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Review

Paclitaxel-Coated Versus Sirolimus-Coated Eluting Balloons for Percutaneous Coronary Interventions: Pharmacodynamic Properties, Clinical Evidence, and Future Perspectives

by
Filippo Luca Gurgoglione
1,2,3,
Mattia De Gregorio
1,
Giorgio Benatti
2,
Davide Donelli
1,*,
Luigi Vignali
2,
Emilia Solinas
2,
Iacopo Tadonio
2,
Andrea Denegri
2,
Marco Covani
1,
Gabriella Dallaglio
1,
Bernardo Cortese
3,4,5,6,† and
Giampaolo Niccoli
1,2,†
1
Division of Cardiology, Parma University Hospital, University of Parma, 43126 Parma, Italy
2
Division of Cardiology, Parma University Hospital, 43126 Parma, Italy
3
DCB Academy, 20143 Milano, Italy
4
Fondazione Ricerca e Innovazione Cardiovascolare, 26900 Milano, Italy
5
University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
6
Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Future Pharmacol. 2024, 4(4), 775-787; https://doi.org/10.3390/futurepharmacol4040041
Submission received: 18 September 2024 / Revised: 21 October 2024 / Accepted: 31 October 2024 / Published: 2 November 2024
Browse Figure
Versions Notes

Abstract

:
Drug-coated balloons (DCBs) have emerged as an increasingly valuable option for the treatment of coronary artery disease (CAD). Percutaneous coronary intervention (PCI) with DCBs enables the localized delivery of antiproliferative drugs directly to the target coronary lesion, avoiding the need for permanent scaffold implantation. Historically, paclitaxel-coated balloons (PCBs) have been the most used device in this context. Paclitaxel interferes with intracellular microtubule function, leading to cell cycle arrest. However, its cytotoxicity at a higher dosage and narrow therapeutic range has raised some safety concerns. To address these issues, sirolimus-coated balloons (SCBs) have been introduced as an alternative. Sirolimus acts as a cytostatic agent with potent anti-inflammatory and antiproliferative properties and is characterized by a wider therapeutic range, potentially offering a safer profile. Several experimental and clinical studies comparing the safety and efficacy of PCBs versus SCBs have yielded mixed results. Recently, a novel DCB (SirPlux Duo), which simultaneously releases both paclitaxel and sirolimus, has been tested in a porcine coronary model with promising results. In this review, we will elucidate the mechanisms of action of paclitaxel and sirolimus, examine contemporary preclinical and clinical evidence comparing PCB and SCB angioplasty, and discuss novel devices that may enhance the safety and efficacy of PCI with DCBs.

1. Introduction

Atherosclerotic coronary artery disease (CAD) remains the leading cause of morbidity and mortality worldwide [1]. Percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) is a cornerstone of CAD treatment [2]. Despite advancements in DES technology, such as thinner stent struts and optimized polymer formulations, PCI failure remains a significant challenge, with in-stent restenosis (ISR) accounting for approximately 10% of PCI procedures in the United States [3].
Drug-coated balloons (DCBs) have emerged as an effective alternative strategy for the treatment of CAD. These balloons, composed of semi-compliant polyurethane and nylon, deliver antiproliferative drugs via a lipophilic matrix to target arterial lesions [4].
Historically, paclitaxel (PTX) has been the primary antirestenotic drug used in drug-coated balloons. However, PTX has a narrow therapeutic window, posing some safety concerns [5]. Commonly marketed PCBs have a drug dosage ranging between 2 and 3.5 µg/mm2 [6].
To mitigate these issues, new drug-coated balloons featuring sirolimus (SRL) have been introduced [7,8]. SRL-coated balloons (SCBs) utilize a different mechanism of action compared to PTX-coated balloons (PCBs) and have a wider therapeutic range. However, clinical and angiographic outcomes associated with SCBs are still subject to ongoing debate.
This narrative review aims to clarify the distinct mechanisms of action of PTX and SRL and discuss contemporary evidence regarding the safety and efficacy of PCBs versus SCBs angioplasty in CAD. Furthermore, we will explore potential novel strategies to enhance PCI outcomes with DCBs, including the innovative combined PTX- and SRL-coated SirPlux Duo balloon.

2. Mechanisms of Action of Paclitaxel and Sirolimus

2.1. Paclitaxel

PTX is an anti-cancer agent derived from the bark of the Pacific yew tree (Taxus brevifolia). While it was initially used in oncology due to its effectiveness in treating ovarian and breast cancers, PTX has progressively broadened its therapeutic role [9], demonstrating notable efficacy in preventing restenosis following arterial angioplasty procedures with balloons and stents [5].
The mechanism of action of PTX relies on interaction with microtubules, which are essential for cell division, specifically in forming the mitotic spindle necessary for chromosome separation. PTX stabilizes microtubules by binding reversibly to the beta subunit of tubulin, promoting the polymerization of alpha and beta tubulin subunits. By inhibiting the natural disassembly of microtubules, PTX halts the progression of the cell cycle from the G2 phase to the mitosis phase, effectively arresting cell division at the mitotic phase [10] (Figure 1).
PTX’s effects vary depending on the cell type and dosage. In cancer cells, PTX induces prolonged mitotic arrest, leading to cytotoxicity and apoptosis through the activation of the caspase pathway [7].
In contrast, PTX’s antirestenotic properties are linked primarily to its inhibition of vascular smooth muscle cell (VSMC) proliferation and migration. VSMCs play a central role in neointimal hyperplasia, a crucial mechanism of target lesion restenosis after angioplasty. PTX exerts a cytostatic effect on VSMCs, preventing excessive VSMC proliferation and migration, thus maintaining the patency of the treated vessel [11,12].
Mechanistic studies have shown that VSMCs respond to PTX differently than cancer cells. Instead of undergoing apoptosis, VSMCs often evade cell death by upregulating anti-apoptotic proteins, such as the inhibitor of apoptosis proteins. Furthermore, VSMCs typically experience only a brief arrest in the G1 phase of the cell cycle without completing division, a phenomenon known as “mitotic slippage”. This mitigates the apoptotic cascade, preserving VSMCs from cell death. PTX also induces β-galactosidase activity in VSMCs, which is a marker of cellular senescence, which further curbs their proliferation and migration, contributing to its effectiveness in preventing restenosis [11,12].
Another important mechanism contributing to the antirestenotic effects of PTX is its inhibition of glycoprotein VI signaling, a pathway that plays a role in platelet activation. By inhibiting glycoprotein VI, PTX minimizes platelet aggregation and thrombus formation, potentially reducing the risk of clotting-related complications in angioplasty patients [13].

2.2. Sirolimus

SRL is a macrocyclic lactone that exhibits cytostatic properties, primarily by inhibiting the mammalian target of rapamycin (mTOR), a key serine/threonine kinase involved in cell growth, proliferation, and survival. mTOR consists of two major subunits, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), both of which are involved in the proliferation of endothelial cells and VSMCs [14] (Figure 1).
SRL exerts its effects by reversibly binding to the cytosolic protein FKBP12, forming an immunosuppressive complex that selectively inhibits mTORC1. This inhibition blocks downstream signaling, primarily targeting crucial effectors like the eukaryotic translation initiation factor 4E-binding protein 1. These molecules play essential roles in promoting cell growth and division. By disrupting these pathways, SRL induces cell cycle arrest in the G0 phase, affecting both VSMCs and endothelial cells. Importantly, the suppression of the ribosomal protein S6 kinase 1 also downregulates cyclin D1, a key regulator of the transition between the G1 and S phases of the cell cycle, further inhibiting cell proliferation [15].
Recent evidence has revealed that SRL may also inhibit mTORC2, which is involved in cell survival and the regulation of the cytoskeleton. Inhibiting mTORC2 can impair endothelial cells survival [16] and disrupt the structural integrity of the endothelial barrier, a critical factor for vascular function [17,18].
The broader inhibition of mTOR pathways helps modulate vascular responses by targeting both cell cycle arrest in VSMCs and the suppression of endothelial cell proliferation, contributing to its long-term therapeutic benefits in preventing target vessel restenosis.

3. Preclinical Evidence of Paclitaxel and Sirolimus Use for the Treatment of Atherosclerotic Lesions

Early studies tested the role of PTX on in vitro and animal models of atherosclerosis, showing promising results in reducing VSMC proliferation.
In swine models, PTX showed long-lasting efficacy, maintaining sufficient inhibitory drug concentrations at coronary levels for up to 3 months [19]. Of interest, PCB exhibited significantly greater neointimal proliferation inhibition compared to uncoated balloons, bare-metal stents, and sirolimus-eluting stents in histomorphometric and quantitative coronary angiography analyses performed in 22 pigs. Importantly, PCB also demonstrated lower rates of delayed re-endothelialization, a predisposing factor for thrombogenic complications and accelerated restenosis, compared to DES [20].
Preclinical studies also tested if there was a difference in terms of safety or efficacy between PTX and SRL. The majority of available evidence has shown that PTX offers more potent antiproliferative effects compared to SRL, although it has been associated with a higher rate of adverse effects, such as distal vessel embolization. Nevertheless, very recent data showed more evident antiproliferative properties and higher rates of distal vessel embolization after SRL administration [21,22].
Wessely and colleagues highlighted the superiority of PTX over SRL in inducing cell’s apoptosis, translating into more the potent inhibition of VSMC proliferation and migration. However, PTX tended to aggregate with neutrophils and leukocytes, forming flow-limiting emboli, which predispose to distal embolization and microvascular obstruction [23,24]. Moreover, higher doses of PTX have been linked to other potential risks, such as intimal hemorrhages, persistent fibrin deposition, and increased inflammation, raising concerns about its safety profile [25].
Clever et al. tested the effects of PTX and SRL in a culture medium rich in human VSMCs and endothelial progenitor cells, as well as in pig coronary arteries. PTX exhibited a dose-dependent and prolonged inhibition of VSMCs, while SRL exhibited a more potent inhibition of endothelial progenitor cells. Moreover, PTX’s higher lipophilicity contributed to its superior efficacy, ensuring greater and more uniform uptake and retention at the target site compared to SRL [26].
Chen et al. investigated the effects of PTX and SRL in an in vitro hypoxic model of atherosclerosis, simulating the human atherosclerotic environment. Hypoxic conditions are characterized by angiogenesis, VSMCs proliferation, increased glycolysis, and inflammation, resulting in accelerated atherosclerosis. Of interest, angiogenesis, a marker of plaque vulnerability, destabilizes atherosclerotic lesions and promotes the onset of acute coronary syndromes. In this model, SRL, delivered via a specialized nanocarrier technology, showed a strong inhibition of hypoxic cell proliferation in a time- and dose-dependent manner, while PTX’s efficacy was significantly weakened in such an environment [21].
More recently, Aihara et al. compared the histological and biological outcomes of three different DCB strategies in the iliac arteries of 18 rabbits: low-dose AGENT PCB (Boston Scientific Corp, Marlborough, MA, USA), regular-dose SeQuent Please NEO PCB (BBraun, Melsungen, Germany), and a MagicTouch SCB (Concept Medical, India). Both PCB formulations demonstrated superior smooth muscle cell loss scores compared to the SCB, indicating greater drug efficacy in inhibiting VSMC proliferation. Conversely, SRL showed a less uniform distribution, with deeper tissue penetration and higher drug levels detected in distal skeletal muscles, raising concerns about the potential for distal embolization with SCBs [22]. This finding has not been previously demonstrated with the available SCBs, and the risk of distal embolization associated with PCBs appears underestimated when compared to current evidence. Additionally, the use of the rabbit model for atherosclerosis remains a potential limitation, as porcine models are considered more suitable for coronary applications due to their greater similarity to human physiology [27,28].

4. Clinical Evidence of Paclitaxel- and Sirolimus-Coated Balloons for the Treatment of Coronary and Peripheral Atherosclerotic Lesions

Ali and colleagues conducted a randomized controlled trial (RCT) comparing the clinical and angiographic outcomes of the SeQuent SCB (BBraun, Melsungen, Germany) and the SeQuent Please Neo PCB in 50 patients with DES-related ISR (DES-ISR). The two groups showed similar quantitative coronary angiography-derived in-segment late lumen loss (LLL) at 6 months (0.21 ± 0.54 mm in the PCB group vs. 0.17 ± 0.55 mm in the SCB group) and comparable rates of major adverse cardiovascular events (MACEs) at 12 months [29]. A larger study by Scheller et al. combined data from two RCTs conducted in Malaysia and Germany/Switzerland, comparing the clinical performance of the SeQuent SCB with the SeQuent Please Neo PCB. The study found no significant differences between the two groups in terms of in-segment LLL (0.20 ± 0.52 mm for PCB vs. 0.26 ± 0.61 mm for SCB, p = 0.639) and MACEs (14% in the PCB group vs. 18% in the SCB group, p = 0.596). Notably, the SCB was found to be non-inferior to the PCB only in Malaysian patients, suggesting potential biological differences in coronary artery diameters and vascular responses after DCB angioplasty between Asian and European populations [30].
Briguori et al. later demonstrated a similar rate of 1-year target lesion failure (TLF) between the Restore PCB (Cardionovum GmbH, Bonn, Germany) (17%) and Devoir SCB (Minvasys SAS, Gennevilliers, France) (the same device as Magic Touch, 15.5%) in patients with DES-ISR using a propensity-score matched analysis. Additionally, the study identified that optimal lesion preparation (balloon-to-stent ratio > 0.91, balloon inflation time > 60 s, and residual percent diameter stenosis < 20%) was the strongest predictor of reduced 1-year TLF (odds ratio = 0.06; 95% confidence interval: 0.01–0.21; p < 0.001) [31].
Consistent with these findings, a recent multicenter RCT by Ahmad et al. showed comparable efficacy of the SeQuent SCB and SeQuent Please Neo PCB concerning angiographic and clinical outcomes in a cohort of 70 patients with de novo lesions in larger (≥2.5 mm) coronary vessels. Clinical outcomes were similar between the groups, but PCBs resulted in a nearly doubled rate of late lumen enlargement (LLE) at follow-up compared to SCBs (60.0% vs. 32.4%, p = 0.019) [32].
In the TRANSFORM I study, which included 121 patients with de novo small vessel CAD and 129 lesions, the MagicTouch SCB showed worse angiographic outcomes compared to the SeQuent Please Neo PCB at 6-month follow-up. The PCB group showed significantly less LLL compared to the SCB (0.00 mm vs. 0.32 mm; p < 0.001) and higher rates of LLE (53.7% vs. 30.0%). Additionally, a positive correlation was observed between optical coherence tomography-derived dissection volume and LLL in the SCB group, suggesting that the diffusion and retention of SRL in deeper coronary wall layers might be inadequate to prevent VSMC proliferation and neointima formation [28,33].
Conversely, a recent RCT by Scheller et al. found no significant differences in in-segment LLL (0.04 mm for PCB vs. 0.11 mm for SCB) and a numerically higher rate of LLE in the PCB group (56% vs. 44% in the SCB group), with comparable clinical outcomes at 12 months [34].
The SIRPAC study aimed to compare the clinical performance of the MagicTouch SCB and Elutax SV PCB (Aachen Resonance, Germany) in patients (62% with ISR and 43% with small vessel CAD). The study found similar rates of MACE at 12 months between the groups (10.3% in the PCB group vs. 10.7% in the SCB group, p = 0.892) with a propensity-score matched comparison [35].
Two recent meta-analyses explored clinical and angiographic outcomes between PCBs and SCBs for either de novo or ISR lesions. Sedhom and colleagues included 6 RCTs and 821 patients, showing worse angiographic results in the limus-DCB group, with a higher occurrence of binary restenosis (risk ratio: 1.89; 95% CI: 1.14–3.12) and LLL (mean difference = 0.16; 95% CI: 0.03–0.28), while LLE occurred in the PCB group (50% vs. 27.5%; RR: 0.59; 95% CI: 0.45–0.77). Finally, the two study groups experienced similar rates of TLR at a mean of 13.4 months (10.3% vs. 7.8%; risk ratio: 1.32; 95% CI: 0.84–2.08) [36]. Shin et al. conducted a larger meta-analysis including five RCTs and three observational studies for a total of 1861 patients. The two study groups demonstrated no differences in terms of LLL (mean difference −0.11, 95% CI −0.23–0.02) and TLR (OR 1.01, 95% CI 0.75–1.35) at 9–12 months [37].
In summary, available clinical studies on PCB vs. SCB angioplasty for the treatment of CAD have yielded controversial angiographic results. This variability can be attributed to differences in the enrolled population (e.g., de novo vs. ISR, ethnicity) and the specific types of DCB evaluated (Table 1). Future RCTs are largely awaited to close this knowledge gap. Interestingly, PCB use was associated with higher rates of LLE, a positive vessel remodeling phenomenon observed after DCB PCI for de novo lesions. LLE is characterized by an increase in minimal lumen diameter and/or volume between the post-PCI procedure and follow-up, which is correlated with lower rates of target vessel restenosis at follow-up [38]. The cytotoxic effect of PTX may underlie these findings.

5. Safety Concerns Regarding the Use of Paclitaxel

Bench models, animal studies, and preclinical investigations, particularly those focusing on peripheral arterial disease (PAD), have raised potential safety concerns regarding the use of PTX (Table 2).
PTX is often delivered in a crystalline form encapsulated in hydrophilic excipients and advanced to the target site through a semi-compliant balloon. This formulation minimizes drug loss to approximately 30% before reaching the target site and enhances drug distribution within the vessel wall for up to two months, thereby increasing its antirestenotic efficacy [39]. Preclinical studies have demonstrated the prolonged retention of PTX in the iliofemoral arteries following balloon delivery, with therapeutic tissue levels (>1 ng/mg) maintained for long time [40]. Notably, the prolonged retention of PTX may increase the risk of adverse events. Animal studies have reported cytotoxic effects on the tunica media of the vessel wall following PTX delivery, with an increased risk of intimal hemorrhage, fibrin deposition, and medial necrosis [24]. Histological studies in healthy swine models have also revealed potential risks of the embolization of particles composed of drug and excipients during PCB angioplasty, which could lead to fibrinoid necrosis of downstream arterioles and secondary low-grade chronic inflammation [41,42].
The landmark IN.PACT DEEP (Randomized AmPhirion DEEP DEB vs. Standard PTA for the Treatment of Below-the-Knee Critical Limb Ischemia) trial assessed the safety and efficacy of PCBs in the treatment of critical limb ischemia, involving 358 patients. At the 1-year follow-up, the study found a significantly higher rate of major amputations in the PCB group compared to standard percutaneous transluminal angioplasty. Although the study did not delve into mechanistic explanations, the authors hypothesized that the downstream embolization of PTX affecting the skeletal muscles of the lower limbs might be implicated [43].
The risk of the systemic diffusion and toxicity of PTX during arterial angioplasty has also been advocated. When used as a chemotherapeutic agent, PTX is known to cause significant systemic adverse effects, including bone marrow suppression, peripheral neuropathy, nausea, and alopecia [8]. However, the dosages employed in the treatment of CAD are approximately 750 times lower than those used in chemotherapy, making it unlikely for these systemic adverse effects to occur in this context [44]. Additionally, anecdotal cases of vasculitis and panniculitis following PCB treatment have been reported [44].
A landmark meta-analysis by Katsanos et al., including 28 RCTs involving 4663 patients, compared the safety and efficacy of PCB versus plain old balloon angioplasty or bare-metal stents for lower extremity interventions. The analysis revealed a significant relative risk increase in all-cause mortality associated with PCB angioplasty—68% at 2 years and 93% at 5 years—compared to the control arm. Notably, a clear association was identified between PTX dose-time exposure and subsequent adverse events. Specifically, the risk of death was higher for balloons with a PTX dosage exceeding 3.5 μg/mm2, and the mortality risk increased by approximately 0.4–1% per PTX milligram-year [45].
However, this meta-analysis had several methodological limitations. Firstly, there was a high rate of patients lost to follow-up. Secondly, mortality rates were calculated using the intention-to-treat principle, which did not account for crossover effects between treatment groups. Thirdly, the specific causes of death were not analyzed, limiting the ability to draw definitive conclusions about the nature of the risk [46]. Additionally, potential confounding factors, such as variations in patient management and adherence to medical therapy, were not controlled for and might be considered [47].
Table 2. Safety studies.
Table 2. Safety studies.
First Author, Year [Ref.]Sample SizeType of LesionComparisonResults
Zeller et al., 2014 [43]358Infrapopliteal diseaseAmPhirion (Paclitaxel) PCB vs. standard PTASimilar clinical outcomes (17.7% versus 15.8%)
Trends towards major amputations at 12 months were observed (8.8% vs. 3.6%; p = 0.080) in PCB group
Scheller et al., 2020 [44]4590Coronary ISR or de novo lesions.PCB vs. alternative treatment (POBA, uncoated scoring balloon angioplasty, BMS or DES)At 3 years, all-cause mortality (RR: 0.73; 95% CI: 0.53 to 1.00; p = 0.047) and cardiac mortality (RR: 0.53; 95% CI: 0.33 to 0.85; p = 0.009) were significantly lower in the DCB group when compared with control treatment
Katsanos et al., 2018 [45]4663Femoropopliteal artery diseaseDCB or DES (Paclitaxel) vs. standard PTASignificant association between exposure to paclitaxel (dose-time dependent) and absolute risk of death (0.4 ± 0.1% excess risk of death per paclitaxel mg-year; p < 0.001).
Schneider et al., 2019 [47]1980Femoropopliteal artery diseasePCB vs. standard PTANo significant difference in all-cause mortality at 5 years
Secemsky et al., 2021 [48]168,553Femoropopliteal artery diseaseDrug-coated devices vs. non–drug-coated devicesDCBs were non-inferior to the control group in mortality rate at a median follow-up of 2.72 years (53.8 vs. 55.1%).
Parikh et al., 2024 [49]2666Femoropopliteal artery diseasePCB vs. non-drug coated deviceNo significant differences in all-cause mortality between the two groups in the intention-to-treat (HR 1.14, 95% CI 0.93–1.40) and as-treated analysis (HR 1.13, 95% CI 0.92–1.39)
Zeller et al., 2020 [50]358Infrapopliteal diseaseAmPhirion (Paclitaxel) DCB vs. standard PTANo differences in freedom from TLR at 5 years (70.9% vs. 76.0%, log-rank p = 0.406) between the two groups. The rate of major amputation was similar between DCBs and PTA (15.4% vs. 10.6%, p = 0.108)
Abbreviations: BMS: bare-mental stents; CI: confidence interval; DCB: drug-coated balloon; DES: drug-eluting stent; HR: hazard ratio; PCB: paclitaxel-coated balloon; POBA: plain old balloon angioplasty; PTA: percutaneous transluminal angioplasty; RR: risk ratio.
The potential late mortality signal associated with PCB use led to a significant decline in PCB usage in clinical practice in the United States over the following six months [48] and spurred the conduction of dedicated patient-level analyses.
Schneider and colleagues conducted a patient-level meta-analysis comparing the clinical performance of the IN.PACT Admiral DCB (Medtronic, Dublin, Ireland) versus standard PTA in 430 patients with PAD. The study utilized a blinded Clinical Events Committee to obtain detailed vital status information and the specific cause of death for each patient. The authors did not find an association between PCB exposure and adverse events at 5-year follow-up, with no cases of neutropenia or peripheral neuropathy being observed. Additionally, the PTX dose was not associated with adverse events, while a clear association was noted between the PTX dose and reduced risk of clinically driven target lesion revascularization at 5 years [47].
The landmark SAFE-PAD (Safety Assessment of Femoropopliteal Endovascular Treatment With Paclitaxel-Coated Devices) study was a large retrospective cohort study, conducted in compliance with the Food and Drug Administration, aimed at investigating the mortality rates between PTA with DCBs or non-coated balloons for femoropopliteal revascularization. Among the 168,553 included patients (41.9% treated with PCB), the cumulative incidence of all-cause mortality was similar between the two groups (53.8% in the PCB group and 55.1% in the control group) at 5 years [48].
A recent patient-level meta-analysis by Parikh et al. found no excess mortality associated with PCB use compared to non-coated balloons when treating femoropopliteal lesions, involving 2.666 patients with a median follow-up of 4.9 years. The strengths of this analysis comprise the inclusion of newer trials with longer follow-up, more detailed information on clinical status and PTX exposure, and the inclusion of both intention-to-treat and as-treated analyses [49]. Additionally, the 5-year follow-up of the IN.PACT DEEP trial did not observe an association between PTX exposure and a heightened risk of major amputations or all-cause mortality [50].
A landmark meta-analysis by Scheller et al. specifically evaluated the clinical performance of PCBs for the treatment of CAD, including 26 RCTs with a total of 4.590 patients. At follow-up, PCBs demonstrated numerically lower event rates after DCB treatment (risk ratio: 0.74; 95% CI: 0.51 to 1.08; p = 0.116) [44].
In summary, initial experimental and clinical studies on PAD have highlighted relevant safety concerns, suggesting a potential increased risk of all-cause mortality following revascularization with PCBs. Conversely, more recent investigations have provided reassurance regarding the safety of PTX-coated devices. Future larger RCTs with extensive investigation of any potential complication are eagerly awaited to draw definitive conclusions on the safety of PCB revascularization.
It is also important to note that there is no class effect in DCB angioplasty—the interaction between the antiproliferative drug, excipient, and type of coating significantly influences drug delivery and, in turn, the clinical safety and efficacy profile. Interestingly, plaque morphology differs significantly between coronary and peripheral vascular beds, potentially influencing the clinical performance of PCBs and SCBs. Matsuo et al. reported a higher prevalence of fibroatheromatous plaques and positive vessel remodeling in coronary arteries, whereas atherosclerotic lesions in peripheral districts were more frequently calcific, fibrotic, and contained fewer inflammatory cells [51]. Additionally, coronary and peripheral beds exhibit rheological differences due to variations in tunica media composition, local pressure, and arterial stiffness [52].

6. Future Perspectives

DCB angioplasty is a relatively recent strategy for treating CAD and a matter of intense research. Several balloon technologies have been implemented in recent years and tested in experimental and clinical investigations.
The SirPlux Duo (Advanced NanoTherapies, Inc) is a fascinating device that releases both PTX and SRL in a 1:9 ratio, encapsulated in biodegradable nanoparticles to enhance prolonged drug distribution into the vessel wall. The aim is to achieve the antirestenotic and anti-inflammatory effects of PTX and SRL while minimizing the risk of cytotoxicity and serious adverse events [53]. Very recently, Kawai et al. found promising results in bench and animal models. When added to a culture of human VSMCs, the SirPlux Duo demonstrated a synergic effect of PTX and SRL in inhibiting intimal cell proliferation through inducing cell cycle arrest, while preventing excessive VSMC loss compared to PCBs. In a porcine coronary model, therapeutic dosages of the SirPlux Duo were associated with a lower risk of cytotoxic effect on the tunica media of the vessel and risk of distal embolization when compared to PCBs [54].
A biolimus-coated balloon (BCB) has been implemented in the last year and tested in clinical studies. Biolimus is a semisynthetic SRL analog, with a higher lipophilicity compared to SRL, with potential advantages of drug distribution at the arterial target site. The first in-human study was conducted by Xu and colleagues, involving 212 patients with small-vessel CAD who underwent PCI with BCBs or POBA in a 1:1 fashion. The BCB group resulted in a significant almost three-fold higher rate of LLE (29.7% in the BCB group vs. 9.8% in the control group, p = 0.007) and experienced a numerically lower occurrence of TLF rates (6.7% in the BCB group vs. 13.9% in the control group) and patient-oriented clinical outcomes (14.3% in the BCB group vs. 21.8% in the control group) [55]. The results of two head-to-head RCTs comparing the clinical performance of BCBs versus PCBs have been recently published. The REFORM study included 201 patients with BMS- or DES-ISR randomized in a 2:1 fashion to receive angioplasty with BA9-BCB (Biosensors Europe SA, Morges, Switzerland) or Sequent Please PCB Braun Melsungen AG, Germany). The BCB group led to a significantly higher percentage of the quantitative coronary angiography-derived percentage in-segment diameter stenosis (41.8% vs. 31.2%) and binary restenosis (32.2% vs. 11.3%) compared to the PCB group [56]. The very recent BIO ASCEND ISR study enrolled 280 patients with ISR randomized 1.1 to PCI with BCBs (BioAscend JWMS China) or PCBs (SeQuent Please NEO [B. Braun Melsungen AG]). The two study groups experienced similar LLL at 9 months (0.23 ± 0.37 mm in the BCB group and 0.25 ± 0.35 mm in the PCB group) and TLF rates (0% in the BCB group and 0.7% in the PCB group (p = 0.498)) at 12 months. The inclusion of different clinical contexts and different BCB formulations might explain these results [57].
A very recent paper by Katsouras et al. investigated the safety and efficacy of a novel balloon coated with everolimus, a semi-synthetic derivative of naturally occurring rapamycin with potent immunosuppressive and anti-proliferative effects. When compared to a non-coated balloon and an SCB (Magic Touch, Concept Medical), everolimus-coated balloons showed promising results in terms of the biocompatibility of the device, as suggested by a numerically lower host reaction, and the inhibition of intimal formation, although these differences were not statistically significant. Future studies are warranted to address the promising results of everolimus-coated balloons in clinical studies [58]. Finally, future technologies, such as the modeling reconstruction and three-dimensional analyses of coronary arteries, could be of paramount importance in refining the role of PTX and SRL in DCB angioplasty.

7. Conclusions

PTX and SRL exhibit different pharmacodynamic properties, which translate into different clinical performance sand safety profiles.
The divergent effects of PTX and SRL observed in preclinical models and varying conditions underscore the complexity of drug selection in clinical settings.
While PTX has demonstrated potent cytotoxicity and antirestenotic effects, concerns about its safety in certain environments persist. Conversely, SRL’s mechanism of action, particularly its inhibition of the mTOR pathway, offers an alternative approach, but raises questions about effective drug distribution in the vessel wall and permanence.
So far, we have sufficient information on when to use the more potent cytotoxic effect of paclitaxel, aiming at observing a higher lumen enlargement, or the more anti-inflammatory effect of sirolimus, with both devices aiming to optimize DCB use in clinical practice.

Author Contributions

F.L.G.: Conceptualization, Data curation, Investigation, Methodology, Project administration, Visualization, Writing—original draft, Writing—review and editing; M.D.G.: Investigation, Visualization, Writing—original draft, Writing—review and editing; G.B.: Data curation, Investigation, Writing—original draft, Writing—review and editing; D.D.: Conceptualization, Formal analysis, Methodology, Project administration, Writing—original draft, Writing—review and editing; L.V.: Conceptualization, Supervision, Validation, Writing—review and editing; E.S.: Validation, Visualization, Writing—original draft, Writing—review and editing; I.T.: Conceptualization, Supervision, Writing—original draft, Writing—review and editing; A.D.: Investigation, Validation, Writing—original draft, Writing—review and editing; M.C.: Investigation, Visualization, Writing—original draft, Writing—review and editing; G.D.: Investigation, Visualization, Writing—original draft, Writing—review and editing; B.C.: Project administration, Resources, Supervision, Validation, Writing—review and editing; G.N.: Project administration, Resources, Supervision, Validation, Writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing is not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

BCBbiolimus-coated balloon
CADcoronary artery disease
DCBdrug-coated balloon
DESdrug-eluting stent
ISRin-stent restenosis
LLElate lumen enlargement
LLLlate lumen loss
MACEmajor adverse cardiovascular event
mTORmammalian target of rapamycin
mTORCmTOR complex 1
PADperipheral artery disease
PCBpaclitaxel-coated balloon
PCIpercutaneous coronary intervention
POBAplain old balloon angioplasty
PTXpaclitaxel
RCTrandomized controlled trial
SCBsirolimus-coated balloon
SRLsirolimus
TLFtarget lesion failure
VSMCvascular smooth muscle cell

References

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Futurepharmacol 04 00041 g001
Figure 1. Mechanisms of action between paclitaxel and sirolimus. Abbreviations. mTOR: mammalian target of rapamycin.
Figure 1. Mechanisms of action between paclitaxel and sirolimus. Abbreviations. mTOR: mammalian target of rapamycin.
Futurepharmacol 04 00041 g001
Table 1. Most relevant clinical studies comparing angiographic and clinical outcomes between PCB and SCB.
Table 1. Most relevant clinical studies comparing angiographic and clinical outcomes between PCB and SCB.
First Author, Year [Ref.]Study DesignStudy PopulationType of LesionComparisonTime of Follow-UpType of OutcomeResults
Ali et al., 2019 [29]RCT50 (25 SCB, 25 PCB)ISRSeQuent SCB vs. SeQuent Please Neo PCB12 monthsLLL/MACE0.17 ± 0.55 mm vs. 0.21 ± 0.54 mm
(p = NS)/
3 (12%) vs. 4 (16%) (p > 0.99)
Scheller et al., 2022 [30]RCT101
(50 SCB, 51 PCB)		ISRSeQuent SCB vs. SeQuent Please Neo PCB12 monthsLLL/MACE0.26 ± 0.61 mm vs. 0.20 ± 0.52 mm
(p = 0.639)/
9 (18%) vs. 7 (14%) (p = 0.596)
Briguori et al., 2023 [31]Observational372
(186 SCB, 186 PCB)		ISRDevoi SCB vs. Restore PCB12 monthsTLF29 (15.5%) vs. 32 (17%)
(p = 0.29)
Ahmad et al., 2022 [32]RCT70
(35 SCB, 35 PCB)		De novo lesionsSeQuent SCB vs. SeQuent Please Neo PCB12 monthsLLL negative/MACE21 (60.0%) vs. 12 (32.4%)
(p = 0.019)/
0 (0%) vs. 2 (6%) ( p = 0.493)
Ninomiya et al., 2023 [33]RCT121
(61 SCB, 60 PCB)		De novo SVD (≤2.5 mm).Magic Touch SCB vs. SeQuent Please Neo PCB6 monthsLLL0.32 mm vs. 0.00 mm; (p < 0.001)
Scheller et al., 2023 [34]RCT70
(35 SCB, 35 PCB)		De novo lesions > 2.5 mmSeQuent SCB vs. SeQuent Please12 monthsLLL/rate LLE0.11 mm vs. 0.04 mm/
44% vs. 56%
Cortese et al., 2021 [35]Observational1090
(596 SCB, 494 PCB)		All lesionsMagicTouch SCB and Elutax SV PCB12 monthsMACE10.7% vs. 10.3% (p = 0.892)
Sedhom et al., 2024 [36]Metanalysis821
(446 LCB, 375 PCB)		All lesionsLimus DCB vs. Paclitaxel DCB13.4 monthsTLR/LLE/MACE10.3% vs. 7.8% (p > 0.05)/
27.5% vs. 50%; (p = 0.0002)/
14.5% vs. 13.6% (p > 0.05)
Shin et al., 2024 [37]Metanalysis1861
(972 SCB, 889 PCB)		All lesionsSCB vs. PCB9–12 monthsLLL/TLRmean difference −0.11 (95% CI −0.23–0.02)/no difference (OR 1.01, 95% CI 0.75–1.35)
Abbreviations: DCB: drug-coated balloon; ISR: in-stent restenosis; LLL: late lumen loss; MACE: major adverse cardiovascular event; OR: odds ratio; PCB: paclitaxel-coated balloon; RCT: randomized controlled trial; SCB: sirolimus-coated balloos; SVD: small-vessel disease; TLF: target lesion failure; TLR: target lesion revascularization.
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MDPI and ACS Style

Gurgoglione, F.L.; De Gregorio, M.; Benatti, G.; Donelli, D.; Vignali, L.; Solinas, E.; Tadonio, I.; Denegri, A.; Covani, M.; Dallaglio, G.; et al. Paclitaxel-Coated Versus Sirolimus-Coated Eluting Balloons for Percutaneous Coronary Interventions: Pharmacodynamic Properties, Clinical Evidence, and Future Perspectives. Future Pharmacol. 2024, 4, 775-787. https://doi.org/10.3390/futurepharmacol4040041

AMA Style

Gurgoglione FL, De Gregorio M, Benatti G, Donelli D, Vignali L, Solinas E, Tadonio I, Denegri A, Covani M, Dallaglio G, et al. Paclitaxel-Coated Versus Sirolimus-Coated Eluting Balloons for Percutaneous Coronary Interventions: Pharmacodynamic Properties, Clinical Evidence, and Future Perspectives. Future Pharmacology. 2024; 4(4):775-787. https://doi.org/10.3390/futurepharmacol4040041

Chicago/Turabian Style

Gurgoglione, Filippo Luca, Mattia De Gregorio, Giorgio Benatti, Davide Donelli, Luigi Vignali, Emilia Solinas, Iacopo Tadonio, Andrea Denegri, Marco Covani, Gabriella Dallaglio, and et al. 2024. "Paclitaxel-Coated Versus Sirolimus-Coated Eluting Balloons for Percutaneous Coronary Interventions: Pharmacodynamic Properties, Clinical Evidence, and Future Perspectives" Future Pharmacology 4, no. 4: 775-787. https://doi.org/10.3390/futurepharmacol4040041

APA Style

Gurgoglione, F. L., De Gregorio, M., Benatti, G., Donelli, D., Vignali, L., Solinas, E., Tadonio, I., Denegri, A., Covani, M., Dallaglio, G., Cortese, B., & Niccoli, G. (2024). Paclitaxel-Coated Versus Sirolimus-Coated Eluting Balloons for Percutaneous Coronary Interventions: Pharmacodynamic Properties, Clinical Evidence, and Future Perspectives. Future Pharmacology, 4(4), 775-787. https://doi.org/10.3390/futurepharmacol4040041

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