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

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.

Figure 1

Diagram of patient and procedural follow-up for Cohorts A, B, and C. Cohort A: 6-month OCT and 12-month OCT, FFR, and angiographic assessments. Cohort B: 12-month OCT, FFR, and angiographic assessments. Cohort C: 12-month FFR and angiographic assessments. EES, everolimus-eluting stent; FFR, fractional flow reserve; FU, follow-up; ITT, intention-to-treat; OCT, optical coherence tomography.

Figure 2

One-year Kaplan–Meier curves for target vessel failure (intention-to-treat population). CI, confidence interval; EES, everolimus-eluting stent; HR, hazard ratio.

Take home figure

Combo Stent Technology in HARMONEE. (A) Combo stent design: with abluminal bioabsorbable polymer-eluting sirolimus and endoluminal anti-CD34+ antibody. (B) Anti-CD34+ antibody mechanism of action: attracting CD34+ endothelial progenitor cells to stent site that mature to functional endothelium. (C) HARMONEE mechanistic ‘healthy endothelium’ surrogate superiority: representative images index procedure (baseline) and 1-year angiographic results with Combo and everolimus-eluting stents that are quantitatively similar, but optical coherence tomography at 1 year shows more complete strut coverage and more homogeneous tissue with Combo than with everolimus-eluting stent. EPC, endothelial progenitor cell; FU, follow-up; OCT, optical coherence tomography.