Evidence base: A description of the key, so far published, studies in the space of drug coated balloons

This chapter discusses the most relevant clinical data from randomized clinical trials (RCTs) evaluating the role of drug coated balloons (DCBs) for the management of coronary artery disease (CAD) with a focus on three different clinical scenarios:

1. in-stent restenosis (ISR),
2. de novo lesions in small vessels
3. de novo lesions in large vessels.

We also explore the potential future directions for this therapy, drawing insights from major ongoing RCTs.

In-stent restenosis 

DCBs represent an appealing alternative to drug eluting stents (DES) for patients present with ISR as it avoids the implantation of multiple layers of metal. Nowadays, ISR remains the clinical scenario with the largest amount of evidence. When compared to plain old balloon angioplasty, DCBs have shown to be superior in terms of reduced lumen loss and need for target lesion revascularization.(1) However, when compared to DES, its efficacy is determined by the initial stent type and mechanism of ISR.(2) In patients presenting with bare-metal stent restenosis, DCBs have shown similar rates of target lesion revascularization, myocardial infarction and all-cause death as compared to DES (Table 1).

Of note, intracoronary imaging is of paramount importance, as re-stenting will be required in cases of stent fracture.(3) In patients presenting with DES restenosis, repeat stenting with DES has shown to be moderately more effective than DCB in terms of TLR (Table 1), holding IA class recommendation in current guidelines.(4)

De novo lesions in small vessels

The use of DCB in de novo lesions which are not appealing for the implantation of DES (i.e. small vessels with diffuse disease) represents a growing indication for DCB, as it follows a strategy of “leaving nothing behind”. Two early RCTs reported conflicting results about the effects of DCB as compared to early-generation DES on angiographic outcomes in patients with native small vessel CAD.(5,6) More recently, RCTs with the use of second-generation DES and novel DCB devices provided new evidence about the clinical and angiographic effects of these treatments.(7–9) Differences in study results might not only be explained by variations in DCB technology and lesion preparation, but also by discrepancies in the definition of a small vessel size which varied from <3 mm and <2.8 mm to even ≤2.75 mm (Table 1).(10) Meta-analysis have shown that the use of paclitaxel-DCB is associated with risks of target vessel revascularization and restenosis that are similar to DES (OR: 0.97; 95%CI: 0.56–1.68; p=0.92; and OR: 1.12; 95%CI 0.69–1.84; p=0.64, respectively), while DCB yielded to a significant reduction in the risk of vessel thrombosis (OR: 0.12; 95%CI: 0.01–0.94; p=0.04), and DES implantation resulted in slightly better angiographic surrogate endpoints at mid-term follow-up.(11)

The only head-to-head comparison between sirolimus-DCB and paclitaxel-DCB in patients with de novo small vessel disease failed to demonstrate the non-inferiority of sirolimus DCB with regard to net lumen gain at 6 months (0.25±0.40 mm with sirolimus-DCB versus 0.48±0.37 mm with paclitaxel-DCB; p value for noninferiority=0.173), suggesting a potential lack of class effect among DCBs. (12)

De novo lesions in large vessels

Evidence supporting the safety and efficacy of DCBs in patients presenting with de novo lesions in large vessels is scarce and conflicting. Two initial small RCTs powered for angiographic outcomes have shown that paclitaxel DCB is non-inferior to DES in terms of late luminal loss at 9-month follow-up (−0.19±0.49mm vs 0.03±0.64mm, p value for noninferiority =0.019).(13) In addition, no significant differences in minimal lumen diameter between DCB and DES were found at 8 months follow-up, with low 12-month MACE rates (14)(Table 1).

The Revelation trial is the only RCT available in patients presenting with STEMI. 120 patients were randomized to paclitaxel-DCB or DES in a single center. At 9-month follow-up, a paclitaxel-DCB strategy was shown to be noninferior to DES in terms of fractional flow reserve with low clinical event rates.(15) However, in the only available RCT powered for a clinically relevant composite endpoint including cardiovascular death, target vessel myocardial infarction and target lesion revascularization, among 2272 patients in 43 centers; a strategy of DCB-PCI did not achieve non-inferiority as compared with DES driven by higher rates of TLR in the DCB group(16) (Table 1). Therefore, the role of DCB in patients with de novo lesions in large vessels is yet to be determined.

Ongoing evidence

Three large clinically powered RCTs are currently enrolling patients to elucidate the role of DCB in patients with de novo lesions in large vessels. Transform II (NCT04893291) is a multicenter noninferiority RCT comparing a sirolimus-DCB to everolimus-DES in terms of target lesion failure in patients presenting with native CAD. A total of 1325 patients with a vessel diameter between 2 mm and 3.5 mm will be enrolled. The SELUTION DeNovo Trial is a multicenter non-inferiority RCT comparing a strategy of sirolimus-DCB PCI with provisional DES to a strategy of PCI with systematic DES implantation. The primary endpoint is target vessel failure at one and five years. A total of 3162 all-comer patients with native CAD will be enrolled with the exception of those presenting with left main disease, chronic total occlusions and ST-segment elevation myocardial infarction. Finally, the COPERNICAN trial (NCT06353594) is evaluating a reduced stent strategy based on paclitaxel-DCB culprit-lesion PCI with conventional DES coronary revascularization among 1272 patients presenting with STEMI. The primary endpoint is target lesion failure at 1 year with an extended follow-up at 10 years.

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The Essentials - Drug-Coated Balloons