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Three-year major clinical outcomes of phosphorylcholine polymer- vs biolinx polymer-zotarolimus-eluting stents

Supplemental Digital Content is available in the text


Introduction
Compared to bare-metal stents (BMS), drug-eluting stents (DES) have reduced target lesion revascularization (TLR) by inhibition of neointimal hyperplasia but increased the risk of fatal stent thrombosis which a major concern. [1,2] Medtronic Vascular (Santa Rosa, CA., USA) and Abbott Laboratories (Abbott Park, Chicago, IL, USA) has developed a new stent, the zotarolimuseluting stent (ZES; Endeavor), combining the approved Driver chromium-cobalt-nickel alloy coronary stent system with an antiproliferative agent, zotarolimus, and a biomimetic phoshorylcholine (P)-polymer. [3] Zotarolimus is equivalent to sirolimus in terms of antiproliferative power but is more lipophilic compared with sirolimus. [4,5] This P-polymer system induced a 75% zotarolimus release within 2 days. In contrast, BioLinx (B)-polymer with more delayed zotarolimus release (50% and 85% released at 7 and 60 days, respectively) and over approximately 180 days after percutaneous coronary intervention (PCI). [6,7] The B-polymer system was developed to decrease restenosis and maintain low stent thrombosis (ST) rates by means of sustained longer duration zotarolimus release. [8] The Endeavor sprint (ZES-S) and the everolimus-eluting stent (Xience stent V; EES) showed similar good results in the treatment of coronary artery disease (CAD). [9,10] The Endeavour Resolute (ZES-R) and the Resolute Integrity (ZES-I) ZES utilize identical polymers (B polymer) and anti-proliferative agents and differ only in their respective strut design, and the clinical performance and safety were similar between ZES-R and ZES-I. [11] Many previous studies compared the efficacy and safety among different classes of DES. [12,13] However, there are limited longterm clinical outcome data comparing the clinical outcomes among the same class of DESs, especially according to different type of polymer system in patients who underwent successful PCI. The aim of this study was to compare the efficacy and safety of B-ZES with P-ZES in patients who underwent PCI during 3-year clinical follow-up periods.

Study design and population
This study is a single-center, retrospective, all-comers registry designed to reflect the "real world" practice since 2004. Data were collected by a trained study-coordinator with a standardized case report form. This study has been examined and approved by the local ethics committee insuring that the subjects gave informed written consent. This study has been performed in accordance with the ethical standards laid down in the 1964 declaration of Helsinki. From January 2004 to December 2014, a total of 4041 patients underwent PCI (Fig. 1). Among above 4 kinds of ZES (Table 1), 2 kinds of ZES (ZES-E and ZES-S) had the same polymer system (P-polymer) and the same stent platform (Driver BMS) but different stent delivery balloon catheter system (TrueStream vs Sprinter). The other 2 kinds of ZES (ZES-R, ZES-I) had the same polymer system (BioLinx, B-polymer) and different stent platforms (Driver BMS vs Integrity) and different stent delivery balloon catheter system (Sprinter vs Micro-Trac). In this study, we classified the above 4 ZES according to the types of polymer system such as P-ZES (ZES-E and ZES-S) and B-ZES (ZES-R, ZES-I). The exclusion criteria are shown in Figure 1.

PCI procedure and medical treatment
A diagnostic coronary angiography (CAG) and PCI were done through either the femoral or the radial artery after an administration of unfractionated heparin (70-100 IU/kg). Patient's activated clotting time was maintained above 250 seconds during the procedure. All patients received a loading dose of 200 to 300 mg aspirin and 300 to 600 mg of clopidogrel as dual antiplatelet therapy (DAPT) and were maintained with 100 mg of aspirin and 75 mg of clopidogrel. The use of cilostazol (Pletaal, Otsuka Pharmaceutical Co., Tokyo, Japan) or platelet glycoprotein IIb/IIIa receptor blockers was left to the discretion of the individual operators. After stent implantation, DAPT (100-mg daily aspirin and 75 mg daily clopidogrel) was prescribed for at least 12 months. During hospitalization, the enrolled patients had taken cardiovascular beneficial medications, including aspirin, clopidogrel, cilostazole, beta-blockers (BB), angiotensin converting enzyme inhibitors (ACEI), or angiotensin receptor blockers (ARB), calcium channel blockers (CCB), diuretics, and lipid lowering agents. After discharge, the patients were encouraged to stay on the same medications that they received during hospitalization.

Study definitions and clinical follow-up
The recording of cardiovascular risk factors and past medical histories were based on the patients' self-report. The primary endpoint was the occurrence of major adverse cardiac events (MACE) defined as total death, non-fatal myocardial infarction (MI), TLR, target vessel revascularization (TVR), non-TVR, and the secondary endpoint was ST. All deaths were classified as cardiac or non-cardiac death. Non-fatal MI was defined as the presence of clinical symptoms, electrocardiographic changes, or abnormal imaging findings of MI, combined with an increase in the creatine kinase myocardial band fraction above the upper normal limits or an increase in troponin-T/troponin-I to greater than the 99th percentile of the upper normal limit. [14] TLR was defined as a revascularization of the target lesion due to restenosis or re-occlusion within the stent or 5 mm in and adjacent of the distal or proximal segment. TVR was defined as a revascularization of the target vessel or any segment of the coronary artery containing the target lesion. Non-TVR was defined as a revascularization of any segment of the non-target coronary artery. Multivessel disease was defined as the presence of a lesion with >50% diameter stenosis in a non-target vessel by visual estimation. ST was defined as acute (0-24 hours), subacute (24 hours-30 days), late (30 days-1 year) and very late (>1 year) according to the onset time of stent thrombosis. [15] The participants were required to visit the outpatient department of cardiology at the end of the first month and then every 3 to 6 months after the index PCI procedure and we followed-up on the clinical data of all enrolled patients through face-to-face interviews at regular outpatient clinic, medical chart reviews, and telephone contacts. Therefore, all enrolled patients finished their follow-up program.

Statistical analysis
All statistical analyses were performed using SPSS 20 (SPSS Inc., Chicago, IL, USA). For continuous variables, differences between the 2 groups were evaluated with the unpaired t test or Mann-Whitney rank test. Data were expressed as mean ± standard deviations. For discrete variables, differences were expressed as counts and percentages and analyzed with x 2 or Fisher exact test between the groups as appropriate. To adjust for any potential confounders, propensity score matching (PSM) analysis was performed using the logistic regression model. We tested all available variables that could be of potential relevance; gender (men), age, left ventricular ejection fraction (LVEF), stable angina, unstable angina, STEMI, NSTEMI, coronary artery disease (CAD) risk factors, chronic kidney disease, laboratory findings, and post-PCI medications. Angiographic and procedural characteristics were also considered as covariate, such as target vessel, American College of Cardiology (ACC) /American Heart Association (AHA) B1/B2/C lesions, extent of CAD, ostial lesion, bifurcation lesion, heavy calcified lesion, diffuse long lesion (>30 mm), small vessel disease ( 2.25 mm), mean total stent length, mean stent diameter, number of stents/patient, total procedure time. The logistic model by which the propensity score was estimated showed a good predictive value (C statistic = 0.730). Subjects were matched with a caliper width equal to 0.01. Various clinical outcomes were estimated with the Kaplan-Meier method, and differences between the 2 groups were compared with the log-rank test. Proportional hazard models were used to assess the hazard ratio of the P-ZES compared with B-ZES adjusted PS. For all analyses, a 2-sided P < .05 was considered statistically significant. Table 2 shows baseline clinical and angiographic characteristics. Before PSM adjustment, the mean age and gender distribution was also similar between the 2 groups. The level of LVEF (55.1 ± 8.6% vs 51.3 ± 10.5%, P < .001), the number of diabetic patients, ACC/AHA type B2 lesion, 3-vessel disease, and stents per each patient were significantly higher in the B-ZES compared Table 1 Characteristics of 4 kinds of zotarolimus-eluting stents. with P-ZES. In contrast, the number of previous PCI, ACC/AHA type C lesion, 1-vessel disease, and mean total stent diameter were significantly higher in the P-ZES group than B-ZES. However, all of these differences disappeared after PSM analysis.

Post-PCI medications
Supplemental Table 1, http://links.lww.com/MD/D162 shows post-PCI medications between the 2 groups. Before and after PSM analysis, the description rates of all drugs (aspirin, clopidogrel, cilostazole, BB, ACEI, ARB, CCB, diuretics, lipid lowering agents) were similar between the 2 groups. Table 3 shows clinical outcomes at 30 days, 1 year and 3 years for the 2 groups. During month 1, the incidences of MACE and ST were not significantly different between the 2 groups. At 1 year, although the incidence of MACE was significantly higher in the P-ZES group before PSM, the incidence of MACE was similar between the 2 groups after PSM. The incidence of ST was not significantly different between the 2 groups before and after PSM. The incidences of TLR and TVR were significantly higher in the P-ZES group compared with the B-ZES group before PSM. However, these differences in TLR and TVR were also similar after PSM. At 3 years, the cumulative incidences of MACE Values are mean ± SD or n (%). The P values for continuous data were obtained from analysis of variance. The P values for categorical data were obtained from chi-square test. ACC/AHA = American college of cardiology/American heart association, B = BioLinx, CK-MB = creatine kinase myocardial band, CRP = C-reactive protein, HDL = high-density lipoprotein, LDL = low-density lipoprotein, LVEF = left ventricular ejection fraction, MI = myocardial infarction, P = phosphorylcholine, PCI = percutaneous coronary intervention, ZES = zotarolimus-eluting stents.  Table 4). The incidences of TLR and TVR were also higher in the P-ZES group compared with the B-ZES group before PSM. After PSM, the 3-year cumulative incidences of TLR and TVR were similar between the 2 groups. Figure 2 shows Kaplan-Meier curved analysis of MACE-free survival, TLR, TVR, and ST at 3-year according to the kinds of polymers (P-polymer vs B-polymer). Figure 3 shows subgroup analysis for MACE up to 3 years. In the cases of male, hypertension, no history of dyslipidemia, not long stent (mean length < 30 mm), ACC/AHA lesion type C, the choice of B-ZES may be preferred rather than P-ZES to reduce MACE after index PCI.

Discussion
This "real-world" all-comers analysis study showed 1. the cumulative incidences of MACE, total death, MI, and total revascularization were similar between P-ZES and B-ZES after PSM during a 3-year follow-up period; and 2. the incidences of ST also were not significantly different between the 2 groups.
These results suggest these P-ZES and B-ZES are equally effective in the treatment of CAD in all-comers regarding the kinds of polymer.

Zotarolimus-eluting stent (ZES)
In April 2003, the sirolimus-eluting stent (SES, Cypher, Cordis Corp., Miami Lakes, Florida) and in March 2004, paclitaxeleluting stents (PES, Taxus, Boston Scientific, Natick, Massachusetts) were approved by the U.S. Food and Drug Administration (FDA). [16] Four years later, ZES-E received FDA's approval and was used widely in clinical practice. [17] Until recently, a total of 5 kinds (ZES-E, ZES-S, ZES-R, ZES-I, and ZES-Resolute Onyx) of Because we wanted to evaluate long-term major clinical outcome in all-comers, among these 5 kinds of ZES, ZES-Resolute Onyx was excluded due to the launching date (April, 2015) was so late in Korea. The Endeavor stent is a cobalt-based alloy stent with a P-polymer loaded with zotarolimus at dose a concentration of 10 mg/mm stent length. P-polymer is a durable polymer composed of hydrophilic monomers is similar to the outer membrane of a red blood cell (90% of phospholipids in the outer membrane of a red blood cell including the phosphorylcholine head group). [5] The B-polymer coating system is composed of 3 different components such as a hydrophilic C19 component, hydrophobic C19 components, and a water soluble polyvinyl pyrrolidinone component which offers potentially improved biocompatibility and extended release of zotarolimus with 85% of drug being released within 60 days and the remainder up to 180 days. [18] In this study, we could not precisely explain the reason for the differences of TLR and TVR rates between ZES-S and ZES-I or ZES-S and ZES-R, the possible mechanisms may be the differences in the types of polymer or stent platform as shown in Table 1. Therefore in this aspect, we can suggest that Bpolymer may be more beneficial than P-polymer to reduce TVR.

Studies concerned with P-ZES
In the ENDEAVOR II study, [19] ZES-E showed improved clinical outcomes and sustained safety compared with Driver BMS in the aspects of target vessel failure (TVF, 15.4% vs 24.4%), TLR (7.5% vs 16.3%), TVR (10.7% vs 20.1%), and MACE (15.4% vs 24.6%). In the ENDEAVOR II study, 1-year TLR rate of ZES-E was 5.9% and TVR rate of ZES-E was 7.5% these rates were comparable with the results of our study. One-year TLR rate of P-ZES was 5.8% and TVR rate of P-ZES was 7.3% in our study after PSM (Table 3). Eisenstein et al [20] reported 3-year comparative results between ZES-E and SES from the ENDEAV-OR III trial. In their study, ZES-E showed reduced 3-year rates/ 100 subjects of death or MI (3.9 vs 10.8; difference, À6.9; 95% CI: À13.0 to 0.8; P = .028) but similar TVR rates compared with SES. (17.9 vs 12.2; difference, 5.7; 95% CI: À3.7 to 15.1; P = .23). Although ZES-E showed better outcomes compared with SES in the ENDEAVOR III study, in the SORT OUT III study, [21] the MACE rate was higher in patients treated with ZES-S than in patients treated with SES (148 [12.9%] vs 116 [10.1%]; HR,1.33; 95% CI, 1.04-1.69; P = .022) and the TVR rate was also higher in the ZES-S group compared with the SES group (103 [9.1%] vs 76 [6.7%]; HR, 1.40; 95% CI, 1.04-1.89; P = .025). In our study, 3-year the MACE rate of P-ZES was 13.8% and TVR rate of P-ZES was 9.1% after PSM. These results of our study also are comparable with the results of the SORT OUT III study.

Comparative studies between P-ZES and B-ZES
Tada et al [24] demonstrated comparable 2-year clinical outcome results between ZES-R and ZES-E. In their study, the incidence of Table 4 Three-year clinical outcomes by Kaplan-Meier Curved analysis and cox-proportional Hazard ratio model analysis.

Cumulative events at 3 years (%)
Outcomes  [25] reported that ZES-E had better neointimal coverage and more stable than ZES-I by angioscopic comparisons. Sim et al [26] suggested that there were similar cumulative incidence of MACE between the ZES-S and ZES-R during 1-year follow-up period. In our study, the cumulative incidence of MACE between P-ZES and B-ZES was also similar before and after PSM during a 3-year follow-up period.

Stent thrombosis
ST is another debatable issue in the DES era. In the ENDEAVOR II study, definite and probable very late ST rate of ZES-E was 0.2% during 5-year follow-up period. [19] In the SORT OUT III [21] study, the incidence of very late ST was 0% in ZES-S. In the TWENTE II trial, [22] the incidence of definite or probable ST of ZES-I was 1.4% during a 3-year follow-up. According to 5-year follow-up result from the ENDEAVOR IV trial, [27] the overall definite/probable ST rate of ZES-E was 1.3% and very late stent thrombosis of ZES-E was 0.4%. In this study, the 3-year overall definite/probable ST rate of P-ZES was 1.8% and very late ST rate of P-ZES was 0%. The very late ST rate of P-ZES in this study was similar with the result of SORT OUT III study.

Others
There are limited long-term clinical outcome data comparing the clinical outcomes among the same class of DES, especially according to different types of polymer systems and the kinds of DES in patients who underwent successful PCI. Therefore, we think that our results provide useful clinical outcome information and trends between P-ZES and B-ZES in patients who underwent PCI during very long-term follow-up periods in the DES era. Finally, findings of this study support the notion that modern DES platforms are nowadays very similar in terms of their efficacy and safety, and further improvements in PCI care will depend on the operator experience, more use of advanced intravascular imaging and patient-oriented individualized approach with post-PCI pharmacotherapy.

Limitations
This study has some limitations. First, because it is a nonrandomized registry design and single center study, several confounding factors such as under-reporting and/or missing value and selection bias may have affected the end results. Second, although PSM analysis and subgroup analysis was done, the proportion of each stents in both groups were not evenly distributed and this method also have some limitations to select appropriate population. Third, the strategy of antiplatelet therapy (e.g., DAPT or triple antiplatelet therapy [TAPT]) was left to the physician's discretion, which may have influenced the major clinical outcomes. Fourth, because the selection of specific type of ZES was depends on physicians' discretion, this may can be a bias of this study. Fifth, this study enrolled only Korean patients; the present results may not be generalizable to all other ethnicities in different parts of the world. Sixth, 9 operators were participated in this study. However, the operators' skills and experiences for PCI were mostly similar but may be different to some degree in particular complex patients and complicated lesion subset such as chronic total occlusion (CTO) lesion. Therefore, these operators' factor may act as bias. Seventh, in this study, the use of intravascular ultrasound (IVUS), optical coherence tomography (OCT), and fractional flow reserve (FFR) in addition to CAG to improve post-PCI outcomes were very low (<10%) due to cost issue. In Korea, currently there is no reimbursement program for IVUS or OCT and FFR is partially available under very limited indications during PCI. Only left main bifurcation or CTO PCI was mainly recommended to use image-guided (IVUS or OCT) or functional study-guided (FFR) for stent optimization. Therefore most physicians' decision for PCI was depend on angiographic findings and clinical information under "real-world clinical practices." Hence, this inter-rater variability could be an important limitation of this study. Although relatively lower rates of imaging or functional studies,  .826 .220 .063 non-randomized design and single center study, this study may be meaningful because we tried to reflect "real world" clinical practice with longer follow-up duration.

Future directions
Although P-ZES and B-ZES showed comparable safety and efficacy, this result may be more precisely defined by future randomized controlled trials or large scale registry studies with long-term follow-up to get final conclusion.
In conclusion, in this single-center, all-comer registry, despite different polymers, P-ZES, and B-ZES showed comparable safety and efficacy during a 3-year follow-up period after PCI.