Impact of Vessel Size on Angiographic and Clinical Outcomes of Revascularization With Biolimus-Eluting Stent With Biodegradable Polymer and Sirolimus-Eluting Stent With Durable Polymer: The LEADERS Trial SubstudyFree Access

Device description

The BES, as used in this study and already described in the preceding text, elutes a highly lipophilic sirolimus analogue (2) (Fig. 1), which inhibits the mammalian target of rapamycin and cell-cycle transition in smooth muscle cells with similar potency as sirolimus. It is eluted from a polylactic acid biodegradable polymer applied to the abluminal surface (Fig. 1). This fully biodegradable polymer polylactic acid is metabolized to water and carbon dioxide and promises to cause less long-term inflammatory reaction. Full resorption occurs within 6 months. In the LEADERS trial the BES was found noninferior to the SES in terms of major adverse cardiac events (MACE) at 9 months as well as in-stent percent diameter stenosis (p = NS) (1).

Study population

The LEADERS trial was a multicenter European non-inferiority trial comparing the safety and efficacy of BES with SES in 1,707 “all-comers” patients. Patients over the age of 18 with chronic stable coronary artery disease or acute coronary syndromes including ST-segment elevation myocardial infarction (MI) were eligible if they had at least 1 lesion with >50% diameter stenosis and reference vessel diameter 2.25 to 3.5 mm. The aim was for the patient population to reflect real world clinical practice, and thus no limits were set on the number or complexity of the lesions stented. The only exclusion criteria were: known allergy to acetylsalicylic acid, clopidogrel, heparin, stainless steel, sirolimus, biolimus, or contrast material that cannot be pre-medicated; planned surgery within 6 months of percutaneous coronary intervention unless the dual anti-platelet therapy could be maintained throughout the perisurgical period; pregnancy or participation in another trial before reaching the primary end point; and lastly, inability to give informed consent. The study complied with the Declaration of Helsinki and was approved by all institutional ethics committees. All patients provided written informed consent for participation in the trial.

Randomization and procedures

Randomization was done centrally after diagnostic cardiac catheterization and before percutaneous coronary intervention (PCI) by use of a telephone allocation service (Limburgia telefonische Antwoord Service, Rotterdam, the Netherlands). The allocation sequence was computer-generated, stratified according to center, and blocked with block sizes of 8 and 16, which varied randomly. We randomly allocated patients on a 1:1 basis to treatment with a BES (Biomatrix Flex, Biosensors, Inc., Newport Beach, California) or an SES (Cypher Select, Cordis, Miami Lakes, Florida) and to active angiographic follow-up at 9 months or clinical follow-up only on a 1:3 basis with a factorial design.

The BES were available in diameters of 2.25, 2.5, 3.0, and 3.5 mm and in lengths of 8, 11, 14, 18, 24, and 28 mm. The SES were available in diameters of 2.25, 2.5, 2.75, 3.0, and 3.5 mm and in lengths of 8, 13, 18, 23, 28, and 33 mm. We performed balloon angioplasty and stent implantation according to standard technique, and direct stenting was allowed. No mixture of drug-eluting stents was permitted within a given patient, unless the operator was unable to insert the study stent, in which case crossover to another device of the operator's choice was possible. Before or at the time of the procedure, patients were given at least 75 mg of acetylsalicylic acid, 300 to 600 mg loading dose of clopidogrel, and unfractionated heparin at a dose at least 70 IU/kg. After the procedure, all patients were advised to take aspirin indefinitely and clopidogrel for at least 12 months. In case of intercurrent revascularization procedures requiring stent implantation, treating cardiologists were encouraged to use the study stent. For other details we refer to the primary end point article (1).

Study end points

Adverse events were assessed in the hospital and at 1, 6, 9, and 12 months. An independent clinical events committee unaware of the patient's treatment assignments adjudicated all end points. One in four patients was asked to return for angiographic follow-up at 9 months. Definitions of all end points are provided elsewhere (1). Briefly, the pre-specified primary end point was the composite of cardiac death, MI, and clinically indicated target vessel revascularization (TVR) within 9 months. Secondary end points were any target lesion revascularization (TLR) (both clinically and nonclinically indicated), which was defined as repeat revascularization due to a stenosis within the stent or within a 5-mm border proximal or distal to the stent; any TVR, cardiac death, death from any cause, MI, stent thrombosis (defined according to the Academic Research Consortium) (12); device success (defined as achievement of a final residual diameter stenosis of <50% during the initial procedure); and lesion success (achievement of <50% stenosis with any approach for PCI).

The pre-specified principal outcome of the angiographic substudy was in-stent percent diameter stenosis. Secondary angiographic outcomes were in-segment percent diameter stenosis, minimal lumen diameter (MLD), late lumen loss, and binary restenosis. We obtained angiographic measurements within the stented segment (in-stent) and over the entire segment consisting of the stent and 5-mm proximal and distal margins (in-segment). We defined percent diameter stenosis as: ([reference vessel diameter − MLD]/reference vessel diameter) × 100%; late lumen loss as the difference between MLD after the procedure and MLD at follow-up; and binary restenosis as percentage diameter stenosis of 50% or greater in the target lesion.

Independent study monitors (D-Target, Montagny-pres-Yverdon, Switzerland) verified all case reports from data on-site. Data were stored in a database (KIKA Medical, Paris, France), which was maintained by a contract research organization (Cardialysis, Rotterdam, the Netherlands) in collaboration with an academic clinical trials unit (CTU Bern, Bern University Hospital, Bern, Switzerland). Clinical follow-up was done at 1, 6, 9, and 12 months. The operators were by necessity aware of the assigned study stent during PCI and angiographic follow-up, but patients and staff involved in follow-up assessment were blinded to the allocated stent type. Angiographies were centrally assessed at 1 angiographic core laboratory (Cardialysis) with assessors unaware of the allocated stent.

Statistical analysis

A stratified post-hoc analysis of clinical and angiographic outcomes, which was specified after completion of patient recruitment, was performed according to vessel size. Methodology similar to the previously published SIRTAX (Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization) trial was used (9). Quantitative coronary angiography served to determine the reference vessel diameter (RVD). Patients who underwent stent implantation in lesions with an RVD ≤2.75 mm were categorized as having undergone treatment of small vessels. Conversely, patients who underwent stent implantation in lesions with RVD >2.75 mm were classified as having had treatment of large vessels. Patients with stent implantations in both small and large vessels were classified as “mixed”. All randomized patients were included in the analysis of primary and secondary clinical end points in the groups that they were originally assigned to (intention-to-treat analysis). Analyses of the angiographic substudy were restricted to lesions from patients who attended follow-up angiography. Angiographic outcomes were analyzed with SAS version 8 Proc Mixed (SAS Institute, Cary, North Carolina) for continuous and Proc Genmod for binominal outcomes, taking into account the within-patient correlation structure of these data. We used a Cox proportional hazards model to compare clinical outcomes between the groups. All analyses were performed with SAS version 8.02 by a dedicated statistician. All p values and confidence intervals were 2-sided.

Baseline clinical, angiographic, and procedural data

A total of 1,707 patients with 2,467 lesions were randomly assigned to treatment with either BES (857 patients, 1,254 lesions) or SES (850 patients, 1,213 lesions). Four hundred twenty-nine patients in the BES group with 576 lesions and 434 patients in the SES group with 557 lesions had only small vessels treated (863 of 1,707 [50.6%] of the entire patient population); 267 patients in the BES arm with 309 lesions and 272 patients in the SES arm with 311 lesions had only large vessels treated (RVD >2.75); and 154 patients in the BES group with 362 lesions and 133 patients with 334 lesions in the SES group had “mixed” disease (Fig. 2).

Baseline clinical and angiographic characteristics are summarized in Tables 1 and 2. There were no significant differences in the numbers of patients with diabetes, hypertension, hypercholesterolemia, smoking history, prior history of MI, stroke, or peripheral vascular disease between the SES and BES groups. These patient characteristics differed, however, when compared for vessel size. There was a higher proportion of women with small vessels (29% vs. 25% overall; p < 0.001), whereas no significant difference in the numbers of diabetic patients across vessel sizes was found. Smokers were more frequently found in the large vessel group (p < 0.001), whereas patients with small vessel disease had a higher frequency of previous MIs (p = 0.007) and past history of PCI (p < 0.001). A high proportion of patients in the entire cohort had presented with acute coronary syndromes (between 51% and 61%) and 13% to 21% of the cases were ST-segment elevation MIs. Lastly, patients with mixed vessel disease had a higher proportion of multivessel disease (p < 0.001).

Mean reference vessel diameters in the BES and SES group were 2.21 ± 0.34 mm and 2.24 ± 0.33 mm for small vessels, respectively, 3.21 ± 0.47 mm and 3.18 ± 0.37 mm for large vessels, and 2.69 ± 0.57 mm and 2.66 ± 0.59 mm for mixed lesions (Table 1). The lesion length did not differ between the 2 treatment groups but differed slightly over the range of 12 to 16 mm between vessel sizes. Percent diameter stenosis was 63 ± 18% in small vessels in both treatment arms, 66 ± 18% in large vessels treated with BES, 69 ± 18% in large vessels treated with SES, 62 ± 18% in the mixed vessels treated with BES, and 61 ± 18% in the mixed vessels treated with SES. The MLD amounted to 0.80 and 0.84 mm in small vessels treated with BES and SES and 1.01 and 1.07 mm in large vessels treated with BES and SES, respectively.

Procedural results are shown in Table 2. Post-stenting MLD in small vessels treated with BES and SES was 2.09 ± 0.35 mm and 2.13 ± 0.35 mm, respectively (p = NS); it was 2.76 ± 0.41 mm and 2.67 ± 0.38 mm in large vessels treated with BES and SES, respectively. There were no significant differences in acute gain after stenting with BES or SES, the acute gain being 1.29 ± 0.45 mm for small vessels, 1.74 ± 0.62 mm for large vessels treated with BES, and 1.59 ± 0.59 mm for large vessels treated with SES. This translated also in equivalent diameter stenosis after PCI in both stent groups.

Angiographic results

Angiographic follow-up at 9 months were obtained in 168 patient in the BES group and 167 patients in the SES group (Table 2). One hundred nine small vessel lesions, 62 large vessel lesions, and 82 mixed vessel lesions were evaluated angiographically at 9 months in the group treated with BES. One hundred fourteen small vessel lesions, 58 large vessel lesions, and 59 mixed lesions were evaluated angiographically in the SES group. In small, large, and mixed vessels there was no significant difference in late luminal loss, MLD, percent diameter stenosis, or binary restenosis between BES and SES groups. In small vessels late loss was 0.17 ± 0.47 mm in the BES group and 0.22 ± 0.51 mm in the SES group (p = NS). Corresponding percent diameter stenosis was 24.9 ± 20.7% and 23.8 ± 21.3% in the BES and SES stent groups, respectively. In the large lesion population, in-stent late luminal loss was 0.14 ± 0.51 in the BES arm and 0.05 ± 0.37 in the SES group (p = NS). The percent diameter stenosis in the large vessel group was 18.2 ± 14.6% in the BES group and 19.2 ± 14.5% in the SES group (p = NS). Late loss, percent diameter stenosis, and binary in-stent restenosis were lower in the “mixed” lesion group treated with BES compared with SES.

Clinical outcomes

Clinical events at 1-year follow-up stratified by vessel size are listed in Table 3 and summarized in Figures 3 and 4. Vessel size seemed to influence the TLR rates in both SES and BES groups. Within the BES treatment arm TLR rate was 9.6% in the small vessel group (41 events) versus 2.6% in the large vessel group (7 events). Within the SES treatment arm TLR rate was 7.4% in the small vessel group (32 events) versus 5.1% in the large vessel group (14 events). There were no differences in the overall rate of MACE or TLR/TVR in patients with small vessels and large vessels treated with BES versus SES stents. There was no significant difference in overall MACE rate between BES- and SES-treated patients with “mixed” vessel disease, although rates of overall percutaneous TLR (7 [4.5%] patients vs. 15 [11.3%] patients; p = 0.037) were lower. Tests for interaction between treatment and vessel size reached statistical significance for TLR and TVR rates in the mixed disease group.

There were 13 definite stent thrombosis events in small vessels in the BES arm (3.0%) and 9 definite stent thrombosis events in the SES arm (2.1%) (p = 0.38).

Study limitations

The study suffers from the usual limitations of post hoc analyses and, for some subgroup analyses, might lack sufficient power to detect superiority of 1 treatment over the other. Some of the key differences in outcomes such as late stent thrombosis in a degradable versus permanent polymer stent might emerge at long-term follow-up.