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Randomized Comparison of the Polymer-Free Biolimus-Coated BioFreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention

The SORT OUT IX Trial
and The Sort Out IX Study Group
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.119.040241Circulation. 2020;141:2052–2063

Abstract

Background:

In patients with increased bleeding risk, the biolimus A9-coated BioFreedom stent, a stainless steel drug-coated stent free from polymer, has shown superiority compared with a bare-metal stent. The aim of this study was to investigate whether the BioFreedom stent is noninferior to a modern ultrathin strut biodegradable polymer cobalt-chromium sirolimus-eluting Orsiro stent in an all-comers patient population treated with percutaneous coronary intervention.

Methods:

The SORT OUT IX trial (Scandinavian Organization for Randomized Trials With Clinical Outcome IX), was a large-scale, registry-based, randomized, multicenter, single-blind, 2-arm, noninferiority trial. The primary end point, major adverse cardiovascular events, was defined as the composite of cardiac death, myocardial infarction not related to any segment other than the target lesion, or target lesion revascularization within 1 year, analyzed by intention-to-treat. The trial was powered to assess noninferiority for major adverse cardiovascular events of the BioFreedom stent compared with the Orsiro stent with a predetermined noninferiority margin of 0.021.

Results:

Between December 14, 2015 and April 21, 2017, 3151 patients were assigned to treatment with the BioFreedom stent (1572 patients, 1966 lesions) or to the Orsiro stent (1579 patients, 1985 lesions). Five patients were lost to follow-up because of emigration (99.9% follow-up rate). Mean age was 66.3±10.9, diabetes mellitus was seen in 19.3% of patients, and 53% of the patients had acute coronary syndromes. At 1 year, intention-to-treat analysis showed that 79 (5.0%) patients, who were assigned the BioFreedom stent, and 59 (3.7%), who were assigned the Orsiro stent, met the primary end point (absolute risk difference 1.29% [upper limit of one-sided 95% CI 2.50%]; Pnoninferiority=0.14). Significantly more patients in the BioFreedom stent group had target lesion revascularization than those in the Orsiro stent group (55 [3.5%] vs 20 [1.3%], rate ratio 2.77 [95% CI, 1.66–4.62]; P<0.0001).

Conclusions:

The biolimus A9-coated BioFreedom polymer-free stent did not meet criteria for noninferiority for major adverse cardiovascular events at 12 months when compared with the ultrathin strut biodegradable polymer sirolimus-eluting Orsiro stent in an all-comers population

Registration:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT02623140.

Clinical Perspective

What Is New?

  • The SORT OUT IX trial (Scandinavian Organization for Randomized Trials with Clinical Outcome IX) showed that the polymer-free drug-coated BioFreedom stent was not noninferior to the ultrathin strut biodegradable polymer Orsiro in unselected patients for major adverse cardiovascular events at 1 year.

  • Safety did not differ significantly. However, the biolimus-eluting BioFreedom stent was associated with an increased risk of target lesion revascularization

  • SORT OUT IX is the first study to compare the biolimus A9-coated BioFreedom stent with a modern drug-eluting stent in a population-based all-comers setting

What Are the Clinical Implications?

  • SORT OUT IX is the first study to demonstrate that the biolimus A9-coated BioFreedom stent is not noninferior to a modern drug-eluting stent in a population-based all-comers setting.

Introduction

Editorial, see p 2064

Drug-eluting stents (DES) with either biodegradable polymers or more biocompatible durable polymers have been developed1–4 and may have the potential to reduce the risk of late events after percutaneous coronary intervention with DES. The durable polymer used for first- and second-generation DES has been suspected to be a potential trigger for vessel wall inflammation and late adverse outcomes.5 The ultrathin strut biodegradable polymer sirolimus-eluting Orsiro stent has shown noninferiority for target lesion failure to the durable polymer everolimus-eluting stents in an all-comer trial,2 a lower target lesion failure rate,6 and late/very late stent thrombosis was found after 2 years in an international trial.7 In the SORT OUT VII trial (Scandinavian Organization for Randomized Trials with Clinical Outcome VII), the sirolimus-eluting Orsiro stent was noninferior to the biodegradable polymer biolimus-eluting Nobori stent.8

Nonpolymeric drug-coated stents have been developed9–11 as an alternative to durable and biodegradable polymeric DES. However, the absence of a drug carrier has previously been associated with lesser efficacy at inhibiting neointimal hyperplasia, most probably caused by insufficient or uncontrolled drug delivery at the target coronary site.9,10 A polymer-free and carrier-free biolimus A9-coated stent, which is a highly lipophilic sirolimus analogue that transfers the biolimus A9 into the vessel wall over a period of 1 month,11 is technologically different, because the stent is drug-coated and free from polymer. In a first-in-human trial, the biolimus A9-coated BioFreedom stent demonstrated noninferiority for late lumen loss within the first year versus the paclitaxel-eluting stent. At 5 years, clinical event rates were similar, without occurrence of stent thrombosis. In patients with high bleeding risk, the biolimus A9-coated BioFreedom stent was superior to a bare-metal stent in patients treated with only 1 month of dual antiplatelet therapy.12,13 However, no study has previously investigated whether the biolimus A9-coated BioFreedom stent has similar outcome results as a modern ultrathin strut drug-eluting stent. The SORT OUT IX trial, a registry-based, randomized, controlled noninferiority trial, using registry detection of clinically driven events, compared the polymer-free biolimus A9-coated BioFreedom stent with the sirolimus-eluting Orsiro stent in an all-comers population.

Methods

Patients and Study Design

SORT OUT IX is a randomized, multicenter, single-blind, all-comer, 2-arm, blinded end point, noninferiority trial, comparing Biolimus A9-coated BioFreedom, a stainless steel drug-coated stent to the biodegradable polymer sirolimus-eluting Orsiro stent in the treatment of atherosclerotic coronary artery lesions. The trial was carried out at 3 university hospitals in Western Denmark (Aarhus, Aalborg, and Odense) and at Copenhagen University Hospital. Patients were eligible if they were >18 years old and had coronary artery disease with >50% diameter stenosis requiring treatment with a drug-eluting stent. If multiple lesions were treated, the allocated study stent had to be used in all lesions. Exclusion criteria were an allergy to aspirin, clopidogrel, ticagrelor, prasugrel, sirolimus, or biolimus; participation in another randomized stent trial; inability to provide written informed consent; or life expectancy of <1 year. The study complied with the Declaration of Helsinki and was approved by the Regional Committees on Health Research Ethics for Southern Denmark (S-20150132) and the Danish Data Protection Agency (15/47707). All patients provided written informed consent for trial participation before randomization. The data, analytical methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.

Randomization

The investigators enrolled the patients who were randomly allocated to treatment groups after diagnostic coronary angiography and before percutaneous coronary intervention. Block randomization by center (permuted blocks of random sizes [2/4/6]) was used to assign patients in a 1:1 ratio to receive the biolimus A9-coated BioFreedom, a stainless steel drug-coated stent (Biosensors, Morges, Switzerland) or the biodegradable polymer sirolimus-eluting stent (Orsiro; Biotronik, Bülach, Switzerland). The allocation sequence, stratified by sex and presence of diabetes mellitus, was computer-generated by an independent organization. Patients were assigned to treatment through a web-based Trial Partner randomization system. All individuals who analyzed the data were blinded, whereas operators were not blinded to treatment assignment.

Study Stent, Procedures, and Antithrombotic Therapy

The biolimus A9-coated BioFreedom stent was available in 6 diameters (2.25, 2.50, 2.75, 3.00, 3.50, and 4.00 mm) and 8 lengths (8, 11, 14, 18, 24, 28, 33, and 38 mm). The stent strut thickness is 120 µm. The stent platform is composed of stainless steel, a polymer-free and carrier-free drug-coated stent. The stent transfers umirolimus (also known as biolimus A9), a highly lipophilic sirolimus analogue (15.6 μg/mm2),14 into the vessel wall over a period of 1 month.

The sirolimus-eluting Orsiro stent was available in 6 diameters (2.25, 2.50, 2.75, 3.00, 3.50, and 4.00 mm) and 9 lengths (9, 13, 15, 18, 22, 26, 30, 35, and 40 mm). The thickness of the stent struts is 60 µm for stents with a nominal diameter of ≤3.0 mm and 80 µm for the 2 larger sizes. The sirolimus-eluting Orsiro stent surface is fully coated with a layer of amorphous hydrogen-rich silicon carbide (aSiC:H), which acts as a diffusion barrier, seals the bare-metal surface, and reduces ion release. The diffusion barrier silicon carbide coating layer consists of silicon carbide, a ceramic material, a chemical compound of the element silicon, and the element carbon. The biodegradable polymer compound, a carrier material for the supply and release of sirolimus, is a high molecular poly-L-lactic acid. The stent body surface is completely coated by a matrix, consisting of the carrier poly-L-lactic acid and the active substance sirolimus, which has an abluminal thickness of 7.5 µm and a luminal coating of 3.5 µm. The polymer is fully degraded in 12 to 24 months. The drug load is 1.4 µg per mm1,2 and the drug will be released over a period of 12 to 14 weeks.

Stents were implanted in accordance with standard techniques. Direct stenting was allowed. Full lesion coverage was attempted by implanting 1 or more stents. DES other than the allocated stent and bare-metal stents were not allowed unless the allocated study stent could not be implanted. In such situations, balloon angioplasty alone or other stents were allowed. Patients were on acetylsalicylic acid (loading dose of 300 mg) before stent implantation and loaded with either ticagrelor 180 mg, clopidogrel 600 mg, or prasugrel 60 mg. Combination of dual antiplatelet therapy was left to the discretion of the participating center. Dual antiplatelet therapy was recommended for 6 months in patients with stable angina pectoris and for 12 months in patients with unstable angina pectoris or acute myocardial infarction. Unfractionated heparin dose (70–100 IU/kg) was given before the procedure. Glycoprotein IIb/IIIa inhibitors or Bivalirudin were used at the operator’s discretion.

Outcome Measures

The primary end point of major adverse cardiovascular events (MACE) was defined as the composite of cardiac death, myocardial infarction not related to any segment other than the target lesion, or target lesion revascularization with percutaneous coronary intervention or coronary artery bypass operation within 12 months. Follow-up was not scheduled, but clinically driven on the basis of patients seeking care from the health system for self-reported angina or equivalent symptoms. Secondary end points comprised the individual components of the primary end point (ie, cardiac death, myocardial infarction, and target lesion revascularization). Other secondary end points included all-cause death (cardiac and noncardiac); target vessel revascularization; stent thrombosis (definite, probable, possible, and overall stent thrombosis, according to the Academic Research Consortium definition);15 and a patient-related composite end point (all death, all myocardial infarctions, or any revascularization).

Definitions

Cardiac death was defined as any death because of an evident cardiac cause, any death related to percutaneous coronary intervention, death from unknown causes or an unwitnessed death.

Myocardial infarction was defined using the third definition used by the European Society of Cardiology, the American Heart Association, the American College of Cardiology and the World Heart Federation.16 Biomarkers were not assessed at the time of the index percutaneous coronary intervention procedure. Myocardial infarction not related to any segment other than the target lesion: any myocardial infarction that is not clearly attributable to a nontarget vessel.

Stent thrombosis was defined using the Academic Research Consortium15 definitions for definite, probable, or possible stent thrombosis.

Target vessel revascularization was defined as any repeat intervention, either with percutaneous coronary intervention or surgical bypass, of any segment within the entire major coronary vessel that was proximal or distal to a target lesion, including upstream and downstream branches, and the target lesion itself.

Target lesion revascularization was defined as repeat revascularization with either percutaneous coronary intervention or surgical bypass caused by a >50% stenosis within the stent or within a 5 mm border proximal or distal to the stent.

Comorbidity data on all hospital diagnoses from the Danish National Registry of Patients, covering all Danish hospitals from 1977 until the implantation date,17 were obtained for all patients and the Charlson Comorbidity Index score18 was computed.

Clinical Event Detection

The study was on the basis of clinically driven event detection, and no dedicated follow-up was scheduled. At 12-months follow-up, data on mortality, hospital admission, coronary angiography, repeat percutaneous coronary intervention, and coronary artery bypass surgery were obtained from the following national Danish administrative and healthcare registries: the Civil Registration System;19 the Western Denmark Heart Registry;20,21 and the Danish National Registry of Patients,17 the latter which maintains records on all hospitalizations in Denmark.

Universal tax-supported health care, guaranteeing residents free access to general practitioners and hospitals, is provided by the Danish National Health Service. The Danish Civil Registration System has kept electronic records on sex, birth date, residence, emigration date, and vital status changes since 1968,19 with daily updates. The 10-digit civil registration number assigned at birth and used in all registries allows accurate record linkage. Loss to follow-up was minimized in the study, as vital status data for our study participants was provided by the Civil Registration System. The National Registry of Causes of Deaths and the Danish National Registry of Patients provided information on causes of death and diagnoses assigned by the treating physician during hospitalizations (coded according to the International Classification of Diseases, 10th revision).17

An independent event committee reviewed all end points and source documents to adjudicate causes of death, reasons for hospital admission, and diagnosis of myocardial infarction. Two dedicated percutaneous coronary intervention operators at each participating center independently reviewed cine films for the event committee to classify stent thrombosis, target lesion revascularization, and target vessel revascularization (with either percutaneous coronary intervention or coronary artery bypass grafting). The independent event committee was blinded to study stent type assignment during the adjudication process. This methodology has been used in previous SORT OUT studies.8,22–25

Statistical Analysis

The SORT OUT IX study was powered for noninferiority of the BioFreedom stent to the Orsiro stent for the primary end point at 12 months. An event rate of 4.2% was assumed in each stent group. With a sample size of 1563 patients in each treatment group, a 2-group, large-sample normal approximation test of proportions with a 1-sided 0.050 significance level would have 90% power to detect noninferiority with a predetermined noninferiority margin of 2.1%. The noninferiority margin was determined at 50% of expected control event rate, on the basis of clinical judgment.26 The sample size of 1563 in each of the 2 treatment groups assumed 0% lost-to-follow-up rate, given the use of the Civil Registration System. Enrolling 3150 patients would allow for a 0.8% loss to follow-up. Noninferiority was tested with a Farrington-Manning test.

Distributions of continuous variables between the 2 study arms were compared using the 2-sample t test (or Cochran test for cases of unequal variance) or the Mann-Whitney U test, depending on whether the data followed a normal distribution. Distributions of categorical variables were compared using the χ2 test. For analyses of all end points, follow-up continued until the date of an end point event, death, or until 12 months after stent implantation or emigration, whichever came first. Incident proportions were calculated and cumulative incidence curves were constructed up to 1 year of follow-up, accounting for the competing risk of death (in cases of death not included in the outcome) according to the approach of Gooley et al.27 In presence of competing risk, the Kaplan–Meier estimator that treats the competing events as independent censoring is an upward biased estimate of the cumulative incidence function. In such cases, the cumulative incidence of the outcome event depends not only on the cause-specific hazard of that event but also on the hazard of a competing event.28 Therefore, cumulative incidence curves were constructed up to 1 year of follow-up, accounting for the competing risk of death following the approach of Gooley et al.27 The reference group comprised the patients randomized to the sirolimus-eluting Orsiro stent for overall and subgroup analyses. Incidence rate ratios (referred to as rate ratios [RR]) were calculated for MACE at 12-months follow-up and for prespecified patient subgroups (on the basis of baseline demographic and clinical characteristics). In all analyses, the intention-to-treat principle was used. Apart from the inferiority testing of the primary end point, a 2-sided P value <0.05 indicated statistical significance. Analyses were performed on a patient level. SAS software (version 9.4) was used for the analyses. This trial is registered with URL: https://www.clinicaltrials.gov; Unique identifier: NCT02623140.

Results

Between December 14, 2015 and April 21, 2017, 3151 patients were randomly assigned to receive either the biolimus-eluting BioFreedom stent (1572 patients (1966 lesions)) or the sirolimus-eluting Orsiro stent (1579 patients (1985 lesions; Figure 1). Five patients were lost to follow-up because of emigration (total follow-up: 99.9%). Baseline patient characteristics (Table 1), lesion, and procedure characteristics did not differ significantly between the 2 stent groups (Table 2). Mean age was 66.3±10.9, diabetes mellitus was seen in 19.3% of the patients, and a high proportion of patients in both groups had acute coronary syndromes, multi-vessel disease, and complex lesions (Table 1). The rate of device delivery failure did not differ significantly between the 2 stent groups (biolimus-eluting BioFreedom stent n=45 [2.3%] vs sirolimus-eluting Orsiro stent n=39 [2.9%]; P=0.48).

Table 1. Baseline Characteristics of the Study Population

BioFreedom Stent (N=1572)Orsiro Stent (N=1579)P Value
Age, mean (SD), years66.4 (10.7)66.1 (11.1)0.35
Men, n (%)1219 (77.5)1221 (77.3)0.88
Diabetes mellitus, n (%)304 (19.3)303 (19.2)0.92
Hypertension, n (%)893 (59.0)850 (56.0)0.21
Hypercholesterolemia, n (%)830 (55.0)777 (51.5)0.16
Current smoker, n (%)443 (29.8)437 (29.3)0.78
Body mass index, mean (SD), kg/m227.8 (7.5)27.6 (8.0)0.47
Previous myocardial infarction, n (%)224 (14.7)234 (15.2)0.53
Previous percutaneous coronary intervention, n (%)322 (20.9)311 (20.9)0.59
Previous coronary artery bypass grafting, n (%)130 (8.4)108 (7.0)0.13
Indication for percutaneous coronary intervention, n (%)0.62
 ST-segment–elevation myocardial infarction367 (23.3)397 (25.1)
 Non–ST-segment–elevation myocardial infarction or unstable angina454 (28.9)453 (28.7)
 Stable angina671 (42.7)645 (40.8)
 Other80 (5.1)84 (5.3)
Comorbidity index score, n (%)0.60
 0852 (54.2)854 (54.0)
 1-2517 (32.9)539 (34.1)
 3+203 (12.9)186 (11.9)

Differences between stents were tested by χ2 statistics in categorical variables presented numbers (n) and proportions (%) and by t test in continuous variables presented as mean and standard deviation (SD) and with Cochran-Cox approximation in case of unequal variances.

Table 2. Baseline Lesion and Procedure Characteristics and Treatment

BioFreedom Stent (N=1572)Orsiro Stent (N=1579)P Value
Number of lesions19661985
Target lesions per patient, n (%)0.57
 11209 (76.9)1196 (75.7)
 2282 (17.9)311 (19.7)
 367 (4.3)59 (3.7)
 >314 (0.9)13 (0.8)
 n per patient, mean (SD)1.3 (0.6)1.3 (0.6)0.70
Target vessel location, n (%)0.81
 Left main artery49 (2.5)44 (2.2)
 Left anterior descending artery845 (43.0)856 (43.0)
 Left circumflex artery465 (23.7)445 (22.4)
 Right artery589 (30.0)621 (31.3)
Saphenous vein graft18 (0.9)17 (0.9)
Lesion type, n (%)0.40
 A211 (10.8)216 (10.9)
 B1561 (28.6)612 (31.0)
 B2526 (26.8)503 (25.5)
 C662 (33.8)645 (32.6)
Chronic total occlusion lesions, n (%)100 (5.1)81 (4.1)0.07
Bifurcation lesions, n (%)368 (18.8)407 (20.6)0.09
Lesion length > 18 mm, n (%)814 (41.5)834 (42.2)0.65
Lesion length (mm), mean (SD)19.9 (14.5)19.3 (13.8)0.18
Lesion length (mm), median (IQR)16 (12–24)16.0 (12–24)0.50
Reference vessel size (mm), mean (SD)3.4 (0.6)3.6 (0.6)0.51
n stents, mean (SD)
 Per patient1.3 (0.6)1.2 (0.6)0.13
 Per lesion1.6 (1.0)1.6 (0.9)0.28
Total stent length (mm), mean (SD)
 Per patient31.1 (21.9)30.6 (19.8)0.0.48
 Per lesion24.3 (13.6)0.32
 Per lesion (mm), median (IQR)18 (14–28)22 (15–30)0.22
Direct stenting, n (%)160 (8.2)194 (9.8)0.21
Stent delivery failure, n (%)45 (2.3)39 (2.0)0.48
Maximum pressure (atm), median (IQR)18.0 (16.0–20.0)18.0 (16.0–20.0)0.92
Length of procedure (minutes), median (IQR)24.0 (15.0–39.0)23.0 (15.0–36.0)0.03
Flouro time (minutes), median (IQR)7.0 (4.0–12.7)7.0 (4.0–12.7)0.08
Contrast (ml), median (IQR)80.0 (50.0–120.0)80.0 (50.0–110.0)0.04
Use of glycoprotein IIb/IIIa inhibitors, n (%)47 (3.0%)50 (3.2)0.77
Use of bivalirudin, n (%)209 (14.2)217 (14.5)0.77

Differences between stents were tested by χ2 statistics in categorical variables presented numbers (n) and proportions (%), by t test in continuous variables presented as mean and standard deviation (SD) and with Cochran-Cox approximation in case of unequal variances, and by Mann-Whitney U test in continuous variables presented as median and interquartile range (IQR).

Figure 1.

Figure 1. SORT OUT IX: CONSORT flow diagram.

At 1 year, the composite end point MACE occurred in 79 patients (5.0%) in the biolimus-eluting BioFreedom group and in 59 patients (3.7%) in the sirolimus-eluting Orsiro group (Figure 2 and Table 3). Noninferiority of the biolimus-eluting BioFreedom stent could not be demonstrated, with an absolute risk difference of 1.29% and the upper limit of 1-sided 95% CI of 2.50% (P=0.14 in 1-sided noninferiority test).

Table 3. Clinical Outcomes

BioFreedom Stent (N=1572)Orsiro Stent (N=1579)Incidence Rate Ratio (95% CI)P Value
Events at 30 days, n patients (%)
Death
 All-cause mortality7 (0.4)14 (0.9)0.50 (0.30–1.24)0.14
 Cardiac7 (0.4)13 (0.8)0.54 (0.21–1.35)0.19
 Non-cardiac01 (0.1)
Myocardial infarction17 (1.1)19 (1.2)0.90 (0.46–1.73)0.74
Target vessel revascularization16 (1.0)31 (2.0)0.51 (0.28–0.94)0.03
Target lesion revascularization6 (0.4)10 (0.6)0.60 (0.22–1.65)0.32
Events at 12 mo, n patients (%)
Major adverse cardiovascular events*79 (5.0)59 (3.7)1.34 (0.96–1.89)0.09
Noninferiority
0.135
Death
 All-cause mortality31 (2.0)43 (2.7)0.72 (0.45–1.14)0.16
 Cardiac16 (1.0)29 (1.8)0.55 (0.30–1.02)0.056
 Noncardiac15 (1.0)14 (0.9)1.07 (0.52–2.21)0.86
Myocardial infarction not related to other lesion26 (1.7)26 (1.6)1.00 (0.58-1.72)0.99
Myocardial infarction37 (2.4)40 (2.5)0.92 (0.59-1.45)0.73
Stent thrombosis
 Definite11 (0.7)11 (0.7)1.00 (0.43–2.30)0.99
  Acute (<24 h)3 (0.2)4 (0.3)0.75 (0.17–3.35)0.71
  Subacute (24 h to 30 days)1 (0.1)5 (0.3)0.20 (0.02–1.71)0.14
  Late (> 30 days)7 (0.4)2 (0.1)3.50 (0.73–16.8)0.12
 Probable5 (0.3)7 (0.4)0.71 (0.23–2.25)0.56
 Definite or probable16 (1.0)18 (1.1)0.89 (0.45–1.74)0.73
 Possible9 (0.6)16 (1.0)0.56 (0.25–1.27)0.17
 Definite, probable, or possible25 (1.6)34 (2.2)0.73 (0.44–1.23)0.24
Target vessel revascularization76 (4.8)56 (3.5)1.35 (0.96-1.92)0.09
Target lesion revascularization55 (3.5)20 (1.3)2.77 (1.66-4.62)0.0001
Patient related end point (death, myocardial infarction, any revascularization)211 (13.4)216 (13.7)0.97 (0.80-1.18)0.75

Differences in incidence rates were tested using χ2 statistics

*Primary end point: Major adverse cardiovascular events - Composite of cardiac death, myocardial infarction not related to other lesion, and target lesion revascularization with either percutaneous coronary intervention or coronary artery bypass grafting).

†Academic Research Consortium definition.

Figure 2.

Figure 2. Cumulative incidences for major adverse cardiac events.A, Major adverse cardiac events. B, Cardiac death. C, Myocardial infarction, D, Target lesion revascularization. E, Definite stent thrombosis. F, Definite or probable stent thrombosis. BES indicates biolimus-eluting stent; RR, incident rate ratio; and SES, sirolimus-eluting stent.

Cumulative incidences of death, cardiac death, and myocardial infarction were comparable up to 1 year across the 2 stent groups (Figure 2), and rates of these end points at 1 year did not differ significantly (Table 3). However, the incidence proportion and the rates of target lesion revascularization were higher in the biolimus-eluting BioFreedom stent treated patients (n=55 [3.5%]) compared with the sirolimus-eluting Orsiro treated patients (n=20 [1.3%]), RR=2.77 [95% CI, 1.66–4.62]; P<0.0001; Figure 2 and Table 3).

The cumulative incidence of definite stent thrombosis up to 1 year showed a comparable pattern in the 2 stent groups, and rates of definite stent thrombosis at 1 year were not different between the 2 stent groups. (Figure 2 and Table 3). Among patients with definite stent thrombosis within the first year, 22 of 22 patients (100%) were on dual antiplatelet therapy with aspirin and clopidogrel/ticagrelor/prasugrel.

Findings for the primary end point MACE were consistent across prespecified subgroup analyses (Figure 3).

Figure 3.

Figure 3. Prespecified subgroup analysis for the primary end point at 1-year follow-up. P values in the Forest plot are all 2-sided for interaction. BES indicates biolimus-eluting stent; LAD, left anterior descending artery; MI, myocardial infarction; PCI, percutaneous coronary intervention; SES, sirolimus-eluting stent; and STEMI, ST-elevation–myocardial infarction.

In a sensitivity analysis, the analysis for the primary end point was performed as a per-protocol/as-treated analysis. The result was similar to that obtained with the intention-to-treat analysis: MACE occurred in 74 patients (4.9%) in the biolimus-eluting BioFreedom group and in 56 patients (3.6%) in the sirolimus-eluting Orsiro group. Noninferiority of the biolimus-eluting BioFreedom stent could also not be demonstrated in the per-protocol/as treated analysis with an absolute risk difference of 1.21% and the upper limit of 1-sided 95% CI of 2.43% (P=0.11 in 1-sided noninferiority test).

A total of 84 lesions were not treated with the study stent. Crossover was seen in 18 lesions: 12 lesions for which the use of biolimus-eluting BioFreedom stent was intended were treated with sirolimus-eluting Orsiro stent and 6 lesions where the use of sirolimus-eluting Orsiro stent was intended were treated with biolimus-eluting BioFreedom stent. Furthermore, 49 lesions were treated with another DES, 6 lesions were treated with a bare-metal stent, and in 11 lesions no stent was implanted.

Finally, we incorporated length of procedure, fluoroscopic time, and contrast use in a sensitivity analysis and the result was similar to that obtained in the main analysis.

Discussion

In the SORT OUT IX trial, the biolimus A9-coated BioFreedom stent did not meet criteria for noninferiority compared with the ultrathin strut biodegradable polymer sirolimus-eluting Orsiro stent for MACE at 12 months in an all-comer population. Rates of cardiac mortality, myocardial infarction, and stent thrombosis did not differ significantly between the 2 groups, whereas the rate of target lesion revascularization was higher in the BioFreedom stent group.

Overall, the SORT OUT IX demonstrated excellent results with low MACE rates and low stent failure rates during implantation in both stent groups. There are important differences in the DES technologies between the 2 stents. Compared with the sirolimus-eluting Orsiro stent, the biolimus-eluting BioFreedom stent is drug-coated and free of polymer, whereas the sirolimus-eluting Orsiro stent has a silicon carbide coating and a polymer that degrades within 12 to 24 months. The biolimus-eluting BioFreedom stent has thicker stent struts (120 µm compared with 60–80 µm for the sirolimus-eluting Orsiro stent), and a faster drug release (1 month vs 3 months). Both strut thickness and drug release time may have contributed to the higher target lesion revascularization rate observed in the biolimus-eluting BioFreedom stent in SORT OUT IX. The target lesion revascularization curves started to diverge after 4 months and continued to do so throughout the study period. In the SORT OUT VII trial,8 in which the biolimus-eluting Nobori stent was compared with the same comparator stent (sirolimus-eluting Orsiro), the biolimus-eluting Nobori stent had the same type of drug, but a longer drug release time, and a similar strut thickness as the BioFreedom stent in SORT OUT IX. However, in SORT OUT VII, the target lesion revascularization rates did not differ significantly between the 2 study stents (biolimus-eluting Nobori stent, 4.6% vs sirolimus-eluting Orsiro stent, 3.8%), but the rates of target lesion revascularization were proportionally higher in the biolimus-eluting Nobori stent in the early phase (1.3% vs 0.6%) because of a higher rate of early stent thrombosis (0.8% vs 0.2%), whereas revascularization rates were not different after 1 month. Strut thickness may have an effect on the increased target lesion revascularization rate; however, in a meta-analysis of randomized trials comparing newer-generation ultrathin strut DES to older second-generation thicker strut DES,29 newer-generation ultrathin strut DES were associated with a reduction in target lesion failure driven by a lower risk of myocardial infarction, but with similar risks of cardiovascular death and target lesion revascularization. Another explanation may be the rapid drug release, which turns the drug-coated stent into a bare-metal–like stent quickly. A similar finding was found in the SORT OUT III24 for the zotarolimus-eluting Endeavor sprint stent with a rapid drug release and a higher short-term restenosis (9-month zotarolimus-eluting Endeavor stent 4% vs sirolimus-eluting Cypher stent 1%) and stent thrombosis (n=13 versus n=4). For both stents, however, the influence of the drug on the tissue may persist for longer than the drug release time. In the NORSTENT trial (Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease)30, the rates of target lesion revascularization were also halved in the drug-eluting stent group compared with the bare-metal stent group (5.3% s 10.3%), whereas the biolimus A9-coated BioFreedom stent has shown superiority to a bare-metal stent (target lesion revascularization biolimus A9-coated BioFreedom stent 5.1% vs 9.8%) in patients treated with only 1 month of dual antiplatelet therapy.12,13

The safety profile of the biolimus-eluting BioFreedom stent was comparable to the sirolimus-eluting Orsiro stent. The rate of definite stent thrombosis did not differ within the first year. Both definite and probable stent thrombosis rates are in line with other drug-eluting stent all-comer trials. In contrast, the definite stent thrombosis rate within 1 year was twice as high in the LEADERS FREE trial (Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk),12 where the BioFreedom stent was compared with a very similar bare-metal stent (1.3% vs 1.4%) in patients with a high bleeding risk. In the LEADERS FREE trial, 3 out of 4 stent thrombosis occurred early in both stent groups in the period during which the patients were treated with dual antiplatelet therapy. Patient, stent, and procedure characteristics may influence the early risk of definite stent thrombosis.

Other polymer-free DES have been tested in larger clinical settings.31–33 In the ReCre8 trial (Randomized All-Comers Evaluation of a Permanent Polymer Zotarolimus-Eluting Stent Versus a Polymer-Free Amphilimus-Eluting Stent),33 the polymer-free amphilimus-eluting stent was noninferior to the zotarolimus-eluting stent (TLF, 6.2% vs 5.8%) and definite or probable stent thrombosis did not differ significantly (1.2% vs 0.8%). Registries with 2 polymer-free DES, the amphilimus-eluting and biolimus-eluting BioFreedom stents,32 have been compared, and comparable safety and efficacy profiles in all-comer patients were observed.

The MACE rate and definite and probable stent thrombosis rate in the SORT OUT IX trial are in line with other all-comer drug-eluting stent trials assessing clinical outcomes of the sirolimus-eluting Orsiro stent.2,6,8,34,35 In the BIONYX trial (Thin Composite Wire Strut, Durable Polymer-Coated (Resolute Onyx) Versus Ultrathin Cobalt-Chromium Strut, Bioresorbable Polymer-Coated (Orsiro) DES in All-Comers With Coronary Artery Disease), the Resolute Onyx stent was noninferior to the Orsiro stent, and had a very low rate of 1-year stent thrombosis (0.1% s 0.7%), which warrants further clinical investigation. An animal study has shown that the thrombogenicity of the coating of the Orsiro stent is low36 and thin stent struts have been associated with less wall shear stress and thrombogenicity.37 However, in the SORT OUT IX trial, we could not demonstrate any difference in risk of definite stent thrombosis. The difference in target lesion revascularization was driven by in-stent restenosis, where the mechanism probably is lesser efficacy on the inhibition of neointimal hyperplasia.

The SORT OUT IX trial, in line with the previous SORT OUT trials,8,22–25 relied on registry-based outcome ascertainment without study-related angiographic or clinical follow-up. Patient care complied with standard clinical practice (hospital outpatient visits after 1 to 3 months). Although the Danish healthcare databases capture events of sufficient severity for patients to seek medical attention, these records might underestimate event rates compared with follow-up by dedicated trial staff. However, this potential to under-report events is likely to be low, should not influence differences detected between treatment groups, and the negligible loss to follow-up may have compensated for this potential limitation. A limitation in the SORT OUT IX trial was that we could not assess the influence of ultrathin stent versus a thicker strut stent on periprocedural myocardial infarction because biomarkers were not drawn in relation to the percutaneous coronary intervention procedure. Our primary end point might be limited by the short follow-up period. Consequently, the safety and performance of the stents included in SORT OUT IX will be assessed on an annual basis up to 5 years after stent implantation. All patients were recommended 6 to 12 months of dual antiplatelet therapy, according to guidelines, but dual antiplatelet therapy adherence could not be reported. Finally, the stent delivery failure was higher than expected, which may be caused by lesion complexity characteristics not measured in this study.

Conclusion

In conclusion, in the SORT OUT IX trial, the biolimus A9-coated BioFreedom polymer-free stent did not meet criteria for noninferiority for MACE at 12 months when compared with the ultrathin strut biodegradable polymer sirolimus-eluting Orsiro stent in an all-comers population. The biolimus-eluting BioFreedom stent had a higher incidence of target lesion revascularization.

Acknowledgments

The SORT OUT IX steering committee formulated the study design, and all authors subsequently accepted. LOJ and JK were responsible for data management and for design and implementation of the statistical analysis. All other authors took part in patient enrollment and data collection. LOJ and EHC contributed to the design of the statistical analysis and the interpretation of results. LOJ, MM, and EHC drafted the article, which was subsequently seen and reviewed by all authors. All authors have seen the final submitted article, and they agree with its contents. LOJ had full access to all the data in the study and had final responsibility for the decision to submit for publication in Circulation.

Supplemental Materials

SORT OUT IX Study Group Members

Appendix

Kristian Thygesen, professor MD DMSci, Department of Cardiology, Aarhus University Hospital, Denmark.

Jacob Thorsted Sørensen, MD, PhD, Department Cardiology, Aarhus University Hospital, Denmark.

Henning Rud Andersen, professor MD DMSci, Department Cardiology, Aarhus University Hospital, Denmark.

Footnotes

Sources of Funding, see page 2062

https://www.ahajournals.org/journal/circ

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The Data Supplement, podcast, and transcript are available with this article at https://www.ahajournals.org/doi/suppl/10.1161/circulationaha.119.040241.

Lisette Okkels Jensen, MD, DMSci, PhD, Odense University Hospital Department of Cardiology, Sdr. Boulevard 29, 5000 Odense C, Denmark. Email

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