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.
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.



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.



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%, pnon-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).



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.



Biotronik, Boston Scientific, and Medtronic.
Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, Netherlands; Department of Health Technology and Services Research, MIRA-Institute of Technical Medicine and Biomedical Technology, University of Twente, Enschede, Netherlands. Electronic address: c.vonbirgelen@mst.nl.
Clemens
C
von Birgelen
Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, Netherlands.
Marlies M
MM
Kok
Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, Netherlands.
Liefke C
LC
van der Heijden
Department of Cardiology, Rijnstate Hospital, Arnhem, Netherlands.
Peter W
PW
Danse
Department of Cardiology, Haga Hospital, The Hague, Netherlands.
Carl E
CE
Schotborgh
Department of Cardiology, Albert Schweitzer Hospital, Dordrecht, Netherlands.
Martijn
M
Scholte
Department of Cardiology, Rijnstate Hospital, Arnhem, Netherlands.
R Melvyn Tjon Joe
RMTJ
Gin
Department of Cardiology, Haga Hospital, The Hague, Netherlands.
Samer
S
Somi
Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, Netherlands.
K G
KG
van Houwelingen
Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, Netherlands.
M G
MG
Stoel
Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, Netherlands.
Frits H A F
FHAF
de Man
Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, Netherlands.
J Hans W
JHW
Louwerenburg
Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, Netherlands.
Marc
M
Hartmann
Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, Netherlands.
Paolo
P
Zocca
Department of Cardiology, Hospital Group Twente, Almelo and Hengelo, Netherlands.
Gerard C M
GCM
Linssen
Department of Epidemiology, Medisch Spectrum Twente, Enschede, Netherlands; Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede, Netherlands.
Job
J
van der Palen
Department of Health Technology and Services Research, MIRA-Institute of Technical Medicine and Biomedical Technology, University of Twente, Enschede, Netherlands.
Carine J M
CJM
Doggen
Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, Netherlands.
Marije M
MM
Löwik
D020341:Absorbable Implants; D054058:Acute Coronary Syndrome / Q000601:surgery*; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003327:Coronary Disease / Q000601:surgery; D054855:Drug-Eluting Stents; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D062645:Percutaneous Coronary Intervention / Q000295:instrumentation / Q000379:methods; D011108:Polymers; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000627:therapeutic use*; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D011108:Polymers; D000068338:Everolimus; C489443:zotarolimus; D020123:Sirolimus