This “real-world” all-comers analysis study showed
- 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
- 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.
4.1 Zotarolimus-eluting stent (ZES)
In April 2003, the sirolimus-eluting stent (SES, Cypher, Cordis Corp., Miami Lakes, Florida) and in March 2004, paclitaxel-eluting stents (PES, Taxus, Boston Scientific, Natick, Massachusetts) were approved by the U.S. Food and Drug Administration (FDA). Four years later, ZES-E received FDA's approval and was used widely in clinical practice. Until recently, a total of 5 kinds (ZES-E, ZES-S, ZES-R, ZES-I, and ZES-Resolute Onyx) of ZES were developed by Medtronic Vascular (Santa Rosa, CA., USA) and Abbott Laboratories (Abbott Park, Chicago, IL, USA). 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 μg/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). 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. 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 B-polymer may be more beneficial than P-polymer to reduce TVR.
4.2 Studies concerned with P-ZES
In the ENDEAVOR II study, 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 reported 3-year comparative results between ZES-E and SES from the ENDEAVOR III trial. In their study, ZES-E showed reduced 3-year rates/100 subjects of death or MI (3.9 vs 10.8; difference, −6.9; 95% CI: −13.0 to 0.8; P = .028) but similar TVR rates compared with SES. (17.9 vs 12.2; difference, 5.7; 95% CI: −3.7 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, 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.
4.3 Studies concerned with B-ZES
Di et al reported the comparative safety and efficacy of ZES-R vs ZES-I. In their report, the rate of MACE (ZES-R [3.2%] vs ZES-I [5.0%], P = .43, HR, 1.37; 95% CI, 0.46–4.07, P = .57), mortality rate, non-fatal MI were similar between the 2 groups during 3-year follow-up period. In TWENTE II trial, ZES-I showed similar clinical outcomes compared with PROMUS Element EES (TVR, 6.0% vs 6.2%, Log-rank P = .87; TVF, 10.7% vs 10.3%, Log-rank P = .77). Piccolo et al also reported that ZES-R and EES provide similar safety and efficacy in patients undergoing PCI (TVR, risk ratio [RR], 1.06; 95% CI, 0.90–1.24; P = .50).
4.4 Comparative studies between P-ZES and B-ZES
Tada et al demonstrated comparable 2-year clinical outcome results between ZES-R and ZES-E. In their study, the incidence of TLR was 12.0% in the ZES-R group and 16.0% in the ZES-E (HR, 0.72; 95% CI, 0.52–1.00; P = .052). Also, the incidence of cardiac death or MI was not different between the 2 groups (5.5% vs 4.8% [HR, 1.15; 95% CI, 0.66–2.02; P = .62]). More recently, Nishimoto et al reported that ZES-E had better neointimal coverage and more stable than ZES-I by angioscopic comparisons. Sim et al 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.
4.5 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. In the SORT OUT III study, the incidence of very late ST was 0% in ZES-S. In the TWENTE II trial, 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, 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.
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.
This study has some limitations. First, because it is a non-randomized 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, 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.
4.8 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.
Conceptualization: Yong Hoon Kim, Ae-Young, Seung-Woon Rha, Tae Soo Kang, Jihun Ahn, Sang-Ho Park, Ji Young Park, Min-Ho Lee, Cheol Ung Choi, Chang Gyu Park, Hong Seog Seo.
Data curation: Yong Hoon Kim, Ae-Young Her, Seung-Woon Rha, Byoung Geol Choi, Se Yeon Choi, Jae Kyeong Byun, Yoonjee Park, Dong Oh Kang, Won Young Jang, Woohyeun Kim, Woong Gil Choi, Tae Soo Kang, Jihun Ahn, Sang-Ho Park, Ji Young Park, Min-Ho Lee, Cheol Ung Choi.
Formal analysis: Yong Hoon Kim, Ae-Young Her, Seung-Woon Rha, Byoung Geol Choi, Se Yeon Choi, Jae Kyeong Byun, Sang-Ho Park, Ji Young Park, Min-Ho Lee, Cheol Ung Choi.
Investigation: Yong Hoon Kim, Ae-Young Her, Seung-Woon Rha, Byoung Geol Choi, Se Yeon Choi, Jae Kyeong Byun, Woong Gil Choi, Jihun Ahn, Sang-Ho Park, Ji Young Park, Min-Ho Lee, Cheol Ung Choi, Hong Seog Seo.
Methodology: Yong Hoon Kim, Ae-Young Her, Seung-Woon Rha, Byoung Geol Choi, Se Yeon Choi, Jae Kyeong Byun, Woong Gil Choi, Jihun Ahn, Sang-Ho Park, Ji Young Park, Min-Ho Lee, Cheol Ung Choi.
Project administration: Seung-Woon Rha, Chang Gyu Park.
Resources: Seung-Woon Rha, Yoonjee Park, Dong Oh Kang, Won Young Jang, Woohyeun Kim, Cheol Ung Choi, Hong Seog Seo.
Software: Yong Hoon Kim, Ae-Young Her, Seung-Woon Rha, Byoung Geol Choi, Jae Kyeong Byun, Yoonjee Park, Dong Oh Kang, Won Young Jang, Woohyeun Kim, Woong Gil Choi, Tae Soo Kang, Jihun Ahn, Sang-Ho Park, Min-Ho Lee, Cheol Ung Choi.
Supervision: Seung-Woon Rha, Chang Gyu Park, Hong Seog Seo.
Validation: Yong Hoon Kim, Ae-Young Her, Seung-Woon Rha, Byoung Geol Choi.
Visualization: Yong Hoon Kim, Ae-Young Her, Seung-Woon Rha, Byoung Geol Choi.
Writing – original draft: Yong Hoon Kim, Ae-Young Her.
Writing – review & editing: Yong Hoon Kim, Ae-Young Her, Seung-Woon Rha.
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BioLinx; clinical outcomes; drug-eluting stent; phoshorylcholine; Polymer; Zotarolimus
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