Procedural and Clinical Evaluation of the Novel Zotarolimus-Eluting Resolute‚Ñ¢ Stent in Patients with Unselected Bifurcated Coronary Stenosis Treated by Provisional Approach: A Multicenter Registry
ABSTRACT: Aims. As data on the use of the latest-generation drug-eluting stents (DES) in bifurcation interventions are lacking, we realized a multicenter registry to assess the procedural and clinical results obtained in patients with unselected bifurcated lesions treated with the novel zotarolimus-eluting Resolute stent (ZRS). Methods and Results. Three Italian centers participated in the study. Consecutive patients with significant stenosis of bifurcated lesions undergoing DES implantation were treated with ZRS. The recommended technique was the “provisional TAP approach” [main-vessel (MV) stent implantation eventually followed by kissing balloon and sidebranch (SB) stenting according to TAP technique]. Clinical characteristics, procedural details and clinical follow-up data were prospectively recorded. Procedural success was defined as post-percutaneous coronary intervention visual stenosis Conclusion. The use of the latest-generation ZRS in unselected bifurcated lesions treated by a provisional approach is associated with excellent procedural results and with promising clinical outcomes.
Bifurcations are complex target coronary lesions in which the adoption of the most suitable treatment technique and selection of the most appropriate coronary stent are of primary importance. An important amount of clinical evidence suggests that drug-eluting stent (DES) implantation using a provisional-T-stenting approach is the gold standard for unselected bifurcated lesions.1 Yet, since various DES types have major differences in platform, polymer system and drug, procedural and clinical outcomes in bifurcation interventions may be influenced by stent selection.2,3
Recently, the novel, zotarolimus-eluting Resolute stent (ZRS) (Medtronic, Inc., Minneapolis, Minnesota) has been released and tested in clinical trials that observed promising angiographic and clinical results.4–6 Interestingly, the ZRS, besides its latest-generation drug-elution technology,7 has a platform design characterized by features (side-cell size, shape and deformability)8,9 which may theoretically facilitate the performance of bifurcation interventions by the provisional approach. In this study, we sought to assess in a prospective multicenter registry the procedural and clinical results obtained in patients with unselected bifurcated lesions treated by the ZRS using a systematic provisional approach strategy.
Methods
Consecutive patients with documented coronary artery disease undergoing percutaneous coronary intervention (PCI) on bifurcated lesions in 3 Italian hospitals were prospectively enrolled in the study. Angiographic criteria to define bifurcated lesions were: visual stenosis > 70% in a major bifurcation point, with main vessel (MV) visual diameter > 2.5 mm and sidebranch (SB) visual diameter > 2.0 mm. Exclusion criteria were: ST-elevation myocardial infarction (STEMI) within the 24 hours prior and possible limited compliance with double antiplatelet therapy. During the study period, all bifurcated lesions scheduled for DES implantation were treated with ZRS, except for patients with exclusion criteria.
Medications. Patients were treated with heparin (initial intravenous bolus of 5,000 U followed by further boluses to obtain an activated clotting time of 250–300 seconds), double antiplatelet therapy with aspirin (75–160 mg/day) and clopidogrel (loading dose of 300 mg, followed by 75 mg/day) for at least 12 months. Administration of glycoprotein IIb/IIIa inhibitors was performed on the basis of operator discretion.
PCI technique. PCI was performed mainly by the transradial approach (with the transfemoral approach alternatively selected according to operator preference) and was attempted according to a provisional TAP stenting technique (systematic provisional stenting with eventual T stenting according to the T And Protrusion technique).10 The steps of this technique have previously been described in detail.11 Briefly, the MV was wired first, followed by the SB with two 0.014-inch coronary guidewires. Predilatation of both the MV and SB was performed according to operator preference or after direct stenting failure. The MV was stented with ZRS. MV post-dilatation and kissing balloon were performed if necessary (due to impairment of SB flow) or according to operator preference. When the operator was not satisfied with the achieved result, a second stent was implanted in the SB according to the TAP stenting technique.10
Stent characteristics. The ZRS is a next-generation, zotarolimus-eluting stent with a low profile and the same platform as the Driver BMS stent. It contains the same concentration of zotarolimus (1.6 mcg/mm2) as the Endeavor stent. The strut thickness is 0.0036 inches. The new polymer coating of the ZRS stent is the BioLinx system and consists of a unique blend of 3 different polymers, a hydrophilic C19 polymer, a water-soluble polyvinyl pyrrolidinone polymer and a hydrophobic C10 polymer. The hydrophilic surface mimics the body’s biological chemistry, reducing the risk of an inflammatory response. These polymers are designed to provide extended drug release, with complete drug elution by 180 days.
Recent data from micro-CT analysis showed that the dilation of the ZRS side cells may allow it to reach a maximal diameter of 6.3 mm and a maximal cell circumference of 19.8 mm,9 thus suggesting a major facilitation of the provisional approach (by theoretically providing appropriate SB ostium patency and scaffolding) across a large variety of SB sizes and take-off angles.
Laboratory tests. All patients underwent pre-PCI sampling for cardiac enzyme assessment (troponin T; creatine-kinase MB, and total creatine-kinase) and baseline electrocardiogram (ECG). After the procedure, patients underwent ECG evaluation and 6-hour and 18–24-hour sampling for troponin T. Further ECG and blood sampling (with eventual evaluation of other cardiac enzyme assessment) were performed only in patients with clinical suspicion of myocardial infarction.
Procedural parameters. According to the study protocol, the following series of technical details of the bifurcation intervention were prospectively reported: MV direct stenting; SB re-wiring attempt; SB re-wiring successful performance; kissing balloon dilatation attempt; kissing balloon dilatation successful performance; SB stent implantation; and final kissing balloon performance after SB stenting.
Study endpoints and definitions. Primary endpoint was major adverse cardiac event (MACE)-free survival at 9-month follow-up, defined as freedom from cardiac death, myocardial infarction (MI) and target vessel revascularization (TVR). The secondary endpoint of the study was procedural success, defined as post-PCI visual stenosis
Cardiac death was defined as any death without clear non-cardiac death. MI was defined as any increase in serum creatine-kinase MB above 99th percentile of the upper reference limit with ST segment or T-wave modifications in at least 2 contiguous leads (ST-elevation MI: > 0.1 mV ST elevation, non ST-elevation-MI: > 0.1 mV ST depression, or T-wave modification) associated with typical angina.
Post-procedural myonecrosis was defined as any increase of troponin T in patients with normal pre-PCI levels or as an increase > 3 times in patients with abnormal baseline levels. However, according to the study protocol, post-procedural myonecrosis was not considered MI in the absence of typical symptoms and/or significant ECG modification.
Stent thrombosis was defined according to ARC definitions12 as “definite” (angiography- or autopsy-confirmed ST), “probable” (any unexplained death within the first 30 days or any myocardial infarction in the territory of the stent and in the absence of any other obvious cause) or “possible” (any unexplained death after 30 days).
All patients were followed by control visit or by telephone interview. Control angiography and eventual repeat revascularization were clinically driven (in the presence of symptoms and/or stress-inducible ischemia).
Statistical analysis. All analyses were made on an intention-to-treat basis. Continuous variables (presented as means ± standard deviations) were compared by paired T, Wilcoxon and Mann-Whitney U tests as appropriate. Chi-square tests (Fisher corrected when appropriate) were used to compare discrete variables (reported as raw numbers and percentages). Analyses were carried out using SPSS for Windows 13.0 (SPSS, Inc., Chicago, Illinois). Statistical significance was defined by two-tailed p
Results
From September 2008 to November 2009, a total of 180 consecutive patients were enrolled in the study.
The main clinical and pre-procedural characteristics are reported in Table 1. Briefly, the 
mean age was 66.4 years and 66.1% were male. Twenty-nine percent of patients were diabetic and 62.8% presented with an acute coronary syndrome. The target bifurcation was located in an unprotected left main in 16.7% of patients and on the left anterior descending/diagonal branch bifurcation in 52.2%. A Medina classification 1,1,1, was present in 36.1% of target lesions, while in 57.8% of cases there was a significant involvement of the SB ostium (Table 2).
The characteristics of the procedure are reported in Table 2. Procedures were performed 
mainly through radial access (Table 2) using 6 Fr guiding catheters (in 5.7% of procedures, only a 7–8 Fr guiding catheter was used). The provisional TAP approach was applied in the majority of patients, as only 3 patients (1.7%) were treated with a different technique (Table 2).
Direct stenting on the MV was successfully performed in 27.2% of the cases, while in the remaining predilatation was deemed necessary. SB rewiring was performed in 134 patients (74.4%) and it was successful in all but 1 case (1 failure to rewire the SB in a patient with pre-intervention subocclusive SB stenosis and asymptomatic SB occlusion after MV stenting due to collateral distal filling). Kissing-balloon inflation was attempted and successfully performed in 68.9% of the patients after MV stenting. SB stent implantation using the TAP technique was performed in 16 patients (8.9%) and was always followed by final kissing-balloon inflation.
The procedural success rate (secondary endpoint) was 98.3%. Indeed, an optimal angiographic result (no visual residual stenosis, TIMI flow grade 3) was achieved in all patients in the MV, while in 3 patients the post-PCI SB flow was
A post-procedural myonecrosis according to routine troponin T assessment was detected in 36 patients (18%); it was clinically silent in all cases and didn’t influence the hospital course.
At 9-month follow-up, MACE-free survival (primary endpoint) was 97.8% (Table 3). The observed MACE were: 1 cardiac death (a patient with non-ST elevation MI complicated by cardiogenic shock died 2 days after PCI on the distal left main), and 3 TVR by repeat PCI. In particular, the TVR were necessary to treat: 1 patient (with MV stent only) presented at 6 months with 
focal in-stent restenosis in the MV after elective PCI on the left main bifurcation; 1 patient (with stent on both the MV and SB) presented at 2 months with atherosclerotic disease progression proximal to the MV stent after double stenting on the left anterior descending artery/diagonal bifurcation; and 1 patient (with MV stent only) presented at 8 months with focal in-stent restenosis after elective PCI on the left circumflex/obtuse marginal. No definite, probable or possible stent thromboses were observed during the study.
Discussion
The present multicenter registry assessing the procedural performance and 9-month clinical outcomes of unselected bifurcated lesions by a systematic provisional TAP approach with the novel ZRS shows excellent procedural results and promising clinical outcomes. No previous study specifically addressed the outcome of bifurcated lesions treated with this latest-generation DES.
Bifurcations are complex target coronary lesions in which the adoption of the most suitable treatment technique and the selection of the most appropriate coronary stent are of primary importance.13 An important amount of clinical evidence suggests that DES implantation using a provisional T-stenting approach is the gold standard for unselected bifurcated lesions.14 However, as the provisional approach is in some cases associated with the need to stent (as a bail-out procedure) the SB, operators using the systematic provisional approach should be familiar with an effective SB stenting technique. We previously reported the feasibility and safety of a systematic provisional approach strategy characterized by the eventual implantation of the SB stent according to the TAP technique with different DES.10 This technique is practical,15 provides ostium coverage, warrants final kissing balloon inflation performance,10 and has been shown to offer promising clinical,10,11,16–18 angiographic,16–18 and ultrasound17 results.
As the treatment of bifurcated lesions with DES is a challenging technical field in which major distortions (an opening of the stent cell to obtain an optimal coverage of SB ostium) of the stent are needed to cover the lesions, the search for the best stent for bifurcated lesions is actually ongoing. Indeed, across the different types of available DES, major differences in the platform, polymer system and drug do exist,8,9 and may influence procedural and clinical outcomes in bifurcation interventions. For instance, we recently observed and reported different clinical outcomes in patients treated by a provisional TAP approach with different DES of the “-limus” family,19 thus supporting the possible relevance of DES selection in bifurcated lesions.
The ZRS is based on a unique platform design which may theoretically facilitate the performance of the provisional approach9 and incorporates a latest-generation drug-eluting technology7 with promising clinical results in the first study in which bifurcated lesions were excluded.4,5 Very recently, the Resolute All Comers trial showed for ZRS equivalent clinical results compared with the everolimus-eluting stent in mainly off-label indications.6 Even if bifurcated lesions were involved in such a trial,6 no previous studies have specifically assessed the procedural and clinical performance of the ZRS stent in the setting of bifurcated lesions, and thus the present registry may provide original insights. Despite the overall high-risk profile (high rate of unstable presentation, diabetes and multivessel disease) of the enrolled patients (which probably reflect the real-world case mix better than randomized trials), the procedural performance was excellent, with a very high rate of success in each step of the provisional approach and a low rate of angiographic failure. Moreover, the 9-month MACE-free survival was impressively high and, together with the absence of stent thrombosis events, suggests that a systematic provisional approach (with a low rate of SB stenting implanted according to the TAP technique) using the latest-generation DES, like the ZRS, may represent a safe and effective approach to treat unselected bifurcated lesions.
Study limitations. Our study presents a series of important limitations. First, the nonrandomized design of the registry, without a selected control group to compare the procedural and the clinical results obtained, does not allow us to draw definitive conclusions about the use of ZRS in coronary bifurcated lesions. Moreover, the study was conducted in 3 high-volume centers so that a restricted number of experienced operators very familiar with the provisional approach was involved.
Regarding the angiographic outcome, no quantitative coronary angiography analysis has been performed and coronary angiography has been performed only in the presence of recurring symptoms or documented myocardial ischemia; therefore, no data regarding the restenosis rate in patients who are asymptomatic or have no documented ischemia can be derived.
Finally, the clinical follow-up is relatively short, as only 9-month results have been investigated (and patients have been recommended to maintain double antiplatelet therapy until 1 year post-PCI).
Conclusion
In this prospective, multicenter registry, the ZRS showed excellent procedural performance and promising clinical results at 9 months in patients with bifurcated lesions undergoing PCI according to a systematic provisional approach.References
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