The treatment of long coronary lesions remains one of the most demanding scenarios in PCI, frequently requiring multiple overlapping DES, creating a “full metal jacket” configuration that is associated with higher risks of restenosis, stent thrombosis, and impaired vascular remodeling (1, 2, 4).

By contrast, growing evidence supports the role of DCBs in complex or long lesions. In a multicenter observational study, Shin et al. evaluated 254 patients with multivessel CAD treated with a DCB-based approach (34.3% DCB-only, 65.7% hybrid DES + DCB) compared with a propensity-matched DES-only cohort. At 2 years, the DCB-based group exhibited a significantly lower incidence of major adverse cardiovascular events (MACE: 3.9% vs. 11.0%; P = 0.002), driven by reductions in cardiac death and major bleeding. Importantly, the DCB-based strategy reduced the number and cumulative length of implanted stents by approximately 65% (43) (Figure 2).

Similarly, a PS-matched study from our group analyzed patients with long LAD lesions (mean treated length 65 mm in the DCB group vs. 56 mm in the DES group), showing a reduced risk for target lesion revascularization (TLR) and target lesion failure (TLF) at 2 years in the DCB cohort [hazard ratio (HR) 0.20, 95% CI: 0.07–0.58; P =  0.003]. Notably, most TLR events in the DCB group clustered within the first 6 months, after which event rates plateaued, whereas the DES cohort exhibited a steady increase in events over time, reflecting progressive stent-related adverse remodeling (44).

In a similar PS-matched analysis, Pan et al. focused on ostial LAD lesions, reporting a TLR rate of 4.9% in the DCB group compared with 16.3% in the DES group, and a lower incidence of MACE (7.8% vs. 19.3%). Moreover, late lumen loss (LLL) was significantly reduced after DCB-based therapy (−0.02 ± 0.57 mm) compared with DES (0.30 ± 0.27 mm; P < 0.001), suggesting sustained vessel patency despite lower acute lumen gain (45).

Coronary bifurcation lesions account for approximately 15%–20% of all PCIs and remain a complex subset due to the inherent risk of side branch (SB) compromise during main branch (MB) stenting. The European Bifurcation Club recommends a provisional stenting strategy in most cases, with SB balloon dilatation or stenting performed only if necessary (46). Nevertheless, MB stenting can alter bifurcation geometry, reduce SB flow, and increase the risk of ischemia, highlighting the potential role of DCBs in preserving SB patency.

Randomized trials provide evidence for the efficacy of DCBs in the SB. In the DCB-BIF trial, 784 patients with true bifurcation lesions and SB diameter stenosis ≥70% after MB stenting were randomized to paclitaxel-coated balloons (n = 391) or non-compliant balloons (n = 393). At 1-year follow-up, major adverse cardiac events (MACE) occurred in 7.2% of the DCB group vs. 12.5% in the control group (HR 0.56; 95% CI: 0.35–0.88; P = 0.013), driven primarily by a reduction in myocardial infarction. Procedural success and crossover to two-stent strategies were similar in both arms (47).

Similarly, the PEPCAD-BIF trial enrolled 64 patients with non-left main bifurcations, randomized to DCB or plain balloon angioplasty (POBA). At 9 months, LLL was 0.13 mm in the DCB group vs. 0.51 mm in the POBA group (P = 0.013), restenosis occurred in 6% vs. 26%, and TLR was required in 1 vs. 3 patients, respectively. The BEYOND trial included 222 patients and demonstrated that target lesion stenosis at 9 months was 28.7% ± 18.7% with DCB vs. 40.0% ± 19.0% with conventional balloons (Δ = −11.3%; P < 0.0001), with LLL of −0.06 ± 0.32 mm vs. 0.18 ± 0.34 mm (P < 0.0001), and no significant difference in MACE (0.9% vs. 3.7%; P = 0.16) (48).

The BABILON trial evaluated paclitaxel-coated balloons (PCBs) in 108 patients with de novo bifurcation lesions, randomized to either sequential MB/SB predilatation with PCB plus BMS implantation in the MB (SB treated only with PCB unless stenting was required) or standard MB/SB predilatation with DES in the MB, with provisional T-stenting of the SB if needed. At 9-month, LLL in the MB was 0.31 ± 0.48 mm in the PCB/BMS group vs. 0.16 ± 0.38 mm in the DES group, with a mean difference of 0.15 mm, confirming non-inferiority. In the SB, LLL was minimal and comparable between the two groups (−0.04 ± 0.76 mm vs. −0.03 ± 0.51 mm). However, MACE occurred more frequently in the PCB group (17.3% vs. 7.1%), as did TLR (15.4% vs. 3.6%), largely due to higher MB restenosis (13.5% vs. 1.8%). Although overall outdated due to the use of BMS in the MB, these findings indicate that PCB are effective in preserving SB patency and bifurcation geometry (49).

Observational studies in more complex bifurcations corroborate the benefit of DCBs. In a multicenter study of 152 patients undergoing PCI for ostial left circumflex lesions using paclitaxel- or sirolimus-coated balloons, 2-year TLF was 19.0% vs. 19.8% in a DES-treated historical cohort (HR 1.05; 95% CI: 0.64–1.75), despite longer lesion lengths (25.5 mm vs. 18.0 mm; P < 0.001) and reduced fluoroscopy time (31.0 vs. 20.0 min) and contrast volume (200 vs. 150 mL) in the DCB group (50). Another study comparing DEB to conventional balloon angioplasty in 50 patients per group undergoing provisional T stenting demonstrated lower LLL (0.09 mm vs. 0.40 mm; P = 0.01), reduced restenosis (7% vs. 20%), and fewer MACE (11% vs. 24%) in the DCB group at 12-month follow-up (51).

Taken together, these data indicate that DCBs provide effective SB treatment in bifurcation lesions, reducing LLL, restenosis, and TLR while preserving bifurcation geometry as compared to DES. However, despite encouraging results, the European Bifurcation Club does not currently recommend routine DCB use for de novo bifurcation lesions due to the limited number of comparative studies against DES (46). Furthermore, evidence supporting the use of DCBs in left main (LM) bifurcation lesions remains scarce (52).

Chronic total occlusions (CTOs) represent one of the most challenging subsets of coronary lesions for PCI, due to their dense fibrotic or calcific nature, frequent underestimation of vessel size, and higher risk of stent under-expansion or malapposition (53). These factors contribute to increased rates of restenosis, stent thrombosis, and adverse cardiac events when conventional BMS or DES are used (54).

Recent multicenter observational studies suggest that DCB-based strategies, either alone or combined with DES, can achieve favorable outcomes in CTOs. In a cohort of 200 patients treated with DCB-based PCI, 49% received DCB alone, while 51% underwent a hybrid approach combining DCB with DES. Bailout stenting was required in only 3.5% of cases. Compared with 661 patients receiving DES-only CTO interventions, the DCB-based group had significantly fewer stents per patient (median 1.0 vs. 2.0), shorter total stent lengths (median 6.5 mm vs. 42 mm), and reduced use of small-diameter stents ≤2.5 mm (9.8% vs. 36.5%). At 2-year follow-up, MACEs occurred in 3.1% of the DCB group vs. 13.2% of the DES-only group, reflecting the clinical benefit of reducing stent burden (55).

While randomized evidence remains limited, available data support a hybrid strategy in which DCBs are used to treat the diffuse lesions, complemented by DES in those segments in which scaffolding is necessary. This approach appears to preserve long-term vessel patency and reduce stent-related complications, offering a promising alternative to conventional stenting in CTO interventions. Conversely, the potential advantages of DCB inflation within the subintimal space, particularly in the setting of an “investment” procedure, warrant further investigation.

Coronary artery calcification (CAC) continues to represent a major procedural challenge in contemporary PCI, even in the era of new-generation DES (56, 57). Calcified lesions are associated with higher rates of restenosis, stent thrombosis, and adverse cardiovascular events, largely due to difficulties in achieving adequate predilation, suboptimal stent expansion, and irregular plaque morphology (58, 59). Consequently, lesion preparation with adjunctive devices such as rotational atherectomy (RA) and orbital atherectomy (OA), is often necessary to optimize outcomes prior to stent implantation.

DCBs have emerged as a promising alternative strategy for CAC, particularly when combined with lesion-modifying techniques, since drug delivery may be hindered by extensive calcification. Several recent studies have investigated DCB outcomes in calcified lesions following RA or OA. In a single-center analysis of 194 lesions treated with RA, subsequent DCB therapy demonstrated comparable 1-year MACE rates to DES (11% vs. 8%, P = 0.30), with similar rates of target lesion revascularization (8% vs. 4%) and negligible differences in cardiac or noncardiac mortality (1 cardiac and 2 noncardiac deaths for each group) (60). Similarly, in patients undergoing OA, 1-year MACE occurred in 9.7% after DCB and 3.4% after DES (P = 0.136), despite thicker calcium plaques and smaller postprocedural lumen areas in the DCB group, suggesting feasibility when adequate lesion preparation is achieved (61).

Long-term data from an intracoronary imaging-guided RA cohort (123 patients, 166 lesions) showed that target lesion revascularization and target vessel revascularization at three years were comparable between DCB and DES (15.6% vs. 16.3% and 15.6% vs. 23.3%, respectively), while late lumen loss was significantly lower with DCB (0.09 mm vs. 0.52 mm, P = 0.009) (62). Moreover, a retrospective study assessed 318 patients with severe CAC undergoing RA-assisted PCI, including 57 patients treated with DCB and 261 with DES. Despite more complex anatomy in the RA/DES group, including left main, bifurcation, and multivessel disease, rates of TLR (13.8% vs. 7.0%) and MACE (18.8% vs. 12.3%) did not differ significantly between groups (P > 0.05) (63).

A meta-analysis encompassing 1,141 patients and 1,176 calcified coronary lesions across five studies confirmed that DCBs are comparable to DES in terms of 12-month MACE (Risk Ratio = 0.86, 95% CI: 0.62–1.19, P = 0.36), cardiac death (RR = 0.59, 95% CI: 0.23–1.53, P = 0.28), myocardial infarction (RR = 0.89, 95% CI: 0.25–3.24, P = 0.87), and TLR (RR = 1.10, 95% CI: 0.68–1.77, P = 0.70). While acute angiographic results were lower with DCBs, including an average acute gain reduction of 0.65 mm and a minimal lumen diameter 0.75 mm smaller than with DES, follow-up at 12 months demonstrated improved LLL (−0.34 mm), suggesting a durable effect of the stent-less strategy (64).

However, randomized data on the use of DCBs in severely calcified coronary lesions are still lacking. Moreover, the presence of extensive calcium may limit drug absorption, potentially reducing antiproliferative efficacy and contributing to higher rates of restenosis in inadequately prepared lesions.

Acute coronary syndromes (ACS) present unique challenges for PCI, as high thrombus burden, vessel spasm, and microvascular obstruction can increase the risk of distal embolization, no-reflow, and stent malapposition. In this context, DCBs have been investigated as an alternative or complement to conventional stenting. Although residual thrombus may interfere with homogeneous drug delivery to the vessel wall and reduce antiproliferative efficacy, the risk of stent undersizing in ACS further reinforces the rationale for a DCB-based strategy, potentially avoiding the complications of malapposition and suboptimal stent expansion (65). Indeed, stent-related complications remain a concern, with cardiac adverse events (including death, MI, or TLR) reported in up to 32.4% of patients at 10-year follow-up (66).

In the STEMI setting, the REVELATION trial randomized 120 patients with non-severely calcified culprit lesions to DCB or DES. At 9 months, mean fractional flow reserve (FFR) was 0.92 ± 0.05 in the DCB group and 0.91 ± 0.06 in the DES group, with only one abrupt vessel closure in the DCB arm and two patients requiring non-urgent target lesion revascularization overall (67). The DEB-AMI trial assessed 150 STEMI patients divided into three groups (BMS, DCB with BMS, and DES) reporting a LLL of 0.74 ± 0.57 mm, 0.64 ± 0.56 mm, and 0.21 ± 0.32 mm, respectively. Corresponding binary restenosis rates were 26.2%, 28.6%, and 4.7%, and MACE occurred in 23.5%, 20.0%, and 4.1% of patients, respectively (68). Gobić et al. further explored DCB-only therapy in STEMI in a feasibility study of 75 patients, randomized to DCB (n = 38) or DES (n = 37). Reinfarction occurred in 5.3% of DCB patients vs. 5.4% in the DES group after 1 month. At six months, no major adverse cardiac events were reported in the DCB group, compared with 5.4% in the DES group. Late lumen loss was notably lower in the DCB arm (−0.09 ± 0.09 mm) compared with the DES group (0.10 ± 0.19 mm, P < 0.05), supporting the safety and feasibility of DCB-only strategies in primary PCI (69).

In NSTEMI, the PEPCAD NSTEMI trial enrolled 210 patients and demonstrated a TLF rate of 3.8% in the DCB group vs. 6.6% in the stent group over an average follow-up of 9.2 months. MACE occurred in 6.7% of DCB-treated patients vs. 14.2% in the stent-treated cohort, with similar results observed in per-protocol analyses. Most patients (85%) received DCB alone, with only 15% requiring additional stenting (70).

Meta-analytic data pooling 497 patients across three randomized trials and one observational study showed comparable rates of MACE (5% vs. 4.4%), all-cause mortality (0.02% vs. 0.04%), cardiac death (0.01% vs. 0.02%), myocardial infarction (0% vs. 1.4%), and TLR (3.7% vs. 2%) between DCB and DES in AMI patients. Late lumen loss was also similar (mean difference 0.04 mm). These findings reinforce that DCB treatment can provide effective vessel patency and clinical safety, particularly in lesions with minimal thrombus burden (71).

Overall, current evidence suggests that DCB therapy in ACS is a safe and viable alternative to conventional stenting in carefully selected patients, offering the advantage of reduced stent implantation while preserving favorable angiographic and clinical outcomes.

Management of patients at high bleeding risk (HBR) undergoing PCI remains a major clinical challenge, given the delicate balance between ischemic protection and avoidance of hemorrhagic complications. In this context, DCB angioplasty has attracted considerable interest as the absence of a permanent metallic implant might potentially allow for more flexible antithrombotic strategies (72). Expert consensus documents currently recommend a shortened course of DAPT, often limited to 4 weeks after DCB-only PCI for patients presenting with chronic coronary syndromes, with the possibility of reducing the duration to as little as 2 weeks in cases of very high bleeding risk (5). Retrospective analyses and small randomized trials have recently suggested that DCB-only PCI can be performed safely with abbreviated DAPT regimens, and in some instances even with single antiplatelet therapy (SAPT) (73, 74). Unlike contemporary DES, for which short DAPT regimens are supported by large randomized trials, robust evidence for abbreviated DAPT following DCB, particularly in thrombotic lesions, remains limited (75).

In a retrospective cohort analyzed by Räsänen et al., SAPT following DCB PCI was associated with low rates of adverse events, with a 1-year incidence of MACE at 4.7% and cardiovascular death at 2.9% (74). Similarly, Cortese et al. observed no significant differences between SAPT and DAPT in terms of MACE or its components, while noting fewer bleeding complications in patients treated with SAPT (76). Two large-scale prospective datasets have recently provided further insights. The REC-CAGEFREE II trial, a multicenter randomized study of 1,948 East Asian ACS patients undergoing DCB-only angioplasty, directly compared a stepwise DAPT de-escalation regimen (one month of aspirin plus ticagrelor, followed by five months of ticagrelor monotherapy and then aspirin alone) with standard 12-month DAPT. The primary endpoint of net adverse clinical events at 12 months occurred in 8.9% of patients in the de-escalation group vs. 8.6% in the standard DAPT group, meeting the criteria for non-inferiority. Importantly, the incidence of major bleeding (BARC 3–5) was significantly reduced in the de-escalation group (0.4% vs. 1.6%, P = 0.008), suggesting that a less intensive approach is both safe and effective in this setting (77).

In the EASTBOURNE registry, which enrolled over 2,100 patients treated with sirolimus-coated balloons, among 113 patients receiving SAPT, no cases of acute vessel occlusion or early target lesion revascularization were observed. At 12 months, the rate of TLR was similar between SAPT and DAPT groups (7.7% vs. 5.6%, P = 0.6), while cumulative MACE rates also showed no significant difference (11.2% vs. 8.9%, P = 0.4). These findings support the safety of SAPT even in complex cohorts, with the potential to mitigate bleeding risks without compromising ischemic protection (78).

Diabetes mellitus (DM) poses a significant challenge for PCI, as affected patients often exhibit diffuse, multivessel disease, longer lesions of smaller diameter, and an elevated risk of restenosis, stent thrombosis, and recurrent myocardial infarction following conventional stent implantation (79–81). Consequently, a stent-free strategy using DCBs has emerged as an appealing alternative in this high-risk population.

A recent meta-analysis pooling six randomized studies and 847 patients with small-vessel disease provided important insights into the comparative efficacy of DCB vs. DES in diabetic patients. The analysis demonstrated a consistent reduction in MACE with DCB (RR: 0.60, 95% CI: 0.39–0.93), as well as a lower risk of myocardial infarction (RR: 0.42, 95% CI: 0.19–0.94) and target lesion revascularization (RR: 0.24, 95% CI: 0.08–0.69). Other favorable outcomes included reduced target vessel revascularization (RR: 0.33, 95% CI: 0.18–0.63), binary restenosis (RR: 0.27, 95% CI: 0.11–0.68), and late lumen loss (mean difference −0.31 mm, 95% CI: −0.36 to −0.27). By contrast, technical success, all-cause mortality, minimal lumen diameter, and net lumen gain were comparable between the two strategies, suggesting that the short-term angiographic and clinical performance of DCB is at least equivalent, and in some respects superior, to DES in this high-risk population (82).

In the EASTBOURNE study, diabetic patients (N = 864) had numerically higher rates of target lesion revascularization at 1 year compared to non-diabetics (6.5% vs. 4.7%, HR 1.38, 95% CI: 0.91–2.08), as well as all-cause death (3.8% vs. 2.6%, HR 1.81, 95% CI: 0.95–3.46) and MACE (12.2% vs. 8.9%, HR 1.26, 95% CI: 0.92–1.74). Importantly, the incidence of spontaneous myocardial infarction was significantly higher among diabetic patients (3.4% vs. 1.5%, HR 2.15, 95% CI: 1.09–4.25), while bleeding complications did not differ. Stratified analyses indicated that SCB outcomes were similar in de-novo lesions and in-stent restenosis, and that diabetic status did not significantly affect device performance, with angiographic success exceeding 97% in both groups (83).

Overall, current evidence indicates that DCB angioplasty is feasible in diabetic patients and may reduce restenosis and repeat revascularization compared with DES, potentially mitigating their usual prognostic disadvantage. However, higher event rates observed in registries highlight the need for further randomized studies to confirm long-term safety and efficacy.