Future directions of drug-coated balloon angioplasty

Fernando Alfonso and Javier Cuesta discuss the growing role of drug-coated balloons as an alternative to stents in percutaneous coronary interventions. Highlighting advantages like reduced in-stent restenosis, they emphasize the need for robust clinical studies to refine DCB use.

Drug-eluting stents (DES) currently represent the strategy of choice during percutaneous coronary interventions (PCI)¹. However, the presence of a permanent foreign body in the artery is associated with a low but persisting risk of late thrombosis and in-stent restenosis (ISR)^1-3. To overcome these concerns “leave nothing behind” strategies, including drug-coated balloons (DCB) and bioresorbable vascular scaffolds (BRS) provide an attractive treatment alternative. The poor results of first-generation BRS as compared with DES leave DCB as the only stentless PCI technology for use in clinical practice⁴. DCB have demonstrated clear value in the treatment of ISR and major expectations in de novo lesions which hold major promise for the near future⁵.

Individualizing the decision-making process in the treatment of patients with ISR

Multiple randomized clinical trials (RCT) support the use of DCB in patients with ISR⁶. The 2018 European Society of Cardiology revascularization guidelines gave an IA recommendation for the use of DCB in ISR¹. Alternatively, the 2024 ESC guidelines on chronic coronary syndromes recommend the use of DES over DCB in patients with DES-ISR (IA recommendation)⁷. This change was based on the superiority of DES to reduce the need for target lesion revascularization (TLR), as initially suggested by the RIBS trials^8,9 and then confirmed in the DAEDALUS patient-level meta-analysis (10 RCT with nearly 2.000 ISR patients)¹⁰. Nevertheless, a safety signal (death or myocardial infarction) favoring DCB was also found¹⁰. Accordingly, the decision-making process involved in the treatment of patients with ISR should be individualized. In patients with ISR and multiple stent layers, persistent stent underexpansion, major bifurcations, or high bleeding risk, DCB may be preferred^5,6. Further studies are warranted to identify clinical and anatomic subsets better suited for DCB versus DES in patients with ISR.

Recently approved in the US

DCB have been recently approved in the US based on a RCT demonstrating their superiority over plain old balloon angioplasty¹¹. In Europe where DCB have been used for nearly 2 decades following the pivotal RCT of Scheller et al demonstrating their superiority over balloon angioplasty, this remains difficult to understand¹². However, opening the US market has major economic implications and currently, all major device companies include a DCB in their portfolio. Novel DCB iterations and disruptive innovations have already entered the clinical arena generation great expectations. However, as emphasized by the guidelines, a class effect should not be expected for all the emerging DCB¹.

"Leave nothing behind" appealing but additional data needed

In de novo lesions the leave nothing behind concept is also highly appealing but additional data is still required to support its widespread clinical adoption⁵. Small vessels, diffuse disease, bifurcations, high bleeding risk patients and, ultimately, any clinical or anatomic scenario where the use of DES may cause concern, are attractive targets for DCB⁵. Consensus documents on DCB highlight the importance of lesion predilation in both ISR and de novo lesions; DCB simply transfer the drug into the vessel wall. Scoring balloons have recently demonstrated to be of major value in ensuring better lesion dilation and facilitating drug transfer¹³. Coronary dissections are involved in the mechanisms for acute lumen gain after balloon angioplasty and they spontaneously heal during follow-up⁵. Recent data suggests that angiographic dissections after DCB are associated with superior late angiographic and clinical outcomes, reinforcing the relevance of optimal lesion preparation⁶.

The role of intracoronary imaging

Intracoronary imaging (ICI) may help to guide DCB procedures. Both intravascular ultrasound (IVUS) and optical coherence tomography (OCT) may be used in this regard although OCT is frequently preferred due to its unsurpassed resolution¹⁴. Although recent guidelines recommend (IA) the use of ICI during DES implantation in complex lesions⁷ it is surprising the limited information currently available on the value of ICI guidance during DCB angioplasty¹⁴. The ability of ICI to accurately measure the lumen and external elastic lamina at the reference segments, assess the type of the target plaque and, evaluate the final result (lumen gain, residual plaque type of dissection) appears ideally suited to inform treatment decisions¹⁴. In ISR lesions, the use of ICI has a IIaC recommendation¹. In de novo lesions, information is more limited but a recent RCT suggested that IVUS was associated with superior angiographic outcomes in patients treated with DCB¹⁵. Further studies are warranted to further understand the role of ICI in DCB angioplasty¹⁴.

Consensus documents suggested the value of physiology in assessing satisfactory results of lesion predilation⁵. Future studies are also required to assess the value of coronary physiology to optimize DCB results.    

Evolving technologies that need further studies

Paclitaxel, a highly lipophilic drug allowing adequate transfer and retention at the vessel wall, has been classically used in DCB. Nevertheless, recent technological advances (phospholipids, nanospheres, microreservoirs, etc) currently allow the use of limus- drugs in DCB⁵. Limus drugs are cytostatic, have a wide therapeutic range, and currently are preferred in DES¹. Preliminary results suggested an equivalent efficacy of limus-DCB compared with paclitaxel-DCB¹⁶. However, some recent RCT failed to meet the noninferiority of limus-DCB compared with paclitaxel-DCB in late angiographic parameters. In a meta-analysis, including 6 RCTs comparing head-to-head the two drugs, we found that paclitaxel-DCB was superior to first-generation limus-DCB in late angiographic outcomes although clinical outcomes were comparable¹⁷. Whether new-generation limus-DCB will be able to improve efficacy and even be superior to paclitaxel-DCB warrants future studies.     

The frequent appearance of late lumen enlargement

Another interesting phenomenon after DCB angioplasty is the frequent appearance of late lumen enlargement (LLE). The involved mechanism has recently been found to be both outward vessel remodelling and regression of plaque burden¹⁸ and appears to be associated with favorable angiographic and clinical outcomes. LLE is more evident with paclitaxel-DCB than with limus-DCB and appears to be particularly beneficial in de novo lesions. Further studies are required to fully elucidate the implications of this unique phenomenon¹⁸. 

The near future

The potential of DCB in the near future is enormous⁵. Market expectations are also huge. Young interventional cardiologists, trained in the DES era, should learn to master DCB angioplasty. However, to further push boundaries and advance the field the scientific basis should be robust. Well-designed studies in different clinical and anatomic scenarios, powered for clinical endpoints and with long-term clinical follow-up, are warranted to refine the role of DCB.

References

1. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019 Jan 7;40(2):87-165.
2. Madhavan MV, Kirtane AJ, Redfors B, Généreux P, Ben-Yehuda O, Palmerini T, et al. Stent-Related Adverse Events >1 Year After Percutaneous Coronary Intervention. J Am Coll Cardiol. 2020 Feb 18;75(6):590-604.
3. Kufner S, Ernst M, Cassese S, et al. 10-Year Outcomes From a Randomized Trial of Polymer-Free Versus Durable Polymer Drug-Eluting Coronary Stents. J Am Coll Cardiol. 2020 Jul 14;76(2):146-158.
4. Alfonso F, Cuesta J. Very Late Bioresorbable Vascular Scaffold Thrombosis: Smoke or Fire? JACC Cardiovasc Interv. 2017 Jan 9;10(1):38-41.
5. Jeger RV, Eccleshall S, Wan Ahmad WA, Ge J, Poerner TC, Shin ES, Alfonso F, Latib A, Ong PJ, Rissanen TT, et al. Drug-Coated Balloons for Coronary Artery Disease: Third Report of the International DCB Consensus Group. JACC Cardiovasc Interv. 2020 Jun 22;13(12):1391-1402.
6. Alfonso F, Coughlan JJ, Giacoppo D, Kastrati A, Byrne RA. Management of in-stent restenosis. EuroIntervention. 2022 Jun 3;18(2):e103-e123.
7. Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024 Sep 29;45(36):3415-3537.
8. 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
9. Alfonso F, Pérez-Vizcayno MJ, Cárdenas A, et al. A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent). J Am Coll Cardiol. 2014 Apr 15;63(14):1378-86.
10. Giacoppo D, Alfonso F, Xu B, et al. Drug-Coated Balloon Angioplasty Versus Drug-Eluting Stent Implantation in Patients With Coronary Stent Restenosis. J Am Coll Cardiol. 2020 Jun 2;75(21):2664-2678.
11. Yeh RW, Shlofmitz R, Moses J, Bachinsky W, Dohad S, Rudick S, et al. Paclitaxel-Coated Balloon vs Uncoated Balloon for Coronary In-Stent Restenosis: The AGENT IDE Randomized Clinical Trial. JAMA. 2024 Mar 26;331(12):1015-1024.
12. Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med. 2006 Nov 16;355(20):2113-24.
13. Kufner S, Joner M, Schneider S, et al. Neointimal Modification With Scoring Balloon and Efficacy of Drug-Coated Balloon Therapy in Patients With Restenosis in Drug-Eluting Coronary Stents: A Randomized Controlled Trial. JACC Cardiovasc Interv. 2017 Jul 10;10(13):1332-1340.
14. Alfonso F, Kundu A. Intracoronary Imaging to Guide Drug-Coated Balloon Angioplasty: Ready for Primetime? JACC Cardiovasc Interv. 2024 Jul 8;17(13):1529-1532.
15. Gao XF, Ge Z, Kong XQ, et al. Intravascular Ultrasound vs Angiography-Guided Drug-Coated Balloon Angioplasty: The ULTIMATE Ⅲ Trial. JACC Cardiovasc Interv. 2024 Jul 8;17(13):1519-1528.
16. Alfonso F, Byrne RA. Limus-Coated Balloons in "de Novo" Coronary Lesions: Quo Vadis? JACC Cardiovasc Interv. 2022 Jun 27;15(12):1227-1230.
17. Sedhom R, Hamed M, Elbadawi A, et al. Outcomes With Limus- vs Paclitaxel-Coated Balloons for Percutaneous Coronary Intervention: Meta-Analysis of Randomized Controlled Trials. JACC Cardiovasc Interv. 2024 Jul 8;17(13):1533-1543.
18. Alfonso F, Rivero F. Late lumen enlargement after drug-coated balloon therapy: turning foes into friends. EuroIntervention. 2024 May 10;20(9):523-5

The Essentials - Drug-Coated Balloons

Authors

Fernando Alfonso

Interventional cardiologist / Cardiologist

Hospital Universitario de La Princesa - Madrid, Spain

Javier Cuesta

@ccuesta2

Interventional cardiologist / Cardiologist

Department of Cardiology, Hospital Universitario de La Princesa - Madrid, Spain