Very thin strut biodegradable polymer everolimus-eluting and sirolimus-eluting stents versus durable polymer zotarolimus-eluting stents in allcomers with coronary artery disease (BIO-RESORT): a three-arm, randomised, non-inferiority trial

Summary

Background

In patients with coronary artery disease, treated with durable polymer-coated drug-eluting stents, the life-long presence of the polymer might delay arterial healing. Novel very thin strut biodegradable polymer stents, which leave only a bare metal stent after polymer resorption, might improve long-term outcome. We investigated in allcomers the safety and efficacy of three stents eluting either everolimus, sirolimus, or zotarolimus, often clinically used but never compared, of which the biodegradable polymer everolimus-eluting stent was never before assessed in allcomers.

Methods

The large-scale, investigator-initiated, multicentre, assessor and patient blinded, three-arm, randomised, BIO-RESORT non-inferiority trial was done at four clinical sites in the Netherlands. All-comer patients were aged 18 years or older, capable of providing informed consent, and required a percutaneous coronary intervention with drug-eluting stent implantation according to clinical guidelines or the operators' judgment. Exclusion criteria were: participation in another randomised drug or device study before reaching the primary endpoint of that study; planned surgery necessitating interruption of dual antiplatelet therapy within the first 6 months; known intolerance to components of the investigational product or medication required; uncertainty about the adherence to follow-up procedures or an assumed life expectancy of less than 1 year; or known pregnancy. Web-based computer-generated allocation sequences randomly assigned patients (1:1:1) to treatment with very thin strut biodegradable polymer everolimus-eluting or sirolimus-eluting stents (which differ substantially in type, amount, distribution, and resorption speed of their respective coating), or thin strut durable polymer zotarolimus-eluting stents. The primary endpoint was a composite of safety (cardiac death or target vessel-related myocardial infarction) and efficacy (target vessel revascularisation) at 12 months of follow up with a very thin strut biodegradable polymer of either everolimus-eluting or sirolimus-eluting stents, compared with durable polymer zotarolimus-eluting stents, analysed by intention to treat (non-inferiority margin 3·5%). This trial was registered with ClinicalTrials.gov, number NCT01674803.

Findings

From Dec 21, 2012, to Aug 24, 2015, 3514 patients were enrolled and analysed, of whom 2449 (70%) had acute coronary syndromes, which included 1073 (31%) ST-elevation myocardial infarctions. 12 month follow-up of 3490 (99%) patients (three lost to follow-up; 21 withdrawals) was available. The primary endpoint was met by 55 (5%) of 1172 patients assigned to everolimus-eluting stents, 55 (5%) of 1169 assigned to sirolimus-eluting stents and 63 (5%) of 1173 assigned to zotarolimus-eluting stents. Non-inferiority of the everolimus-eluting stents and sirolimus-eluting stents compared with zotarolimus-eluting stents was confirmed (both −0·7% absolute risk difference, 95% CI −2·4 to 1·1; upper limit of one sided 95% CI 0·8%, p_{non-inferiority}<0·0001). Definite stent thrombosis (defined by the Academic Research Consortium) occurred in four (0·3%) of 1172 patients who were allocated to everolimus-eluting stents, four (0·3%) of 1169 patients who were allocated to sirolimus-eluting stents, and three (0·3%) of 1173 patients who were allocated to zotarolimus-eluting stents (log-rank p=0·70 for both comparisons with zotarolimus-eluting stents).

Interpretation

At 12 month follow-up, both very thin strut drug-eluting stents with dissimilar biodegradable polymer coatings (eluting either everolimus or sirolimus) were non-inferior to the durable polymer stent (eluting zotarolimus) in treating allcomers with a high proportion of patients with acute coronary syndromes. The absence of a loss of 1 year safety and efficacy with the use of these two biodegradable polymer-coated stents is a prerequisite before assessing their potential longer-term benefits.

Funding

Biotronik, Boston Scientific, and Medtronic.

Introduction

The implantation of a drug-eluting stent is considered the standard approach for percutaneous coronary intervention.¹ The elution of antiproliferative drugs from the stent's polymer coating reduces the risk of lesion recurrence.1, 2 However, the lifelong presence of a durable polymer in a coronary artery might induce vessel wall inflammation, delay arterial healing, and occasionally cause serious complications such as stent thrombosis and myocardial infarction.³

Growing awareness of this risk motivated the development of stents with biodegradable coatings that leave only a bare metal stent after polymer resorption.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 Early biodegradable polymer stents had thick stainless steel struts (120 μm) and in a large allcomers trial,6, 7 showed similar efficacy and better long-term safety as compared with early-generation durable polymer stents that also had thick struts. However, in another allcomers trial,⁸ similar thick-strut biodegradable polymer stents did not show non-inferiority as compared with early-generation durable polymer stents. Moreover, equivocal results were reported when comparing early biodegradable polymer stents with new-generation durable polymer stents with thin cobalt chromium struts,11, 12, 13, 14 which are in line with previous research showing that thick struts increase the risk of stent thrombosis and lesion recurrence.¹⁵

Today, novel biodegradable polymer stents are available that have uncoated struts that are up to half as thick as the struts of the early biodegradable polymer stents. These very thin strut (60–81 μm) biodegradable polymer stents have flexible designs and thin, refined coatings.⁴ The present trial assesses two stents that share these characteristics, but differ in the type, amount, distribution, and degradation speed of their respective coatings.¹⁶ One device, the everolimus-eluting platinum chromium stent (Synergy, Boston Scientific; Natick, MA, USA),4, 17, 18 is the first and currently only biodegradable polymer stent with US Food and Drug Administration approval. While the device has rapidly gained clinical acceptance, there are still no data from a randomised trial with allcomers. The other novel device is a sirolimus-eluting cobalt chromium stent (Orsiro, Biotronik; Bülach, Switzerland) that has shown its usefulness outside of the USA.19, 20, 21, 22

So far, neither of these stents has been compared with the new-generation, thin-strut durable polymer zotarolimus-eluting stent (Resolute Integrity, Medtronic, Santa Rosa; CA, USA), an established device with excellent clinical outcomes.12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 Therefore, the randomised, three-arm, BIO-RESORT non-inferiority trial assessed in allcomers the safety and efficacy of the two novel stents versus the zotarolimus-eluting stent.