1.07–2.24)
0.02
2.35 (1.60–3.45)
<0.001
Prior coronary artery bypass graft T A B L E 4 Clinical Outcomes on Follow-Up
Overall (N ¼ 807)
In-Stent CTO (n ¼ 96)
De Novo CTO (n ¼ 711)
p Value
119 (14.8)
20 (20.8)
99 (13.9)
0.07
Cardiac death
29 (3.6)
4 (4.2)
25 (3.5)
0.75
Target-vessel myocardial infarction
26 (3.2)
3 (3.1)
23 (3.2)
0.95
Ischemia-driven target-vessel revascularization
83 (10.3)
Major adverse cardiac events
Values are n (%). CTO ¼ chronic total occlusion.
16 (16.7)
67 (9.4)
0.03
1.73 (0.99–3.01)
0.05
eGFR (per 10 ml/min/1.73 m2 increment)
0.89 (0.84–0.95) <0.001 0.92 (0.85–0.99)
0.04
Acute coronary syndrome presentation
1.66 (1.11–2.50)
Number of diseased vessels (per 1-vessel increment)
1.68 (1.34–2.10)
0.02
1.92 (1.19–3.12)
<0.001 1.44 (1.03–2.01)
0.008 0.03
J-CTO score (per 1-point increment)
1.35 (1.16–1.56)
<0.001 1.08 (0.88–1.34)
0.46
PROGRESS-CTO score (per 1-point increment)
1.48 (1.21–1.80)
<0.001
1.41 (1.08–1.84)
0.01
1.19 (0.71–2.00)
0.51
Use of dissection/re-entry techniques
1.61 (1.05–2.45)
0.03
Drug-eluting stent implantation
1.62 (0.78–3.37)
0.19
Procedural success
0.38 (0.25–0.58) <0.001
Major procedural complications
5.60 (2.59–12.11)
<0.001
CI ¼ confidence interval; eGFR ¼ estimated glomerular filtration rate; HR ¼ hazard ratio; other abbreviations as in Table 2.
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Outcomes of In-Stent CTO PCI
F I G U R E 3 Long-Term Outcomes of IS-CTO PCI
F I G U R E 4 Procedural Success Rates of IS-CTO PCI
in the Literature
IS-CTO ¼ in-stent chronic total occlusion; PCI ¼ percutaneous coronary intervention.
incidence of IS-CTO PCI was 10.9%. The retrograde approach was used in approximately one-third of procedures, similar to our data. Procedural success rate was high and did not differ between groups (86.0% and 90.3% in IS-CTO vs. de novo CTO, respectively), which mirrors our results (86.5% in both groups). Figure 4 compares procedural success
rates
of
IS-CTO
PCI
in
the
literature
over time. The advancement of wires and microcatheters is greatly impaired by the presence of stent struts in close proximity with the subadventitial space. In such setting, the use of CrossBoss might represent a very efficient alternative (Central Illustration), as it allows for an easy, within-stent, true-to-true occlusion crossing, due to its higher crossing profile combined with its effective dissecting action. In a small single-arm study of selected patients with IS-CTO, CrossBoss showed a 90% success rate, with good procedural metrics (median crossing time of 8 min, despite a mean CTO length of 39 mm) (15). The role of this device for the treatment of IS-CTO deserves further investigation.
Adjusted 2-year curves of survival free from (A) major adverse cardiac events (MACE) and
In comparison with the aforementioned reports
(B) target vessel revascularization (TVR), for patients with and without in-stent chronic total occlusion (CTO). Adjusted curves were generated with Cox regression controlling for
(2–5,14,15),
the independent predictors of MACE shown in Table 5. CI ¼ confidence interval;
our
study
has
several
strengths,
including a larger sample size, comparison with a
HR ¼ hazard ratio.
de novo CTO PCI group, a detailed angiographic analysis, and, remarkably, the availability of data Following
systematic
implementation
of
the
on long-term clinical outcomes. Additionally, we
hybrid algorithm, IS-CTO PCI success rates have
performed
an
adjusted
remarkably improved. In an all-comer patient popu-
IS-CTO
an
independent
lation from the PROGRESS-CTO registry (5), the
(driven
as by
TVR)
on
analysis
that
predictor
follow-up.
identified of
MACE
This
latter
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Outcomes of In-Stent CTO PCI
C ENTR AL I LL U STRA T I O N Risk Factors, Angiographic Characteristics, Histopathology, and Techniques to Recanalize In-Stent Chronic Total Occlusions
Azzalini, L. et al. J Am Coll Cardiol Intv. 2017;10(9):892–902.
899
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Outcomes of In-Stent CTO PCI
observation had already been reported (6), and
challenging
parallels similar findings from the non-CTO inter-
attention. The use of more potent antiplatelet
patient
population
deserve
special
ventional practice, where PCI for in-stent restenosis
therapy might improve patient outcomes, although
had been identified as a predictor of future rest-
such a hypothesis has not been tested yet. Also,
enotic events (16).
systemically administered colchicine can decrease
The pathophysiology of such in-stent occlusions is
neointimal hyperplasia following stent implantation
largely unknown. Although neointima formation may
and has been associated with a decreased in-
be involved, we also know that such phenomenon is
stent restenosis rate (23). Finally, CABG might
dramatically reduced with DES. We hypothesize
be
that a significant proportion of IS-CTOs were the re-
disease and IS-CTO to reduce the risk of TVR, pro-
sults of other factors (e.g., stent thrombosis, stent
vided that full arterial revascularization can be
fracture, neoatherosclerosis) (Central Illustration).
achieved (24,25).
considered
for
patients
with
multivessel
It is reasonable to say that the patient’s biological
Our adjusted analysis also identified prior CABG,
factors that were involved in the first episode of
worse renal function, procedural indication for acute
stent occlusion are likely again triggered in the
coronary syndrome, higher number of diseased
newly implanted stent in the same segment, and
vessels, and higher PROGRESS-CTO score as inde-
may involve abnormal local inflammation, adverse
pendent predictors of MACE on follow-up. While
reaction
antiplatelet
most of these variables are well known to be
agents, stent malapposition or underexpansion, or
associated with adverse events, the observation that
others. In a seminal study in the BMS era, Mehran
an angiographic tool such as the PROGRESS-CTO
et
al.
to
(17)
polymer,
indicated
resistance
that
up
to
to
one-half
of
score
is
able
to
predict
clinical
outcomes
in
IS-CTO cases had suffered a prior episode of in-stent
patients undergoing CTO PCI (similar to the SYNTAX
restenosis and that IS-CTO was an independent
score in all-comers) (26) is novel. As compared
predictor of target-lesion revascularization after
with the J-CTO score, the PROGRESS-CTO score
recanalization.
does
not
account
for
the
operator-dependent
In some cases, stent occlusion might have been the
component (i.e., retry CTO PCI) in the prediction of
result of thrombosis rather than restenosis. Indeed,
successful revascularization using the hybrid algo-
asymptomatically
rithm (9). Therefore, the PROGRESS-CTO score
several months after implantation (18). This phe-
exclusively evaluates occlusion complexity, which in
nomenon might be especially relevant after recana-
our study was associated with higher risk of MACE on
lization of chronically occluded arteries. In registries
follow-up.
where multidetector computed tomography was
research.
routinely performed 6 months after bioresorbable
STUDY LIMITATIONS. First, it shares the limitations
scaffold implantation, asymptomatic restenosis or
of all observational studies. Second, no data was
reocclusion was detected in up to 5.7% of patients
available on the specific type of stent (DES vs. BMS)
(19,20).
that had suffered occlusive restenosis in the IS-CTO
stent
thrombosis
can
develop
This
observation
warrants
further
The improvement in clinical outcomes for IS-CTO
group and the time frame between stent implanta-
patients will likely stem from the development of
tion and development of IS-CTO, due to the fact that
newer-generation DES, with better antiproliferative
most patients were referred to our CTO PCI programs
characteristics as well as eliciting lower inflamma-
from other centers. However, we do not think that
tory
knowing this would have altered clinical decision
response.
Additionally,
intravascular
ultra-
sound (IVUS) can provide useful information about
making
the
(after
implanted in all IS-CTO cases. Third, IVUS use was
pre-dilatation with a small balloon) and, more
low in the IS-CTO group, in order not to prolong
importantly,
to
these already lengthy procedures and due to cost-
minimize the risk of adverse outcomes on follow-up
related issues. Additionally, IVUS findings were not
mechanisms to
underlying
optimize
stent
IS-CTO
implantation
because
drug-eluting
platforms
were
(21). Indeed, recent data from the Multicenter
captured by our database, which prevented identifi-
Korean CTO Registry indicated that IVUS-guided
cation of the mechanisms leading to IS-CTO in our
CTO PCI was associated with lower risk of stent
study. Finally, our observations might not be gener-
thrombosis, and possibly target-lesion revasculari-
alizable to other institutions where expert hybrid
zation in the subset of long lesions (22). Addition-
CTO PCI operators and dedicated devices are not
ally, pharmacologic strategies to deal with this
available.
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Outcomes of In-Stent CTO PCI
CONCLUSIONS
PERSPECTIVES
IS-CTO PCI is frequently performed with excellent success rates in the hands of experienced operators using the hybrid algorithm. Although, as compared with de novo CTO, IS-CTO was not associated with lower procedural success, it was found to be independently associated with a higher risk of MACE (driven by TVR) on follow-up. Novel strategies and stents are therefore needed to improve the outcomes of IS-CTO PCI.
WHAT IS KNOWN? IS-CTOs have traditionally been associated with suboptimal success rates of PCI. Little data exist on the outcomes of this challenging patient subgroup on follow-up. WHAT IS NEW? This multicenter registry analyzed the outcomes of a large cohort of patients with IS-CTO versus de novo CTO. Procedural success was high and similar in the 2 groups. At long-term follow-up, the rate of MACE was higher in IS-CTO versus de novo CTO, driven by TVR. IS-CTO was an independent predictor of MACE.
ADDRESS FOR CORRESPONDENCE: Dr. Stéphane
Rinfret, McGill University, Division of Interventional Cardiology,
Cardio-Thoracic-Vascular
Department,
McGill University Health Centre, Royal Victoria Glen Site (B03.7200), 1001 Boulevard Décarie, Montreal (Québec) H4A 3J1, Canada. E-mail: stephane.rinfret@
WHAT IS NEXT? The development of newer-generation DES, with better antiproliferative characteristics as well as eliciting lower inflammatory response, warrants further research, to improve the long-term outcomes of this challenging patient population.
mcgill.ca.
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Outcomes of In-Stent CTO PCI
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KEY WORDS chronic total occlusion, in-stent restenosis, percutaneous coronary intervention
A PPE NDI X For a supplemental figure, please see the online version of this article.
VOL. 10, NO. 9, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
ISSN 1936-8798/$36.00 http://dx.doi.org/10.1016/j.jcin.2017.01.047
Procedural and Long-Term Outcomes of Percutaneous Coronary Intervention for In-Stent Chronic Total Occlusion Lorenzo Azzalini, MD, PHD, MSC,a Rustem Dautov, MD, PHD,b,c Soledad Ojeda, MD, PHD,d Susanna Benincasa, MD,a Barbara Bellini, MD,a Francesco Giannini, MD,a Jorge Chavarría, MD,d Manuel Pan, MD, PHD,d Mauro Carlino, MD,a Antonio Colombo, MD,a Stéphane Rinfret, MD, SMb,c
ABSTRACT OBJECTIVES The study sought to investigate the long-term outcomes and predictors of adverse events of percutaneous coronary intervention (PCI) for in-stent chronic total occlusion (IS-CTO). BACKGROUND IS-CTO PCI has traditionally been associated with suboptimal success rates. METHODS We performed a multicenter registry of consecutive patients undergoing CTO PCI at 3 specialized centers. Patients were divided in IS-CTO and de novo CTO. The primary endpoint (major adverse cardiac events [MACE]) was a composite of cardiac death, target-vessel myocardial infarction, and ischemia-driven target-vessel revascularization (TVR) on follow-up. Independent predictors of MACE were sought with Cox regression. RESULTS We included 899 patients (n ¼ 111 IS-CTO, n ¼ 788 de novo CTO). Baseline clinical and angiographic characteristics were balanced between the 2 groups. Overall mean J-CTO (Japanese-Chronic Total Occlusion) score was 1.88 1.24 and mean PROGRESS-CTO (Prospective Global Registry for the Study of Chronic Total Occlusion InterventionCTO) score was 1.04 0.88. Antegrade wire escalation was used in 59.0% of IS-CTO and 48.1% of de novo CTO patients (p ¼ 0.08). Procedural success was achieved in 86.5% in both groups (p ¼ 0.99). After a median follow-up of 471 (interquartile range: 354 to 872) days, MACE were observed in 20.8% versus 13.9% in IS-CTO versus de novo CTO (p ¼ 0.07), driven by TVR (16.7% vs. 9.4%; p ¼ 0.03). IS-CTO was an independent predictor of MACE (hazard ratio: 2.16; 95% confidence interval: 1.18 to 3.95; p ¼ 0.01), together with prior surgical revascularization and renal function, CTO PCI indicated for acute coronary syndrome, number of diseased vessels, and PROGRESS-CTO score. CONCLUSIONS Procedural success was high and similar in patients with IS-CTO, as compared with de novo CTO. However, IS-CTO was independently associated with MACE (driven by TVR) on follow-up. (J Am Coll Cardiol Intv 2017;10:892–902) © 2017 by the American College of Cardiology Foundation.
C
hronic total occlusion (CTO) percutaneous
(IS-CTOs) have traditionally been associated with
coronary intervention (PCI) has witnessed a
suboptimal procedural success rates (63% to 71%)
remarkable improvement in success rates
(2–4), albeit these figures improved in the recent
(>90%) as well as procedural metrics and safety
report from the PROGRESS-CTO (Prospective Global
during the past few years (1).
Registry for the Study of Chronic Total Occlusion
However, specific patient and lesion subsets still
Intervention-CTO) registry (86%) (5). Additionally,
represent a challenge. In particular, in-stent CTOs
treatment of in-stent occlusive segments has been
From the aDivision of Interventional Cardiology, Cardio-Thoracic-Vascular Department, San Raffaele Scientific Institute, Milan, Italy; bDivision of Interventional Cardiology, McGill University Health Centre, Montreal, Canada; cDivision of Interventional Cardiology, Quebec Heart and Lung Institute and Laval University, Quebec City, Canada; and the dDivision of Interventional Cardiology, Reina Sofia Hospital, University of Córdoba, Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), Córdoba, Spain. Dr. Rinfret has served as a consultant for Boston Scientific and SoundBite medical; has received honoraria for proctorship and lectures for Boston Scientific, Abbott Vascular, and Terumo; and has received research funding from Medtronic and Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received October 7, 2016; revised manuscript received December 21, 2016, accepted January 27, 2017.
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893
Outcomes of In-Stent CTO PCI
identified as an independent predictor of the need for
Specifically, the use of CrossBoss for IS-CTO
ABBREVIATIONS
revascularization after CTO PCI (6).
was considered a true-to-true crossing, if
AND ACRONYMS
Little data exist on the outcomes of this challenging
not followed by Stingray.
patient subgroup on follow-up. Similarly, predictors
Technical success was defined as a residual
of major adverse cardiac events (MACE) on follow-up
stenosis <30% with antegrade TIMI flow
are poorly characterized. The aim of the present
grade 3 in the CTO target vessel (5). Proce-
study is to address these important questions.
dural
SEE PAGE 903
METHODS PATIENT POPULATION. We queried the CTO PCI
database of the 3 participating centers (San Raffaele Hospital, Milan, Italy; Quebec Heart and Lung Institute, Quebec City, Canada; Reina Sofia Hospital, Córdoba, Spain) to identify all consecutive patients with and without IS-CTO who underwent CTO PCI. A total of 991 procedures were performed in 899 patients by experienced CTO PCI operators (>80% success rate) (7) between January 2009 and December 2015. Only the first procedure for each patient was considered for analyses. All procedures were indicated according to the presence of angina, ischemia or both, and were performed electively (ad hoc PCI was discouraged) (1). Baseline, procedural and hospitalization data were recorded. Follow-up was performed by means of phone interview, revision of hospital records or outpatient visit. The study was approved by the institutional review boards of the 3 participating hospitals. Figures 1 and 2 show 2 cases of IS-CTO PCI.
success
was
defined
as
technical
success plus the absence of in-hospital adverse events (all-cause death, Q-wave myocardial infarction [MI], stroke, recurrent angina requiring target vessel revascularization [TVR] with PCI or coronary artery bypass graft [CABG], tamponade requiring pericardiocentesis or surgery) (5).
BMS = bare-metal stent(s) CABG = coronary artery bypass graft
CTO = chronic total occlusion DES = drug-eluting stent(s) eGFR = estimated glomerular filtration rate
HR = hazard ratio IS-CTO = in-stent chronic total occlusion
IVUS = intravascular ultrasound
Major procedural complications included:
MACE = major adverse cardiac
procedure-related death, stroke, periproce-
event(s)
dural type 4a MI (10), major bleeding (bleeding
MI = myocardial infarction
requiring transfusion, vasopressors, surgery
PCI = percutaneous coronary
or
intervention
percutaneous
intervention),
coronary
perforation with cardiac tamponade requiring
TVR = target vessel
intervention
revascularization
(pericardiocentesis,
coiling,
covered stent implantation or surgery), and contrastinduced nephropathy (increase in serum creatinine >25% or >0.5 mg/dl at 48 h post-procedure). MACE on follow-up were defined as the composite of cardiac death, target-vessel MI (Q-wave and non–Q-wave MI) and ischemia-driven TVR, defined as any revascularization in the CTO vessel, including proximal segments or distal branches, driven
by
angina
or
ischemia
on
noninvasive
imaging tests.
DEFINITIONS. CTO was defined as an occlusive (100%
STATISTICAL ANALYSIS. Continuous variables are
stenosis) coronary lesion with antegrade Thrombol-
presented as mean SD and Student t test was used
ysis In Myocardial Infarction flow grade 0 for at least
for comparisons. Categorical variables are presented
3 months (5). A CTO was considered to be IS if the
as frequency (percentage) and were compared using a
occlusion was located within a previously deployed
chi-square test.
stent or within the 5 mm proximal and distal to it (5).
Predictors of MACE on follow-up were sought
The J-CTO (Japanese-Chronic Total Occlusion) score
using multivariate Cox regression. Variables showing
(8) and the PROGRESS-CTO score (9) were calculated
a p < 0.20 in univariate analysis or deemed to be
for each lesion.
associated with the outcome of interest according to
A dissection/re-entry crossing was defined by the
clinical judgment were used as candidate predictors
use of any wire-based (with knuckled or straight
for multivariate analysis. Variable selection was
wires) or CrossBoss-based (Boston Scientific, Marl-
performed by fitting a penalized Cox regression
borough, Massachusetts) access to the subintimal
model with LASSO (Least Absolute Shrinkage and
space, followed by a re-entry technique (either ante-
Selection Operator) penalty and a tuning parameter
grade or retrograde, contrast guided or non–contrast
selected by cross-validation (lambda ¼ 0.01237) (11).
guided, or involving the Stingray [Boston Scientific]
The candidate variables were: IS-CTO, center, age,
system). True-to-true crossing was considered the
diabetes, prior MI, prior CABG, estimated glomerular
most likely mechanism with the use of guidewire
filtration rate (eGFR), acute coronary syndrome
escalation (either retrograde or antegrade) or when
presentation, number of diseased vessels, J-CTO
the CrossBoss passed the occlusion reaching the true
score, PROGRESS-CTO score, use of dissection/
lumen (i.e., without Stingray-facilitated re-entry).
re-entry
techniques,
drug-eluting
stent
(DES)
894
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Outcomes of In-Stent CTO PCI
eGFR,
F I G U R E 1 Left Anterior Descending IS-CTO Recanalized With the Retrograde
acute
coronary
syndrome
presentation,
number of diseased vessels, J-CTO score, PROGRESS-
Approach
CTO score, use of dissection/re-entry techniques. The results of this analysis are presented as hazard ratios (HRs) and 95% confidence intervals. Survival curves were plotted to ascertain if the presence of
IS-CTO
was
independently
associated
with
MACE and TVR on follow-up, after adjustment for the independent predictors of MACE previously identified. For all tests, a p < 0.05 was considered significant. Statistical analysis was performed using SPSS version 20 (IBM Corporation, Armonk, New York) and R 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria).
Penalized
Cox
regression
model
with
LASSO penalty was performed using the glmnet package for R (12).
RESULTS BASELINE CLINICAL CHARACTERISTICS. The study
population included 899 patients (n ¼ 111 with IS-CTO and n ¼ 788 with de novo CTO). The prevalence of IS-CTO PCI was therefore 12.3%. Clinical characteristics of the study population are shown in Table 1. There were no differences between IS-CTO and de novo CTO patients with regards to age, gender, prevalence of cardiovascular risk factors, renal function, ejection fraction and indication of CTO PCI. Subjects with IS-CTO had a higher prevalence of prior MI and prior PCI. BASELINE
ANGIOGRAPHIC
CHARACTERISTICS.
Baseline angiographic data are presented in Table 2. Compared to the de novo CTO group, IS-CTO patients had a lower burden of coronary artery disease. No differences were observed regarding the target CTO A 67-year-old man with ostial left anterior descending in-stent occlusion (A [dotted line]
vessel, J-CTO and PROGRESS-CTO scores, and the
and B). J-CTO (Japanese-Chronic Total Occlusion) score was 2 (blunt stump, length
amount of collateralization. The IS-CTO group had
>20 mm) and PROGRESS-CTO (Prospective Global Registry for the Study of Chronic Total
lower prevalence of moderate/severe calcifications
Occlusion Intervention-CTO) score was 1 (proximal cap ambiguity). Both ipsilateral and contralateral collaterals were observed; the distal cap was at the bifurcation with a
and bifurcation at the distal cap. However, IS-CTO
diagonal branch (A and B). A retrograde approach was chosen. (C) A Sion guidewire
also had a lower prevalence of adequate landing
(Asahi Intecc, Nagoya, Japan) was advanced through a Corsair microcatheter (Asahi
zone beyond the distal cap, as well as a higher prev-
Intecc) (arrow) from the right coronary artery. (D) The stent was penetrated
alence of occlusion length >20 mm and ostial
retrogradely with a Confianza guidewire (Asahi Intecc), supported by the microcatheter
location.
(arrow). The wire was externalized and standard chronic total occlusion percutaneous coronary intervention techniques followed. (E) The result after pre-dilatation; (F) the final result after implantation of 2 overlapping drug-eluting stents.
PROCEDURAL CHARACTERISTICS. Table 3 shows
procedural data. There was a trend toward lower use of radial access in IS-CTO patients, as compared with de novo CTO subjects. Antegrade wire escalation was implantation, procedural success, and major proce-
the most frequent successful crossing strategy (59.0%
dural complications. The final model obtained after
in IS-CTO vs. 48.1% in de novo CTO; p ¼ 0.08). The
penalization
variables
retrograde approach and dissection/re-entry tech-
(Online Figure 1): IS-CTO, diabetes, prior CABG,
niques were used less often in IS-CTO patients. The
included
the
following
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Outcomes of In-Stent CTO PCI
F I G U R E 2 Right Coronary Artery IS-CTO Recanalized With a CrossBoss-Based Antegrade Approach
(A) A 65-year-old man with mid right coronary artery in-stent occlusion (dotted line). J-CTO (Japanese-Chronic Total Occlusion) score was 2 (blunt stump, length >20 mm) and PROGRESS-CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention-CTO) score was 0. (A) Contralateral epicardial collaterals were observed. (B) An antegrade approach was chosen. The CrossBoss (Boston Scientific, Marlborough, Massachusetts) was used to cross the in-stent segment (arrow). (C) A Confianza guidewire (Asahi Intecc, Nagoya, Japan) was subsequently used to reach the distal true lumen, using the CrossBoss (Boston Scientific, Marlborough, Massachusetts) as a support microcatheter (arrow). (D) The final result, after implantation of 2 overlapping drug-eluting stents.
use of CrossBoss was 4-fold higher in IS-CTO (26.1%
Technical (87.4% vs. 87.2%; p ¼ 0.95) and proce-
vs. 6.6%; p < 0.001). Second-generation DES were the
dural (86.5% vs. 86.5%; p ¼ 0.99) success rates
preferred stents in both cohorts, although bio-
were similar between the 2 groups. The incidence of
resorbable scaffolds were used more frequently in
major procedural complications was also similar
de novo CTO lesions. Despite the fact that dissection/
between groups (2.7% vs. 2.4%; p ¼ 0.84). In partic-
re-entry
of
ular, 1 perforation with tamponade, 1 case of major
IS-CTO patients, true-to-true crossing of the occlu-
bleeding, and 1 case of contrast-induced nephropathy
sion segment containing the restenosed stent was
were observed in the IS-CTO group. In patients treated
always possible in our experience, and in no case
for de novo CTO, we observed 8 cases of perforation
subintimal crushing of the previous stent was
with tamponade (2 of these patients subsequently
required. Total stent length tended to be longer in
died), 1 case of major bleeding, 4 cases of stroke (2 of
IS-CTO. Procedural metrics were similar between the
them
2 groups.
nephropathy, and 3 periprocedural MIs.
techniques
were
utilized
in
30%
later
died),
3
cases
of
contrast-induced
895
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Outcomes of In-Stent CTO PCI
CLINICAL OUTCOMES ON FOLLOW-UP
T A B L E 1 Baseline Clinical Characteristics
Age, yrs
Overall (N ¼ 899)
In-Stent CTO (n ¼ 111)
De Novo CTO (n ¼ 788)
p Value
65.1 10.7
65.1 10.3
65.1 10.8
0.98
Follow-up was available for 807 of 899 (89.8%) patients. Median follow-up was 471 (interquartile range: 354 to 872) days. Table 4 shows clinical outcomes on
Male
778 (86.5)
92 (82.9)
686 (87.1)
0.23
Body mass index, kg/m2
28.9 5.3
29.2 5.4
28.9 5.3
0.68
follow-up. IS-CTO patients tended to have a higher
Diabetes
335 (37.8)
45 (41.3)
290 (37.3)
0.42
incidence of MACE (20.8% vs. 13.9%; p ¼ 0.07) driven
Dyslipidemia
714 (80.4)
91 (85.0)
623 (79.8)
0.20
by TVR (16.7% vs. 9.4%; p ¼ 0.03). No differences
Hypertension
665 (74.9)
85 (79.4)
580 (74.3)
0.25
were observed regarding cardiac death and target-
Current smoker
193 (23.1)
22 (21.6)
171 (23.3)
0.69
424 (48.2)
76 (70.4)
348 (45.1)
<0.001
vessel MI.
Prior myocardial infarction Prior PCI
545 (60.7)
111 (100)
434 (55.1)
<0.001
Prior coronary artery bypass graft eGFR, ml/min/1.73 m2 eGFR <60 ml/min/1.73 m2
Table 5 shows univariate and multivariate predictors of MACE on follow-up. Treatment of IS-CTO
191 (21.3)
22 (19.8)
169 (21.5)
0.69
83.4 28.3
82.7 26.5
83.6 28.5
0.76
remained
83 (9.6)
11 (10.4)
72 (9.5)
0.78
(HR: 2.16; 95% confidence interval: 1.18 to 3.95;
independently
associated
with
MACE
16 (1.9)
3 (2.8)
13 (1.7)
0.43
p ¼ 0.01), in addition to post-CABG status (HR: 1.73;
53.0 11.4
52.1 11.5
53.1 11.4
0.39
p ¼ 0.05), eGFR (HR: 0.92; p ¼ 0.04), acute coro-
Symptoms
527 (59.1)
65 (59.1)
462 (59.2)
0.74
Silent ischemia
175 (19.6)
20 (18.2)
155 (19.8)
number of diseased vessels (HR: 1.44; p ¼ 0.03),
Acute coronary syndrome
163 (18.3)
20 (18.2)
143 (18.3)
26 (2.9)
5 (4.5)
21 (2.7)
eGFR <30 ml/min/1.73 m2 Left ventricular ejection fraction, %
nary syndrome presentation (HR: 1.92; p ¼ 0.008),
Indication of CTO PCI
Other
and the PROGRESS-CTO score (HR: 1.41; p ¼ 0.01). Figure
3
presents
adjusted
2-year
curves
of
survival free from MACE and TVR. Patients with IS-CTO had a >2-fold increase in the risk of adverse
Values are mean SD or n (%). CTO ¼ chronic total occlusion; eGFR ¼ estimated glomerular filtration rate; PCI ¼ percutaneous coronary intervention.
outcomes, with events accumulating throughout follow-up.
DISCUSSION
T A B L E 2 Baseline Angiographic Characteristics
Overall (N ¼ 899)
In-Stent CTO (n ¼ 111)
De Novo CTO (n ¼ 788)
p Value
The main findings of our study are as follows: 1)
1.83 0.81
1.66 0.75
1.86 0.82
0.02
IS-CTO PCI is performed in about 12% of consecu-
Left anterior descending
254 (28.4)
30 (27.0)
224 (28.6)
0.82
Circumflex
174 (19.4)
20 (18.0)
154 (19.6)
Number of diseased vessels
tive CTO interventions in large CTO PCI programs;
Target-vessel CTO
Right coronary artery
2)
these
patients
and
lesions
do
not
present
marked differences regarding clinical and proce-
467 (52.2)
61 (55.0)
406 (51.8)
Blunt stump
410 (46.0)
55 (49.5)
355 (45.5)
0.43
Moderate or severe calcifications
392 (43.8)
21 (19.1)
371 (47.2)
<0.001
>45 bending
274 (31.0)
35 (32.1)
239 (30.8)
0.78
Lesion length >20 mm
404 (45.7)
74 (68.5)
330 (42.5)
<0.001
Retry
211 (23.4)
26 (23.4)
185 (23.4)
1.00
independently associated with a 2-fold increase in
dural characteristics, and therefore success rates are high and similar to de novo CTO PCI in the hands of experienced operators using the hybrid algorithm;
3)
despite
this
observation,
IS-CTO
is
J-CTO score
1.88 1.24
1.90 1.21
1.88 1.24
0.84
the adjusted risk of MACE (driven by TVR) on
J-CTO score $2
534 (59.3)
72 (64.9)
462 (58.6)
0.21
follow-up.
Proximal cap ambiguity
379 (43.4)
42 (38.9)
337 (44.1)
0.31
Absence of interventional collaterals
181 (20.7)
25 (23.1)
156 (20.4)
0.51
Moderate or severe tortuosity
181 (20.6)
22 (20.2)
159 (20.7)
0.90
Circumflex CTO
174 (19.4)
20 (18.0)
154 (19.6)
0.69
1.04 0.88
1.01 0.79
1.05 0.89
0.65
traditionally been associated with suboptimal suc-
PROGRESS-CTO score $2
248 (28.4)
28 (25.9)
220 (28.8)
0.54
cess rates (2–4). Abbas et al. (2) studied the out-
Ostial CTO
135 (15.2)
31 (27.9)
104 (13.3)
<0.001
comes of a cohort of patients undergoing IS-CTO PCI
Distal cap at bifurcation
299 (34.3)
26 (24.3)
273 (35.7)
0.02
during the bare-metal stent (BMS) era (25% of the
Good distal landing zone
662 (75.9)
69 (64.5)
593 (77.5)
0.003
study population). Success rates were similar for IS-
CC0
57 (6.8)
5 (4.9)
52 (7.1)
0.44
CC1
455 (54.2)
63 (61.2)
392 (53.2)
CC2
328 (39.0)
35 (34.0)
293 (39.8)
PROGRESS-CTO score
Werner’s CC class
Prior to the development and widespread adoption of the hybrid algorithm (13) and dedicated devices (e.g., CrossBoss), PCI of IS-CTO lesions had
CTO versus de novo CTO (63% vs. 70%). Although inability to wire the occlusion was the primary mechanism of failure in both groups, inability to advance or fully dilate the balloon was more
Values are mean SD or n (%).
frequent in the IS-CTO group. Werner et al. (4) re-
CC ¼ collateral channel; CTO ¼ chronic total occlusion; J-CTO ¼ Japanese-CTO; PROGRESS-CTO ¼ Prospective Global Registry for the Study of Chronic Total Occlusion Intervention-CTO.
ported that only 5% of all CTO treated at their institution were IS-CTO. Success rate was 70%, lower
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897
Outcomes of In-Stent CTO PCI
T A B L E 3 Procedural Characteristics
Overall (N ¼ 899)
In-Stent CTO (n ¼ 111)
De Novo CTO (n ¼ 788)
p Value
374 (41.6)
38 (34.2)
336 (42.7)
0.09
Antegrade wire escalation
392 (49.5)
59 (59.0)
333 (48.1)
0.08
Antegrade dissection/re-entry
139 (17.6)
16 (16.0)
123 (17.8)
Radial access* Successful crossing technique
Retrograde wire escalation Retrograde dissection/re-entry
77 (9.7)
11 (11.0)
66 (9.5)
184 (23.2)
14 (14.0)
170 (24.6)
Successful crossing technique: retrograde approach
261 (33.0)
25 (25.0)
236 (34.1)
0.07
Successful crossing technique: dissection/re-entry
323 (40.8)
30 (30.0)
293 (42.3)
0.02
80 (9.0)
29 (26.1)
51 (6.6)
<0.001 0.03
Use of CrossBoss Type of stent Bare-metal stents
14 (1.8)
0 (0)
14 (2.0)
Bioresorbable scaffolds
72 (9.1)
2 (2.1)
70 (10.0)
708 (89.1)
93 (97.9)
615 (87.9)
57 (8.1)
4 (4.3)
53 (8.6)
651 (91.9)
89 (95.7)
562 (91.4)
DES First-generation DES Second-generation DES
0.15
Number of stents implanted
2.21 1.27
2.34 1.31
2.20 1.27
0.29
Total stent length, mm
70.1 42.0
77.3 49.7
69.1 40.7
0.07
Use of intravascular ultrasound
116 (12.9)
11 (9.9)
105 (13.3)
0.39
Contrast volume, ml
328 137
302 134
332 137
0.06
Fluoroscopy time, min
55 34
51 37
55 33
0.24
Total procedure time, min
127 70
115 75
128 69
0.10
Major procedural complications
22 (2.4)
3 (2.7)
19 (2.4)
0.84
Technical success
784 (87.2)
97 (87.4)
687 (87.2)
0.95
Procedural success
778 (86.5)
96 (86.5)
682 (86.5)
0.99
Values are n (%) or mean SD. *Cases with dual radial access or cases with a single access, being radial. CTO ¼ chronic total occlusion; DES ¼ drug-eluting stent(s).
than for de novo CTO (85%), despite the availability of retrograde techniques. In the small series by
T A B L E 5 Predictors of Major Adverse Cardiac Events on Follow-Up
Abdel-Karim et al. (3) success rate was 71%. Failure was due to inability to cross the occlusion in all cases. de la Torre et al. (14) recently reported a procedural success rate of 82% in a single-arm study on 233 patients with IS-CTO. However, patient in-
In-stent CTO
Univariate HR (95% CI)
p Value
Adjusted HR (95% CI)
p Value
1.44 (0.88–2.35)
0.15
2.16 (1.18–3.95)
0.01
1.10 (0.69–1.75)
0.70
Center
0.09
Center 2 vs. Center 1
1.53 (0.94–2.50)
0.09
Center 3 vs. Center 1
0.98 (0.58–1.64)
0.93
clusion spread across a decade, and this study is
Age (per 10-yr increment)
1.17 (0.98–1.40)
0.08
therefore not representative of a modern approach
Diabetes
1.61 (1.12–2.33)
0.01
to IS-CTO PCI.
Prior myocardial infarction
1.55 (1.07–2.24)
0.02
2.35 (1.60–3.45)
<0.001
Prior coronary artery bypass graft T A B L E 4 Clinical Outcomes on Follow-Up
Overall (N ¼ 807)
In-Stent CTO (n ¼ 96)
De Novo CTO (n ¼ 711)
p Value
119 (14.8)
20 (20.8)
99 (13.9)
0.07
Cardiac death
29 (3.6)
4 (4.2)
25 (3.5)
0.75
Target-vessel myocardial infarction
26 (3.2)
3 (3.1)
23 (3.2)
0.95
Ischemia-driven target-vessel revascularization
83 (10.3)
Major adverse cardiac events
Values are n (%). CTO ¼ chronic total occlusion.
16 (16.7)
67 (9.4)
0.03
1.73 (0.99–3.01)
0.05
eGFR (per 10 ml/min/1.73 m2 increment)
0.89 (0.84–0.95) <0.001 0.92 (0.85–0.99)
0.04
Acute coronary syndrome presentation
1.66 (1.11–2.50)
Number of diseased vessels (per 1-vessel increment)
1.68 (1.34–2.10)
0.02
1.92 (1.19–3.12)
<0.001 1.44 (1.03–2.01)
0.008 0.03
J-CTO score (per 1-point increment)
1.35 (1.16–1.56)
<0.001 1.08 (0.88–1.34)
0.46
PROGRESS-CTO score (per 1-point increment)
1.48 (1.21–1.80)
<0.001
1.41 (1.08–1.84)
0.01
1.19 (0.71–2.00)
0.51
Use of dissection/re-entry techniques
1.61 (1.05–2.45)
0.03
Drug-eluting stent implantation
1.62 (0.78–3.37)
0.19
Procedural success
0.38 (0.25–0.58) <0.001
Major procedural complications
5.60 (2.59–12.11)
<0.001
CI ¼ confidence interval; eGFR ¼ estimated glomerular filtration rate; HR ¼ hazard ratio; other abbreviations as in Table 2.
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Outcomes of In-Stent CTO PCI
F I G U R E 3 Long-Term Outcomes of IS-CTO PCI
F I G U R E 4 Procedural Success Rates of IS-CTO PCI
in the Literature
IS-CTO ¼ in-stent chronic total occlusion; PCI ¼ percutaneous coronary intervention.
incidence of IS-CTO PCI was 10.9%. The retrograde approach was used in approximately one-third of procedures, similar to our data. Procedural success rate was high and did not differ between groups (86.0% and 90.3% in IS-CTO vs. de novo CTO, respectively), which mirrors our results (86.5% in both groups). Figure 4 compares procedural success
rates
of
IS-CTO
PCI
in
the
literature
over time. The advancement of wires and microcatheters is greatly impaired by the presence of stent struts in close proximity with the subadventitial space. In such setting, the use of CrossBoss might represent a very efficient alternative (Central Illustration), as it allows for an easy, within-stent, true-to-true occlusion crossing, due to its higher crossing profile combined with its effective dissecting action. In a small single-arm study of selected patients with IS-CTO, CrossBoss showed a 90% success rate, with good procedural metrics (median crossing time of 8 min, despite a mean CTO length of 39 mm) (15). The role of this device for the treatment of IS-CTO deserves further investigation.
Adjusted 2-year curves of survival free from (A) major adverse cardiac events (MACE) and
In comparison with the aforementioned reports
(B) target vessel revascularization (TVR), for patients with and without in-stent chronic total occlusion (CTO). Adjusted curves were generated with Cox regression controlling for
(2–5,14,15),
the independent predictors of MACE shown in Table 5. CI ¼ confidence interval;
our
study
has
several
strengths,
including a larger sample size, comparison with a
HR ¼ hazard ratio.
de novo CTO PCI group, a detailed angiographic analysis, and, remarkably, the availability of data Following
systematic
implementation
of
the
on long-term clinical outcomes. Additionally, we
hybrid algorithm, IS-CTO PCI success rates have
performed
an
adjusted
remarkably improved. In an all-comer patient popu-
IS-CTO
an
independent
lation from the PROGRESS-CTO registry (5), the
(driven
as by
TVR)
on
analysis
that
predictor
follow-up.
identified of
MACE
This
latter
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Outcomes of In-Stent CTO PCI
C ENTR AL I LL U STRA T I O N Risk Factors, Angiographic Characteristics, Histopathology, and Techniques to Recanalize In-Stent Chronic Total Occlusions
Azzalini, L. et al. J Am Coll Cardiol Intv. 2017;10(9):892–902.
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Outcomes of In-Stent CTO PCI
observation had already been reported (6), and
challenging
parallels similar findings from the non-CTO inter-
attention. The use of more potent antiplatelet
patient
population
deserve
special
ventional practice, where PCI for in-stent restenosis
therapy might improve patient outcomes, although
had been identified as a predictor of future rest-
such a hypothesis has not been tested yet. Also,
enotic events (16).
systemically administered colchicine can decrease
The pathophysiology of such in-stent occlusions is
neointimal hyperplasia following stent implantation
largely unknown. Although neointima formation may
and has been associated with a decreased in-
be involved, we also know that such phenomenon is
stent restenosis rate (23). Finally, CABG might
dramatically reduced with DES. We hypothesize
be
that a significant proportion of IS-CTOs were the re-
disease and IS-CTO to reduce the risk of TVR, pro-
sults of other factors (e.g., stent thrombosis, stent
vided that full arterial revascularization can be
fracture, neoatherosclerosis) (Central Illustration).
achieved (24,25).
considered
for
patients
with
multivessel
It is reasonable to say that the patient’s biological
Our adjusted analysis also identified prior CABG,
factors that were involved in the first episode of
worse renal function, procedural indication for acute
stent occlusion are likely again triggered in the
coronary syndrome, higher number of diseased
newly implanted stent in the same segment, and
vessels, and higher PROGRESS-CTO score as inde-
may involve abnormal local inflammation, adverse
pendent predictors of MACE on follow-up. While
reaction
antiplatelet
most of these variables are well known to be
agents, stent malapposition or underexpansion, or
associated with adverse events, the observation that
others. In a seminal study in the BMS era, Mehran
an angiographic tool such as the PROGRESS-CTO
et
al.
to
(17)
polymer,
indicated
resistance
that
up
to
to
one-half
of
score
is
able
to
predict
clinical
outcomes
in
IS-CTO cases had suffered a prior episode of in-stent
patients undergoing CTO PCI (similar to the SYNTAX
restenosis and that IS-CTO was an independent
score in all-comers) (26) is novel. As compared
predictor of target-lesion revascularization after
with the J-CTO score, the PROGRESS-CTO score
recanalization.
does
not
account
for
the
operator-dependent
In some cases, stent occlusion might have been the
component (i.e., retry CTO PCI) in the prediction of
result of thrombosis rather than restenosis. Indeed,
successful revascularization using the hybrid algo-
asymptomatically
rithm (9). Therefore, the PROGRESS-CTO score
several months after implantation (18). This phe-
exclusively evaluates occlusion complexity, which in
nomenon might be especially relevant after recana-
our study was associated with higher risk of MACE on
lization of chronically occluded arteries. In registries
follow-up.
where multidetector computed tomography was
research.
routinely performed 6 months after bioresorbable
STUDY LIMITATIONS. First, it shares the limitations
scaffold implantation, asymptomatic restenosis or
of all observational studies. Second, no data was
reocclusion was detected in up to 5.7% of patients
available on the specific type of stent (DES vs. BMS)
(19,20).
that had suffered occlusive restenosis in the IS-CTO
stent
thrombosis
can
develop
This
observation
warrants
further
The improvement in clinical outcomes for IS-CTO
group and the time frame between stent implanta-
patients will likely stem from the development of
tion and development of IS-CTO, due to the fact that
newer-generation DES, with better antiproliferative
most patients were referred to our CTO PCI programs
characteristics as well as eliciting lower inflamma-
from other centers. However, we do not think that
tory
knowing this would have altered clinical decision
response.
Additionally,
intravascular
ultra-
sound (IVUS) can provide useful information about
making
the
(after
implanted in all IS-CTO cases. Third, IVUS use was
pre-dilatation with a small balloon) and, more
low in the IS-CTO group, in order not to prolong
importantly,
to
these already lengthy procedures and due to cost-
minimize the risk of adverse outcomes on follow-up
related issues. Additionally, IVUS findings were not
mechanisms to
underlying
optimize
stent
IS-CTO
implantation
because
drug-eluting
platforms
were
(21). Indeed, recent data from the Multicenter
captured by our database, which prevented identifi-
Korean CTO Registry indicated that IVUS-guided
cation of the mechanisms leading to IS-CTO in our
CTO PCI was associated with lower risk of stent
study. Finally, our observations might not be gener-
thrombosis, and possibly target-lesion revasculari-
alizable to other institutions where expert hybrid
zation in the subset of long lesions (22). Addition-
CTO PCI operators and dedicated devices are not
ally, pharmacologic strategies to deal with this
available.
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Outcomes of In-Stent CTO PCI
CONCLUSIONS
PERSPECTIVES
IS-CTO PCI is frequently performed with excellent success rates in the hands of experienced operators using the hybrid algorithm. Although, as compared with de novo CTO, IS-CTO was not associated with lower procedural success, it was found to be independently associated with a higher risk of MACE (driven by TVR) on follow-up. Novel strategies and stents are therefore needed to improve the outcomes of IS-CTO PCI.
WHAT IS KNOWN? IS-CTOs have traditionally been associated with suboptimal success rates of PCI. Little data exist on the outcomes of this challenging patient subgroup on follow-up. WHAT IS NEW? This multicenter registry analyzed the outcomes of a large cohort of patients with IS-CTO versus de novo CTO. Procedural success was high and similar in the 2 groups. At long-term follow-up, the rate of MACE was higher in IS-CTO versus de novo CTO, driven by TVR. IS-CTO was an independent predictor of MACE.
ADDRESS FOR CORRESPONDENCE: Dr. Stéphane
Rinfret, McGill University, Division of Interventional Cardiology,
Cardio-Thoracic-Vascular
Department,
McGill University Health Centre, Royal Victoria Glen Site (B03.7200), 1001 Boulevard Décarie, Montreal (Québec) H4A 3J1, Canada. E-mail: stephane.rinfret@
WHAT IS NEXT? The development of newer-generation DES, with better antiproliferative characteristics as well as eliciting lower inflammatory response, warrants further research, to improve the long-term outcomes of this challenging patient population.
mcgill.ca.
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KEY WORDS chronic total occlusion, in-stent restenosis, percutaneous coronary intervention
A PPE NDI X For a supplemental figure, please see the online version of this article.