Japan-United States of America Harmonized Assessment by Randomized Multicentre Study of OrbusNEich’s Combo StEnt (Japan-USA HARMONEE) study: primary results of the pivotal registration study of combined endothelial progenitor cell capture and drug-eluting stent in patients with ischaemic coronary disease and non-ST-elevation acute coronary syndrome

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Abstract

Aims

Harmonized Assessment by Randomized Multicentre Study of OrbusNEich’s Combo StEnt (HARMONEE) (NCT02073565) was a randomized pivotal registration trial of the Combo stent, which combined sirolimus and an abluminal bioabsorbable polymer with a novel endoluminal anti-CD34+ antibody coating designed to capture endothelial progenitor cells (EPC) and promote percutaneous coronary intervention (PCI) site healing.

Methods and results

Clinically stabilized PCI subjects were randomized 1:1 to receive Combo or everolimus-eluting stents (EES). Between February 2014 and June 2016, 572 subjects with 675 coronary lesions underwent 1-year angiography and fractional flow reserve, with optical coherence tomography (OCT) in the first 140 patients. The primary clinical endpoint was non-inferior 1-year target vessel failure (TVF). The primary mechanistic endpoint of EPC capture activity was superior strut coverage by OCT. Target vessel failure occurred in 7.0% Combo (20/287) vs. 4.2% EES (12/285), a 2.8% [95% confidence interval (95% CI) −1.0%, 6.5%] difference, meeting the non-inferiority hypothesis ( P = 0.02). There were no cardiac deaths, with one stent thrombosis observed in the EES group. Quantitative coronary angiography late loss with Combo was equivalent to EES. Optical coherence tomography strut coverage at 1 year was superior with Combo vs. EES [91.3% (95% CI 88.7%, 93.8%) vs. 74.8% (95% CI 70.0%, 79.6%), P < 0.001], with homogeneous tissue in 81.2% vs. 68.8%, respectively.

Conclusion

Combo stent demonstrated non-inferior 1-year TVF and late loss in a randomized comparison to EES, with superior strut-based tissue coverage by OCT as a surrogate of EPC capture technology activity.

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Most cited references 11

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Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization.

Aloke V. Finn, Michael Joner, Gaku Nakazawa … (2007)

Late stent thrombosis (LST) after Cypher and Taxus drug-eluting stent placement has emerged as a major concern. Although the clinical predictors of LST have been reported, specific morphological and histological correlates of LST remain unknown. From a registry totaling 81 human autopsies of drug-eluting stents, 46 (62 lesions) had a drug-eluting stent implanted >30 days. We identified 28 lesions with thrombus and compared those with 34 of similar duration without thrombosis using computer-guided morphometric and histological analyses. LST was defined as an acute thrombus within a coronary artery stent in place >30 days. Multiple logistic generalized estimating equations modeling demonstrated that endothelialization was the best predictor of thrombosis. The morphometric parameter that best correlated with endothelialization was the ratio of uncovered to total stent struts per section. A univariable logistic generalized estimating equations model of occurrence of thrombus in a stent section versus ratio of uncovered to total stent struts per section demonstrated a marked increase in risk for LST as the number of uncovered struts increased. The odds ratio for thrombus in a stent with a ratio of uncovered to total stent struts per section >30% is 9.0 (95% CI, 3.5 to 22). The most powerful histological predictor of stent thrombosis was endothelial coverage. The best morphometric predictor of LST was the ratio of uncovered to total stent struts. Heterogeneity of healing is a common finding in drug-eluting stents with evidence of LST and demonstrates the importance of incomplete healing of the stented segment in the pathophysiology of LST.

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Vascular responses to drug eluting stents: importance of delayed healing.

Michael Joner, Frank Kolodgie, Aloke V. Finn … (2007)

Polymer-based sirolimus- (Cypher) and paclitaxel-eluting (Taxus) drug eluting stents have become the treatment of choice for patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention (PCI). Although these stents reduce rates of restenosis compared with bare metal stents (BMS), late thrombosis, a life threatening complication, has emerged as a major safety concern. Our understanding of the pathophysiology of late DES thrombosis is derived from animal and human pathologic samples taken after implantation of these devices. These data indicate that both DES cause substantial impairment in arterial healing characterized by lack of complete reendothelialization and persistence of fibrin when compared with BMS. This delayed healing is the primary substrate underlying all cases of late DES thrombosis at autopsy. Several additional risk factors for late stent thrombosis such as penetration of necrotic core, malapposition, overlapping stent placement, excessive stent length, and bifurcation lesions represent additional barriers to healing and should be avoided if DES are to be used to minimize the risk of late thrombosis. Because the time course of complete healing with DES in man is unknown, the optimal duration of antiplatelet treatment remains to be determined.

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Short- and long-term outcomes with drug-eluting and bare-metal coronary stents: a mixed-treatment comparison analysis of 117 762 patient-years of follow-up from randomized trials.

Nicholas Amoroso, Mario Fusaro, Deepak Bhatt … (2012)

Drug-eluting stents (DES) have been in clinical use for nearly a decade; however, the relative short- and long-term efficacy and safety of DES compared with bare-metal stents (BMS) and among the DES types are less well defined. PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials, until March 2012, that compared any of the Food and Drug Administration-approved durable stent and polymer DES (sirolimus-eluting stent [SES], paclitaxel-eluting stent [PES], everolimus-eluting stent [EES], zotarolimus-eluting stent [ZES], and ZES-Resolute [ZES-R]) with each other or against BMS for de novo coronary lesions, enrolling at least 100 patients and with follow-up of at least 6 months. Short-term (≤ 1 year) and long-term efficacy (target-vessel revascularization, target-lesion revascularization) and safety (death, myocardial infarction, stent thrombosis) outcomes were evaluated and trial-level data pooled by both mixed-treatment comparison and direct comparison analyses. From 76 randomized clinical trials with 117 762 patient-years of follow-up, compared with BMS, each DES reduced long-term target-vessel revascularization (39%-61%), but the magnitude varied by DES type (EES~SES~ZES-R>PES~ZES>BMS), with a >42% probability that EES had the lowest target-vessel revascularization rate. There was no increase in the risk of any long-term safety outcomes, including stent thrombosis, with any DES (versus BMS). In addition, there was reduction in myocardial infarction (all DES except PES versus BMS) and stent thrombosis (with EES versus BMS: Rate ratio, 0.51; 95% credibility interval, 0.35-0.73). The safest DES appeared to be EES (>86% probability), with reduction in myocardial infarction and stent thrombosis compared with BMS. Short-term outcomes were similar to long-term outcomes, with SES, ZES-R, and everolimus-eluting stent being the most efficacious and EES being the safest stent. DES are highly efficacious at reducing the risk of target-vessel revascularization without an increase in any safety outcomes, including stent thrombosis. However, among the DES types, there were considerable differences, such that EES, SES, and ZES-R were the most efficacious and EES was the safest stent.

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Author and article information

Journal

Journal ID (nlm-ta): Eur Heart J

Journal ID (iso-abbrev): Eur. Heart J

Journal ID (publisher-id): eurheartj

Title: European Heart Journal

Publisher: Oxford University Press

ISSN (Print): 0195-668X

ISSN (Electronic): 1522-9645

Publication date (Print): 07 July 2018

Publication date (Electronic): 21 June 2018

Publication date PMC-release: 21 June 2018

Volume: 39

Issue: 26 , Focus Issue on Interventional Cardiology

Pages: 2460-2468

Affiliations

[1 ]Shonan Kamakura General Hospital, Kamakura, Japan, and Sapporo Higashi Tokushukai Hospital, Sapporo, Japan

[2 ]Duke University Medical Center and Duke Clinical Research Institute, Durham, NC, USA

[3 ]Kyoto Katsura Hospital, Kyoto, Japan

[4 ]Mount Sinai School of Medicine, New York, NY, USA

[5 ]Cardiovascular Research Foundation and Columbia University, New York, NY, USA

[6 ]OrbusNeich Medical, Inc., Fort Lauderdale, FL, USA

[7 ]OrbusNeich Japan, Tokyo, Japan

[8 ]Miyazaki Medical Association Hospital, Miyazaki, Japan

[9 ]Cardiology Associates of North Mississippi, Tupelo, MS, USA

[10 ]Atlantic Clinical Research Collaborative - Cardiology, Atlantis, FL, USA

[11 ]Morristown Medical Center, Morristown, NJ, USA

[12 ]University Hospitals of Cleveland, Cleveland, OH, USA

Author notes

Corresponding author. Tel: +1-919-668-8422, Fax: +1-919-668-7518, Email: mitchell.krucoff@ 123456duke.edu

Article

Publisher ID: ehy275

DOI: 10.1093/eurheartj/ehy275

PMC ID: 6037087

PubMed ID: 29931092

SO-VID: e9b3e200-4e29-4280-aa5f-b2ffacac4d01

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 12 December 2017

Date revision received : 02 March 2018

Date accepted : 13 June 2018

Page count

Pages: 9

Funding

Funded by: OrbusNeich Medical, Inc

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Most cited references 11

Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization.

Vascular responses to drug eluting stents: importance of delayed healing.

Short- and long-term outcomes with drug-eluting and bare-metal coronary stents: a mixed-treatment comparison analysis of 117 762 patient-years of follow-up from randomized trials.

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