Long-Term Clinical Benefit of Sirolimus-Eluting Stents Compared to Bare Metal Stents in the Treatment of Saphenous Vein Graft Disease

doi:10.1016/j.jacc.2008.08.025 2008;52;1621-1627 J. Am. Coll. Cardiol.

Camino Bañuelos, Alfonso Suárez, Carlos Macaya, for the RIBS-II Investigators César Morís, Angel Cequier, Manel Sabaté, Javier Escaned, Pilar Jiménez-Quevedo,

Bethencourt, Vicens Martí, José R. López-Mínguez, Juan Angel, Andrés Iñiguez, Fernando Alfonso, María-José Pérez-Vizcayno, Rosana Hernández, Armando

angioplasty vs. elective sirolimus-eluting Stenting) StudyIn-Stent Restenosis: Results of the RIBS-II (Restenosis Intra-stent: Balloon

Long-Term Clinical Benefit of Sirolimus-Eluting Stents in Patients With

This information is current as of May 10, 2011

http://content.onlinejacc.org/cgi/content/full/52/20/1621located on the World Wide Web at:

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Journal of the American College of Cardiology Vol. 52, No. 20, 2008© 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00P

Long-Term Clinical Benefit of Sirolimus-ElutingStents in Patients With In-Stent RestenosisResults of the RIBS-II (Restenosis Intra-stent: Balloonangioplasty vs. elective sirolimus-eluting Stenting) Study

Fernando Alfonso, MD,* Marıa-José Pérez-Vizcayno, MD,* Rosana Hernandez, MD,*Armando Bethencourt, MD,† Vicens Martı, MD,‡ José R. Lopez-Mınguez, MD,§ Juan Angel, MD,�Andrés Iñiguez, MD,¶ César Morıs, MD,# Angel Cequier, MD,** Manel Sabaté, MD,‡Javier Escaned, MD,* Pilar Jiménez-Quevedo, MD,* Camino Bañuelos, MD,* Alfonso Suarez, MD,*Carlos Macaya, MD,* for the RIBS-II Investigators

Madrid, Palma de Mallorca, Barcelona, Badajoz, Vigo, and Oviedo, Spain

Objectives We sought to assess the long-term effectiveness and safety of sirolimus-eluting stents (SES) in patients with in-stent restenosis (ISR).

Background Treatment of patients with ISR remains a challenge. The long-term outcome of patients with ISR treated withSES remains unknown.

Methods The RIBS-II (Restenosis Intra-stent: Balloon angioplasty vs. elective sirolimus-eluting Stenting) study was a ran-domized trial conducted in 150 patients with ISR (76 SES, 74 balloon angioplasty [BA]). The long-term (�1 year)clinical outcome and pre-specified subgroup analyses were pre-defined secondary study end points.

Results At 1 year, the event-free survival (death, myocardial infarction, target vessel revascularization [TVR]) was betterin the SES group (88% vs. 69%, p � 0.005). Additional long-term (�3 years) clinical follow-up was obtained in97% of patients (median 3.3 years). After the first year, 3 patients died (1 SES, 2 BA), 5 suffered myocardialinfarction (4 SES, 1 BA), and 7 required TVR (4 SES, 3 BA). At last follow-up, definitive/probable/possible stent throm-bosis was similar in both groups (2/2/1 SES vs. 1/0/3 BA, p � NS). At 4 years, the event-free survival was 76% inthe SES arm and 65% in the BA arm (p � 0.019). On multivariate analysis, SES implantation was an independentpredictor of event-free survival. Subgroup analyses were consistent with the main outcome measure.

Conclusions In patients with ISR, SES implantation remains effective and safe at very long-term clinical follow-up. (J AmColl Cardiol 2008;52:1621–7) © 2008 by the American College of Cardiology Foundation

ublished by Elsevier Inc. doi:10.1016/j.jacc.2008.08.025

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rug-eluting stents (DES) are highly effective in patientsith in-stent restenosis (ISR) (1–4). In this challenging

etting both sirolimus-eluting stents (SES) and paclitaxel-luting stents have been shown to reduce the restenosis rateompared with balloon angioplasty (BA) (1,2). Further-ore, in these patients DES are also superior to brachy-

herapy (3,4). Therefore, currently most patients with bare-etal ISR are treated with DES.The efficacy of DES has been demonstrated in several

dverse scenarios (1–5). More recently, however, safety

rom the University Hospitals: *Clinico San Carlos, Madrid, Spain; †Son Dureta,alma de Mallorca, Spain; ‡San Pablo, Barcelona, Spain; §Infanta Cristina, Badajoz,pain; �Valle de Hebron, Barcelona, Spain; ¶Meixoeiro, Vigo, Spain; #Centralsturias, Oviedo, Spain; and **Bellvitge, Barcelona, Spain.

eManuscript received June 12, 2008; revised manuscript received August 11, 2008,

ccepted August 19, 2008.

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ssues have been raised suggesting an increased risk of latehrombosis, primarily when DES have been used withoff-label” indications in “real world” clinical practice (6,7).

All randomized studies confirming the efficacy of DES inatients with ISR had a relatively short clinical follow-up,anging from 9 months to 1 year (1–4). Therefore, theong-term safety and efficacy of SES for patients with ISRemains to be established. The present report describes theery long-term clinical outcome (3 to 4 years) of theseatients.

ethods

atient selection and study design. The RIBS-II (Reste-osis Intra-stent: Balloon angioplasty vs. elective sirolimus-

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1622 Alfonso et al. JACC Vol. 52, No. 20, 2008ISR: Long-Term Results of SES November 11, 2008:1621–7

randomized trial designed tocompare these 2 therapeuticstrategies in patients with ISR(see Online Appendix). Inclu-sion/exclusion criteria have beenpreviously defined in detail (2).Briefly, patients with ischemiasecondary to bare-metal ISRwere eligible. Patients with ISRon small vessels (�2.5 mm) orvery diffuse ISR (�32 mm) wereexcluded (2). The study was aninvestigator-driven initiative, and8 Spanish University Hospitalsparticipated in the trial.

oronary interventions. Careful lesion pre-dilation (un-ersized and short balloons) followed by full lesion coverageas recommended in the SES arm. Relatively high pres-

ures (�12 atm) were used in both arms (2). After inter-ention, patients received aspirin indefinitely and clopi-ogrel (75 mg/day) for at least 9 months. Thereafter, theuration of extended clopidogrel use was left to the attend-

ng cardiologist’s discretion.ollow-up and definitions. Initially, patients were followed-p at 1 month, 9 months, and 1 year. Subsequently, all patientsere prospectively followed on a yearly basis with a detailed,

tandardized, structured questionnaire. Noninvasive tests toetect ischemia were recommended in these visits. Detailed

nformation on antiplatelet therapy was collected. Tele-hone contact was obtained in patients not seen at thelinics. Consistency checks were performed at the coordi-ating center, and whenever needed, queries were sent backo sites. Clinical records of all patients with potential eventsere reviewed. All major events were verified against sourceocumentation. Clinical events (death, myocardial infarc-ion [MI], target vessel revascularization [TVR]), as previ-usly defined (2), were adjudicated by an independentlinical Events Committee blinded to the assigned treat-ent. The protocol emphasized that reinterventions at

ollow-up required previous demonstration of myocardialschemia.

The original protocol analyzed angiographic SES throm-osis. However, because this definition is now consideredoo restrictive, the Academic Research Consortium (ARC)ierarchical definition was used to readjudicate cases of SEShrombosis (8).

Initial results of the RIBS-II study have been previouslyeported (2). Patients assigned to SES had a lower restenosisate (11% vs. 39%, p � 0.001), a reduced neointimalroliferation on intravascular ultrasound, and a better 1-yearutcome compared with the BA group (2).The objective of the present study was to assess the very

ong-term (�1 year) clinical outcome in these patients. Theomposite of death, MI, and TVR at late follow-up was are-specified secondary end point. We also evaluated the

Abbreviationsand Acronyms

BA � balloon angioplasty

CI � confidence interval

DES � drug-eluting stent(s)

HR � hazard ratio

ISR � in-stent restenosis

MI � myocardial infarction

SES � sirolimus-elutingstent(s)

TVR � target vesselrevascularization

ole of 10 pre-defined variables and extended dual antiplate- ncontent.onlinejDownloaded from

et therapy on late clinical events. Finally, we sought tossess predictors of clinical outcome.tatistical analysis. Data are presented as values and per-entages or mean � SD. Median and interquartile rangeere used when data were not normally distributed

Kolmogorov-Smirnov test). Event-free survival was esti-ated by Kaplan-Meier analysis and compared with thereslow’s exact test. Cox proportional hazard analyses weresed to assess long-term clinical outcome (hazard ratiosHRs] and 95% confidence intervals [CIs]) and the influ-nce of 10 pre-specified relevant baseline variables. Interac-ions were also studied. Multivariate Cox analyses were usedo study independent predictors of major events. Unlesstherwise specified, analyses were performed according tohe intention-to-treat principle with the SPSS package,ersion 12.0 (SPSS Inc., Chicago, Illinois). A p value �0.05as considered statistically significant.

esults

ne-year follow-up was obtained in all 150 randomizedatients. A clinical follow-up �1 year was obtained in 146atients (97.3%) and �3 years in 145 patients (96.7%) (97%ES, 96% BA). The last clinical follow-up was at 3.3 yearsmedian: 1,195 days; interquartile range: 1,123 to 1,274ays; mean: 1,151 � 262 days). Table 1 summarizes adversevents. Overall, clinical events at long-term follow-up wereore frequent in the BA group (HR: 1.92; 95% CI: 1.03 to

.59), largely as the result of a higher requirement for TVRHR: 2.35; 95% CI: 1.17 to 4.70). The early benefitchieved with SES during the first year was maintained atong-term follow-up. Figure 1 displays survival estimates atate follow-up. Figure 2 shows late clinical outcome accord-ng to 10 pre-specified variables. No significant interactionsere found with the main outcome measure.linical events after the first year. In the SES group 1atient (without clopidogrel) died after a non–Q-wave MIpossible stent thrombosis). In the BA group, 2 patientsied, 1 suddenly (on clopidogrel), 2 weeks after revascular-zation of a nontarget vessel (possible stent thrombosis), andnother from a major bleeding and a non–Q-wave MI thatomplicated an urotelioma resection (clopidogrel previouslyithdrawn).Three patients in the SES arm suffered from large-wave MIs after 1 year (1 definitive, 2 probable SES

hromboses). The first patient (on clopidogrel) suffered aefinitive SES thrombosis treated with thrombectomy andew SES implantation; the second (on clopidogrel) sufferedhrombosis in an SES immediately distal to the target SEShat eventually needed bare-metal stenting; the third patientwithout clopidogrel) required thrombolysis for an ST-egment elevation MI, but 2 days later angiography revealedthrombus-free SES. In the BA group, only the previouslyescribed patient with urotelioma surgery developed a

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BA � balloon angioplasty; CI � confidence interval; HR � hazard ratio; MIvessel revascularization; — � undefined.

1623JACC Vol. 52, No. 20, 2008 Alfonso et al.November 11, 2008:1621–7 ISR: Long-Term Results of SES

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In the SES group 3 patients required late TVR forymptomatic recurrent ISR: 2 had “real” late restenosis (noestenosis at 9 months), and 1 had asymptomatic restenosist 9 months. Three patients in the BA arm requiredeintervention (1 surgical, 2 percutaneous) for late restenosisnot present at 9 months).tent thrombosis. Table 2 summarizes episodes of stenthrombosis according to the ARC definition, time ofccurrence, and clopidogrel status. During the first year,patients suffered angiographic (definitive) stent throm-

osis and developed large Q-wave MI (1 in each arm).he patient in the SES arm had hyperhomocysteinemia

nd questionable adherence to the dual antiplatelet reg-men. The patient in the BA arm suffered thrombosis (onlopidogrel) 1 month after an SES was implanted to treatn early recurrent ISR. During the first year, 2 BAatients died suddenly (1 with and 1 without clopidogrel)nd were classified as possible stent thrombosis. After therst year, 1 patient in the SES group experiencedefinitive very late stent thrombosis and 2 experienced

l Events

BA Group (n � 74) p Value HR (95% CI)

0 (0) 0.49 —

0 (0) 1 1

0 (0) 1 1

0 (0) 1 1

0 (0) 1 1

0 (0) 0.49 —

3 (4.1) 0.98 1.02 (0.21–5.05)

2 (2.7) 0.99 1.01 (0.14–7.17)

22 (29.7) 0.003 3.16 (1.40–7.09)

18 (24.3) 0.01 2.83 (1.18–6.76)

4 (5.4) 0.16 4.12 (0.46–36.9)

23 (31.1) 0.004 2.90 (1.34–6.28)

2 (2.9)

1 (1.4)

3 (4.3)

2 (2.9)

1 (1.4)

4 (5.8)

5 0.71 1.12 (0.34–4.77)

3 0.33 0.51 (0.13–2.03)

24 0.01 2.35 (1.17–4.70)

20 0.05 2.04 (0.98–4.26)

5 0.08 1.92 (0.02–3.59)

26 0.037 1.92 (1.03–3.59)

cal end points, although each event is listed separately (nonexclusive)ts after 1 year are presented, but they might have previously sufferedisons between groups are not performed.� myocardial infarction; SES � sirolimus-eluting stent; TVR � target

43210

100

80

60

40

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69%

76%

65%

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Figure 1 Kaplan-Meier Estimates of Event-Free Survival

Kaplan-Meier estimates of event-free survival (death, myocardial infarction, andtarget vessel revascularization). Red line � sirolimus-eluting stent; blue line �

balloon angioplasty.

In-Hospital, 1 Year, and Very Late Clinical Events

Table 1 In-Hospital, 1 Year, and Very Late Clinica

Event SES Group (n � 76)

Hospital events, n (%)

Death 1 (1.3)

MI 0 (0)

TVR 0 (0)

Coronary angioplasty 0 (0)

Coronary surgery 0 (0)

Any major hospital event 1 (1.3)

At 1 yr, n (%)

Death 3 (3.9)

MI 2 (2.6)

TVR 8 (10.5)

Coronary angioplasty 7 (9.2)

Coronary surgery 1 (1.3)

Any major event at 1 yr 9 (11.8)

After 1 yr, n (%)*

Death 1 (1.4)

MI 4 (5.6)

TVR 4 (5.6)

Coronary angioplasty 4 (5.6)

Coronary surgery 0 (0)

Any major event, last follow-up 7 (9.9)

Total, last follow-up, n (%)

Death 4

MI 6

TVR 12

Coronary angioplasty 11

Coronary surgery 1

Any major event, last follow-up 16

Patients with more than 1 event are counted only once for the composite cliniin the corresponding category. p values from Cox analysis.*Patients with evenevents within the first year. This could bias the results, and therefore compar

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1624 Alfonso et al. JACC Vol. 52, No. 20, 2008ISR: Long-Term Results of SES November 11, 2008:1621–7

s Q-wave MIs). Finally, 1 patient in each arm sufferedossible very late stent thrombosis (2 unexpected deathsreviously described).Notably, in the BA arm the patient with definitive

tent thrombosis and 1 of the 3 patients with possiblehrombosis suffered this event only after SES implanta-ion was required for recurrent ISR at the target lesion.herefore, in a “per final treatment analysis,” 7 of the 9

pisodes of definitive/probable/possible stent thrombosisccurred in patients who were initially treated with orventually required SES implantation. In fact, only 2atients treated with BA “alone” experienced this prob-

Figure 2 Long-Term Clinical Outcome According to 10 Pre-Spec

No patient with in-stent restenosis of a coil stent (1st ST Coil) was included. BA �

ratio; CI � confidence interval; LAD � left anterior descending coronary artery; RE

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redictors of adverse clinical events. Univariate and mul-ivariate predictors of adverse events and TVR are presentedn Table 3. On Cox analyses the use of SES was anndependent predictor of event free survival.

lopidogrel therapy. All patients in the SES group receivedlopidogrel for 12 months (median 17 � 13 months). After 1ear, clopidogrel therapy could not be determined with cer-ainty or was unknown in 5 of 71 patients. In the remaining 66atients, clopidogrel was maintained for �1 year in 22 patients33%), �2 years in 16 (24%), and was used indefinitely in 15atients (23%). Clopidogrel status at the time of stent throm-osis is detailed in Table 2. Of the 4 patients with definitive/

Variables

on angioplasty; B/A � balloon-arterytenosis; SES � sirolimus-eluting stent.

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1625JACC Vol. 52, No. 20, 2008 Alfonso et al.November 11, 2008:1621–7 ISR: Long-Term Results of SES

lopidogrel therapy. Adverse events, at any time or after therst year of follow-up, were not related to clopidogrel status.

iscussion

his study demonstrates that in patients with ISR theeneficial clinical effects of SES are maintained up to 4 years

pisodes of Stent Thrombosis:irst Year and Very Late

Table 2 Episodes of Stent Thrombosis:First Year and Very Late

EventSES Group(n � 76)

BA Group(n � 74) p Value

During the 1st yr

Definitive 1 (1†) 1 (1*) 1

Probable 0 0 1

Possible 0 2 (1*, 1†) —

Definitive/probable 1 (1†) 1 (1*) 1

Definitive/probable/possible 1 (1†) 3 (2*, 1†) 0.30

After the 1st yr

Definitive 1 0 —

Probable 2 (1†) 0 —

Possible 1 (1†) 1 1

Definitive/probable 3 (1†) 0 —

Definitive/probable/possible 4 (2†) 1 0.17

Total (last follow-up)

Definitive 2 (1†) 1 (1*) 0.57

Probable 2 (1†) 0 —

Possible 1 (1†) 3 (1*, 1†) 0.30

Definitive/probable 4 (2†) 1 (1*) 0.17

Definitive/probable/possible 5 (3†) 4 (2*, 1†) 0.76

tent thrombosis following the Academic Research Consortium definition. p values from Coxnalysis. *Patients in the balloon arm who suffered thrombosis but only after an SES was

mplanted for in-stent restenosis. †Patients without clopidogrel therapy at time of event.Abbreviations as in Table 1.

Predictors of Very Long-Term Clinical Outcome

Table 3 Predictors of Very Long-Term Clinic

HR

Any major adverse event

Age �65 yrs 1.85

Unstable angina 2.19

Time to ISR �6 months 2.79

Ostial location 2.29

Calcium 1.93

Mehran classification (II/III) 2.63

Therapy (BA vs. SES) 1.92

TVR

Previous MI 0.48

Unstable angina 2.37

ISR length (/mm) (QCA) 1.04

Time to ISR �6 months 2.72

Ostial location 2.37

ACC/AHA lesion classification (B2/C) 4.81

Mehran classification (II/III) 4.63

Minimal lumen diameter pre-intervention (QCA) 0.31

Therapy (BA vs. SES) 2.35

p values from Cox analysis.

other abbreviations as in Table 1.

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fter intervention. The lower event rate seen in the SESroup was mainly driven by a reduced need for target lesionevascularization. Late events were rare and equivalent inoth groups. Notably, after 1 year, the clinical requirementor TVR was very low. This dissipates potential concerns ofpotential late “catch-up” phenomenon elicited by SES thatight diminish their long-term efficacy. Moreover, pre-

pecified analyses of relevant subgroups were consistent withhis main outcome measure. In addition, the incidence oftent thrombosis after 1 year was also very low. Althoughery late stent thrombosis was numerically more frequent inhe SES arm, the difference was not statistically significant.herefore, our study with systematic, prospective, and

omplete clinical follow-up provides important reassuranceegarding long-term safety concerns after SES implantationn this challenging setting.ong-term results after DES implantation. Initial con-erns suggesting an increased rate of major adverse clinicalvents (death, MI) associated with DES (6,7) have beenecently dissipated. Meta-analysis with independent adjudi-ation and exhaustive assessment of late events—withatient-level data—failed to confirm an increased event ratefter DES (5). Furthermore, although some initial realorld registries also suggested the possibility of a higher

vent rate after DES (7), recent larger observational studiesailed to confirm any risk increase and even suggested thatES might be beneficial in this regard (9). Conversely, the

ssue of very late thrombosis after DES implantation stillemains of concern (10). The delayed endothelization pro-ess detected in some patients seems to be associated with aarginal but definitive higher risk for late thrombosis (10).

tcome

iate Analysis Multivariate Analysis

CI) p Value Adjusted HR (95% CI) p Value

3.48) 0.05

4.09) 0.01

5.1) 0.001 2.92 (1.57–5.43) 0.001

4.81) 0.04 2.34 (1.10–4.98) 0.04

3.59) 0.04

7.4) 0.04 3.04 (1.06–8.75) 0.02

3.59) 0.04 2.30 (1.21–4.40) 0.01

0.94) 0.03 0.47 (0.24–0.94) 0.03

4.69) 0.01

1.07) 0.03

5.24) 0.003 2.74 (1.40–5.38) 0.004

5.22) 0.05 2.32 (1.05–5.27) 0.06

20.04) 0.006 3.50 (0.82–14.9) 0.05

19.33) 0.008 3.92 (0.88–17.3) 0.03

0.85) 0.02

4.7) 0.01 2.88 (1.39–5.96) 0.003

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ISR � in-stent restenosis; QCA � quantitative coronary angiography;

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1626 Alfonso et al. JACC Vol. 52, No. 20, 2008ISR: Long-Term Results of SES November 11, 2008:1621–7

herefore, it is conceivable that in particularly adversecenarios, such as ISR, DES implantation might be associ-ted with a higher thrombotic risk.ong-term follow-up in patients with ISR. Until very

ecently brachytherapy was considered the standard of careor patients with ISR (3,4). Recent studies, however, dem-nstrated a reduction in efficacy overtime, suggesting aelayed endothelization process (increasing late thrombosisisk) and a late restenotic response (11). These reasons,ogether with emerging data suggesting the superiority ofES (3,4), led to the widespread abandonment of this form

f therapy. However, the 2 large randomized studies dem-nstrating the superiority of DES over brachytherapy (3,4)ad a limited (9 months) clinical follow-up. This is ofelevance, because in the SISR (Sirolimus-Eluting Stentsersus Vascular Brachytherapy for In-Stent Restenosis)

rial (3), 2 SES patients suffered late stent thrombosis and 6eveloped MIs, but none of these events occurred duringollow-up in the brachytherapy arm. More recently, in aetrospective, single-center, observational study, Lee et al.12) compared the long-term outcome of SES versusrachytherapy in patients with diffuse ISR. The event-freeurvival was significantly better (92.5% vs. 84.2%) in the 120atients treated with SES (follow-up 35 � 8 months).owever, during this period, 2 SES patients suffered

ngiographic stent thrombosis, 1 had an MI, and 4 died.evertheless, these findings are difficult to compare with

hose of the 2 landmark randomized studies (3,4), becauseutting-balloon or rotational atherectomy were systemati-ally used and rhenium-188 balloons were selected as theeta-source (12).The ISAR-DESIRE (Intracoronary Stenting and Angio-

raphic Results: Drug-Eluting Stents for In-Stent Resteno-is) randomized trial (1) demonstrated that both paclitaxel-luting stents and SES were superior to BA in reducingVR at 12 months. During this first year no early angio-raphic occlusions were detected, but late total occlusionsere observed in 1 SES patient, 3 patients treated withaclitaxel-eluting stents, and in 2 BA patients (1). However,longer clinical follow-up was not available. Yet, a recent

bservational study (13) assessing the 2-year clinicalollow-up of 138 ISR patients treated with SES providedorrisome results: major events occurred in 5.8%, 14.3%,

nd 25% of patients at 6, 12, and 24 months, respectively.herefore, the assessment of the very long-term safety and

fficacy of SES in patients with ISR, especially as comparedith simpler strategies such as BA, remains of paramount

linical importance.resent study. The long-term follow-up of this random-

zed study demonstrates the superiority of SES over BA inatients with ISR. SES maintained their effectiveness ineducing clinical events during this uniquely long period ofollow-up. Furthermore, SES proved to be safe in theseatients who had a very low frequency of late events such asVR and stent thrombosis. Notably, on multivariate

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redictor of very long-term event-free survival. In oureries, time to restenosis and the Mehran and Americanollege of Cardiology/American Heart Association an-

iographic classifications were also independent predic-ors of adverse clinical events (14).

The present study is the first to use the ARC definition toystematically assess thrombosis rates in patients treated forSR (8). The dilemma as to whether to attribute thrombosis tohe initial strategy or to the final intervention used to treat ISRas been previously highlighted (8). In our series, the higherequirement of TVR in the BA group might help to explainome cases of late thrombosis after subsequent reinterventionsith SES. In fact, ISR restenosis is not always a benign clinical

ntity, and recently, repeated procedures have been associatedith a higher risk of MI and stent thrombosis (15). In our

ntention-to-treat analysis no differences were detected regard-ng this complication in the 2 arms. However, when throm-otic episodes of patients in the BA arm—but eventuallyequiring an SES implantation for ISR recurrences—wereomputed as belonging to the SES strategy (worst casecenario), a trend favoring BA was detected. Further studiesncluding larger series of patients and longer periods ofollow-up are still warranted to address this issue.

Finally, the potential role of extended use of clopi-ogrel beyond 12 months in complex patients such ashose with ISR remains to be defined. In our study, lateiscontinuation of dual antiplatelet therapy was notssociated with an increased frequency of major events.owever, a minority of patients treated with SES ex-

ended the dual antiplatelet for �1 year. Of the 4pisodes of definitive/probable/possible very late throm-osis in the SES group, 2 occurred in patients receivinglopidogrel.tudy limitations. First, only a relatively small number ofatients were analyzed. Therefore, the power to detect smallifferences in clinical event rates after 1 year was limited.his problem particularly affects our subgroup analyses.ikewise, the low number of late events limits the value of

he multivariate analysis (over-fitting) to identify eventredictors. Further studies including a larger number ofatients with ISR are required to confirm the very long-erm safety and efficacy of SES in this setting. Second, themplications of an extended dual antiplatelet duration couldot be definitively elucidated from our series, consideringhat the use of clopidogrel �1 year was left to the criteria ofhe attending physician (not randomized) and only retro-pectively ascertained during clinical visits. Whether a veryrolonged dual antiplatelet therapy might offer clinicalenefit in selected patients receiving SES for ISR remains toe elucidated.

onclusions

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1627JACC Vol. 52, No. 20, 2008 Alfonso et al.November 11, 2008:1621–7 ISR: Long-Term Results of SES

f SES is safe and highly effective, providing long-termlinical results superior to BA.

eprint requests and correspondence: Dr. Fernando Alfonso,ardiologıa Intervencionista, Instituto Cardiovascular, Hospitalniversitario “San Carlos,” Ciudad Universitaria, Plaza de Cristoey, Madrid 28040 Spain. E-mail: [email protected].

EFERENCES

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ey Words: angiography y angioplasty y restenosis y sirolimus-elutingtents.

APPENDIX

or the organization of the trial, coinvestigators, and

by on May 10, 2011 acc.org

doi:10.1016/j.jacc.2008.08.025 2008;52;1621-1627 J. Am. Coll. Cardiol.

Camino Bañuelos, Alfonso Suárez, Carlos Macaya, for the RIBS-II Investigators César Morís, Angel Cequier, Manel Sabaté, Javier Escaned, Pilar Jiménez-Quevedo,

Bethencourt, Vicens Martí, José R. López-Mínguez, Juan Angel, Andrés Iñiguez, Fernando Alfonso, María-José Pérez-Vizcayno, Rosana Hernández, Armando

angioplasty vs. elective sirolimus-eluting Stenting) StudyIn-Stent Restenosis: Results of the RIBS-II (Restenosis Intra-stent: Balloon

Long-Term Clinical Benefit of Sirolimus-Eluting Stents in Patients With

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