Journal of the American College of Cardiology Vol. 54, No. 13, 2009 © 2009 by the American College of Cardiology Foundation ISSN 0735-1097/09/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2009.06.018

CLINICAL RESEARCH Interventional Cardiology

Incidence and Management of Restenosis After Treatment of Unprotected Left Main Disease With Drug-Eluting 70 Restenotic Cases From a Cohort of 718 Patients: FAILS (Failure in Left Main Study)

Imad Sheiban, MD,* Dario Sillano, MD,* Giuseppe Biondi-Zoccai, MD,* Alaide Chieffo, MD,† Antonio Colombo, MD,† Sabine Vecchio, MD,‡ Massimo Margheri, MD,‡ Julian P. Gunn, MD,§ Tushar Raina, MD,§ Francesco Liistro, MD,ʈ Leonardo Bolognese, MD,ʈ Michael S. Lee, MD,¶ Jonathan Tobis, MD,¶ Claudio Moretti, MD, PHD* Turin, Milan, Ravenna, and Arezzo, Italy; Sheffield, United Kingdom; and Los Angeles, California

Objectives This study sought to retrospectively appraise the incidence and management of restenosis after drug-eluting (DES) implantation for unprotected left main (ULM) disease.

Background The promising role of DES for ULM has been reported. However, no detailed data are available on subsequent restenosis.

Methods From the total sample of patients with ULM treated with DES, we identified those presenting with angiographic ULM restenosis. The primary end point was the long-term rate of major adverse cardiac events (MACE), that is, death, (MI), or target lesion revascularization (TLR). We also adjudicated stent according to the Academic Research Consortium.

Results Post-DES restenosis in ULM occurred in 70 of 718 patients (9.7%). Of these, 59 (84.3%) were treated percutane- ously (34 [48.6%] with additional DES, 22 [31.4%] with standard or cutting balloons, 2 [2.9%] with rotational atherectomy, and 1 [1.4%] with a bare-metal stent), whereas 7 (10%) patients underwent bypass surgery and 4 (5.7%) were treated medically. In-hospital MACE included no periprocedural MI and only 1 (1.4%) death. After 27.2 Ϯ 15.4 months, MACE occurred cumulatively in 18 (25.7%) patients, with death in 4 (5.7%), MI in 2 (2.9%), and TLR in 15 (21.4%). Patients treated with medical, interventional, and surgical therapy had the fol- lowing MACE rates, respectively: 50%, 25.4%, and 14.3%. Definite, probable, and possible stent thrombosis oc- curred in 0 (0%), 1 (1.4%), and 1 (1.4%) patient, respectively.

Conclusions DES restenosis in the ULM can be managed in most cases with a minimally invasive approach, achieving favorable early and late results. (J Am Coll Cardiol 2009;54:1131–6) © 2009 by the American College of Cardiology Foundation

Significant unprotected left main disease (ULM) occurs in 5% the 1970s, coronary artery bypass grafting (CABG) has been to 10% of patients undergoing coronary , and since considered its preferred treatment (1). Balloon-only percuta- neous coronary intervention (PCI) for ULM is complicated by early elastic recoil, abrupt closure, and late restenosis. Bare- From the *Division of Cardiology, University of Turin, Turin, Italy; †St. Raffaele metal stents have improved immediate results, but restenosis Hospital and Centro Cuore Columbus, Milan, Italy; ‡Division of Cardiology, Ravenna with ensuing repeat target lesion revascularization (TLR) or Hospital, Ravenna, Italy; §Division of Cardiology, University of Sheffield, Sheffield, United Kingdom; ʈDivision of Cardiology, San Donato Hospital, Arezzo, Italy; and sudden death remain major limitations (2). the ¶Division of Cardiology, UCLA Medical Center, Los Angeles, California. Dr. Drug-eluting stents (DES) significantly reduce the risk of Biondi-Zoccai has consulted for Boston Scientific, Cordis, Invatec, and Medtronic, and has lectured for Medtronic. Dr. Lee has received lecture fees from Boston restenosis, and in some institutions, it has become common Scientific, Bristol-Myers Squibb, and AstraZeneca. Dr. Tobis has received lecture fees practice to perform PCI with DES for ULM (3,4). Despite from Boston Scientific. Drs. Sheiban, Sillano, and Biondi-Zoccai contributed equally the relatively common occurrence of DES restenosis in to this work. Manuscript received February 2, 2009; revised manuscript received June 1, 2009, ULM (reaching 10% to 20%), there are no data on the accepted June 1, 2009. optimal management of such patients. The purpose of this 1132 Sheiban et al. JACC Vol. 54, No. 13, 2009 Restenosis After ULM Stenting September 22, 2009:1131–6

Abbreviations multicenter, international, retro- Interventional procedures and post-intervention medica- and Acronyms spective study was to assess the tions. Coronary and stent implantation during outcome of patients with ULM coronary artery index PCI were performed according to current practice and ؍ CABG bypass grafting restenosis after PCI with DES. guidelines. The choice of devices, techniques (including the

-creatine kinase approach to bifurcation stenting, kissing balloon, and post ؍ CK Methods /drug-eluting stent(s) dilatation), and drug therapy (including glycoprotein IIb ؍ DES IIIa inhibitors) for the index procedure was at the cardiol- -major adverse Study design and patient popu ؍ MACE cardiovascular events lation. All consecutive patients ogist’s choice. After the procedure, all patients were advised to myocardial infarction with an angiographic diagnosis continue lifelong aspirin and either 250-mg ticlopidine twice ؍ MI Ͼ daily or 75-mg clopidogrel for 6 to 12 months or more. The percutaneous of significant restenosis ( 50% ؍ PCI coronary intervention diameter at coronary an- choice between angiographic and clinical follow-up was at the stent thrombosis giography) in the ULM were operator’s and referring physician’s discretion, but often took ؍ ST into account the patient’s preference and comorbidities. None- target lesion retrospectively selected after PCI ؍ TLR revascularization with DES of the ULM (July theless, in most cases angiographic follow-up was recom- unprotected left 2002 to October 2006). All pa- mended irrespective of symptoms or signs of ischemia 6 to 12 ؍ ULM main disease tients were included in the study months after the index PCI. Treatment of restenosis was also independent of the subsequent completely at the cardiologist’s discretion, but usually each case decision for medical, interven- was collectively discussed and the final management decision tional, or surgical treatment. At least 6 months of clinical was based on the patient’s symptoms/signs of ischemia, coro- follow-up beyond the documentation of ULM restenosis nary anatomy, surgical risk, PCI feasibility, and overall life was required for inclusion. Subjects with protected left main expectancy. In case of repeat PCI, the choice of technique and vessels, defined as the presence of at least 1 patent arterial or device was also at the interventionist’s discretion. venous graft to the left coronary artery, were excluded. End point definitions and follow-up. The primary end Written informed consent was obtained by all patients, point of the study was the occurrence of major adverse and ethical committee approval was obtained for database cardiovascular events (MACE), that is, death, myocardial review. infarction (MI), or TLR (defined as repeat PCI or CABG

Figure 1 Study Profile

angio ϭ angiographic; CABG ϭ coronary artery bypass grafting; DES ϭ drug-eluting stent(s); PCI ϭ percutaneous coronary intervention; ULM ϭ unprotected left main. JACC Vol. 54, No. 13, 2009 Sheiban et al. 1133 September 22, 2009:1131–6 Restenosis After ULM Stenting

BaselineTable 1 CharacteristicsBaseline Characteristics

All Medical Therapy Only Repeat PCI CABG (7 ؍ n) (59 ؍ n) (4 ؍ n) (70 ؍ n) Age, yrs 65.4 Ϯ 12.8 67.6 Ϯ 21.2 64.8 Ϯ 12.7 69.7 Ϯ 8.9 Men 59 (84.3) 3 (75.0) 49 (83.1) 7 (100) Diabetes mellitus 18 (26.1) 0 18 (31.0) 0 Noninsulin-dependent 12 (66.7) 0 12 (20.7) 0 Insulin-dependent 6 (33.3) 0 6 (10.3) 0 Hypertension 50 (72.5) 3 (75.0) 43 (74.1) 4 (57.1) Dyslipidemia 49 (70.9) 3 (75.0) 41 (69.5) 5 (71.4) Current smoking 5 (7.4) 0 3 (5.3) 2 (28.6) Left ventricular ejection fraction, % 52.4 Ϯ 9.4 43.0 Ϯ 23.4 53.9 Ϯ 9.5 45.0 Ϯ 7.1 Prior myocardial infarction 20 (43.5) 2 (50.0) 18 (45.0) 0 Prior CABG 6 (13.0) 0 6 (15.0) 0 Clinical presentation of restenosis Elective control 15 (22.1) 1 (25.0) 13 (22.8) 1 (14.3) Silent myocardial ischemia 12 (17.6) 0 11 (19.3) 1 (14.3) Stable 20 (29.4) 1 (25.0) 16 (28.1) 3 (42.9) Unstable angina 19 (27.9) 2 (50.0) 15 (26.3) 2 (28.6) Acute myocardial infarction 2 (2.9) 0 2 (3.5) 0 Cardiogenic shock 1 (1.5) 0 1 (1.8) 0 EuroSCORE 6.9 Ϯ 11.7 7.0 Ϯ 6.1 7.1 Ϯ 13 5.0 Ϯ 1.9

Values are mean Ϯ SD or n (%). CABG ϭ coronary artery bypass grafting; PCI ϭ percutaneous coronary intervention. for significant restenosis in the previously stented segment upper limit for normal and a concomitant increase of or in the adjacent 5 mm). Diagnosis of MI at follow-up was CK-MB over the upper limit of normal and/or ratio of peak based on peak of total creatine kinase (CK) Ն2 times the CK-MB/peak total CK Ն0.10 and/or CK-MB Ն3 times

AngiographicProcedure inAngiographic the and ULM, Procedural Before and Characteristics theProcedural Diagnosis Characteristics of of Restenosis* the First of the First Table 2 Procedure in the ULM, Before the Diagnosis of Restenosis*

All Medical Therapy Only Repeat PCI CABG (7 ؍ n) (59 ؍ n) (4 ؍ n) (70 ؍ n) Lesion location Ostium only 12 (17.1) 1 (25.0) 9 (15.3) 2 (28.6) Ostium and/or shaft 9 (12.9) 0 8 (13.6) 1 (14.3) Distal and/or bifurcational 49 (70.0) 3 (75.0) 42 (71.2) 4 (57.1) PCI in the ULM Atherectomy 2 (3.6) 0 2 (4.2) 0 No. of implanted stents 1.7 Ϯ 0.8 2.0 Ϯ 0.8 1.7 Ϯ 0.9 1.4 Ϯ 0.8 Only SES 38 (55.9) 3 (75.0) 33 (57.9) 2 (28.6) Only PES 25 (36.8) 1 (25.0) 20 (35.1) 4 (57.1) Only ZES 2 (2.9) 0 1 (1.8) 1 (14.3) SES and PES 1 (1.5) 0 1 (1.8) 0 DES and BMS 2 (2.9) 0 2 (3.5) 0 Total stent length per patient, mm 26.7 Ϯ 13.6 36.0 Ϯ 21.4 26.5 Ϯ 13.3 23.0 Ϯ 11.3 Maximum balloon diameter, mm 3.33 Ϯ 0.56 2.94 Ϯ 0.13 3.40 Ϯ 0.55 2.96 Ϯ 0.59 Maximum dilation pressure, atm 15.9 Ϯ 3.8 15.0 Ϯ 4.2 16.1 Ϯ 3.9 14.4 Ϯ 2.2 Bifurcation stenting 52 (74.3) 3 (75.0) 45 (76.3) 4 (57.1) Main branch only 14 (26.9) 0 13 (28.9) 1 (25.0) T 9 (17.3) 0 9 (20.0) 0 V 5 (9.6) 0 4 (8.9) 1 (25.0) Crushing 11 (21.2) 0 10 (22.2) 1 (25.0) Culottes 2 (3.8) 0 2 (4.4) 0 Simultaneous kissing stenting 10 (19.2) 3 (100) 6 (13.3) 1 (25.0) Final kissing balloon inflation 47 (90.4) 2 (75.0) 41 (91.1) 4 (100)

Values are mean Ϯ SD or n (%). *Defined as ULM and/or ostial left anterior descending and/or ostial left circumflex and/or ostial ramus. BMS ϭ bare-metal stent(s); PCI ϭ percutaneous coronary intervention; PES ϭ -eluting stent(s); SES ϭ sirolimus-eluting stent(s); ULM ϭ unprotected left main; ZES ϭ -eluting stent(s). 1134 Sheiban et al. JACC Vol. 54, No. 13, 2009 Restenosis After ULM Stenting September 22, 2009:1131–6 the upper limit of normal. Stent thrombosis (ST) was symptoms/signs of myocardial ischemia in 46.2%. Patients adjudicated according to the Academic Research Consor- undergoing routine angiographic follow-up were signifi- tium (5). Data were obtained by direct visits, telephone cantly younger (74.5 Ϯ 11.0 years vs. 64.0 Ϯ 9.1 years, p Ͻ interviews, and queries of institutional electronic databases, 0.001 at Gosset t test) and had a lower European System for referring physicians, or municipal civil registries. Cardiac Operative Risk Evaluation (EuroSCORE) (5.4 Ϯ Statistical analysis. Continuous variables are expressed as 5.9 vs. 2.2 Ϯ 0.7, p Ͻ 0.001 at Gosset t test) than those not mean Ϯ SD and were compared by analysis of variance or performing such follow-up. Gosset t test. Categorical variables are presented as counts Restenosis in the ULM after PCI with DES occurred in and percentages, and were compared by chi-square test. The 70 of 718 patients (9.7%). Of these, 5.7% were treated with p values unadjusted for multiplicity are reported throughout, medical therapy only, 84.3% by repeat PCI, and 10% with statistical significance set at the 2-tailed 0.05 level. underwent CABG (Table 1). The repeat PCI group was Statistical analyses were performed with SPSS version 12.0 characterized by a trend toward a higher prevalence of (SPSS, Inc., Chicago, Illinois). diabetes (0% vs. 31% vs. 0%, p ϭ 0.10 at chi-square test) but also by higher ejection fraction (43.0 Ϯ 23.4 vs. 53.9 Ϯ 9.5 Results vs. 45.0 Ϯ 7.1, p ϭ 0.02 at analysis of variance). Globally, Baseline clinical characteristics. From a total of 718 22.1% of restenoses were diagnosed during routine follow-up patients, with follow-up status available in 97.5%, 5.1% died angiogram and 30.8% had an admission diagnosis of acute (2.5% suddenly) before 6 months without any angiographic coronary syndrome. follow-up (Fig. 1). Angiographic follow-up was ultimately Angiographic and procedural characteristics. Angio- performed in 62.8% of subjects, being clinically driven in graphic and procedural characteristics of the first procedure 16.6% and routinely performed even in the absence of in the ULM (before the diagnosis of restenosis) are reported

Angiographicof the ProcedureAngiographic and Showing Procedural and the Characteristics ULMProcedural Restenosis* Characteristics Table 3 of the Procedure Showing the ULM Restenosis*

All Medical Therapy Only Repeat PCI CABG (7 ؍ n) (59 ؍ n) (4 ؍ n) (70 ؍ n) Lesion characteristics Ostium only 12 (16.9) 1 (25.0) 10 (16.9) 1 (14.3) Ostium and/or shaft 14 (20.0) 0 12 (20.3) 2 (28.6) Distal and/or bifurcational 44 (62.9) 3 (75.0) 37 (62.7) 4 (57.1) Restenosis involving ostial left anterior descending 22 (47.8) 0 19 (51.4) 3 (50.0) Restenosis involving ostial left circumflex 35 (76.1) 3 (100) 30 (81.1) 2 (33.3) Restenosis involving ramus 6 (13.0) 0 4 (10.8) 2 (33.3) Diffuse restenosis 12 (17.1) 0 10 (16.9) 2 (28.6) PCI for ULM restenosis Balloon-only PCI — — 16 (27.1) — Cutting balloon — — 6 (10.2) — Directional atherectomy — — 2 (3.4) — PCI with BMS — — 1 (1.7) — PCI with DES — — 34 (57.6) — Number of implanted stents — — 1.3 Ϯ 0.5 — Only SES — — 13 (39.4) — Only PES — — 20 (60.6) — Maximum balloon diameter, mm — — 3.3 Ϯ 0.4 — Total stent length per patient, mm — — 17.7 Ϯ 10.4 — Maximum dilation pressure, atm — — 17.7 Ϯ 5.0 — Bifurcation stenting — — 27 (45.8) — Main branch only — — 15 (62.5) — T — — 2 (8.3) — V — — 3 (12.5) — Crushing — — 0 — Culottes — — 1 (4.2) — Simultaneous kissing stenting — — 3 (12.5) — Final kissing balloon inflation — — 21 (87.5) — Glycoprotein IIb/IIIa inhibitors — — 9 (13.8) — Intra-aortic balloon pump — — 5 (7.2) —

Values are mean Ϯ SD or n (%). *Defined as ULM and/or ostial left anterior descending and/or ostial left circumflex and/or ostial ramus. Abbreviations as in Table 2. JACC Vol. 54, No. 13, 2009 Sheiban et al. 1135 September 22, 2009:1131–6 Restenosis After ULM Stenting in Table 2, whereas angiographic and procedural character- ST, 1 case of probable ST, and no cases of definite ST were istics of the procedure showing the ULM restenosis, that is, identified (all in the PCI group). the index procedure for the purpose of this work, are reported in Table 3. The location of restenosis was not significantly associated with the subsequent management Discussion strategy, even if PCI was the most common approach in all cases. Specifically, distal ULM disease was managed by PCI Drug-eluting stenting in the ULM has become a common in 84.1%, by CABG in 9.1%, and by medical therapy in practice in several tertiary care centers. Despite encouraging 6.8%, whereas ostial or shaft disease was managed by PCI in results, restenosis is still a challenging issue, especially in 84.6%, by CABG in 3.9%, and by medical therapy in 11.5% such a delicate anatomic position. In the scientifically (p ϭ 0.839 at chi-square test comparing distal versus rigorous and randomized SYNTAX (SYNergy Between nondistal location). Among the 59 patients treated inter- PCI With TAXUS and ) trial, 12-month ventionally (repeat PCI group), 57.6% underwent a new MACE rates reached 17.8% in the PCI group and 12.1% in DES implantation. In contrast to the previous baseline the CABG group, with repeat revascularization rates of procedure, paclitaxel-eluting stents were used predomi- 13.7% and 5.9% (4). Seung et al. (6) compared in a nantly (60.6%), followed by sirolimus-eluting stents nonrandomized fashion PCI versus CABG, showing after (39.4%). Among the 70 restenotic patients, CABG was 33 months that they did not differ significantly for death performed only for in-stent restenosis with no case of rates or the composite of death, MI, or stroke. However, CABG for disease progression elsewhere. DES were associated with higher rates of TLR (9.7% vs. In-hospital and long-term outcomes. The immediate 1.6%). Similar results were also reported by other investi- outcome was quite favorable (Table 4), with 1 (1.7%) death gators (3). in the PCI group. No patient had periprocedural MI or Despite the increasing frequency of ULM restenotic cases needed urgent CABG. Long-term follow-up data were in clinical practice (as it occurs in up to 16.7% of subjects available in 100% of restenotic subjects after an average of treated with DES in the ULM) (7) and its important 25.6 Ϯ 16.5 months since diagnosis of restenosis (36.7 Ϯ clinical impact, ULM restenosis after PCI with DES has 15.3 months of follow-up from the first PCI with DES in been incompletely characterized. The present retrospective the ULM), with 44.3% of subjects undergoing repeat PCI nonrandomized study is the first to evaluate the outcome of having repeat angiographic follow-up after 8.1 Ϯ 8.3 such patients. Our major findings evaluating 70 restenotic months. The MACE rate was 25.7%, with death in 5.7%, cases of 718 initial ULM patients are 2-fold: 1) significant MI in 2.9%, TLR in 21.4% (including CABG in 5.7%), and ULM DES restenosis is often characterized by a stable clinical PCI on other vessels in 21.4%. Finally, 1 case of possible condition; and 2) after 24 months of clinical follow-up from

In-HospitalTable 4 andIn-Hospital Long-Term and Follow-Up Long-Term Events Follow-Up Events

All Medical Therapy Only Repeat PCI CABG (7 ؍ n) (59 ؍ n) (4 ؍ n) (70 ؍ n) In-hospital events Death 1 (1.4) 0 1 (1.7) 0 Cardiac death 1 (1.4) 0 1 (1.7) 0 Myocardial infarction 0 0 0 0 CABG 0 0 0 0 Long-term events Follow-up completed 70 (100) 4 (100) 59 (100) 7 (100) Follow-up from restenosis, months 25.6 Ϯ 16.5 27.1 Ϯ 18.5 23.9 Ϯ 16.8 32.4 Ϯ 9.2 Follow-up from first PCI in ULM, months* 36.7 Ϯ 15.3 45.1 Ϯ 17.4 35.5 Ϯ 15.7 44.3 Ϯ 10.8 MACE 18 (25.7) 2 (50.0) 15 (25.4) 1 (14.3) Death 4 (5.7) 1 (25.0) 3 (5.1) 0 Cardiac death 2 (2.9) 1 (25.0) 1 (1.7) 0 Myocardial infarction 2 (2.9) 0 2 (3.4) 0 CABG 4 (5.7) 0 3 (5.1) 1 (14.3) ULM TLR 15 (21.4) 1 (25.0) 13 (22.0) 1 (14.3) Non-ULM* PCI 15 (21.4) 1 (25.0) 14 (23.7) 0 Stent thrombosis Definite 0 0 0 0 Probable 1 (1.4) 0 1 (1.7) 0 Possible 1 (1.4) 0 1 (1.7) 0

Values are mean Ϯ SD or n (%). *Defined as ULM and/or ostial left anterior descending and/or ostial left circumflex and/or ostial ramus revascularization. Abbreviations as in Table 2. 1136 Sheiban et al. JACC Vol. 54, No. 13, 2009 Restenosis After ULM Stenting September 22, 2009:1131–6 the diagnosis of restenosis, MACE rates seem quite favorable primary end point (16.9% to 37.0% for the total population, in both the interventional and surgical therapy groups. 15.0% to 85.0% for medical therapy, 16.1% to 37.8% for Almost 70% of patients with a diagnosis of significant repeat PCI, and 2.6% to 51.3% for CABG). However, DES restenosis in ULM were elective angiographic control restenosis in the ULM remains uncommon, and only a subjects or presented with silent ischemia or stable angina, study pooling several dozen tertiary care centers could but an unstable presentation of ULM restenosis in over 30% provide much larger data than our study. of cases suggests that restenosis is not a benign entity even in the ULM. Nonetheless, repeat PCI is often possible and Conclusions successful in these subjects. Notably, paclitaxel-eluting stents were used more frequently for repeat PCI, possibly This multicenter, international registry suggests that PCI because of availability subsequent to sirolimus-eluting can be a safe and effective treatment of ULM restenosis after stents, larger sizes, and preference for different DES strategy DES implantation. (8). Regarding the midterm clinical outcome (more than 2 years of median follow-up after the diagnosis of restenosis), Reprint requests and correspondence: Dr. Giuseppe Biondi- this study showed low mortality and MI rates in patients Zoccai, Interventional Cardiology, Division of Cardiology, Uni- treated by PCI and CABG. Differences in MACE, death, versity of Turin, S. Giovanni Battista Molinette Hospital, Corso Bramante 88-90, 10126 Turin, Italy. E-mail: gbiondizoccai@ MI, and TLR rates between these 2 groups are, however, gmail.com. limited by the small size of the CABG group, and should be viewed as hypothesis-generating only. It should also be REFERENCES borne in mind that follow-up intervention results are largely dependent on the initial patient characteristics and inter- 1. Sheiban I, Sillano D, Biondi-Zoccai GG, et al. 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