Drug-coated balloons in percutaneous coronary interventions: existing evidence and emerging hopes

Abstract

Drug-coated balloons (DCB) have been developed as an alternative to drug-eluting stents (DES) as a part of the “leave nothing behind” strategy following percutaneous coronary interventions (PCI). DCBs facilitate revascularization and delivery of an antiproliferative agent directly to a coronary artery lesion, without the need for DES implantation. Subsequently, DCBs promote positive vascular remodeling and allow for a shorter duration of dual antiplatelet therapy. Since the first reports on the successful treatment of coronary in-stent restenosis (ISR) with paclitaxel-coated balloon catheters in the year 2006, the use of DCBs has been growing, driven by reports of DCB application to treat ISR, bifurcation lesions, and small vessel disease. Contemporary clinical trials evaluating DCBs in large vessel disease and chronic total occlusions might further expand the indications for this technology. Attention has also been brought to the use of DCBs in patients with diabetes mellitus and acute coronary syndrome, especially those at high bleeding risk. This review aims to discuss the existing evidence and emerging hopes associated with DCBs, including technical aspects of DCB PCI and the use of DCBs in different clinical scenarios.

Introduction

The first percutaneous coronary intervention (PCI) was performed in 1977 using a catheter-mounted balloon [1]. After the introduction of stents, PCI has become a standard revascularization strategy in patients with coronary artery disease (CAD). The initially used bare metal stents (BMS) were then replaced with the first generation of drug-eluting stents (G1-DES), which consisted of stainless-steel struts and durable polymers releasing paclitaxel or sirolimus. Subsequently, a second generation of DES (G2-DES), built of thin alloy struts and durable or biodegradable polymers releasing sirolimus derivates, was developed [2, 3]. Considerable improvement in stent technology reduced the rates of in-stent restenosis (ISR) (30% vs. 10% vs. 5% for BMS, G1-DES, and G2-DES, respectively) [4]. Nevertheless, CAD remains the leading cause of morbidity and mortality worldwide, accounting for almost seven million deaths annually [5]. Thereby, new techniques to improve long-term PCI outcomes have been investigated.

Drug-coated balloons (DCB) were developed as an alternative to DESs. DCBs facilitate revascularization and delivery of an antiproliferative agent, predominantly paclitaxel, directly to a coronary artery lesion, without the need for DES implantation (Fig. 1). The absence of polymer or metallic materials in the vessel wall prevents platelet adhesion and activation, as well as inflammatory processes leading to neointimal hyperplasia and neoatherosclerosis. Thereby, by fulfilling the “leave nothing behind” strategy, DCB PCIs have the potential to reduce the risk of thrombosis and restenosis [6]. Furthermore, DCB PCIs for de novo coronary lesions are associated with late lumen enlargement, although this requires further confirmation in clinical studies [7]. Short-term exposition to antiproliferative agents released by DCB allows for early re-endothelialization and vessel healing, and hence, DCB PCIs promote positive vascular remodeling and even atherosclerotic plaque regression [8]. In addition, comparable vasomotor function was found in DCB-treated lesions and angiographically normal coronary segments [9].

Figure 1.

Drug-coated balloon (DCB) angioplasty. (1) DCB is inserted into a coronary artery lesion via a catheter. (2) Following inflation, the DCB releases an antiproliferative agent into the vessel wall. (3) Revascularization is obtained and the DCB removed

Moreover, DCB PCIs allow for dual antiplatelet therapy (DAPT) de-escalation [10, 11]. Recent studies have shown that one- to three-month DAPT might pose a lower bleeding risk and is non-inferior to 6- to 12-month DAPT in preventing post-PCI major adverse cardiovascular events (MACE) in patients treated with stent implantation [12]. In the same population, aspirin-free antiplatelet therapy is emerging as a feasible alternative to DAPT [13]. However, an optimal DAPT duration following stent implantation is a matter of ongoing discussion, especially in patients with acute coronary syndrome [14]. Although shorter DAPT seems reasonable after DCB PCI and could be beneficial for patients at high bleeding risk, the supporting evidence is limited. The ongoing REC-CAGEFREE II trial has shown that in ACS patients, a strategy of DAPT (aspirin plus ticagrelor) for one month followed by ticagrelor monotherapy for six months, and then aspirin alone up to 12 months, was noninferior to the standard 12-month DAPT regimen for the composite endpoint of MACE [15]. In addition, single antiplatelet therapy following DCB PCI has been suggested as a safe and efficient strategy in very high bleeding-risk patients [16, 17].

DCBs have been widely investigated alone or in combination with stenting in a so-called “hybrid approach” in various lesions, including ISR, diffuse lesions, and bifurcation lesions (BL), and in different clinical scenarios, including patients with diabetes mellitus (DM), multivessel disease, or acute coronary syndrome (ACS). Although some studies have shown non-inferior safety of DCB compared to stents, data on the efficiency and long-term outcome of DCB PCI is inconsistent and mostly based on modest-sized clinical trials with heterogenous design and primary endpoints [6]. Considering this evidence gap, we aim to discuss the existing data and emerging hopes associated with DCB. We describe the current evidence on technical aspects of DCB PCI and the use of DCBs in different clinical scenarios, including (i) ISR, (ii) BL, (iii) small vessel disease (SVD), (iv) large vessel disease, (LVD), and (v) chronic total occlusions (CTO). Furthermore, we highlight DCB use in patients with DM and acute coronary syndrome (ACS). Finally, we propose an algorithm for DCB-only coronary angioplasty.

Technical aspects of drug-coated balloon angioplasty

Type of antiproliferative agent

Stent implantation generates vessel injury that may result in neointimal hyperplasia and negative vessel remodeling [18]. Despite technological improvements, stent implantation is inevitably associated with the risk of extensive neointimal hyperplasia. Therefore, antiproliferative agents are essential to avoid restenosis [6]. Currently, sirolimus and its derivates are applied in the majority of 2G-DES. Conversely, paclitaxel is used in most of 1G-DES and DCB [19].

A comparison of the main characteristics of sirolimus and paclitaxel is shown in Figure 2. Both sirolimus and paclitaxel inhibit proliferation and migration of endothelial progenitor cells and human coronary artery smooth muscle cells. However, they present different biological effects, depending on the time of exposure [20]. Sirolimus might require prolonged application due to lower transfer rates [21]. Therefore, it is suitable for use in DESs, which elute the antiproliferative agent gradually after implantation [2]. In contrast, the effect of DCBs is based on the rapid release and retention of the antiproliferative agent in the vessel wall [6]. Hence, paclitaxel, requiring shorter exposure, has been traditionally applied in DCBs. The efficacy and safety of paclitaxel-coated balloons were reported both in in vivo models [22] and clinical trials [23, 24]. Currently, there are 13 paclitaxel-coated balloons registered for coronary use in Europe. In the United States, only one DCB has recently been approved for ISR treatment [25].

Figure 2.

Comparison of the main characteristics of sirolimus- and paclitaxel-coated balloons

Clinical trials investigating sirolimus and its derivates in DCBs are emerging as well. In in vivo models, therapeutic tissue concentration and reduction of percentage diameter stenosis (%DS) were obtained following the delivery of sirolimus nanoparticles via a porous balloon [26]. Subsequently, sirolimus-coated balloons were shown to be safe and effective in the treatment of ISR [19, 27] with 12-month late lumen loss (LLL) and clinical event rate comparable to paclitaxel-coated balloons [19]. However, sirolimus tissue retention differed depending on the dose and coating formulation. Regarding the rate of drug transfer, a crystalline coating was more effective than an amorphous coating [28]. In vivo studies revealed similar results for zotarolimus-coated balloons [29, 30], which reduced neointimal hyperplasia with the uptake increasing with inflation time, and the drug concentration decreasing with transmural depth [30]. Recently, the randomized REFORM trial compared the efficacy and safety of a biolimus-coated balloon versus a paclitaxel-coated balloon for ISR. The results with the biolimus-coated balloon were encouraging but did not meet the criteria for non-inferiority compared with paclitaxel-coated balloon [31]. Another randomized trial compared outcomes after sirolimus- and paclitaxel-coated balloons in small de novo lesions, with balloon sizing determined using optical coherence tomography. The sirolimus-coated balloon failed to demonstrate noninferiority for angiographic net lumen gain at six months compared to the paclitaxel-coated balloon [32]. Similarly, a randomized trial comparing a novel sirolimus-coated balloon with a crystalline coating showed similar angiographic outcomes in treating coronary de novo disease at six months compared with a paclitaxel-coated balloon [33].

Overall, current data show similar clinical outcomes of sirolimus derivates in DCB compared with the best investigated paclitaxel-coated balloons, but better angiographic outcomes in patients randomized to paclitaxel-coated balloons [34]. Considering a lack of class effect, the interaction between drug doses, formulations, release kinetics, and clinical outcomes should be investigated separately for each DCB device.

Lesion preparation

Rapid and homogenous release of an antiproliferative agent into the vessel wall must be established to prevent restenosis following DCB PCI [6]. Microinjuries have been shown to enhance local drug uptake [35]. Thereby, lesion preparation prior to DCB PCI is crucial for procedural success.

Semi-compliant balloons in a balloon-to-vessel ratio of 1:1 are recommended for preparation of uncomplicated lesions. In complex cases, high-pressure noncompliant balloons and scoring or cutting balloons should be considered [6]. Furthermore, rotablation, atherectomy, and lithotripsy might be used if balloon angioplasty is unsuccessful, e.g., in severely calcified lesions [6, 25]. In DES-ISR, neointimal modification with a scoring balloon reduced the rate of in-segment %DS (35 ± 16.8% vs. 40.4 ± 21.4%; p = 0.047) and binary angiographic restenosis (18.5% vs. 32%; p = 0.026) at six- to eight-month follow-up compared to standard therapy [36]. Similarly, the use of cutting balloon together with DCB in patients with DES-ISR resulted in greater lumen diameter and lower rates of LLL, restenosis, and MACE (p < 0.05) [37]. Moreover, greater pre-dilatation using a plain balloon was associated with lower risk of target lesion revascularization (TLR) at 12-month follow-up in patients with SVD [38]. Therefore, an optimal lesion preparation before DCB is fundamental to obtain a satisfactory effect.

Construction of drug-coated balloons

Associations between DCB construction and drug distribution are summarized in Figure 3. Absorption of an antiproliferative agent is associated with the contact area and the pressure between the vessel wall and the DCB. Thereby, along with lesion preparation, drug uptake might be enhanced by modification of the DCB structure (39). Generally, short delivery and sufficient inflation time are advised to maximize the efficacy of DCB PCI. In addition, structural modification of the DCB has been proposed to enhance the delivery of the antiproliferative agent. For example, microneedle DCBs, which cause microinjuries, might facilitate drug transfer without the need for extensive lesion preparation. The use of microneedle DCB was associated with higher paclitaxel tissue concentrations compared to amorphous coating [40]. Furthermore, linear-patterned DCB was shown to deliver a 2.3-fold higher amount of drug to the vascular tissue than conventional DCB due to increased contact pressure [41]. However, clinical trials regarding head-to-head comparison of theses novel DCB technologies with standard DCB are not available yet.

Figure 3.

Drug distribution with different structures of drug-coated balloons (DCB)

Imaging guidance in DCB angioplasty

Recent studies highlight the importance of intravascular imaging (IVUS) in optimizing DCB angioplasty outcomes. A few weeks ago, the results of the first trial (ULTIMATE III) comparing IVUS-guided versus angiography-guided DCB angioplasty were published. The study demonstrated that the IVUS-guided strategy was associated with lower late lumen loss (LLL), suggesting a potential advantage of this approach in precise drug delivery and in evaluating vessel structure and the target lesion for angioplasty.

Drug-coated balloons in different clinical scenarios

Initially, DCBs were implemented to assist in stenting. However, due to considerable technological improvement, DCBs have become an independent treatment method applied in the treatment of (i) ISR, (ii) BL, (iii) SVD, (iv) LVD, and (v) CTO. Furthermore, attention has been brought to DCB use in patients with DM or ACS [6].

In-stent restenosis

Stent implantation results in vascular injury, which might lead to neointimal hyperplasia and finally to ISR, defined as > 50% stenosis of a stented coronary artery segment. ISR is a common cause of PCI failure. In the United States, about 10% of PCIs are performed to treat ISR, which is associated with worse outcomes than the treatment of de novo lesions [42]. In the case of ISR, current guidelines of the European Society of Cardiology recommend repeated DES implantation or DCB PCI (Class: I, Level of Recommendation: A) [43].

In a meta-analysis of 10 randomized clinical trials, DCB PCI was associated with greater risk of TLR at three-year follow-up compared to DES implantation (hazard ratio [HR]: 1.32; 95% CI [confidence interval]: 1.02–1.70; p = 0.035). However, rates of all-cause death, myocardial infarction (MI), and target lesion thrombosis were comparable between the two treatment arms [44]. Interestingly, DCB PCI was less effective than DES implantation in the treatment of DES-ISR (HR: 1.58; 95% CI: 1.16–2.13) but not in the treatment of BMS-ISR (HR: 0.83; 95% CI: 0.51–1.37) [45, 46]. Another study reported low (4.3%) and moderate (18.7%) rates of TLR at one and five years after DCB PCI, respectively. The study identified the length of DCB and the use of multiple DCBs per vessel as a risk factor for TLR (HR: 1.038; 95% CI: 1.007–1.069; and HR: 4.7; 95%CI: 1.6–13.8; respectively). Age, comorbidities, and prior bypass surgery were also associated with adverse outcomes [47].

Overall, current data demonstrate no superiority of DCB over DES in patients with ISR, and both methods seem similarly efficient and safe. Hence, the treatment choice should be based on individual patient characteristics, including (i) technical aspects of previous PCI, (ii) type of restenotic stent, and (iii) clinical aspects, including the bleeding risk. Regarding technical aspects, it is crucial to determine the mechanism of ISR using intravascular imaging, which enables the differentiation between neoatherosclerosis and stent failure due to underexpansion. In the latter case, the use of DCB only, without aggressive post-dilation, will not ensure a good outcome. Considering the type of restenotic stent, BMS-ISR is more likely to profit from DCB compared to DES-ISR. Finally, a possibility to deescalate DAPT or discontinue P2Y12 inhibitors within one month following DCB PCI might be seen as an advantage of DCB over DES in ISR patients at high bleeding risk.

Bifurcation lesions

In bifurcation lesions (BL), the main branch (MB) lesion is adjacent to or involves a side branch (SB) of a coronary artery. BLs are present in about 20% of patients referred to PCI. Due to technical complexity and suboptimal SB results, BLs are associated with worse outcomes compared to non-bifurcation lesions [48].

DCB PCI has been investigated using (i) a stent in the MB and DCB in the SB, and (ii) a DCB-only approach. The former strategy led to good SB results using both BMS [49] and DES [50]. In a recent randomized clinical trial, SB dilation with DCB in de novo non-left main coronary artery bifurcation lesions treated with provisional T stenting was associated with better angiographic results at nine months compared to standard balloon angioplasty [51]. Furthermore, the DCB-only approach was associated with low TLR rates and was superior to standard balloon angioplasty in distal MB and SB [52].

Currently, DESs are still recommended in patients with BL, but DCBs seem to be a promising tool, especially in the case of small diameter SB treatment.

Small vessel disease

CAD in vessels with a diameter < 2.5 mm is considered as small vessel disease (SVD) [53] and occurs in around 40% of patients undergoing PCI. SVD is associated with higher risk of ISR and lower rates of event-free survival compared to LVD [54]. Numerous studies have investigated DCB PCIs in the treatment of SVD, as summarized in Figure 4.

Figure 4.

Trials investigating drug-coated balloon angioplasty in small vessel disease. DCB — drug-coated balloon; LL — lumen loss; LLL — late lumen loss; MACE — major adverse cardiac event; POBA — plain old balloon angioplasty; QFR — quantitative flow ratio; SVD — small vessel disease; TLR — target lesion revascularization

In SVD patients, DCBs were found non-inferior to 2G-DES regarding the risk of MACE and target lesion failure (TLF) at one-year follow-up [55, 56]. There were no differences between DCB and DES regarding functional outcomes using a quantitative flow ratio [57]. Although patients treated with DCBs had numerically higher %DS [58], DCBs were superior to DESs regarding the risk of in-lesion LLL (0.04 mm vs. 0.17 mm; p = 0.03 for superiority) [59, 60]. Interestingly, no complete occlusions were reported in the DCB group, whereas some occurred in the DES group [61]. Considering long-term outcomes, similar rates of MACE, TLR, and TLF persisted through the follow-up period of two and three years [56]. Lower rates of major bleeding events were reported in the DCB group, which might result from shorter DAPT duration [62].

Altogether, current evidence from randomized controlled trials supports the non-inferiority of DCB to DES in SVD patients in up to three years of follow-up.

Large vessel disease

In contrast to SVD, DCBs have not been widely investigated in large vessel disease (LVD) (vessel diameter > 3 mm [63]). Nevertheless, preliminary evidence suggests that DCB PCI is safe and efficient also in this patient population.

Studies have shown relatively low rates of MACE and TLR in LVD patients treated with DCB PCI, ranging between 1 and 5% at 12 months [64, 65]. LLL was similar in the DCB and the DES group [66]. One study highlighted a 35% rate of coronary dissection following DCB PCI, which did not result in an increased risk of MACE [67]. At five-year follow-up, DCB PCI was not associated with increased mortality, compared with G2-DES [68].

Hence, DCB might be a noninferior alternative to DES in carefully selected LVD patients, with no flow-limiting dissections, residual restenosis ≤ 30%, and/or fractional flow reserve (FFR) > 0.80 following DCB PCI (central illustration).

Central illustration.

A proposed algorithm for drug-coated balloon (DCB)-only angioplasty. Green fields — recommended attention points/desirable outcomes; orange fields – attention points to be considered; red fields — undesirable outcomes. FFR — fractional flow reserve; LVD — large vessel disease; SB — side branch; SVD — small vessel disease; TIMI — thrombolysis in myocardial infarction

Chronic total occlusions

Chronic total occlusions (CTO) are defined as total occlusion of a coronary artery segment with a thrombolysis in myocardial infarction (TIMI) grade zero antegrade flow for at least three months. CTOs are present in about 20% of coronary angiograms. Due to the technical complexity and high risk of ISR or stent thrombosis, only 50% of patients with a CTO undergo interventional treatment [69]. Recently, DCBs have been investigated in the CTO setting as an alternative to DESs.

In the first feasibility and safety study in a group of 34 patients, DCB-only angioplasty allowed for satisfactory recanalization in 79.4% of patients, leading to significant improvement in terms of Canadian Cardiovascular Society angina class (p < 0.001) [70]. In a study investigating the use of DCBs in CTO PCI in patients with SVD, the use of DCB only was associated with non-significantly higher rates of TLR (17% vs. 3%; p = 0.19) and binary restenosis (17% vs. 7%; p = 0.32) compared to non-CTO lesions [71]. In the hitherto largest multicenter, observational study including 591 patients with both SVD and LVD, 290 patients were treated using DCB only or combined with DES. The rate of restenosis (20.5% vs. 19.7%) and major adverse cardiovascular events at three years (11.8% vs. 12.0%) were similar in both groups. In the DCB group, 147 (50.7%) lesions were treated using DCB only, and the bailout stenting rate was relatively low (3.1%). The authors concluded that PCI with DCB might be a potential stent-free therapy for de novo CTO lesions with satisfactory long-term outcomes, compared to the standard DES approach [72].

Altogether, using DCB only or combined with DES seems a feasible strategy in CTO PCI, provided that the result is no flow-limiting dissection and acceptable residual diameter stenosis. Because the available evidence is limited to observational studies and registries, the use of DCBs in CTO PCI remains an explanatory field. Randomized trials comparing DCB to DES strategy in CTO PCI, which are currently in progress, will provide more data on the use of DCBs in this complex setting.

Patients with diabetes mellitus

DM results in endothelial, vascular, and platelet dysfunction [73]. Thereby, DM patients are at greater risk of CAD and MI compared to non-DM patients [74]. Moreover, DM is associated with higher rates of MACE and TLR following PCI [75]. Hence, DM patients referred to PCI constitute a challenging population.

Both DCB PCI and DES implantation have been investigated in DM patients. Compared to DES implantation, DCB PCI was associated with similar rates of MACE, cardiac death, and nonfatal MI. The rate of target vessel revascularization was lower in DM patients treated with DCBs than in those treated with DESs (9.1% vs. 15%; HR: 0.4; 95% CI: 0.17–0.94; p = 0.036) [76]. A meta-analysis of three trials reported similar PCI outcomes following DCB and 1G-DES use, and highlighted the lower risk of TLR in DM patients treated with DCBs (odds ratio [OR]: 0.51; 95% CI: 0.25–1.06; p = 0.07) [77]. Moreover, a comparison of DCB and DES in treating ISR in DM patients showed no significant difference in safety or efficiency [78]. Overall, DCB PCI was associated with a higher risk of TLR (1.9% vs. 4.15%; OR: 2.233; 95% CI: 1.083–4.602; p = 0.026) in DM patients compared to non-DM patients [79]. Additionally, another study found that DM patients undergoing DCB PCI might be at higher risk of MACE (12.5% vs. 19.1%; HR: 2.049; 95% CI: 1.056–4.284; p < 0.05) than non-DM patients [80].

Altogether, DCB showed promising results regarding CAD treatment in DM patients, with a potential to reduce TLR risk. Nonetheless, further studies are necessary to compare DCB with G2-DES.

Patients with acute coronary syndrome

ACS patients undergoing PCI present higher rates of stent thrombosis compared to those with chronic coronary syndromes [81]. DCB PCI leaves no implants in the vessel wall and thus is associated with lower thrombotic risk than stent implantation [6]. Thereby, DCB PCI was investigated in ACS patients.

In 210 non-ST-segment elevation MI (NSTEMI) patients, DCB PCI was found to be non-inferior to stent implantation. At nine-month follow-up, the rate of TLF was 3.8% vs. 6.6% (p = 0.53), whereas the rate of MACE was 6.7% vs. 14.2% (p = 0.11) for the DCB and the stent group, respectively [81]. Similarly, among 100 ST-segment elevation MI patients (STEMI), 59 of whom were treated with DCB alone, DCB PCI was associated with a 5% risk of MACE at one-year follow-up [82]. In the prospective, randomized REVELATION trial including 120 patients with STEMI, DCB was found to be non-inferior to DES in terms of FFR at nine-month follow-up [83]. However, in a prospective registry-based study including STEMI patients, DESs were superior to DCBs regarding the risk of LLL (0.51 ± 0.59 mm vs. 0.21 ± 0.32 mm; p < 0.01) and restenosis (22.2% vs. 4.5%; p = 0.07) [84]. The authors concluded that a DCB-only strategy might be a potential treatment alternative in patients with contraindications to DES. In contrast, in the randomized REVELATION study, comprising 120 patients with STEMI, non-severely calcified native coronary culprit lesion, and a residual stenosis of < 50% after pre-dilatation, the use of DCB was non-inferior to DES in terms of FFR assessed at nine months (0.92 ± 0.05 in the DCB vs. 0.91 ± 0.06 in the DES group) [83]. The rate of major adverse cardiac events at two years was also comparable in both groups (5.4% vs. 1.9%, p = 0.34), although the overall number of events was low.

Overall, DCB PCI might constitute a promising strategy in both NSTEMI and STEMI patients [85], but further trials with higher patient numbers and longer follow-up are required to compare the efficacy and safety of DCBs and DESs in ACS setting.

Procedural aspects of drug-coated balloon-only angioplasty

A proposed algorithm for DCB-only angioplasty is shown in the Central illustration. As in all technologies used during PCI, patient selection is crucial to ensure procedural success. DCB should be taken into account in patients at high bleeding risk, according to the Academic Research Consortium for High Bleeding Risk at the time of PCI, defined as age ≥ 75 years, concomitant use of oral anticoagulants, non-steroidal anti-inflammatory drugs, or steroids, previous spontaneous intracranial hemorrhage, active malignancy in the last 12 months, history of spontaneous major bleeding or ischemic stroke in the past six months, major surgery in the past month, concomitant chronic kidney disease, anemia or thrombocytopenia, or planned major surgery on DAPT [86]. With the overall aging of the population, the above-mentioned risk factors are present in most patients undergoing PCI. On the other hand, DCB might be applicable in patients at high risk on stent restenosis, such as patients with DM, multivessel, premature (< 45 years) or accelerated CAD, or history of complex revascularization [85]. The angiographic characteristics making patients suitable for DCB include ISR (class I recommendation according to European Society of Cardiology), SVD (reference diameter of < 2.5 mm), BL – especially if the side branch dilation is required or if the stenosis is limited to the SB (medina 0,0,1), aorto-coronary ostial lesions – where long-term results after stenting are worse than those achieved in non-ostial locations due to the differences in plaque composition and the risk of geographic miss, and calcified, likely non-expandable lesions despite the use of extensive calcium modification techniques [79, 87]. Recently, the feasibility of DCB use in LVD and CTO is also being investigated, with favorable preliminary results.

Intravascular imaging helps to identify the presence and distribution of calcium, determine plaque burden, and plan the intervention by measuring the vessel lumen diameter and lesion length, and identifying the DCB landing zone [88]. Subsequently, the lesion preparation technique can be chosen based on the angiographic and intravascular imaging findings. Generally, pre-dilation with non-compliant balloons, including super high-pressure balloons, or cutting and scoring balloons is advised prior to DCB-PCI [6]. In a randomized trial including 252 patients with clinically significant DES restenosis, pre-dilatation with a scoring balloon prior to DCB reduced the incidence of binary angiographic restenosis, compared to standard therapy (18.5% vs. 32.0%) [36]. More aggressive calcium modification techniques, including rotational or orbital atherectomy, intravascular lithotripsy, or excimer laser should be considered for severely calcified lesions, with the caveat that the first two atherectomy devices are not registered for ISR.

The cracks in the intimal layer during lesion preparation are crucial to maximize the effect of the DCB, because they enable higher retention and deeper delivery of the antiproliferative drug. Following successful lesion preparation, preferably confirmed in intravascular imaging, the DCB can be delivered. Both paclitaxel- and sirolimus-coated balloons seem similarly safe and efficient in terms of angiographic and clinical results, so the choice of DCB remains at the operator’s discretion [88,90]. Regardless of the DCB type, the transit time, balloon inflation time, and DCB oversize are the key variables to ensure the effective drug transfer from the DCB to the vessel wall [91]. A recent ex vivo study in isolated porcine carotid arteries demonstrated that after 30 seconds of transit, the DCB coating was still intact, whereas after three minutes, the peeling of the DCB coating was clearly visible. Similarly, in the case of a DCB-artery ratio of 1:1, the mean drug loss from one hour to one day was over 80%, whereas in the case of a DCB-artery ratio of 1.25:1 — only 10%. Hence, a successful DCB-PCI requires a delivery time < 30 seconds, inflation time > 60 seconds, and slight artery overstretch. Given that DCB are relatively bulky, especially the short transit time might be challenging. In case of delivery problems, a guide extension catheter, buddy wire, buddy balloon, or anchor balloon technique might be helpful [91, 92].

The final step in DCB PCI is to decide whether DCB-only use ensures the optimal procedure result, or if bail-out stenting is required. Optimal angiographic results, including TIMI grade 3 flow, residual stenosis < 30%, and minor dissection (type A or B, i.e., luminal haziness or linear dissection of the intima, with no persistence of contrast) are associated with a lower risk of repeat ISR compared to suboptimal angiographic findings (20.3% vs. 35.5% at two years [88, 93]. Post-procedural intravascular imaging is also useful to evaluate minimal lumen area, residual plaque burden, and the extension of dissection. Finally, functional assessment may be an option to aid decision-making, with post-DCB PCI FFR values > 0.80 (0.75–0.85, depending on the study) associated with better clinical outcomes [88]. One should bear in mind, however, that the optimal FFR/iFR (instantaneous wave-free ratio) cutoff values, which define a suboptimal PCI result and should trigger PCI optimization, remain a matter of debate [94]. Post-PCI FFR/ iFR measurements might also be biased due to acute microvascular impairment after prolonged DCB inflation. In addition, the location of the physiological assessment is an important factor when interpreting post-PCI FFR/iFR, with absolute post-PCI iFR values on average 0.06 points lower in the LAD than in other vessels [95]. Hence, the European Association of Percutaneous Cardiovascular Interventions Consensus Document has advised against overreacting to abnormal postprocedural FFR/iFR values and recommends abstaining from aggressive post-dilation or additional stenting until clarifying the cause of abnormal values and establishing whether it might be optimized by additional maneuvers [96].

Conclusions

Evidence from multiple trials suggests that DCB-only angioplasty is a safe and efficient alternative to stenting, especially in patients with ISR, BL, and SVD, as well as in DM patients undergoing PCI. The contemporary clinical trials evaluating DCB in LVD, CTO PCI, and ACS settings might further expand the indications for this technology. The development of DCBs, including the implementation of new antiproliferative drugs and structural modifications, may further reduce the risk of thrombosis and restenosis. Currently, superior trials, including a larger number of patients with longer follow-up and clinically relevant hard endpoints, are required to compare DCB- and DES-based strategies and to establish the guidelines for a patient-tailored PCI strategy.