Magic Touch sirolimus-coated balloon: animal and clinical evidence of a coronary sirolimus drug-coated balloon

Abstract

The Magic Touch sirolimus-coated balloon (SCB) was recently introduced in Europe and features robust clinical technology different from other devices on the market. This device is able to deliver a sufficient sirolimus dose to the target segment to reduce neointimal proliferation with very little exposure downstream and no apparent adverse effects at sustained high drug concentrations. The SCB represents a promising novelty within the drug-coated balloon arena due to its mid-term efficacy and safety in the treatment of coronary artery disease, especially in de novo and small-vessel coronary lesions. The purpose of this article is to provide an up-to-date overview of the currently available animal and clinical trial results, as well as to highlight ongoing trials on the Magic Touch SCB.

Tweetable Abstract

Among modern drug-coated balloons, Magic Touch features Nanolutè technology, which allows effective and rapid sirolimus release and retention for 8–12 weeks. Previous and ongoing trials are showing good clinical performance with sustained safety.

Graphical Abstract

In the EASTBOURNE section of the graphical abstract, the statistical data, including numbers and percentages, were taken from the EASTBOURNE trial [1] to create the graphs.

Plain language summary

Article Highlights.

Background

• The development of drug-coated balloons (DCBs) has improved the management of coronary artery disease (CAD), the leading cause of death worldwide.

• The Magic Touch Sirolimus DCB was recently introduced in Europe and features Nanolutè technology to deliver sirolimus to the vessel wall, ensuring that it is sustained for the duration required to achieve therapeutic effects.

• The objective of this review is to provide an up-to-date overview and summary of the most recent animal and clinical trial data on the Magic Touch sirolimus DCB, as well as to highlight ongoing investigations analyzing the role of this sirolimus-coated balloon (SCB) in various clinical settings.

Pre-clinical & clinical data of Magic Touch SCB

• This article demonstrates that the SCB is a promising novelty within the DCB arena due to its mid-term efficacy and safety in the treatment of CAD, particularly in de novo and small-vessel coronary lesions, at least from the Magic Touch perspective, as the other two SCBs on the market lack clinical evidence.

• In addition, preclinical studies have demonstrated that this device is capable of delivering sirolimus to the target segment in a sufficient amount to reduce neointima proliferation in a vascular model with minimal exposure to downstream organs, with no apparent adverse effects when sustained high drug concentrations in the target vessel are maintained.

Conclusion

• In conclusion, SCBs represent a new option in the treatment of CAD, especially in patients with in-stent restenosis, de novo artery disease, and small coronary arteries, in addition to a few well-known and effective paclitaxel-coated balloons. Currently, ongoing trials will have to clarify the performance of this device compared with drug-eluting stents.

1. Background

Drug-coated balloons (DCBs) represent a relatively novel tool for the management of coronary artery disease (CAD), which is the third leading cause of mortality worldwide with 17.8 million deaths per year. Advances in the treatment of CAD are responsible for a decline in mortality, particularly in the treatment of acute coronary syndrome (ACS) [2,3]. DCBs were developed primarily to address the mid- and long-term adverse events associated with the failure of stents. Their approach is based on rapid and uniform delivery of an antiproliferative drug into the vessel wall after the inflation of a single balloon, without the need for long-term implants [4]. Although the use of DCBs for in-stent restenosis (ISR) of drug-eluting stents (DES) is well established, recent randomized clinical data suggest a favorable efficacy and safety profile in de novo small-vessel disease and in patients at high risk of bleeding. ACS, lesions in patients with diabetes mellitus, and complex patient populations are other emerging indications for DCB angioplasty [4]. Until 2016, all available DCBs in Europe eluted paclitaxel, a drug with inherent advantages but also limitations. In April 2016 the first sirolimus-coated balloon (SCB) received the Conformité Européenne (CE) Mark; this device (Magic Touch, Concept Medical, FL, USA) uses a next-generation delivery technique and is capable of releasing a therapeutic dose of sirolimus in seconds [5]. Notably, the global DCB market size is increasing and it will also be available in the USA soon.

The purpose of this article is to summarize and present the preclinical and clinical trial results of this sirolimus DCB.

2. Overview of DCB technology, specifically Magic Touch

During the past decade, efforts have been made to address concerns associated with previous revascularization techniques, leading to an increase in the clinical use of DCBs for coronary care. The first DCB was developed in the early 2000s and was introduced to the European market in 2007. DCBs are semi-compliant angioplasty balloons coated with an anti-restenosis drug that is released rapidly into the vessel wall upon contact with the balloon. This technology consists of three essential components: a semi-compliant angioplasty balloon, an antiproliferative medication, and a drug carrier. Its purpose is to combine mechanical balloon expansion with biological drug release in the arterial wall without requiring permanent implants. One of the most important aspects of this approach is a rapid and steady delivery of the antiproliferative drug to the vessel wall at the precise moment of balloon inflation, with the persistence of the drug for the following weeks, when neointimal proliferation in response to angioplasty is at its peak [5–7].

The drug is usually released from DCB within 30–60 s. Consequently, the DCB coating must be lipophilic or the drug carrier must possess sufficient adhesive properties to secure the drug to the vessel wall in order for this to occur [8]. Therefore, the theory behind DCB is based on the fact that the release of the drug promotes rapid antiproliferative action to counteract the restenotic process.

DCB offers several advantages over DES:

1. There is no implant of prosthesis into the body of the patient, thus preventing changes to the original anatomical structure of the coronary artery, as well as complications such as late stenting thrombosis and allergies;

2. It provides easier opportunities for subsequent interventional therapies or other surgical treatment in case of failure;

3. DCBs can distribute the drug more evenly on the arterial wall due to the larger contact area, which is different from the uneven distribution of the stent metal rods;

4. The use of DCBs is consistent with a shorter duration of dual antiplatelet therapy (DAPT), thus theoretically reducing the risk of bleeding;

5. For certain types of lesions, such as those long and in small coronary vessels (like in diabetic patients) DES are associated with a high risk of failure [9];

6. DCBs can overcome the limitations of previous techniques such as dissection and vascular recoil.

Dissections remaining after DCBs (type A–B with thrombolysis in myocardial infarction [TIMI] 3 flow) are not associated with any cases of acute or late occlusion. The recoil is counteracted by the antiproliferative effect of DCB, as shown in the angiographic follow-up of many studies [10–12].

The lack of a stent scaffold is one of the primary advantages of DCBs; however, this could also be considered a disadvantage. The acute results are similar to those of percutaneous transluminal angioplasty, with higher elastic recoil, lower acute gain, and a higher incidence of dissections than with a stent platform. Therefore, prior to performing coronary angioplasty with DCB, adequate lesion preparation is required to facilitate DCB delivery, reduce the risk of recoil, facilitate determination of the ideal or true size and length of the lesion, and increase the probability of favorable outcomes [13,14]. According to our experience, semi-compliant balloons that are 1:1 to the distal reference diameter should be used to achieve an effective lesion preparation. However, in more complex or calcified lesions, or in case of a suboptimal result, other specialty balloons (cutting/scoring) or calcium ablative therapies should be considered. Prior to DCB drug delivery, it is usually recommended to achieve <30% residual stenosis with TIMI flow grade 3 and non-flow-limiting dissections. Rotational atherectomy, lithotripsy, or prolonged balloon dilation may be required in severely calcified lesions [7,10,13–16].

All DCB devices have been eluting paclitaxel for over a decade. While the paclitaxel-coated balloon (PCB) has a number of benefits, including favourable binding properties and high lipophilicity that allow for rapid transport and retention at high concentrations, it also has some limitations. The therapeutic window of paclitaxel is limited and its potential for cytotoxicity at higher dosages (>50–80 g/ml or >100 mmol/l) must be carefully considered with multiple balloon usage [17].

The first sirolimus DCB Magic Touch was launched in Europe in 2016. In contrast to paclitaxel, sirolimus is expected to have a stronger cytostatic and immunosuppressive effect and a lower cytotoxic effect due to a wider therapeutic window and safety margin. Because of the potency of sirolimus as an antirestenotic drug, only a low dose is required to achieve a significant antiproliferative effect. Furthermore, this drug slows down the cell cycle through its cytostatic properties. Several in vitro studies have shown that sirolimus inhibits the growth of smooth muscle in the vascular system by half at a relatively low dosage (Table 1) [5,18].

Table 1.

Comparison of sirolimus with paclitaxel (effect of each drug, without specific carrier or technology).

	Sirolimus	Paclitaxel
Therapeutic range	++++	++
Mode of action	Cytostatic	Cytotoxic (at high dosages)
Margin of safety	10,000-fold	100-fold
Tissue absorption	Slow	Fast
Tissue retention	Short	Long
Anti-inflammatory effect	+++	+
Anti-restenotic impact	++++	++++

+: Greater.

The macrolide drug sirolimus, also known as rapamycin, was first identified as an immunosuppressant. Sirolimus is a cytostatic drug that effectively inhibits cell proliferation by combining with the mammalian target of rapamycin and arresting cell cycle progression at the G1- and S-phase junction (Figure 1). Therefore, it can prevent cell division without affecting blood vessels. Due to its immunosuppressive impact through the inhibition of the mammalian target of rapamycin, which is in charge of gene transcription and expression (protein synthesis), it is linked to anti-inflammatory and antiproliferative effects (Figure 2) [19,20].

Figure 1.

Magic Touch sirolimus-coated balloon structure.

Figure 2.

Inhibition of mTOR through the RAPAMYCIN-FKBP-12 complex.

The Magic Touch SCB features a monorail delivery system compatible with 5-Fr guiding catheters. Sirolimus is encapsulated in a protective lipophilic package with NANOLUTE^® technology, which allows the drug to diffuse and penetrate the artery wall during balloon inflation (Figure 2). This technology aims to improve the bioavailability of sirolimus by converting the active drug into submicron particles and encapsulating them in a highly biocompatible carrier phospholipid with two lipophilic tails and one hydrophilic head (Figure 3). Coating methods result in 100% coverage of the balloon surface, allowing for very low drug loss during transport, low particulate content, and improved diffusion of the drug, as well as retention in the artery and penetration into the deep layers of the coronary artery, resulting in improved bioavailability. The total drug dose is 1.25 mg/mm² balloon surface, well within the therapeutic window of sirolimus. According to preclinical studies, only 10% of the drug is lost during transport and about 56% is released when the balloon is first inflated for 40–60 s. The phospholipid component demonstrates excellent overall performance and has received Investigational Device Exemption (IDE) approval from the US FDA [5,20].

Figure 3.

Sirolimus-DCB NANOLUTE technology with specialized spray coating on surface balloon technique.

The use of DCBs for drug-eluting stent-in-stent restenosis (DES-ISR) is well established, according to numerous randomized clinical trials. Habara et al. demonstrated that DCBs provided better clinical and angiographic outcomes at 6-month follow-up compared with percutaneous old balloon angioplasty (BA) alone in patients with DES-ISR [21]. Following that, the efficacy of DCB compared with percutaneous old BA in DES-ISR was confirmed in a multicenter, randomized PEPCAD-DES (Prospective Randomized Trial of a Paclitaxel-Coated Balloon Versus Uncoated Balloon Angioplasty in Patients with Drug-Eluting Stent Restenosis) trial involving patients with any type of DES-ISR (limus or paclitaxel-eluting stents) [22]. In another controlled trial, PEPCAD-China-ISR (a Prospective, Multicenter, Randomized Trial of Paclitaxel-Coated versus Paclitaxel-Eluting Stent for the Treatment of Drug-Eluting Stent In-Stent Restenosis), DCB was found to be equivalent to paclitaxel-DES in patients with DES-ISR after 9 months' follow-up [23]. The larger randomized ISAR-DESIRE 3 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 3) trial also found that DCB was noninferior to paclitaxel-DES and that both DCB and DES were superior to BA alone at 6–8 months [24]. In the RIBS IV (Restenosis Intra-Stent of Drug-Eluting Stents: Drug-Eluting Balloon vs Everolimus-Eluting Stent) trial, both angiographic and clinical outcomes favored second-generation DES over DCB at 6–9 months' follow-up [25]. The efficacy of DCB was improved further in the recently published ISAR DESIRE 4 (Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug-Eluting Stent In-Stent Restenosis 4) randomized trial by optimal lesion preparation using scoring/cutting balloons. Scoring balloon predilation was shown to have significantly lower primary end point rates (diameter stenosis [DS]: 35.0 ± 16.8% vs 40.4 ± 21.4%; p = 0.047) and binary angiographic restenosis rates (18.5% vs 32.0%; p = 0.026) than conventional treatment [26]. Regarding bare-metal stent (BMS) ISR lesion treatment, the PACCOCATH ISR-I (Treatment of In-Stent Restenosis by Paclitaxel Coated PTCA Balloons) trial demonstrated for the first time that DCB was superior to BA alone, with significantly improved angiographic and major adverse cardiovascular events (MACE) results [27]. In the larger PEPCAD II (Paclitaxel-Eluting PTCA-Balloon Catheter in Coronary Artery Disease II) trial, DCB significantly reduced the primary endpoint compared with paclitaxel-DES treatment in BMS-ISR at 6 months' follow-up (late lumen loss [LLL]: 0.17 ± 0.42 mm in DCB vs 0.38 ± 0.61 mm in DES; p = 0.03) [28].

Recent randomized clinical data also suggest a favorable efficacy and safety profile in de novo small-vessel disease in patients at high risk of bleeding, and in native coronary vessels. In recent years, the use of DCBs in native vessel disease, including small CAD, has increased, as evidenced by numerous clinical trials. The BELLO (Balloon Elution and Late Loss Optimization) trial (2012) showed that MACE rates were reduced with the paclitaxel-coated In.Pact balloon compared with a first-generation DES (Taxus) after 3 years of follow-up, and angiographic results were improved [29]. The BASKET-SMALL 2 (Basel Kosten Effektivitäts Trial-DCBs versus Drug-eluting Stents in Small Vessel Interventions 2) trial also showed noninferiority of DCB in terms of MACE at 12 and 36 months [30]. In the recent PICCOLETO II (Drug Eluting Balloon Efficacy for Small Coronary Vessel Disease Treatment) trial with the aim of comparing Xience DES and Elutax SV, the latter showed superior LLL (0.04 vs 0.17 mm; p = 0.001) and no difference in MACE at 12 months (5.6% vs 7.5%; p = 0.55) [31]. Notably, the TRANSFORM II trial (ClinicalTrials.gov Identifier: NCT04893291), an international randomized controlled trial (RCT), is currently enrolling patients with native vessel disease (between 2.0 and 30 mm diameter), and will compare SCB with current-generation DES with a primary endpoint of target lesion failure (TLF) at 1 year where the noninferiority versus SCB is hypothesized [32].

Presently, the use of a DCB in the treatment of ISR including both BMS-ISR and DES-ISR lesions carries a class I recommendation (level of evidence A) in guidelines from the European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) [33], while its application in a broader range of lesions or in patients with obstructive CAD may be hastened by its potential expansion for larger vessels (4.0 mm).

3. Insights from preclinical studies of Magic Touch

The aim of the first studies performed in animal models was to deeply investigate drug transfer efficiency, drug loss, safety, and bioavailability. After the administration of Magic Touch DCB to the vessels of a porcine animal model, variations in the duration of drug delivery and concentration over a period of up to 120 days were analyzed. After treatment of swine ilio-femoral vessels, the initial blood dose of the drug was approximately 15 and 27 ng/ml after 5 min; levels then dropped to 13 ng/ml after 1 h. A second peak occurred after 3 h (16 ng/ml) and dropped to almost zero within 24 h (Figure 4).

Figure 4.

Sirolimus levels in blood after Magic Touch application in a swine ilio-femoral segment (unpublished data, 2023).

Regarding drug concentration in the ilio-femoral target segment, the authors found that it increases to the highest value after 1 h (=1200 ng/g), then decreases to about 700 ng/g within 24 h, then decreases to 400 ng/mg within 3 days, then gradually decreases and remains at this level for about 60 days, and then remains detectable for up to 120 days (Figure 5).

Figure 5.

Sirolimus bioavailability and retention at the ilio-femoral segment over time after Magic Touch application (swine animal model, unpublished data, 2023).

This study concluded that Magic Touch SCB is able to deliver a sufficient dose to the target segment to reduce neointimal proliferation in the vascular model, with very low exposure of downstream structures comprising the lungs, and no apparent adverse effects at sustained high drug concentrations in the target vessel. The drug-eluting properties are the key to these findings. The highly potent anti-restenotic sirolimus is encapsulated in a protective lipophilic package using NANOLUTE^® technology, which enables uniform and rapid diffusion of the drug in the arterial wall when the balloon is inflated. This technology aims to improve the bioavailability of sirolimus by converting the active drug into submicron particles and encapsulating it in a highly biocompatible carrier phospholipid with two lipophilic tails and a hydrophilic head. This enables very low loss of the drug during transportation, low particulate content, and improved diffusion of the drug, as well as retention in the artery and penetration into the deep layers of the coronary artery [34].

4. Clinical data of Magic Touch SCB

4.1. FASICO study

The Fatebenefratelli Sirolimus Coated-Balloon (FASICO) is a prospective all-comer registry of the first consecutive 32 European patients (34 lesions) treated with SCB. A total of 11 patients (35%) had diabetes mellitus and 26 patients (83%) were male. Notably, SCB was used in half of the cases to treat ISR (16 patients), mainly DES restenosis (12 patients). The mean reference vessel diameter was 2.69 mm (standard deviation [SD]: 0.54 mm) and the mean lesion length was 18.58 mm (SD: 8.44 mm). The purpose of the study was to demonstrate the acute performance and 6-month safety and efficacy of this device in a real-world population. In the study, the primary endpoint of procedural success, defined as a final stenosis diameter <50% with TIMI flow 3 and the absence of adverse events during hospitalization, was achieved in 100% of cases without in-hospital complications, with three cases of target lesion revascularization (TLR; all occurring in ISR lesions) and no death or myocardial infarction after 6 months (Table 2).

Table 2.

Summary of the real-world clinical evidence of Magic Touch sirolimus-coated balloons.

Study	Design	n	DCB type	Comp arator	Aim	Primary study endpoint	Secondary study endpoints	Angiographic follow-up	MACE	TLR	Ref.
FASICO	All-comer registry	32	SCB	–	Demonstrate the acute performance and 6-month safety and efficacy of this device in a real-world population	Procedural success, absence of MACE during hospitalization, and 6-month follow-up	Cardiac death, all-cause death, MI, TLR	–	3M (9.4%)	3M (9.4%)	[33]
FASICO NATIVES	All-comer, investigator driven, prospective registry	27	SCB	–	Assess the SCB angiographic performance in patients with de novo coronary disease	LLL at 6 months' follow-up angiography	Binary restenosis	Mean percent diameter stenosis 31.01 ± 17.8, LLL 0.09 ± 0.34 mm	–	–	[34]
SIRPAC*	Comparison of two studies by propensity matching	1090	Magic Touch SCB	ELUTAX SV PCB	Compare indirectly, through propensity score-based matching, the clinical outcomes of 2 studies on SCB-EASTBOURNE and PCB-DCB RISE study	MACE, TLR	Cardiac death, all-cause death, MI, TLR, bleedings	–	10.7% (for EASTBOURNE) vs 10.3% (for DCB RISE) (p = 0.892)	8.3% (for EASTBOURNE) vs 7.9% (for DCB RISE) (p = 0.879)	[35]
NANOLUTE	Prospective, multicenter clinical registry	332	SCB	–	Demonstrate the acute performance and 24-month safety and efficacy of this device in a real-world population	DOCE at 12 months	TLR, cardiac mortality, and target-vessel myocardial infarction	–	4.2%	3.6%	[36,37]
EASTBOURNE**	Prospective, multicenter, investigator-led clinical study	2123	SCB	–	To evaluate the safety and efficacy of this device in real-world patients with coronary artery disease (de novo and ISR)	TLR	MACE and its determinants; bleedings	–	9.9%	5.9%	[38]
TRANSFORM I	Prospective, multicentre, mechanistic, randomized trial	121	Magic Touch SCB	SeQuent Please Neo PCB	To compare angiographic outcomes at 6-months following treatment of de novo SVD with PCB or SCB	Net lumen gain at 6 months	Percent diameter stenosis; LLL	NLG: 0.26 mm, SD 0.40 vs. 0.48 mm, SD:0.38 (P non-inferiority = 0.150)	–	–	[39]
TRANSFORM II (ongoing trial)**	Prospective, randomized, open-label, investigator-initiated, multicenter, clinical trial	1820	Magic Touch SCB	EES	To compare the clinical outcomes in the treatment of native coronary vessels with a 2–3.5 mm diameter between this device and DES	Target lesion failure co-primary endpoint: net adverse cardiovascular events	All determinants of TLF and NACE; TLF and NACE during the 5-year follow up	–	–	–	[30]

DCB: Drug-coated balloon; DOCE: Device-oriented composite endpoints; EES: Everolimus-eluting stent; LLL: Late luminal loss; MACE: Major adverse cardiac events; MI: Myocardial infarction; MLD: Minimal lumen diameter; NACE: Net adverse clinical event; NLG: Net lumen gain; PCB: Paclitaxel-coated balloon; SCB: Sirolimus-coated balloon; SD: Standard deviation; TLF: Target lesion failure; TLR: Target lesion revascularization.

This study has some evident limitations, including the small sample size. However, it is important to emphasize the significance of this initial preliminary research in a real-world, complex population with a novel device that is the first sirolimus-eluting device approved for human use in Europe.

In conclusion, the authors demonstrated that the SCB is an effective alternative to the currently used DCB, with excellent immediate technical performance and acceptable efficacy and safety at short-term follow-up in a real world, complex population [35].

4.2. FASICO NATIVES study

The FASICO NATIVES study aimed to assess core laboratory-assessed angiographic performance in patients with de novo coronary lesions from April 2016 to May 2017. The authors of this investigator-driven study enrolled 27 patients with an average lesion length of 20.52 ± 6.88 mm and a reference mean DS of 67.64 ± 11.78%. The primary endpoint was LLL, defined as the difference in minimal lumen diameter (MLD) between the immediate post-percutaneous coronary intervention (PCI) result and the result at 6 months' follow-up angiography.

At the angiographic follow-up the mean percent DS was 31.01 ± 17.85%. In comparison to the immediate results of the index operations, LLL was 0.09 ± 0.34 mm, the mean MLD was 1.68 ± 0.48 mm, and mean percent DS was 25.86 ± 14.31% (Figure 6). The results of this prospective study, in which consecutive patients with small CAD (mean reference vessel diameter: 2.32 mm) were treated with SCB, showed that this treatment was effective in maintaining good arterial patency at mid-term angiographic follow-up, with interesting performance regarding late lumen gain (Table 2) [36].

Figure 6.

Graphical demonstration of the FASICO NATIVES results (MOD***: FASICO NATIVES registry).

Reproduced with permission from [36].

4.3. SIRPAC study

Awaiting more robust data about the performance of this SCB, the SIRPAC (SIRolimus-PAClitaxel) study aimed to compare indirectly, through propensity score-based matching, the clinical outcomes of two separate studies: the EASTBOURNE registry, a prospective, all-comer registry on Magic Touch (at the time of this study only interim analysis data were available) and the DCB RISE study, a registry on the efficacy and safety of ELUTAX SV (a PCB by AR Baltic, Lithuania). Of the 1090 patients analyzed, 494 came from DCB RISE and 596 from EASTBOURNE. After propensity score matching, 290 from each group were analyzed for the 12-month clinical outcome. Small-vessel lesions (<2.5 mm) were more frequent in the EASTBOURNE study (n = 330; 55%) in comparison to the DCB RISE study (n = 204; 41%; p < 0.001), while in-stent restenosis was more frequent in the DCB RISE study (n = 281, 57% vs n = 274, 46%; p < 0.001).

Primary endpoint MACEs were similar between the groups (10.7 vs 10.3%, respectively; p = 0.892); TLR occurred in a similar number of patients as well (8.3 vs 7.9%, respectively; p = 0.879), showing no significant differences between the two studies, which included a broad population of patients with native coronary vessel disease and ISR. Additionally, there was no statistically significant difference regarding myocardial infarction (MI) and mortality, which occurred in 2.1% in DCB RISE and 1.7% in EASTBOURNE (p = 0.737; Figure 7). The SIRPAC study authors came to the conclusion that SCB and PCB had similar therapeutic effects; nevertheless, larger prospective and randomized studies were required to support these findings (Table 2) [37].

Figure 7.

SIRPAC study outcome***.

MACE: Major adverse cardiac events; TLR: Target lesion revascularization.

***MOD in figure legends refers to using solely numbers and percentages from the reference to create the graph.

Reproduced with permission from [37].

4.4. NANOLUTE’ REGISTRY-Clinical outcomes at 12 and 24 months' follow-up

The Nanoluté registry is a prospective, multicenter clinical registry comprising a real-world, all-comer patient population from multiple interventional cardiology centers in India. The aim of this registry was to monitor the clinical performance of SCB for the treatment of de novo and restenotic coronary lesions. Between July 2012 and September 2015, a total of 332 patients with 356 lesions were enrolled. Patients received 394 SCBs and were clinically monitored after 12 months. Of the patients enrolled, 154 (46.4%) had a history of diabetes while 143 (43.1%) had small-vessel disease (diameter <2.75 mm) and 153 (46.1%) had ISR. The average lesion diameter was 2.7 ± 0.4 mm, while the lesion length was 22.3 ± 7.1 mm. The mean balloon length and diameter were 21.83 ± 6.70 mm and 2.69 ± 0.45 mm, respectively. The primary endpoints were procedural success and device-oriented composite end points (DOCE), defined as the composite of TLR, cardiac mortality, and target-vessel myocardial infarction at 12 months. The primary endpoint of the study was met in 331 (99.7%) patients. The overall DOCE rate was 4.2% (n = 14), including death 0.3% (n = 1), TLR 3.6% (n = 12), and MI 0.3% (n = 1) (Table 2) [38].

All patients with a 24-month follow-up were included in this further analysis of the Nanolutè registry. The overall MACE rate occurred in 17 patients (4.2%), with 13 TLR (3.2%), 1 MI (0.2%), and 3 cardiac deaths (0.7%). This updated follow-up in an Indian population showed the persistence of a good safety and efficacy profile of the device, despite the lack of clinical monitoring and central adjudication of events, centralized events committee (CEC) being major limitations [1].

4.5. EASTBOURNE study

EASTBOURNE (All-Comers Sirolimus-Coated Balloon European Registry) is a prospective, multicenter, investigator-led clinical study that enrolled 2123 real-world patients (2440 lesions) treated with SCB at 38 study sites in Europe and Asia between September 2016 and November 2020. This is the largest prospective clinical study on DCB so far. The mean age of the patients was 66.6 ± 11.3 years and 41.5% had diabetes mellitus. Lesions treated included de novo small-vessel lesions (56%) and ISR (44%). The reference vessel diameter was 2.62 ± 0.58 mm and the lesion length was 18.76 ± 9.14 mm. The recommended inflation time was 60 s, with a minimum of 30 s. Lesion preparation, despite being mandated in the protocol, was only performed in 91.6% of the lesions, slightly more in ISR patients (94.9% vs 88.9%; p = 0.001). Notably, there was a significantly low rate of bailout stenting (7.7%) either due to flow-limiting dissection or acute vessel recoil: 8.7% in de novo and 6.5% in ISR lesions (p = 0.059). Procedural success occurred in 97.6% of the cases.

At 12-month follow-up, the primary endpoint TLR occurred in 5.9% (n = 127) of lesions without thrombotic occlusions; TLR was more common in patients with ISR than in patients with native vessel disease (10.5 vs 2.0%; RR: 1.90; 95% CI: 1.13–3.19) and MACE was observed in 9.9% of cases (4.9% in the de novo, and 14.9% in the ISR group; p < 0.001). Spontaneous MI occurred in 2.4% of patients, all-cause mortality in 2.5%, cardiac death in 1.5%, and Bleeding Academic Research Consortium (BARC) category 3 or 5 bleeding in 0.7% (Figure 8 & Table 2) [39].

Figure 8.

EASTBOURNE registry clinical outcome at 1-year follow-up, ISR, and de novo population (MOD***: [39]).

ISR: In-stent restenosis; MACE: Major adverse cardiac events; MI: Myocardial infarction; TLR: Target lesion revascularization.

***MOD in figure legends refers to using solely numbers and percentages from the reference to create the graph.

According to the results of the multivariate Cox regression model, ISR and reference vessel diameter were the main determinants for the occurrence of the primary endpoint TLR within 12 months. In conclusion, this was the largest DCB study in CAD and demonstrated that this SCB was safe and effective at a mid-term follow-up in a broad spectrum of CAD patients.

The 2-year outcome of the EASTBOURNE registry was presented in 2023 (B Cortese et al., EuroPCR 2023 [40]).

4.6. TRANSFORM I study

The objective behind the TRANSFORM I (Treatment of Small Coronary Vessels: Magic Touch Sirolimus Coated Balloon) trial was to compare the angiographic performance of Magic Touch SCB compared with SeQuent Please Neo PCB in patients undergoing treatment for de novo small-vessel CADs (<2.75 mm). This study is an industry-sponsored, 1:1 randomized, mechanistic, clinical trial that expected noninferiority of SCB in terms of angiographic net lumen gain compared with Sequent Please PCB (baseline MLD and 6-month MLD). A total of 114 patients received lesion preparation with semi- or noncompliant balloons, and in case of absence of flow-limiting dissection and TIMI 3 flow underwent optical coherence tomography analysis to guide correct device size selection. At 6 months follow-up, Magic Touch failed to demonstrate noninferiority in terms of core-laboratory angiographic net lumen gain (0.26 mm, SD 0.40 vs 0.48 mm, SD 0.38), because the 0.30-mm criterion for noninferiority was not met (p noninferiority = 0.150). Similarly, PCB achieved a smaller late luminal loss (0.01 mm, SD 0.31 vs 0.32 mm, SD 0.48; p < 0.001) and a greater late lumen enlargement (51.9% vs 29.3%; odds ratio: 2.60; 95% CI: 1.21 to 5.74; p = 0.016) (Table 2). This mechanistic study did not show any relevant clinical differences at the 1-year follow-up between the two devices [41,42].

4.7. TRANSFORM II RCT (ongoing clinical trial)

Another pivotal study on the Magic Touch SCB is the TRANSFORM II trial. Thus far, the only limitations are information on the performance of a DCB versus DES, currently the gold standard treatment of an all-comer native vessel disease population. This lack of clinical data along with the ‘leave nothing behind’ concept inspired the TRANSFORM II trial. This study is an investigator-initiated, multicenter, noninferiority, randomized clinical trial comparing clinical outcomes in the treatment of native coronary vessels with a 2–3.5-mm diameter between the Magic Touch SCB or everolimus-eluting stent. The primary endpoint is target-lesion failure (a composite of cardiac death, target vessel MI, and TLR) over the course of a 12-month follow-up and the co-primary endpoint is net adverse cardiovascular events (including BARC types 3–5 bleedings) (Table 2). This trial, with a dedicated data safety monitoring board and an independent and blinded central events committee, is expecting noninferiority between the two treatment arms in terms of TLF, with hypothetical superiority of the DCB with regard to net adverse clinical events and TLF during the 5-year follow up, according to the information from other trials with long-term follow-up after DCB angioplasty [43]. The TRANSFORM II trial is actively recruiting patients from Europe, Asia, and America, and is expected to complete enrollment of the 1820 patients by 2025 [32].

5. Bleeding risk & DAPT duration post-DCB

The absence of metallic components in DCB may provide advantages in high bleeding risk (HBR) patients, allowing for shorter DAPT or, in cases of life-threatening bleeding, the ability to discontinue antiplatelet therapy at any point during therapy. A recent prespecified subgroup analysis of BASKET-SMALL 2 aimed to assess the effect of DCB versus DES between patients with and without HBR treated with PCI in small coronary arteries (<3 mm). In this multicenter, randomized, noninferiority trial, 758 patients with de novo lesions in coronary vessels and an indication for PCI were randomly assigned to DCB (n = 382) or second-generation DES (n = 376). The rates of major bleeding events (BARC type 3–5 bleeding) after DCB were significantly lower compared with DES (1.6% vs 3.7%; p = 0.064) and were similar in patients with HBR (4.5% vs 3.4%) but less frequent in DCB-versus DES-treated patients without HBR (0.9% vs 3.8%). As a consequence, investigators concluded that at 3 years follow-up, there was a trend toward a reduction of severe bleeding events in patients treated with DCBs [44].

The current consensus for DAPT duration after DCB-only PCI in stable CAD patients is 4 weeks, for both in-stent restenosis and de novo lesions. Initially, the German Consensus Group recommended the necessary DAPT duration of 4 weeks if the DCB is used alone and 6–12 months if combined with a BMS [45]. For bifurcation lesion treatment, the recommended duration of DAPT is 4 weeks if the DCB is used alone without stenting and 6–12 months if stents are used either before or after the DCB procedure. In addition, the recommended duration of DAPT for ACS is 12 months, regardless of whether a BMS, DES, or DCB is used [46]. Similarly, Cortese et al. from the Italian Position Group recommended a DAPT duration of at least 1 month in the case of DCB-only treatment and 3 months in the case of BMS implantation [7]. The European Society of Cardiology Guidelines on DAPT, on the other hand, recommended that a DAPT duration of 6 months should be considered in patients with stable CAD treated with DCB, and a 3-month duration should be considered in patients with stable CAD who are at high risk of bleeding. Notably, in patients with stable CAD, DAPT for 1 month may be considered if 3-month DAPT poses safety concerns [47]. The Asia-Pacific Consensus Group recently updated the DCB treatment protocols for CAD with the recommendation of DAPT duration for at least 3–6 months in cases of de novo stable coronary disease with DCB plus bail-out BMS and in cases of the DCB-only approach without stenting in treating bifurcation disease. In addition, a minimum of 6–12 months is advised for DAPT duration when using the DCB method in combination with stenting. Comparable to other guidelines, DAPT is advised for a minimum of 12 months in patients with ACS, irrespective of whether BMS, DCB, or DES are used [48,49]. Moreover, the current ESC guidelines for patients with stable coronary disease who are not at high risk of bleeding and are treated with DCB recommend 6 months of DAPT with a class IA recommendation and an additional 6 months of DAPT (aspirin and clopidogrel) with a class IIb A recommendation. For patients at a high risk of bleeding treated with DCB, a 1-month duration of DAPT has a class IIb C recommendation, with 3 months of DAPT duration having a class IIa B recommendation [50].

6. Regulatory affairs

Up to now, SCBs have been used in several European and Asian countries, with three of them having obtained the CE mark and begun commercial distribution: Magic Touch (2016), Selution (Medalliance, Switzerland, 2020) and Sequent Sirolimus (BBraun, Germany, 2022). On May 24, 2023, the FDA awarded Concept Medical's Magic Touch with IDE approval for a clinical trial investigating this SCB for the treatment of native coronary small vessels. With the previous three IDEs, the third one being issued on April 25 2023, by the FDA [51], the company's SCB now holds four IDE approvals in total [52], including coronary ISR and peripheral artery disease management. Thus far, no coronary DCB is currently approved for commercial use in the USA.

7. Conclusion

SCBs represent a promising novelty within the DCB arena thanks to a good amount of mid-term clinical data showing adequate efficacy and safety in treating CAD. Nanocapsule technology allows sirolimus to be effectively and quickly delivered to the vessel wall and retained there for the duration that is optimal for therapeutic action (the first 8–12 weeks after angioplasty). In addition to a few well-known and effective PCBs, this SCB represents a novel, interesting therapeutic alternative for our CAD patients, with reduced angiographic performance compared with PCBs, but with good clinical outcomes. Currently, ongoing trials will have to clarify the performance of this device compared with DESs.

Financial disclosure

B Cortese serves as an Advisory Board member for Concept Medical and ANT, and as a Consultant for Concept Medical, ANT, Medtronic, Medalliance, Cordis, BBraun, Innova HTS, and AR Baltic. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.