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Immediate and mid-term outcomes of sirolimus-eluting stent implantation for chronic total occlusions

Lei Ge, Ioannis Iakovou, John Cosgrave, Alaide Chieffo, Matteo Montorfano, Iassen Michev, Flavio Airoldi, Mauro Carlino, Gloria Melzi, Giuseppe M. Sangiorgi, Nicola Corvaja, Antonio Colombo
DOI: http://dx.doi.org/10.1093/eurheartj/ehi191 1056-1062 First published online: 7 April 2005

Abstract

Aims To evaluate the outcomes of sirolimus-eluting stent (SES) implantation for the treatment of chronic total occlusion (CTO).

Methods and results We identified 122 patients who underwent revascularization in CTO lesions with SES from April 2002 to April 2004 (SES group). A control group was composed of 259 consecutive patients with CTO lesions treated with bare metal stents (BMS) in the 24 months immediately before the introduction of SES (BMS group). At 6-month follow-up, the cumulative rate of major adverse cardiac events (MACE) was 16.4% in the SES group and 35.1% in the BMS group (P<0.001). The incidence of restenosis was 9.2% in the SES group and 33.3% in the BMS group (P<0.001). The need for revascularization in the SES group was significantly lower, both target lesion revascularization (7.4 vs. 26.3%, P<0.001) and target vessel revascularization (9.0 vs. 29.0%, P<0.001). BMS implantation (HR: 2.97; 95% CI: 1.80–4.89; P<0.001), lesion length (>20 mm) (HR: 2.02; 95% CI: 1.37–2.99; P=0.0004), and baseline reference vessel diameter (>2.8 mm) (HR: 0.62; 95% CI: 0.42–0.92; P=0.02) were identified as predictors of MACE during 6-month follow-up.

Conclusion Compared with BMS, SES implantation in CTO lesions appears to be effective in reducing the incidence of restenosis and the need for revascularization at 6 months.

  • Stents
  • Occlusion
  • Angioplasty
  • Revascularization
  • Restenosis

See page 1049 for the editorial comment on this article (doi:10.1093/eurheartj/ehi243)

Introduction

Percutaneous coronary intervention of chronic total occlusion (CTO) is one of the major challenges in interventional cardiology. With recent advances in technology, and increased operator experience, the initial success rate of opening occlusions is high, but the long-term results of bare metal stent (BMS) are disappointing because of a high restenosis rate.18 The introduction of sirolimus-eluting stent (SES) (CypherTM, Cordis, Johnson & Johnson Company, Warren, NJ, USA) has shown promising results in selected lesions.9,10 Recently, paclitaxel-eluting stent (Boston Scientific Corp., Natick, MA, USA) implantation in CTO lesions appears to be associated with favourable outcomes.11 However, few data is available about SES implantation in CTO lesions.12 Thus, the aim of this report is to evaluate the clinical and angiographic outcomes of SES in CTO lesions.

Methods

Study population

Demographic and procedural data regarding all patients undergoing angioplasty in our centre were prospectively entered into a dedicated database. All patients treated with SES in CTO lesions between April 2002 and April 2004 were identified (SES group). A control group was composed of patients who underwent percutaneous treatment in CTO lesions with BMS in the 24 months immediately prior to the introduction of SES (BMS group).

A CTO lesion was defined as an obstruction of a coronary artery with thrombolysis in myocardial infarction flow grade 0 with an estimated duration of at least 3 months. The duration of the occlusion was determined by the interval from the last episode of acute coronary syndrome consistent with the location of the occlusion or proved by previous angiography.8,13 Restenotic lesion, CTO lesions located in saphenous vein grafts, and the lesions treated with TaxusTM (Boston Scientific Corp.) were excluded from the present study.

During the study period, a total of 598 patients with CTO lesions were treated in our centre. Of these patients, 502 (83.9%) patients had successful recanalization and underwent stent implantation. After excluding 36 patients treated with Taxus and 85 patients treated with BMS during the period of April 2002 to April 2004, the remaining 122 patients were treated with SES and 259 patients were treated with BMS, and they represented the study population of the present study.

Procedures and post-intervention medications

All patients were pre-treated with aspirin and either ticlopidine or clopidogrel. A 300 mg loading dose of clopidogrel before the index procedure was administered if patients were not pre-treated. The most common approach to recanalize a CTO lesion was the usage of a 1.5 mm over-the-wire balloon combined with a guide wire from Asahi Intecc (Asahi Intecc Co., Ltd, Seto, Japan) including Intermediate, Miracle 3, and Conquest. When there were good contra-lateral collaterals, dual injection technique was employed (16.7% of the patients). During the procedure, patients received intravenous unfractionated heparin (100 IU/kg) to maintain activated clotting time between 250 and 300 s. A decision to use a glycoprotein IIb/IIIa inhibitor was always made following guide wire successfully crossing the occlude lesion. All stents were implanted with high deployment pressure (>12 atm). The following BMS were used: BX Velocity (Cordis/Johnson & Johnson) in 81 (28.3%) lesions, Diamond-Flex (Phytis, Dreieich, Germany) in 46 (16.1%), Sorin Carbon (Sorin Biomedica, Saluggia, Italy) in 33 (11.5%), Multi-Link Tetra (Guidant Corp., Santa Clara, CA, USA) in 27 (9.5%), AVE S670 and S7 (Medtronic AVE, Minneapolis, MN, USA) in 25 (8.7%), Multi-Link Penta (Guidant Corp., Santa Clara, CA, USA) in 20 (7.0%), Biodiv Ysio SV (Biocompatibles, Galway, Ireland) in 13 (4.6%), NIR stent (Medinol, Jerusalem, Israel) in 6 (2.1%), and other stents (BeStent, Jomed stents, AMG stents) in 35 (12.2%).

Biochemical markers (CK and CK-MB) of acute myocardial infarction (MI) were routinely measured after the procedure in all patients. All patients were on maintenance aspirin therapy, and clopidogrel or ticlopidine was administered for at least 3 months following SES implantation and 1 month following BMS implantation.

Clinical definitions and follow-up

Clinical follow-up was performed by telephone contact or office visit at 1 and 6 months after the index procedure. Angiographic follow-up was scheduled for between 6 and 8 months post-procedure unless clinically indicated at an earlier time.

Major adverse cardiac events (MACE) were defined as cardiac death, MI, and target vessel revascularization (TVR), either percutaneous or surgical. All deaths were considered cardiac unless otherwise documented. A non-Q-wave MI was defined as CK-MB enzyme elevation three or more times the upper limit of the normal value; when, in addition to enzyme elevation, there were new pathological Q-waves in the electrocardiogram, the event was defined as a Q-wave MI. Target lesion revascularization (TLR) was defined as a repeat intervention with a stenosis ≥50% within the stent or in the 5 mm distal or proximal segments adjacent to the stent. TVR was defined as repeat revascularization within the treated vessel. Stent thrombosis was defined as an acute coronary syndrome with angiographic documentation of either vessel occlusion or thrombus within or adjacent to a previously successfully stented vessel or, in the absence of angiographic confirmation, either acute MI in the distribution of the treated vessel or death not clearly attributable to other causes.1416 In order not to miss late thrombotic events, the follow-up time period for thrombosis was extended beyond 1 month until the end of clinical follow-up.

Quantitative coronary angiographic (QCA) analysis

Coronary angiograms were analysed using validated edge detection system (CMS, version 5.2, MEDIS, The Netherlands). On the pre-intervention angiogram, reference vessel diameter (RVD) and lesion length were measured. The occlusion length was measured from beginning of bridging collaterals filling to distal vessel reconstitution, from proximal occlusion to distal retrograde filling from contra-lateral collaterals through dual injection technique, or from the length of the lesion visible after the guide wire crossing. Minimal lumen diameter (MLD), RVD, and per cent diameter stenosis (DS%) at post-procedure and at follow-up were measured, respectively. Late lumen loss was defined as the difference between the MLD immediately after the procedure and at follow-up.17 Angiographic restenosis was defined as DS≥50% by QCA within a previously stented vessel segment (stent and 5 mm proximal and distal) at the follow-up angiography. Focal restenosis was defined as a restenotic lesion ≤10 mm in length. Diffuse restenosis was defined as a restenotic lesion >10 mm in length.18

Statistical analysis

Continuous variables with normal distribution were presented as mean±standard deviation (SD). Continuous variable with non-normal distribution (the duration of CTO) was presented as a median with interquartile ranges. Categorical variables were presented as frequencies (%). Differences between groups in normal and non-normal distributed variables were assessed with the independent sample t-test or the Mann–Whitney U-test, respectively. Categorical variables were compared with χ2 statistics. To avoid the inflation of the type I error due to multiple testing, the primary objective of the study was the comparison of SES relative to BMS, employing cumulative 6 months MACE as primary endpoint. All others comparisons and outcomes were considered as secondary study objectives.

Baseline lesion and procedural characteristics and QCA continuous data were analysed by means of mixed linear models with ‘Stent Type’ as fixed effect and using ‘Patient Indicators’ as random terms in order to take into account clustered data (more lesions within the same subject), whereas a logistic regression with generalized estimating equations and compound symmetry variance–covariance matrix was employed for binary categorical data. Survival free of MACE was estimated with the Kaplan–Meier method, and the differences between curves were evaluated by the log-rank test. Cox proportional hazards regression model was used to identify the independent predictors of MACE at 6 months follow-up. According to the hypothesis of this study, the literature data1921 and the rule of thumb ‘number of events/number of covariates>10’, the following predictors were entered into the multivariable model: stent type, multivessel disease, diabetes, lesion length, and baseline RVD. The results are presented as hazard ratios (HR) with 95% confident interval (CI). A P-value of <0.05 was considered to be statistically significant, and all reported P-values are two-sided. Statistical analysis was performed with SPSS 11.5 (SPSS Inc., Chicago, IL, USA).

Results

Baseline clinical characteristics

Baseline clinical characteristic are shown in Table 1. Compared with the BMS group, the patients of the SES group had higher prevalence of established risk factors of coronary heart disease and had a trend towards higher per cent of diabetes and multivessel diseases. Mean duration of occlusion could be determined in 101 (82.8%) patients of the SES group and in 205 (79.2%) patients of the BMS group.

View this table:
Table 1

Baseline clinical characteristics

SES group (n=122 patients)BMS group (n=259 patients)P-value
Age, years161±10161±100.79
Male [n (%)]107 (87.7)226 (87.3)0.96
Smoker [n (%)]62 (50.8)95 (36.7)0.01
Family history of CAD [n (%)]42 (34.4)65 (25.1)0.07
Hypercholesterolaemia [n (%)]77 (63.1)111 (42.9)<0.001
Hypertension [n (%)]61 (50.0)111 (42.9)0.23
Diabetes mellitus [n (%)]34 (27.9)49 (18.9)0.06
Prior MI [n (%)]67 (54.9)164 (63.3)0.14
Prior CABG [n (%)]15 (12.3)19 (7.3)0.13
Unstable angina [n (%)]23 (18.9)41 (15.8)0.56
Multivessel coronary disease [n (%)]96 (78.7)180 (69.5)0.08
Duration of occlusion (months)a7.0 (3.1–29.0)6.2 (3.4–13.0)0.65
GP IIb/IIIa inhibitors [n (%)]40 (32.8)66 (25.5)0.17
LVEF (%)152.9±10.4153.4±10.50.69

Values are presented as numbers (%) or mean±standard deviation. CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; GP, glycoprotein; LVEF, left ventricular ejection fraction.

aMedian (interquartile range).

Angiographic and procedural characteristics

Angiographic and procedural characteristics are shown in Table 2. Of note, the stent length was longer in the SES group than in the BMS group (41.6±19.5 vs. 21.7±9.2 mm, P<0.001). The ratio of stent length to lesion length was 1.79±1.48 in the SES group and 1.16±0.53 in the BMS group (P<0.001).

View this table:
Table 2

Baseline lesion and procedural characteristics

SES group (n=144 lesions)BMS group (n=286 lesions)P-value
Lesions characteristics
 Target vessel, n (%)1.0
  LAD148 (33.3)195 (33.2)
  LCX140 (27.8)179 (27.6)
  RCA156 (38.9)112 (39.2)
 Occlusion morphology0.97
  Centre109 (75.7)217 (75.9)
  Blunt135 (24.3)169 (24.1)
 Collateral circulation189 (61.8)183 (64.0)0.70
Procedural characteristics
 Number of stents per lesion (n)1.36±0.611.20±0.430.002
 Mean diameter of finally balloon (mm)2.97±0.423.19±0.48<0.001
 Mean length of stent (mm)41.6±19.521.7±9.2<0.001
 Stent length/lesion length1.79±1.481.16±0.53<0.001
 Mean maximal of deployed pressure (atm)15.9±2.914.5±2.7<0.001

Values are presented as numbers (%) or mean±standard deviation. LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.

QCA analysis is shown in Table 3. Angiographic follow-up was available in 101 (82.8%) patients in the SES group (with 119 lesions) and 208 (80.3%) patients in the BMS group (with 228 lesions). Mean time to angiographic follow-up was 6.8±3.0 months in the SES group and 7.2±2.4 months in the BMS group (P=0.21). Compared with the BMS group, late lumen loss of the SES group was significantly lower (0.28±0.56 vs. 1.04±0.87 mm, P<0.001). In-segment stent restenosis occurred less frequently in the SES group (9.2 vs. 33.3%, P<0.001). Among 11 restenotic lesions in the SES group, eight (72.7%) of them were focal restenosis (six located within the stent, two at the margin of the stent) and three were re-occlusion. The pattern of restenosis in the BMS group was composed of 34 (44.7%) focal restenosis (29 located within the stent, five at the margin of the stent), 27 (35.5%) diffuse restenosis, and 15 re-occlusion.

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Table 3

Serial QCA analysis

SES groupBMS groupP-value
Baselinen=144 lesionsn=286 lesions
 RVD (mm)2.67±0.432.76±0.520.11
 Mean lesion length (mm)26.5±13.422.3±9.70.007
Post-procedure
 RVD (mm)3.05±0.443.05±0.550.99
 MLD (mm)2.67±0.492.69±0.530.77
 DS (%)13.0±7.411.7±8.70.12
Six-month follow-upn=119 lesionsn=228 lesions
 RVD (mm)2.89±0.462.78±0.670.12
 MLD (mm)2.39± 0.881.63±0.98<0.001
 DS (%)17.6±16.144.0±28.9<0.001
 Mean lesion length (mm)10.4±10.29.6±6.90.55
 Late lumen loss (mm)0.28±0.561.04±0.87<0.001
 Restenosis rate [n (%)]11 (9.2)76 (33.3)<0.001
 Re-occlusion at follow-up [n (%)]3 (2.5)15 (6.6)0.17

Values are presented as numbers (%) or mean±standard deviation.

In-hospital results and clinical follow-up outcomes

In-hospital results and clinical follow-up outcomes are shown in Table 4. Clinical follow-up at 6 months was available in all patients. The cumulative rate of MACE at 6 months was 16.4% in the SES group and 35.1% in the BMS group (P<0.001). There were no statistical differences in the incidence of death and MI between the two groups. Three patients in the SES group died during follow-up. One patient died 3.5 months after the index procedure because of vascular complications after surgical repair of abdominal aortic aneurysm. Another patient died at 6.5 months; a prior angiogram showed the target vessel re-occluded without evidence of thrombosis. The last patient died of renal failure. There were three cardiac deaths in the BMS group. One patient was documented stent thrombosis. Compared with the BMS group, the rates of TLR and TVR were significantly lower in the SES group (TLR: 7.4 vs. 26.3%, P<0.001; TVR: 9.0 vs. 29.0%, P<0.001). MACE-free survival was 83.6% in the SES group and 64.9% in the BMS group (P<0.001) (Figure 1). By Cox regression analysis, BMS implantation (HR: 2.97; 95% CI: 1.80–4.89; P<0.001), lesion length (>20 mm) (HR: 2.02; 95% CI: 1.37–2.99; P=0.0004), and baseline RVD (>2.8 mm) (HR: 0.62; 95% CI: 0.42–0.92; P=0.02) were identified as predictors of MACE during 6-month follow-up.

Figure 1 Kaplan–Meier survival curves for freedom from MACE at 6-month follow-up.

View this table:
Table 4

In-hospital results and clinical outcomes at 6-month follow-up

SES group (n=122 patients)BMS group (n=259 patients)P-value
In-hospital [n (%)]
 Cardiac death00
 Non-cardiac death00
 Q-wave MI00
 Non-Q-wave MI9 (7.4)17 (6.6)0.83
 TLR00
 TVR00
 In-hospital MACE9 (7.4)17 (6.6)0.83
 Stent thrombosis00
Six-month follow-up [n (%)]
 Death3 (2.5)3 (1.2)0.61
  Cardiac death1 (0.8)3 (1.2)0.81
  Non-cardiac death2 (1.6)00.19
 MI10 (8.2)20 (7.7)0.97
  Q-wave MI1 (0.8)2 (0.8)0.57
  Non-Q-wave MI9 (7.4)18 (6.9)0.95
 TLR9 (7.4)68 (26.3)<0.001
 TVR11 (9.0)75 (29.0)<0.001
 Cumulative 6-month MACE20 (16.4)91 (35.1)<0.001
 Stent thrombosis01 (0.4)0.70

Values are presented as numbers (%).

Discussion

The main findings of this report are that SES implantation in CTO lesions appears safe and reduces the incidence of restenosis with a lower rate of revascularization at 6 months when compared with BMS.

The remarkable improvement in the treatment of CTO lesions began with the introduction of stenting. Several randomized studies proved clear benefits in reducing restenosis and the need for revascularization when stent was compared with balloon angioplasty in this lesion subset. However, the incidence of restenosis following BMS implantation remains as high as 57.3%.18 The logical extension of the benefit of SES already demonstrated in the treatment of non-occlusive lesions is to broaden their application to treatment of CTO lesions.9

The present report has shown significant improvement with SES implantation in CTO lesions compared with the historical data.18 It is worth emphasizing that the favourable outcomes of SES vs. BMS were observed despite the more unfavourable characteristics present in the SES group. In our report, the SES group had a higher incidence of diabetes (27.9 vs. 18.9%), multivessel disease (78.7 vs. 69.5%), and longer lesion length (26.5 vs. 22.3 mm). At follow-up, the late lumen loss was remarkably lower in the SES group than in the BMS group (0.28±0.56 vs. 1.04±0.87 mm, P<0.001), resulting in lower incidence of in-segment restenosis (9.2 vs. 33.3%, P<0.001). Despite these findings, the late lumen loss in our report appears larger than that observed in non-occlusive native coronaries9,10 and also larger than the one presented in a recently published report which evaluated SES implantation in CTO lesions.12 It is not clear whether the higher late lumen loss observed in our report, compared with that reported in randomized studies dealing with non-occlusive lesions, is due to specific features of CTO lesions or depends on the longer lesions and stents. An increase in late lumen loss was observed in studies dealing with non-occlusive lesions when the stent and lesion length increased.9,22 A similar explanation can be applied to a prior report dealing with SES implanted on CTO lesions, in which mean lesion length was 11.3 mm and mean stent length was 23.89 mm.12

A unique finding in our report is the large ratio of stent length to lesion length (1.79 vs. 1.16, P<0.001). This finding can be attributed to an attempt by the operator to fully cover the lesion when implanting one SES. In the era of BMS, longer stented segment length is an independent predictor of restenosis and adverse events.23,24 However, the subgroup analysis of the SIRIUS study (Sirolimus-Eluting Balloon-Expandable Stents in the Treatment of Patients with de novo Natives Coronary Artery Lesions study) showed that incomplete lesion coverage with SES was one of the reasons of restenosis.9 In the present report, most of the restenotic lesions in the SES group were focal (72.7%). This observation is concordant with the findings in prior studies.9,25 Among these focal restenotic lesions, 75% were located in the body of the stent. This observation is different from the finding of the SIRIUS study in which most of the restenotic lesions were located near the stents margins or at the site of a gap between two stents.9 Following the previously mentioned observations, it has become our practice to fully cover the entire baseline lesion.

As in all randomized studies dealing with SES or other drug-eluting stents, the benefit in reducing MACE was obtained because of the reduction of restenosis and the need for revascularization.9,22,26 This finding is even more understandable when dealing with a CTO lesion and when the follow-up is limited in time.1,27 In the present report, the rate of MACE at 6 months was reduced by 53.3%, entirely driven by the reduction in the need for repeat revascularization (TLR and TVR reduced by 71.9 and 69.0%, respectively). There was no statistically significant difference between the two groups regarding the incidence of MI and death.

Implantation of SES in total occlusions with very long stents could be perceived as a high-risk procedure due to the potential of compromising the side branches, incomplete endothelization, and subsequent stent thrombosis. In the present report, regarding the lesions located in the left anterior descending artery, compromised side branches found in six (12.5%) cases in the SES group and nine (9.5%) cases in the BMS group (P=0.79). This specific setting was associated with the incidence of in-hospital MI, 8.3% in the SES group and 6.3% in the BMS group (P=0.92). One study showed that stent length was associated with the occurrence of intra-procedural stent thrombosis.28 However, in our report, the benefits of SES in reduction of the need for revascularization were obtained without an increase in MI, death, or other events possibly attributable to stent thrombosis.

Using Cox regression analysis, BMS implantation, lesion length (>20 mm), and baseline RVD (>2.8 mm) were identified as predictors of MACE during 6-month follow-up. These results are consistent with the prior studies.9,19,29 Small vessel and long lesion reflects the lesion complexity and the extension of the disease burden at risk for restenosis and re-intervention.

Limitations

The major limitations of this report are the non-randomized study design, clinical follow-up limited to 7 months, and some imbalance in the risk factors for restenosis. Angiographic follow-up was not performed in all patients and a selection bias cannot be excluded. The fact that angiographic follow-up was similar in both groups (80.3% in BMS group and 82.8% in SES group) may limit this problem. Also, the fact that 85 patients with CTO lesions were treated with BMS between April 2002 and April 2004 cannot be ignored. It may be perceived as another selection bias. The reasons for utilizing BMS in these patients were: (i) a lesion <10 mm in length which was considered to be at low risk of restenosis, (ii) RVD of target vessel >3.5 mm for which there were no appropriately sized SES available. If anything, these patients represent a lower risk cohort for TLR. The fact that the two groups were treated sequentially may also introduce a bias, still we need to recognize that operator experience, which has an impact in successful crossing a CTO, is less likely to affect restenosis. Despite these limitations, this report represents a large cohort of patients treated for CTO lesions utilizing SES with complete clinical follow-up.

Conclusions

SES implantation in CTO lesions appears effective in reducing the incidence of restenosis and the need for further revascularization, without increasing the risk of MI or death when compared with historical data with BMS.

References

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