Retrospective analysis of the drug-coated balloon-only strategy for chronic total occlusion coronary lesions

Introduction

Background

Chronic total occlusions (CTOs) of coronary arteries pose a significant challenge for interventional cardiologists (1,2). The prevalence of CTOs in patients with significant coronary artery disease (CAD) has been reported to range from 18% to 20% (1,2). In recent years, the success rate of recanalizing CTOs through percutaneous coronary intervention (PCI) with stenting has increased. However, it is important to be aware that the longer the stent is implanted, the higher the risk of late side effects (3). To address this issue, drug-coated balloons (DCBs) have emerged as a potential alternative to drug-eluting stents (DES). However, to date, the research on this topic has been limited (4,5).

Objectives

As previously observed, the procedural success rate was higher in patients with in-stent restenosis (ISR) CTOs than those with de novo CTOs when DES were used (6). However, it is worth noting that individuals who underwent an ISR CTO PCI had a notably poorer prognosis than those who underwent a de novo CTO PCI (6,7). Currently, there are limited published data available on the procedural success rates and long-term clinical outcomes of patients with ISR CTOs and de novo CTOs treated with DCB. Hence, the aim of this study was to compare the procedural success rates and long-term clinical outcomes of ISR CTO and de novo CTO patients who were treated with DCBs. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-969/rc).

Methods

Setting and participants

A retrospective cohort study was conducted. Between 1 January 2016 and 1 May 2021, a total of 80 patients underwent PCI to treat CTO lesions using the DCB-only treatment at Beijing Hospital. De novo CTO was defined as the complete blockage of the coronary artery, with no blood flow according to a thrombolysis in myocardial infarction (TIMI) anterograde flow grade of 0, and an estimated occlusion duration of more than three months (8). An ISR CTO was defined as a CTO that occurred within a previously implanted stent or occlusive segments located within 5 mm proximal or distal to the stent edges. Each CTO lesion was assessed using the Japanese-Chronic Total Occlusion (J-CTO) score, where a J-CTO score ≥3 indicated a complex CTO (9). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board of Beijing Hospital (approval No. 2016BJYYEC-121-02). Informed consent was taken from all the patients.

All the patients received aspirin (range, 100–300 mg) and were administered either a loading dose of clopidogrel (300 mg) or ticagrelor (180 mg) before undergoing the PCI. Aspirin at a daily dosage of 100 mg was prescribed indefinitely, while clopidogrel at 75 mg/day or ticagrelor at 90 mg twice daily was continued for a minimum period of three months following the DCB implantation. Both groups of patients were retrospectively analysed for clinical and procedural characteristics.

Angiographic and intervention procedural variables

The German Consensus Recommendations (10) were used as a default strategy for the DCB interventions for all the patients. Following the recommendations for native vessels, we pre-dilated the stenotic areas with a balloon-to-vessel ratio of 0.8–1.0 prior to DCB application. The recanalization and pre-dilatation were considered successful and suitable for a DCB-only strategy if a visual residual stenosis of 30% or less was achieved with TIMI III flow, and no major dissections (type C or higher) were detected according to the National Heart, Lung, and Blood Institute classification system (11), were detected. Because it is often impossible to make a visual distinction between a stenosis of 30% and 40%, we considered all residual stenosis up to 40% according to a quantitative analysis as a visual stenosis of ≤30%. All the DCBs were coated with 3.0 µg/mm² paclitaxel (SeQuentPlease by B. Braun, Germany) as the carrier (matrix) for the drug.

Assessment of coronary lesions

The coronary lesions of the enrolled patients were assessed using the integrated quantitative coronary analysis (QCA) software package (Allura Xper FD20 Angiography System, Philips Healthcare, Amsterdam, The Netherlands). Two individuals, unaware of the study protocol, measured or calculated and recorded routine clinical parameters, including the minimal luminal diameter (MLD), lesion length, percent stenosis diameter, and percent stenosis area. Each lesion was measured three times, and the average values were used for the analysis.

Data collection and follow-up

Demographic characteristics, clinical status, associated risk factors, CAD features, previous stent implantation history, and DCB properties were examined. Inpatient and outpatient data were collected from medical records, along with patient interviews and analyses of the patients’ coronary angiograms. The analyzed outcomes included target lesion revascularization (TLR), acute gain measurement, and late lumen loss (LLL). TLR was defined as any repeated percutaneous intervention or coronary artery bypass grafting performed on the target lesion due to restenosis exceeding 50% in the treated segment.

Endpoints

The primary objective of this study was to assess the success rate of the procedure, specifically focusing on achieving complete revascularization of the CTO. As a secondary objective, we aimed to determine the occurrence of major adverse cardiac events (MACEs) over a period of 5 years. MACEs were defined as a combination of all-cause mortality, non-fatal myocardial infarction (MI), or TLR. TLR was further defined as either a repeat PCI or coronary artery bypass grafting due to evidence-based indications of ischemia related to restenosis at the target lesion.

Statistical methods

The continuous variables are presented as the mean ± standard deviation, or the median (interquartile range) as appropriate. The categorical variables are expressed as the number and percentage. The Chi-square test or Fisher’s exact test was used to compare the categorical variables. The Kaplan-Meier method was used to calculate the survival estimates, and the log-rank test was used for comparisons across groups. The odds ratios (ORs) with the 95% confidence intervals (CIs) for the clinical outcomes were calculated using the Cox proportional hazard model. Variables with a P value <0.10 in the univariate analysis or that appeared to be related to the outcome of interest according to clinical consideration were adopted as candidate predictors for the multivariate analysis. Two-sided P values <0.05 were considered statistically significant. The statistical analyses were performed using the SAS statistical software package, Version 9.4 (SAS Institute, Cary, NC, USA).

Results

Baseline demographic variables

Between 1 January 2016 and 1 May 2021, a total of 80 patients underwent a PCI for CTO lesions using the DCB-only treatment at the Beijing Hospital. During the study period, 12 patients were lost to follow-up. Thus, ultimately, 68 patients completed the follow-up. These patients were divided into two groups according to the type of the CTO: the ISR CTO group (n=30), and the de novo CTO group (n=38). All the patients in the ISR CTO group had previously undergone DES implantation.

The clinical characteristics of the entire cohort are shown in Table 1. The age of the patients in the de novo group was much younger than that of the patients in the ISR CTO group (59 vs. 69 years, P=0.005). Additionally, there were more male patients (60.5% vs. 93.3%, P=0.002) and more patients with diabetes mellitus (28.9% vs. 53.3%, P=0.04) in the de novo group than the ISR CTO group. However, there were no significant differences between the patients who underwent an ISR CTO PI and those who underwent a de novo CTO PCI in terms of hypertension, dyslipidemia, current smoker status, renal function, left ventricular ejection fraction, and low-density lipoprotein cholesterol. There was also no statistically significant difference between the two CTO groups in terms of their clinical presentations.

Angiographic and procedural characteristics

The angiographic characteristics of both groups are shown in Table 2. There were no significant differences between the two groups in terms of the proportion of the target CTO vessel. The J-CTO score and the proportion of patients with a J-CTO score ≥3 (36.8% vs. 26.7%) were higher in the ISR CTO group than the de novo CTO group. Special balloons (including Lacrosse NSE balloons and non-compliant balloons) were used to predilate the lesions in all the patients, and there was no statistically significant difference between two groups in terms of the proportion of special balloons used.

In relation to the DCBs, the mean length was 26.9±6.9 mm, the mean diameter was 2.8±0.4 mm, and the mean dilation pressure was 8.8±2.5 atm. All the de novo CTO lesions underwent dissection after DCB use. There were no statistically significant differences in the DCB data between the two groups.

QCA

The general post-PCI MLD (Table 3) increased from 0 to 2.24±0.57 mm. The post-PCI MLD was higher in the ISR group than the de novo group (2.46±0.6 vs. 1.97±0.40 mm, P<0.001). No immediate complications related to the PCI were observed. During the follow-up period, a total of 30 patients underwent repeat coronary angiography. The acute gain in the ISR group was much better than that in the de novo group. However, the follow-up MLD was much larger in the de novo group than the ISR group (1.98±0.65 vs. 1.03±1.10 mm, P=0.01). The LLL of the de novo group was −0.04±0.83 mm.

Clinical outcomes during follow-up

Table 4 shows the clinical outcomes based on a nearly 3-year follow-up period. Clinical follow-up data were available for all the patients. The median follow-up period was 8 months (interquartile range, 6–20 months). No deaths had occurred at the end of the follow-up period. However, MACEs had occurred in 26.4% (n=18) of all the patients. Three patients (two in the ISR group, and one in the de novo group) suffered acute MI (all non-ST segment-elevation MI). However, during the follow-up period, more patients who received a successful re-PCI underwent repeated coronary angiography in the ISR CTO group than the de novo CTO group (34.2% vs. 6.6%, P=0.006), and the ISR CTO group had a higher re-occlusion rate than the de novo CTO group.

The results of the univariable Cox proportional hazard analyses (Table 5) showed that the incidence of MACEs was independently associated with the type of stenosis (ISR vs. de novo) [odds ratio (OR): 7.28; 95% CI: 1.494–35.464, P=0.01), sex (male) (OR: 3.726; 95% CI: 1.014–12.818, P=0.03), and body mass index (BMI) (OR: 1.246; 95% CI: 1.022–1.518, P=0.03). However, after adjusting for age, gender, and BMI, ISR was not significantly associated with TLR (OR: 4.156, 95% CI: 0.734–23.522, P=0.11).

Discussion

The current study made two significant findings. First, this retrospective analysis examined the long-term effects of using a DCB-only strategy to treat both ISR and de novo CTO lesions, making it one of the most extensive studies conducted on this topic. Regardless of the successful revascularization of the CTOs, patients in the ISR CTO group exhibited notably worse clinical outcomes than those in the de novo CTO group, particularly in relation to TLR. Second, when it comes to revascularizing CTOs, employing a DCB-only strategy promotes positive vascular re-modeling, especially in de novo CTO lesions.

DCBs were developed to avoid the use of permanent foreign objects in coronary vessels, and mitigate potential issues associated with stents. There are limited data available on the use of DCBs to treat CTOs, and to date, no randomized trials directly comparing DCBs and DES have been conducted; however, one trial showed that combining a bare-metal stent with a DCB was a feasible alternative to paclitaxel-eluting stents (5).

The successful revascularization of ISR CTO lesions remains challenging. Previous reports have indicated success rates ranging from 70% to 86% for PCI procedures performed on ISR CTO cases and de novo CTO cases between 2005 and 2010 (12,13). Similar to recent research findings (14), our study observed a high incidence of long-term adverse events (over 30%) among patients with ISR CTOs. This might be due to various factors, such as inadequate stent expansion or sizing, stent fracture or deformation along its length, and malapposition. Consequently, additional specialized pretreatment is often necessary before implementing either DCB or DES interventions.

DCBs have been used to replace or combine with DES in de novo CTO lesions. In de novo CTO lesions, the success rate of recanalization using a DCB-only strategy (SeQuent Please, B. Braun, Germany) was found to be satisfactory in 79.4% of patients (4). Additionally, another study indicated that there were no significant disparities in the occurrence of restenosis between DESs and DCBs for de novo CTO lesions (15). Our study yielded similar results with only one patient experiencing restenosis of all those treated. A retrospective study showed that DCB treatment appeared to be safe and effective in treating de novo CTO lesions during long-term follow-up, and the recanalization results and long-term outcomes were comparable between the hybrid (a DCB in combination with a DES) group and DCB-only group despite there being more complicated lesions in the hybrid group (16). The use of DCBs is advantageous in de novo CTO lesions, as DCBs do not require additional metal layers, and DCBs also reduce the risks associated with permanent implants, such as inflammation and thrombosis (15). Further, they offer an additional potential benefit, as they minimize the risk of late or very late stent malapposition and subsequent adverse events due to frequent misunderstandings regarding correct vessel size during CTO recanalization and subsequent failures in selecting appropriate stent sizing, which are not uncommon (17).

It is important to acknowledge that certain DCBs (specifically those eluting paclitaxel) have demonstrated an intriguing effect on late lumen enlargement by directly impacting the tunica adventitia. This technology holds promise for treating CTOs, as it creates a favorable environment (18). In our study, we also observed luminal enlargement in patients with de novo CTOs, with an average late luminal gain of 0.04±0.83 mm. However, we did not observe positive re-modeling in the ISR CTO group.

A significant proportion of individuals presenting with CTOs often suffer from multivessel CAD and have comorbidities that increase the risk of bleeding. To improve clinical outcomes in these complex cases, it may be beneficial to limit the length of stents used for native coronary disease in higher-risk patients (14). A prospective observational study indicated that the re-vascularization of CTO lesions involving DCBs appeared to be safe, and potentially lowered the MACCE rates compared to those of DES-alone treatments. Importantly, using DCBs for CTO treatment may reduce the total stent length, which determines PCI outcomes (19). Nonetheless, interventions without DES implantations do have drawbacks, such as reduced acute gain and an increased likelihood of acute recoil. DES stenting remains the more prevalent and widely accepted treatment option for CTO.

In summary, based on the comprehensive analysis and meticulous research conducted in our study, it can be reasonably inferred that the implementation of a unilateral DCB treatment strategy would produce notably positive outcomes for individuals suffering from CTO coronary lesions. Importantly, our findings specifically highlight that this therapeutic approach was efficacious in individuals presenting with de novo lesions, and effectively addressed the challenges associated with these novel cases.

Limitations

This study had a number of limitations. First, the absence of randomization in the registry data might have led to selection bias. There were notable differences in the baseline characteristics between the two groups, and it was at the discretion of the physician to decide whether or not to perform a PCI for CTO. Additionally, due to the retrospective nature of our registry study, we could not thoroughly capture all instances in which the patients’ medical therapy strategies were modified during the follow-up period. Finally, it is important to note that this observational study was conducted at a single center.

Conclusions

Treatment using a DCB-only strategy proved beneficial for patients suffering from CTO coronary lesions, especially those presenting with de novo lesions.

Acknowledgments

Funding: This work was supported by the Beijing Capital Citizen Health Cultivation Project (No. Z171100000417041) and the CAMS Innovation Fund for Medical Sciences (CIFMS No. 2021-I2M-1-001).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-969/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-969/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-969/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-969/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board of Beijing Hospital (approval No. 2016BJYYEC-121-02). Informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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