The Role of Everolimus-Eluting and Resolute Zotarolimus-Eluting Stents in the Treatment of Coronary Bifurcations

Abstract: Objectives. To compare the long-term clinical outcomes of everolimus-eluting (EES) and Resolute zotarolimus-eluting (R-ZES) stents in the treatment of coronary bifurcation lesions. Background. Recent studies have suggested that the R-ZES is comparable to the EES in the treatment of de novo coronary artery disease. Available data on how these compare in the treatment of bifurcation lesions are limited. Methods. We retrospectively analyzed consecutive de novo bifurcation lesions, including left main stem lesions, treated with either EES or R-ZES between October 2006 and October 2011. Study endpoints examined included major adverse cardiac events (MACEs), defined as the composite of all-cause death, myocardial infarction (MI), including periprocedural MI, and target vessel revascularization (TVR). Target lesion revascularization (TLR) per patient and per bifurcation as well as stent thrombosis (ST) were also analyzed. Results. We identified 235 bifurcation lesions treated with either EES (157 lesions in 154 patients) or R-ZES (78 lesions in 73 patients). Baseline clinical and procedural characteristics were broadly similar between the two groups. No significant differences in MACE (14.6% vs 11.5%; P=.99) or TVR (8.0% vs 7.3%; P=.45) rates were noted between the two groups at 2-year follow-up. The incidence of ST was low and similar in both groups (0% vs 1.4%). Conclusions. EES and R-ZES are associated with acceptable and comparable long-term clinical outcomes when used in the treatment of bifurcation lesions. Further evaluation into the role of currently available drug-eluting stents in bifurcation percutaneous coronary intervention is required.

J INVASIVE CARDIOL 2013;25(9):436-440

Key words: coronary bifurcation, everolimus-eluting stent, zotarolimus-eluting stent, stent thrombosis, target vessel revascularization

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Despite advances in percutaneous coronary intervention (PCI) techniques and the introduction of drug-eluting stents (DESs), bifurcation lesions continue to be associated with higher revascularization rates as compared to non-bifurcation lesions.^1-3 Recent randomized trials with second-generation DESs, in particular everolimus-eluting stents (EESs) and zotarolimus-eluting stents (ZESs), have demonstrated excellent results in the treatment of coronary lesions, with no significant differences between EESs and ZESs.^4,5 However, their role in bifurcated lesions remains to be fully evaluated. Herrador et al suggested that EES was superior to ZES in the treatment of bifurcation lesions with regard to clinical outcomes when the provisional T-stent strategy was utilized.⁶ However, in this study, the Endeavor ZES (E-ZES) platform (Medtronic, Inc) was used as opposed to the more efficacious Resolute ZES (R-ZES) (Endeavor Resolute; Medtronic, Inc). Recently, it has been suggested that the R-ZES may be associated with improved performance at bifurcations sites, at least when compared to sirolimus-eluting stents (SESs).⁷ On the other hand, the EES has been shown to be associated with good long-term clinical outcomes when utilized at bifurcations, with results similar to those observed in non-bifurcation lesions.⁸ However, no studies to date, to the best of our knowledge, have compared R-ZES versus EES at bifurcation sites. We thus aimed to examine the long-term clinical outcomes of patients with bifurcated lesions treated with either R-ZES or EES.

Methods

Study population. All consecutive patients with bifurcation lesions, including left main stem lesions, treated with  either EES (Xience Prime and Xience V, Abbott Vascular; or Promus and Promus Element, Boston Scientific) or R-ZES (Endeavor Resolute, Medtronic, Inc) between October 2006 and October 2011 at two centers (San Raffaele Hospital and EMO-GVM Centro Cuore Columbus in Milan, Italy) were included in this study. We thus identified 154 patients treated with EES (157 bifurcations) and 73 patients treated with R-ZES (78 bifurcations). Patients with restenotic or trifurcation lesions, patients treated with a bare-metal stent, as well as patients who received an EES or R-ZES at the same bifurcation site were excluded.

Procedure. Written consent was obtained both for the procedure as well as subsequent data collection and analysis. All patients were pretreated with aspirin and a thienopyridine, either ticlopidine or clopidogrel. A 300 mg loading dose of clopidogrel was administered the day before the index procedure if patients were not pretreated. Intravenous heparin was administered to maintain an activated clotting time >250 seconds during the procedure. Interventional approach and platelet glycoprotein IIb/IIIa receptor inhibitor use were at operator’s discretion. Stent selection was also left to the discretion of the operator. Following the procedure, all patients were prescribed life-long aspirin therapy and either clopidogrel or ticlopidine for at least 6 months as per guidelines.⁹

Clinical definitions and follow-up. Clinical follow-up was performed by telephone contact or office visit. Angiographic follow-up was not encouraged unless clinically indicated. Study endpoints were death, myocardial infarction (MI), target vessel revascularization (TVR), target lesion revascularization (TLR), and stent thrombosis (ST). A major adverse cardiac event (MACE) was defined as the composite of all-cause death, MI, including periprocedural MI, and TVR. TLR was also analyzed separately per patient and per lesion (bifurcation as a whole). All deaths were considered cardiac unless otherwise documented. We defined postprocedural non-Q wave MI as a creatinine kinase-myocardial band (CK-MB) elevation of >3 times the upper limit of normal.¹⁰ CK-MB was routinely measured after PCI in all patients at both centers. Non-procedural or after-discharge MI was defined as an elevation of troponin above the upper range limit in combination with at least 1 of the following: symptoms of ischemia; electrocardiographic changes indicative of new ischemia; or the development of new pathological Q-waves on electrocardiogram. TLR was defined as repeat revascularization in either the main or side branch (SB), secondary to a stenosis ≥50% within the stent, within the 5 mm proximal or distal to the stent edge, or at the site of balloon inflation in the SB. TVR was defined as any repeat revascularization of the target vessel. ST was defined according to the Academic Research Consortium.¹¹ True bifurcations were defined as those with lesions both in the main-branch (MB) and SB >50%. A one-stent strategy refers to a strategy in which a stent was implanted either in the MB or SB, whereas a two-stent strategy involved stenting of both the MB and SB. Procedural success was defined as completion of the procedure with no in-lab complications, final TIMI flow 3 and residual stenosis <20%. All adverse effects were verified by reviewing the medical records of the patients, whether those were followed up at our institutions or elsewhere. 

Statistical analysis. Continuous variables are presented as mean ± standard deviation or median and interquartile range (IQR), and categorical variables as frequency and percentage. The normality of the distribution of all continuous variables was assessed by the Kolmogorov-Smirnov test. Continuous variables were compared by the independent sample t-test or Mann-Whitney U-test. Categorical variables were compared by the Chi-square statistic or Fisher’s exact test. A P-value of <.05 was considered to be statistically significant and all reported P-values are two-sided. Time-to-event curves were generated with the Kaplan-Meier method and compared by the log-rank test. Analyses were carried out using SPSS for Windows, version 19.0 (SPSS, Inc).

Results

Baseline clinical and procedural data. Baseline clinical characteristics are summarized in Table 1. Mean age was 64.9 ± 9.7 years in the EES group and 64.6 ± 9.3 years in the R-ZES group (P=.66). The majority of patients were male in both groups (83.1% vs 84.9; P=.73). There were no significant differences between the 2 groups with regard to their risk factor profile, mode of presentation, or left ventricular ejection fraction. Angiographic and procedural data are presented in Table 2. Bifurcation site was similar in both groups (P=.72). In both groups, a left anterior descending/diagonal branch bifurcation was more commonly treated (54.8% vs 48.7%). The absence of any statistically significant differences in Medina classification, type of lesion, or final kissing balloon inflation (FKBI) suggests analogous bifurcation lesion complexity in the two populations studied. A provisional stent strategy was chosen in approximately two-thirds of the cases (65.0% vs 69.2%). Of the two-stent strategies utilized, the culotte and crush techniques were used most frequently. SB stenting was the result of cross-over from a provisional stent approach in 12.7% of patients treated with EES and in 9.3% of the patients who received R-ZES (P=.42). Reasons for SB stenting were usually branch dissection and suboptimal result following FKBI. As expected, FKBI was more common when a two-stent strategy was utilized (94.9% vs 59.1%; P<.001). 

Clinical outcomes. Clinical outcomes according to stent type and stent strategy (one- vs two-stent) are presented in Tables 3 and 4. None of the procedures were associated with ST or death during the patients’ in-hospital stays. Periprocedural MI was recorded in 11 cases, 7 out of which were treated with a two-stent strategy. In 1 case, this was due to slow flow requiring glycoprotein IIb/IIIa receptor inhibitor infusion. In the remaining 10 cases, no procedural complications were noted and no patient symptoms were reported. The elevation CK-MB in these remaining cases likely reflects procedural complexity. With regard to mortality, 7 all-cause deaths were identified during follow-up, 6 of which were in the EES group (median follow-up, 22.4 months; IQR, 18.2-50.8) and 1 in the R-ZES group (median follow-up, 24.6 months; IQR, 19.8-33.4). Three all-cause deaths were attributed to cardiac causes, 2 of which were due to sudden death (EES group). There was 1 recorded ST-segment elevation MI secondary to subacute (1-30 days) definite ST in a diagonal branch treated with an R-ZES as part of a culotte bifurcation technique. Patient-based analysis did not show any statistical differences in TLR, TVR, or MACE between the EES and R-ZES groups despite slight differences in the two follow-up periods. When TVR was performed, this was the result of documented ischemia in the targeted vessel. A bifurcation-based analysis also did not show any significant differences in TLR between the two DES types (6.4% vs 5.1%; P=.74). Outcome rates for TVR at 2-year follow-up were 8.0% for the EES group and 7.3% for the R-ZES group (P=.45). MACE rates (Figure 1) over the same follow-up period were 14.6% and 11.5%, respectively (P=.99). With regard to stent strategy, no significant differences were noted in MACE (12.6% vs 15.8%; P=.35) and TVR (6.3% vs 9.6%; P=.17) at 2-year follow-up when the overall one- and two-stent strategies were considered.

Discussion 

The results of our study regarding the role of R-ZES and EES in the treatment of bifurcation lesions suggest that both DES types are associated with acceptable and comparable clinical outcomes in terms of TVR (8.0% vs 7.3%; P=.45) and MACE (14.6% vs 11.5%; P=.99) at 2-year follow-up.

Second-generation DESs have proven their safety and efficacy in the treatment of simple and complex coronary artery disease. However, studies comparing different second-generation DESs in bifurcation PCI are limited. In the bifurcation study by Herrandor et al, better clinical outcomes were reported with EES as compared to ZES at 1-year follow-up.⁶ In this study, however, the older-generation E-ZES was used, which markedly differs from the newer and more commonly used R-ZES. The coating of R-ZES is based on the BioLinx polymer system that allows more controlled drug elution as compared to the phosphorylcholine-based polymer of E-ZES. Furthermore, the polymer of R-ZES is considered to be more biocompatible, with less inflammatory and prothrombotic effects. This may explain the results of the Endeavor III (A Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) and Endeavor IV (A Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) trials, in which E-ZES failed to demonstrate clear superiority over the first-generation sirolimus- and paclitaxel-eluting stents.^12,13 In addition, Talarico et al have recently reported that the R-ZES is associated with better clinical outcomes as compared to E-ZES in “real-world” patients.¹⁴ Furthermore, the multicenter, non-randomized RESOLUTE-AC (Randomized, Two-Arm, Non-Inferiority Study Comparing Endeavor-Resolute Stent With Abbott Xience-V Stent) trial comparing R-ZES to EES in a cohort of 2292 patients demonstrated comparable clinical outcomes between the two DES types at 12-month follow-up.⁴ Importantly, in each DES arm, 17% of the lesions treated were at a bifurcation site. The subsequent, randomized TWENTE (The Real-World Endeavor Resolute Versus XIENCE V Drug-Eluting Stent Study in Twente) trial, comparing the same two DESs, confirmed the non-inferiority of R-ZES to EES in treating real-world patients.⁵ In our study, we specifically examined the clinical efficacy of the EES and R-ZES in the treatment of bifurcation lesions. Results suggested that both EES and R-ZES are associated with good clinical outcomes in bifurcation PCI with acceptable MACE and TVR rates at long-term follow-up. DES choice did not seem to impact on clinical outcomes irrespective of bifurcation technique, one- or two-stent strategy, lesion type, and treated vessel. Further studies are required in order to evaluate fully the roles of EES, R-ZES,  and other newly available DESs in bifurcation PCI.

Study limitations. Limitations to our study include its retrospective design, lack of randomization, small patient number, and use of various bifurcation techniques. These factors resulted in some differences in baseline and procedural characteristics between the two groups. Finally, the lack of angiographic follow-up may also be considered to be a limitation since this does not allow us to compare late lumen loss at a bifurcation site, which may be important when evaluating newer-generation DESs. 

Conclusions

Our study suggests that both EES and R-ZES are associated with acceptable and comparable long-term clinical outcomes when used in the treatment of bifurcation lesions.  Further studies are required in order to evaluate further the role of currently available DESs and how these compare in bifurcation PCI.

References

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*Joint first authors.

From the ¹Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy, ²Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy, and ³Imperial College London, London, United Kingdom.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted March 19, 2013, provisional acceptance given April 8, 2013, final version accepted May 6, 2013.

Address for correspondence: Azeem Latib, MD, EMO-GVM Centro Cuore Columbus, 48 Via M. Buonarroti, 20145 Milan, Italy. Email: info@emocolumbus.it