Drug-coated Balloons: From Treatment of In-stent Restenosis to Extended Indications. What's Next?

Domitilla Gentile; Mario Iannaccone; Alaide Chieffo


Eur Heart J. 2023;44(15):1357-1359. 

Graphical Abstract

Already established and emerging indications for drug-coated balloons (DCBs) according to patient characteristics, coronary anatomy, and clinical subset. HBR, high bleeding risk; ISR, in-stent restenosis; ACS, acute coronary syndrome; CCS, chronic coronary syndrome.

The use of drug-eluting stents (DESs) represents a milestone in the treatment of coronary artery disease; however, the possibility of coating balloons with drugs represents an alternative treatment as it implies the use of drug-coated balloons (DCBs).

The effect of DCBs is based on the transfer of antiproliferative drugs into the vessel wall during single balloon inflation by means of a lipophilic matrix without the use of permanent implants, which fulfils the concept of 'leaving nothing behind'.[1] DCBs were first considered for the treatment of in-stent restenosis (ISR), for which their use is now well established.

The ISAR-DESIRE 3 was a prospective, open-label, randomized clinical trial. The aim of the study was to compare the safety and efficacy of plain balloons (PBs), paclitaxel-coated balloons (PCBs), and paclitaxel-eluting stents (PESs) for percutaneous coronary intervention (PCI) of DES-ISR.

At 10-year clinical follow-up, the study's primary and secondary endpoints, reported in this issue of the European Heart Journal, showed no significant difference when using PCBs vs. PESs, whereas expected worst outcomes were reported with PBs. PCBs and PESs significantly reduced target lesion revascularization compared with PBs.[2]

Notably, the adverse events reported in the study mainly occurred within the first year of follow-up. Similar outcomes are described in a large-scale, individual patient data pooled study, in which very late stent-related events occurred between 1 and 5 years after PCI at a rate of ~2%/year for all stent types, with no hint of reaching a plateau.[3]

In ISAR-DESIRE 3, the composite endpoint of death or myocardial infarction was not significantly different between the treatment groups, but the time-varying coefficient flexible parametric regression models resulted in a significant risk increase associated with PESs compared with PCBs. An increased risk of death or myocardial infarction within the first 5 years was observed in the PES group even though the treatment-by-time period interaction for PES vs. PCB was not statistically significant (P = 0.104).

The long-term follow-up of ISAR-DESIRE 3 raises several important points of discussion.

Firstly, the increased risk of death and cardiac death in the PES group was not fully addressed by the authors: the likelihood of an accidental finding is strong, especially due to the lack of demonstration after 10 years. Even though a meta-analysis raised the concern of increased mortality in patients affected by peripheral arterial disease treated with paclitaxel stents and balloons,[4] the 'Difference in Anti-restenotic Effectiveness of Drug-eluting stent and drug-coated balloon AngiopLasty for the occurrence of coronary in-Stent restenosis' (DAEDALUS) study, a subsequent meta-analysis which included patients treated with DCBs for coronary ISR did not show increased mortality associated with PCBs. Similarly, another meta-analysis by Scheller et al., including patients treated with DCBs for coronary de novo stenosis, did not show increased mortality up to 2 years, whereas mortality was lower at 3 years for PCBs compared with DES.[5,6]

No further safety issues in terms of composite and individual ischaemic endpoints after treatment with PCBs were observed.

In addition, in this study, only first-generation paclitaxel-eluting DESs, with thicker stent struts, were used. We cannot exclude that this might have impacted the results. Additionally, the treatment of patients experiencing device-oriented endpoints and the rate of crossover among groups was not reported.

Finally, these results also support the conclusions that higher target lesion revascularization is observed in ISR compared with de novo coronary disease treatment.

Interestingly, preliminary results showed a good safety and efficacy profile of DCBs also in other clinical scenarios such as de novo small-vessel disease (SVD), high bleeding risk patients, and other emerging indications (e.g. bifurcation lesions, large-vessel disease, and diffuse disease).

It is important to consider that not all DCBs share the same characteristics: different delivery balloon designs, doses, formulations, coating drugs, and release kinetics of the drugs contribute to creating devices with a wide range of performances.[1]

The best interventional strategy for the treatment of SVD is still debated, and no data from randomized trials beyond 3-year follow-up are available.[7] However, in the setting of SVD, the use of DESs is still challenging and associated with suboptimal results due to an increased risk of ISR and stent thrombosis.[8]

The International DCB Consensus Group suggested that a vessel of <3 mm should be considered as 'small' and SVD is therefore described as a lesion with a reference vessel diameter of <3 mm.[1]

In the 'Drug eluting balloon efficacy for small coronary vessel disease treatment' (PICCOLETO II) study, a new-generation of DCBs were reported to be superior to everolimus-eluting stents in terms of late lumen loss and comparable in terms of clinical outcome in patients with de novo SVD lesions.[9] Several trials including PICCOLETTO II and 'Long-term efficacy and safety of drug-coated balloons vs. drug-eluting stents for small coronary artery disease' (BASKET-SMALL 2) evaluated the outcomes of 1-month dual antiplatelet therapy (DAPT) following DCB as potentially advantageous for patients at high bleeding risk.[9,10] In this setting, patients treated with DCBs did not experience any thrombotic events, whereas only two stent thrombosis events were reported in the BASKET-SMALL 2 trial during a 3-year follow-up.[10] These results suggest that DCBs may provide significant advantages over DESs in treating SVD, such as a lower risk of stent thrombosis, shorter duration, and less dependence on DAPT.[11]

DCBs have also been proposed for treatment of coronary bifurcation lesions, as an alternative to non-compliant balloon angioplasty for a side branch in the stepwise provisional stenting approach of true coronary bifurcation lesions (MEDINA) (1,1,1). The DCB in bifurcation treatment trial (DCB-BIF trial)[12] evaluated their safety in this setting, and possibly offers new indications for use, especially in the case of short lesions in side branches with diameters <3 mm.

Another possible indication, which requires further investigation, is the combination of bioabsorbable scaffold (BRSs) and DCBs. Following the recall of the first generation of bioabsorbable poly-L-lactide acid DES Absorb (Abbot vascular, CA, USA) due to long-term safety concerns, and their de-escalation to a Class III indication in ESC guideline for revascularization,[13] several observational experiences have reported good results when combining a BRS in the proximal/medium segment with a DCB in SVD.[14] This may be a potential option for long-vessel disease reconstruction as it avoids vessel caging, which may reduce motility and limit further surgical options. In this context, a new generation of magnesium resorbable scaffolds (MRSs), Magmaris (Biotronik, Germany), showed good 5-year outcomes;[15] however, no experience with combined MRSs and DCBs has yet been published.

Finally, when it comes to diffuse coronary disease, recent propositions suggest using a combined treatment with a DCB and spot stenting or debulking and a DCB alone using functional guidance, even in larger coronary segments. Poerner et al.[16] reported encouraging short-term outcomes of fractional flow reserve (FFR)-guided DCB-only PCI of de novo lesions in chronic coronary syndrome with short dual antiplatelet therapy (4 months), showing a trend towards positive vessel remodelling without lumen loss at 6 months.

Based on these findings, a randomized control trial is ongoing to evaluate the impact of this approach compared with DESs (NCT03376646).

In conclusion, the long-term results of the ISAR-DESIRE 3 trial may be considered as a milestone in the treatment of ISR with DCBs, yet further studies are needed to evaluate the role of DCBs in different clinical subsets and lesion anatomies.