Efficacy and safety of zotarolimus-eluting and sirolimus-eluting coronary stents in routine clinical care (SORT OUT III): a randomised controlled superiority trial

Summary

Background

In low-risk patients, the zotarolimus-eluting stent has been shown to reduce rates of restenosis without increasing the risk of stent thrombosis. We compared the efficacy and safety of the zotarolimus-eluting stent versus the sirolimus-eluting stent in patients with coronary artery disease who were receiving routine clinical care with no direct follow-up.

Methods

We did a single-blind, all-comer superiority trial in adult patients with chronic stable coronary artery disease or acute coronary syndromes, and at least one target lesion. Patients were treated at one of five percutaneous coronary intervention centres between January, 2006, and August, 2007. Computer-generated block randomisation and a telephone allocation service were used to randomly assign patients to receive the zotarolimus-eluting or the sirolimus-eluting stent. Data for follow-up were obtained from national Danish administrative and health-care registries. The primary endpoint was a composite of major adverse cardiac events within 9 months: cardiac death, myocardial infarction, and target vessel revascularisation. Intention-to-treat analyses were done at 9-month and 18-month follow-up. This trial is registered with ClinicalTrials.gov, number NCT00660478.

Findings

1162 patients (1619 lesions) were assigned to receive the zotarolimus-eluting stent, and 1170 patients (1611 lesions) to receive the sirolimus-eluting stent. 67 patients (72 lesions) had stent failure, and six patients were lost to follow-up. All randomly assigned patients were included in analyses at 9-month follow-up; 2200 patients (94%) had completed 18-month follow-up by the time of our assessment. At 9 months, the primary endpoint had occurred in a higher proportion of patients treated with the zotarolimus-eluting stent than in those treated with the sirolimus-eluting stent (72 [6%] vs 34 [3%]; HR 2·15, 95% CI 1·43–3·23; p=0·0002). At 18-month follow-up, this difference was sustained (113 [10%] vs 53 [5%]; 2·19, 1·58–3·04; p<0·0001). For patients receiving the zotarolimus-eluting stent and those receiving the sirolimus-eluting stent, all cause-mortality was similar at 9-month follow-up (25 [2%] vs 18 [2%]; 1·40, 0·76–2·56; p=0·28), but was significantly different at 18-month follow-up (51 [4%] vs 32 [3%]; 1·61, 1·03–2·50; p=0·035).

Interpretation

The sirolimus-eluting stent is superior to the zotarolimus-eluting stent for patients receiving routine clinical care.

Funding

Cordis and Medtronic.

Introduction

Introduction of sirolimus and paclitaxel drug-eluting stents more than halved the need for new revascularisations after implantation of coronary artery stents.1, 2, 3, 4, 5, 6 However, the safety of these first-generation drug-eluting stents was questioned after reports of their association with an increased risk of late and very late stent thrombosis.4, 7 This risk might be explained by insufficient healing of the vessel wall caused by delayed neointimal stent coverage, and by late-acquired incomplete stent apposition associated with inflammation and late remodelling, leaving naked stent struts as a nidus for thrombotic events.8, 9, 10 Whether adverse vessel wall reactions to implantation of drug-eluting stents are related to the type of drug eluted from the stent or to the polymer coating of the stent is unknown.8, 9, 10

Such safety concerns led to recommendations for long-term dual antiplatelet therapy after implantation of drug-eluting stents.¹¹ In this context, the second-generation zotarolimus-eluting stent seemed to be a safer alternative to sirolimus-eluting and paclitaxel-eluting stents. The zotarolimus-eluting stent induced uniform and complete neointimal coverage of the stent struts, and was associated with a reduced occurrence of late-acquired incomplete stent apposition.12, 13 Also, the polymer phosphorylcholine coating used for drug elution from the zotarolimus-eluting stent is a synthetic copy of the predominant phospholipid in the outer membrane of red blood cells and seemed to be a safer, non-inflammatory alternative to the polymers used for sirolimus-eluting and paclitaxel-eluting stents.¹⁴

Findings from the first randomised trials generated optimism regarding the clinical effectiveness of the zotarolimus-eluting stent.15, 16, 17 However, these trials were restricted to patients with a single artery stenosis, excluded complex lesions such as bifurcation lesions and chronic total occlusions, were limited by angiographic inclusion criteria, excluded patients with recent myocardial infarction, and were powered to assess only angiographic late lumen loss or target vessel failure.15, 16, 17 We therefore aimed to compare the efficacy and safety (defined by cardiac death, myocardial infarction, and stent thrombosis) of the zotarolimus-eluting stent versus the extensively used and validated sirolimus-eluting stent in a routine clinical setting with no direct follow-up.