Drug-eluting Balloon Research Articles

Drug-eluting Balloon Angioplasty Versus Uncoated Balloon Angioplasty For Peripheral Arterial Disease of the Lower Limbs: A Cochrane Systematic Review Update

Drug-eluting Balloon Angioplasty Versus Uncoated Balloon Angioplasty For Peripheral Arterial Disease of the Lower Limbs: A Cochrane Systematic Review Update

Comparisons of drug-eluting balloon versus drug-eluting stent for the treatment of cancer patients presenting with acute myocardial infarction

BackgroundTreatment for cancer patients presenting with acute myocardial infarction (AMI) remains challenging. The objective of the study was to investigate the safety and efficiency of drug eluting balloon (DEB) versus drug eluting stent (DES) in this high-risk group.MethodsBetween 1st January 2017 and 1st January 2022, cancer patients admitted to Beijing Chaoyang Hospital with AMI were retrospectively enrolled. The primary endpoint was major adverse cardiovascular event (MACE). The secondary endpoints included major bleeding events, heart failure and cardiac complications.ResultsA total of 164 cancer patients presenting with AMI were included in the final analysis. Patients treated with DEB had a numerically lower rate of MACE than those treated with DES during a median follow-up of 21.8 months (22.9% vs. 37.1%, p = 0.23). Patients treated with DEB had a trend towards lower rate of major bleeding events than patients treated with DES (6.3% vs. 18.1%, HR 2.96, 95% CI [0.88, 9.92], p = 0.08). There were no significant differences between the two groups with regards to the rate of heart failure (4.2% vs. 9.5%, p = 0.32) and cardiac complications (0.0% vs. 2.6%, p = 0.56).ConclusionsThe present study demonstrated that in cancer patients with AMI, DEB had a trend towards lower rate of major bleeding events and a numerically lower rate of MACE compared with DES.Graphical

Treatment of In-stent Restenosis of the Internal Carotid Artery Using Drug-eluting Balloons.

In-stent restenosis (ISR) following internal carotid artery (ICA) stenting is relatively common with an estimated incidence of 5%. Treatment options include repeat angioplasty with conventional or drug-eluting balloons (DEB), repeat stent angioplasty and surgical intervention. Application of DEB in ISR of the coronary and peripheral arteries is an established method; however, data on DEB treatment of ICA ISR are sparse. In this work, results from aretrospective cohort of 45patients harboring 46ICA ISR lesions treated with DEB angioplasty are presented. Clinical, procedural and imaging data from DEB angioplasty treatment of 46high-grade ICA ISR lesions in 45patients, performed between 2013 and 2021 were collected. Asingle type of DEB (Elutax, Aachen Resonance, Aachen, Germany) was used in all procedures. Imaging follow-up was performed by regular Doppler ultrasound (DUS), verified by computed tomography angiography (CTA) in cases suspicious for arecurrent ISR. Technical success was 100%. Intraprocedural and postprocedural complications were not encountered. Clinical follow-up was obtained in all patients. Recurrent stroke in the affected territory was not encountered. Arecurrent ISR following DEB treatment was confirmed by DUS and CTA in 4/46(8.7%) of the lesions and were retreated with DEB. Athird recurrent ISR occurred in asingle case (2%) and following asecond DEB retreatment there were no signs of afourth recurrence after 36months follow-up. The use of DEB angioplasty is asafe and effective treatment of ICA ISR lesions, yielding significantly better results compared to other modalities. Randomized multicenter studies are warranted.

First-in-Human Drug-Eluting Balloon Treatment of Vulnerable Lipid-Rich Plaques: Rationale and Design of the DEBuT-LRP Study.

Patients with non-obstructive lipid-rich plaques (LRPs) on combined intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) are at high risk for future events. Local pre-emptive percutaneous treatment of LRPs with a paclitaxel-eluting drug-coated balloon (PE-DCB) may be a novel therapeutic strategy to prevent future adverse coronary events without leaving behind permanent coronary implants. In this pilot study, we aim to investigate the safety and feasibility of pre-emptive treatment with a PE-DCB of non-culprit non-obstructive LRPs by evaluating the change in maximum lipid core burden in a 4 mm segment (maxLCBImm4) after 9 months of follow up. Therefore, patients with non-ST-segment elevation acute coronary syndrome underwent 3-vessel IVUS-NIRS after treatment of the culprit lesion to identify additional non-obstructive non-culprit LRPs, which were subsequently treated with PE-DCB sized 1:1 to the lumen. We enrolled 45 patients of whom 20 patients (44%) with a non-culprit LRP were treated with PE-DCB. After 9 months, repeat coronary angiography with IVUS-NIRS will be performed. The primary endpoint at 9 months is the change in maxLCBImm4 in PE-DCB-treated LRPs. Secondary endpoints include clinical adverse events and IVUS-derived parameters such as plaque burden and luminal area. Clinical follow-up will continue until 1 year after enrollment. In conclusion, this first-in-human study will investigate the safety and feasibility of targeted pre-emptive PE-DCB treatment of LRPs to promote stabilization of vulnerable coronary plaque at risk for developing future adverse events.

JET+PCB strategy in the treatment of superficial femoral artery occlusion: a case report

Сritical limb ischemia (CLI) is becoming more and more common among patients worldwide. This is a comorbid condition, which is accompanied by chronic pain, sometimes trophic ulcers and gangrene, as well as a decrease in the quality of life. Despite the chronic nature of ischemia, the absence of treatment is accompanied by a high incidence of limb amputation and death. Patients with lower limb atherosclerosis had the higher risk of cardiovascular events and death. This publication proposes to consider minimally invasive interventional arterial revascularization in a 63-year-old patient with intermittent claudication, stage III critical limb ischemia, with a history of bilateral superficial femoral artery (SFA) stenting. Control lower limb angiography showed bilateral SFA occlusion and thrombosis. Taking into account the restenosis of the previously implanted stent, JET+PCB strategy was considered: first stage — rotational atherectomy followed by SFA angioplasty with a drug-eluting balloon catheter. The correct choice of minimally invasive surgery method in combination with non-pharmacological (smoking cessation, training walking) and pharmacological methods made it possible to restore viability and preserve the lower limb without negative consequences for the patient's health.

1197 RandomSTOP Vessel Prep Trials – Real Life or Alternative Reality?

Abstract Aim During the last ten years there have been two notable studies within vessel preparation for peripheral vascular disease; the DEFINITIVE AR prospective multi-centre randomised study (evaluating the use of atherectomy prior to drug-eluting balloon catheters (DCB)) and the DISRUPT PAD III randomized control trial (evaluating the use of intravascular lithotripsy (IVL)). This study aimed to analyse a true cohort of vascular patients who underwent vessel prep and whether this reflects those included in the studies. Method Data was collected on patients with SFA disease in 14 countries across 17 centres. We applied the inclusion criteria for the DEFINITIVE AR and DISRUPT PAD III studies to our cohort. Results Data was collected on n = 974 patients who received at least one form of vessel prep. Of these patients, 202 (20.7%) underwent atherectomy and 22 (2.26%) underwent lithotripsy. 50.1% (n = 103) of those who underwent atherectomy would have been eligible to participate in the DEFINITVE AR study. 18% (n = 4) of patients who underwent lithotripsy would have been eligible to participate in the DISRUPT PAD III trial. Conclusions Both the DEFINITIVE AR and DISRUPT PAD III trials have shown promising results however in this large multicentre study we have shown that the study participants reflect only a small percentage of the patients seen within a real vascular ward. We would advise caution when interpreting the results from these studies considering the disparity, we have shown between the study cohorts and the real life vascular population.

Perioperative intravenous Iloprost therapy in addition to percutaneous transluminal angioplasty improves patency for peripheral arterial occlusive disease.

Introduction: In this study, we aimed to evaluate and compare whether perioperative additional intravenous (IV) Iloprost therapy to percutaneous balloon angioplasty for peripheral arterial occlusive disease improves patency and reintervention.Methods: Between January 2018 and August 2020, 183 patients underwent Percutaneous transluminal angioplasty (PTA) with Drug-Eluting Balloons (DEB) for femoropopliteal lesions (TASC 2 A-C) due to claudication, and 161 patients (133 male, 28 female, mean age 63.65 ± 11.16years, range 30-86years) were included in this study. The patients were divided into two groups as DEB+ Intravenous Iloprost administration and DEB alone. Primary patency, reintervention, bailout stenting, and survival rates were analyzed in this retrospective study.Results: Primary patency rate at 12months (79 vs 57 patients, 89.7 vs 78%, p = 0.041) and assisted primary patency rate (81 vs 59 patients, 92 vs 80.8%, p = 0.035) were found to be higher and Bailout stent deployment was lower in DEB + Iloprost group (3 vs 9 patients, 3.4 vs 12.3% p = 0.031). The reinterventions rate at 12months was also lower among the DEB + Iloprost group (9 vs 16 patients, 10.2 vs 21.9%, p = 0.041).Conclusion: The present study demonstrated that primary patency at 12months and assisted primary patency rates, freedom from reintervention was significantly higher and bailout stenting was found to be significantly lower. We believe that perioperative Intravenous Iloprost therapy is beneficial for PTA and improves outcomes.

Registro español de hemodinámica y cardiología intervencionista. XXXII informe oficial de la Asociación de Cardiología Intervencionista de la Sociedad Española de Cardiología (1990-2022)

Introduction and objectivesThis article presents the annual activity report of the Interventional Cardiology Association of the Spanish Society of Cardiology (ACI-SEC) for the year 2022. MethodsAll Spanish centers with catheterization laboratories were invited to participate. Data were collected online and were analyzed by an external company in collaboration with the members of the board of the ACI-SEC. ResultsA total of 111 centers participated. The number of diagnostic studies increased by 4.8% compared with 2021, while that of percutaneous coronary interventions (PCI) remained stable. PCIs on the left main coronary artery increased by 22%. The radial approach continued to be preferred for PCI (94.9%). There was an upsurge in the use of drug-eluting balloons, as well as in intracoronary imaging techniques, which were used in 14.7% of PCIs. The use of pressure wires also increased (6.3% vs 2021) as did plaque modification techniques. Primary PCI continued to grow and was the most frequent treatment (97%) in ST-segment elevation myocardial infarction. Most noncoronary procedures maintained their upward trend, particularly percutaneous aortic valve implantation, atrial appendage closure, mitral/tricuspid edge-to-edge therapy, renal denervation, and percutaneous treatment of pulmonary arterial disease. ConclusionsThe Spanish cardiac catheterization and coronary intervention registry for 2022 reveals a rise in the complexity of coronary disease, along with a notable growth in procedures for valvular and nonvalvular structural heart disease.

Comparison of atherectomy, drug-eluting balloon, and combined treatment efficiency by near infrared spectroscopy

Comparison of atherectomy, drug-eluting balloon, and combined treatment efficiency by near infrared spectroscopy

Endovascular treatment of re-stenotic iliac artery stents with drug-eluting balloons.

To evaluate the results of revascularization of stenotic iliac stents using drug-eluting balloons (DEBs). Seventy-four patients with various levels of iliac stent restenosis were enrolled to study. All restenotic stents were treated using paclitaxel-coated balloons. Through a follow-up median period of 24months (4-24months), there were no in-stent re-restenosis in 55 patients (74.3%) and there was one in class 1 (1.4%), four in class 2 (5.4%), and fourteen in class 3 (18.9%). We conclude that; DEBs can be used for restenotic iliac artery stents for some Type C and D lesions, in addition to Types A and B with satisfacting results.

The Contemporary Indications, Safety, and Outcomes of Drug-Eluting Balloons in Queensland Public Hospitals

The Contemporary Indications, Safety, and Outcomes of Drug-Eluting Balloons in Queensland Public Hospitals

Comparison of 7-Year, Real-World Clinical Outcomes between Drug-Coated Balloon Angioplasty versus Drug-Eluting Stent Implantation in Patients with Drug-Eluting Stent In-Stent Restenosis.

There are no data available comparing the real-world, long-term clinical outcomes of drug-eluting balloon (DEB) angioplasty and drug-eluting stent (DES) implantation in DES in-stent restenosis (ISR) lesions. We aimed to compare the real-world, long-term data available between DEBs and DESs in DES-ISR lesions. We analyzed consecutive DES-ISR lesions (225 lesions from 205 patients; male: 66.3%; mean age: 62.4 years) treated with either DEB or DES. The primary endpoint was target lesion revascularization (TLR), and the primary safety endpoint was the lesion-oriented composite outcome (LOCO). The LOCO is composed of cardiac death, myocardial infarction, and target lesion thrombosis during follow-up. During the 7-year follow-up period, TLR did not differ significantly between the DEB (n = 108) and the DES groups (n = 117) (HR: 1.07; 95% CI: 0.59-1.93, p = 0.83). The LOCO was significantly lower in the DEB group compared to the DES group (HR: 0.40; 95% CI: 0.16-0.98, p = 0.04), which was mainly driven by the lower levels of myocardial infarction (HR: 0.24; 95% CI: 0.06-0.94, p = 0.04) and the absence of target lesion thrombosis in the DEB group (vs. DES group 6%, p = 0.02). Additionally, cardiac death was found to be similar between the DEB and DES groups (HR: 0.56; 95% CI: 0.18-1.75, p = 0.32). DEB angioplasty showed favorable safety with a similar efficacy to that of DES implantation in DES-ISR lesions during the long-term follow-up period.

P308 REAL–WORD MONOCENTRIC EXPERIENCE OF DRUG ELUTING BALLOON PERFORMANCE

Abstract Introduction Recently, drug eluting balloon (DEB) angioplasty has gained increased interested for both in stent restenosis lesions and de novo coronary lesions. Objectives This study aimed to evaluate performance of DEB in a single center real world experience and to assess predictors of outcome after DEB angioplasty. Methods We retrospectively evaluated patients undergoing angioplasty with drug coated balloon in the Cath Lab of Mater Salutis Hospital (Legnago). Clinical and angiographic characteristics of the groups were analyzed. The primary endpoint was a composite of all–cause mortality, any coronary revascularization and acute coronary syndromes assessed as per patients analysis at last available follow–up. Secondary endpoint was evaluation of target lesion failure (TLR) in a per lesion analysis. Results Between January 2018 and September 2022, 99 patients received angioplasty with DEB implantation at the Mater Salutis CathLab, Legnago, accounting for a total of 103 procedures and 112 lesions. Most patients were male (83,8%) and mean age was 66,73±9,5 years. Among 112 lesions treated, 63,4% were in stent restenosis lesions while 36,6% were de novo lesions. DEB used for de novo lesions were significantly smaller than ones used for in stent restenosis (2,23±0,30 mm vs 3,01±0,52 mm; p value<0.001). 19 patients were lost at follow up soon after discharge. Among the 81 patients remaining, with a median of 24 months (IQ1–3 6–37), composite endpoint occurred in 15 patients (18,5%) leading to an overall events–free survival of 81,5%. TLF occurred in 4 out of 99 lesions avalaible at clinical follow–up (4.3%), with a TLF free–survival of 95.7%. In all 4 failure cases, DEB were used for in stent restenosis. Accordingly, TLF free–survival for de novo lesions was 100%. Conclusion In our real–world monocentric experience, patients undergoing DEB angioplasty had good cardiovascular events free survival. Of note, DEB performance proved excellent outcome in de novo coronary artery lesions.

O067 Vessel prep trials – real life or alternative reality?

Abstract Introduction During the last ten years there have been two notable studies within vessel preparation for peripheral vascular disease; the DEFINITIVE AR prospective multi-centre randomised study (evaluating the use of atherectomy prior to drug-eluting balloon catheters (DCB)) and the DISRUPT PAD III randomized control trial (evaluating the use of intravascular lithotripsy (IVL)). This study aimed to analyse a true cohort of vascular patients who underwent vessel prep and whether this reflects those included in the studies. Methods Data were collected on patients with SFA disease in 14 countries across 17 centres. We applied the inclusion criteria for the DEFINITIVE AR and DISRUPT PAD III studies to our cohort. Results Data were collected on n=974 patients who received at least one form of vessel prep. Of these patients, 202 (20.7%) underwent atherectomy and 22 (2.26%) underwent lithotripsy. 50.1% (n=103) of those who underwent atherectomy would have been eligible to participate in the DEFINITVE AR study. 18% (n=4) of patients who underwent lithotripsy would have been eligible to participate in the DISRUPT PAD III trial. Conclusion Both the DEFINITIVE AR and DISRUPT PAD III trials have shown promising results however in this large multicentre study we have shown that the study participants reflect only a small percentage of the patients seen within a real vascular ward. We would advise caution when interpreting the results from these studies considering the disparity we have shown between the study cohorts and the real life vascular population.

Selective NLRP3 Inflammasome Inhibitor MCC950 Suppresses Inflammation and Facilitates Healing in Vascular Materials.

Minimally invasive interventions using drug-eluting stents or balloons are a first-line treatment for certain occlusive cardiovascular diseases, but the major long-term cause of failure is neointimal hyperplasia (NIH). The drugs eluted from these devices are non-specific anti-proliferative drugs, such as paclitaxel (PTX) or sirolimus (SMS), which do not address the underlying inflammation. MCC950 is a selective inhibitor of the NLRP3-inflammasome, which drives sterile inflammation commonly observed in NIH. Additionally, in contrast to broad-spectrum anti-inflammatory drugs, MCC950 does not compromise global immune function due this selective activity. In this study, MCC950 is found to not impact the viability, integrity, or function of human coronary endothelial cells, in contrast to the non-specific anti-proliferative effects of PTX and SMS. Using an in vitro model of NLRP3-mediated inflammation in murine macrophages, MCC950 reduced IL-1β expression, which is a key driver of NIH. In an in vivo mouse model of NIH in vascular grafts, MCC950 significantly enhanced re-endothelialization and reduced NIH compared to PTX or SMS. These findings show the effectiveness of a targeted anti-inflammatory drug-elution strategy with significant implications for cardiovascular device intervention.

Drug-loaded balloon with built-in NIR controlled tip-separable microneedles for long-effective arteriosclerosis treatment

Drug-eluting balloon (DEB) angioplasty has emerged as an effective treatment for cardiovascular and cerebrovascular diseases. However, distal embolism and late lumen restenosis could be caused by drug loss during DEB handling and rapid drug metabolization. Here, a drug-loaded balloon equipped with tip-separable microneedles on the balloon surface (MNDLB) was developed. Inbuilt near-infrared (NIR) ring laser inside the catheter inner shaft was introduced to activate the biodegradable microneedle tips for the first time. The drug-loaded tips thus could be embedded in the vasculature and then released antiproliferative drug - paclitaxel slowly via polymer degradation for more than half a year. A significant increase in drug delivery efficiency and superior therapeutic effectiveness compared with the standard DEB were demonstrated using an atherosclerosis rabbit model.

Structural and temporal dynamics analysis on drug-eluting stents: History, research hotspots and emerging trends.

This review aims to explore the history, research hotspots, and emerging trends of drug-eluting stents(DES)in the last two decades from the perspective of structural and temporal dynamics. Publications on DES were retrieved from WoSCC. The bibliometric tools including CiteSpace and HistCite were used to identify the historical features, the evolution of active topics, and emerging trends on the DES field. In the last 20 years, the field of DES is still in the hot phase and there is a wide range of extensive scientific collaborations. In addition, active topics emerge in different periods, as evidenced by a total of 41 disciplines, 511 keywords, and 1377 papers with citation bursts. Keyword clustering anchored five emerging research subfields, namely #0 dual antiplatelet therapy, #3 drug-coated balloon, #4 bifurcation, 5# rotational atherectomy, and 6# quantitative flow ratio. The keyword alluvial map shows that the most persistent research concepts in this field are thrombosis, restenosis, etc., and the emerging keywords are paclitaxel eluting balloon, coated balloon, drug-eluting balloon, etc. There are 7 recent research subfields anchored by reference clustering, namely #2 dual antiplatelet therapy, #4 drug-coated balloon, #5 peripheral artery disease, #8 fractional flow reserve, #10 bioresorbable vascular scaffold, # 13 intravascular ultrasound, #14 biodegradable polymer. The findings based on the bibliometric studies provide the current status and trends in DES research and may help researchers to identify hot topics and explore new research directions in this field.

Evaluation of safety and efficacy of rapamycin-eluting balloon in patients with intracranial atherosclerotic stenosis: a cohort study

ObjectiveThe safety and efficacy of drug-eluting balloon on the treatment of intracranial atherosclerotic stenosis (ICAS) remain unclear. Here, we present our observation in a cohort study on the safety and efficacy of rapamycin-eluting balloon for patients with ICAS.MethodsA total of 80 ICAS patients with stenosis degree of 70–99% were included. All patients were treated with rapamycin-eluting balloon and were followed up for 12 months after operation.ResultsAll patients were successfully treated, where the mean stenosis severity reduced from 85.1 ± 7.6 to 6 ± 4.9%. 8 patients experienced immediate post-operational complications. Two patients passed away during the first month of the follow-up period. Recurrent ischemic syndrome and angiographic restenosis only appeared 7 days after operation. During later follow-up period, none of the patients had clinical angiographic restenosis or needed target vessel revascularization.ConclusionOur data suggest that intracranial stenting with rapamycin-eluting balloon seems to be safe and effective, although more clinical data are needed to support this notion.

Long-term Outcomes for Drug-eluting Balloons versus Drug-eluting Stents in the Treatment of Small Vessel Coronary Artery Disease: A Systematic Review and Meta-analysis.

Background: This systematic review and meta-analysis compares long-term outcomes follow-up data comparing drug-eluting balloons (DEBs) and drug-eluting stents (DESs) in interventional treatment of small coronary artery disease (<3 mm). Methods: A systematic review was undertaken along with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The primary outcome was 1-3-year performance of DEB versus DES in major adverse cardiac events. Secondary outcomes include all-cause mortality, MI, cardiac death, vessel thrombosis, major bleeding, target vessel revascularisation and target lesion revascularisation. Two independent reviewers extracted data. All outcomes used the Mantel-Haenszel and random effects models. ORs are presented with a 95% CI. Results: Of 4,661 articles, four randomised control trials were included (1,414 patients). DEBs demonstrated reduced rates of non-fatal MI at 1 year (OR 0.44; 95% CI [0.2-0.94]), and BASKET-SMALL 2 reported a significant reduction in 2-year bleeding rates (OR 0.3; 95% CI [0.1-0.91]). There was no significant difference in all other outcomes. Conclusion: Long-term follow-up of DEB and DES use in small coronary arteries demonstrates DEBs be comparable with DESs in all outcomes at 1, 2 and 3 years of follow-up. A significant reduction was found in rates of non-fatal MI at 1 year in the DEB arm, and a reduction in major bleeding episodes at 2 years in the BASKET-SMALL 2 trial. These data highlight the potential long-term utility of novel DEBs in small coronary artery disease revascularisation.

Long-Term Outcome of Drug-Coated Balloon vs Drug-Eluting Stent for Small Coronary Vessels: PICCOLETO-II 3-Year Follow-Up

BackgroundNative vessel coronary artery disease represents 1 of the most attractive fields of application for drug-coated balloons (DCBs). To date, several devices have been compared with drug-eluting stents (DESs) in this setting with different outcomes. ObjectivesThe authors sought to compare the short- and long-term performance of the paclitaxel DCB with the everolimus-eluting stent in patients with de novo lesions in small coronary vessel disease. MethodsPICCOLETO II (Drug Eluting Balloon Efficacy for Small Coronary Vessel Disease Treatment) was an academic, international, investigator-driven, multicenter, open-label randomized clinical trial in which patients were allocated to a DCB (n = 118) or DES (n = 114). We previously reported the superiority of DCBs regarding in-lesion late lumen loss at 6 months. Herein we report the final 3-year clinical follow-up with the occurrence of major adverse cardiac events (MACEs), a composite of cardiac death, nonfatal myocardial infarction, target lesion revascularization, and its individual components. ResultsThe 3-year clinical follow-up (median 1,101 days; IQR: 1,055-1,146 days) was available for 102 patients allocated to DCB and 101 to DES treatment. The cumulative rate of all-cause death (4% vs 3.9%; P = 0.98), cardiac death (1% vs 1.9%; P = 0.56), myocardial infarction (6.9% vs 2%; P = 0.14), and target lesion revascularization (14.8% vs 8.8%; P = 0.18) did not significantly differ between DCBs and DESs. MACEs and acute vessel occlusion occurred more frequently in the DES group (20.8% vs 10.8% [P = 0.046] and 4% vs 0% [P = 0.042], respectively). ConclusionsThe long-term clinical follow-up of the PICCOLETO II randomized clinical trial shows a higher risk of MACEs in patients with de novo lesions in small vessel disease when they are treated with the current-generation DES compared with the new-generation paclitaxel DCB. (Drug Eluting Balloon Efficacy for Small Coronary Vessel Disease Treatment [PICCOLETO II]; NCT03899818)