ABSTRACT
Background
DESyne BDS Plus represents a novel triple drug therapy (TRx) applied on a coronary stent platform eluting the antiproliferative drug Sirolimus along with two anticoagulants (Rivaroxaban and Argatroban) to reduce the site‐specific thrombotic risk.
Aims
To assess the feasibility and safety of this novel device against a contemporary drug‐eluting stent.
Methods
This prospective, multicenter randomized (1:1) trial included 202 patients assigned between the device group (DESyne BDS Plus) and the control group (DESyne X2). A subgroup of 58 patients underwent imaging follow‐up at 6 months. The blood pharmacokinetics of Sirolimus and both anticoagulants were assessed in 11 nonrandomized patients.
Results
The primary endpoint, target lesion failure (TLF) at discharge or 3‐day postprocedure, whichever occurred first, was 0.0% (0/98) in the device and 5.0% (5/100) in the control group (p noninferiority < 0.001). The secondary endpoint, late lumen loss at 6 months, was 0.14 mm [90% CI: 0.06; 0.23] and 0.09 mm [90% CI: 0.01; 0.18] in the device (n = 28) and control group (n = 27), respectively (p noninferiority < 0.001). Through 24 months, stent thrombosis (definite/probable) was 0.0% (0/97) versus 1.0% (1/96) in the control, p = 0.497, and TLF was 2.1% (2/97) versus 11.3% (11/97), p = 0.010, respectively. Optical coherence tomography findings including strut coverage and neointimal hyperplasia thickness/volume were similar between the groups. The pharmacokinetic study indicated median maximum blood concentrations (Cmax) of Rivaroxaban and Argatroban of 1.38 ng/mL and 1.99 ng/mL, respectively.
Conclusions
This is the first clinical evidence of the feasibility of site‐specific antithrombotic therapeutic with two anticoagulants and an antiproliferative mTOR inhibitor.
Keywords: anticoagulant, drug‐eluting stent, stent thrombosis
1. Introduction
Stent thrombosis after percutaneous coronary interventions (PCI) is a catastrophic event associated with myocardial infarction and poor outcomes, with mortality rates of up to 50% for early (< 30 days) stent thrombosis. Recent evidence suggests that the 1‐year risk of stent thrombosis has been reduced to less than 1% with new‐generation drug‐eluting stents (DES) [1, 2, 3, 4]. However, given the life‐threatening implication and accounting for the number of PCIs performed, stent thrombosis still represents a public health problem [5, 6], and balancing the ischemic and bleeding risks in patients at high thrombotic risk and high bleeding risk often requires a compromise [7]. The ongoing risk of stent thrombosis is particularly relevant following complex procedures, as well as in patients with early dual antiplatelet therapy (DAPT) disruption (e.g., patients with high bleeding risk and medication noncompliance) [5, 6]. Further, in patients with atrial fibrillation the bleeding risk of systemic triple‐drug therapy need to be balanced against the ischemic risk.
The novel DESyne BDS Plus triple drug therapy (TRx) eluting coronary stent platform (Elixir Medical, Milpitas, CA) aims to address this thrombotic risk at the site of the implant. Its bioresorbable coating includes three drugs: two anticoagulants (Rivaroxaban and Argatroban), along with Sirolimus. The dual anticoagulants eluted from the bioresorbable coating affect two critical steps of the coagulation cascade, that is, inhibition of Factor Xa (Rivaroxaban) and Factor IIa (Argatroban) activities [8, 9], controlling the site‐specific thrombin generation at the stent struts postimplantation.
The aim of the DESyne BDS Plus Randomized Controlled Trial is to evaluate the feasibility of the DESyne BDS Plus compared to a contemporary durable polymer DES in a population with stable angina or acute coronary syndrome and de novo lesions.
2. Methods
2.1. Study Design
The DESyne BDS Plus Randomized Clinical Trial is a prospective, multicenter, single blind, randomized controlled trial (RCT, 1:1) conducted in 14 centers in Europe, New Zealand and Brazil.
Clinical follow‐up was scheduled at 3 days or hospital discharge (whichever was first), at 30 days, and at 6, 12, 24, and 36 months postprocedure. In up to 60 of the randomized patients (approximately 30 per arm), angiography and optical coherence tomography (OCT) were planned at the index procedure and at the 6‐month follow‐up.
The pharmacokinetic substudy was scheduled to enroll approximately 10 nonrandomized subjects treated only with the DESyne BDS Plus devices to assess the blood pharmacokinetics of Sirolimus, Rivaroxaban, and Argatroban eluted from the DESyne BDS Plus after implantation. The measurements were obtained by one plasma and one whole blood sample at: pretreatment, posttreatment at 10 min, 30 min, 1, 2, 4, 6, 12, 24, and 72 h, and at 7 days. In addition, all pharmacokinetic substudy subjects were scheduled for the same clinical follow‐up assessments as the randomized groups. The pharmacokinetic substudy subjects were not considered part of the primary analysis population.
The study is conducted according to ISO14155:2020, the Declaration of Helsinki, and applicable regulations, was approved by the responsible ethics committees, and all patients provided written informed consent. A clinical events committee adjudicated all safety endpoint events, a steering committee was responsible for the clinical and scientific decision‐making, and core laboratories were used for imaging assessments (CERC‐Cardiovascular European Research Center, Massy, France) and for quantification of Sirolimus, Rivaroxaban, and Argatroban using validated, specific and sensitive high‐performance liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) assays (iC42 Clinical Research and Development, University of Colorado, Aurora, CO, USA). The trial is registered at Clinicaltrials.gov (NCT 05033964).
2.2. Patients
Patients with stable angina or acute coronary syndrome requiring treatment of de novo coronary artery lesions ≤ 34 mm in length in vessels ≥ 2.25 and ≤ 3.5 mm in diameter were permitted to be enrolled. Up to two target lesions, located in separate epicardial vessels could be treated with the assigned study device. Alternatively, one target lesion could be treated with the assigned study device after successful, uncomplicated treatment of a nontarget lesion located in a separate epicardial vessel with a commercially available DES of similar materials and drug (“limus‐eluting”). Main exclusion criteria were acute myocardial infarction with Killip class III and IV, or acute myocardial infarction requiring resuscitation, intra‐aortic balloon pump or ventilation support, and patients who had fibrinolysis before PCI. The full list of inclusion and exclusion criteria is available in Table S1.
2.3. Randomization
Patients were stratified per center. Randomization (1:1) was performed after successful predilatation of the target lesion and vessel sizing using an electronic data capture database. 3400 sequence numbers were generated from 1 to 3400 for 17 centers, containing 200 sequences for each center with random blocks of two (578 blocks) and four (561 blocks) so that each center had a variable number of blocks.
The study is single‐blinded. The patients, the clinical events committee and the imaging core laboratory assessors were blinded to the allocated treatment.
2.4. Study Device and Procedure
The DESyne BDS Plus is an 81 µm cobalt‐chromium device loaded with approximately 7 µg Sirolimus, 8 µg Rivaroxaban and 8 µg Argatroban per mm of stent length delivered via a bioresorbable poly‐lactic‐co‐glycolic acid polymer that resorbs over 6 months. An initial bolus is released up to 3 days followed by a sustained release of site‐specific antithrombotic drugs over 6 months. Available stent diameters ranged from 2.25 to 3.5 mm and lengths from 14 to 38 mm. The control device, the CE‐marked DESyne X2 Novolimus‐eluting coronary stent system was available in the same size range and was loaded with approximately 5 µg Novolimus per mm stent length released from a durable methacrylate polymer coating [10, 11]. Of note, the DESyne BDS Plus stent has the same thin‐strut stent design and delivery system as the contemporary DESyne X2.
Predilatation was mandatory. An additional assigned device or any other approved “limus‐eluting” DES could be used as bailout treatment whereas crossover between the assigned study devices was not allowed.
Preprocedural antithrombotic treatment was per the standard institutional practices. Dual antiplatelet therapy was recommended for 6 months for stable patients and for 12 months for patients with acute coronary syndrome according to the 2018 guidelines on myocardial revascularization [5].
Details of the imaging analysis are provided in the Supporting Information.
2.5. Endpoints and Definitions
The primary endpoint was target lesion failure (TLF) through hospital discharge or 3 days postprocedure, whichever came first. The rationale for the primary endpoint was to capture the incidence of procedural ischemic events at the time of the initial bolus release from the study device and thereby to assess the feasibility of the site‐specific antithrombotic therapy. TLF was defined as composite of cardiovascular death, target‐vessel myocardial infarction (TV‐MI), and clinically‐indicated target lesion revascularization (CI‐TLR). The powered secondary endpoint was lesion‐level in‐stent late lumen loss (LLL) by quantitative coronary angiography at 6 months postprocedure. Procedural endpoints are device success (successful delivery of the device and a final residual stenosis < 30% by quantitative coronary angiography, QCA) and procedure success (device success and no TLF through hospital discharge with a maximum of 7 days postindex procedure). Further endpoints and definitions are provided in the Supporting Information; the clinical endpoints were adjudicated according to Academic Research Consortium‐2 definitions [12].
2.6. Statistics
This study was designed to assess the feasibility, safety, and effectiveness of the DESyne BDS Plus device. The sample size was selected to ensure adequate power to assess noninferiority of TLF at 3 days or discharge (whichever was earlier) and for the powered secondary endpoint of late lumen loss (LLL) in the imaging subset. To provide 80% power with a one‐sided type 1 error rate of 0.025 using a margin of 8%, assuming a 3‐day TLF rate of 4% in each arm adopted from periprocedural/30‐day event rates reported in literature [2, 13, 14, 15, 16], 190 patients were required, and 10 patients were added to account for a potential loss‐to‐follow‐up, leading to a sample size of 200 patients.
For the noninferiority of in‐stent LLL at 6 months postprocedure, the sample size calculation was based on a power of 80% and a 1‐sided 0.05 type 1 error rate. A pooled standard deviation of 0.35 mm was assumed, and the design allows for a maximum difference of 0.15 mm between the test and control LLL. The non‐inferiority margin of 0.4 mm was determined based on clinical judgment about the magnitude of a meaningful difference. Based on these assumptions, 50 evaluable subjects were required. Assuming ~15% loss‐to‐follow‐up by the 6‐month evaluation, 60 subjects were calculated to be enrolled in the imaging group (30 per arm). The sample size was calculated using SAS version 9.4. Sequential testing was used to control type‐I error; the hypothesis test for the secondary endpoint LLL was to be performed only if the null hypothesis was rejected for the primary endpoint.
Results are based on the intention‐to‐treat population. Continuous data were summarized with the mean, standard deviation or median and interquartile ranges (for the pharmacokinetic substudy), and number of evaluable observations. Categorical variables were summarized with frequency counts and percentages. Unless otherwise specified, two‐sided confidence intervals were calculated based on the t‐distribution for continuous variables and the exact binomial distribution for differences in proportions. Data were compared using the t‐test for continuous variables and the χ 2 or Fisher′s Exact Test for categorical variables. A one‐sided p value was calculated from the Farrington‐Manning test for noninferiority. The confidence interval for TLF was calculated using the noninferiority hypothesis test, all other confidence intervals binary endpoints used the exact test. The angiographic powered endpoint was assessed using a mixed model for repeated measures.
Missing data are not imputed; analyses are based on available data. The statistical analysis of clinical data was performed using SAS version 9.4 or later (SAS Institute Inc., Cary, NC). Noncompartmental pharmacokinetic analysis of the time‐concentration data of all three drugs was carried out using Phoenix, version 8.3 (Certara, Princeton, NJ).
3. Results
From December 2021 to December 2022, 202 patients were randomized and 11 patients were included in the pharmacokinetic substudy (Figure 1).
Figure 1.
Study flow diagram. One patient in the DESyne BDS Plus group did not receive the allocated study device due to a dissection after predilatation. Four patients in the DESyne X2 group did not receive the study stent (three due to unavailability of the correct device size, one due to dissection). *Physician withdrew patient due to end‐stage lung cancer. FUP, follow‐up; ICF, informed consent form; PK, pharmacokinetic.
The baseline characteristics were similar across the groups, except for diabetes mellitus, which occurred more frequently in the DESyne BDS Plus group (28.0% vs. 14.9% in the control group, p = 0.023 (Table 1).
Table 1.
Baseline patient and lesion characteristics.
| DESyne BDS Plus (N = 100) | DESyne X2 (N = 102)a | |
|---|---|---|
| Age (years) | 63.2 ± 9.9 | 62.7 ± 9.9 |
| Female sex | 22.0% (22/100) | 26.5% (27/102) |
| Male sex | 78.0% (78/100) | 73.5% (75/102) |
| Current smoker | 23.0% (23/100) | 18.8% (19/101) |
| Comorbidities | ||
| Diabetes mellitus | 28.0% (28/100) | 14.9% (15/101) |
| Dyslipidemia | 70.0% (70/100) | 72.3% (73/101) |
| Hypertension | 68.0% (68/100) | 61.4% (62/101) |
| Cerebrovascular disease (stroke, CVA, TIA) | 5.0% (5/100) | 1.0% (1/101) |
| Previous myocardial infarction | 24.0% (24/100) | 21.8% (22/101) |
| Previous CABG | 2.0% (2/100) | 2.0% (2/101) |
| Previous PCI | 25.0% (25/100) | 25.7% (26/101) |
| Angina/ischemia status | ||
| Stable angina | 38.0% 38/100) | 38.6% (39/101) |
| Unstable angina | 8.0% (8/100) | 5.9% (6/101) |
| Silent ischemia | 18.0% (18/100) | 16.8% (17/101) |
| Asymptomatic postmyocardial infarction | 3.0% (3/100) | 1.0% (1/101) |
| ST‐elevation myocardial infarction | 6.0% (6/100) | 5.0% (5/101) |
| Non‐ST‐elevation myocardial infarction | 18.0% (18/100) | 24.8% (25/101) |
| Other | 9.0% (9/100) | 7.9% (8/101) |
| Medications | ||
| ASA | 94.0% (94/100) | 91.1% (92/101) |
| P2Y12 inhibitor | 72.0% (72/100) | 72.3% (73/101) |
| Statins | 83.0% (83/100) | 86.1% (87/101) |
| ACE inhibitor | 37.0% (37/100) | 33.7% (34/101) |
| Beta blocker | 49.0% (49/100) | 48.5% (49/101) |
| Nitrates/nitric oxide donors | 15.0% (15/100) | 17.8% (18/101) |
| Diuretics | 20.0% (20/100) | 18.8% (19/101) |
| Angiotensin II antagonist | 20.0% (20/100) | 12.9% (13/101) |
| Calcium channel antagonist | 25.0% (25/100) | 19.8% (20/101) |
| Lesion characteristics | DESyne BDS Plus (N = 99 patients, 105 lesions) b | DESyne X2 (N = 101 patients, 103 lesions) b |
|---|---|---|
| Number of patients with one lesion | 93.9% (93/99) | 98.0% (99/101) |
| Number of patients with two lesions | 6.1% (6/99) | 2.0% (2/101) |
| Segment length (mm) | 21.74 ± 7.06 | 24.00 ± 7.96 |
| Obstruction length in‐segment (mm) | 12.97 ± 5.92 | 12.66 ± 5.63 |
| Reference vessel diameter (mm) | 2.74 ± 0.47 | 2.70 ± 0.47 |
| Lesion classification | ||
| A | 24.8% (26/105) | 25.2% (26/103) |
| B1 | 24.8% (26/105) | 22.3% (23/103) |
| B2 | 41.9% (44/105) | 48.5% (50/103) |
| C | 7.6% (8/105) | 3.9% (4/103) |
| Target vessel | ||
| LAD | 42% (44/105) | 37% (38/103) |
| LCX | 26% (27/105) | 32% (33/103) |
| RCA | 31% (33/105) | 28% (29/103) |
| Ramus | 1% (1/105) | 3% (3/103) |
| Bifurcation | 16.2% (17/105) | 22.3% (23/103) |
| Calcified lesion (moderate/severe) | 13.3% (14/105) | 18.4% (19/103) |
| Tortuous lesion (moderate/severe) | 19.0% (20/105) | 19.4% (20/103) |
| TIMI flow—Preprocedure | ||
| 0 | 3.8% (4/105) | 1.0% (1/103) |
| 1 | 1.0% (1/105) | 1.9% (2/103) |
| 2 | 2.9% (3/105) | 6.8% (7/103) |
| 3 | 91.4% (96/105) | 90.3% (93/103) |
| TIMI flow—Postprocedure | ||
| 0 | 0% (0/105) | 0% (0/103) |
| 1 | 0% (0/105) | 1.0% (1/103) |
| 2 | 0% (0/105) | 0% (0/103) |
| 3 | 100% (105/105) | 99.0% (102/103) |
Note: Data are displayed as mean ± SD or % (n/N).
Abbreviations: ACE, angiotensin‐converting‐enzyme; ASA, acetyl salicylic acid; CABG, coronary artery bypass graft; CVA, cerebrovascular accident; LAD, left anterior descending; LCX, left circumflex; PCI, percutaneous coronary intervention; RCA, right coronary artery; TIA, transient ischemic attack; TIMI, thrombolysis in myocardial infarction.
For one patient that discontinued immediately after randomization without receiving a study stent, only demographics were reported.
One patient in each group discontinued immediately after randomization.
Device success was 99.0% (104/105) in DESyne BDS Plus treated lesions versus 94.2% (97/103) in DESyne X2 treated lesions. Procedure success was achieved in 99.0% (98/99) and 89.1% (90/101) patients, respectively.
The primary endpoint, TLF through the first of 3 days or discharge was 0.0% (0/98) for DESyne BDS Plus treated patients and 5.0% (5/100, all periprocedural TV‐MI) for DESyne X2 treated patients (difference of −5.0% [95% CI: −11.8; 1.8], p noninferiority < 0.001) (Central Illustration 1). The 24‐month TLF‐rate was 2.1% (consisting of two CI‐TLR) versus 11.3% (consisting of one cardiovascular death, eight target‐vessel myocardial infarction, and two CI‐TLR) (difference of −9.3% [95% CI: −17.5; −2.4]), p = 0.010 (Table 2). No definite or probable stent thrombosis was observed in the DESyne BDS Plus group nor any additional bleeding risk.
Central Illustration 1.
Main outcomes of the DESyne BDS Plus randomized controlled trial. The null‐hypotheses of the primary endpoint target lesion failure and of the secondary endpoint late lumen loss were rejected and noninferiority was demonstrated (p noninferiority < 0.001, Farrington‐Manning test). All TLF events (n = 5) in the control group, through earliest of 3 days or discharge, were peri‐procedural myocardial infarction without cardiac death or target vessel revascularization. Late lumen loss values are adjusted for multiple lesions within a subject. DES, drug‐eluting stent, OCT, optical coherence tomography; RCT, randomized controlled trial, TRx, triple drug.
Table 2.
Clinical endpoints.
| DESyne BDS Plus | DESyne X2 | Difference [95% CI] | |
|---|---|---|---|
| 6‐month outcomes | |||
| TLF | 1.0% (1/98) | 8.2% (8/97) | −7.2% [−14.8; −1.3%] |
| TVF | 1.0% (1/98) | 9.3% (9/97) | −8.3% [−16.0%; −2.2%] |
| Death | 0.0% (0/98) | 2.0% (2/98) | −2.0 [−7.3% to 1.9%] |
| Cardiovascular death | 0.0% (0/98) | 1.0% (1/97) | −1.0% [−5.8; 2.8%] |
| MI (target vessel) | 0.0% (0/98) | 6.3% (6/96) | −6.3% [−13.1; −1.8] |
| Q‐wave | 0.0% (0/98) | 0.0% (0/96) | / |
| Non‐Q‐wave | 0.0% (0/98) | 6.3% (6/96) | −6.3% [−13.1; −1.8%] |
| Nontarget vessel MI | 0.0% (0/98) | 2.1% (2/96) | −2.1% [−7.4; 1.8] |
| Q‐wave | 0.0% (0/98) | 0.0% (0/96) | / |
| Non‐Q‐wave | 0.0% (0/98) | 2.1% (2/96) | −2.1% [−7.4; 1.8] |
| CI‐TLR | 1.0% (1/98) | 1.0% (1/96) | −0.0% [−4.8; 4.7] |
| CI TVR | 1.0% (1/98) | 2.1% (2/96) | −1.1% [−6.4; 3.8] |
| Non‐CI TLR | 1.0% (1/98) | 0.0% (0/96) | 1.0% [−3.0; 5.6] |
| Non‐CI TVR | 1.0% (1/98) | 0.0% (0/96) | 1.0% [−3.0; 5.6] |
| Stent thrombosis (definite/probable) | 0.0% (0/98) | 0.0% (0/97) | / |
| 12‐month outcomes | |||
| TLF | 2.1% (2/97) | 9.3% (9/97) | −7.2% [−15.1; −0.7] |
| TVF | 2.1% (2/97) | 10.3% (10/97) | −8.2% [−16.5; −1.6] |
| Death | 0.0% (0/97) | 2/98 (2.0%) | −2.0% [−7.2; 1.9] |
| Cardiovascular death | 0.0% (0/97) | 1.0% (1/97) | −1.0% [−5.7; 2.9] |
| MI (target vessel) | 0.0% (0/97) | 7.3% (7/96) | −7.3% [−14.4; −2.6] |
| Q‐wave | 0.0% (0/97) | 0/96 (0.0%) | / |
| Non‐Q‐wave | 0.0% (0/97) | 7/96 (7.3%) | −7.3% [−14.4; −2.6] |
| Nontarget vessel MI | 0.0% (0/97) | 3.1% (3/96) | −3.1% [−8.9; 0.8] |
| Q‐wave | 0.0% (0/97) | 1.0% (1/96) | −1.0% [−5.8; 2.8] |
| Non‐Q‐wave | 0.0% (0/97) | 2.1% (2/96) | −2.1% [−7.4; 1.8] |
| CI‐TLR | 2.1% (2/97) | 1.0% (1/96) | 1.0% [−3.9; 6.4] |
| CI TVR | 2.1% (2/97) | 2.1% (2/96) | −0.0% [−5.7; 5.5] |
| Non‐CI TLR | 1.0% (1/97) | 0/96 (0.0%) | 1.0% [−2.9; 5.8] |
| Non‐CI TVR | 1.0% (1/97) | 0/96 (0.0%) | 1.0% [−2.9; 5.8] |
| Stent thrombosis (definite/probable) | 0.0% (0/97) | 1.0% (1/96) | −1.0% [−5.8; 2.8] |
| 24‐month outcomes | |||
| TLF | 2.1% (2/97) | 11.3% (11/97) | −9.3% [−17.5; −2.4] |
| TVF | 2.1% (2/97) | 12.4% (12/97) | −10.3% [−18.7; −3.3] |
| Death | 0.0% (0/97) | 2/98 (2.0%) | −2.0% [−7.2; 1.9] |
| Cardiovascular death | 0.0% (0/97) | 1.0% (1/97) | −1.0% [−5.7; 2.9] |
| MI (target vessel) | 0.0% (0/97) | 8/96 (8.3%) | −8.3% [−15.8; −3.4] |
| Q‐wave | 0.0% (0/97) | 0/96 (0.0%) | / |
| Non‐Q‐wave | 0.0% (0/97) | 8/96 (8.3%) | −8.3% [−15.8; −3.4] |
| Nontarget vessel MI | 0.0% (0/97) | 3.1% (3/96) | −3.1% [−8.9; 0.8] |
| Q‐wave | 0.0% (0/97) | 1.0% (1/96) | −1.0% [−5.8; 2.8] |
| Non‐Q‐wave | 0.0% (0/97) | 2.1% (2/96) | −2.1% [−7.4; 1.8] |
| CI‐TLR | 2.1% (2/97) | 2.1% (2/96) | −0.0% [−5.7; 5.5] |
| CI TVR | 2.1% (2/97) | 4.2% (4/96) | −2.1% [−8.6; 3.7] |
| Non‐CI TLR | 1.0% (1/97) | 0/96 (0.0%) | 1.0% [−2.9; 5.8] |
| Non‐CI TVR | 1.0% (1/97) | 0/96 (0.0%) | 1.0% [−2.9; 5.8] |
| Stent thrombosis (definite/probable) | 0.0% (0/97) | 1.0% (1/96) | −1.0% [−5.8; 2.8] |
Note: Data are displayed as % (n/N) and % [95% CI].
Abbreviations: CI, clinically indicated; MI, myocardial infarction; TLF, target lesion failure; TLR, target lesion revascularization; TVF, target vessel failure; TVR, target vessel revascularization.
The imaging subset included 58 randomized patients (29 in each group) with 63 lesions. The angiographic assessments of the imaging subset at baseline and at the 6‐month follow‐up were similar between the groups and are presented in Table 3. The powered secondary endpoint, in‐stent LLL at 6 months, was 0.14 mm [90% CI: 0.06; 0.23] in the DESyne BDS Plus group and 0.09 mm [90% CI: 0.01; 0.18] in the DESyne X2 group (difference: 0.05 mm [90% CI: −0.07; 0.17], p noninferiority < 0.001) (Central Illustration 1).
Table 3.
QCA‐analysis at baseline and follow‐up (Core laboratory data).
| Preprocedure | Postprocedure | Six monthsc | ||||
|---|---|---|---|---|---|---|
| DESyne BDS Plus (L = 32)a | DESyne X2 (L = 30) | DESyne BDS Plus (L = 33) | DESyne X2 (L = 30) | DESyne BDS Plus (L = 28) | DESyne X2 (L = 27) | |
| Segment length (mm) | 21.6 ± 6.1b | 22.4 ± 6.4 | 20.8 ± 6.4 | 21.6 ± 6.3 | 20.6 ± 6.0 | 21.9 ± 6.8 |
| MLD diameter (mm) | 1.14 ± 0.40 | 1.09 ± 0.35 | 2.70 ± 0.43 | 2.63 ± 0.40 | 2.51 ± 0.45 | 2.50 ± 0.47 |
| % Diameter Stenosis | 59.6 ± 12.7 | 60.0 ± 12.1 | 8.8 ± 3.6 | 9.9 ± 3.3 | 11.5 ± 6.1 | 12.3 ± 6.3 |
| Reference diameter (mm) | 2.81 ± 0.47b | 2.75 ± 0.51 | 2.96 ± 0.43 | 2.91 ± 0.44 | 2.82 ± 0.42 | 2.85 ± 0.46 |
| Obstruction length (mm) | 10.8 ± 3.6b | 12.8 ± 5.3 | 3.0 ± 1.3 | 3.1 ± 1.2 | 3.1 ± 1.4 | 3.9 ± 1.3 |
| Acute gain (mm) | / | / | 1.58 ± 0.4a | 1.54 ± 0.4 | / | / |
| Acute recoil (%) | / | / | 8.8 ± 8.54 | 11.4 ± 7.42 | / | / |
Note: Data are displayed as mean ± SD and refer to the in‐lesion respective in‐device section.
Abbreviations: L, lesion; MLD, minimum lumen diameter; QCA, quantitative coronary angiography.
QCA analysis was performed with 32 lesions because one case had preprocedure not filmed.
QCA analysis was performed with 31 lesions because one case had TIMI 0.
At 6‐month follow‐up, QCA analysis was conducted on 55 lesions because seven patients did not complete the 6‐month follow‐up visit (each of these patients had one lesion), and one lesion's image was not analyzable.
The OCT assessments were similar between the groups, the neointimal hyperplasia volume was 25.20 ± 14.41 mm3 in the DESyne BDS Plus group versus 28.43 ± 11.39 mm3 in the DESyne X2 group, and strut malapposition was present in 0.50 ± 1.61% versus 0.11 ± 0.42%, respectively. A thrombus was present in one lesion per group, with a thrombus score of 4 and 34 and 0% and 2.14% of struts malapposed, respectively (Table 4, Figure 2, Central Illustration 1).
Table 4.
OCT analysis at baseline and follow‐up (Core laboratory data).
| Postprocedure | Six months | |||
|---|---|---|---|---|
| DESyne BDS Plus (L = 28) | DESyne X2 n (L = 27) | DESyne BDS Plus (L = 28) | DESyne X2 (L = 27) | |
| Strut coverage (%) | 1.04 ± 0.74 | 1.48 ± 1.86 | 93.39 ± 7.83 | 94.93 ± 8.04 |
| Strut malapposition (%) | 0.39 ± 0.6 | 0.69 ± 2.1 | 0.50 ± 1.61 | 0.11 ± 0.42 |
| Malapposition volume (mm3) | 7.88 ± 4.08 | 7.81 ± 7.77 | 1.22 ± 1.87 | 1.42 ± 3.14 |
| NIH volume (mm3) | / | / | 25.20 ± 14.41 | 28.43 ± 11.39 |
| Mean NIH area (mm2) | / | / | 1.09 ± 0.48 | 1.11 ± 0.46 |
| NIH thickness (mm) | / | / | 0.10 ± 0.05a | 0.10 ± 0.04 |
| Mean in lesion/in stent MLD (mm) | 2.80 ± 0.42 | 2.81 ± 0.36 | 2.61 ± 0.44 | 2.63 ± 0.45 |
| Mean in lesion/in stent cross section lumen area (mm2) | 7.13 ± 2.23 | 6.89 ± 1.83 | 6.24 ± 1.96 | 6.31 ± 2.18 |
| Mean in‐stent cross section stent area (mm2) | 6.91 ± 2.17 | 6.65 ± 1.71 | 7.28 ± 2.15 | 7.44 ± 2.24 |
| In‐stent lumen volume (mm3) | 162.99 ± 71.14 | 165.56 ± 72.8 | 139.93 ± 55.91 | 156.00 ± 68.77 |
| In‐stent stent volume (mm3) | 148.53 ± 66.84 | 153.3 ± 63.33 | 147.88 ± 59.85 | 159.83 ± 62.45 |
| Thrombus (present) | 14.3% (4/28) | 14.8% (4/27) | 3.6% (1/28) | 3.7% (1/27) |
| Thrombus score | 10.25 ± 7.27 | 20.00 ± 29.53 | 4 | 34 |
Note: Data are displayed as mean ± SD or % (n/N).
Abbreviations: MLD, minimum lumen diameter; NIH, neointimal hyperplasia; OCT, optical coherence tomography.
Available for 27 patients.
Figure 2.
Optical coherence tomography at 6 months. Data are core laboratory read and displayed as mean ± SD. L, lesions.
The median maximum blood concentrations (Cmax) were 1.72 ng/mL (IQR: 1.04–2.12) for Sirolimus, 1.38 ng/mL (IQR: 1.19–1.82) for Rivaroxaban, and 1.99 ng/mL (IQR: 1.35–2.11) for Argatroban. Sirolimus was still quantifiable 1 week after stent implantation (lower limit of quantification: 0.1 ng/mL), while no participant had Rivaroxaban concentrations above the lower limit of quantification (0.5 ng/mL) at or after the 72‐h timepoint, and no participant had Argatroban concentrations above the lower limit of quantification (0.5 ng/mL) at or after the 24‐h timepoint. Further details (time to reach Cmax, Tmax, apparent half‐life, T1/2, and the area‐under‐the‐concentration‐time curve over the observation period, AUClast) are provided in Table S2.
4. Discussion
This randomized controlled trial showed that the combination of two anticoagulants and an antiproliferative drug on a stent is feasible for the management of the antithrombotic risk in patients undergoing PCI. The pharmacokinetic substudy confirmed that systemic anticoagulation drug levels are below systemic therapeutic levels for both Rivaroxaban and Argatroban, meeting the technology design objectives.
Earlier attempts to inhibit local thrombus formation on stents employing heparin‐coated stents were met with limited success [17], despite the multiple therapeutic targets in the coagulation cascade. In contrast, the two direct‐acting anticoagulants, Rivaroxaban and Argatroban, previously used separately for systemic management of coagulation in patients undergoing PCI [9, 18, 19, 20], when combined locally on the implant surface have a synergistic thrombo‐inhibitory effect and thus have the potential to minimize thrombus formation in a site‐specific manner. Factor Xa acts at the convergence of the intrinsic and extrinsic coagulation pathways to catalyze the conversion of prothrombin to thrombin, wherein one molecule of Factor Xa results in the generation of more than 1000 thrombin molecules [21]. Thus, it is conceivable that a certain amount of thrombin could be generated even when Factor Xa is strongly inhibited with Rivaroxaban, a potent reversible inhibitor of Factor Xa [22]. To further complement Rivaroxaban and effectively inhibit the coagulation process, Argatroban, a direct Factor IIa inhibitor that is known to act on both fluid phase and fibrin‐bound Factor IIa [23], is coeluted from the stent. Therefore, releasing the two anticoagulants locally through the bioresorbable polymer has the potential of enhanced site‐specific antithrombotic effects while preventing systemic drug effects.
A preclinical pharmacokinetic study with DESyne BDS Plus implants in a porcine animal model showed that the systemic anticoagulant concentrations in the blood remained below the systemic therapeutic levels while the site‐specific anticoagulant concentration remained at or above therapeutic levels for both anticoagulants up to 1 year at the site of implantation (adjoining tissue) of the stent (data on file at Elixir Medical). Likewise, the current pharmacokinetic substudy indicated that the median maximum blood concentrations (Cmax) of Rivaroxaban and Argatroban were 1.38 and 1.99 ng/mL, respectively, and below the systemic therapeutic levels after administration of clinically active doses [18, 24]. The subtherapeutic systemic concentrations of the anticoagulants from DESyne BDS Plus thus provide the potential to achieve sufficient site‐specific antithrombotic therapy and potentially reduce the need for oral DAPT, thereby reducing the systemic bleeding risk.
The DESyne DBS Plus RCT was designed to validate the novel concept of site‐specific delivery of TRx therapy for the management of ischemic and thrombotic risk in PCI. The primary endpoint was met, showing similar predischarge TLF between the study arms. Through 24 months, the TLF‐rate was significantly lower for DESyne BDS Plus than for the control device; the 24‐month TLF‐rate for DESyne BDS Plus was 2.1% and trending lower to best‐in‐class devices [3, 25]. Importantly, results also showed the absence of definite or probable stent thrombosis, and target‐vessel myocardial infarction in the DESyne BDS Plus group through the 24‐month follow‐up. Furthermore, the 24‐month target‐vessel myocardial infarction rate was significantly lower in the DESyne BDS Plus group compared to the control. Collectively, these encouraging findings suggest that the site‐specific delivery of anticoagulants may reduce thrombotic events and the need for DAPT after cardiovascular interventions, which would be particularly important for patients with contraindication for systemic DAPT, for patients with upcoming surgeries, or for patients who have an elevated thrombotic or bleeding risk.
The secondary endpoint, in‐stent LLL at 6 months postprocedure, was also met based on noninferiority between the groups (p noninferiority < 0.001): 0.14 mm [90% CI: 0.06; 0.23] in the DESyne BDS Plus group and 0.09 mm [90% CI: 0.01; 0.18] in the DESyne X2 group. The LLL at 6 months for both groups were low and comparable to contemporary DES [4, 26, 27].
In summary, the clinical and imaging outcomes from the primary and secondary endpoints along with observational clinical findings suggest the feasibility of addressing implant‐related injury and thrombotic risk locally without inducing additional bleeding risk elsewhere using the site‐specific delivery of TRx in patients undergoing PCI. Nonetheless, there are limitations. The trial was primarily designed for feasibility and was powered for noninferiority, not superiority. Although the difference in TLF through 24 months was statistically significant, the modest sample size limits conclusions regarding generalizability, particularly in complex lesions or high‐risk cohorts such as left main disease, or chronic total occlusions. Additionally, operators could not be blinded to the randomization assignment with the associated potential for bias, such as selection of concomitant medication. However, the patients, the clinical events committee and the core laboratories were all blinded. Another limitation is the challenge in estimating the periprocedural event rate and associated non‐inferiority margin from previous studies. Nevertheless, it was reassuring that the observed 3‐day TLF rates (0 vs. 5%) agreed with the prospectively estimated event rate (4%) without triggering a discernible safety signal.
For safety reasons, all patients remained on standard antiplatelet regimens throughout the study; therefore, the putative benefit in bleeding risk reduction remains theoretical at this stage. A future clinical trial testing reduced or abbreviated DAPT regimens in patients treated with DESyne BDS Plus would be required to confirm the findings. The DESyne BDS Plus is designed for the sustained release of site‐specific antithrombotic drugs over 6 months, following an initial bolus of up to 3 days. In this study, systemic pharmacokinetic measurements focused on the first 7 days postprocedure to validate the feasibility of site‐specific antithrombotic therapy for managing ischemic and thrombotic risk in PCI. While systemic levels of Rivaroxaban and Argatroban remained well below therapeutic thresholds during the monitoring period, and no related safety signal was detected, long‐term systemic safety, local vascular pharmacodynamics, and cost effectiveness of site‐specific antithrombotic therapy warrant further investigation.
Looking ahead, the concept of site‐specific TRx therapy may also broader applications and could also be explored with a range of cardiovascular devices, such as left ventricular assist devices, left atrial appendage implants or patent foramen ovale closure devices to reduce the burden of managing ischemic and thrombotic risk.
5. Conclusions
The DESyne BDS Plus RCT demonstrated the feasibility, procedural safety, and promising efficacy of the novel TRx therapy based on noninferior early TLF‐rates and 6‐month LLL compared to a contemporary DES, with absence of any thrombotic event or safety signal associated with the addition of two anticoagulants to the DESyne BDS Plus platform. The observed clinical outcomes and pharmacokinetic profile suggest that localized anticoagulation may allow for safer PCI in patients with high thrombotic and bleeding risk. This study established a critical foundation for this next‐generation DES platform, though this will require further validation in future studies with larger, higher‐risk, and DAPT‐modulated populations.
Conflicts of Interest
S.V., B.F., J.B., R.S., S.E.J., P.T., A.A., I.B., D.S., M.M,. G.W., D.M.C., T.K., M.W. were investigators of the study. S.V. reports consulting fees and payment/honoraria from Elixir and Shockwave. J.B. reports consulting fees from Elixir Medical, Biotronik and Boston Scientific, honoraria/speaker fees from Elixir Medial, Biotronik and Medtronic, and participates in advisory board of Elixir Medical. P.T. reports research grants from OpSense and Biosensors, lecture fees from Medtronic, participates in an advisory board for OpSense, is a DSMB member for the ELITE study, and the chair of the Dutch Working Group Transcatheter Heart Valve Interventions. A.N. is a core laboratory member and shareholder of CERC. Z.M. is an independent core laboratory specialist at CERC. P.C.S. reports institutional research grants from Abbott Vascular and SMT, consulting fees from Abbott Vascular, Microport, and Terumo, honoraria from Terumo, Abbott Vascular and SMT, participates in the DSMB of the Legacy and Proctor Trial, and is a shareholder of CERC. M.M.C. is a minor shareholder of Electroducer, and a shareholder and CEO of CERC. The other authors declare no conflicts of interest.
Supporting information
Supporting Table S1: Inclusion and exclusion criteria. Supporting Table S2: Pharmacokinetics of Sirolimus, Rivaroxaban and Argatroban.
Acknowledgments
We thank Beatrix Doerr, consultant medical writer, for her assistance in preparing this manuscript, and April Slee, consultant biostatistician, reimbursed by Elixir Medical. The study was funded by Elixir Medical.
Data Availability Statement
Data are available from the corresponding author upon reasonable request, but with an embargo of 12 months.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Table S1: Inclusion and exclusion criteria. Supporting Table S2: Pharmacokinetics of Sirolimus, Rivaroxaban and Argatroban.
Data Availability Statement
Data are available from the corresponding author upon reasonable request, but with an embargo of 12 months.