Applications and challenges of paclitaxel- coated balloons beyond coronary atherosclerotic heart disease

Abstract

Although drug-coated balloons (DCBs) were initially used for treating peripheral vascular diseases, with the growing popularity of the implant-free concept, they have gained increasing attention as a novel therapeutic strategy for coronary atherosclerotic heart disease. The clinical application scope of DCBs, represented by paclitaxel-coated balloons (PCBs), is constantly expanding. Their application fields are no longer limited to lesions of coronary artery and peripheral vascular diseases, and relevant research is also being actively advanced. In the field of arterial diseases, the application of PCBs has significantly extended. They are used in lower extremity arteries and hemodialysis access and play a role in renal artery fibromuscular dysplasia, and carotid/vertebrobasilar/intracranial arteries. PCBs also show unique value in the treatment of Takayasu arteritis, Kawasaki disease, coronary myocardial bridge, and pulmonary artery diseases. In the venous system, PCBs also have therapeutic potential, with research and clinical investigations now extending to lower extremity, central, and pulmonary vein diseases, and innovative solutions for graft stenosis. The application of PCBs is no longer confined to vascular diseases. They are gradually breaking through traditional boundaries in treating luminal disorders such as urethral, biliary, and esophageal strictures. This mini-review synthesizes existing clinical evidence and basic research findings to concisely analyze the mechanisms of action and biological effects of PCBs in noncoronary applications. A comprehensive analysis of current studies provides a reference for subsequent research and clinical practice in this field and explicitly identifies the challenges faced by current research, explores future directions, and facilitates the in-depth extension of DCB applications.

Key Words: Paclitaxel-coated balloons; Vascular disease; Luminal diseases; Restenosis; Interventional therapy; Peripheral artery; Renal artery; Vascular access; Atherosclerosis

Core Tip: This review describes the applications of paclitaxel-coated balloons beyond coronary atherosclerotic diseases, including the practical experience and research achievements of drug-coated balloons in arterial diseases such as peripheral arteries, renal arteries, and intracranial arteries, as well as venous and vascular access, arterial inflammatory diseases, and non-vascular diseases. It also explores the molecular biological mechanisms of paclitaxel drug balloons under different anatomical characteristics, providing references for further clinical applications and research.

INTRODUCTION

Although drug-eluting stents (DESs) remain the default choice for interventional therapy of coronary artery disease, drug-coated balloons (DCBs) have some value in complex coronary or small-vessel lesions where stent implantation yields poor outcomes[1]. Currently, various types of DCBs are available for treating vascular stenosis, with paclitaxel-coated balloons (PCBs) being the most widely used due to the lipophilicity and antiproliferative effects of paclitaxel on endothelial and vascular smooth muscle cells (VSMCs) proliferation[2]. With the deepening of clinical research and accumulation of practical experience, the application of PCBs has gradually extended from arteriosclerotic diseases to other vascular and non-vascular conditions. PCBs achieve rapid paclitaxel release and sustained retention through a lipophilic matrix, forming a high-efficiency drug concentration distribution at the site of vascular injury[3,4]. Studies have shown that this unique drug delivery mechanism inhibits intimal hyperplasia and maintains the native vascular anatomy, while significantly reducing target lesion revascularization (TLR) rates compared with traditional balloon angioplasty[5-7]. PCBs offer clinical advantages of shortening dual antiplatelet therapy duration and reducing bleeding risk[8]. Their implant-free technical features make them an ideal alternative for patients who are intolerant of stents or with recurrent stenosis.

With the continuous accumulation of clinical evidence, the therapeutic spectrum of PCBs is expanding. Beyond classic atherosclerotic lesions, their anti-inflammatory and antifibrotic effects in vascular inflammatory lesions offer new insights for treating complex vascular diseases[9,10]. Existing clinical studies have demonstrated the efficacy of PCBs in treating lower extremity arterial diseases and hemodialysis access stenosis[11,12]. However, in conditions such as renal, intracranial, vertebrobasilar, and carotid artery stenosis, as well as stenosis due to arterial inflammatory diseases, symptomatic myocardial bridge (MB) disease, venous stenosis, and nonvascular luminal stenosis, treatment outcomes show significant heterogeneity due to differences in histological characteristics and hemodynamics. These key clinical challenges highlight the need for high-quality clinical studies to comprehensively evaluate the safety and long-term outcomes of PCBs at different anatomical sites. This review aims to provide a reference for clinical decision-making by summarizing progress in the application of PCBs in noncoronary diseases.

APPLICATION OF PCBs IN LOWER LIMB ARTERIAL STENOSIS

Peripheral artery diseases (PADs) have a prevalence similar to coronary artery disease and have shown an upward trend[13]. They have a high disability rate, and for those with related symptoms requiring revascularization, there is a high risk of death due to extensive atherosclerosis and multisite arterial diseases (i.e., multivessel disease)[14]. Although traditional treatments such as plain old balloon angioplasty (POBA), metallic stents [including bare-metal stents (BMSs) or DESs] and bypass surgery are widely used, their clinical efficacy is still limited. POBA is restricted by a high restenosis rate and high TLR rate within 1 year[15-17]. Stent implantation in areas of moving joints (such as the femoropopliteal artery) is prone to fracture or restenosis, while bypass surgery is affected by major trauma and many complications[1]. The dynamic biomechanics characteristics of lower extremity vessels affect disease progression and treatment option selection, posing unique challenges for clinical management[18]. PCBs inhibit intimal hyperplasia by locally releasing the antiproliferative drug paclitaxel, combining the dual advantages of mechanical vascular opening and drug intervention.

As early as 2008, the THUNDER trial[19] demonstrated the efficacy of PCBs in peripheral arteries, significantly reducing late lumen loss and TLR. Although a systematic review and meta-analysis by Katsanos and colleagues suggested that PCBs and stents in the femoropopliteal artery might increase mortality risk[20], subsequent studies with confounding factor correction confirmed their safety, and pure PCB treatment did not increase treatment-related mortality[21,22]. While reports exist of distal embolization from paclitaxel particle shedding[23], Boitet et al[24] compared five types of PCBs with saphenous vein bypass grafting for distal paclitaxel embolization and found no increased mortality with PCBs.

Randomized controlled trials (Table 1) have shown that in lower extremity PAD, patients treated with PCBs exhibited better 2-year primary patency rates compared with the POBA group, with lower restenosis rates, TLR, major amputation rates, and late lumen loss[21,22,25-29]. These studies indicate that PCBs have more advantages in preserving vascular structure and function, do not increase the risk of all-cause mortality, and confirm the effectiveness and safety of their clinical application.

Table 1 Comparative efficacy and safety of paclitaxel-coated balloons vs uncoated balloon angioplasty in femoropopliteal and below-the-knee arteries.

Clinical trials identifier/Ref.	Target vessel	Sample size (PCBs vs POBA)	Follow-up duration	Primary end point	Efficacy outcomes	Major adverse events rate (%)
Liistro et al[26], 2013	BTK vessel; with: Diabetes; critical limb ischemia (rutherford class ≥ 4), significant stenosis; occlusion > 40 mm)	65 vs 67	12 months	Binary in-segment restenosis (%); 27 vs 75; P < 0.001	Occlusion (%); 17.6 vs 55.4; complete index ulcer healing (%); 86 vs 67; P = 0.01	31 vs 51; P = 0.02; (mainly by a reduction in TLR and better ulcer healing)
Zeller et al[21], 2015	Stenosis; restenosis; occlusion of the infrapopliteal arteries (excluding in-stent restenosis and experiencing claudication or CLI)	36 vs 36	12 months	All-cause mortality, target vessel, amputation, thrombosis, revascularization (30 days) (%); 0% vs 8.3%; P = 0.239	Patency loss (6 months) (%); 17.1 vs 26.1; P = 0.298; major amputations of the target extremity (12 months) (%); 3.3 vs 5.6; P = 0.631	41.1 vs 39.1; P = 0.957
Rosenfield et al[25], 2015	With symptomatic femoropopliteal peripheral artery disease	316 vs 16	12 months	Primary patency of the target lesion (%); 65.2% vs 52.6%, P = 0.02	Primary safety end point	Restenosis without target lesion revascularization (%); 62% vs 62.5%; target lesion revascularization; 38% vs 37.5%
Kinstner et al[22], 2016	ISR of the SFA; P1 segment of the popliteal artery (accompanied by clinical symptoms)	35 vs 39	12 months	Primary patency (%); 40.7 vs 13.4; P = 0.02	Freedom from clinically driven TLR (%); 49.0 vs 22.1	Not mentioned
Iida et al[27], 2019	Superficial femoral; artery; proximal popliteal; artery	68 vs 32	24 months	Primary patency (%); 79.8 vs 46.9; P < 0.001	Free from CD-TLR (%); 90.8 vs 80.3; CD-TLR (%); 9.1 vs 20.7	15.4 vs 24.1; P = 0.384
Teichgräber et al[28], 2020	SFA; the proximal popliteal artery up to the P1 segment (with a lesion length ≤ 15 cm, accompanied by clinical symptoms)	85 vs 86	6 months	LLL after 6 months (mm); 0.14 vs 1.06; P < 0.001	TLR (%); 1.3 vs 17.1%; P < 0.001; restenosis (%); 13.2 vs 31.6; P = 0.011; primary patency (%); 94 vs 75; P < 0.001	Not mentioned
Krishnan et al[29], 2024	Rutherford clinical category 2 to 4 femoropopliteal PAD (accompanied by clinical symptoms)	200 vs 100	60 months	All-cause mortality (%); 20.6 vs 20.2; P = 0.934	Primary patency; TLR (%); 68.2 vs 67.2; P = 0.623	41.0 vs 44.6; P = 0.597

PCBs: Paclitaxel-coated balloons; POBA: Plain old balloon angioplasty; CD-TLR: Clinicallydriven target lesion revascularization; TLR: Target lesion revascularization; SFA: Superficial femoral artery; BTK: Below-the-knee; CLI: Critical limb ischemia; LLL: Late lumen loss; ISR: In-stentrestenosis; SFA: Superficial femoral artery; PAD: Peripheralartery disease.

A meta-analysis of the ILLUMENATE randomized controlled trial[30] found that when Stellarex PCBs and POBA were used to treat PADs, the PCB group had lower incidence of target lesion major adverse events, major amputation rate, TLR rate, and late lumen loss than the POBA group. There was no significant difference in all-cause mortality between the two groups (13.8% vs 13.5%), confirming the good long-term safety of PCBs[31].

In real-world studies, a mean follow-up of 52 months for 1579 of 7357 patients with femoropopliteal lesions (514 POBA and 1065 PCBs) showed that the mortality rate in the PCB group (16.9%) was significantly lower than that in the POBA group (27.8%), with multivariate analysis reinforcing this conclusion[32]. Studies on special populations demonstrated that after propensity score matching analysis of 278 dialysis patients, the 2-year binary restenosis-free rate (52.4% vs 18.6%) and clinically driven TLR-free rate (56.4% vs 25.9%) of PCBs in treating femoropopliteal diseases were significantly better than those of POBA, with comparable risks of amputation, cardiac events, and death between the two groups, confirming the superior efficacy and consistent safety of PCBs in this population[33]. Additionally, a retrospective analysis of 624 patients with femoropopliteal ulcers and gangrene (197 POBA and 427 PCBs) with a mean follow-up of 33.3 months found that the mortality rate in the POBA group (81.7%) was significantly higher than that in the PCB group (59.0%)[34]. Multivariate analysis showed that treatment type, age, coronary heart disease, renal insufficiency, and stroke were predictors of all-cause mortality, confirming that PCBs had no survival disadvantage in this population[34].

Randomized clinical trials[35] have shown that residual stenosis > 30%, smaller preoperative reference vessel diameter, and higher Rutherford classification are risk predictors for patency loss within 1 year after PCB treatment for femoropopliteal artery disease. Due to the small diameter and high mobility of infrapatellar arteries, extensive medial calcification can lead to decreased vascular compliance, thus promoting blood stasis and thrombosis[36,37], significantly increasing the difficulty and risk of PCB treatment. A meta-analysis[38] integrating 16 randomized controlled trials (1805 patients) found that while PCBs can reduce TLR rates, the quality of evidence supporting this is mostly low to moderate. The MERLION study[39] used iVascular Luminor™ DCBs alone or in combination with Angiolite™ DEBs for tibial occlusive lesions in patients with limb-threatening ischemia. The technical success rate reached 100%, with 1-year patency rate of 69.4%, limb salvage rate of 74.0%, wound healing rate of 65.7%, and significant improvement in Rutherford scores, which confirmed the safety and efficacy of this therapy. The DEBATE-BTK study demonstrated that PCBs were superior to POBA in improving wound healing rates in patients with critical limb ischemia of the infrapatellar artery (79.8% vs 46.9%)[26].

Although the incidence of restenosis after PCB treatment for lower extremity arteries is low, insufficient balloon size or inadequate pre-dilation may increase the risk of residual stenosis[24], while excessive balloon dilation can raise the risk of aneurysm formation[40]. The intravascular ultrasound (IVUS)-DCB trial[41] indicated that optimizing luminal area under intravascular ultrasound guidance is crucial for maintaining target vessel patency. Additionally, for patients with chronic total occlusion of the femoropopliteal artery, laser atherectomy and noncompliant balloon pre-dilation (≥ 180 s) followed by PCB dilation can be used to optimize drug release, reduce dissection, and improve efficacy[42]. Therefore, adequate pretreatment under IVUS guidance, selection of DCBs with appropriate specifications, and the shift from empirical strategies to precision treatment strategies are key to improving efficacy and reducing complications.

APPLICATION OF PCBs IN HEMODIALYSIS ACCESS

Hemodialysis access dysfunction is a major burden in end-stage renal disease. The proinflammatory state of chronic kidney disease, different anatomical configurations of dialysis access, neointimal hyperplasia, and resulting hemodynamic changes with repeated access punctures all promote the development of dialysis access stenosis. Stenosis in arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) carries risks of thrombosis and vascular access loss, with restenosis and reintervention rates remaining high at 60% and 70% at 6 and 12 months, respectively[43]. Traditional treatments like POBA are limited by high restenosis rates. While high-pressure balloons and cutting balloon angioplasty can effectively restore revascularization, they may cause excessive vascular injury, including pressure injuries from balloon inflation, irregular intimal tears, and neointimal hyperplasia, ultimately leading to recurrent restenosis[15]. BMSs and surgical repairs face challenges of stent fracture or surgical complexity, respectively.

Smooth muscle cell migration and inflammatory responses are important causes of AVF stenosis[44]. Paclitaxel locally released by PCBs can induce cell apoptosis and inhibit the migration of VSMCs to the intima, thereby improving stenosis[12,45]. Randomized trials have shown that PCBs are superior to POBA in treating AVF, AVG stenosis, anastomotic stenosis, and in-stent stenosis. By summarizing multiple randomized controlled trials (Table 2) comparing the application of PCBs and POBA in dialysis access, clinical outcomes are similar to those in lower extremity vessels. PCBs are superior to POBA in terms of primary patency rate and TLR in dialysis access, with comparable safety[12,45-49].

Table 2 Comparative analysis of the efficacy of paclitaxel-coated balloons angioplasty and conventional balloon angioplasty in the hemodialysis pathway.

Clinical trials identifier/Ref.	Study design	Types of pathological coronary vessels	Sample size (PCBs vs POBA)	Follow-up duration	Primary end point	Efficacy outcomes	Major adverse events rate (%)
Irani et al[12], 2018	Prospective Randomized Single-center Clinical Trial	AVF and AVG stenosis	63 vs 62	12 months	Primary patency restenosis rates a (6 months) (%); 34 vs 62.9; P = 0.01	Circuit primary patency (6 months) (%); 76 vs 56; P = 0.048; target lesion primary patency (6 months) (%); 51 vs 34; P = 0.04	Not mentioned
Liao et al[46], 2020	Single-center Prospective Randomized Controlled Trial	Venous anastomotic stenosis in dysfunctional AV grafts	22 vs 22	12 months	Target lesion primary patency (6 months) (%); 41 vs 9; P = 0.006	Circuit primary patency (6 months) (%); 36 vs 9; P = 0.013; target lesion primary patency (6 months) (%); 23 vs 9; P = 0.019	Have no statistical differences
Therasse et al[47], 2021	Prospective, Single-blinded, Randomized Multi-Center Clinical Trial	Dysfunctional arteriovenous fistulae	60 vs 60	12 months	LLL after 6 months (mm) (non-adjusted) (mm); 0.64 ± 1.20 vs 1.13 ± 1.51; P = 0.082	Restenosis rate (6 months) (%); 56.5 vs 81.1%; P = 0.008	53.3 vs 75.0; P = 0.013
Yin et al[48], 2021	Multicenter, Prospective, Randomized, Open-label, Blinded-endpoint, Controlled Trial	Consecutive adult patients with fistula dysfunction	78 vs 83	12 months	Target lesion primary patency (6 months) (%); 65 vs 37; P < 0.001	Target lesion (12 months) (%); 73 vs 58 P = 0.04; target shunt (12 months) (%) 73 vs 57; P = 0.04	41.1 vs 39.1; P = 0.957
Hsieh et al[45], 2023	Prospective, Single-Blinded, Randomised Controlled Study	Stent-graft stenosis in haemodialysis vascular access	20 vs 20	6 months	LLL after 6 months (mm); 1.82 ± 1.83 vs 3.63 ± 1.08; P = 0.001	Primary patency restenosis rates (6 months) (%); 80 vs 42; P = 0.005; circuit primary patency (6 months) (%); 35 vs 15; P = 0.086	Not mentioned
Zhao et al[49], 2024	Prospective, Multicenter, Randomized Controlled Study	Dysfunctional arteriovenous fistulae	122 vs 122	12 months	Primary patency (6 months) (%); 91 vs 67; P < 0.001	Primary patency restenosis rates (12 months) (%); 66 vs 46; P = 0.004	0 vs 2.5; P = 0.3

PCBs: Paclitaxel-coated balloons; POBA: Plain old balloon angioplasty; AV: Arteriovenous; AVF: Arteriovenous fistula; AVG: Arteriovenous graft; LLL: Late lumen loss.

A study on PCBs for hemodialysis AVF restenosis after POBA showed that the mean time from surgery to target lesion restenosis in the PCB group was 7.9 months, which was significantly longer than 6.4 months in the POBA group. The 2-year target lesion restenosis-free rate was 32.8%, with primary patency, primary assisted patency, and secondary patency rates of 40.8%, 73.1%, and 82.5%, respectively, confirming that PCBs safely and effectively reduced restenosis risk[50]. Although thrombosis affects PCB efficacy, a retrospective analysis[51] of 33 thrombotic AVF patients found a 69.7% success rate of percutaneous angioplasty and 57.9% 12-month patency rate. The PCB group had higher 6- and 12-month patency rates than the POBA group, indicating safe and effective treatment with better PCB outcomes. Thrombectomy (thrombus aspiration or high-efficiency thrombolysis) before PCB treatment helps improve efficacy.

Soon et al[52] divided 130 end-stage renal failure patients (mean age 66.0 ± 10 years, 61% male) into two groups (65 each), most patients used arteriovenous fistulas as hemodialysis access (94%), received treatment for decreased access blood flow (76%), and a total of 172 Lesions were managed (51% being juxta-anastomosis lesions). Compared with the POBA group, the Ranger™ PCB group had longer reintervention times for target lesions and hemodialysis access, with no difference in safety outcomes between the two groups, and 12% of deaths were all attributed to patients' underlying comorbidities. A meta-analysis including 16 studies (n = 1086) revealed no significant difference in all-cause mortality between PCBs and POBA groups at 6, 12, and 24 months post-intervention. The benefits of PCBs in maintaining dialysis access patency significantly outweighed concerns about paclitaxel-related mortality risks[53]. Additionally, the use of appropriate excipients can enhance therapeutic efficacy of PCBs. Studies have shown that PCBs with resveratrol excipients improve primary patency rates after failed AVF or AVG treatment[54], offering new insights for optimizing PCBs drug delivery design.

Due to the pathological specificity of vascular stenosis in hemodialysis access, the use of PCBs requires special operational protocols to optimize drug delivery efficiency. Key points include ensuring sufficient vessel dilation (residual stenosis < 30%), maintaining a precise 1:1 match between balloon size and vessel diameter, controlled dissection, and extending balloon inflation time to 2-3 minutes[55-57].

A systematic review and meta-analysis of 11 randomized controlled trials[58] (487 PCBs vs 489 POBA) showed no significant differences in 6- and 12-month primary patency rates of target lesions between PCBs and POBA for treating hemodialysis access stenosis, with comparable complication risks. These findings suggest that PCBs do not significantly improve access patency, indicating cautious application of PCBs in treating hemodialysis access stenosis.

APPLICATION OF PCBs IN RENAL ARTERY STENOSIS

Atherosclerosis is the main cause of renal artery stenosis (RAS), accounting for 70%-90%of cases. Such patients are often characterized by inflammatory plaque formation, endothelial dysfunction, and turbulent shear stress changes. Lesions mostly involve the opening of the main renal artery and the proximal one-third segment, prone to creating a microenvironment promoting restenosis[59-61]. The incidence of RAS caused by non-atherosclerosis is low, among which fibromuscular dysplasia (FMD)[62] is more common. FMD is characterized by noninflammatory fibroproliferative remodeling, with obvious pathological distribution differences from atherosclerosis. Lesions mainly concentrate in the middle to distal arterial segments, leading to stenosis of small and medium arteries[59,63]. Takayasu arteritis (TAK) is also one of the causes of nonatherosclerotic RAS, and relevant studies can be found in the chapter "APPLICATION OF PCBs IN ARTERIAL INFLAMMATORY DISEASES".

In traditional treatment modalities, both POBA and BMSs cause high restenosis rates in RAS treatment. Especially for renal arteries with a diameter > 5 mm, the use of BMSs carries significant risks, with efficacy constrained by multiple factors. Six-month follow-up data shows a restenosis rate of 15%-20%, indicating overall unsatisfactory outcomes[61,64,65]. Although DEBs reduce restenosis rates, they also introduce risks of stent fracture, late thrombosis, and geometric mismatch with tortuous renal arteries[62,65]. PCBs, however, can overcome these limitations by virtue of their unique advantages. PCBs deliver drugs more uniformly, and their lipophilic properties enable persistent retention of the carried drug within the arterial wall, significantly enhancing antiproliferative effects[65,66].

Early clinical studies[67] have shown that PCBs can bring short-term benefits in the treatment of transplant renal artery stenosis (TRAS) and in-stent restenosis (ISR). A 2018 trial[65] indicated that PCBs have a high efficiency in treating TRAS, serving as an effective means to restore and maintain arterial blood flow and renal function. The BASKET-SMALL 2 study[66] showed that the long-term safety and efficacy of the PCB group were similar to those of the POBA group, but after PCB treatment, the proportion of antiplatelet drug use and the incidence of major bleeding events were lower. Currently, data on the safety and efficacy of PCBs in chronic kidney disease patients, especially long-term follow-up data, are scarce, and more studies are urgently needed to clarify their efficacy and safety.

APPLICATION OF PCBs IN CAROTID, VERTEBROBASILAR, AND INTRACRANIAL ARTERY STENOSIS

Lesions in carotid, vertebrobasilar, and intracranial arteries are important causes of ischemic stroke, with 10%-15% of acute cerebral infarctions triggered by atherosclerotic plaques[68]. Intracranial and cervicobasilar arteries have anatomical specificities, such as thin vessel walls, tortuous pathways, and lack of external elastic lamina, leading to poor device deliverability and proneness to complications such as dissection or thrombosis during interventional therapy[69,70]. The small lumen of intracranial and vertebral arteries is associated with high ISR rates, mainly related to excessive intimal hyperplasia and limited stent expansion[70,71]. PCBs are feasible and safe for treating intracranial ISR and can effectively reduce ISR in vertebral and carotid arteries[72-74]. Although administered locally, the risks of paclitaxel neurotoxicity and distal embolization from coating particles still require attention.

Studies have shown that PCBs combined with stent implantation significantly increase the 12-month patency rate of carotid artery procedures and reduces the restenosis rate[75,76]. For intracranial stenosis, preliminary studies by Gruber et al[68] using new DCBs (such as SeQuent Please NEO) have shown a 28% decrease in the median degree of stenosis at 3 months, with no perioperative complications, confirming that PCBs for symptomatic severe intracranial stenosis are feasible and safe, although long-term follow-up data for further evaluation are lacking. However, the vertebral artery, especially at the origin, has high elastin content and is affected by respiratory movement traction, leading to increased mechanical stress, proneness to stent fracture, and high restenosis rate[77,78]. Even the second-generation DES s can have a restenosis degree of 80% at 15 months, requiring retreatment[71], which needs careful vascular preparation and higher technical requirements. The implant-free feature of PCBs may reduce stent-related complications. Zhao et al[74] confirmed that in the treatment of vertebral artery origin stenosis, a 30-day follow-up found that the restenosis rate of PCBs was lower than that of the stent group (18.8% vs 28.8%), and no ischemic events occurred during the entire follow-up period, indicating its safety and effectiveness. At present, most studies on PCBs in intracranial, vertebrobasilar, and carotid arteries are case studies and preliminary research, lacking large clinical randomized controlled trials. Due to the particularity of anatomical sites, optimizing balloon design is important for improving PCB efficacy and reducing the occurrence of adverse events.

APPLICATION OF PCBs IN MB OF THE CORONARY ARTERIES

MB is a common anatomical variation mainly involving the mid-distal segments of the left anterior descending artery. It causes ischemia and severe myocardial infarction through myocardial contraction compressing the coronary artery and accelerating atherosclerotic plaque formation, characterized by segmental systolic compression of the epicardial coronary artery enclosed by myocardial tissue[79,80]. For nonobstructive symptomatic MB, drug therapy is often used to reduce myocardial oxygen consumption by controlling heart rate. Severe obstructive MB with or without atherosclerosis may lead to acute coronary syndrome[80]. Although stent implantation has been successful in such cases, stent implantation for MB is clinically restricted due to the risks of coronary artery rupture, increased restenosis, and severe consequences[10,80-82]. PCBs, without metal residues, can reduce the risk of vascular rupture. Successful application of DCBs in MB with acute coronary syndrome has been reported, with no angina recurrence within 1 year postoperatively and no residual stenosis in 1-year coronary angiography follow-up[10]. However, current PCB applications in MB are limited to case reports, requiring more clinical practice to verify their efficacy.

APPLICATION OF PCBs IN ARTERIAL INFLAMMATORY DISEASES

Arterial inflammatory diseases, such as Kawasaki disease (KD) and TAK, pose unique clinical challenges due to inflammation-driven arterial stenosis. These diseases are characterized by inflammatory cell infiltration, vascular wall thickening, fibrosis, sclerosis, calcification, and vascular remodeling, leading to high restenosis rates after traditional balloon angioplasty or BMS implantation[9,83,84]. Such lesions are often associated with luminal stenosis, thrombosis, and blood flow disturbance, which aggravate ischemic complications. Additionally, the thin vascular wall is prone to aneurysm formation[85].

Patients with KD often have fibrosis and calcification, leading to a high incidence of restenosis. POBA is not an effective revascularization treatment for patients with KD sequelae. In calcified coronary lesions complicated with KD, rotational atherectomy followed by PCB treatment can reduce the restenosis rate and improve the prognosis of KD patients[86,87]. However, rare complications such as postoperative vasculitis[88] and infectious aneurysms[89] indicate that the safety of PCB treatment needs attention. Percutaneous coronary intervention for KD complicated with coronary aneurysm stenosis often faces problems such as incomplete stent apposition and allergic reactions to stents in some patients[90]. Existing evidence supports PCBs as a potential treatment option for arteritis stenosis. Xu et al[86] used PCBs to treat a case of coronary stenosis caused by KD, and the patency was still good after 6 months of evaluation, which is related to PCBs playing a role in stabilizing plaques by inducing apoptosis, inhibiting neointimal tissue proliferation, reducing macrophage activity, and inhibiting proinflammatory factor release[84]. PCBs can also reduce the incidence of restenosis after POBA and DESs[91]. However, the risk of new aneurysms formed by intimal tears caused by balloon angioplasty should also be considered[92].

TAK is a large-vessel vasculitis that mainly causes stenosis and obstruction of the aorta and its branches, leading to clinical symptoms. Vasculitis involves all arterial layers (intima, media, and adventitia), manifested as inflammatory cell infiltration, adventitial fibrous thickening, medial smooth muscle cell loss, elastic fiber destruction, and intimal thickening[83,93]. Percutaneous transluminal angioplasty, as a less invasive treatment option, has achieved good efficacy in the treatment of renal lesions in TAK. However, the currently high rates of restenosis and reintervention remain a problem[93]. Yamamoto et al[83] confirmed through clinical cases that the use of PCBs can achieve good patency for 2 years in RAS caused by TAK. Hecht et al[9] used PCBs to treat a child with TAK. Renal artery angiography 3 months after treatment showed no restenosis or progression of stenosis, and blood pressure remained at the upper limit of normal, demonstrating good efficacy. Nevertheless, the long-term efficacy and safety of this therapy still need to be verified.

APPLICATION OF PCBs IN VENOUS LESIONS

Venous stenosis is less common than arterial stenosis and is closely associated with endothelial injury, hemodynamic abnormalities, and inflammatory fibrosis. It commonly occurs in procedure-related complications (such as surgery or catheterization) and post-thrombotic states[94-96]. Stent implantation is an effective intervention method for venous stenosis[97], but ISR and thrombosis remain challenges, limiting stent application. Venous ISR is primarily driven by neointimal hyperplasia and fibrotic remodeling, while recurrent thrombosis accelerates stenosis progression through endothelial injury and inflammatory responses, which can cause severe circulatory disorders[98,99].

A multicenter single-arm retrospective analysis[100] in Europe showed that PCBs were significantly more effective than traditional high-pressure balloons in treating central venous stenosis (CVS) and venous stent restenosis in dialysis patients. The PCB group achieved a 6-month patency rate of 62.7% with a lower incidence of adverse events. Additionally, a retrospective analysis comparing PCBs and POBA for treating CVS found similar target lesion primary patency rates, with PCBs showing a trend toward prolonged re-intervention time[101]. Another retrospective study comparing the efficacy of POBA and PCBs in treating symptomatic central venous restenosis in patients with hemodialysis fistula dysfunction showed that the restenosis interval in the PCB group was longer than that in the POBA group. PCB treatment for central venous restenosis can significantly prolong the time patients are free from TLR[102].

Preliminary experience in treating left/right upper pulmonary vein stenosis with balloon pre-dilation, PCB implantation, and post-dilation suggests that PCBs can significantly reduce pressure gradients and improve stenosis, with patients remaining asymptomatic at 6-month follow-up[103]. A case report[104] showed that PCBs may be safe but less effective for infants with pulmonary vein stenosis (PVS) after total anomalous pulmonary venous connection repair. A retrospective single-center study analyzed the efficacy of stent implantation (No-PCB) vs PCB in PVS and pulmonary vein total occlusion caused by pulmonary vein isolation, which showed that PCB angioplasty followed by stent implantation was effective and safe, significantly reducing restenosis (No-PCB: 26% vs PCB: 14.3%) and TLR (No-PCB: 34.2% vs PCB: 10.7%)[98]. Although long-term efficacy data were lacking, case reports documented asymptomatic outcomes up to 12-month follow-up[105].

A single-center retrospective analysis[106] showed no advantages of PCBs over POBA in primary and assisted primary patency rates, as well as clinical and hemodynamic improvements for infrageniculate venous bypass stenosis. However, a retrospective multicenter cohort study[107] demonstrated that PCBs can reduce the need for repeated re-intervention in autologous infrageniculate venous bypass grafts and improve patients' quality of life.

A single-arm observational study[97] including 13 patients with iliofemoral deep vein thrombosis showed that PCBs can target and inhibit intimal hyperplasia. After PCB treatment, the mean stenosis rate decreased from 87.69% ± 13.48% to 14.6% ± 14.36%, indicating that PCB dilation is safe and effective for treating ISR. PCBs have also been reported to significantly relieve symptoms of chronic venous stenosis and improve thrombotic occlusion (6- and 12-month patency rates)[108].

The above studies all suggest that PCBs can improve the patency rate of venous stenosis. Studies by Isaji et al[108] and Björkman et al[109] have shown that compared with POBA, PCBs have no significant differences in improving TLR, primary patency rate, secondary patency rate, and graft occlusion, and there is no obvious benefit in treating venous graft stenosis. The reasons may be that venous ISR leads to delayed endothelial repair due to low hemodynamics shear stress, and the vein has obvious fibrosis, less neovascularization, and the proliferative venous intima has a collagen-rich matrix without elastin[97], which affects the distribution of paclitaxel and reduces the efficacy. The anatomical structure of veins is significantly different from that of arteries, which may lead to the efficacy of PCBs in venous stenotic lesions being less than that in arterial stenosis. At present, the effectiveness and safety of PCBs in preventing and treating venous intimal hyperplasia lack a comprehensive evaluation.

APPLICATION OF PCBs IN LUMINAL DISEASES

Currently, nonvascular luminal stenosis (such as urethral, biliary, and esophageal) mainly relies on surgery, stent implantation, plain balloon dilation, and other treatments. However, due to fibroproliferative restenosis, the recurrence rate of urethral stenosis within 12 months is still 50%[110]. In the biliary tract, the complication rate of permanent stents is 47%; mainly related to stent migration, occlusion, neostenosis, infection, or tissue hyperplasia[111]. By combining mechanical dilation with local drug delivery, PCBs can inhibit smooth muscle hyperplasia and collagen deposition under the antifibrotic and antiproliferative effects of paclitaxel, and better maintain luminal patency[112,113], providing an innovative solution for ductal stenosis.

Currently, research on PCBs in nonvascular luminal tissues mainly focuses on urethral stricture. An animal study by Li et al[112] showed that, after PCB dilation for porcine urethral stricture, the average diameter of the strictured site increased from 2.8 to 5.6 mm. Paclitaxel blood concentrations remained within a safe range while ensuring effective target tissue concentration, preliminarily indicating the safety and efficacy of PCBs for endoscopic treatment of ureteral strictures. A systematic review and meta-analysis[114] (encompassing 457 patients across seven studies) demonstrated that Optilume PCBs, by combining mechanical dilation with local paclitaxel delivery to inhibit scar formation, significantly reduced the International Prostate Symptom Score (IPSS), improved urinary flow rate, achieved a recurrence-free rate of 80.83%, and had a complication rate of only 9.5%, confirming its durable efficacy and safety as a minimally invasive alternative to standard treatment. A randomized study[115] (127 patients) showed that Optilume PCBs had a 6-month anatomical success rate of 75%, significantly higher than 27% for dilation/DVIU (direct vision internal urethrotomy), with superior outcomes in multiple indicators such as freedom from retreatment during 1-year follow-up, except for a higher incidence of hematuria and dysuria. Due to the high recurrence rate of endoscopic treatments like DVIU, PCBs, as an innovative minimally invasive therapy, have been incorporated into management guidelines for recurrent bulbar strictures < 3 cm in length by inhibiting excessive collagen deposition with paclitaxel. They significantly reduce the re-intervention rate compared to endoscopic therapy, but their durability in complex or longer strictures and role as a salvage therapy after urethroplasty require further study[116]. Additionally, the ROBUST I trial[117] (53 patients with recurrent bulbar strictures ≤ 2 cm in length) confirmed that Optilume PCBs achieved a 3-year functional success rate of 67%, freedom from retreatment rate of 77%, significant improvements in IPSS and other indices, and no impact on erectile function, maintaining long-term symptom improvement in high-risk recurrence populations. A retrospective analysis by Mahenthiran et al[118] of 43 patients found that PCBs provide a safe, minimally invasive treatment for iatrogenic and recurrent urethral strictures, reducing indwelling catheter time compared to urethroplasty, with a complication rate < 5% and potentially lower impact on erectile function. Although urethral fibrous tissue is dense with poor drug permeability, Liourdi et al[113] found that paclitaxel can still distribute in the urothelium, submucosa, and muscularis layers, inhibiting urothelial proliferation, alleviating inflammatory responses, and acting in a dose-dependent manner, which is the mechanism for preventing ureteral stricture caused by fibrotic reactions.

Ren et al[119] established a rabbit model of benign esophageal stricture, whose pathological manifestations included inflammatory cell infiltration, squamous epithelium thickening, and collagen fiber deposition. The study confirmed that PCBs alleviated local inflammatory responses and collagen deposition, thus improving benign esophageal strictures. There are fewer studies on airway strictures. In vivo and in vitro studies have shown that local application of paclitaxel can inhibit the formation of airway granulation tissue and scars. PCB dilation for benign strictures has certain short-term effects on improving and maintaining airway patency[10].

Available evidence supports PCBs as a complementary option for luminal stenosis treatment. In nonvascular ductal stenosis, paclitaxel does not flow systemically with blood, potentially offering higher safety, although it is still affected by bodily fluid flow. Long-term efficacy and tissue-specific pharmacokinetic optimization require further study[120]. Due to significant differences in anatomical structures between luminal diseases and arterial/venous vessels (such as lumen diameter, vessel wall architecture, hemodynamic characteristics, etc.), targeted research is needed to systematically explore key parameters of PCBs, including dose optimization, excipient formulation, and delivery method design, to enhance efficacy and reduce risks.

APPLICATION OF PCBs IN PERIPHERAL VASCULAR IN-STENT RESTENOSIS

Animal experiments[121] have shown that PCBs can inhibit restenosis after coronary stent implantation in pigs, with a reduction in neointimal formation comparable to that of DESs. As early as 2006, a study[122] demonstrated that PCB catheters significantly reduced the incidence of coronary ISR compared with POBA. A 2009 study[123] showed that PCBs were superior to paclitaxel-eluting stents in primary angiographic endpoints for treating coronary ISR. A 2008 study[124] indicated that PCBs were more effective than POBA in inhibiting femoropopliteal restenosis. Although advancements in endovascular stent technology have addressed the limitations of traditional POBA in patients with chronic PAD[125], a significant proportion of PAD patients treated with stents require secondary intervention due to ISR, particularly in long-segment complex lesions[126]. The absence of additional permanent metal implants makes PCBs one of the optimal minimally invasive alternatives for treating ISR[127].

A retrospective study[128] involving patients with ISR in the femoropopliteal and iliac arteries showed that the combination of the Rotarex^®S rotational atherectomy and thrombectomy device with PCB angioplasty is highly effective and safe. A 3-year randomized controlled trial[129] (ISAR-DESIRE 3) found that, compared with paclitaxel-eluting stents, PCBs reduce metal stent-related risks (such as stent fracture and chronic inflammation), showing similar efficacy and safety in ISR treatment with superior long-term patency (3-year TLR: 33.3% vs 50.8%). The implant-free strategy minimizes the risk of late thrombotic events and allows for repeat interventions if necessary. Recent evidence confirms that when used properly, PCBs maintain consistent safety in PAD treatment without demonstrating a dose-dependent mortality risk[20,21].

In theory, PCBs can be used for restenosis after all the above-mentioned applications, including restenosis after drug balloon angioplasty. However, organized thrombus and severe calcification may hinder the delivery of antiproliferative drugs to the vascular wall, leading to incomplete inhibition of neointimal hyperplasia. For patients with DES restenosis treated with PCBs, achieving a higher acute lumen gain may be the key to reducing the risk of recurrent restenosis[130]. Currently, the increasing research on endovascular treatment of PAD with PCBs can further verify the efficacy and safety of ISR treatment in peripheral vessels.

MOLECULAR BIOLOGICAL MECHANISMS OF PCBs

PCBs locally release paclitaxel, which relies on its microtubule-stabilizing properties to bind with the β-subunit of VSMCs tubulin. This blocks the G2/M phase of the cell cycle, inhibits the expression of molecules such as matrix metalloproteinases, NLRP3, and MAPKAP kinase 2, as well as inflammatory factors such as tumor necrosis factor-α and interleukin-6. Thereby, it suppresses VSMCs proliferation and migration, and alleviates vascular remodeling and inhibits neointimal hyperplasia by regulating the NLRP3 inflammasome pathway[26,74,80-82,113,131-134]. The brief drug release of 30-60 s by the balloon, combined with the lipophilicity and excipients of paclitaxel, prolongs the antiproliferative effect and maintains drug concentration in the vascular wall. Its low water solubility allows it to bind to the vascular wall in a granular state without residual foreign substances, with a plasma concentration < 10 ng/mL, significantly reducing systemic toxicity[4,7,135]. Clinically, PCBs leverage the above mechanistic advantages to be suitable for complex structures such as bifurcation lesions in coronary artery disease, reducing the risk of ISR[7]. In PAD, sustained drug retention can alleviate restrictive remodeling in chronic total occlusions of the femoropopliteal artery. However, it should be noted that the thick media of peripheral arteries requires maximizing coating transfer efficiency to achieve transmural penetration[10,135-137].

Restenosis after peripheral angioplasty originates from negative vascular remodeling, elastic recoil, or neointimal hyperplasia, with the core mechanisms being endothelial- injury-induced VSMCs phenotypic transformation and chronic inflammation dominated by macrophages[138]. Studies[131] have found that paclitaxel can activate NLRP3, and mediate VSMCs proliferation/migration and paclitaxel resistance through the NLRP3/IL-1β/BRD4/LIN9/AURKA/FOXM1 pathway, leading to restenosis after PCB treatment. JQ1 can inhibit this pathway and produce a synergistic effect with paclitaxel Additionally, stress-induced MK2 activation is a driver of VSMCs phenotypic transformation, and convective or coated balloon delivery of MK2 inhibitory peptides can enhance angioplasty efficacy[139]. Light calponin inhibits VSMCs growth/migration and neointimal formation by regulating the cytoskeletal tension/FAK/ERK axis[140]. Although current antiproliferative drugs can inhibit restenosis, they affect endothelial repair. Immunotherapy inducing macrophage polarization to the M2 subtype has become a potential direction, while precise targeting of therapeutic sites remains a key challenge[138]. Future studies should optimize PCBs design for different target lesions to achieve efficient drug delivery[3].

CONCLUSION

Since DCBs were first used in peripheral vessels in 2004 and later introduced into coronary artery treatment in 2006, their applications have gradually extended to various vascular and luminal diseases over the past two decades, including intracranial vessels and pulmonary arteriovenous lesions. DCBs offer superior efficacy and safety compared to plain balloons. However, adverse events can be further reduced by optimizing pretreatment lesion preparation, preventing or pretreating paclitaxel-related complications, refining nanocrystal coatings, conducting prognostic analyses, improving balloon design, and selecting appropriate balloon sizes and paclitaxel concentrations for specific target lesions.

ACKNOWLEDGEMENTS

First, we sincerely thank the Second People's Hospital of Jiangyou for establishing an academic and research platform for this study and providing strong support for the formation of the collaborative team. Additionally, we specially acknowledge the relevant departments that provided support during the research process, especially the full cooperation of the Scientific Research Department and the Information Department.