Abstract

Aims

Percutaneous coronary intervention with bare metal stent (BMS) in chronic total coronary occlusions (CTOs) is associated with a higher rate of angiographic restenosis and reocclusion than that observed in subtotal stenoses. Preliminary reports have suggested a better performance of drug-eluting stents in CTO. In this multicentre, randomized trial, we compared the mid-term angiographic and clinical outcome of sirolimus-eluting stent (SES) or BMS implantation after successful recanalization of CTO.

Methods and results

Patients with CTO older than 1 month, after successful recanalization, were randomized to implantation of SES (78 patients) or BMS (74 patients) in 13 Italian centres. Clopidogrel therapy was prescribed for 6 months. The primary endpoint was in-segment minimal luminal diameter (MLD) at 8-month follow-up. Secondary clinical endpoints included death, myocardial infarction (MI), target lesion revascularization (TLR), and target vessel revascularization (TVR) at 24 months. Patients treated with SES showed, at in-segment analysis, a larger MLD (1.98 ± 0.57 vs. 0.98 ± 0.80 mm, P < 0.001), a lower late luminal loss (−0.06 ± 0.49 vs. 1.11 ± 0.79 mm, P < 0.001), and lower restenosis (9.8 vs. 67.7%, P < 0.001) and reocclusion (0 vs. 17%, P = 0.001) rates. At 24-month follow-up, patients in the SES group experienced fewer major adverse cardiac events (50.0 vs. 17.6%, P < 0.001) mainly due to a lower rate of both TLR (44.9 vs. 8.1%, P < 0.001) and TVR (44.9 vs. 14.9%, P < 0.001).

Conclusion

In CTO, SES is markedly superior to BMS in terms of restenosis and reocclusion rate, and incidence of repeat revascularization at 24 months.

Clinicaltrials.gov identifier: NCT00220558

Introduction

Percutaneous coronary intervention is an established treatment for selected patients with chronic total coronary occlusions (CTOs), although the long-term results are limited by a higher restenosis rate than that observed in subtotal stenosis. At present, due to the availability of dedicated equipment and increased operator experience, the acute success rate of percutaneous intervention in CTOs has improved.1 However, a more aggressive approach,2 while increasing the success rate, may provoke long dissections and require implantation of long or multiple stents, with an anticipated increase in restenosis risk.

Several studies, mostly observational, have evaluated drug-eluting stents (DES) implantation in CTOs3–10 with favourable results, reporting restenosis rates varying between 08 and 19.2%7 and total reocclusion rates up to 11.5%.7 However, even using DES, CTOs present a higher restenosis rate than subtotal lesions.11 In addition, to date, no DES has an unlimited worldwide license for use in CTO despite the practice being widespread.

Given the paucity of dedicated randomized data, we thus designed in 2004 a prospective, multicentre, randomized study— Gruppo Italiano di Studio sullo Stent nelle Occlusioni Coronariche —supported by GISE (Società Italiana di Cardiologia Invasiva), or GISSOC II-GISE, in order to compare the angiographic and clinical outcome after implantation of bare metal stent (BMS) or sirolimus-eluting stent (SES) in CTOs.

Methods

The GISSOC-2 trial was performed in 13 Italian centres in order to compare a SES (Cypher, Cordis, Miami, FL, USA) with the BMS with similar design (Bx Sonic, Cordis) in CTOs, which were defined as total occlusions with no visible luminal continuity of at least 30 days of duration. The duration of the occlusion was estimated from previous angiographic data, from the date of a myocardial infarction (MI) in the distribution of the occluded vessel, or from beginning or worsening of anginal symptoms.

The study was conducted according to the principles of the Declaration of Helsinki, approved by the institutional review board at each participating centre, and registered at clinicaltrials.gov (NCT00220558). All patients gave written informed consent.

Patient selection

Patients older than 18 years, with a de novo CTO on a native coronary artery, with an estimated vessel size between 2.75 and 3.75 mm, and with a clinical presentation including angina, silent ischaemia, or myocardial viability, were considered for the study. The occlusion had to be dilated by the balloon and the lesion had to be fully coverable, according to the operator judgment, by ≤2 stent of ≤33 mm in length.

Main exclusion criteria included inability to give informed consent, MI within 30 days in the territory of the target CTO or within 3 days in another territory, left ventricular ejection fraction <30%, renal failure with serum creatinine >3 mg/dL, other comorbid condition with life expectancy <2 years, contraindications to aspirin or clopidogrel therapy, women with child bearing potential, left main disease, and CTO involving a bifurcation with side branch larger than 2 mm.

Treatment

Eligible patients were randomly assigned in a 1:1 ratio to treatment with SES or BMS by means of sealed envelopes. All patients received aspirin 100–300 mg/day and clopidogrel 75 mg/day. A loading dose of 300 mg of clopidogrel was administered the day before the procedure in patients who were not pre-treated. Clopidogrel discontinuation was recommended 6 months after the index procedure in all patients, while aspirin was prescribed indefinitely. During the procedure, unfractionated heparin was given to maintain the activated clotting time >250 s. Creatinine kinase and MB isoenzyme levels were measured before, and 8 and 24 h after the procedure.

Clinical and angiographic follow-up

A clinical evaluation was scheduled at 1, 8, 12, and 24 months. Coronary angiography was repeated at 8 months or earlier when clinically indicated in all consenting patients. An unscheduled angiogram obtained any time before 6 months substituted for the follow-up angiogram only if an in-segment diameter stenosis ≥50% by quantitative coronary angiography was found, otherwise the patients were required to undergo a repeat angiography at 8 months.

Quantitative coronary angiography

Quantitative coronary angiography was performed off-line at an independent core laboratory (Mediolanum Cardio Research, Milan, Italy) by experienced personnel who was unaware of the type of the stent implanted. The projection that best showed the stenosis severity was selected. Matched projections were obtained at baseline, at the end of the procedure, and at the 8-month follow-up after intracoronary injection of nitroglycerin and were analysed using a validated edge-detection software (CMS Medis Medical Imaging Systems, Leiden, the Netherlands). The tip of the coronary catheter was used for calibration. Quantitative parameters included interpolated reference diameter, minimal luminal diameter (MLD), diameter stenosis, and late luminal loss.

On the pre-intervention angiogram, reference vessel diameter and lesion length were measured. The CTO length was assessed either using the visualization of the distal vessel by collaterals or after balloon pre-dilatation. In the post-procedural and follow-up angiograms, both in-stent and in-segment analyses were performed. In-segment analysis included both the proximal and distal edges of the stent(s), each 5 mm long.

Endpoints and definitions

The primary endpoint of the study was the in-segment MLD at 8 months.8,12 Secondary angiographic endpoints were in-segment late luminal loss and restenosis rate, the latter defined as the rate of patients showing an in-segment diameter stenosis greater ≥50% at follow-up.

Secondary clinical endpoints were major adverse cardiac event rate at 24 months, defined as death, MI (with or without ST elevation), emergent bypass surgery, or repeat target lesion revascularization (TLR) or target vessel revascularization (TVR). Target vessel revascularization was defined clinically driven when core laboratory quantitative coronary angiography identified a >70% stenosis in the target vessel, or alternatively a >50% stenosis associated with angina or evidence of myocardial ischaemia.13 Myocardial infarction related to a revascularization procedure was defined as elevation of the creatine kinase-MB greater than three times the upper normal limit. Myocardial infarction during follow-up was defined as elevation of the creatine kinase-MB greater than two times the upper normal limit with either ischaemic symptoms or ischaemic electrocardiographic changes. In addition, MI was defined as ST elevation when ≥1 mm ST elevation was recorded in two contiguous electrocardiographic leads. Stent thrombosis was defined as an acute coronary syndrome with angiographic documentation of either occlusion of the target lesion or thrombus within the previously stented segment. Stent thrombosis was also adjudicated using the Academic Research Consortium definitions13 that was not available at the time of conception of the study.

Data management

Independent study monitors verified all study data at the participating centres. All major adverse cardiac events and stent thrombosis were adjudicated by an independent committee blinded to treatment allocation after review of original source documentation.

Statistical analysis

Follow-up MLD after BMS implantation in CTOs was preliminarily estimated to be 1.7 ± 0.8 mm.12,14–17 Assuming that the in-segment MLD at follow-up after SES implantation in CTOs should be 2.18 mm,4,6,9 a sample size of 120 patients (60 in each arm) will have the power of 0.80 to detect a difference between the two group with a two-tailed alpha error of 0.05. The sample size was prudentially increased to 150 patients to compensate for losses at follow-up.

Categorical variables are expressed as absolute numbers and percent value. Continuous variables are expressed as mean value ± standard deviation or as median and interquartile range for non-Gaussian distributed data. Differences between groups for categorical variables were assessed with the Fisher's exact test. Differences between groups for continuous variables were evaluated with the two-tailed unpaired Student's t-test or the Mann–Whitney U test for non-Gaussian distributed data. Event-free survival rates were estimated using the Kaplan–Meier method, with differences between the two treatment groups assessed with the use of the log-rank test of significance. A two-sided P-value < 0.05 was considered significant. All evaluations were performed according to the intention to treat principle. All analyses were performed using BMDP 2009 Statistical Software (Statistical Solutions Ltd, Cork, Ireland).

Results

From May 2005 to September 2007, 152 patients were enrolled in the study: 78 were randomized to BMS implantation and 74 assigned to SES treatment, with no violation of allocation (Figure 1). As shown in Table 1, no significant difference was observed in the baseline clinical characteristics of the two patient groups. The angiographic and procedural variables (Table 2) were comparable in both groups, except for a slightly larger maximal balloon diameter in the BMS group (P = 0.025). Also, patients treated with BMS showed a slightly larger postprocedural MLD (Table 3, P = 0.023). These differences are possibly related to the unblinded design of the study. One patient treated with SES was lost to follow-up.

Table 1

Baseline clinical characteristics

 BMS (n = 78) SES (n = 74) 
Age (years) 63.9 ± 9.8 63.9 ± 9.6 
Male 68 (87.1) 58 (78.3) 
Diabetes mellitus 15 (19.2) 19 (25.7) 
Hypertension 51 (65.4) 49 (66.2) 
Smoking 41 (52.6) 45 (60.8) 
Hypercholesterolaemia 59 (75.6) 54 (73.0) 
Prior myocardial infarction 24 (30.8) 24 (32.4) 
Prior coronary bypass surgery 4 (5.1) 5 (6.7) 
Prior percutaneous revascularization 15 (19.2) 11 (14.9) 

 
Angina 
 None 24 (30.8) 18 (24.3) 
 Class I or II 30 (38.5) 25 (33.8) 
 Class III or IV 9 (11.5) 14 (18.9) 
 Unstable angina 15 (19.2) 17 (23.0) 
 BMS (n = 78) SES (n = 74) 
Age (years) 63.9 ± 9.8 63.9 ± 9.6 
Male 68 (87.1) 58 (78.3) 
Diabetes mellitus 15 (19.2) 19 (25.7) 
Hypertension 51 (65.4) 49 (66.2) 
Smoking 41 (52.6) 45 (60.8) 
Hypercholesterolaemia 59 (75.6) 54 (73.0) 
Prior myocardial infarction 24 (30.8) 24 (32.4) 
Prior coronary bypass surgery 4 (5.1) 5 (6.7) 
Prior percutaneous revascularization 15 (19.2) 11 (14.9) 

 
Angina 
 None 24 (30.8) 18 (24.3) 
 Class I or II 30 (38.5) 25 (33.8) 
 Class III or IV 9 (11.5) 14 (18.9) 
 Unstable angina 15 (19.2) 17 (23.0) 

Values expressed as number (%) or mean ± SD. Angina severity according to Canadian Cardiovascular Society classification. All differences between the study groups are not significant.

BMS, bare metal stent; SES, sirolimus-eluting stent.

Table 2

Angiographic and procedural variables

 BMS (n = 78) SES (n = 74) 
Ejection fraction (%) 55.4 ± 11.3 55.1 ± 8.8 
One vessel disease 25 (32.0) 26 (35.1) 
Two vessels disease 28 (35.9) 21 (28.4) 
Three vessels disease 25 (32.0) 27 (36.5) 

 
Target vessel 
 Left anterior descending 20 (25.6) 24 (32.4) 
 Left circumflex 21 (26.9) 15 (20.3) 
 Right coronary 37 (47.4) 35 (47.3) 

 
Duration of the occlusion 
 1–3 months 4 (5.1) 6 (8.1) 
 >3 months 23 (29.5) 28 (37.8) 
 Not determinable 51 (65.4) 40 (54.1) 

 
Moderate/severe calcification 15 (19.2) 8 (10.8) 
Baseline TIMI flow grade 0 61 (78.2) 52 (70.2) 
Baseline TIMI flow grade 1 15 (19.2) 20 (27.0) 
No. of coronary guidewires/occlusion 1.68 ± 0.90 1.67 ± 0.75 
Use of specialized stiff or hydrophilic guidewires 69 (88.5) 67 (90.5) 
Contralateral injection 9 (11.5) 9 (12.2) 
No. of stents on the CTO 1.55 ± 0.70 1.64 ± 0.75 
Total stent length on the CTO (mm) 37.5 ± 16.6 40.5 ± 18.0 
Max balloon diameter (mm) 3.02 ± 0.28 2.92 ± 0.27* 
Max inflation pressure (atm) 14.3 ± 2.7 14.8 ± 2.5 
 BMS (n = 78) SES (n = 74) 
Ejection fraction (%) 55.4 ± 11.3 55.1 ± 8.8 
One vessel disease 25 (32.0) 26 (35.1) 
Two vessels disease 28 (35.9) 21 (28.4) 
Three vessels disease 25 (32.0) 27 (36.5) 

 
Target vessel 
 Left anterior descending 20 (25.6) 24 (32.4) 
 Left circumflex 21 (26.9) 15 (20.3) 
 Right coronary 37 (47.4) 35 (47.3) 

 
Duration of the occlusion 
 1–3 months 4 (5.1) 6 (8.1) 
 >3 months 23 (29.5) 28 (37.8) 
 Not determinable 51 (65.4) 40 (54.1) 

 
Moderate/severe calcification 15 (19.2) 8 (10.8) 
Baseline TIMI flow grade 0 61 (78.2) 52 (70.2) 
Baseline TIMI flow grade 1 15 (19.2) 20 (27.0) 
No. of coronary guidewires/occlusion 1.68 ± 0.90 1.67 ± 0.75 
Use of specialized stiff or hydrophilic guidewires 69 (88.5) 67 (90.5) 
Contralateral injection 9 (11.5) 9 (12.2) 
No. of stents on the CTO 1.55 ± 0.70 1.64 ± 0.75 
Total stent length on the CTO (mm) 37.5 ± 16.6 40.5 ± 18.0 
Max balloon diameter (mm) 3.02 ± 0.28 2.92 ± 0.27* 
Max inflation pressure (atm) 14.3 ± 2.7 14.8 ± 2.5 

Values expressed as number (%) or mean ± SD.

BMS, bare metal stent; SES, sirolimus-eluting stent; CTO, chronic total coronary occlusion.

*P = 0.025, other differences between the study groups are not significant.

Table 3

Quantitative coronary angiography parameters

 BMS (n = 78) SES (n = 74) P-value 
Baseline 
 Proximal vessel diameter (mm) 2.65 ± 0.38 2.62 ± 0.31 0.582 
 Occlusion length (mm) 15.5 ± 8.4 15.3 ± 7.3 0.880 

 
After stenting 
 Reference vessel diameter (mm) 2.91 ± 0.34 2.80 ± 0.45 0.080 
 MLD (mm) 
  Proximal edge 2.77 ± 0.53 2.73 ± 0.58 0.607 
  In-stent 2.59 ± 0.35 2.46 ± 0.35 0.023 
  Distal edge 2.08 ± 0.45 1.95 ± 0.56 0.116 
  In-segment 2.13 ± 0.46 1.94 ± 0.50 0.015 
 Diameter stenosis (% of vessel diameter) 
  Proximal edge 13.7 ± 12.7 13.5 ± 14.4 0.915 
  In-stent 14.2 ± 8.1 16.2 ± 7.8 0.139 
  Distal edge 22.8 ± 12.9 26.6 ± 14.2 0.086 
  In-segment 26.9 ± 12.2 30.8 ± 12.6 0.055 

 
Follow-up 
 Reference vessel diameter (mm) 2.79 ± 0.49 2.86 ± 0.48 0.360 
 MLD (mm) 
  Proximal edge 2.64 ± 0.74 2.65 ± 0.60 0.893 
2.71 (2.24–3.12) 2.69 (2.32–3.03) 
  In-stent 1.01 ± 0.84 2.26 ± 0.61 <0.001 
0.77 (0.26–1.78) 2.37 (1.93–2.72) 
  Distal edge 1.75 ± 0.93 2.21 ± 0.47 0.012 
2.06 (1.22–2.39) 2.16 (1.88–2.55) 
  In-segment 0.98 ± 0.80 1.98 ± 0.57 <0.001 
0.77 (0.26–1.62) 1.97 (1.69–2.31) 
 Diameter stenosis (% of vessel diameter) 
  Proximal edge 15.3 ± 17.6 14.7 ± 15.9 0.839 
10.2 (3.0–21.6) 9.6 (3.0–23.3) 
  In-stent 65.4 ± 28.0 22.4 ± 17.6 <0.001 
71.6 (39.1–91.1) 17.8 (10.6–27.8) 
  Distal edge 30.9 ± 33.3 16.3 ± 12.5 0.040 
19.0 (7.2–40.0) 13.4 (8.1–25.3) 
  In-segment 66.4 ± 26.8 31.0 ± 17.2 <0.001 
71.6 (42.3–91.1) 26.7 (18.0–40.3) 
 Late luminal loss (mm) 
  Proximal edge 0.11 ± 0.59 0.03 ± 0.47 0.499 
−0.01 (−0.28–0.39) −0.09 (−0.24–0.20) 
  In-stent 1.57 ± 0.85 0.20 ± 0.49 <0.001 
1.66 (0.85–2.27) 0.07 (−0.11–0.45) 
  Distal edge 0.29 ± 0.83 −0.29 ± 0.43 <0.001 
0.19 (−0.34–0.71) −0.31 (−0.52–0.06) 
  In-segment 1.11 ± 0.79 −0.06 ± 0.49 <0.001 
1.10 (0.50–1.65) −0.10 (−0.35–0.16) 
 Binary restenosis 
  Proximal edge 4 (6.15) 1 (1.64) 0.186 
  In-stent 44 (67.7) 5 (8.2) <0.001 
  Distal edge 12 (18.5) 1 (1.64) 0.001 
  In-segment 44 (67.7) 6 (9.8) <0.001 
 Total reocclusion 11 (16.9%) 0 (0%) 0.001 
 Restenosis pattern 
  Focal 14 (21.5) 6 (9.8) 0.072 
  Diffuse 19 (29.2) <0.001 
  Proliferative – 
 BMS (n = 78) SES (n = 74) P-value 
Baseline 
 Proximal vessel diameter (mm) 2.65 ± 0.38 2.62 ± 0.31 0.582 
 Occlusion length (mm) 15.5 ± 8.4 15.3 ± 7.3 0.880 

 
After stenting 
 Reference vessel diameter (mm) 2.91 ± 0.34 2.80 ± 0.45 0.080 
 MLD (mm) 
  Proximal edge 2.77 ± 0.53 2.73 ± 0.58 0.607 
  In-stent 2.59 ± 0.35 2.46 ± 0.35 0.023 
  Distal edge 2.08 ± 0.45 1.95 ± 0.56 0.116 
  In-segment 2.13 ± 0.46 1.94 ± 0.50 0.015 
 Diameter stenosis (% of vessel diameter) 
  Proximal edge 13.7 ± 12.7 13.5 ± 14.4 0.915 
  In-stent 14.2 ± 8.1 16.2 ± 7.8 0.139 
  Distal edge 22.8 ± 12.9 26.6 ± 14.2 0.086 
  In-segment 26.9 ± 12.2 30.8 ± 12.6 0.055 

 
Follow-up 
 Reference vessel diameter (mm) 2.79 ± 0.49 2.86 ± 0.48 0.360 
 MLD (mm) 
  Proximal edge 2.64 ± 0.74 2.65 ± 0.60 0.893 
2.71 (2.24–3.12) 2.69 (2.32–3.03) 
  In-stent 1.01 ± 0.84 2.26 ± 0.61 <0.001 
0.77 (0.26–1.78) 2.37 (1.93–2.72) 
  Distal edge 1.75 ± 0.93 2.21 ± 0.47 0.012 
2.06 (1.22–2.39) 2.16 (1.88–2.55) 
  In-segment 0.98 ± 0.80 1.98 ± 0.57 <0.001 
0.77 (0.26–1.62) 1.97 (1.69–2.31) 
 Diameter stenosis (% of vessel diameter) 
  Proximal edge 15.3 ± 17.6 14.7 ± 15.9 0.839 
10.2 (3.0–21.6) 9.6 (3.0–23.3) 
  In-stent 65.4 ± 28.0 22.4 ± 17.6 <0.001 
71.6 (39.1–91.1) 17.8 (10.6–27.8) 
  Distal edge 30.9 ± 33.3 16.3 ± 12.5 0.040 
19.0 (7.2–40.0) 13.4 (8.1–25.3) 
  In-segment 66.4 ± 26.8 31.0 ± 17.2 <0.001 
71.6 (42.3–91.1) 26.7 (18.0–40.3) 
 Late luminal loss (mm) 
  Proximal edge 0.11 ± 0.59 0.03 ± 0.47 0.499 
−0.01 (−0.28–0.39) −0.09 (−0.24–0.20) 
  In-stent 1.57 ± 0.85 0.20 ± 0.49 <0.001 
1.66 (0.85–2.27) 0.07 (−0.11–0.45) 
  Distal edge 0.29 ± 0.83 −0.29 ± 0.43 <0.001 
0.19 (−0.34–0.71) −0.31 (−0.52–0.06) 
  In-segment 1.11 ± 0.79 −0.06 ± 0.49 <0.001 
1.10 (0.50–1.65) −0.10 (−0.35–0.16) 
 Binary restenosis 
  Proximal edge 4 (6.15) 1 (1.64) 0.186 
  In-stent 44 (67.7) 5 (8.2) <0.001 
  Distal edge 12 (18.5) 1 (1.64) 0.001 
  In-segment 44 (67.7) 6 (9.8) <0.001 
 Total reocclusion 11 (16.9%) 0 (0%) 0.001 
 Restenosis pattern 
  Focal 14 (21.5) 6 (9.8) 0.072 
  Diffuse 19 (29.2) <0.001 
  Proliferative – 

Values expressed as number (%), mean ± SD or median (IQR). The follow-up measurements refer to 66 patients in the BMS group and 62 patients in the SES group, because 12 patients in each group did not undergo the angiographic follow-up.

IQR, interquartile range; MLD, minimal luminal diameter; BMS, bare metal stent; SES, sirolimus-eluting stent.

Figure 1

Patient-flow diagram of the GISSOC-II GISE Study. QCA, quantitative coronary angiography.

Figure 1

Patient-flow diagram of the GISSOC-II GISE Study. QCA, quantitative coronary angiography.

Angiographic follow-up was obtained in 128 patients (84%) 8.4 ± 1.3 months after the procedure. Twelve patients in the BMS group and 11 patients in the SES group, all asymptomatic, refused the repeat angiography. All the baseline, procedural, angiographic, and clinical data were re-analysed excluding patients without angiographic follow-up, but the differences between the study groups remained substantially unchanged. These results are reported in the supplementary material online, Tables S1–S4.

As shown in Table 3 and Figure 2, patients in the BMS group showed, at follow-up, a smaller MLD, and larger late luminal loss and binary restenosis rate at both in-stent and in-segment analyses. In addition, both diffuse and occlusive patterns of restenosis were significantly higher in the BMS group. No stent fracture was identified in either group. No coronary artery aneurysm developed in the target vessel.

Figure 2

Cumulative rate of in-segment minimal luminal diameter.

Figure 2

Cumulative rate of in-segment minimal luminal diameter.

The clinical events are displayed in Table 4, while Figure 3 shows the freedom from major cardiac adverse event. Two sudden cardiac deaths occurred, one in the BMS group and the other in the SES group, respectively, 23 months and 11 months after the procedure. One patient in the SES group died from metastatic cancer 22 months after the procedure. In the BMS group, four periprocedural non-ST elevation MIs were observed. One ST elevation MI in the SES group was caused by a subacute stent thrombosis occurring 4 days after the procedure. One non-ST elevation MI in the SES group was related to a non-target vessel PCI occurring during follow-up. The major adverse cardiac event rate was significantly higher in the BMS group: this difference was mainly due to a higher rate of TLR and TVR. Moreover, 80% of the TVR was clinically driven. Three patients underwent elective coronary bypass surgery, two in the BMS group and one in the SES group, all determining TLR. Only two TVR (one in each group) occurred after 12 months. Overall, two stent thromboses were observed, one acute (BMS group) and one subacute (SES group). They were both definite according to the ARC definition.13 No event qualifying as probable stent thrombosis was observed, while the two patients with sudden deaths (one in each group) could meet the ARC criteria for late or very late possible stent thrombosis.13 Lastly, angina or inducible silent ischaemia occurring during follow-up was significantly more frequent in the patients assigned to BMS.

Table 4

Clinical events and symptomatic status at 24 months

 BMS (n = 78) SES (n = 74)a P-value 
Death, all causes 1 (1.3) 2 (2.7) 0.613 
Death, cardiac 1 (1.3) 1 (1.4) 1.0 
Myocardial infarction 4 (5.1) 2 (2.7) 0.682 
Coronary bypass surgery 2 (2.6) 1 (1.4) 1.0 
TLR 35 (44.9) 6 (8.1) <0.001 
TVR 35 (44.9) 11 (14.9) <0.001 
Clinically driven TVR 29 (37.2) 8 (10.8) <0.001 

 
Stent thrombosis 1 (1.3) 1 (1.4) 1.0 
 Acute 1 (1.3) 1.0 
 Subacute 1 (1.4) 0.483 
 Late or very late – 

 
Stroke 1 (1.3) 1.0 
Any major adverse cardiac events 39 (50.0) 13 (17.6) <0.001 
Angina or silent ischaemia during follow-up 25 (32.1) 11 (15.1) 0.014 
 BMS (n = 78) SES (n = 74)a P-value 
Death, all causes 1 (1.3) 2 (2.7) 0.613 
Death, cardiac 1 (1.3) 1 (1.4) 1.0 
Myocardial infarction 4 (5.1) 2 (2.7) 0.682 
Coronary bypass surgery 2 (2.6) 1 (1.4) 1.0 
TLR 35 (44.9) 6 (8.1) <0.001 
TVR 35 (44.9) 11 (14.9) <0.001 
Clinically driven TVR 29 (37.2) 8 (10.8) <0.001 

 
Stent thrombosis 1 (1.3) 1 (1.4) 1.0 
 Acute 1 (1.3) 1.0 
 Subacute 1 (1.4) 0.483 
 Late or very late – 

 
Stroke 1 (1.3) 1.0 
Any major adverse cardiac events 39 (50.0) 13 (17.6) <0.001 
Angina or silent ischaemia during follow-up 25 (32.1) 11 (15.1) 0.014 

Values expressed as number (%). In-hospital events are included. Four patients had more than one event. In the BMS group, one patient had an acute thrombosis and a TLR, and another patient had a MI and a TLR. In the SES group, one patient had a subacute thrombosis, a MI and a TLR, and another patient had a MI and a TVR).

BMS, bare metal stent; SES, sirolimus-eluting stent; TLR, target lesion revascularization; TVR, target vessel revascularization.

aOne patient in the SES group was lost to follow-up: therefore, post-discharge events and symptomatic status in the SES group refer to 73 patients.

Figure 3

Freedom from major adverse cardiac events (death, MI, emergent bypass surgery, TLR, or TVR).

Figure 3

Freedom from major adverse cardiac events (death, MI, emergent bypass surgery, TLR, or TVR).

Discussion

The present study shows that implantation of SES in CTOs confers mid-term angiographic and clinical results much more favourable than those obtained using a BMS of similar design. At 8-month follow-up, the patients treated with SES presented a two-fold increase of in-segment MLD, which was the primary endpoint. In the SES group, the in-segment late luminal loss was slightly negative, when compared with an in-segment late luminal loss of 1.11 mm in the BMS arm. Likewise, SES use resulted in an 85% relative risk reduction of in-segment restenosis (9.8 vs. 67.7%), In addition, restenoses were all focal in the SES group, but predominantly diffuse or occlusive in the BMS group. In particular, the total reocclusion rate was observed in 16.9% of patients in the BMS group and in none of the SES treated patients (P < 0.001). It should be noted that a total occlusion found at angiographic follow-up could result either from asymptomatic stent thrombosis or from restenosis progressing to 100% occlusion. Indeed, the latter appears to be the most probable cause, being much more frequent in the BMS group.

This better angiographic outcome translated into a reduced occurrence of TLR and TVR together with a significantly lower incidence of angina or inducible silent ischaemia in the SES group at 24-month follow-up.

The adverse clinical events other than repeat revascularization and the stent thromboses were low in both group, supporting the safety of SES in CTO. However, the trial was not designed or powered to assess the incidence of such relatively rare events nor the possible difference of them between the study groups.

Drug-eluting stents and bare metal stent in chronic total coronary occlusions

Since market approval, the benefit of DES on restenosis reduction in simple coronary lesions has prompted their use in increasingly complex lesions that were not tested in the pivotal trials. In particular, CTOs were excluded or were marginally represented in the main trials comparing DES to BMS.

Drug-eluting stents implantation in CTOs has been described in several observational, often retrospective, studies,3–7,10 in a post hoc subgroup analysis of a trial including various types of complex lesions,8 and in a single prospective randomized trial.9 In these studies, the 6-month recurrence rates are generally low, with a restenosis rate varying between 08 and 19.2%,7 and a total reocclusion rate varying from 03,8 to 11.5%.7

However, these reports are not fully comparable because of several methodological differences, regarding inclusion criteria, definitions of angiographic parameters, concomitant therapy, angiographic follow-up, single centre vs. multicentre design, and independent assessment of angiographic parameters and clinical events. On the other hand, the present study is comparable to the only published randomized trial of DES vs. BMS in CTOs, the Primary Stenting of Totally Occluded Native Coronary Arteries II (PRISON II),9 although a few differences regarding the study design and the patients characteristics should be noted.

The duration of the double antiplatelet therapy was 6 months in both studies: however, in the PRISON II study, the follow-up angiography was scheduled at 6 months, while in the GISSOC II study the angiography was performed at 8 months, 2 months after stopping clopidogrel. This timing could have favoured the detection of possible late stent thromboses associated to discontinuation of such therapy. When compared with PRISON II, GISSOC II patients presented markers of a more extensive coronary artery disease that may denote a higher risk of restenosis. In fact, they were about 4 years older, with a higher prevalence of diabetes mellitus (22 vs. 13%), and three-vessel disease (34 vs. 9%).

Moreover, the total stent length was longer in GISSOC II patients (39 vs. 30 mm) with a smaller stent diameter (3.0 vs. 3.25 mm). These differences may explain the higher binary restenosis rate (68 vs. 41%) and late luminal loss (1.11 vs. 0.64 mm) observed in the BMS arm of the GISSOC II when compared with the PRISON II.

On the other hand, focusing on the SES arm, the restenosis rate is very similar in GISSOC II and PRISON II (9.9 and 11%, respectively) with an almost identical late luminal loss (−0.06 and −0.07 mm, respectively).

It is noteworthy that, after BMS implantation in CTOs, the restenosis seems to be highly variable but consistent with the risk associated to baseline and procedural characteristics. On the contrary, after SES implantation in CTOs, the restenosis seems to be not only much lower, but also less variable. In other words, SES seems to be less influenced than BMS by patients and lesion factors known to increase the restenosis risk, such as diabetes, lesion length, and vessel size.

Duration of the chronic total coronary occlusion

According to the current definition,1,18 a coronary occlusion is defined as chronic when older than 3 months. Although in the present study, coronary occlusions older than 1 month could be included, the occlusions with the duration between 1 and 3 months were only 6.6%.

In most CTOs (60%), the duration could not be determined, but there was no clinical or angiographic reason to estimate them as more recent than 3 months. Then, these CTOs have a high likelihood to be older than 3 months.18 In addition, according to the available evidence, the duration of the occlusion does not appear to influence the restenosis risk.9

Study limitations

The sample size may be an important limitation, because the study did not have the power to detect potential differences between the two study groups with regard to infrequent clinical events, such as death, MI, and stent thrombosis. However, the study size was adequate to assess differences of the primary endpoint between the study groups.

The unblinded design of the study is another relevant limitation that may have driven a few differences in procedural variables, such as slight but significantly larger maximal balloon diameter and post-stenting MLD in the BMS group, when compared with the SES group. However, both quantitative coronary angiography and adjudication of all major adverse cardiac events and stent thrombosis were carried out by independent personnel blinded to treatment allocation.

Twelve patients in both groups (16%) did not undergo the follow-up angiography, preventing the assessment of the primary endpoint. However, the equivalence of the rate of control angiography in both study groups, and the marked difference in the study endpoints between the two groups, makes very unlikely a biasing effect from incomplete angiographic follow-up on the main results of the study.

Although the patients of the BMS group showed a significantly higher incidence of angina or inducible silent ischaemia at follow-up, we acknowledge that the difference in repeat revascularization was probably amplified by the protocol mandated angiography at 8 months.

Conclusions

Implantation of a SES after successful PTCA of a CTO results in a larger MLD at follow-up and decreases the restenosis and reocclusion rates. Accordingly, patients treated with a SES experience a significant reduction of repeat revascularization procedures. Thus, SES implantation could be the preferred treatment option in patients with CTO that can be recanalized percutaneously.

Supplementary material

Supplementary material is available at European Heart Journal online.

Funding

This work was supported by an unrestricted grant from Cordis Italia, Sesto San Giovanni, Italy.

Conflict of interest: none declared.

Acknowledgements

We thank the participating investigators to the GISSOC II–GISE Trial (see Supplementary material online).

References

1
Stone
GW
Kandzari
DE
Mehran
R
Colombo
A
Schwartz
RS
Bailey
S
Moussa
I
Teirstein
PS
Dangas
G
Baim
DS
Selmon
M
Strauss
BH
Tamai
H
Suzuki
T
Mitsudo
K
Katoh
O
Cox
DA
Hoye
A
Mintz
GS
Grube
E
Cannon
LA
Reifart
NJ
Reisman
M
Abizaid
A
Moses
JW
Leon
MB
Serruys
PW
Percutaneous recanalization of chronically occluded coronary arteries: a consensus document: part I
Circulation
 , 
2005
, vol. 
112
 (pg. 
2364
-
2372
)
2
Rathore
S
Matsuo
H
Terashima
M
Kinoshita
Y
Kimura
M
Tsuchikane
E
Nasu
K
Ehara
M
Asakura
Y
Katoh
O
Suzuki
T
Procedural and in-hospital outcomes after percutaneous coronary intervention for chronic total occlusions of coronary arteries 2002 to 2008: impact of novel guidewire techniques
JACC Cardiovasc Interv
 , 
2009
, vol. 
2
 (pg. 
489
-
497
)
3
Nakamura
S
Muthusamy
TS
Bae
JH
Cahyadi
YH
Udayachalerm
W
Tresukosol
D
Impact of sirolimus-eluting stent on the outcome of patients with chronic total occlusions
Am J Cardiol
 , 
2005
, vol. 
95
 (pg. 
161
-
166
)
4
Hoye
A
Tanabe
K
Lemos
PA
Aoki
J
Saia
F
Arampatzis
C
Degertekin
M
Hofma
SH
Sianos
G
McFadden
E
van der Giessen
WJ
Smits
PC
de Feyter
PJ
van Domburg
RT
Serruys
PW
Significant reduction in restenosis after the use of sirolimus-eluting stents in the treatment of chronic total occlusions
J Am Coll Cardiol
 , 
2004
, vol. 
43
 (pg. 
1954
-
1958
)
5
Werner
GS
Krack
A
Schwarz
G
Prochnau
D
Betge
S
Figulla
HR
Prevention of lesion recurrence in chronic total coronary occlusions by paclitaxel-eluting stents
J Am Coll Cardiol
 , 
2004
, vol. 
44
 (pg. 
2301
-
2306
)
6
Ge
L
Iakovou
I
Cosgrave
J
Chieffo
A
Montorfano
M
Michev
I
Airoldi
F
Carlino
M
Melzi
G
Sangiorgi
GM
Corvaja
N
Colombo
A
Immediate and mid-term outcomes of sirolimus-eluting stent implantation for chronic total occlusions
Eur Heart J
 , 
2005
, vol. 
26
 (pg. 
1056
-
1062
)
7
Migliorini
A
Moschi
G
Vergara
R
Parodi
G
Carrabba
N
Antoniucci
D
Drug-eluting stent-supported percutaneous coronary intervention for chronic total coronary occlusion
Catheter Cardiovasc Interv
 , 
2006
, vol. 
67
 (pg. 
344
-
348
)
8
Kelbaek
H
Helqvist
S
Thuesen
L
Kløvgaard
L
Jørgensen
E
Saunamäki
K
Krusell
LR
Bøtker
HE
Engstrøm
T
Jensen
GV
SCANDSTENT investigators
Sirolimus versus bare metal stent implantation in patients with total coronary occlusions: subgroup analysis of the Stenting Coronary Arteries in Non-Stress/Benestent Disease (SCANDSTENT) trial
Am Heart J
 , 
2006
, vol. 
152
 (pg. 
882
-
886
)
[PubMed]
9
Suttorp
MJ
Laarman
GJ
Rahel
BM
Kelder
JC
Bosschaert
MA
Kiemeneij
F
Ten Berg
JM
Bal
ET
Rensing
BJ
Eefting
FD
Mast
EG
Primary Stenting of Totally Occluded Native Coronary Arteries II (PRISON II): a randomized comparison of bare metal stent implantation with sirolimus-eluting stent implantation for the treatment of total coronary occlusions
Circulation
 , 
2006
, vol. 
114
 (pg. 
921
-
928
)
10
Kandzari
DE
Rao
SV
Moses
JW
Dzavik
V
Strauss
BH
Kutryk
MJ
Simonton
CA
Garg
J
Lokhnygina
Y
Mancini
GB
Yeoh
E
Buller
CE
ACROSS/TOSCA-4 Investigators
Clinical and angiographic outcomes with sirolimus-eluting stents in total coronary occlusions: the ACROSS/TOSCA-4 (Approaches to Chronic Occlusions With Sirolimus-Eluting Stents/Total Occlusion Study of Coronary Arteries-4) trial
JACC Cardiovasc Interv
 , 
2009
, vol. 
2
 (pg. 
97
-
106
)
11
Kastrati
A
Dibra
A
Mehilli
J
Mayer
S
Pinieck
S
Pache
J
Dirschinger
J
Schömig
A
Predictive factors of restenosis after coronary implantation of sirolimus- or paclitaxel-eluting stents
Circulation
 , 
2006
, vol. 
113
 (pg. 
2293
-
2300
)
12
Rubartelli
P
Verna
E
Niccoli
L
Giachero
C
Zimarino
M
Bernardi
G
Vassanelli
C
Campolo
L
Martuscelli
E
Tommasini
G
Gruppo Italiano di Studio sullo Stent nelle Occlusioni Coronariche Investigators
Stent implantation versus balloon angioplasty in chronic coronary occlusions: results from the GISSOC trial. Gruppo Italiano di Studio sullo Stent nelle Occlusioni Coronariche
J Am Coll Cardiol
 , 
1998
, vol. 
32
 (pg. 
90
-
96
)
13
Cutlip
DE
Windecker
S
Mehran
R
Boam
A
Cohen
DJ
van Es
GA
Steg
PG
Morel
MA
Mauri
L
Vranckx
P
McFadden
E
Lansky
A
Hamon
M
Krucoff
MW
Serruys
PW
Academic Research Consortium
Clinical endpoints in coronary stent trials—a case for standardized definitions
Circulation
 , 
2007
, vol. 
115
 (pg. 
2344
-
2351
)
14
Sirnes
PA
Golf
S
Myreng
Y
Mølstad
P
Emanuelsson
H
Albertsson
P
Brekke
M
Mangschau
A
Endresen
K
Kjekshus
J
Stenting in Chronic Coronary Occlusion (SICCO): a randomized, controlled trial of adding stent implantation after successful angioplasty
J Am Coll Cardiol
 , 
1996
, vol. 
28
 (pg. 
1444
-
1451
)
15
Buller
CE
Dzavik
V
Carere
RG
Mancini
GB
Barbeau
G
Lazzam
C
Anderson
TJ
Knudtson
ML
Marquis
JF
Suzuki
T
Cohen
EA
Fox
RS
Teo
KK
Primary stenting versus balloon angioplasty in occluded coronary arteries: the Total Occlusion Study of Canada (TOSCA)
Circulation
 , 
1999
, vol. 
100
 (pg. 
236
-
242
)
[PubMed]
16
Höher
M
Wöhrle
J
Grebe
OC
Kochs
M
Osterhues
HH
Hombach
V
Buchwald
AB
A randomized trial of elective stenting after balloon recanalization of chronic total occlusions
J Am Coll Cardiol
 , 
1999
, vol. 
34
 (pg. 
722
-
729
)
17
Rahel
BM
Suttorp
MJ
Laarman
GJ
Kiemeneij
F
Bal
ET
Rensing
BJ
Ernst
SM
ten Berg
JM
Kelder
JC
Plokker
HW
Primary stenting of occluded native coronary arteries: final results of the Primary Stenting of Occluded Native Coronary Arteries (PRISON) study
Am Heart J
 , 
2004
, vol. 
147
 (pg. 
e16
-
e20
)
18
Di Mario
C
Werner
G
Sianos
G
Galassi
A
Büttner
J
Dudek
D
Chevalier
B
Lefèvre
T
Schofer
J
Koolen
J
Sievert
H
Reimers
B
Fajadet
J
Colombo
A
Gershlick
A
Serruys
PW
Reifart
N
for the EuroCTO Club
European perspective in the recanalisation of Chronic Total Occlusions (CTO): consensus document from the EuroCTO Club
EuroIntervention
 , 
2007
, vol. 
3
 (pg. 
30
-
43
)
[PubMed]

Supplementary data

Comments

0 Comments