Clinical application and expansion of paclitaxel-coated balloons in coronary atherosclerotic disease

Abstract

Drug-coated balloon angioplasty has become one of the important means of interventional treatment for atherosclerotic cardiovascular diseases, and its application in clinical practice is becoming more and more common. Although several expert consensuses and a small number of scattered guideline recommendations have been issued, there is a lack of comprehensive and systematic guideline guidance. However, relevant clinical research and practice are still making continuous progress. This article reviews the clinical research progress of the indications for the treatment of coronary artery stenosis with paclitaxel drug-coated balloons, focusing on introducing its application overview and techniques in in-stent restenosis, bifurcation lesions, new lesions in large and small blood vessels, acute and chronic coronary syndromes and other situations, the management of special complications, and the dual antiplatelet strategy after drug balloon angioplasty, revealing new perspectives on the use of drug-coated balloons in different coronary artery disease scenarios. This article also discusses the cellular and molecular mechanisms related to the anti-atherosclerotic and anti-restenosis effects of paclitaxel, with the hope of providing direct guidance for the daily clinical practice of cardiologists and interventionalists.

Key Words: Drug-coated balloon; Coronary artery disease; In-stent restenosis; Bifurcation lesion; Large blood vessel; Small blood vessel; Coronary artery dissection; Complication; Interventional treatment

Core Tip: Drug-coated balloon (DCB) angioplasty plays a pivotal role in the interventional management of atherosclerotic cardiovascular disease. This review focuses on the application of paclitaxel DCB in coronary artery stenosis, encompassing their use in in-stent restenosis, large or small vessel disease, bifurcation lesions, and other lesion types. Key topics include lesion preparation techniques, DCB delivery strategies, complication management, safety evaluations, and post-procedural dual antiplatelet therapy strategies. Additionally, the review explores cellular and molecular mechanisms underlying anti-atherosclerotic and anti-restenotic effects, including endothelial repair, inhibition of neointimal hyperplasia, and modulation of inflammatory pathways. Current challenges and future directions in optimizing DCB-based therapies are also discussed.

INTRODUCTION

Coronary atherosclerotic heart disease (CAHD) is characterized by the formation of arterial plaques composed of lipid infiltration, calcium deposition, fibrous tissue, and endothelial hyperplasia, which lead to stenosis of the arterial lumen. Its hallmark is reduced myocardial blood supply, typically caused by stenosis or obstruction of the coronary arteries, resulting in a mismatch between myocardial oxygen supply and demand. This increases the risk of angina pectoris, heart failure, and sudden cardiac death. The instability and progression of coronary atherosclerotic plaques are one of the causes of acute and chronic coronary syndromes (CCS) and sudden cardiac death. Coronary artery disease (CAD) is also one of the main causes of death and disability worldwide, posing a serious threat to human health[1]. Since Gruntzig performed percutaneous transluminal coronary angioplasty (PTCA) in 1977, percutaneous coronary intervention (PCI) has become a key treatment for obstructive CAD. However, PTCA faces challenges and pain points due to unpredictable acute occlusion of target lesions and high restenosis rates, primarily caused by plaque prolapse, vascular elastic recoil[2], contractile remodeling, neointimal hyperplasia, and negative remodeling.

Cutting balloons and scoring balloons in PTCA (compared with ordinary balloons, they have the advantages of reducing vascular wall stretching injury and lowering the risk of restenosis caused by elastic recoil and dissecting hematoma), as well as arterial rotational atherectomy (RA), can directly resect atherosclerotic plaques in coronary arteries to increase coronary blood flow. These techniques have better efficacy for complex lesions such as eccentric and ulcerative lesions, as well as calcified lesions with restenosis after PTCA. However, they have poor effects on severely calcified lesions, highly tortuous or angulated vessels, and diffuse lesions longer than 20 mm. They involve difficult surgical operations and high risks, which may lead to complications such as vascular perforation and acute vascular occlusion, thereby increasing the potential risk of restenosis. Excimer laser utilizes the synergistic effects of photochemical, photothermal, and photomechanical effects to promote the volume reduction of components such as thrombus, lipids, and cells. The shock wave-like effect generated by the combined contrast agent injection technology can effectively crack calcified lesions. In particular, for in-stent restenosis (ISR) lesions with a homogeneous intimal tissue pattern shown by optical coherence tomography, it can achieve greater immediate post-operative lumen benefit, but it has relatively poor effects on ISR lesions with a heterogeneous pattern. Additionally, the equipment cost is high, the operation technology requirements are strict, and improper energy control can cause thermal damage to the vascular wall, trigger inflammatory reactions, and increase the possibility of restenosis. Vascular brachytherapy inhibits the proliferation and migration of vascular smooth muscle cells and reduces neointimal formation by releasing radioactive substances locally in the blood vessel. It has a certain preventive and therapeutic effect on some lesions prone to restenosis after conventional treatment, such as ISR. However, it carries the risk of radioactive injury, which may lead to adverse effects on perivascular tissues such as vascular wall fibrosis and aneurysm formation. Moreover, it requires long-term close follow-up after treatment, and various factors such as individual sensitivity to radiation can affect its long-term efficacy. All these treatments are effective technical means for the treatment of vascular lesion restenosis and can play an important role under specific indications. However, in clinical applications, their therapeutic effects on restenosis are affected by multiple factors, their use is cumbersome, and they have certain limitations.

Although the implantation of bare-metal stents (BMS) is crucial for resisting acute and late mechanical contractile forces, thoroughly solving the problem of elastic recoil, stent implantation increases acute vascular injury during PCI and enhances the healing response, leading to varying degrees of neointimal hyperplasia. ISR has become a major drawback of BMS. While drug-eluting stents (DES) have reduced the incidence of restenosis, long-term implantation raises concerns about late stent thrombosis, allergies, and other issues. DES shows suboptimal therapeutic effects in small vessels, bifurcated vessels, and de novo lesions, and the challenges of long-term dual antiplatelet therapy (DAPT) cannot be ignored. In the exploration of coronary artery implantation-free therapies, bioresorbable stents offer advantages such as good biocompatibility, the ability to restore natural vascular status after stent degradation (which is more conducive to long-term vascular health), and avoidance of metal residue. However, they have complex production processes, harsh transportation and storage conditions, resulting in relatively high costs, a narrow spectrum of applicable lesions, insufficient long-term efficacy and safety data, relatively high operational difficulty, potential to cause local inflammation, and a higher risk of device thrombosis[3]. For these reasons, they have been suspended or withdrawn from the market in European and American countries.

Against this backdrop, DCB have emerged as an innovative treatment strategy. Among them, paclitaxel DCB have garnered significant attention in the field of CAD treatment due to their unique pharmacological properties. Their clinical applications and research continue to expand and deepen, bringing new hope to CAD patients[4]. The traditional concept inherent in balloon angioplasty - "the more you gain, the more you lose" - has been challenged[5]. Currently, DCB have been widely used in ISR and de novo small vessel disease (SVD), with broader clinical indications still being explored. Although stent designs have continuously improved to reduce metal residue and achieved encouraging success in improving outcomes[6,7], the fundamental problem of substantial metal residue has not been solved, making it impossible to thoroughly address arteriosclerosis. While the clinical efficacy of DCB [higher target lesion revascularization (TLR) rates] is inferior to that of new-generation DES[8], there is no significant difference in safety. Moreover, DCB technology eliminates the need for further stent implantation, preserving the inherent elasticity of the vascular anatomy. Its efficacy is generally acceptable, and it can be repeatedly applied to target lesion restenosis during follow-up. Therefore, DCB remain a viable option for various conditions, including acute and CCS, regardless of vessel diameter[9], particularly for populations in whom DES may be unsuitable. Issues such as poor stent apposition, overlapping stent placement, and excessively long stents can lead to incomplete arterial endothelialization and late stent thrombosis with DES[10]. Using DCB after adequate predilation can reduce these risk factors and minimize the risk of late thrombosis. There is a growing industry call for "implant-free" and "minimal-implant" approaches in coronary interventions. Over the past decade, clinical trends in coronary interventions have shown a significant decline in the sole use of DES, a notable increase in the sole use of drug-coated balloons, and a steady but slow rise in hybrid treatments[11,12]. The concepts of "implant-free" and "minimal-implant" have gained widespread acceptance, though many key questions remain unresolved, and formal guideline recommendations are still pending. DES remain the primary method for treating de novo coronary lesions due to their significant efficacy. However, in certain clinical scenarios (e.g., high bleeding risk patients, young patients, diabetes) and anatomical situations (e.g., bifurcations, small vessels, diffuse lesions), DES implantation may be challenging or at least less preferable. Drug balloon angioplasty now stands before us, requiring continuous learning and exploration.

THE MECHANISM OF ACTION OF PACLITAXEL DCB

The antiproliferative effect of paclitaxel plays a crucial role in the regulation of the cell cycle. During the cell cycle progression of vascular smooth muscle cells, paclitaxel binds tightly to the β-subunit of tubulin and promotes the α and β subunits of tubulin. This leads to the obstruction of the cell division process, effectively preventing the normal assembly of the spindle[13,14]. As a result, the cell cycle is arrested at the M phase, and the cells gradually undergo apoptosis. In drug-coated balloons, paclitaxel can rapidly diffuse through the vascular intima into the vessel wall. Paclitaxel particles of different sizes exhibit significant differences in their distribution within the vessel wall[15,16], and the drug continues to exert its effect over an extended period, thus continuously inhibiting the cells in the deeper layers of the vessel wall.

Vascular restenosis mainly occurs through three mechanisms: Elastic recoil, negative remodeling, and neointimal hyperplasia. Currently, neointimal hyperplasia is the most common pathogenesis of vascular restenosis[17], in which matrix metalloproteinases (MMPs), actin, MAPKAP kinase 2 (MK2), nucleotide-binding domain-like receptor protein 3 (NLRP3), and inflammatory factors play major roles[18-21]. MMPs play a key role in the degradation of proteins such as collagen and elastin. Among them, MMP-2 and MMP-9 are involved in the migration of smooth muscle cells to the intima. Actin and the microtubule cytoskeleton form a single mechanically integrated system. MK2-induced stress causes vascular smooth muscle cells to transform from a healthy contractile phenotype to a pathological synthetic phenotype, leading to intimal hyperplasia. NLRP3 promotes the proliferation and migration of vascular smooth muscle cells and also activates the secretion of the inflammatory cytokine interleukin-1β (IL-1β), resulting in the upregulation of Bromodomain-containing protein 4 and Lin-9 Homolog (LIN9). The recruitment of IL-1β enhances the expression of LIN9. The transcription factor LIN9 binds to the promoter region of the cell cycle regulator AURKA, thereby promoting its transcription. Eventually, the expression of the molecule Fork head Box M1 related to cell proliferation factors is upregulated, ultimately mediating the proliferation and migration of vascular smooth muscle cells. In addition, inflammatory factors such as tumor necrosis factor-α, IL-1, IL-6, and interferon-γ also promote the proliferation and migration of vascular smooth muscle cells. Paclitaxel inhibits the proliferation and migration of vascular smooth muscle cells by affecting their cell activity, thus achieving the therapeutic effect of drug-coated balloons.

CLINICAL APPLICATION INDICATIONS

ISR

In 1984, the PTCA registration study of the National Heart, Lung, and Blood Institute (NHLBI) in the United States defined restenosis as an increase of at least 30% in the stenosis immediately after PTCA compared with that during follow-up, or a reduction of at least 50% in the benefits obtained from PTCA[22]. In 1987, Emory University Hospital[23] simplified the definition of restenosis. The angiography-based definition is that a diameter stenosis (DS) of ≥ 50% during follow-up is defined as restenosis. In 1993, some studies believed that ISR was a traditional binary definition of coronary restenosis based on the angiographic measurements 6-9 months after PCI[2,24]. It was identified when the luminal DS was ≥ 50%. Since restenosis is a continuous process, how should restenosis occurring within less than 6 months or more than 9 months be defined? The guidelines state that ISR refers to the occurrence of luminal restenosis of ≥ 50% within the stent or at the stent edge after coronary stent implantation (evaluated by coronary angiography), which may lead to the recurrence of myocardial ischemia or the deterioration of symptoms[25]. We put forward a new perspective on this, defining the criteria for ISR as follows: During follow-up angiographic monitoring, evidence of new DS ≥ 50% in the previously treated target lesion or within 5 mm proximal or distal to the target lesion shall serve as the criterion for imaging restenosis. If there is evidence of target lesion-related myocardial ischemia or symptoms, it shall be judged as clinical restenosis after balloon treatment. For the consistency of clinical research, it is recommended to use 6, 9, and 12 months, as well as 3 years and 5 years post-operation as follow-up assessment points for incidence rates, similar to ISR. Restenosis is a gradual process, and outcomes vary at different time points. It is difficult to require patients to undergo examinations strictly at the above-mentioned time points. However, when patients present with new evidence of myocardial ischemia or symptoms, it is easy to complete reexaminations at symptom-related time points. Since the specific time points for individual patients are uncertain, calculating the cumulative incidence of restenosis and the rate of repeat restenosis of the target lesion within the studied population over the specified period provides a more objective and realistic assessment.

For the evaluation of ISR, in addition to angiography or coronary computed tomography, guidelines recommend using radiological stent enhancement techniques and intracoronary imaging techniques (when feasible) to determine the mechanism of ISR[25], so as to guide subsequent treatment choices. Methods for treating restenosis include balloon angioplasty, scoring/cutting balloon, vascular brachytherapy, atherectomy, DCB angioplasty, DES, and coronary artery bypass grafting (CABG). The current common treatments are DCB angioplasty and DES. However, not all ISR requires intervention. Studies[26] show that for ISR in target vessels without "ischemia-driven (triggered by significant angina or positive exercise test results, or both)", even with > 50% late-stage stenosis, similar favorable long-term clinical outcomes are observed. For patients with moderate (40%-70%) late-stage stenosis after stent implantation or atherectomy but without evidence of ischemia, a conservative treatment strategy is supported. For ISR with 50%-90% stenosis, although delayed intervention based on fractional flow reserve (FFR) > 0.75 leads to very good clinical outcomes in ISR patients[27], revascularization decisions for such lesions require FFR assessment. Considering the cost-benefit relationship and that DCB angioplasty is a no-implant strategy, we believe that direct DCB intervention may be an appropriate choice for large-vessel restenosis lesions > 50% with important clinical significance and diffuse restenosis lesions. For other restenosis lesions with 50%-70% stenosis, a clinical observation strategy can be adopted, and direct DCB intervention may be appropriate for stenosis ≥ 70%. Of course, this requires further clinical trials to provide evidence.

The 2010 European Society of Cardiology (ESC) guidelines for PCI recommended considering drug-eluting balloons (DEB) for ISR after prior BMS treatment (IIa, b)[28]. By 2018, ESC guidelines upgraded the recommendation for DCB to treat ISR in both BMS and DES (IA)[29]. However, the 2024 revascularization guidelines[25] acknowledged DCB angioplasty’s efficacy for BMS-ISR but withdrew recommendations for DES-ISR, as DCB showed inferior efficacy compared to repeat paclitaxel DES implantation in DES-ISR. In all ISR types, DCB was associated with similar 1-year target vessel revascularization (TVR) risk but increased 3-year TVR and TLR risk compared to everolimus-eluting stents. For BMS-ISR, DCB angioplasty and repeat DES implantation showed comparable efficacy and safety, while for DES-ISR, DCB was significantly less effective than repeat DES in efficacy, with no significant difference in primary composite safety endpoints[30]. Notably, the 2020 DAEDALUS study[31] demonstrated no difference in 10-year clinical endpoints between DCB angioplasty and DES implantation for ISR. Thus, recommending DES over DCB solely based on DCB’s poorer segmental TLR prevention in long-term follow-up is debatable. The 2025 United States guidelines for acute coronary syndrome (ACS) management[32] did not explicitly restrict PCI methods to DCB or DES in the PCI section, allowing clinicians and patients to choose comprehensively (including DCB angioplasty). While DES reduces revascularization needs for ISR, both therapies show no significant safety endpoint differences. DCB’s “no-implant” feature enables multiple interventions without residual metal, a clear advantage since repeated metal stent implantation increases restenosis risk. Despite this, DES for ISR remains a class IA indication in guidelines[25]. For recurrent ISR in patients refusing CABG, we favor the 2018 guideline recommendations, particularly for refractory ISR - even four sequential paclitaxel DCB uses in the same lesion were safe[33]. We recommend DCB angioplasty as first-line for ISR in patients with a life expectancy > 10 years[34]. A study[35] showed higher cardiac mortality but lower TLR rates in ≥ 75-year-old patients 10 years after DES-ISR PCI. It is widely agreed[36-38] that DCB outperforms plain balloons for ISR, and while DCB lags newer stents in TLR, safety profiles are comparable. Key measures for preventing ISR include: Controlling cardiovascular risk factors, minimizing stent length as much as possible, completing stent implantation under intravascular imaging guidance to avoid inadequate stent expansion, and screening for stent-related component allergies in patients with allergic constitution[39,40].

Bifurcation lesions

The treatment of coronary bifurcation lesions (CBL) is complex, and current guidelines have not explicitly recommended DCB. However, clinical practice shows that hybrid strategies using DCB alone or in combination with DES have the potential to simplify procedures, reduce radiation time during surgery, minimize contrast agent usage, and decrease metal load. Therefore, DCB-based treatment regimens may become a safe and effective alternative to DES. While the European Bifurcation Club White Paper and current revascularization guidelines do not address DCB applications, multiple studies have confirmed their safety and efficacy in bifurcation lesions, particularly in side branch (SB) protection and reducing restenosis[41,42].

Even in the treatment of unprotected left main coronary artery bifurcation lesions[43], DCB-based therapy showed similar clinical outcomes to pure DES therapy at 2-year follow-up. A meta-analysis[42] revealed that, during medium-term follow-up, DCB treatment for both de novo lesions and ISR lesions in left main bifurcation lesions achieved angiographic and clinical results comparable to or even superior to those of DES or conventional balloon therapy. Notably, DCB intervention in side branches induces late lumen enlargement (LLE), which may be the unique advantage of DCB in SB protection.

The application scenarios of DCB in bifurcation lesions include the following:

Pure drug-coated balloon angioplasty strategy: (1) DCB angioplasty for side branches only: Suitable for bifurcation lesions with no proximal main branch lesions, especially ostial SB lesions. The PEPCAD-BIF trial[44] showed that in bifurcation lesions with SB diameters of 2-3.5 mm, DCB treatment for type B lesions (not exceeding NHLBI classification) with ≤ 30% lumen recoil resulted in significantly lower 9-month restenosis rates (6% vs 26% in plain balloon group) and late lumen loss (LLL, 0.13 mm vs 0.51 mm), with only 1 case requiring TLR. This confirms its efficacy for mild-to-moderate dissection lesions; (2) DCB angioplasty for main branches: Her et al[45] conducted a study on pure DCB treatment for main branches (reference diameter 2.5-3.5 mm). The 9-month follow-up showed extremely low LLL in the main branches, with positive vascular remodeling, and significantly increased ostial lumen area in side branches, indicating good safety. This suggests that DCB can effectively improve main branch outcomes and protect side branches in bifurcation lesions; and (3) DCB angioplasty for both main and side Branches: Dual-DCB strategies (main and side branch) and multi-branch DCB strategies (only reported in case studies)[46].

Hybrid strategies combining DCB with other coronary treatment modalities: (1) Hybrid Strategy of Main Branch DES Combined with Side Branch DCB: Although the Tryton SD stent[23] can reduce stent overlap and demonstrates clinical outcomes comparable to provisional stenting in complex bifurcation anatomies with extensive large SB lesions, along with favorable angiographic results[7,47], its use in small side branches increases the risk of peri-procedural myocardial infarction[26]. Additionally, the absence of a drug coating may affect long-term efficacy. Provisional stenting often leads to suboptimal outcomes when SB stenting is required, whereas a hybrid strategy of main branch stenting combined with SB DCB angioplasty can reduce the risk of 1-year major adverse cardiac events[48]. While DCB cannot currently replace conventional stents in large-vessel lesions, its precise drug delivery technology enables full coverage of SB ostial lesions[49], inhibits intimal hyperplasia, and enhances treatment efficacy. For true bifurcation lesions, the strategy of main branch DES combined with SB DCB can simplify procedures and reduce stent implantation. For example, in Kasbaoui et al's study[50], this approach reduced the emergency SB rescue stenting rate to 11.1%, with a mid-term follow-up restenosis rate of only 2.2%, and significantly reduced contrast agent dosage and radiation time. Li et al's research[51] showed that SB DCB use can decrease 12-month SB LLL and major adverse cardiovascular events (MACE) risk. Although preliminary studies[52] indicate promising outcomes for the main branch DES add SB DCB strategy in bifurcation lesions, the lack of large-scale randomized trials currently poses significant challenges for its clinical implementation; (2) Coronary multifurcation lesions: Both interventional therapy and CABG face numerous challenges in treating coronary multifurcation lesions[53]. Using DCB angioplasty or hybrid strategies combining DCB with stents can simplify procedures. For multifurcation lesions, a hybrid approach of main branch DES combined with multiple SB DCB is feasible. Alternatively, DCB can be used for both the main branch and other side branches to reduce the risk of branch involvement[46]; and (3) "Sandwich" strategy for true CBLA hybrid approach involving stent implantation in the main vessel (MV) and SB, with additional DCB deployment at the SB ostium[54].

Small vessel lesions

The REC-CAGEFREE I study[9], a large-scale randomized controlled trial (RCT), first demonstrated that DCB is inferior to stents in overall efficacy for de novo coronary lesions. However, in small vessels (diameter ≥ 2.2 mm and < 3.0 mm), DCB show comparable efficacy to DES while avoiding metallic stent implantation, potentially reducing complications such as stent fracture and restenosis. This provides an evidence-based rationale for precise DCB application, although its clinical positioning requires further clarification through technical improvements and long-term follow-up data. Currently, DCB is increasingly used in the treatment of primary coronary lesions, particularly in small vessels with a reference diameter of 2-2.75 mm and stenosis > 70%. Compared with first- or second-generation DES, some studies show that DCB achieves favorable angiographic and clinical outcomes in CAD patients. The PICCOLETO II study[55] compared the long-term efficacy and safety of a new-generation paclitaxel DCB (paclitaxel dose 2.2 mg/mm², dextran matrix) with everolimus-eluting stents. A preliminary 3-year clinical follow-up found that the new-generation DES was associated with a higher risk of MACE than the new-generation paclitaxel DCB in patients with de novo small vessel lesions. Notably, this study’s primary endpoint did not include traditional target vessel failure. The BASKET-SMALL 2 study[56] also confirmed that DCB is non-inferior to second-generation DES for primary small vessel lesions < 3 mm in diameter.

Pooled data from multiple RCTs (Table 1) show that in the treatment of small vessel lesions, DCB demonstrates a trend of superiority compared with DES in the incidence of TLR (DCB 3.1%-8.8% vs DES 1.2%-14.8%) and MACE (DCB 6.4%-14.4% vs DES 3.4%-20.8%), with some results reaching statistical significance (e.g., MACE in PICCOLETO II, P < 0.05)[9,55,57-59]. Additionally, the DCB group exhibits less LLL (0.04 ± 0.28 mm vs DES 0.17 ± 0.39 mm), indicating that DCB has better biocompatibility in reducing lumen stenosis.

Table 1 Clinical research on drug - coated balloon angioplasty for coronary small vessel disease.

Trial	Intervention	Primary end point	Secondary end point	Follow-up time	TLR/TVR	MACE	LLL
RCT; RVD: < 3.0[9], 2024	DCB: 1133; DES: 1139	A DoCE (a composite of cardiovascular death, TV-MI, and CPI-TLR)	The rates of DoCE at 1 month and 12 months; rates of the individual components of the DoCE (i.e., cardiovascular death, TV-MI, CPI-TLR)	2 years	CPI-TLR: DCB vs DES; 3.1% vs 1.2%; P = 0.0021. CPI-TVR: DCB vs DES; 3.3% vs 1.6%, P = 0.0084	At 24 months, the DoCE occurred in 72 (6.4%) in the DCB group and 38 (3.4%) in the DES group	NR
RCT; RVD: 2-2.75[55], 2023	DCB: 118; DES: 114	The angiographic in-lesion LLL	Angiographic success and the absence of in-hospital cardiovascular complications, and MACEs, a composite of cardiac death, all MIs, TLR, and the individual components of MACEs at 1 year and 3 years	3 years	DCB vs DES; 8.8% vs 14.8%; P = 0.18	MACE: PCB vs PES; 10.8% vs 20.8%	The DCB vs the DES in terms of in-lesion LLL (0.04 ± 0.28 mm vs 0.17 ± 0.39 mm)
RCT; RVD ≤ 2.8[57], 2020	PCB: 90; POBA: 45	TVF	TLR and LLL	2 years	No significant difference in TVF	NR	The PCB vs the POBA in terms of in-lesion LLL (0.01 ± 0.31 mm vs 0.32 ± 0.34 mm)
RCT; RVD < 3[58], 2022	DCB: 546; DES: 212	MACEs	All-cause death, probable or definite stent thrombosis	3 years	1 year: No significant difference between DCB and DES; 3 years: Similar major adverse cardiac event rates	The consistently lower rates of MACE and its components in DCB	NR
RCT; RVD < 2.8[59], 2025	PCB: 90; PES: 92	Angiographic in-stent (or in-balloon) late lumen loss at follow-up angiography at 6 months	MACE	3 years	1100 days; TLR: PCB vs PES; 6.7% vs 13%, P = 0.14; TVR: PCB vs PES; 3.3% vs 6.5%, P = 0.32	1100 days; MACE: PCB vs PES; 14.4% vs 30.4%, P = 0.015	NR

RVD: Reference vessel diameter (mm); RCT: Randomized controlled trial; DES: Drug-eluting stents; DCB: Paclitaxel-coated balloon angioplasty; PCB: Paclitaxel-coated balloon; PES: Paclitaxel-eluting stents; POBA: Plain old balloon angioplasty; TV-MI: Target vessel myocardial infarction; MIs: Myocardial infarctions; CPI-TLR: Clinically and physiologically indicated target lesion revascularisation; DoCE: Device-oriented composite endpoint, including cardiovascular death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularisation; TVF: Target vessel failure; TLR: Target lesion revascularization; TVR: Target vessel revascularisation; LLL: Late lumen loss; MACEs: Major adverse cardiac events; NR: Not report.

Smallest vessel lesions

In cardiovascular interventional therapy, vessels with a diameter < 2.2 mm that cannot accommodate stents are defined as smallest vessel lesions, which are often overlooked by interventional cardiologists. Although these vessels are small and have a relatively limited blood supply area, some are functionally critical. Occlusion of such vessels can still cause ischemic symptoms or even severe risks, and complete revascularization is essential for maintaining the synchrony and coordination of cardiac systole and diastole. The development of DCB technology has made revascularization of smallest vessels feasible. Currently, DCB with a diameter of 2 mm are available, along with predilation balloons of 0.8 mm, 1.2 mm, and 1.5 mm, which are primarily used for graded dilation in chronic total occlusion (CTO) lesions and are also applicable to smallest vessels. Unfortunately, DCB with smaller diameters are not yet available[60].

Take septal perforator vessels as an example, the acute outcomes of angioplasty and long-term clinical efficacy for septal perforator vessels have garnered significant attention. Severe stenosis in larger septal perforator arteries can induce obvious myocardial ischemia. As CABG often cannot reach these sites, balloon angioplasty has become a favorable alternative for revascularization. Among them, the first septal perforator branch is anatomically unique, supplying blood to the atrioventricular node and His bundle in approximately 50% of the population. Ischemia in this area can easily lead to severe consequences such as angina, infarction, biventricular failure, and ventricular arrhythmias[60-64].

Large vessel lesions

In the research field of the treatment of new lesions in large coronary vessels (generally, coronary arteries with a diameter of more than 3.0 mm are regarded as large vessels, and some studies consider vessels with a diameter of more than 2.75 mm), the efficacy of DCB has long been controversial. Based on the data of multiple studies (Table 2)[12,65-69], in the treatment of large vessel lesions, compared with DES, there is no significant difference in the incidence of TLR (DCB 1.22%-6.8% vs DES 1.27%-14.6%) and MACE (DCB 0%-7.84% vs DES 5.7%-19.39%) (in most cases, P > 0.05). However, the LLL in the DCB group is better (-0.19 ± 0.49 mm vs DES 0.03 ± 0.64 mm, and in some cases, P < 0.05), and the duration of DAPT is significantly shortened (DCB 1-3 months vs DES 6-12 months, and the compliance rate shows P < 0.002). This indicates that DCB has potential advantages in reducing lumen stenosis and shortening the anticoagulation cycle, but the long-term clinical benefits need to be further verified.

Table 2 Clinical research on drug-coated balloon angioplasty for coronary large vessel disease.

Trial	Intervention	Primary end point	Secondary end point	Follow-up time	TLR/TVR	MACE	LLL	DAPT
RCT; RVD: 3.08 ± 0.48[65], 2016	DCB: 27; DES: 33	TLR; LLL	NR	8-month	8-month, TLR: DCB vs DES 0% vs 6.1%, P = 0.193; TVR: NR	8-month, MACE: None of the patients in the LVD; group experienced MACE	8-month, LLL: DCB vs DES; 0.25 ± 0.25 mm vs 0.37 ± 0.40 mm, P = 0.185	NR
RCT; RVD: > 3.0[12], 2023	DCB: 544; DES: 693	All-cause mortality	Cardiovascular mortality, ACS, stroke or transient ischaemic attack, major bleeding and TLR	Median follow-up: DCB: 3.7 years DES: 3.6 years	DCB-only strategy has no increased all-cause mortality or any other major cardiovascular endpoints, including unplanned TLR, compared to DES	DCB-only angioplastyis safe compared to DES as part of routine clinical practice, in terms of all-cause mortality and MACE	NR	NR
RCT; RVD: 2.5-4.0[66], 2022	DCB: 108; DES: 108	TLR	MACE, cardiac death, TVMI, and vessel thrombosis	2 years	24-month, TLR: DCB vs DES 4.9% vs 16.33%, P = 0.008; TVR: NR	24-month, MACE: DCB vs DES 7.84% vs 19.39%, P = 0.01718	NR	NR
SCRS; RVD: ≥ 2.8[67], 2019	LVD: 200; SVD: 327	The efficacy and safety of DCB in the treatment of de novo lesions in large blood vessels	Indices related to the complexity of lesion preparation; LLL, TLR	Mean follow-up duration was 10.1 months	10.1-month, TLR/TVR: LVD vs SVD; 0% vs 0.30%	10.1-month, MACE: LVD vs SVD; 0% vs 1.40%	10.1-month, LLL: LVD vs SVD-0.17 ± 0.62 mm vs -0.17 ± 0.43 mm, P = 0.993	DCB-only therapy without stenting confers; the additional advantage of safety without the need for prolonged; DAPT
SCRS; RVD: > 2.75[68], 2024	DCB: 708; DES: 704	CD-TLR	All-cause mortality, major bleeding, MACE	24 months	CD-TLR: DCB vs DES: 5.5% vs 3.1%, P = 0.028	MACE: DCB vs DES: 7.6% vs 5.7%, P = 0.143	NR	NR
SCRS; RVD: > 2.75[69], 2023	PCB: 73; DES: 81	TLF	Angiographic restenosis	PCB: 1536 ± 538 days; DES: 1344 days ± 606 days	TLF: PCB vs DES; 6.8% vs 14.6%, P = 0.097	NR	NR	NR

Angiographic restenosis: Defined as a follow-up percent diameter stenosis > 50; LVD: Large vessel diameter; SVD: Small vessel diameter; DAPT: Double anti-platelet therapy; CD: Cardiac death; CD-TLR: Clinically driven target lesion revascularization; TLF: Target lesion failure; ACS: Acute coronary syndrome; SCRS: Single-center retrospective study; RVD: Reference vessel diameter (mm); RCT: Randomized controlled trial; DES: Drug-eluting stents; DCB: Paclitaxel-coated balloon angioplasty; PCB: Paclitaxel-coated balloon; PES: Paclitaxel-eluting stents; POBA: Plain old balloon angioplasty; TV-MI: Target vessel myocardial infarction; MIs: Myocardial infarctions; CPI-TLR: Clinically and physiologically indicated target lesion revascularisation; DoCE: Device-oriented composite endpoint, including cardiovascular death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularisation; TVF: Target vessel failure; TLR: Target lesion revascularization; TVR: Target vessel revascularisation; LLL: Late lumen loss; MACE: Major adverse cardiac events; NR: Not report.

ACS

Currently, evidence regarding the safety and efficacy of DCB in patients with ACS remains limited[70]. Some studies using pure DCB angioplasty strategies in the context of primary PCI (PPCI) have demonstrated favorable 1-year clinical outcomes, providing some support for DCB use in ACS patients. However, further research is still needed for validation.

There are some challenges in the application of DCB in ACS patients. Thrombus at the lesion site may hinder the drug from entering the vessel wall and may also cause acute vessel occlusion. The REVALATION study[71] found that in patients with non-ST-segment elevation myocardial infarction (NSTEMI), DCB treatment of de novo coronary lesions was not inferior to implantation of BMS or DES.

Current guidelines do not provide recommendations for the use of DCB angioplasty in ACS[32,72]. After successful thrombus aspiration and predilation in 40 STEMI patients, Nijhoff et al[73] performed PPCI with DEB, achieving a procedural success rate of 97.5%. Emergency stenting was required in 10% of patients, and no acute or late thrombotic events occurred in the pure DEB group, suggesting that pure DEB may be a potential alternative for PPCI. A systematic review and meta-analysis[74] showed that paclitaxel-coated balloon angioplasty is feasible for treating de novo lesions in ACS patients compared with emergency DES implantation. However, in acute ST-segment elevation myocardial infarction (STEMI), variable thrombus burden hinders contact between the paclitaxel coating on the balloon surface and the vascular endothelium, not only reducing the therapeutic efficacy of DCB but also increasing the risk of no-reflow, which adversely affects long-term outcomes. Therefore, the use of DCB in STEMI patients is limited, and current data on DCB use in PPCIs are scarce. Nevertheless, for patients with contraindications to DES, pure DEB may be a potential PPCI option after successful thrombus aspiration or coronary thrombolysis to thoroughly clear the thrombus at the target lesion and complete predilation[73,75]. It is worth noting that the FFR assessed at 9 months showed no inferiority of the DCB strategy compared with the DES strategy. However, the primary steps in limited DCB use include intracoronary thrombolysis or thrombectomy, followed by adequate predilation, and then DCB application.

The 2024 Expert Consensus of the Japanese Society for Cardiovascular Interventions and Therapeutics[76] states that DCB angioplasty without stent implantation may be a favorable treatment strategy for STEMI, considering the lack of superiority of stents in hard clinical endpoints and their potential short- and long-term drawbacks.

CTO

In CCS, research on CTO is even scarcer, particularly regarding drug applications in CTO. Although DES have increased the success rate of CTO interventional therapy to 90%, the ISR rate remains as high as 15%-20%, with significantly increased risks of delayed stent malapposition and thrombosis[1]. DCB, by delivering local antiproliferative drugs while avoiding permanent metallic implantation, reducing total stent length (especially for small-diameter stents), and lowering the risk of MACE, have emerged as a potential alternative to DES[77]. A study[78] involving DCB use in CCS showed that the TLR rate was only 1.4%.

Sanchez-Jimenez et al[79] showed that DCB treatment for selected primary CTO lesions demonstrated good safety and efficacy in long-term follow-up. Even though lesions in the hybrid group were more complex, this group showed comparable revascularization outcomes and long-term efficacy to the pure DCB group. A prospective, observational, multicenter study[80] involving 591 CTO patients compared the efficacy of DCB monotherapy or combined with DES vs pure DES for primary coronary CTO lesions. One-year angiographic follow-up revealed significantly smaller LLL in the DCB group than in the DES group (-0.08 ± 0.65 mm vs 0.35 ± 0.62 mm, P < 0.001). There was no statistically significant difference in restenosis rates between the two groups, and the 3-year Kaplan-Meier estimates of MACE were similar. These findings suggest that DCB is a potential "stent-free" approach for primary CTO lesions in coronary intervention, with satisfactory long-term clinical outcomes. A study[81] including 200 CTO patients compared those who successfully received DCB or DCB combined with DES with those treated with second-generation DES alone. The 2-year MACE incidence was significantly lower in the DCB group than in the pure DES group. DCB-based PCI significantly reduced stent burden (especially the use of small-diameter stents) and the risk of MACE.

CTO within a stent (IS-CTO) represents a unique challenge in PCI. A retrospective study[82] comparing DCB and DES for IS-CTO treatment showed that DCB angioplasty is an effective alternative strategy to DES re-stenting for IS-CTO, with similar long-term outcomes. However, both approaches are associated with a high long-term incidence of MACE. Notably, chronic kidney disease and stent layers ≥ 3 are independent predictors of MACE, while switching to other antiproliferative drugs is an independent protective factor against MACE (P < 0.05).

For complex CTO cases, DCB combined with subintimal plaque modification strategies can improve subsequent procedural success rates, and unscheduled "CTO modification" for first-time failed cases offers safety advantages[83,84]. With adequate predilation[85], the 2-year MACE incidence of DCB for CTO is acceptable (only 3.0% late vessel re-occlusion). However, it is important to note that the incidence of coronary artery aneurysm (CAA) after DCB treatment reaches 8.0%, mostly located at the lesion entrance (85.7%), which is associated with the severity of dissection, though it does not increase the risk of MACE[85,86]. In contrast, the CAA incidence of paclitaxel DCB in non-CTO lesions is only 0.8%, suggesting that the complexity of CTO procedures exacerbates the risk of vascular injury[86].

Available data support DCB as a safe alternative strategy for CTO[87], but large-scale randomized trials are needed to further clarify its long-term efficacy, particularly for personalized treatment of patients with complex anatomical features[77,84,85]. Future research should focus on how to balance the vascular repair advantages of DCB with the risk of aneurysms, while exploring the long-term benefits of combined techniques (such as plaque modification add DCB)[83,86,88].

Hybrid therapy

A synergistic hybrid treatment strategy combining DCB and DES has gained attention in the treatment of patients with complex high-risk indications for PCI (CHIP)[89]. CHIP patients typically include the elderly, those with multiple comorbidities, and those with complex coronary artery anatomy. Such patients often require extensive DES implantation (e.g., in bifurcation and/or severe coronary calcification lesions), exposing them to risks associated with increased stent burden. DCB can overcome some limitations of DES through hybrid strategies (combined use of DCB and DES) or pure DCB use. Although most current data are from observational studies, they generally support lowering the threshold for DCB use in patients with multiple concurrent CHIP factors. For patients with comorbidities predisposing to bleeding events (e.g., advanced age, diabetes, end-stage renal disease), pure DCB use can shorten the duration of DAPT. Additionally, in PCI for bifurcation lesions and CTO lesions, DCB can simplify procedures by reducing total stent length, and hybrid strategies may facilitate LLE. For diffuse long lesions with important side branches[90], DCB can be used in segments with more branches to reduce the risk of branch involvement, while DES can be used in other segments to protect branches.

A study[91] on FFR after PCI in patients with diffuse long lesions treated with long stent (≥ 30 mm) implantation showed that FFR outcomes after PCI were suboptimal in most patients receiving long DES, particularly when the total stent length exceeded 50 mm. A DCB-DES hybrid treatment strategy for diffuse long lesions can significantly reduce the risk of target lesion failure. For example, cohort study data on long lesions of the left anterior descending artery showed that patients receiving hybrid DCB-DES had an 80% lower risk of target lesion failure at 2-year follow-up compared with those receiving DES alone[92]. Basavarajaiah et al[93] further confirmed that DEB has better efficacy in patients with diffuse lesions.

In summary, multiple stent implantation for long lesions has obvious disadvantages. Therefore, combining DES with DCB to reduce stent implantation length may be a good option, which requires more RCT studies to provide evidence.

SB protection

The long-term clinical prognosis of patients with CBL is closely related to the status of the MV after stent implantation, while the protection of important side branches is equally critical. Involvement of side branches may significantly affect patient prognosis or trigger relevant clinical symptoms. Traditional SB protection methods mainly include guidewire protection, jailed balloon technique, and stent implantation when necessary. In the DCB era, a treatment protocol combining main branch stenting with SB DCB is commonly used in clinical practice. A systematic review and meta-analysis on the protective effect of DCB angioplasty for side branches in CBL[94] showed that although there were no significant differences between DCB and non-drug-coated balloons in terms of immediate SB protection effect, target lesion failure (TLF) incidence, and procedural success rate, DCB significantly reduced LLL, DS, branch restenosis, and MACE, while significantly increasing the minimum lumen diameter of side branches. For lesions where side branches cannot tolerate stents or DCB, a hybrid strategy of main branch stenting combined with DCB can be used, i.e., avoiding the SB ostium through main branch stenting and covering the lesion sites not involved by the stent via DCB dilation in the SB area. This strategy can not only reduce the number of stents implanted and achieve SB protection but also reduce the risk of acute MV occlusion. It is worth noting that although hybrid treatment strategies have been widely used in clinical practice, high-quality research data specifically for SB protection strategies remain relatively scarce[77].

High bleeding risk population

The DEBUT trial[95] enrolled patients in the intention-to-treat population with ischemic de novo lesions, at least one bleeding risk factor, and a reference vessel diameter of 2.5-4.0 mm. After successful predilation of the target lesion, the study compared DCB with BMS in PCI. Results showed that DCB-based treatment was superior to BMS in patients with bleeding risk. Additionally, the BASKET-SMALL 2 trial[56] compared DCB with DES for coronary lesions with a diameter < 3 mm. The results indicated that DCB was comparable to current DES in terms of safety and efficacy regardless of the patient’s bleeding risk. Notably, DCB-treated patients showed a trend toward fewer severe bleeding events at 3 years due to the ability to shorten the duration of DAPT and the absence of permanent implants.

For patients with extremely high bleeding risk, such as those with peptic ulcer, gastrointestinal cancer, or severe thrombocytopenia, who may not tolerate even 1 month of DAPT, stent-free PCI with short-term (< 1 month) DAPT or single antiplatelet therapy theoretically represents a suitable revascularization approach for these individuals[3]. In patients with low thrombus risk but high bleeding risk, the duration of DAPT or single antiplatelet therapy after pure DCB treatment may be further shortened[96].

Other scenarios

Diabetes is considered a CAD equivalent, with diabetes accounting for up to 48.2% (6373/13970) of patients with cardiovascular disease or at high cardiovascular risk[97]. In the treatment of cardiovascular diseases in special populations such as diabetes, regardless of the treatment modality chosen, diabetic patients may face specific challenges, such as relatively high rates of restenosis and occlusion after PCI or CABG[28]. DCB offer more uniform drug delivery, avoiding platelet aggregation, inflammation, and ISR caused by cracks or uneven coating distribution in DES[98]. Therefore, DCB may serve as an alternative to DES in these types of lesions.

Older patients with type 2 diabetes often exhibit severe and rapidly progressing SVD. While some studies show higher rates of TLF and TLR after DCB angioplasty in diabetic vs non-diabetic patients[99], conflicting results exist[100]. In multivessel CAD, DCB-based revascularization strategies appeared to confer more pronounced clinical benefits in diabetic patients compared to non-diabetic patients after 2 years of follow-up. A study on DES restenosis[101] found no difference in LLL between DCB angioplasty in single-layer DES-ISR, multi-layer DES-ISR, PES-ISR, and non-PES ISR subgroups. After DCB treatment, LLL did not differ significantly between diabetic and non-diabetic patients, suggesting amplified efficacy advantages of DCB in diabetic populations. A meta-analysis[102] demonstrated that DCB had significant advantages over DES in treating de novo lesions in high-risk patients (primarily diabetic patients), reducing overall mortality, MACE, and TLR. Long-term results from the BASKET-SMALL 2 trial showed that DCB provided more sustained benefits than permanent stents in diabetic patients 2-5 years after initial intervention[103]. For diabetic small vessel lesions[104], pure DCB treatment exhibited low rates of TLF and MACE, with no significant difference in 1-year MACE, though the diabetic group had a significantly higher target lesion failure rate than the non-diabetic group. However, most of these studies compared DCB with BMS or conventional balloon angioplasty, and their findings still require validation from additional clinical data and subgroup analyses.

The Japanese expert consensus indicates that DES implantation is not suitable for young patients[105]. We treated young CAD patients with high bleeding risk using DCB angioplasty without stent implantation. The four-year follow-up results showed that the patients met the criteria for imaging and clinical cure, which is rare in the field of CAD treatment[75].

APPLICATION TECHNIQUES

Patient and lesion assessment

For non-ACS patients, evaluate symptoms, medical history (particularly renal function, high bleeding risk, medication adherence, allergy history, and uncontrollable risk factors), and physical signs. Complete relevant examinations including electrocardiogram (ECG), basic blood tests, resting echocardiography, chest X-ray imaging, and pulmonary function tests. Use a risk factor-weighted clinical pre-test probability model to estimate the likelihood of obstructive CAD before testing. For a pre-test probability > 85% (very high), perform invasive coronary angiography[25]. Guide treatment strategy selection through precise intravascular imaging and functional assessment. Regardless of vessel size, FFR-guided DCB-only PCI is feasible, safe, and effective. Small non-flow-limiting type A or B dissections with an FFR > 0.80 do not require stent implantation, yielding good clinical outcomes and a reduced rescue stenting rate[106].

Precision DCB therapy

The ULTIMATE III trial[107], a prospective, multicenter, randomized, controlled, open-label study in high bleeding risk patients with de novo coronary lesions, showed that IVUS-guided DCB angioplasty was associated with lower LLL compared to angiography guidance, particularly in patients with complex CBL. Compared to angiography-guided PCI, OCT-guided PCI was associated with a lower 2-year MACE incidence. Hemodynamic significance is assessed using FFR, instantaneous wave-free ratio, or quantitative flow ratio, with intervention decisions combined with imaging findings to comprehensively evaluate interventional indications from multi-dimensional aspects including symptoms, anatomy, function, and risk. The most suitable revascularization strategy is selected based on individual conditions, coronary anatomy, procedural factors, left ventricular ejection fraction, patient preferences, and expected outcomes. It is critical to identify which patients benefit most from intravascular imaging-guided PCI. Although the OCCUPI study demonstrated that OCT guidance reduced the incidence of major adverse cardiac events at 1 year compared to angiography guidance in patients requiring drug-eluting stent implantation for complex lesions[108], OCT-guided DCB angioplasty also predicts future LLE[109]. While IVUS guidance promotes favorable outcomes after PCI, IVUS is unavailable in many catheterization laboratories worldwide. The GUIDE-DES trial[110] showed that quantitative coronary angiography (QCA) and IVUS guidance during PCI resulted in similar target lesion failure rates at 12 months. However, in patients with STEMI or extremely high-risk NSTEMI with multivessel coronary disease, FFR-guided complete revascularization did not reduce the risk of a composite endpoint of all-cause death, myocardial infarction, or unplanned revascularization at 4.8 years compared to culprit lesion-only PCI[111]. In catheterization laboratories without IVUS or OCT, QCA may serve as an equivalent alternative guidance method.

Lesion preparation

DCB require meticulous lesion preparation to ensure satisfactory long-term angiographic and clinical outcomes. Lesion predilation and final optimization are typically performed using conventional angiography alone. However, angiography cannot reveal the underlying structure of the target lesion beyond two-dimensional lumen imaging. Additionally, due to vascular remodeling, angiography systematically underestimates the extent and severity of atherosclerotic disease in reference segments. Inadequate lesion preparation (especially for severe coronary calcification) is associated with poor delivery, release, apposition, and expansion of devices, which can lead to ISR and/or thrombosis. For DCB, this can result in incomplete drug uptake, suboptimal immediate effects, and compromised long-term efficacy. Therefore, thorough lesion preparation before DCB dilation is of particular importance. Currently, multiple techniques are used for plaque modification and debulking, including: Balloon angioplasty: Represented by compliant balloons, high-pressure balloons, semicompliant and noncompliant balloons, cutting balloons, and scoring balloons. Atherectomy techniques: Such as excimer laser coronary atherectomy (ELCA), RA, directional atherectomy, orbital atherectomy (OA). Intravascular lithotripsy (IVL): A calcium modification technique. These methods should be selected through lesion assessment using coronary angiography, IVUS, OCT, FFR, etc., to develop individualized pretreatment and evaluation protocols. Calcified lesions affect both DCB and DES efficacy. Intravascular debulking measures, particularly using shockwave balloons after RA or OA to create calcium fractures, facilitate drug penetration. The passability and efficacy of DCB in calcified lesions are influenced by calcification severity, and corresponding pretreatment strategies should be formulated based on calcification lesion stratification[112].

Predilation

Use a predilation balloon catheter of appropriate length and diameter for dilation, or perform pretreatment with directional or rotational coronary atherectomy, laser, or cutting/scoring balloons, ensuring residual stenosis ≤ 50% and dissection ≤ NHLBI type C; target lesion thrombolysis in myocardial infarction (TIMI) flow > grade 2. In the PTCA era, studies showed that selecting a balloon catheter diameter-to-vessel diameter ratio within 0.9-1.3 was associated with a low dissection rate (4%), while oversized balloons with a ratio > 1.3 had a dissection rate of 37%, with some cases causing severe arterial lumen damage. Therefore, selecting an angioplasty balloon diameter similar to or slightly larger than the normal arterial diameter can achieve optimal angiographic results with minimal dissection and residual stenosis[113]. Expert consensus[105,114,115] recommends a balloon-to-vessel diameter ratio of 0.8-1.0, but to achieve sufficient acute and long-term effects, overexpansion with a higher ratio (1.15-1.27) appears more effective under safe conditions. In fact, the balloon-to-vessel ratio is merely a reference for pretreatment; predilation at nominal pressure within this range is safe. More importantly, dilation to the reference vessel size and adequate predilation should be performed to induce controlled moderate dissection as much as possible. The use of cutting balloons or scoring balloons facilitates the formation of controlled dissection, which is critical for drug absorption. Angioplasty without media dissection may affect the efficacy of DCB angioplasty. The predilation strategy for target lesions prepared for DCB angioplasty differs slightly from that for stent implantation. We recommend slow inflation to the target diameter after fully exhausting the pretreatment balloon, followed by stable pressure for 20-30 seconds (extendable to 60-120 seconds in special cases), then slow decompression until complete deflation, to reduce the risk of high-grade dissection. Multiple dilations can be performed to increase the probability of small dissections and improve the utilization of paclitaxel during DCB dilation.

Treatment recommendations for calcified lesions

For patients with fibrotic or severely calcified lesions, plaque modification via OA, balloon atherectomy, laser angioplasty, or IVL may be considered to improve procedural success[116]. Although data supporting RA for improving long-term outcomes are lacking, it remains a critical tool for appropriately "preparing" lesions for stent implantation in certain scenarios. A study on calcified coronary lesions[117] confirmed that the OA followed by DCB strategy was non-inferior to DES in 1-year clinical outcomes for calcified lesions and may reduce late lumen area loss. In ostial lesions or those associated with ISR, cutting balloons and scoring balloons have a lower slippage rate compared to traditional balloons. Excimer laser coronary angioplasty can disrupt calcified lesions beneath stent struts, facilitate stent expansion, and improve balloon crossability. While IVL, atherectomy, cutting balloons, or laser techniques are clinically applied, they lack robust large-scale data support. Intravascular imaging studies in CCS patients with predominantly non-calcified lesions have shown that multiple balloon dilations significantly increase lumen area and dissection angles, potentially enhancing the utilization of key drugs during DCB angioplasty. Pretreatment with scoring balloons or even atherectomy devices before DCB use is recommended. Results from the PASSWORD study[118] indicate that for de novo lesions suitable for DCB, scoring balloon angioplasty achieves high procedural success rates, a low 9-month TLF rate, and only 1.3% of de novo lesions require rescue stenting. The 2020 DCB International Consensus Third Report[114] recommends that using special balloons and adjuvant techniques for complex lesion preparation can enhance pretreatment efficacy, improve procedural outcomes, and optimize patient prognosis.

DCB delivery

Due to their larger outer diameter, DCB are more challenging to deliver than standard balloons. In cases of distal lesions, extreme tortuosity, or significant proximal calcification, caution is required for potential DCB delivery failure. Techniques such as using guide catheters with better support, extension catheters, dual guidewires, deep guide catheter insertion, or even anchoring may be necessary. After thorough pretreatment, the passability of the balloon can be tested using the used predilation balloon in a non-negative pressure state. After removing the DCB from its packaging, avoid contact with hands or liquids. Use a small syringe to thoroughly exhaust air with a 1:1.5 diluted contrast agent, then insert the DCB after fully opening the Y-valve. Deliver the DCB to the target lesion as quickly as possible. If tortuosity, calcification, or angulation prevents one-time placement, repeated use of the same balloon is not recommended, though the balloon can be used to test passability after further pretreatment. The DCB should cover at least 2-3 mm proximal or distal to the pretreated site[115]. Slowly increase the pressure to the nominal pressure (or higher pressure). Before fixing the pressure, use fluoroscopy to observe the balloon's filling degree and its matching with the diameter of the target lesion vessel. Then maintain the pressure for a sufficient duration, generally recommended for 60 seconds (30 seconds is sufficient for complete drug release, but extending it to 120 seconds is better, which can reduce the incidence of dissection). After that, slowly decompress until the balloon is completely emptied. After withdrawing the DCB, do not withdraw the guidewire immediately. Wait for 5-10 minutes for angiographic evaluation to check for severe dissection, acute occlusion, and whether redilation or stent placement is needed (although the incidence is low, it is still possible).

MANAGEMENT OF SPECIAL COMPLICATIONS

Dissection during pretreatment

Early studies on DCB-only angioplasty for de novo stenosis showed high conversion rates to stent implantation (11.9%-32.8%). However, the OCTOPUS-2 study demonstrated a very low conversion rate to urgent stenting (6%) under FFR guidance, indicating that pure DCB angioplasty is effective and safe. Even with 4 weeks of DAPT, there was no subacute vessel occlusion, and the incidence of MACE was low (4.7% at 6 months)[106]. During PTCA, adequate predilation inevitably causes coronary dissection of varying degrees. Moderate dissection facilitates paclitaxel penetration, exerting its antiproliferative effect and promoting positive vascular remodeling to reduce restenosis rates. In de novo coronary lesions, stratified plaques and extensive medial dissection after DCB angioplasty are associated with LLE[119]. A study on symptomatic de novo femoropopliteal lesions showed that DCB angioplasty for spiral dissection (SD) without hemodynamic obstruction had a significantly lower 1-year primary patency rate than lesions without SD[120]. Data on coronary SD are limited. The 2024 expert consensus[25] recommends stent implantation, but we suggest that stents can be implanted in vessels with a diameter > 2.2 mm. For SD in vessels with a diameter < 2.2 mm, if hemodynamics are stable and symptoms are mild, observation based on the operator’s experience may be considered.

Rescue stenting strategies

According to NHLBI criteria, dissections are classified into types A-F. For cases with evidence of flow-limiting dissection (TIMI flow grade < 3) after predilation or DCB angioplasty, stent implantation is recommended. For NHLBI type C-E dissections that are not flow-limiting, functional assessment methods such as the ratio of distal coronary pressure to aortic pressure (Pd/Pa)[121] or FFR may be considered. FFR is commonly used clinically, although the critical FFR value after DCB has never been studied. Shin ES proposed using DCB if plain old balloon angioplasty (POBA)-FFR is good (≥ 0.85), and preferring stent implantation if POBA-FFR < 0.85. Multiple expert consensuses[105,114,115] have used > 0.8 as the post-intervention FFR threshold to reduce the rescue stenting rate. Therefore, when conditions permit, measuring FFR based on angiographic evaluation after balloon dilation during a DCB-only strategy can be more safe and effective.

We believe that for type A and B dissections (non-flow-limiting, residual stenosis < 30%), sequential delivery of DCB is appropriate, while type C-F dissections (such as SD, contrast agent retention, flow limitation) generally require comprehensive evaluation based on factors including vessel diameter, blood supply range, TIMI flow, hemodynamic status, symptoms, and presence of collateral circulation protection. For vessels with a diameter ≥ 2 mm that are hemodynamically unstable, symptomatic, without collateral circulation protection, or at high risk for subsequent DCB angioplasty, active management with rescue DES should be selected. If dissection causes TIMI flow < grade 3 or distal perfusion impairment, rescue stenting must be performed immediately to prevent events such as acute vessel occlusion. For branch vessels with a diameter < 2 mm that are hemodynamically stable, asymptomatic, and at low risk for subsequent DCB angioplasty, DCB angioplasty can be cautiously used by experienced operators even with TIMI flow < grade 3. Vessels with collateral circulation protection may also be managed with cautious DCB angioplasty based on the operator’s experience. According to our experience, stent implantation for dissections in small vessels should be more cautious; observation is acceptable even with TIMI flow < grade 2 if there are no ischemic symptoms or hemodynamic disturbances. Controlled dissection after pretreatment is beneficial for local paclitaxel transfer to the subendothelial tissue, thereby inducing LLE of the coronary artery.

Dissection after DCB angioplasty

A study investigating the outcomes of untreated non-flow-limiting dissections after DCB use[122] showed that 93.8% of dissections completely healed on angiographic follow-up at 9 months, without increasing the risk of LLL or TVF. Therefore, in the absence of acute blood flow impairment or coronary occlusion, the use of drug-coated balloons may provide favorable conditions for the healing of coronary artery dissections. In most studies, BMS are commonly used for cases requiring rescue stent implantation. However, given the extremely low drug coating concentration of DCB, the risk of drug interaction between DCB and DES is manageable even if DES is selected for rescue, with specific management principles referable to the content on dissection management during pretreatment.

Acute occlusion

Acute occlusion is defined as complete (TIMI 0) or severe reduction (TIMI 1-2) of coronary blood flow in the dilated segment with clinical or ECG evidence of myocardial ischemia during or after PTCA, occurring either in the catheterization laboratory (immediate occlusion) or post-procedurally in the hospital (early occlusion). The incidence of sudden coronary occlusion during PTCA ranges from 4.4% to 7.3% and is associated with major procedural complications including death, myocardial infarction, and urgent bypass surgery[123].

New dual antiplatelet strategies[124] and GP IIb/IIIa antagonists can prevent impending or abrupt vessel closure after PTCA by reducing thrombus formation at the target lesion, thereby lowering the risk of acute occlusion[125]. In a study of 104 NSTEMI patients treated with DCB, no cases of acute vessel occlusion were observed[126]. In our clinical experience with 725 DCB angioplasties for de novo coronary lesions in 605 patients, coronary occlusion occurred in 3 patients (4 instances): One STEMI patient experienced recurrent STEMI 85.3 hours post-DCB and required PPCI with stenting; in another case involving hybrid treatment, slow flow and subsequent occlusion of a septal perforator branches occurred 4 minutes after stenting the main branch following DCB angioplasty of the septal perforator branches, with flow restored after expanding the stent mesh in the LAD 15 minutes later; in a third case, sequential DCB angioplasty of the diagonal and obtuse marginal branches resulted in no-reflow and sequential occlusion of both vessels within 2 minutes despite no significant dissection, managed by redilation of the diagonal branch via PTCA and stenting of the obtuse marginal branch, with no post-procedural chest pain or troponin elevation, suggesting that for small branch vessel occlusions after DCB angioplasty, repeated balloon dilation without rescue stenting may be a viable option if there are no symptoms or hemodynamic compromise.

Residual stenosis after DCB angioplasty

Expert consensuses[106,115,116] recommend delivering DCB only when residual stenosis is < 30%. However, more precise thresholds require further randomized controlled studies stratified by lesion characteristics. A study has suggested that DCB can be used for final target lesion dilation when POBA results are adequate, residual stenosis < 40%, FFR > 0.8, and no severe dissection is present[127]. We believe that residual stenosis (> 50%) after DCB angioplasty in small branches may be acceptable if there is no hemodynamic compromise or symptoms.

Target lesion restenosis after PTCA

In related studies, Kuntz and Baim[2] referred to target lesion restenosis following PTCA as "in-balloon restenosis" by analogy with the definition of ISR. However, we believe this terminology is imprecise, as neither plain balloon PTCA nor DCB angioplasty leaves a "balloon" within the target lesion post-procedure. We propose using "post-balloon restenosis" as a more accurate descriptor. Studies from the PTCA era on post-balloon restenosis have identified risk factors including family history of coronary heart disease, unstable angina, target vessel diameter, degree of target lesion stenosis, and residual stenosis[128]. For management of "in-balloon restenosis", repeat DCB dilation or DES implantation may be considered, with detailed information referenced in the ISR chapter.

PACLITAXEL ALLERGY

Although systemic paclitaxel allergy is well-documented in chemotherapy settings, occurring in 10%-40% of patients[129], paclitaxel-eluting device (PED)-related allergic reactions remain extremely rare. Only three cases of acute anaphylactic reactions from peripheral vascular use of paclitaxel-coated DCB (PDB) have been reported[130,131]. In our series of 518 patients undergoing 596 coronary PDB procedures, only one patient experienced two confirmed severe paclitaxel allergic reactions. This translates to an estimated incidence of 0.19% for first exposure and 0.34% for cumulative exposure, significantly lower than rates reported for systemic paclitaxel chemotherapy and lower than the 0.87%-0.93% rate noted by Horita et al[132]. The allergic manifestations in our coronary PDB cases differed notably from those in peripheral vascular applications, with atypical presentations potentially leading to under recognition and underestimation of their true frequency. Specific management strategies for allergic reactions are referenced in this guideline[133].

DUAL ANTIPLATELET STRATEGY AFTER DCB ANGIOPLASTY

The optimal duration of DAPT after DCB implantation remains undefined. Antithrombotic regimens follow the guidelines of GISE (Italian Society of Interventional Cardiology)[134], recommending at least 30 days of DAPT for stable CAD patients and 6-12 months for ACS patients. China’s REC-CAGEFREE II study[135] evaluated a "stepwise DAPT de-escalation strategy" in 1948 ACS patients treated with drug-coated balloons: After 1 month of DAPT, ticagrelor monotherapy for 5 months was followed by aspirin monotherapy for 6 months, replacing the standard 12-month DAPT. The strategy proved safe and effective. These findings suggest a potential trend in future guidelines toward shorter DAPT durations for select populations, particularly those undergoing DCB angioplasty or at high bleeding risk, though patients with diabetes and ACS may be an exception.

SAFETY

Early concerns about paclitaxel-coated devices (PCD) increasing mortality risk have not been widely confirmed in coronary or recent femoropopliteal artery studies, with most research supporting their safety and some showing survival benefits. A 2018 meta-analysis suggested that PCD in femoropopliteal interventions might increase mortality risk[136]. The DAEDALUS study[31] demonstrated comparable all-cause mortality between paclitaxel DCB and repeat DES implantation in coronary ISR patients. A meta-analysis of coronary RCTs[55] showed that DCB did not increase mortality compared with plain angioplasty, BMS, or DES, and significantly reduced 3-year mortality. Temporary implantation of paclitaxel-eluting stents (double dose) for residual stenosis after femoropopliteal DCB showed no local or systemic toxicity/complications over 24 months of follow-up[137]. A French national analysis (259137 patients) found that PCD treatment was associated with a lower mortality risk (hazard ratio = 0.86, 95%CI: 0.84-0.89, P < 0.001), with consistent results in propensity score-matched analysis[138]. A Veterans Health Administration study[139] also showed no increase in long-term all-cause mortality with PCD in femoropopliteal interventions, with no differences in cause-specific mortality compared with controls. In femoropopliteal disease, DCB offers higher patency rates and lower revascularization needs than BMS, with no significant differences in mortality, amputation rates, or thrombosis risk[138].

Among 380 PCI patients treated with DCB, 3 cases of CAA (incidence 0.8%) were observed, indicating no significant increase in CAA risk with DCB[140]. Clinical use of double doses (e.g., DCB combined with DES) and animal experiments with triple doses did not induce aneurysms, suggesting that CAA occurrence is unrelated to paclitaxel dose and may be associated with arterial medial structural abnormalities (e.g., fibromuscular dysplasia, Kawasaki disease) or over-dilation injury[137,141-143]. Studies have found that paclitaxel-related aneurysms may undergo spontaneous repair[144]. The BASKET-SMALL 2 trial (3-year follow-up) showed similar safety and efficacy between DCB and second-generation DES in coronary lesions < 3 mm, with a lower risk of severe bleeding in the DCB group[145].

CONCLUSION

Despite the potential of DCB technology to serve as an alternative to DES, it faces multiple challenges. Current evidence is predominantly derived from registries and observational studies with small sample sizes and short follow-up periods, limiting its ability to fully displace new-generation DES as the mainstream treatment. Large-scale RCTs are urgently needed to validate the long-term efficacy and safety of DCB, particularly for de novo lesions. While the stalled development of bioresorbable stents (BRS) may accelerate DCB adoption, cautious evaluation of indication expansion is warranted, especially for de novo lesions in large vessels and ACS scenarios, where a cautiously optimistic approach is advised. Future research should focus on optimizing pretreatment protocols - particularly intravascular imaging-guided pretreatment to characterize target vessel dissections associated with optimal outcomes and guide precise predilation - while enhancing drug delivery systems to improve therapeutic efficiency. Personalized strategies for special populations (e.g., diabetes, chronic kidney disease, diffuse long lesions, young patients, high bleeding risk) and complex lesions (e.g., bifurcations, ostial lesions) are essential, along with further investigations into residual stenosis thresholds after pretreatment and DCB angioplasty stratified by vessel diameter to establish individualized clinical guidelines. RCTs across diverse DCB application scenarios are needed to accumulate robust data for clinical guidance, while OCT-based studies of post-procedural plaque and endothelial evolution should clarify the optimal duration of DAPT after DCB-only treatment. With the deepening of the "no-implant, minimal-intervention" philosophy, DCB technology integrated with functional assessment, precise pretreatment, and novel pharmacotherapies - holds promise to provide advanced solutions for CAD management.

ACKNOWLEDGEMENTS

First and foremost, we would like to extend our special gratitude to the Second People's Hospital of Jiangyou for establishing an academic platform for this study and providing strong support for team collaboration. Additionally, we specially acknowledge the relevant departments that supported the research process, including the Department of Cardiology, Medical Laboratory Department, Department of Oncology, Science and Education Department, and Information Department. Meanwhile, we appreciate Mr. Deng-Zhi Gao contribution to audio production.