Treatment of in-stent restenosis (ISR) is challenging. Drug-coated balloons (DCB) are widely used in this setting to avoid deploying another metal layer to the vessel wall. This first-in-man study sought to assess the safety and efficacy of a novel everolimus-DCB (CVT-DCB) using a new coating formulation and crystalline everolimus in patients with ISR. A total of 51 patients (mean age 69.2 years) with single ISR lesions (≤24 mm in length) were prospectively enrolled at nine sites in Europe. The primary safety endpoint, freedom from target lesion failure at 180 days, was 92.2%, with the lower bound of the 95% CI (81.1%), above the protocol-defined objective performance criterion (65% for conventional balloon angioplasty, p <0.05). The primary efficacy endpoint, in-stent late lumen loss, was 0.40 mm, lower than the protocol-defined objective performance criterion of balloon angioplasty historical control (late lumen loss 0.80 mm, p <0.001). Three-year clinical follow-up was obtained in all (100%) patients. During the first year, 4 patients required ischemia-driven target lesion revascularization. No new episodes of target vessel failure (cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization) occurred beyond the first year. The target lesion failure rate at 3 years was 9.8% (95% CI 3.3%–21.4%). The clinical follow-up of this first-in-man study confirms the sustained safety and efficacy of this novel everolimus DCB in patients with ISR. (Clinical Trials Registration: NCT05731700).
Despite recent advancements in coronary interventions, in-stent restenosis (ISR) remains a major clinical and technical challenge. ,, Both drug-eluting stents (DES) and drug-coated balloons (DCB) are widely used in the treatment of these patients. ,, The DAEDALUS patient-level meta-analysis (1,976 patients from 10 randomized studies) compared DES versus paclitaxel DCB in patients with ISR and demonstrated that DES are more effective than paclitaxel DCB in reducing target lesion revascularization (TLR) at 3 years. However, this benefit was only observed in patients with DES-ISR but not in patients with bare-metal stent (BMS)-ISR. In addition, no differences were found in hard clinical events between these distinct treatment modalities.
Classically, paclitaxel has been preferred for DCB due to its lipophilicity which facilitates transfer and retention at the vessel wall. , However, recent technological advancements allowed the implementation of limus-drugs in DCB. Limus-drugs are cytostatic, rather than cytotoxic, have potent antiproliferative efficacy, and, therefore, are universally used in new generation DES. , Recent studies have suggested the safety and efficacy of some limus-DCB in patients with ISR or de novo lesions. , However, the potential value of “everolimus” DCB remains unsettled. In a first in-man (FIM) study, we previously reported the initial safety and efficacy of a new everolimus-DCB in patients with ISR. The present report examines the 3-year clinical follow-up of patients treated with this novel everolimus-DCB.
Methods
The CVT-ISR trial is a prospective, multicenter, single-arm, FIM study assessing the safety and efficacy of the novel everolimus CVT-DCB (Chansu Vascular Technologies [CVT], Sunnyvale, CA, USA) in patients with ISR (Clinical Trials Registration: NCT05731700). A total of 51 patients with ISR were enrolled at nine European sites. The study protocol was approved by the corresponding ethics committees, and all patients gave written informed consent. The design, 6-month angiographic and 1-year clinical follow-up of this study have been reported. Patients with ISR (>50% diameter stenosis within the stent on visual assessment) with angina or demonstration of ischemia were included. ISR lesions had to be ≤24 mm in length and entirely confined within a stent (bare-metal stent or DES) in vessels ≥2.0 to ≤3.5 mm in diameter. Careful lesion preparation was performed following the DCB international consensus document. Successful predilation (residual stenosis of <30%, no ≥ grade C or flow-limiting dissection) was required before inclusion. Then, the everolimus-DCB (1:1 balloon to artery ratio) was inflated for 60 seconds. By protocol, a prespecified, prospective, clinical follow-up was scheduled at 6 and 12 months, and yearly thereafter, up to 3 years. This was predefined in the case record form and independently monitored. Adjudication of adverse events was performed by an independent academic Clinical Events Committee after reviewing the corresponding source documents following predefined definitions by the Academic Research Consortium (ARC)-2. Myocardial infarction (MI) was defined following the recommendations of the Society for Cardiovascular Angiography and Interventions.
The primary safety endpoint was freedom from target lesion failure (TLF) (cardiovascular death, target vessel MI, and clinically-driven TLR) at 6 months. TLF was compared to a predefined safety Objective Performance Criterion (OPC) of conventional balloon angioplasty (BA) set at 65%, according to published historical studies. The primary efficacy endpoint, assessed in the first 25 patients undergoing prespecified late angiographic surveillance, was in-stent late lumen loss (LLL) at 180 days. The LLL at 6 months was compared to an OPC of 0.80 mm of LLL after BA in historical studies. Quantitative coronary angiography analysis was performed in an independent accredited Corelab (Yale Cardiovascular Research Group, Angiographic Core Laboratory, New Haven, CT, USA).
Statistical analysis
Categorical variables were expressed as counts and percentages. Continuous variables were reported as mean ± standard deviation, as median with interquartile range, or 95% confidence intervals (CI), depending on data distribution. OPC compared with BA (65% for TLF and 0.8 mm for LLL) was established from previous historical studies in patients with ISR, as previously described in detail. Kaplan–Meier survival curves were used to assess 3-year TLF event-free survival. All statistical analyses were performed using a two-sided hypothesis test at an overall 5% level of significance. Statistical analyses were performed using Microsoft Excel and NCSS 9 Statistical Software (2013 NCSS, LLC, Kaysville, Utah).
Results
From October 2021 to April 2022, 51 consecutive patients with ISR meeting the inclusion criteria and with no exclusion criteria were included. The mean age was 69.2 ± 11.2 years, 38 patients (74.5%) were male, and half of them were diabetics ( Table 1 ). Median time from stent implantation to ISR treatment was 78 ± 59 months (median 63 months), and only 7 patients (14%) presented with ISR within the first year after initial treatment. The primary effectiveness endpoint of LLL was 0.4 ± 0.5 mm (median of 0.3 mm), superior to the predefined OPC of the historical BA control (0.8 mm, p-value <0.001) ( Table 2 ). The primary safety endpoint, freedom from TLF at 6 months, was 92.2% (95% CI 81.1%–97.8%) with the lower limit of the 95% CI (81.1%) above the protocol-defined OPC of 65% (p <0.05). During the first 6 months after ISR treatment, 1 patient died of an undetermined cause (and conservatively considered cardiovascular), and 3 patients underwent clinically driven TLR. From 6 to 12 months, 1 patient died from noncardiac causes, and 1 additional patient required clinically driven TLR. Therefore, freedom from TLF at 12 months was 90.2% (95% CI 78.6%–96.7%). During the second year of follow-up, 1 patient died from noncardiac causes, but no episodes of MI or TLR occurred. Likewise, during the third year, no additional episode of TLF (cardiac death, MI, and TLR) occurred. At 3 years, freedom from TLF was 90.2% (95% CI 78.6%–96.7%), confirming the sustained safety and efficacy of this everolimus DCB. The 3-year clinical follow-up cumulative results are summarized in Figure 1 and Table 3 .
Table 1
Baseline clinical, angiographic and procedural characteristics
| Characteristic | |
|---|---|
| Clinical characteristics: | |
| Age (years) | 69.2 ± 11.2 |
| Male | 38 (74.5%) |
| Ever smoked | 26 (51%) |
| Hypertension | 44 (86.3%) |
| Hyperlipidemia | 27 (52.9%) |
| Diabetes mellitus | 25 (49%) |
| Clinical presentation | |
| Angina Pectoris | 26 (51%) |
| Unstable angina | 12 (23.5% |
| Myocardial infarction | 3 (5.9%) |
| Angiographic findings: | |
| Vessel location | |
| RCA: | 22 (43.1%) |
| LAD: | 19 (37.3%) |
| LCX: | 10 (19.6%) |
| Mehran ISR classification | |
| Type 1: | 14 (27.4% |
| Type 2: | 37 (72.6%) |
| Types 3 & 4: | 0 (0%) |
| Type of underlying stent | |
| Bare metal: | 7 (13.7%) |
| DES: | 44 (86.3%) |
| >1 Stent layer | 5 (9.8%) |
| Time from stent implantation to ISR (months) | 78 ± 59 |
| Procedural Characteristics | |
| Lesion Predilation: | 51 (100%) |
| Pre-dilatation balloon diameter | 3.1 ± 0.4 |
| Pre-dilatation balloon length | 15.8 ± 3.3 |
| Duration of device inflation (sec) | 67.9 ± 21.6 |
| Procedural success: | 51 (100%) |
DCB = drug-coated balloon; DES = drug-eluting stent; LAD = left anterior descending coronary artery; LCX = left circumflex coronary artery; RCA = right coronary artery.
Table 2
Quantitative coronary angiography results
| Procedural results (N = 51 Patients) | Mean±SD |
|---|---|
| Proximal RVD (mm) | 2.9 ± 0.4 |
| Distal RVD (mm) | 2.5 ± 0.4 |
| MLD (mm) | 0.8 ± 0.4 |
| Diameter stenosis (%) | 70.7 ± 13.1 |
| Lesion length (mm) | 14.8 ± 4.9 |
| Diameter stenosis after pre-dilatation (%) | 25.5 ± 10.7 |
| Diameter stenosis after DCB (%) | 16.5 ± 7.8 |
| MLD after DCB (mm) | 2.3 ± 0.4 |
| Acute gain (mm) | 1.48 ± 0.4 |
| Results at 6 months in patients ( N = 21) with scheduled angiographic control | |
| Proximal RVD (mm) | 2.9 ± 0.4 |
| Distal RVD (mm) | 2.5 ± 0.4 |
| Diameter stenosis (%) | 29.8 ± 15.8 |
| MLD (mm) | 1.95 ± 0.5 |
| Late lumen loss (mm) * | 0.40 ± 0.48 |
| Late lumen loss (mm) (median; min/ max) | 0.30 (−0.2/1.5) |
| Net gain (mm) | 1.18 ± 0.1 |
| Binary restenosis (n, %) | 5 (23.8%) |
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