We aimed to assess the clinical, angiographic, and outcome profiles of patients undergoing chronic total occlusion (CTO) percutaneous coronary intervention (PCI) with the use of drug-coated balloon (DCB)-only approach in a retrospective multicenter international registry. Data from 309 patients with 312 CTO lesions undergoing successful CTO PCI with DCB-only approach at 42 sites were collected. Angiographic and clinical follow-up was performed at 3 and 6 months, respectively. The primary endpoint was target lesion failure (TLF), defined as composite of cardiac death, target vessel myocardial infarction, or clinically-driven target lesion revascularization (TLR). Secondary endpoints included binary restenosis (≥50% stenosis) and late lumen loss (LLL) on angiography. The mean age was 67 ± 10 years, and 58.9% patients were male. The main indication for DCB was small vessel disease (37.1%), and most CTO were recanalized with intraplaque wiring (93%). TLF was 3.5% with no cardiac death at 6 months. Of 157 CTO with angiographic follow-up (50.3%) at a median of 99 days (IQR: 85 to 136 days), the LLL was −0.1 mm (IQR: −0.3 to 0.3 mm), and 47.8% vessels showed positive remodelling. Binary restenosis and re-occlusion were 24.2% and 4.0%, respectively. Coronary CTO with binary restenosis had significantly higher residual stenosis directly post-PCI (p <0.001) than CTO without restenosis. In conclusion, treatment of CTO with a DCB-only approach is safe, with a low number of TLF at 6-month follow-up. In selected population with angiographic follow-up, suboptimal predilatation result was associated with an increased rate of restenosis and warrants further investigation.
Central illustration
Data from randomized clinical trials support the role of percutaneous revascularization of coronary chronic total occlusions (CTO) in improving the quality of life. ,, Yet percutaneous management of CTO––often involving long, calcified lesions with diffuse distal disease––is still associated with higher risk of stent failure and potentially increased rates of major adverse cardiac events compared with subtotal stenoses. This has prompted a growing interest in the “leave-nothing-behind” strategies based upon the use of drug-coated balloons (DCB) as an alternative for metallic stents in CTO percutaneous coronary intervention (PCI). , Particularly germane to this concept, DCB can preserve coronary vasomotor function, promote late lumen enlargement, and potentially reduce the risk of restenosis and thrombosis. ,, Although clinical data support DCB safety and efficacy for in-stent restenosis, de novo small vessel disease, and high bleeding risk patients, evidence for a DCB-only approach in de-novo CTO is still limited to small and mostly single-center studies. ,, In this multicenter international registry, we aimed to assess: 1) target lesion failure at 6 months and 2) detailed angiographic outcomes at 3 months in patients undergoing successful CTO recanalization with the use of DCB-only approach.
Methods
Study design and population
The CTO-DENOVO study ( www.clinicaltrials.gov identifier, NCT05977842) is a multicenter retrospective registry of consecutive patients who underwent successful CTO PCI using a DCB-only strategy between December 2012 and June 2024 (42 sites, Supplementary Table 1 ). Exclusion criteria were: in-stent CTO and de novo coronary CTO undergoing successful recanalization with the use of drug-eluting stent (DES) at the occlusion site. The use of DES ≥5 mm outside of the occlusion site was not deemed as the exclusion criterion. Study design is presented in Figure 1 . The study was conducted in accordance with the Declaration of Helsinki, and institutional review board approval was obtained at the participating centers. The study informed consent was waived based on the retrospective nature of the study.
Study flow chart. CTO = chronic total occlusion; DCB = drug coated balloon; DES = drug eluting stent; IVUS = intravascular ultrasound.
CTO PCI
CTO PCI was performed in accordance with standard guidelines by experienced CTO PCI operators acquainted with all crossing strategies (antegrade wiring, antegrade dissection and re-entry, retrograde wiring and retrograde dissection and re-entry). After successful CTO recanalization, lesion preparation with a balloon-to-artery ratio of approximately 1:1 was performed, followed by DCB delivery and inflation for at least 30 seconds. A DCB strategy was preferred provided a satisfactory angioplasty result after lesion preparation was achieved including the following criteria: 1) a fully inflated balloon of the correct size for the vessel ; 2) Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 , ; 3) <40% residual stenosis; and 4) the absence of a flow-limiting dissection. , Bail-out stenting and use of intravascular ultrasound (IVUS) were at the operator’s discretion. A subgroup of patients with successful DCB use at the intended CTO lesion, and without the need for bail-out stenting were invited to undergo follow-up invasive coronary angiography (ICA) with optional IVUS at 3 months at discretion of the operator and irrespective of whether it was clinically indicated by the presence of symptoms.
Quantitative coronary angiography
Baseline and follow-up angiograms were analyzed offline by an experienced reader (M.D.) blinded to IVUS measurements using a dedicated software tool (Medis Medical Imaging, Leiden, The Netherlands). Angiographic end-diastolic frames from the region of interest were selected for analysis. The reference diameter of the vessel was determined by marking segments with minimal coronary atherosclerosis within 5 mm of the occlusion site. The coronary artery was automatically delineated, and manual correction was applied if necessary. Proximal and distal markers of the lesion were aligned with the corresponding locations of the DCB-treated segments. The minimal lumen diameter (MLD) was measured and residual percent diameter stenosis was calculated. Acute recoil was defined as the difference between balloon diameter and post-procedural MLD (balloon diameter—postprocedural MLD), whereas late lumen loss (LLL) was defined as a difference between post-procedural and follow-up MLD (post-procedural MLD—follow-up MLD).
IVUS imaging
Baseline and follow-up IVUS were analyzed by an experienced reader (M.D.) using the CAAS IntraVascular software (Pie Medical Imaging BV, Maastricht, The Netherlands). Proximal and distal reference segments were selected according to the procedural ICA images as adjacent to the location of the DCB inflation. In each cross-sectional image, the external elastic lamina and the lumen area were manually traced. For each lesion, the minimal lumen area (MLA) was measured. Plaque burden was defined as plaque and media cross-sectional area divided by the external elastic lamina cross-sectional area. Remodeling was defined as vessel cross-sectional area at the lesion divided by the vessel cross-sectional area at the reference segment. IVUS-defined LLL was calculated using the following formula: (post-procedural MLA—MLA at follow-up)/ post-procedural MLA.
Definitions and study endpoints
Coronary CTO was defined as a complete luminal occlusion on ICA with TIMI flow grade 0 lasting ≥3 months. TIMI flow grade was assessed as previously defined. The CTO PCI difficulty was assessed using J-CTO score as previously described. CTO crossing success was defined as angiographic confirmation of guidewire placement in the true lumen beyond the occluded segment according to the coronary CTO Academic Research Consortium.
Device success was defined as successful delivery and inflation of the allocated DCB at the intended target lesion within 30 to 60 seconds during a first-use attempt (DCB not previously used), successful withdrawal of the device system, and attainment of TIMI grade 2 or 3 antegrade flow with a final in-segment or in-lesion residual stenosis <40%. , Procedure success was defined as device success and both, freedom from in-hospital cardiovascular death, peri-procedural myocardial infarction, target lesion revascularization, any stroke, Bleeding Academia Consortium Scale 3 to 5 bleeding and freedom from bail-out stenting.
The primary endpoint was target lesion failure defined as a composite of cardiac death, target vessel-related myocardial infarction or clinically-driven target lesion revascularization at 6-months. Target lesion was considered as the DCB-treated coronary segment plus 1 mm proximal and distal to the balloon. Myocardial infarction was defined using the fourth universal definition of myocardial infarction. The clinical endpoints were derived from patient records and via a phone contact if necessary. The secondary endpoints were assessed at 3-months and included: binary restenosis (≥50% degree of stenosis in the target segment), LLL, target lesion closure, ICA-driven target lesion revascularization, and MLA on IVUS.
Statistical analysis
Data are presented as mean with standard deviation or median with interquartile range (IQR) for continuous variables and frequency (percentage) for categorical variables. A paired sample T test was used for comparison of normally distributed data, while non-normally distributed continuous data were compared using the Wilcoxon signed-rank test. Categorical data were analyzed using the Fisher’s exact test, excluding cases with missing data for the variable of interest. Statistical significance was defined as a p-value of <0.002 after Bonferroni correction for comparison between coronaries with versus without ≥50% diameter stenosis at follow-up. A p-value of <0.05 was considered statistically significant for all other analyses. Analyses were performed using SPSS software, version 29 (IBM Corp., Armonk, NY, USA).
Results
Baseline clinical characteristics
Of the 333 patients with 336 lesions receiving intention-to-treat DCB-based CTO PCI at the 42 centers, 24 patients required bail-out stenting (7.2%). Consequently, a total of 309 patients with 312 CTO lesions who underwent CTO PCI using a DCB-only approach were included in the final analysis ( Figure 1 ). The mean age was 67 ± 10 years, and 58.9% were male. The prevalence of diabetes and chronic kidney disease were 36% and 16.9%, respectively. The most common indication for DCB use was small vessel disease (37.1%), followed by diffuse coronary artery disease (34.2%). Baseline clinical characteristics are presented in Table 1 .
Table 1
Clinical characteristics.
| Baseline clinical characteristics | N = 309 |
|---|---|
| Age, years | 67 ± 10 |
| Male | 182 (58.9%) |
| BMI, kg/m 2 | 29.1 ± 4.6 |
| Diabetes mellitus | 111 (36%) |
| Diabetes mellitus on insulin | 38 (12.4%) |
| Hypertension | 264 (85.6%) |
| Dyslipidaemia | 266 (86.2%) |
| Current smoker | 53 (17.5%) |
| Family history of coronary artery disease | 57 (18.4%) |
| Prior myocardial infarction | 119 (38.4%) |
| Prior percutaneous coronary intervention | 141 (45.6%) |
| Prior coronary artery bypass grafting | 13 (4.2%) |
| Prior stroke | 19 (6.1%) |
| Heart failure | 119 (38.4%) |
| Chronic kidney disease | 52 (16.9%) |
| Left ventricular ejection fraction, % | 50.4 ± 11.2 |
| Clinical presentation | |
| Stable angina | 254 (82.2%) |
| Unstable angina | 10 (3.2%) |
| NSTEMI | 24 (7.8%) |
| Silent ischemia | 21 (6.8%) |
| Symptoms | |
| CCS I | 58 (18.8%) |
| CCS II | 128 (41.4%) |
| CCS III | 43 (13.5%) |
| CCS IV | 21 (6.8%) |
| Major reason for DCB PCI | |
| Small vessel | 115 (37.1%) |
| Diffuse disease | 106 (34.2%) |
| Not planned but stent-like result after predilatation | 42 (13.8%) |
| High bleeding risk | 11 (3.6%) |
| Bifurcation CTO | 20 (6.6%) |
| Aneurysmatic vessel | 3 (1%) |
| Usual practice for all comer CTO PCI | 8 (2.6%) |
BMI = body mass index; CCS = Canadian cardiovascular society; CTO = chronic total occlusion; DCB = drug coated balloon; NYHA = New York Heart Association; NSTEMI = Non-ST elevated myocardial infarction; PCI = percutaneous coronary intervention
Baseline angiographic and procedural characteristics
The majority of patients had single-vessel disease (36.6%). The most common target CTO vessel was the left anterior descending artery (37.9%), followed by the right coronary artery (36.2%), and the left circumflex artery (25.9%). The mean J-CTO score was 1.5 ± 1.1. The vast majority of CTO treated with a DCB-only approach were recanalized using the antegrade wiring or retrograde wiring strategies (93%), and IVUS guidance was utilized in 32.1% of cases. In almost half of the cases, single access (48.1%) was used, while single CTO wire was sufficient to recanalize CTO in 34.4% of cases. The use of cutting and/or scoring balloons was 18.1%, while mechanical atherectomy was applied in 4.2% of cases. The median number of DCB per CTO lesion was 1 (IQR: 1 to 2), while the mean DCB diameter and the mean DCB length were 2.7 ± 0.4 mm and 29.7 ± 7.7 mm, respectively. The most frequently used DCB was Sequent Please Neo (59.9%). At the end of CTO PCI, 52.9% of the vessels had angiography-detected dissections ( Table 2 ). The device success was 81.7%.
Table 2
Angiographic and procedural characteristics
| Baseline angiographic characteristics | N = 312 |
|---|---|
| Number of diseased vessels | |
| One-vessel disease | 114 (36.6%) |
| Two-vessel disease | 104 (33.3%) |
| Three-vessel disease and/or left main coronary artery | 94 (30.1%) |
| Target CTO vessel | |
| Left anterior descending coronary artery | 118 (37.9%) |
| Left circumflex coronary artery | 81 (25.9%) |
| Right coronary artery | 113 (36.2%) |
| Target CTO vessel characteristics | |
| Blunt stump | 91 (29.2%) |
| Any calcium within CTO segment | 126 (40.4%) |
| Bending ≥45° within CTO segment | 61 (19.5%) |
| Lesion length ≥20mm | 142 (45.5%) |
| Re-try lesion | 14 (4.5%) |
| J-CTO Score | |
| 0 | 60 (19.2%) |
| 1 | 65 (20.8%) |
| 2 | 68 (21.8%) |
| 3 | 43 (17.2%) |
| 4 | 13 (5.2%) |
| 5 | 1 (0.3%) |
| Access site | |
| Single access | 150 (48.1%) |
| Radial | 135 (43.3%) |
| Double access | 126 (40.3%) |
| Biradial | 68 (21.8%) |
| Bifemoral | 8 (2.5%) |
| Radial and femoral | 43 (13.8%) |
| Sheath size | |
| 6 Fr | 42 (13.4%) |
| 7 Fr | 196 (62.8%) |
| 8 Fr | 5 (1.6%) |
| Successful final strategy | |
| Antegrade wiring | 283 (90.7%) |
| Retrograde wiring | 7 (2.3%) |
| Antegrade dissection and re-entry | 21 (6.7%) |
| Retrograde dissection and re-entry | 1 (0.3%) |
| CTO wire number | |
| 1 | 107 (34.4%) |
| 2 | 62 (19.9%) |
| 3 | 37 (11.8%) |
| ≥4 | 36 (11.5%) |
| CTO lesion modification | |
| Semi-compliant balloon only | 67 (21.4%) |
| Non-compliant balloon | 241 (77.4%) |
| Scoring and/or cutting balloon | 57 (18.1%) |
| Intracoronary lithotripsy | 6 (1.9%) |
| Coronary atherectomy | 13 (4.2%) |
| Largest pre-dilatation balloon diameter | 2.8 ± 0.5 |
| Any dissection | 155 (52.9%) |
| Drug-coated balloon | |
| Paclitaxel-coated balloon | 275 (91.9%) |
| Sirolimus-coated balloon | 24 (8.1%) |
| DCB type | |
| Sequent Please Neo | 180 (59.9%) |
| Pantera Lux | 33 (11.1%) |
| Agent | 14 (4.7%) |
| RX Essential Pro | 22 (7.4%) |
| Selution | 11 (3.7%) |
| Magic Touch | 12 (4.0%) |
| Prevail | 8 (2.4%) |
| Biostream | 11 (3.7%) |
| Restore | 2 (0.6%) |
| Elutax | 1 (0.3%) |
| Ever Flow | 1 (0.3%) |
| Protege | 1 (0.3%) |
| Sequent SCB | 1 (0.3%) |
| Number of DCB used | 1 (1–2) |
| DCB diameter (mm) | 2.7 ± 0.4 |
| DCB to reference vessel ratio | 1.3 ± 0.3 |
| DCB length (mm) | 29.7 ± 7.7 |
| Procedural details | |
| Fluoroscopic time (min) | 28.1 (17.0–49.5) |
| Contrast volume (ml) | 200 (149–266) |
| Total absorbed dose (mGy) | 1463.3 ± 1092.7 |
| Total radiation Dose Area Product (µGy*m2) | 6605 (1340–12088) |
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