Drug-Eluting Balloons Versus Conventional Balloons in Treatment of Coronary Bifurcation Lesions in Small Vessels

Introduction

Coronary bifurcation lesions, particularly those occurring in small coronary vessels (defined as arteries with a diameter of less than 2.5 mm), represent a unique challenge in interventional cardiology due to their complex anatomical structure and high risk of restenosis [1]. These account for approximately 15–20% of percutaneous coronary interventions (PCI) [2]. Effectively managing these cases requires careful consideration of both procedural strategy and long-term vessel patency. Small vessels are especially prone to restenosis and late adverse events following conventional balloon angioplasty or stent implantation [3]. Consequently, identifying an optimal treatment strategy for such lesions is essential to improving patient outcomes and minimizing the need for repeat revascularization.

The introduction of drug-eluting balloons (DEBs) has provided a promising alternative to conventional balloons (CBs) and stents in the treatment of coronary bifurcation lesions, particularly in small vessels where stenting may be less desirable due to the risks of late stent thrombosis and altered flow dynamics. DEBs deliver antiproliferative agents, such as paclitaxel or sirolimus, directly to the vessel wall without leaving a permanent scaffold [4–6]. This mechanism reduces the incidence of restenosis and avoids complications associated with stents, including neointimal hyperplasia and stent fracture. DEBs have gained attention for their efficacy in specific clinical scenarios, such as de novo lesions, in-stent restenosis, and high-risk anatomical locations [7]. These high-risk sites – particularly bifurcations – are challenging due to complex vascular geometry, turbulent flow, and a higher likelihood of restenosis. While CBs remain useful for lesion preparation and initial angioplasty, their ability to prevent restenosis in small vessels and bifurcations remains limited [8]. Without drug delivery, CBs are associated with a greater risk of elastic recoil and neointimal proliferation [9,10]. Furthermore, CB use often necessitates adjunctive stent implantation, which can complicate bifurcation procedures and increase the risk of side branch occlusion and stent-related adverse events [11].

This study aimed to provide a comparative analysis of the clinical efficacy and safety of DEBs versus CBs in the interventional treatment of coronary bifurcation lesions in small vessels, with a focus on key clinical endpoints such as restenosis rates, major adverse cardiovascular events (MACE), and the need for repeat revascularization. By evaluating these outcomes, the study seeks to offer new insights into optimizing treatment strategies for this complex patient population. The findings may further guide clinical decision-making by clarifying the advantages and limitations of these 2 approaches in a setting where therapeutic choices continue to evolve.

Material and Methods

STUDY DESIGN:

This retrospective study was conducted at our hospital to evaluate the clinical efficacy and safety of DEBs compared to CBs in the interventional treatment of coronary bifurcation lesions in small vessels. The study included patients treated between April 2022 and May 2024, with inclusion criteria comprising adults aged 18 years or older diagnosed with coronary artery disease involving de novo bifurcation lesions in small vessels (defined as a vessel diameter ≤2.5 mm), confirmed by angiographic evidence. Eligible patients were those assessed as suitable for either DEB or CB treatment based on clinical evaluation and angiographic findings, including those with stable coronary artery disease, unstable angina, or non-ST-elevation myocardial infarction (NSTEMI) qualifying for percutaneous coronary intervention (PCI). Written informed consent was obtained from all participants. Exclusion criteria included severe comorbidities such as end-stage renal disease requiring dialysis, advanced heart failure (New York Heart Association Class IV), life expectancy of less than 6 months, chronic total occlusions in the target vessel, prior intervention in the target lesion within the past 6 months, hypersensitivity to antiplatelet therapy or DEB drugs, and severe vessel calcification precluding effective balloon expansion. A total of 118 patients were enrolled, with 56 assigned to the CB group and 62 to the DEB group based on the type of balloon used during coronary dilation. The study protocol adhered to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines [12]. Informed consent was obtained from all subjects. The study was approved by the ethics committee of our hospital (2024-153) and conducted in accordance with relevant guidelines and the Declaration of Helsinki. All methods adhered to ethical principles for human research. Data were handled confidentially, with personal identifiers removed before analysis to ensure participant privacy.

INTERVENTIONAL PROCEDURE:

The intervention followed a standardized protocol involving routine puncture, guidewire insertion, and catheter placement. After pre-dilation of the target lesion, a drug-eluting stent (DES) was deployed in the main branch, with protective measures taken for the side branch. Following stent deployment, the guidewire was exchanged and advanced through the stent struts to the distal end of the side branch. An appropriately sized balloon was then delivered along the guidewire into the side branch and inflated at a pressure of 8–10 atm for 50–60 seconds. Patients were assigned to 1 of 2 groups based on the type of balloon used: the CB group or the DEB group. In the CB group, a conventional balloon was used for side branch dilation, whereas the DEB group utilized a drug-eluting balloon. Subsequently, the DES in the main branch was re-expanded to ensure optimal apposition and alignment with the side branch balloon dilation. After the side branch balloon was removed, the main branch stent was further post-dilated using a dedicated stent balloon. Final angiographic assessment was performed to confirm procedural success and evaluate the patient’s status.

The procedure was considered successful if the following criteria were met: 1) residual stenosis in the main branch was <20% on immediate postoperative coronary angiography; 2) TIMI (Thrombolysis in Myocardial Infarction) grade 3 forward flow in the main branch; 3) residual stenosis in the side branch was ≤50%; and 4) TIMI grade 3 forward flow in the side branch.

PERIOPERATIVE AND LONG-TERM ANTITHROMBOTIC STRATEGY:

During the perioperative period, all patients received dual antiplatelet therapy (DAPT) consisting of aspirin (100 mg once daily) combined with either clopidogrel (75 mg once daily) or ticagrelor (90 mg twice daily), tailored to the individual patient’s clinical condition and tolerance.

Postoperatively, patients were advised to continue DAPT based on their clinical presentation: 1) for patients with stable angina, DAPT was maintained for 1–3 months; and 2) for patients with acute coronary syndrome (ACS), DAPT was extended to 6 months. After the prescribed DAPT duration, all patients transitioned to long-term single antiplatelet therapy and were closely monitored.

FOLLOW-UP PROTOCOL:

All patients underwent structured and regular follow-up after the procedure, with coronary angiography scheduled at 6 months postoperatively for re-evaluation. Additional follow-ups were conducted as needed, depending on changes in the patient’s clinical condition, either at local healthcare facilities or at our institution. The follow-up regimen included: monitoring of blood pressure, lipid profiles, and blood glucose levels; repeat electrocardiograms and cardiac ultrasound examinations; and documentation of symptom changes, adverse events, and medication adherence. Data were obtained from the hospital’s electronic medical record system and verified during follow-up by clinical staff with more than 6 years of professional experience. All reported events were adjudicated by 2 independent interventional cardiologists with over 8 years of clinical experience, who were blinded to the treatment allocation.

DATA COLLECTION AND STUDY ENDPOINTS:

Baseline data for both patient groups were retrospectively retrieved from the hospital’s electronic medical record (EMR) system. The collected variables included demographic information such as age and sex, medical history encompassing underlying comorbidities and pre-existing conditions, and preoperative laboratory results, including blood tests and relevant biomarkers. Additionally, diagnostic findings from preoperative imaging and functional tests were documented. Intraoperative data captured procedural details, including technical and clinical parameters, while follow-up information included clinical outcomes at 1 year postoperatively.

The minimum lumen diameter (MLD) was measured immediately following the procedure using coronary angiography. The smallest lumen diameter of the treated lesion was recorded from the angiographic images. The measurements were performed by an interventional cardiologist with more than 8 years of clinical experience using standard angiographic analysis techniques. All measurements were blinded to the group allocation to reduce measurement bias. Late lumen loss was defined as the difference between the post-procedure MLD and the MLD measured at the 1-year follow-up. MLD and late lumen loss were evaluated using standardized methods to ensure consistency and reliability.

The study endpoints were divided into primary and secondary categories. The primary endpoint was the incidence of MACE during the postoperative follow-up period. Secondary endpoints included the immediate procedural success rate of the interventional procedure, the incidence of in-hospital complications during the perioperative period, the degree of luminal stenosis in the target lesion at the 1-year follow-up as assessed by coronary angiography, the rate of restenosis at the target lesion during the 1-year follow-up, and the target lesion revascularization (TLR) rate within 1 year after the procedure.

STATISTICAL ANALYSIS:

Statistical analyses were conducted using SPSS software (version 27.0) to ensure accuracy and reliability. For continuous variables following a normal distribution, independent sample t tests were employed to evaluate differences between groups, with results reported as mean±standard deviation. Categorical variables were summarized as frequencies and percentages, and their independence or association was assessed using the chi-square (χ²) test. When the conditions for the chi-square test were not met, Fisher’s exact test was applied as an alternative. All statistical tests were two-tailed, and a significance level of P<0.05 was considered indicative of statistical significance.

Results

BASELINE CHARACTERISTICS OF CB AND DEB GROUPS:

The baseline characteristics of the CB and DEB groups were comparable, with no statistically significant differences observed across all measured variables (P>0.05). The mean age of patients in the CB group was 62.1±7.0 years, while the DEB group had a similar mean age of 61.5±8.3 years. The proportion of male patients was slightly higher in the DEB group (69.4%) compared to the CB group (66.1%), but this difference was not statistically significant. In terms of comorbidities, the prevalence of diabetes mellitus and hypertension was comparable between the groups, with 17.9% and 25.0% in the CB group, respectively, versus 19.4% and 38.0% in the DEB group. The BMI values were nearly identical, averaging 25.1±3.1 kg/m2 in the CB group and 25.0±3.3 kg/m2 in the DEB group (Table 1).

Biochemical parameters, including blood glucose, total cholesterol, triglycerides, and ALT, showed no significant differences between the 2 groups. The mean blood glucose levels were slightly higher in the CB group (6.7±1.2 mmol/L) compared to the DEB group (6.4±1.3 mmol/L), but this was not statistically significant. Similarly, triglycerides were marginally higher in the DEB group (2.8±0.6 mmol/L) than in the CB group (2.6±0.5 mmol/L), with a P value approaching significance (P=0.053). ALT levels and systolic blood pressure (SBP) were consistent across both groups, reflecting the overall homogeneity of the patient populations (Table 1). In summary, the baseline characteristics demonstrated balanced demographic, clinical, and biochemical profiles between the CB and DEB groups, ensuring the validity of subsequent comparisons in outcomes.

CORONARY INTERVENTION-RELATED INFORMATION:

The coronary intervention-related parameters were similar between the CB and DEB groups, with no statistically significant differences observed in terms of disease distribution, lesion location, or procedural characteristics (P>0.05). Among patients undergoing coronary interventions, the prevalence of acute coronary syndrome and stable angina was comparable, with acute coronary syndrome being the predominant clinical presentation in both groups. Lesion locations were primarily in the LAD and diagonal branches, accounting for the majority of cases in both groups, while lesions in the LCX or obtuse marginal arteries were less common. The distribution of lesions did not differ significantly between the groups, indicating a balanced allocation of anatomical complexity. Procedural characteristics, including the main-to-side branch angle and stenosis percentages, demonstrated similar values between the 2 groups. The main-to-side branch angle averaged 48.5±6.5° in the CB group and 49.3±7.1° in the DEB group. Both groups exhibited high degrees of stenosis in the main and side branches, reflecting the severity of coronary artery disease in the studied population. Main branch stenosis percentages were 93.8±6.1% in the CB group and 94.9±6.3% in the DEB group, while side branch stenosis percentages were 89.5±5.0% and 91.2±6.1%, respectively (Table 2). Overall, the coronary intervention-related parameters highlight the similarity in disease characteristics and lesion complexity between the CB and DEB groups, supporting the validity of comparative analysis in treatment outcomes.

POSTOPERATIVE AND FOLLOW-UP OUTCOMES:

The comparison of postoperative and follow-up outcomes between the CB and DEB groups revealed notable differences in key clinical parameters, particularly in restenosis rates, MLD, and late lumen loss. Perioperative complications were infrequent in both groups, with no statistically significant difference observed (P=0.621). Similarly, the incidence of MACE at 1-year follow-up showed no significant disparity between the groups (P=0.259). While the rate of target lesion revascularization was slightly lower in the DEB group (3 cases) compared to the CB group (8 cases), the difference did not reach statistical significance (P=0.078). However, significant differences were observed in restenosis rates, with the DEB group demonstrating a markedly lower rate (3 cases, 4.8%) compared to the CB group (15 cases, 26.8%; P<0.001). Additionally, the DEB group achieved superior outcomes in luminal parameters. The MLD was significantly higher in the DEB group (2.48±0.23 mm) than in the CB group (2.11±0.21 mm; P<0.001), indicating better vessel patency (Figure 1A). Similarly, late lumen loss was reduced in the DEB group (0.07±0.02 mm) compared to the CB group (0.10±0.03 mm; P<0.001), reflecting enhanced long-term vascular remodeling (Figure 1B). These findings highlight the advantages of DEB over CB in reducing restenosis and improving luminal outcomes, suggesting that DEB can provide superior efficacy in the interventional treatment of coronary bifurcation lesions in small vessels (Table 3).

WEIGHTED POST HOC POWER ANALYSIS:

A weighted post hoc power analysis was conducted to assess the overall effectiveness of the study in detecting significant treatment effects across key clinical factors. The analysis incorporated the following factors: MLD, restenosis rate, late lumen loss, TLR, and MACE, each weighted according to its relative contribution to the study outcomes. The final weighted overall post hoc power was calculated to be 0.903 (90.3%), which exceeds the generally accepted threshold of 80%, confirming that the sample size was sufficient to detect clinically meaningful differences with adequate statistical rigor.

Discussion

Coronary bifurcation lesions, particularly in small vessels, present a significant challenge in interventional cardiology due to their complex anatomy and increased risk of restenosis. Small vessels, typically defined as those with a diameter of ≤2.5 mm, are particularly prone to procedural complications and late adverse events, making their management a critical area of study. CBs, widely used in PCI, rely solely on mechanical dilatation to restore vessel patency [13,14]. However, this approach is often associated with significant neointimal hyperplasia, elastic recoil, and high rates of restenosis, especially in the challenging bifurcation anatomy. DEBs have emerged as a promising alternative, combining the benefits of mechanical dilatation with the localized delivery of antiproliferative drugs. Unlike stents, DEBs leave no permanent scaffolding, minimizing inflammation and stent-related complications such as late thrombosis. Their unique ability to deliver drugs directly to the vessel wall offers the potential to significantly reduce restenosis while maintaining optimal flow dynamics in bifurcation lesions [15,16]. This study provides valuable insights into the comparative efficacy and safety of DEBs and CBs in the interventional treatment of coronary bifurcation lesions in small vessels. The findings highlight significant differences in key clinical outcomes, despite the baseline equivalence in demographic, clinical, and procedural characteristics, underscoring the superior performance of DEBs in reducing restenosis and improving luminal parameters.

The balanced baseline characteristics between the CB and DEB groups ensure the validity of our comparative analysis. Both groups exhibited similar distributions of age, sex, comorbidities, and biochemical profiles. Additionally, procedural factors such as lesion location, main-to-side branch angle, and degrees of stenosis in the main and side branches were statistically comparable. These similarities suggest that the observed differences in clinical outcomes are primarily attributable to the specific balloon technologies rather than confounding baseline or procedural factors. One of the most notable findings was the significantly lower restenosis rate in the DEB group compared to the CB group (4.8% vs 26.8%; P<0.001). This difference can be attributed to the localized delivery of antiproliferative agents by DEBs, which inhibit neointimal hyperplasia – a primary driver of restenosis. Unlike CBs, which rely solely on mechanical dilatation, DEBs provide pharmacological modulation of vascular healing processes without leaving a permanent scaffold. This mechanism minimizes inflammatory responses and late-stage complications, leading to improved long-term vessel patency [17,18].

The DEB group demonstrated significantly higher minimum lumen diameter (MLD) and lower late lumen loss compared to the CB group. The superior MLD in the DEB group (2.48±0.23 mm vs 2.11±0.21 mm; P<0.001) indicates enhanced vessel patency following treatment, which directly translates to better perfusion and clinical outcomes. Similarly, reduced late lumen loss in the DEB group (0.07±0.02 mm vs 0.10±0.03 mm; P<0.001) reflects better long-term vascular remodeling. These results align with the pharmacodynamic effects of DEBs, which promote controlled vascular healing while minimizing restenosis risk. Perioperative complications were infrequent and comparable between the 2 groups, indicating that DEBs do not pose additional procedural risks compared to CBs. Similarly, the incidence of MACE at 1-year follow-up was low and statistically similar between the groups, further supporting the safety of DEBs in clinical practice [19].

DEBs deliver antiproliferative drugs, such as paclitaxel, directly to the vessel wall, effectively targeting smooth muscle cell proliferation and reducing neointimal thickening without requiring stent implantation, thereby preserving vascular integrity. Additionally, by eliminating the need for permanent stents, DEBs mitigate the risks associated with stent-related complications, including late stent thrombosis, chronic inflammation, and endothelial dysfunction, which are common contributors to restenosis and adverse vascular events. Furthermore, in bifurcation lesions, the absence of a stent enhances hemodynamic flow in both the main and side branches, reducing turbulence and shear stress that can exacerbate restenosis, ultimately promoting better long-term vascular remodeling and outcomes [20,21].

The clinical benefits observed with DEBs, particularly the significantly lower rates of restenosis and reduced late lumen loss, suggest improved long-term cost-effectiveness. The decreased need for repeat revascularization procedures and hospital readmissions could potentially offset the higher initial cost of DEBs. This advantage is consistent with previous health economic models, which suggest that DEBs can be cost-saving in selected patient populations – especially in cases involving small vessels or bifurcation lesions, where the inherent risk of restenosis is elevated. Our findings support the expanding role of DEBs as a practical alternative to conventional balloons, particularly in anatomically complex scenarios where stent implantation may be technically challenging or clinically undesirable. The relatively straightforward procedural integration of DEBs, combined with their favorable safety and efficacy profile, enhances their applicability in routine interventional cardiology practice. Further prospective clinical trials and cost-effectiveness studies are needed to validate these findings and support future reimbursement policy development.

The findings of this study suggest that DEBs are a more effective option for treating coronary bifurcation lesions in small vessels, especially in patients at high risk of restenosis or those unsuitable for stent implantation. However, there are several limitations to consider. Firstly, the retrospective and non-randomized design introduces potential selection bias and residual confounding, which were not fully addressed due to the lack of multivariate adjustments or propensity score matching. Additionally, while the baseline characteristics between the CB and DEB groups were comparable, unmeasured confounders may still have influenced the outcomes. Secondly, data collection relied on existing medical records, which may have introduced information bias due to incomplete or inconsistently documented variables. Despite efforts to minimize missing data through rigorous chart review, some clinical or procedural parameters could not be fully retrieved. Thirdly, the study’s follow-up period of 1 year may not have captured the long-term outcomes, such as very late restenosis or MACE. Finally, although the sample size was sufficient to detect significant differences in key endpoints, it may limit the generalizability of the findings to broader populations or more complex lesion subsets. Future research should involve prospective, multicenter, randomized studies with larger sample sizes and longer follow-up durations to further validate these findings. In addition, sensitivity analyses and multivariate adjustments should be incorporated to better control for potential biases and unmeasured confounders, enhancing the robustness of the results. These future studies would also provide a more comprehensive understanding of the long-term benefits and cost-effectiveness of DEBs in a wider range of patient populations.

Conclusions

Drug-eluting balloons demonstrated superior efficacy in significantly reducing restenosis rates and late lumen loss in patients with coronary bifurcation lesions, particularly in side branches. Additionally, they exhibited a favorable safety profile, with low perioperative complications and comparable long-term outcomes to conventional balloons, highlighting their potential as an effective and safe treatment strategy for this challenging patient population.