CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Incidence and Management of Restenosis After Treatment of Unprotected Left Main Disease With Drug-Eluting Stents70 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||,
Leonardo Bolognese, MD||,
Michael S. Lee, MD¶,
Jonathan Tobis, MD¶ and
Claudio Moretti, MD, PhD*
* Division of Cardiology, University of Turin, Turin, Italy
St. Raffaele Hospital and Centro Cuore Columbus, Milan, Italy
Division of Cardiology, Ravenna Hospital, Ravenna, Italy
Division of Cardiology, University of Sheffield, Sheffield, United Kingdom
|| Division of Cardiology, San Donato Hospital, Arezzo, Italy
¶ Division of Cardiology, UCLA Medical Center, Los Angeles, California
Manuscript received February 2, 2009;
revised manuscript received June 1, 2009,
accepted June 1, 2009.
* Reprint requests and correspondence: Dr. Giuseppe Biondi-Zoccai, Interventional Cardiology, Division of Cardiology, University of Turin, S. Giovanni Battista Molinette Hospital, Corso Bramante 88-90, 10126 Turin, Italy (Email: gbiondizoccai{at}gmail.com).
 |
Abstract
|
|---|
Objectives: This study sought to retrospectively appraise the incidence and management of restenosis after drug-eluting stent (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, myocardial infarction (MI), or target lesion revascularization (TLR). We also adjudicated stent thrombosis 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 percutaneously (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 ± 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 following MACE rates, respectively: 50%, 25.4%, and 14.3%. Definite, probable, and possible stent thrombosis occurred in 0 (0%), 1 (1.4%), and 1 (1.4%) patient, respectively.
Conclusions: DES restenosis in the ULM artery can be managed in most cases with a minimally invasive approach, achieving favorable early and late results.
Key Words: coronary artery disease • drug-eluting stent • left main coronary artery • percutaneous coronary intervention • restenosis
|
Abbreviations and Acronyms
| | CABG = coronary artery bypass grafting | | CK = creatine kinase | | DES = drug-eluting stent(s) | | MACE = major adverse cardiovascular events | | MI = myocardial infarction | | PCI = percutaneous coronary intervention | | ST = stent thrombosis | | TLR = target lesion revascularization | | ULM = unprotected left main disease |
|
Significant unprotected left main disease (ULM) occurs in 5% to 10% of patients undergoing coronary angiography, and since the 1970s, coronary artery bypass grafting (CABG) has been considered its preferred treatment (1). Balloon-only percutaneous coronary intervention (PCI) for ULM is complicated by early elastic recoil, abrupt closure, and late restenosis. Bare-metal stents have improved immediate results, but restenosis with ensuing repeat target lesion revascularization (TLR) or sudden death remain major limitations (2).
Drug-eluting stents (DES) significantly reduce the risk of restenosis, and in some institutions, it has become common practice to perform PCI with DES for ULM (3,4). Despite the relatively common occurrence of DES restenosis in ULM (reaching 10% to 20%), there are no data on the optimal management of such patients. The purpose of this multicenter, international, retrospective study was to assess the outcome of patients with ULM restenosis after PCI with DES.
|
Methods
|
|---|
Study design and patient population.
All consecutive patients with an angiographic diagnosis of significant restenosis (>50% diameter stenosis at coronary angiography) in the ULM were retrospectively selected after PCI with DES of the ULM (July 2002 to October 2006). All patients were included in the study independent of the subsequent decision for medical, interventional, or surgical treatment. At least 6 months of clinical follow-up beyond the documentation of ULM restenosis was required for inclusion. Subjects with protected left main vessels, defined as the presence of at least 1 patent arterial or venous graft to the left coronary artery, were excluded. Written informed consent was obtained by all patients, and ethical committee approval was obtained for database review.
Interventional procedures and post-intervention medications.
Coronary angioplasty and stent implantation during index PCI were performed according to current practice and guidelines. The choice of devices, techniques (including the approach to bifurcation stenting, kissing balloon, and post-dilatation), and drug therapy (including glycoprotein IIb/IIIa inhibitors) for the index procedure was at the cardiologist's choice. After the procedure, all patients were advised to continue lifelong aspirin and either 250-mg ticlopidine twice daily or 75-mg clopidogrel for 6 to 12 months or more. The choice between angiographic and clinical follow-up was at the operator's and referring physician's discretion, but often took into account the patient's preference and comorbidities. Nonetheless, in most cases angiographic follow-up was recommended irrespective of symptoms or signs of ischemia 6 to 12 months after the index PCI. Treatment of restenosis was also completely at the cardiologist's discretion, but usually each case was collectively discussed and the final management decision was based on the patient's symptoms/signs of ischemia, coronary anatomy, surgical risk, PCI feasibility, and overall life expectancy. In case of repeat PCI, the choice of technique and device was also at the interventionist's discretion.
End point definitions and follow-up.
The primary end point of the study was the occurrence of major adverse cardiovascular events (MACE), that is, death, myocardial infarction (MI), or TLR (defined as repeat PCI or CABG for significant restenosis in the previously stented segment or in the adjacent 5 mm). Diagnosis of MI at follow-up was based on peak of total creatine kinase (CK)  2 times the upper limit for normal and a concomitant increase of CK-MB over the upper limit of normal and/or ratio of peak CK-MB/peak total CK 0.10 and/or CK-MB 3 times the upper limit of normal. Stent thrombosis (ST) was adjudicated according to the Academic Research Consortium (5). Data were obtained by direct visits, telephone interviews, and queries of institutional electronic databases, referring physicians, or municipal civil registries.
Statistical analysis.
Continuous variables are expressed as mean ± SD and were compared by analysis of variance or Gosset t test. Categorical variables are presented as counts and percentages, and were compared by chi-square test. The p values unadjusted for multiplicity are reported throughout, with statistical significance set at the 2-tailed 0.05 level. Statistical analyses were performed with SPSS version 12.0 (SPSS, Inc., Chicago, Illinois).
|
Results
|
|---|
Baseline clinical characteristics.
From a total of 718 patients, with follow-up status available in 97.5%, 5.1% died (2.5% suddenly) before 6 months without any angiographic follow-up (Fig. 1). Angiographic follow-up was ultimately performed in 62.8% of subjects, being clinically driven in 16.6% and routinely performed even in the absence of symptoms/signs of myocardial ischemia in 46.2%. Patients undergoing routine angiographic follow-up were significantly younger (74.5 ± 11.0 years vs. 64.0 ± 9.1 years, p < 0.001 at Gosset t test) and had a lower European System for Cardiac Operative Risk Evaluation (EuroSCORE) (5.4 ± 5.9 vs. 2.2 ± 0.7, p < 0.001 at Gosset t test) than those not performing such follow-up.
View larger version (26K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Study Profile
angio = angiographic; CABG = coronary artery bypass grafting; DES = drug-eluting stent(s); PCI = percutaneous coronary intervention; ULM = unprotected left main.
|
|
Restenosis in the ULM after PCI with DES occurred in 70 of 718 patients (9.7%). Of these, 5.7% were treated with medical therapy only, 84.3% by repeat PCI, and 10% underwent CABG (Table 1). The repeat PCI group was characterized by a trend toward a higher prevalence of diabetes (0% vs. 31% vs. 0%, p = 0.10 at chi-square test) but also by higher ejection fraction (43.0 ± 23.4 vs. 53.9 ± 9.5 vs. 45.0 ± 7.1, p = 0.02 at analysis of variance). Globally, 22.1% of restenoses were diagnosed during routine follow-up angiogram and 30.8% had an admission diagnosis of acute coronary syndrome.
Angiographic and procedural characteristics.
Angiographic and procedural characteristics of the first procedure in the ULM (before the diagnosis of restenosis) are reported in Table 2, whereas angiographic and procedural characteristics of the procedure showing the ULM restenosis, that is, 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 strategy, even if PCI was the most common approach in all cases. Specifically, distal ULM disease was managed by PCI in 84.1%, by CABG in 9.1%, and by medical therapy in 6.8%, whereas ostial or shaft disease was managed by PCI in 84.6%, by CABG in 3.9%, and by medical therapy in 11.5% (p = 0.839 at chi-square test comparing distal versus nondistal location). Among the 59 patients treated interventionally (repeat PCI group), 57.6% underwent a new DES implantation. In contrast to the previous baseline procedure, paclitaxel-eluting stents were used predominantly (60.6%), followed by sirolimus-eluting stents (39.4%). Among the 70 restenotic patients, CABG was performed only for in-stent restenosis with no case of CABG for disease progression elsewhere.
View this table:
[in this window]
[in a new window]
|
Table 2 Angiographic and Procedural Characteristics of the First Procedure in the ULM, Before the Diagnosis of Restenosis*
|
|
In-hospital and long-term outcomes.
The immediate outcome was quite favorable (Table 4), with 1 (1.7%) death in the PCI group. No patient had periprocedural MI or needed urgent CABG. Long-term follow-up data were available in 100% of restenotic subjects after an average of 25.6 ± 16.5 months since diagnosis of restenosis (36.7 ± 15.3 months of follow-up from the first PCI with DES in the ULM), with 44.3% of subjects undergoing repeat PCI having repeat angiographic follow-up after 8.1 ± 8.3 months. The MACE rate was 25.7%, with death in 5.7%, MI in 2.9%, TLR in 21.4% (including CABG in 5.7%), and PCI on other vessels in 21.4%. Finally, 1 case of possible ST, 1 case of probable ST, and no cases of definite ST were identified (all in the PCI group).
|
Discussion
|
|---|
Drug-eluting stenting in the ULM has become a common practice in several tertiary care centers. Despite encouraging results, restenosis is still a challenging issue, especially in such a delicate anatomic position. In the scientifically rigorous and randomized SYNTAX (SYNergy Between PCI With TAXUS and Cardiac Surgery) trial, 12-month MACE rates reached 17.8% in the PCI group and 12.1% in the CABG group, with repeat revascularization rates of 13.7% and 5.9% (4). Seung et al. (6) compared in a nonrandomized fashion PCI versus CABG, showing after 33 months that they did not differ significantly for death rates or the composite of death, MI, or stroke. However, DES were associated with higher rates of TLR (9.7% vs. 1.6%). Similar results were also reported by other investigators (3).
Despite the increasing frequency of ULM restenotic cases in clinical practice (as it occurs in up to 16.7% of subjects treated with DES in the ULM) (7) and its important clinical impact, ULM restenosis after PCI with DES has been incompletely characterized. The present retrospective nonrandomized study is the first to evaluate the outcome of such patients. Our major findings evaluating 70 restenotic cases of 718 initial ULM patients are 2-fold: 1) significant ULM DES restenosis is often characterized by a stable clinical condition; and 2) after 24 months of clinical follow-up from the diagnosis of restenosis, MACE rates seem quite favorable in both the interventional and surgical therapy groups.
Almost 70% of patients with a diagnosis of significant DES restenosis in ULM were elective angiographic control subjects or presented with silent ischemia or stable angina, but an unstable presentation of ULM restenosis in over 30% of cases suggests that restenosis is not a benign entity even in the ULM. Nonetheless, repeat PCI is often possible and successful in these subjects. Notably, paclitaxel-eluting stents were used more frequently for repeat PCI, possibly because of availability subsequent to sirolimus-eluting stents, larger sizes, and preference for different DES strategy (8). Regarding the midterm clinical outcome (more than 2 years of median follow-up after the diagnosis of restenosis), this study showed low mortality and MI rates in patients treated by PCI and CABG. Differences in MACE, death, MI, and TLR rates between these 2 groups are, however, limited by the small size of the CABG group, and should be viewed as hypothesis-generating only. It should also be borne in mind that follow-up intervention results are largely dependent on the initial patient characteristics and interventional approach, as, for instance, in our study multiple stents were commonly implanted, limiting the role of subsequent CABG. These findings can also be compared with those reported on DES restenosis in other coronary locations. Specifically, Mishkel et al. (9) reported 12-month rates of death, MI, and TLR of 8.7%, 2.2%, and 30.6%, respectively, in unselected DES restenotic cases.
Study limitations.
This study has several critical limitations, including the retrospective nonrandomized design and the descriptive scope, which leaves ample room for bias in patient and management strategy selection. Thus, comparative data between treatments are hypothesis-generating only. In addition, no blinded adjudication committee was set up, but the risk of data acquisition and adjudication bias was kept to a minimum by relying on hard clinical end points and established definitions. Lack of national registries may lead to underestimations of long-term event rates. However, losses to follow-up were overall lower than 3.0%, thus largely limiting the risk of underestimating the primary end point. Most of the patients had good cardiac systolic function; thus, our findings cannot be directly applied to patients with left ventricular systolic dysfunction. Finally, the study size seems relatively small, especially in comparison with studies on non-ULM restenosis, and as also testified by the large 95% confidence intervals for the primary end point (16.9% to 37.0% for the total population, 15.0% to 85.0% for medical therapy, 16.1% to 37.8% for repeat PCI, and 2.6% to 51.3% for CABG). However, restenosis in the ULM remains uncommon, and only a study pooling several dozen tertiary care centers could provide much larger data than our study.
|
Conclusions
|
|---|
This multicenter, international registry suggests that PCI can be a safe and effective treatment of ULM restenosis after DES implantation.
|
Footnotes
|
|---|
Dr. Biondi-Zoccai has consulted for Boston Scientific, Cordis, Invatec, and Medtronic, and has lectured for Medtronic. Dr. Lee has received lecture fees from Boston Scientific, Bristol-Myers Squibb, and AstraZeneca. Dr. Tobis has received lecture fees from Boston Scientific. Drs. Sheiban, Sillano, and Biondi-Zoccai contributed equally to this work.
|
References
|
|---|
1. Sheiban I, Sillano D, Biondi-Zoccai GG, et al. Current management of unprotected left main coronary artery disease: run-in survey of the RITMO (Registro Italiano sul Trattamento del tronco coMune non protettO) study http://dx.doi.org/10.1016/j.ijcard.2008.05.009Accessed August 4, 2009.2. Takagi T, Stankovic G, Finci L, et al. Results and long-term predictors of adverse clinical events after elective percutaneous interventions on unprotected left main coronary artery Circulation 2002;106:698-702.[Abstract/Free Full Text] 3. Biondi-Zoccai GG, Lotrionte M, Moretti C, et al. A collaborative systematic review and meta-analysis on 1278 patients undergoing percutaneous drug-eluting stenting for unprotected left main coronary artery disease Am Heart J 2008;155:274-283.[CrossRef][Medline] 4. Serruys PW, Morice MC, Kappetein AP, et al. SYNTAX Investigators Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease N Engl J Med 2009;360:961-972.[CrossRef][Medline] 5. Cutlip DE, Windecker S, Mehran R, et al. Academic Research Consortium Clinical end points in coronary stent trials: a case for standardized definitions Circulation 2007;115:2344-2351.[Abstract/Free Full Text] 6. Seung KB, Park DW, Kim YH, et al. Stents versus coronary-artery bypass grafting for left main coronary artery disease N Engl J Med 2008;358:1781-1792.[CrossRef][Medline] 7. Price MJ, Cristea E, Sawhney N, et al. Serial angiographic follow-up of sirolimus-eluting stents for unprotected left main coronary artery revascularization J Am Coll Cardiol 2006;47:871-877.[Abstract/Free Full Text] 8. Cosgrave J, Melzi G, Corbett S, et al. Repeated drug-eluting stent implantation for drug-eluting stent restenosis: the same or a different stent Am Heart J 2007;153:354-359.[CrossRef][Web of Science][Medline] 9. Mishkel GJ, Moore AL, Markwell S, Shelton MC, Shelton ME. Long-term outcomes after management of restenosis or thrombosis of drug-eluting stents J Am Coll Cardiol 2007;49:181-184.[Abstract/Free Full Text]
Related Article
-
Inside This Issue
J. Am. Coll. Cardiol. 2009 54: A27.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
J.-Y. Lee, D.-W. Park, Y.-H. Kim, S.-C. Yun, W.-J. Kim, S.-J. Kang, S.-W. Lee, C.-W. Lee, S.-W. Park, and S.-J. Park
Incidence, Predictors, Treatment, and Long-Term Prognosis of Patients With Restenosis After Drug-Eluting Stent Implantation for Unprotected Left Main Coronary Artery Disease
J. Am. Coll. Cardiol.,
March 22, 2011;
57(12):
1349 - 1358.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Lee, P. Bokhoor, S.-J. Park, Y.-H. Kim, G. W. Stone, I. Sheiban, G. Biondi-Zoccai, D. Sillano, J. Tobis, and D. E. Kandzari
Unprotected Left Main Coronary Disease and ST-Segment Elevation Myocardial Infarction: A Contemporary Review and Argument for Percutaneous Coronary Intervention
J. Am. Coll. Cardiol. Intv.,
August 1, 2010;
3(8):
791 - 795.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Dixon, C. L. Grines, and W. W. O'Neill
The Year in Interventional Cardiology
J. Am. Coll. Cardiol.,
May 18, 2010;
55(20):
2272 - 2286.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. DeMaria, J. J. Bax, O. Ben-Yehuda, G. K. Feld, B. H. Greenberg, J. Hall, M. Hlatky, W. Y.W. Lew, J. A.C. Lima, A. S. Maisel, et al.
Highlights of the Year in JACC 2009
J. Am. Coll. Cardiol.,
January 26, 2010;
55(4):
380 - 407.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods