{'fraction_non_alphanumeric': 0.03811070848431838, 'fraction_numerical': 0.01911783081344496, 'mean_word_length': 4.9157427937915745, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Final five‐year results of the REMEDEE Registry: Real‐world experience with the dual‐therapy COMBO stent

Abstract Objectives This final report from the REMEDEE Registry assessed the long‐term safety and efficacy of the dual‐therapy COMBO stent in a large unselected patient population. Background The bio‐engineered COMBO stent (OrbusNeich Medical BV, The Netherlands) is a dual‐therapy pro‐healing stent. Data of long‐term safety and efficacy of the this stent is lacking. Methods The prospective, multicenter, investigator‐initiated REMEDEE Registry evaluated clinical outcomes after COMBO stent implantation in daily clinical practice. One thousand patients were enrolled between June 2013 and March 2014. Results Five‐year follow‐up data were obtained in 97.2% of patients. At 5‐years, target lesion failure (TLF) (composite of cardiac death, target‐vessel myocardial infarction, or target lesion revascularization) was present in 145 patients (14.8%). Definite or probable stent thrombosis (ST) occurred in 0.9%, with no additional case beyond 3‐years of follow‐up. In males, 5‐year TLF‐rate was 15.6 versus 12.6% in females (p = .22). Patients without diabetes mellitus (DM) had TLF‐rate of 11.4%, noninsulin‐treated DM 22.7% (p = .001) and insulin‐treated DM 41.2% (p < .001). Patients presenting with non‐ST segment elevation acute coronary syndrome (NSTE‐ACS) had higher incidence of TLF compared to non‐ACS (20.4 vs. 13.3%; p = .008), while incidence with STE‐ACS was comparable to non‐ACS (10.7 vs. 13.3%; p = .43). Conclusion Percutaneous coronary intervention with the dual‐therapy COMBO stent in unselected patient population shows low rates of TLF and ST to 5 years. Remarkably, no case of ST was noted beyond 3 years.

Conclusion: Percutaneous coronary intervention with the dual-therapy COMBO stent in unselected patient population shows low rates of TLF and ST to 5 years.
Remarkably, no case of ST was noted beyond 3 years.

K E Y W O R D S
drug-eluting stent, dual-therapy stent, percutaneous coronary intervention

| INTRODUCTION
After the early experience with first-generation drug-eluting stents (DES), long-term follow-up in clinical stent trials became unequivocally important. Although first-generation DES significantly reduced in-stent restenosis by its cytostatic or cytotoxic drug, 1,2 long-term follow-up revealed accrual of late adverse events, in particular stent thrombosis (ST). 3 These antiproliferative drugs concomitantly impede endothelial regeneration. 4 A delayed healing response may lead to increased incidence of ST, impaired vasomotor response, and delayed restenosis at long term follow-up. 5,6 Therefore, facilitating and accelerating endothelial healing after stent implantation is desirable. Re-endothelialization is a multistep process in which circulating endothelial progenitor cells (EPCs) play an important role. 7,8 EPCs are immature cells that are capable of differentiating into healthy endothelial cells. The dual-therapy COMBO stent (OrbusNeich Medical BV, The Netherlands) is a DES with a biodegradable polymer and actively captures EPCs with its anti-CD34+ antibody layer in order to accelerate endothelial healing; which could also improve long-term outcomes. 9 We have previously reported on outcomes up to 4 years with this stent from the REMEDEE registry. [10][11][12][13] In this final report from the REMEDEE registry, we aim to assess long-term safety and performance of the dual-therapy COMBO stent at 5-year follow-up in a large unselected patient population.

| Study design
The study design, endpoint definitions, and primary results have previously been described in detail. 10 In brief, the REMEDEE Registry is a prospective, multicenter, international, investigator-initiated registry evaluating the safety, and performance of the COMBO stent in daily clinical practice. The procedure and antiplatelet therapy were at investigators' The study is registered at clinicaltrials.gov (NCT01874002).

| Analysis
The main purpose of the current report was to evaluate the efficacy and safety of the COMBO stent throughout 5-year follow-up. The primary endpoint was TLF. Furthermore, we performed post hoc analysis for the 5-year clinical outcomes according to sex, diabetes status, and clinical presentation.

| Study endpoints and definitions
The primary focus of the current analysis is TLF, defined as a compos-  (stable angina, documented ischemia, angiography, other) were categorized as non-ACS.

| Statistical analysis
Data are shown as counts with valid percentages for categorical vari-    Table S3.

| Subgroup analysis
The performance of the COMBO stent did not differ between the sexes (Figure 2). Also after correcting for baseline dissimilarities, no statistically significant sex-differences in 5-year clinical outcomes were found (Table S4) Table S5.

| Long-term efficacy of dual-therapy COMBO stent
Long-term follow-up is essential to determine the true safety and efficacy of coronary artery devices beyond early procedural outcomes. 18 Although comparison between different studies must be done with caution-reported events rates are affected by a range of factors other than the stent-we try to interpret our results by comparing to other studies. The incidence of cardiac death and TLR in our registry were similar to those reported at 5 years in the BIOSCIENCE, 19 RESOLUTE, 20   polymer everolimus-eluting stents. 19 Especially beyond 3 years the curves of ST accrue. 19 Also, the TWENTE trial shows that the risk of ST continues beyond 1 year and ST occurred throughout 5-years of follow-up. 23 In the current registry, we see no ST cases beyond 3 years. Moreover, we found that despite the unselected patient population, the overall incidence of definite ST was encouragingly low and only 0.8% at 5-years. The majority of ST cases occurred acute in STE-ACS patients. A propensity-matched analysis showed that the 2-year rate of definite ST did not differ between COMBO stent and Promus or Resolute stent. 24 These findings support the hypothesis behind the dual-therapy technology of low very late ST risk due to functional endothelialization. 25 Failure to uphold a functional endothelial barrier within the stented segment has been hypothesized as a mechanism for the development of neoatherosclerosis. 26 And neoatherosclerosis is often observed in patients with very late ST. 27 In addition, an optical coherence tomography (OCT) serial followup study demonstrated that the COMBO stent was associated with an increase in strut coverage from 77% at 2 months to 95% at 5 months. 28 In addition, a regression of neointimal hyperplasia between 9 and 24 months was observed. 28 The Japan-

| Subgroups
Estrogen is associated with improved function and recruitment of EPCs from the bone-marrow. 30  In vitro studies showed that low EPC count or impaired EPC function is a strong predictor of in-stent restenosis, progression of atherosclerosis, and cardiovascular events. 33 reported previously, 46 with worse outcomes, compared to non-ACS patients. The results of these post hoc analysis should be interpreted with caution. The numerical lower rate of ischemic events in STE-ACS compared with non-ACS is probably caused by the small groups.

| LIMITATIONS
This is the first large cohort to report long-term results of the COMBO stent in an unselected patient population. All events were monitored and adjudicated by an independent clinical event committee. However, this study is limited by its observational single-arm design and no direct comparison to other DES can be made. In addition, the sub-group analysis is subject to small sample size and possible confounding.

| CONCLUSIONS
This is the first study to report five-year follow-up of the dual-therapy COMBO stent in a large cohort. The final clinical outcomes of the REMEDEE Registry show low rates of TLF and ST. Remarkably, no case of ST was noted beyond 3 years. More data are needed to confirm this late benefit of the dual-therapy COMBO stent.