randomized all-comers evaluation of a permanent polymer ...zuyderland medical center heerlen both in...

10.1161/CIRCULATIONAHA.118.037707

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Randomized All-Comers Evaluation of a Permanent Polymer Zotarolimus-Eluting Stent Versus a Polymer-Free Amphilimus-Eluting

Stent: (ReCre8) A Multicenter, Non-Inferiority Trial

Running Title: Rozemeijer et al.; The ReCre8 Trial

Rik Rozemeijer, MD, MSc, PharmD1*; Mera Stein, MD, PhD1,2*; Michiel Voskuil, MD, PhD1;

Rutger van den Bor, MSc, PhD3; Peter Frambach, MD4; Bruno Pereira, MD4;

Stefan Koudstaal MD, PhD1,5; Geert E. Leenders, MD, PhD1; Leo Timmers, MD, PhD1; Saskia

Z. Rittersma, MD, PhD1; Adriaan O. Kraaijeveld, MD, PhD1;

Pierfrancesco Agostoni, MD, PhD1,6; Kit Roes, MSc, PhD3;

Pieter A. Doevendans, MD, PhD, FESC1; Pieter Stella, MD, PhD1;

The ReCre8 Study Investigators.

1Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands;

2Department of Cardiology, Zuyderland Medical Center, Heerlen, The Netherlands;

3Department of Biostatistics and Research Support, University Medical Center Utrecht, Utrecht,

The Netherlands; 4National Institute of Cardiac Surgery and Interventional Cardiology,

Luxembourg, Luxembourg; 5Farr Institute of Health Informatics, University College London,

United Kingdom; 6Department of Cardiology, St. Antonius Hospital, Nieuwegein,

The Netherlands

*Shared first authorship since both authors contributed substantially and equally.

Address for Correspondence:

Pieter R. Stella, MD, PhD

University Medical Center Utrecht

Department of Cardiology

Heidelberglaan 100

room E.04.201, 3584 CX

Utrecht, The Netherlands

Tel: +31 88 7556167

Fax: +31887555427

Email: [email protected]

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Abstract

Background: Polymer-free amphilimus-eluting stents (PF-AES) represent a novel elution-

technology in the current era of drug-eluting stents. The clinical safety and efficacy of PF-AES

as compared to latest-generation permanent-polymer zotarolimus-eluting stents (PP-ZES) have

not yet been investigated in a large randomized trial.

Methods: In this physician-initiated, prospective, multicenter, randomized, non-inferiority trial,

an all-comers population requiring percutaneous coronary intervention was enrolled across three

European sites. Randomization (1:1 ratio) to PP-ZES or PF-AES was performed after

stratification for troponin-status, and diabetes. In both treatment arms, troponin-positive patients

were planned for 12-month dual antiplatelet therapy (DAPT), whereas troponin-negative patients

were planned for 1-month DAPT. Outcome assessors were blinded to the allocated treatment.

The device-oriented primary endpoint of target-lesion failure was defined as cardiac death,

target-vessel myocardial infarction, or target-lesion revascularization at 12-months as analyzed

by modified intention-to-treat (80% power, and a 3∙5% non-inferiority margin).

Results: In total 1502 patients were randomized and 1491 treated with the assigned stent and

available for follow-up. The primary endpoint occurred in 42 (5.6%) of the 744 patients

receiving PP-ZES versus 46 (6∙2%) of the 747 patients receiving PF-AES. PF-AES were

clinically non-inferior to PP-ZES (risk difference 0∙5%, upper limit one-sided 95% confidence

interval 2∙6%, pnon-inferiority=0∙0086). Cardiac death occurred in 10 (1∙3%) vs. 10 patients (1∙3%, p-

value for difference 1∙00), target-vessel myocardial infarction occurred in 18 (2∙4%) vs. 17

patients (2∙3%, p-value for difference 0∙87), and target-lesion revascularization occurred in 22

(2∙9%) vs. 20 patients (2∙6%, p-value for difference 0∙75) for PF-AES as compared to PP-ZES.

Overall, definite or probable stent thrombosis occurred in 1∙0%.

Conclusions: PF-AES were non-inferior to PP-ZES regarding target-lesion failure at 12 months.

Findings regarding the secondary endpoint and pre-specified subgroups were generally

consistent with that of the primary endpoint.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier:

NCT02328898.

Key Words: Coronary Artery Disease; Drug-eluting Stents; Dual Antiplatelet Therapy;

Polymer-free; Stent Trombosis

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http://www.clinicaltrials.gov/


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Clinical Perspective

What is new ?

• The ReCre8 study is a prospective, randomized, multicenter study comparing polymer-

free amphilimus-eluting stents (PF-AES) and permanent polymer zotarolimus-eluting

stents (PP-ZES) in patients undergoing percutaneous coronary intervention.

• Based on troponin level at the time of randomisation, troponin-positive patients were

treated with 12 months dual antiplatelet therapy (DAPT), whereas troponin-negative

patients were treated with 1 month of DAPT.

• Stratification was performed for troponin status and the presence of diabetes.

What are the clinical implications ?

• PF-AES is non-inferior to PP-ZES in regard to the primary endpoint of target-lesion

failure at 12 months follow-up.

• Low rates of stent thrombosis were observed using these latest-generation drug-eluting

stents, even with short duration of DAPT.

• A future dedicated trial on PF-AES in diabetic patients is required in order to explore

efficacy of this novel drug-eluting technology in this specific subgroup.

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Introduction

Drug-eluting stents (DES) that release antiproliferative agents have lower rates of restenosis than

bare-metal stents and are now considered the standard of care in patients undergoing

percutaneous coronary intervention.1, 2 Development of new-generation DES focused on

improving (1) stent alloy composition or stent design, (2) biocompatibility of the drug-eluting

polymer coating, or (3) properties and release of the antiproliferative agent.

One of the incentives to improve the biokinetics of the polymer coating was based on

several reports3, 4 that linked presence of permanent polymers to impaired arterial healing and

incomplete stent strut endothelialisation, leading to late stent thrombosis5 particularly in

multimorbid patients with complex lesions. In an attempt to circumvent these late adverse

events, one of the latest-generation DES is polymer-free and releases the antiproliferative drugs

by means of an amphipilic carrier stored in abluminal laser-dug wells. As a result, this stent

exhibits the properties of a DES in the first months after implantation6, and potentially without

the risk on late polymer-induced adverse events. A previous study7 showed that polymer-free

amphilimus-eluting stents (PF-AES) were associated with a reduction in late restenosis

compared to a permanent polymer paclitaxel-eluting stent. However, the clinical safety and

efficacy of PF-AES have not yet been compared to the latest-generation permanent polymer

coated stents in a large randomized all-comers population. The main study interest was a head-

to-head comparison between both stents, however an explorative subanalysis was performed on a

reduced duration of dual antiplatelet therapy (DAPT) in troponin-negative patients, and diabetic

status.

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To address these important issues, the ReCre8 trial was designed to evaluate clinical non-

inferiority of PF-AES as compared to latest-generation permanent polymer zotarolimus-eluting

stents (PP-ZES) in all-comers requiring percutaneous coronary intervention.

Methods

Study Design and Participants

ReCre8 (Randomized All-comers Evaluation of a Permanent Polymer Zotarolimus-eluting Stent

Versus a Polymer-Free Amphilimus-eluting Stent: a Multicenter, Non-inferiority Trial) was a

physician-initiated, prospective, multicenter, randomized trial comparing latest-generation PP-

ZES versus PF-AES across three European centers (University Medical Center Utrecht, and

Zuyderland Medical Center Heerlen both in The Netherlands, and the National Institute of

Cardiac Surgery and Interventional Cardiology in Luxembourg (Appendix I in the online

Supplement). The study design and rationale has been reported and described previously.8

Briefly, this study used broad eligibility criteria and minor exclusion criteria to reflect routine

clinical practice. Patients were eligible if they were capable of providing informed consent, aged

18 years or older, and had clinical evidence of ischemic heart disease presenting with stable

coronary artery disease or acute coronary syndromes including myocardial infarction with or

without ST-segment elevation. Angiographic inclusion criterion was a reference vessel diameter

of 2.5 to 4.5 mm. There were no restrictions for lesion types, lesion length, or number of treated

lesions. The exclusion criteria were: participation in another randomized stent study before

reaching the primary endpoint, planned surgery within the first three months, assumed life-

expectancy of less than one year, and revascularization prior to transcatheter aortic valve

implantation. The study protocol was designed and executed according to Good Clinical

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Practice, and was approved by the Medical Research Ethics Committee Utrecht and the

institutional review boards of each participating center. The trial is conducted in accordance with

the Declaration of Helsinki and reported in accordance with the CONSORT 2010 Statement9.

The manuscript adheres to Transparency and Openness Promotion Guidelines, and data will be

made available based upon reasonable request and contact to the corresponding author. This

study was monitored by an independent clinical research organization. Each participating patient

provided written informed consent to participate in this study. This study is registered with

ClinicalTrials.gov, number NCT02328898.

Randomization and blinding

Patients were randomly assigned after diagnostic coronary angiography and before percutaneous

coronary intervention to receive either PP-ZES or PF-AES in a 1:1 ratio in random blocks of 4

after stratification for troponin-status, and the presence of diabetes. Randomisation was done

using a web-based system that was designed and maintained by an independent research

organization. Healthcare providers were aware of the treatment allocation. Outcome assessors

and the members of the independent clinical event committee were blinded to the allocated

treatment.

Procedures

Percutaneous coronary intervention was performed according to standard techniques. Lesion

predilatation, the use of glycoprotein IIb/IIIa receptor antagonists, techniques such as rotational

atherectomy, direct stenting, bifurcation strategy, advanced chronic total occlusion techniques,

and post-dilatation were left to the operators discretion. Full lesion coverage was attempted by

the implantation of one or more assigned study stents. A patient with multiple lesions was treated

with the allocated study stent for all lesions. Staged procedures using the same stent according to

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randomization were permitted within six weeks after index procedure. PP-ZES (Resolute

Integrity, Medtronic Vascular, Santa Rosa, USA) available for use in this trial were 2∙50, 2∙75,

3∙00, 3∙50, and 4∙00 mm, with stent length of 8 to 38 mm. PF-AES (Cre8, Alvimedica, Istanbul,

Turkey) available for use were similar in diameter and lengths of those of the PP-ZES (i.e. 2∙50

to 4∙00 mm, and up to 38 mm).

Prior to stent implantation, patients received aspirin and clopidogrel in elective

procedures, and ticagrelor (or prasugrel) in case of non-elective procedures, together with an

intravenous dose of 70 to 100 IU/kg unfractionated heparin. After the procedure troponin-

negative patients received 1-month DAPT (i.e. 100 mg aspirin and 75 mg clopidogrel daily).

Patients who were troponin-positive received 12-month DAPT (i.e. 100 mg aspirin and 90 mg

ticagrelor twice daily or 10 mg prasugrel once daily). Electrocardiographs were systematically

performed before and within 24 h after the intervention, or for any suspected recurrent symptoms

or signs of ischemia. Cardiac markers (e.g. creatine kinase, creatinine kinase myocardial band,

and troponin T or I) were drawn within 24 hours before percutaneous coronary intervention and

approximately three to six hours after the procedure. No routine angiographic follow-up was

specified in the study protocol.

Outcomes

The device-oriented primary endpoint was target-lesion failure, defined as a composite of safety

(cardiac death, target-vessel myocardial infarction) and efficacy (target-lesion revascularization)

at 12 months. The patient-oriented secondary endpoint was a composite of death, stroke,

myocardial infarction, any unplanned repeated revascularization or major bleeding. Clinical

endpoints were defined as proposed by the Academic Research Consortium10. Death was

considered cardiac when due to an evident cardiac cause, when related to percutaneous coronary

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intervention, unwitnessed death, or death from unknown causes. Myocardial infarction was

classified by the electrocardiogram according to the Minnesota code into Q-wave or Non Q-

wave myocardial infarction, and defined according to the Academic Research Consortium

criteria10. Periprocedural myocardial infarction was defined as a typical rise and fall in cardiac

markers of at least three times the upper reference limit. Spontaneous myocardial infarction was

defined a typical rise and fall in cardiac markers of at least one time the upper reference limit.

Stent thrombosis was defined and classified according to criteria provided by the Academic

Research Consortium.10 Target-lesion revascularization was defined as any repeat percutaneous

coronary intervention or coronary bypass surgery caused by a more than 50% stenosis within a 5

mm border adjacent to the study stent. Target-vessel revascularization was defined as a repeat

percutaneous coronary intervention or bypass surgery for the coronary artery with the target-

lesion. Revascularization was deemed clinically driven if any of the target lesion or vessel

showed at least 50% stenosis in the presence of objective evidence of ischemia from non-

invasive or invasive testing, and/or symptoms. Any unplanned revascularization was defined as

any repeat revasculization that was not detected during the index coronary angiogram and

demanded treatment by percutaneous coronary intervention. Bleeding events were classified

according to Bleeding Academic Research Criteria11, and considered major if BARC3 or above.

Data were captured in dedicated web-based electronic case report forms that were

designed by an independent research organization (i.e. Julius Clinical Research, Zeist, The

Netherlands). On-site monitoring was performed by independent trained personnel of Julius

Clinical Research with data complete source verification of serious adverse events. An

independent clinical event committee that was blinded to the allocated treatment reviewed and

adjudicated all clinical endpoints.

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Statistical Analysis

The study was powered to evaluate clinical non-inferiority of PF-AES versus PP-ZES regarding

the device-oriented primary endpoint and patient-oriented secondary endpoint at 12-months. A

proportion of approximately 5∙5% for the primary device-oriented endpoint, and 8∙0% for the

secondary patient-oriented endpoint in both treatment arms was assumed as was found on event

endpoints in similar previous trials12, 13. We chose a non-inferiority margin of 3∙5% as an

acceptable difference. Consequently, to evaluate clinical non-inferiority on both the 12-months

device-oriented primary and the patient-oriented secondary endpoint, we estimated that 1486

patients were required (743 patients in each group) to obtain a power of at least 80%, a one-sided

alpha level of 0∙05. To account for a maximum lost-to-follow-up of 3∙0% we anticipated the

required number of patients to be 1532. Sample size calculations were performed using PASS

2008 version 08.0.16 (NCSS, Kaysville, USA).

In the primary analysis a risk difference was calculated (i.e. the proportion of patients

with a primary or secondary endpoint following the PF-AES minus the proportion of patients

following PP-ZES) along with the upper bound of the one-sided 95% Newcombe hybrid score

confidence interval and the Farrington-Manning’s test for non-inferiority. In a secondary

analysis, Cox proportional-hazards regression with covariate adjustment of stratification factors

and study site included as stratum was performed to regress the time-to-first endpoint for the

allocated study stent for the primary and secondary endpoint. Pre-specified subgroup analysis

were troponin-status and diabetes mellitus, whereas sex, age, and complex lesions were

analyzed post-hoc to investigate the consistency of the primary endpoint including a possible

interaction with the allocated stent type. Finally, a Fine and Gray competing risk regression

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model was used to evaluate non-cardiovascular death as a competing risk. Analyses were

performed based on the modified intention-to-treat principle.

Time-to-first-event for the primary and secondary endpoint and separate components

were analyzed using Kaplan-Meier methods with log-rank tests, and reported in accordance with

good practice14. Time-to-event was defined as the number of days between intervention and

occurrence of any component of the primary or secondary endpoints. Patients were censored at

one year, or the time of their last follow-up, whichever came first. All statistical analyses were

performed using SAS version 9.4 (SAS Institute, Cary, USA).

Results

Between Nov 3, 2014, and July 10, 2017, 1502 eligible all-comers patients with 2133 lesions,

aged 29-93 years, consented to study enrollment. The study flowchart is shown in Figure 1.

Almost all patients (>99%) were successfully treated with at least one assigned study stent, and

the proportion of patients with deviation from the allocated treatment was <0∙3% and similar for

both groups (2 patients in PP-ZES and 2 in PF-AES). Of the remaining patients, 5 receiving PP-

ZES and 2 receiving PF-AES were lost-to-follow-up or withdrew study consent. We obtained

12-months follow-up for 1491 patients, which were used for clinical endpoint analysis.

Baseline characteristics were well-balanced between the two study groups (Table 1). A

total of 599 (40%) patients presented with troponin-positive acute coronary syndrome and were

treated with 12-month DAPT, and 892 (60%) patients were troponin-negative and were treated

with 1-month DAPT. The study population was characterized by patients with ST-segment

elevation myocardial infarction in about a quarter of patients (24%), multivessel disease in 44%,

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and complex lesions in 59%. Diabetes mellitus was diagnosed in 20% of the patients and equally

distributed.

Lesion and procedural characteristics (Table 2) including direct stenting (30%), and the

use of glycoprotein IIb/IIIa antagonists (15%) were comparable for both groups, except for a

higher rate of post-dilatation in PF-AES (60 vs. 68%, p<0∙001). The frequency of procedural

success was 98∙9% and did not differ in both groups. Patient compliance regarding the use of

DAPT and aspirin was high, and comparable for both groups (Appendix II Table 1 in the online

Supplement). Clinical outcomes at 12-months are presented in Table 3. The device-oriented

primary endpoint occurred in 42 (5∙6%) of the 744 patients receiving PP-ZES, and 46 (6∙2%) of

the 747 patients PF-AES. Clinical non-inferiority of the PF-AES was confirmed (risk difference

of 0∙5% between PF-AES and PP-ZES, upper limit one-sided 95% confidence interval 2∙6%,

pnon-inferiority=0∙0086). The individual components of the device-oriented primary endpoint did not

significantly differ between groups (Figure 2). The patient-oriented secondary endpoint occurred

in 86 (11∙6%) of the 744 patients receiving PP-ZES, and 91 (12∙2%) of the 747 patients PF-AES,

confirming clinical non-inferiority of PF-AES (risk difference of 0∙6% between PF-AES and PP-

ZES, upper limit one-sided 95% confidence interval 3∙4%, pnon-inferiority=0∙043, (Appendix III

Figure 1 in the online Supplement).

Results of the Cox proportional-hazards analysis were consistent with the results of the

primary analysis on both the primary and secondary endpoints. Regarding troponin-positive

patients the rate of target-lesion failure was 4∙7%, whereas in troponin-negative patients this was

7∙1% at 12-months. Subgroup analyses indicated consistency of the treatment effect for the

device-oriented primary endpoint across various subgroups (Figure 3).

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Definite or probable stent thrombosis occurred in 6 (0∙8%) of 744 patients receiving PP-ZES

versus 9 (1∙2%) of 747 patients receiving PF-AES (p=0∙44). Detailed information on the clinical

circumstances and consequences regarding definite stent thrombosis was provided (Appendix IV

Table 2 in the online Supplement).

Discussion

The ReCre8 study shows that PF-AES are clinically non-inferior to latest-generation PP-ZES

regarding target-lesion failure at 12-months. The overall rates of the device-oriented primary

endpoint of target-lesion failure, a composite of cardiac death, target-vessel myocardial

infarction, or target-lesion revascularization did not differ significantly for both stents, nor did

any of the individual components. The patients included in the current trial consisted of a true

all-comers population as reflected by a high proportion of patients with ST-segment elevation

myocardial infarction in this study, and was among the highest of recently published all-comer

trials13, 15-17. Also, the population was characterized by a high number of left main disease,

bifcation lesions, and chronic total occlusions. The number of complex type C lesions was

equivalent to previous reports12, 13, 15, 18.

The frequency of target-lesion failure at 12-months in PP-ZES in this study was low, and

consistent with those reported in previous studies using PP-ZES12, 13, that used similar endpoint

definitions. In DUTCH PEERS12 target-lesion failure defined as cardiac death, target-vessel

related myocardial infarction or clinically-driven target-lesion revascularization for PP-ZES was

5∙1% at 12-months. In SORT OUT VI13 target-lesion failure defined as cardiac death, myocardial

infarction not clearly attributable to non-target lesion and clinically indicated target-lesion

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revascularization, and 5∙3%. These results are consistent with the 5∙6% rate of the primary

endpoint at 12-months in the ReCre8 trial.

The rate of target-lesion failure for PF-AES at 12-months matched those with a previous

non-randomized report19 on this novel device, despite a higher baseline risk in our study

population. The increased frequency of post-dilatation in PF-AES was not anticipated, and the

reason for this finding remains unclear to us. It seems unlikely, however, that this may have

substantially influenced clinical outcomes. Counterintuitively, the rate of target-lesion failure

observed in troponin-positive patients was lower than that of troponin-negative patients. This

might be explained by more complex lesions in troponin-negative patients. Based on our

findings, however, a negative effect of short DAPT on target-lesion failure cannot be ruled out.

The possibility that short DAPT may have caused an increase in TLF in troponin-negative

patients needs further investigation. These findings do not support deviating from current

guidelines on DAPT duration20.

The proportion of patients with target-vessel myocardial infarction were similar in both

arms and correspond well to those reported by previous studies ranging from 2%12, 18, 21 to even

up to 6%22, depending on study population and definitions used. Myocardial infarction related to

the target-vessel occurred within the periprocedural period in the majority of patients (80%).

The occurrence of definite or probable stent thrombosis, as an important safety indicator, did not

differ between the two DES types (0∙8% versus 1∙2%), and was comparable to other reports12, 15,

21. It should be empathized, however, that this trial did not yield the power to detect differences

for endpoints with such low incidences. Six cases of definite stent thrombosis were observed

after one month in the troponin-negative arm. Indeed, the finding that most cases of definite stent

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thrombosis occurred in complex lesions using multi-overlapping stents, treatment of bifurcations,

or chronic total occlusions may need further investigation.

Current literature shows that stent performance in diabetic patients is still worse than

those in non-diabetics, with high rates of in-stent restenosis and target-lesion revascularization

reaching up to 13.5%23. The amphilimus formulation – a mixture of sirolimus and long-chained

fatty acids – used in PF-AES enhances the uptake of antiproliferative agents24 and may be

associated with a higher antirestenotic potency in diabetics. The abluminal reservoirs (figure 4)

that are filled with the amphilimus formulation reflect a novel strategy that needs further

investigation. As previous clinical reports7, 25 revealed encouraging results on PF-AES in

diabetes, a pre-specified analysis of PF-AES versus PP-ZES was performed.8 No between stent

differences were detected in the diabetic subgroup. Most likely this was due to a relatively low

enrolment of diabetic patients, and a lower-than-expected event rate in this subgroup. Since

significant differences in target-lesion revascularization and target-vessel revascularization were

found at 3 years clinical follow-up in the Next trial7 , the duration of follow-up may also be a

factor that explains the observed event rate.

This trial has several limitations we should acknowledge. First, like most coronary stent

studies ReCre8 was an open-label study, where physicians were not blinded to the allocated

treatment. We believe, however, that this does not change our findings since we used well-

standardized clinical endpoints10, 11 with rigorous event adjudication by an independent clinical

event committee which was blinded to the allocated treatment. Second, even though this large-

scale study has established clinical non-inferiority of PF-AES, the non-inferiority margin of

3∙5% was relatively large which needs to be taken into consideration in the interpretation of the

results limiting the precision with which non-inferiority could be established. It was not powered

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to address potential differences in adverse clinical events that occur at low rates. Third, one

center did not provide data on the screening for enrollment of the corresponding 20% of the

patients which may have caused selection bias. Even though we acknowledge it would be best to

have a screenings log of all patients, we believe that the risk of selection bias was low and did

not change the overall conclusions of this study. Fourth, this trial was conducted at three North-

western European sites, and may therefore not be applicable to other geographical regions with

differences in clinical baseline characteristics (such as diabetes or lesion complexity), or

procedural characteristics.

Conclusions

This trial demonstrates that PF-AES is non inferior to a latest-generation PP-ZES with regards to

target-lesion failure at 12-months follow-up. Findings regarding the secondary endpoint and pre-

specified subgroups were generally consistent with that of the primary endpoint. Further clinical

follow-up until 3 years will be performed in order to test the long-term outcomes of these

devices.

Sources of Funding

The University Medical Center Utrecht was the main sponsor of the study. No funding by

industry was involved. The stent manufacturers had no role in the design of the study, collection,

analysis or interpretation of the data, nor in the writing of this report, or in the decision to submit

this manuscript for publication. The corresponding author had full access to all of the data in the

study and had the final responsibility for the decision to submit for publication.

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Acknowledgments

To all involved (research) nurses, technicians, and personnel who made great efforts for the

successful enrolment and completion of this study. Special thanks goes out to Yvonne Breuer,

manager of the R&D department, UMCU, Astrid Links, data manager, UMCU, and all fellows

and physicians involved in study enrolment and data collection.

Disclosures

PRS is member of speakersbureau, Alvimedica, all other authors have no conflicts of interest to

declare.

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Table 1. Baseline characteristics

Overall

(n=1491)

PP-ZES

(n=744)

PF-AES

(n=747)

p-value

Clinical Characteristics

Age (years) 64∙9 ± 11∙0 65∙1 ± 10∙6 64∙7 ± 11∙3 0∙55

Male Sex 1142 (76∙6) 577 (77∙6) 565 (75∙6) 0∙38

Body-Mass Index (kg/m2) 27∙3 ± 4∙43 27∙2 ± 4∙40 27∙5 ± 4∙46 0∙34

Hypertension 823 (55∙2) 411 (55∙2) 412 (55∙2) 0∙85

Hypercholesterolemia 665 (44∙6) 340 (45∙8) 325 (43∙5) 0∙49

Diabetes Mellitus 304 (20∙4) 149 (20∙0) 155 (20∙8) 0∙67

Insulin-treated 96 (6.4) 47 (6∙3) 49 (6∙6) 0.97

Current smoker 384 (25∙8) 191 (25∙7) 193 (25∙9) 0∙71

Family history of cardiovascular disease 566 (38∙0) 275 (37∙0) 291 (39∙0) 0∙70

Renal insufficiency (eGFR<60)* 164 (16∙8) 80 (16∙3) 84 (17∙3) 0∙67

Relevant Medical History

Previous Myocardial Infarction 297 (19∙9) 158 (21∙2) 139 (18∙6) 0∙40

Previous Percutaneous Coronary intervention 304 (20∙4) 166 (22∙3) 138 (18∙5) 0∙06

Previous Coronary Artery Bypass Grafting 138 (9∙3) 71 (9∙5) 67 (9∙0) 0∙69

Clinical Presentation

Stable Angina 633 (42∙5) 315 (42∙3) 318 (42∙6) 0∙93

Acute Coronary Syndrome 708 (47∙5) 356 (47∙9) 352 (47∙1) 0∙78

Unstable Angina 109 (7∙3) 55 (7∙4) 54 (7∙2) 0∙90

NSTEMI 249 (16∙7) 133 (17∙9) 116 (15∙5) 0∙22

STEMI 350 (23∙5) 168 (22∙6) 182 (24∙4) 0∙42

Coronary Anatomy

Left Main 51 (3∙4) 25 (3∙4) 26 (3∙5) 0∙90

Left Anterior Descending Artery 834 (55∙9) 407 (54∙7) 427 (57∙2) 0∙33

Left Circumflex Artery 514 (34∙5) 255 (34∙3) 259 (34∙7) 0∙87

Right Coronary Artery 667 (44∙7) 329 (44∙2) 338 (45∙3) 0∙69

Arterial Bypass Graft 9 (0∙60) 5 (0∙67) 4 (0∙54) 0∙75

Venous Bypass Graft 40 (2∙7) 23 (3∙1) 17 (2∙3) 0∙33

Lesion characteristics

De-novo coronary lesions† 1414 (94∙8) 704 (94∙6) 710 (95∙0) 0∙71

At least one complex lesion‡ 873 (58∙6) 437 (58∙7) 436 (58∙4) 0∙88

At least one bifurcation lesion 323 (21∙7) 147 (19∙8) 176 (23∙6) 0∙07

At least one chronic total occlusion 98 (6∙6) 47 (6∙3) 51 (6∙8) 0∙69

At least one ostial lesion 43 (2∙9) 20 (2∙7) 23 (3∙1) 0∙65

At least one restenotic lesion 48 (3∙2) 24 (3∙2) 24 (3∙2) 0∙99

At least one moderate or severely calcified lesion 401 (27∙0) 205 (27∙7) 196 (26∙3) 0∙53

At least one venous graft lesion 29 (2∙0) 16 (2∙2) 13 (1∙7) 0∙57

At least one small vessel (RVD < 2∙75 mm) 399 (26∙9) 199 (26∙9) 200 (26∙9) 1∙00

At least one long lesion (length >20 mm) 744 (50∙2) 415 (56∙1) 329 (44∙3) <0∙001

Procedural characteristics

Radial approach 1372 (92∙2) 680 (91∙4) 692 (92∙6) 0∙55

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Number of diseased coronary vessels 0∙67

One 839 (56∙3) 433 (58∙2) 406 (54∙4)

Two 425 (28∙5) 200 (26∙9) 225 (30∙1)

Three or more 227 (15∙2) 111 (14∙9) 116 (15∙5)

Data are n (%), or means (SD). * Renal insufficiency was defined as an estimated glomerular filtration

rate of less than 60 mL per min per 1∙73 m². † De-novo coronary lesions include chronic total occlusions,

but not grafts or in-stent restenosis. ‡ Complex lesions were defined as lesion classification type B2 or C

according to the American College of Cardiology/American Heart Association.

ACS = Acute Coronary Syndrome, DAPT = Dual Antiplatelet Therapy, NSTEMI = non-ST-segment

elevation-myocardial infarction, PF-AES = Polymer-free Amphilimus-eluting Stents, PP-ZES =

Permanent Polymer Zotarolimus-eluting stents, RVD = reference vessel diameter, SD = Standard

Deviation, STEMI = ST-segment elevation-myocardial infarction.

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Table 2. Lesion and procedural characteristics

Overall

(2111 lesions)

PP-ZES

(1024 lesions)

PF-AES

(1087 lesions)

p-value

Procedural characteristics

No of stents per lesion* 1∙27 ±0∙58 1∙25±0∙57 1∙29±0∙59 0∙12

No of stents per patient* 1∙81 ± 1∙18 1∙73 ± 1∙09 1∙89 ± 1∙25 0∙05

Total stent length (mm)† 47∙7 ± 21∙2 47∙7 ± 21∙4 47∙7 ± 21∙2 0∙68

Stent diameter (mm) 3∙02 ± 0∙45 3∙01 ± 0∙45 3∙03 ± 0∙45 0∙14

Multi overlapping stents 394 (18∙7) 177 (17∙4) 219 (20∙02) 0∙13

Pre-dilatation 1886 (69∙8) 904 (70∙5) 973 (69∙2) 0∙48

Post-dilatation 1699 (64∙0) 757 (59∙6) 942 (68∙0) <0∙001

Lesion Complexity‡ 0∙99

ACC/AHA class A 238 (11∙3) 117 (11∙5) 121 (11∙1)

ACC/AHA class B1 771 (36∙6) 370 (36∙3) 401 (36∙9)

ACC/AHA class B2 505 (24∙0) 244 (24∙0) 261 (24∙0)

ACC/AHA class C 592 (28∙1) 288 (28∙3) 304 (28∙0)

Pre-procedural TIMI flow 0∙07

Grade 0 302 (14∙3) 137 (13∙4) 165 (15∙1)

Grade 1 75 (3∙6) 43 (4∙5) 29 (2∙7)

Grade 2 180 (8∙6) 81 (8∙03) 99 (9∙1)

Grade 3 1546 (73∙5) 754 (74∙1) 792 (73∙0)

Post-procedural TIMI flow* 0∙70

Grade 0 14 (0∙7) 7 (0∙7) 7 (0∙65)

Grade 1 4 (0∙2) 3 (0∙3) 1 (0∙1)

Grade 2 14 (0∙7) 8 (0∙8) 6 (0∙6)

Grade 3 2076 (98∙5) 997 (98∙2) 1070 (98∙7)

GPIIb/IIIa antagonist use 256 (14∙9) 112 (13∙4) 144 (16∙4) 0∙08

Procedural success 2076 (98∙9) 1008 (99∙3) 1068 (98∙5) 0∙08

Data are n (%), means (SD). Continuous variables were evaluated by means of a t-test, unless visual

inspection indicated non-normality, in which case a Wilcoxon-Mann-Whitney test was performed instead.

Categorical variables were evaluated using a chi-square test, unless observed counts < 5 were observed, in

which case an exact test was performed instead. * These variable were tested using an exact test. † As

analyzed by Wilcoxon two sample test. ‡ Lesion complexity according to the American College of

Cardiology/American Heart Association classification.

ACC = American College of Cardiology, AHA = American Heart Association, PCI = Percutaneous

Coronary Intervention, PF-AES = Polymer-free Amphilimus-eluting Stents, PP-ZES = Permanent

Polymer Zotarolimus-eluting stents, SD = Standard Deviation, TIMI = Thrombolysis In Myocardial

Infarction, GPIIb/IIIa antagonist = glycoprotein IIb/IIIa antagonist.

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Table 3. Clinical events at 12 months after stent implantation

Overall

(n=1491)

PP-ZES

(n=744)

PF-AES

(n=747)

p-value

Device-oriented primary endpoint* 88 (5∙9) 42 (5∙6) 46 (6∙2) 0∙67

Patient-oriented secondary endpoint† 177 (11∙9) 86 (11∙6) 91 (12∙2) 0∙69

Any death 35 (2∙3) 18 (2∙4) 17 (2∙3) 0∙86

Cardiac death 20 (1∙3) 10 (1∙3) 10 (1∙3) 1∙00

Myocardial infarction 53 (3∙6) 24 (3∙2) 29 (3∙8) 0∙49

Target-vessel myocardial

infarction

35 (2∙3) 17 (2∙3) 18 (2∙4) 0∙87

Stent thrombosis (definite, or probable)‡ 15 (1∙0) 6 (0∙8) 9 (1∙2) 0∙61

Acute (< 24 h) 4 (0∙3) 0 4 (0∙5) 0∙12

Subacute (24 h to 30 days) 5 (0∙3) 2 (0∙3) 3 (0∙4) 1∙00

Late (31 days to 12 months) 6 (0∙4) 4 (0∙5) 2 (0∙3) 0∙45

Any unplanned revascularization 73 (4∙9) 38 (5∙1) 35 (4∙7) 0∙71

Target-lesion revascularization 42 (2∙8) 20 (2∙6) 22 (2∙9) 0∙75

Stroke 12 (0∙8) 6 (0∙8) 6 (0∙8) 1∙00

Major Bleeding (BARC ≥ 3) 25 (1∙7) 13 (1∙7) 12 (1∙6) 0∙84

Data are n (%). Clinical outcomes were evaluated using Kaplan-Meier method using log-rank test, with p-

values that were indicative for superiority. * Device-oriented primary outcome of target-lesion failure was

defined as cardiac death, target-vessel myocardial infarction, or clinically driven target-lesion

revascularization. † Patient-oriented primary outcome of net adverse cardiac events was defined as: death,

myocardial infarction, stroke, any unplanned revascularization, or major bleeding (BARC>3) according

to bleeding academic research consortium. ‡ Stent thrombosis according to Academic Research

Consortium definitions.

BARC = Bleeding Academic Research Consortium, DAPT = Dual Antiplatelet Therapy, PF-AES =

Amphilimus Eluting Stent, PP-ZES = Permanent Polymer Zotarolimus Eluting Stent, TLF = Target-lesion

Failure, ST = Stent Thrombosis.

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Figure Legends

Figure 1. Trial profile.

PCI = Percutaneous Coronary Intervention, TAVI = Transcatheter Aortic Valve Implantation,

PF-AES = Polymer-free Amphilimus-eluting Stent, PP-ZES = Permanent Polymer Zotarolimus-

eluting Stent.

Figure 2. Kaplan-Meier estimates of the device-oriented primary endpoint, and individual

components.

(A) Target-lesion Failure, (B) Cardiac Death, (C) Target-vessel Myocardial Infarction, and (D)

Target-lesion Revascularisation. PF-AES = Polymer-free Amphilimus-eluting Stent, PP-ZES =

Permanent Polymer Zotarolimus-eluting Stent.

Figure 3. Subgroup analysis on the primary endpoint at 12-months.

Troponin-status and diabetes mellitus were pre-specified subgroups whereas sex, age, and

complex B2/C lesions were performed post-hoc.

AES = Amphilimus-eluting Stent, B2/C lesions according to the American College of

Cardiology/American Heart Association classification, DAPT = Dual Antiplatelet Therapy, HR

= Hazard Ratio, CI = Confidence Interval, PF-AES = Polymer-free Amphilimus-eluting Stent,

PP-ZES = Permanent Polymer Zotarolimus-eluting Stent, ZES = Zotarolimus-eluting Stent.

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Figure 4. Principal characteristics of the Polymer-free Amphilimus-eluting Stent.

The coronary stent platform is made from a thin-strut (80µm) cobalt-chromium alloy, coated

with an ultra-thin (<0.3 mm) passive layer (Bio-inducer Surface) to accelerate

endothelialization24. Sustained and homogeneous release of sirolimus (90 pg/cm2) is facilitated

according to Fick’s law and completed over 90 days by laser-dug wells (Abluminal Reservoirs)

that are filled with a mixture of the drug and long-chained fatty acids (Amphilimus Formulation).

This distinct feature acts as an active drug-carrier to enhance drug-penetration and modulates

bioavailability directly into the vessel wall.

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