Percutaneous Coronary Intervention With the Agent Paclitaxel-Coated Balloon: A Real-World Multicenter Experience

Abstract: Background. The Agent paclitaxel-coated balloon is a new drug-coated balloon (DCB) with few available real-world data. Our study sought to assess the safety and efficacy of the Agent DCB during percutaneous coronary intervention (PCI) in different coronary lesion types in a prospective registry. Methods and Results. All patients undergoing PCI with the Agent DCB at three Italian centers between September 2014 and March 2018 were included in this registry. Major adverse cardiac event (MACE) rate was defined as the composite of cardiac death, recurrent non-fatal myocardial infarction (MI) ,and target-lesion revascularization (TLR). Procedural success was also evaluated. Among the 354 patients included in the registry (450 lesions treated with 508 DCBs), Agent DCBs were used for the treatment of in-stent restenosis (ISR) in 34%, small-vessel disease (SVD) in 29%, bifurcation lesions in 26%, and “stent-like result” (SLR) lesions obtained after balloon predilation in 11%. The implantation of Agent DCBs was safe and had a high DCB lesion success rate of 92%. One-year MACE rate was 5.7% in the overall population. A higher MACE rate was observed in the ISR group (8.3%) vs the SVD group (3.6%; P=.03), with a trend toward higher event rates vs both BL (3.7%; P=.09) and SLR patients (5.5%; P=.54). Conclusions. The use of Agent DCBs during PCI appears safe and effective in a large real-world registry. These results were maintained in all subgroups, with a slightly higher trend of events rates in the ISR setting, consistent with the higher-risk nature of this patient subset.

Key words: drug-coated balloons, multicenter registry, paclitaxel-coated balloons, percutaneous coronary intervention  

New-generation drug-eluting stent (DES) implantation represents the current approach for the percutaneous treatment of coronary artery disease. Despite the favorable long-term clinical outcomes, the presence of a definitive metallic frame in the vessel wall may confer a non-negligible risk of long-term events in specific anatomic conditions, such as small-vessel disease (SVD) and bifurcation lesions in side branches.¹ Drug-coated balloons (DCBs) have emerged as an effective treatment for in-stent restenosis (ISR) after both bare-metal stent and DES implantation.^2,3 In addition, recent studies showed favorable results when DCBs were used for the treatment of de novo lesions, especially in the setting of SVD and BLs.^4-9 As a class effect cannot be assumed for this therapeutic modality, outcomes research focused on individual DCB designs is needed.²

The Agent DCB catheter (Boston Scientific) is a new device that provides a targeted, therapeutic dose of proven, antiproliferative paclitaxel to the lesion. Based on the bench studies, the main advantages of the Agent DCB are the optimized drug transfer, the good deliverability, and the enhanced coated integrity. There are limited clinical data available for the Agent DCB. The aim of our study was therefore to evaluate, in a large, real-world population, the efficacy and safety of the Agent DCB when utilized in coronary lesions where DCB treatment has shown favorable results, ie, for cases of ISR, SVD, and bifurcation lesions, as well as in “stent-like result” (SLR) lesions obtained after balloon predilation in which DCBs were subsequently inflated. 

Methods

Study design and population. In this prospective multicenter registry, we investigated consecutive patients undergoing percutaneous revascularization of ISR, SVD, bifurcation lesions, and SLR lesions performed after balloon predilation with the Agent DCB in three high-volume Italian centers (Centro Cuore Columbus, Milan, Italy; Valduce Hospital, Como, Italy; and San Raffaele Scientific Institute, Milan, Italy) between September 2014 and March 2018. The prospective Agent DCB registry has been approved by the local ethics committee and all patients provided written informed consent. The present study was conducted in accordance with the Declaration of Helsinki. 

All patients provided informed consent for both the procedure and subsequent data collection and analysis. Interventional approach, intravascular ultrasound use, and administration of glycoprotein IIb/IIIa receptor inhibitors during the procedure were left to the discretion of the operator. As currently recommended, careful lesion preparation was performed prior to DCB use when the operator deemed it necessary. The Agent DCB was then inflated with 1:1 balloon-to-artery ratio using nominal pressure (8 atm) for 60 seconds. Bail-out stenting was undertaken either as part of a hybrid approach incorporating DCB and DES to treat very long disease¹⁰ or to treat a dissection with signs of lumen compromise or reduced flow, or when the residual stenosis was evaluated to be >50%.

Clinical follow-up and definitions. For every study participant, demographic, clinical, and procedural data were prospectively collected into a dedicated database, which included follow-up data. Clinical follow-up was achieved for all subjects by clinic visit or telephone interview. The study endpoints were major adverse cardiac event (MACE) rate, defined as a composite of cardiac death, recurrent non-fatal myocardial infarction (MI), and target-lesion revascularization (TLR). The impact of the type of indication for DCB (ISR, SVD, bifurcation lesion, or SLR) on the outcome was also evaluated. TLR was defined as repeat PCI or coronary artery bypass grafting (CABG) for the lesion in the previously treated segment or within the 5 mm proximal or distal to the stent edge or site of drug-eluting balloon inflation.¹⁰ Coronary ISR was defined as the angiographic detection of a recurrent stenosis with diameter >50% at the stent segment or its 5 mm adjacent segments.¹¹ SVD was defined as reference vessel diameter (RVD) <2.8 mm by visual estimation.⁷ Bifurcation lesion was defined as a lesion occurring at, or adjacent to, a significant division of a major epicardial coronary artery.¹² SLR lesions included those that obtained a stent-like result after balloon predilation in which DCBs were subsequently inflated. DCB lesion success was defined as completion of the procedure with no in-lab complications, final Thrombolysis in Myocardial Infarction (TIMI) flow 3, and residual stenosis <30%.

Quantitative coronary angiographic measurements. Coronary angiograms were analyzed offline using a validated edge-detection system (CMS, version 5.2; Medis Medical Imaging Systems BV). Quantitative coronary analysis measurements were performed at baseline and after device inflation with matched orthogonal views. Minimal luminal diameter, percent diameter stenosis, and RVDs were measured for each treated segment.

Statistical analysis. Categorical variables are presented as counts with percentages and continuous variables are presented as means ± standard deviations or medians with interquartile ranges (IQRs), as appropriate. Cumulative clinical event rates are reported as Kaplan-Meier estimates. Follow-up length for the endpoint occurrence was censored at 1 year. The proportional hazards assumption of the Cox regression model was checked by using time-dependent Cox models. 

Results

Baseline patient characteristics. During the study period, a total of 354 patients with 450 lesions were treated with 540 Agent DCBs. Baseline demographic characteristics are reported in Table 1. Mean age was 71 years and 86% were men. The cardiovascular estimated risk of the cohort was high (36% diabetics, 43% previous MI, 75% previous PCI, and 18% previous CABG). The majority of patients (83% of the elective PCIs) had stable coronary artery disease. 

Angiographic and procedural details. Lesion and procedural characteristics are presented in Table 2. The main indications for DCB treatment were similarly represented (34% ISRs, 29% SVDs, and 26% bifurcation lesions). Fifty lesions (11%) were treated with DCB following “stent-like results” after balloon predilation and comprised the SLR group. Among bifurcation lesions, most were true bifurcations (Medina class 1,1,1 or 1,0,1 or 0,1,1) and the adopted treatment strategy for all patients was provisional stenting (DES implantation in the main branch and DCB inflation in the side branch). Overall, most of the treated lesions were complex (>50% were B2 or C lesions). The balloons adopted for predilation were mainly non-compliant, with a 1:1 diameter ratio compared with RVD. Fifty-seven lesions (13%) were severely calcified, and Angiosculpt, cutting balloon, or Rotablation were performed for adequate lesion preparation. The number of DCBs per lesion was 1.1 ± 0.3. A hybrid approach using a combination of DES and DCB was adopted to treat very long disease in 199 lesions (44.2%). Procedural and clinical outcomes are reported in Table 3. DCB lesion success was obtained in 416 lesions (92%). Bail-out stenting was required in 22 lesions (4.8%) because of residual dissection and residual stenosis >50%. Coronary dissection requiring bail-out stenting was more frequent in the SVD group. Self-limiting minor perforations were observed in 4 lesions (0.6%). No major periprocedural coronary complications were reported.

Clinical follow-up. The median follow-up period was 544 days (IQR, 370-735 days). Kaplan-Meier estimates of clinical outcomes at 1 year are summarized in Table 3 and Figure 1. One-year MACE rate estimate was 5.7%, primarily driven by TLR (4.0%) due to lesion restenosis in most cases. MI occurred in 7 patients (Kaplan-Meier estimate, 3.8%), of which 3 patients had target-lesion related MI (1 lesion restenosis, 1 stent thrombosis in a hybrid approach case, and 1 lesion dissection). 

Higher MACE rate (8.3%), TLR rate (6.0%), and MI rate (3.0%) estimates were observed when the DCB was used to treat ISR as compared with SVD (MACE, 3.6% [P=.03]; TLR, 1.4% [P=.03]; MI, 2.2% [P=.26]), whereas a trend toward higher events rates was observed in the ISR group compared with both bifurcation lesion (MACE, 3.7% [P=.09]; TLR, 3.7% [P=.12]; MI, 0.0% [P=.10]) and SLR (MACE, 5.5% [P=.54]; TLR, 3.3% [P=.32]; MI, 5.5% [P=.60]).

Discussion

 The main findings of this study are: (1) the use of the Agent DCB during PCI according to current clinical practice appears safe and effective in a large real-world experience; and (2) the overall safety and efficacy of the Agent DCB was maintained in all subgroups (ISR, bifurcation lesion, SVD, and SLR), with a slightly higher trend toward more events in the ISR setting, which is consistent with the higher-risk nature of this subset.

The Agent DCB is a paclitaxel-eluting balloon built on the Emerge balloon catheter technology. It is coated with a formulation of 2 μg/mm² paclitaxel and a citrate ester excipient (acetyltributyl citrate) known as TransPax (Boston Scientific). The Agent DCB was designed to offer good deliverability, with an ultra-low profile tip that measures 0.017˝ and the bisegment inner shaft of the Emerge balloon catheter technology, to optimize drug transfer and minimize downstream particulates during the procedure due to the balanced hydrophobic and hydrophilic properties of the TransPax coating. In the Agent ISR non-inferiority randomized controlled study, the Agent DCB was compared with the commercially available SeQuent Please paclitaxel-eluting DCB (B. Braun) in 125 patients undergoing ISR percutaneous treatment (data presented at the 2018 EuroPCR). The Agent DCB met its primary angiographic endpoint of non-inferiority of 6-month in-stent late loss (0.397 ± 0.43 mm for Agent DCB vs 0.393 ± 0.53 mm for SeQuent Please; P_{non-inferiority}=.046), and showed a numerically lower occurrence of 12-month target-lesion failure (9.2% vs 11.7% vs SeQuent Please). 

Our study represents the first large real-world experience of Agent DCB applied in coronary lesions where DCB treatment has previously shown favorable results (ISR, bifurcation lesion, SVD, and SLR lesions obtained after balloon predilation in which DCBs were subsequently inflated). The study population was classified as high cardiovascular risk and the lesions treated were overall complex in nature (>50% were type B2 or C lesions). The Agent DCB was inflated with a 1:1 balloon-to-artery ratio using nominal pressure (8 atm) for 60 seconds after adequate lesion preparation with a non-compliant balloon in the majority of cases. More aggressive lesion preparation with Angiosculpt, cutting balloon, or Rotablation was adopted in 13% of lesions due to severe calcification. Despite high lesion complexity and calcific burden, the procedural outcomes were almost optimal,  with a favorable DCB lesion success rate and no major complications. The clinical events at 1 year were low, with a MACE rate of 5.7%, which was primarily due to TLR (4%) because of coronary restenosis. 

The subgroup with the highest clinical event rate at follow-up was the ISR group (8.3% of MACE), which is in line with the higher TLR-driven event rates reported for this PCI subset in the literature.^2,13 Importantly, the observed MACE occurrence was comparable with the 1-year MACE rate of 9.2% from a similar population with ISR lesions treated with an everolimus-eluting stent,¹⁴ and appeared to be lower as compared with studies where the SeQuent Please DCB was adopted for the treatment of ISR (reported 1-year MACE rates range between 10% and 16%).^15,16 

In the bifurcation lesion subgroup, the treated bifurcations were mainly true bifurcations (84%) and the adopted stent strategy was provisional, with DES implantation in the main branch and DCB in the side branch. The procedural and clinical outcomes at 1 year were optimal (3.7% MACE, all TLR events). Our bifurcation lesion cohort represents the largest cohort described in the literature adopting the provisional DES-DCB strategy, with the lowest reported clinical event rates at follow-up. Previous studies evaluated the efficacy of different DCB platforms in bifurcation lesions either with a different DES-DCB strategy^17,18 (eg, DCBs in both branches or bare-metal stent implantation in the main branch) or with the same strategy but with small patient cohorts.^9,19 

In our de novo lesion subgroups (SVDs and SLRs), the DCB lesion success rate was lower compared with the other subgroups. These results might be due to the aggressive lesion preparation adopted in our cohort of patients, due to the lesion complexity and high calcium burden, which might have caused a higher rate of dissections requiring bail-out stenting. However, in other studies evaluating the efficacy of different DCB platforms in SVD lesions, the bail-out stenting rate ranged from 7% to 36%.^7,20,21 The final lesion success rate and the clinical outcomes at follow-up were as optimal as the other subgroups in the present study.  

Importantly, the use of the Agent DCB was shown to be at least non-inferior in 1-year MACE rate as compared with both other DCB platforms and DES implantation in populations with similar clinical and anatomical characteristics.⁸

Study limitations. Several limitations of this study must be acknowledged. First, our study is a retrospective analysis with all inherent restraints. Accurate index data collection and detailed follow-up were completed in order to obviate this limitation. Second, routine angiographic follow-up was not performed, which may have influenced the timing of TLR. Third, this was a registry study with no control group. Finally, this study did not contain the results of intravascular imaging; therefore, pathophysiologic factors related to ISR (including stent under-expansion) were not examined, which might have been useful in deciding whether or not to use DCBs. In the context of these limitations, the present study describes data from the first real-life registry on the new Agent DCB.

Conclusion

Utilization of the Agent DCB during PCI appears safe and effective in a large real-world experience of patients with coronary lesions where DCB treatment has shown favorable results. 

From the ¹Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy and Division of Cardiology, Laboratory of Interventional Cardiology, Maggiore Hospital, Bologna, Italy; ²Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy and Interventional Cardiology Unit, GVM Care & Research Maria Cecilia Hospital, Cotignola, Italy; ³Università Vita-Salute San Raffaele, Milano, Italy; ⁴Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy and Cardio Center, Humanitas Research Hospital, Rozzano-Milan, Italy; ⁵Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy and Henry Dunant Hospital, Athens, Greece; ⁶Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy; ⁷Interventional Cardiology Unit, GVM Care & Research Maria Cecilia Hospital, Cotignola, Italy and EMO GVM Centro Cuore Columbus, Milan, Italy; and ⁸Cardiology Division, Valduce Hospital, Como, Italy.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Montorfano reports proctor income from Boston Scientific. Dr Durante reports consultant income from Boston Scientific. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted January 15, 2020, accepted January 20, 2020.

Address for correspondence: Alessandro Durante, MD, Cardiology Division, Valduce Hospital, Via Dante Alighieri, 11, 22100 Como CO, Italy. Email: durante.alessandro@gmail.com

1. Hassan AKM, Bergheanu SC, Stijnen T, et al.  Late stent malapposition risk is higher after drug-eluting stent compared with bare-metal stent implantation and associates with late stent thrombosis. Eur Heart J. 2010;31:1172-1180.  
2. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019;40:87-165.  
3. Cortese B, Palma G Di, Nerla R, Micari A. Nuove tecnologie e applicazioni per il pallone medicato nel 2017. G Ital Cardiol 2017;18:22–30.  
4. Rissanen, Uskela, Eränen, Mäntylä, Olli, Romppanen et al. Drug-coated balloon for treatment of de-novo coronary artery lesions in patients with high bleeding risk (DEBUT): a single-blind, randomised, non-inferiority trial. Lancet. 2019;S0140-6736(19):31126–31122. 
5. Venetsanos D, Lawesson S, Panayi G, Tödt T, Berglund U, Swahn E AJ. Long-term efficacy of drug coated balloons compared with new generation drug-eluting stents for the treatment of de novo coronary artery lesions. Catheter Cardiovasc Interv. 2018;92(5):E317–E326. 
6. Giannini F, Latib A, Ancona MB, et al. A propensity score matched comparative study between paclitaxel-coated balloon and everolimus-eluting stents for the treatment of small coronary vessels. Catheter Cardiovasc Interv. 2017;90(3):380–386. 
7. Latib A, Ruparelia N, Menozzi A, et al. 3-Year Follow-Up of the Balloon Elution and Late Loss Optimization Study (BELLO). JACC Cardiovasc Interv. 2015;8:1132–1134.  
8. Jeger RV, Farah A OM. Drug-coated balloons for small coronary artery disease (BASKET-SMALL 2): an open-label randomised non-inferiority trial. Lancet. 2018;392:849–856.  
9. Worthley S, Hendriks R, Worthley M, et al. Paclitaxel-eluting balloon and everolimus-eluting stent for provisional stenting of coronary bifurcations: 12-month results of the multicenter BIOLUX-I study. Cardiovasc Revascularization Med. 2015;16:413–417.  
10. Costopoulos C, Latib A, Naganuma T, et al. The role of drug-eluting balloons alone or in combination with drug-eluting stents in the treatment of de novo diffuse coronary disease. JACC Cardiovasc Interv. 2013;6:1153–1159.
11. Alfonso F, Byrne RA, Rivero F, Kastrati A. Current treatment of in-stent restenosis. J Am Coll Cardiol. 2014;63:2659–73.  
12. Lassen JF, Holm NR, Stankovic G, et al.  Percutaneous coronary intervention for coronary bifurcation disease: Consensus from the first 10 years of the European Bifurcation Club meetings. EuroIntervention. 2014;10:545–560.
13. Siontis GC, Stefanini GG, Mavridis D, et al. Percutaneous coronary interventional strategies for treatment of in-stent restenosis: A network meta-analysis. Lancet. 2015; 386:655-664. 
14. Baan J, Claessen BE, Dijk KB van, et al. A Randomized Comparison of Paclitaxel-Eluting Balloon Versus Everolimus-Eluting Stent for the Treatment of Any In-Stent Restenosis: The DARE Trial. JACC Cardiovasc Interv. 2018; 11:275-283.
15. Pleva L, Kukla P, Kusnierova P, Zapletalova J, Hlinomaz O. Comparison of the efficacy of paclitaxel-eluting balloon catheters and everolimus-eluting stents in the treatment of coronary in-stent restenosis. Circ Cardiovasc Interv. 2016; 9:e003316 
16. Alfonso F, Pérez-Vizcayno MJ, Cárdenas A, et al. A prospective randomized trial of drug-eluting balloons versus everolimus-eluting stents in patients with in-stent restenosis of drug-eluting stents the RIBS IV Randomized Clinical Trial. J Am Coll Cardiol. 2015;66:23-33.
17. Schulz A, Hauschild T, Kleber FX. Treatment of coronary de novo bifurcation lesions with DCB only strategy. Clin Res Cardiol. 2014;103:451-456. 
18. López Mínguez JR, Nogales Asensio JM, Doncel Vecino LJ, et al.  BABILON Investigators. A prospective randomised study of the paclitaxel-coated balloon catheter in bifurcated coronary lesions (babilon trial): 24-month clinical and angiographic results. EuroIntervention. 2014;10:50-57.  
19. Jim M-H, Lee MK, Fung RC, Chan AK-C, Chan K-T, Yiu K-H. Six month angiographic result of supplementary paclitaxel-eluting balloon deployment to treat side branch ostium narrowing (SARPEDON). Int J Cardiol. 2015;187:594–597.  
20. Cortese B, Micheli A, Picchi A, et al. Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a prospective randomised clinical trial. The PICCOLETO study. Heart. 2010;16:1291–1296.  
21. Unverdorben M, Kleber FX, Heuer H, et al. Treatment of small coronary arteries with a paclitaxel-coated balloon catheter. Clin Res Cardiol. 2010;99:165-174.