Chinese expert consensus on the clinical application of drug-coated balloon (2^nd Edition)

Abstract

Percutaneous coronary interventions have progressed through the era of plain balloon dilation, bare-metal stent insertion to drug-eluting stent treatment, which has significantly reduced the acute occlusion and restenosis rates of target vessels and improved patient prognosis, making drug-eluting stents the mainstream interventional treatment for coronary artery disease. In recent years, drug-coated balloons (DCBs) have become a new treatment strategy for coronary artery disease, and the drugs used in the coating and the coating technology have progressed in the past years. Without permanent implant, a DCB delivers antiproliferative drugs rapidly and uniformly into the vessel wall via the excipient during a single balloon dilation. Many evidence suggests that DCB angioplasty is an effective measure for dealing with in-stent restenosis and de novo lesions in small coronary vessels. As more clinical studies are published, new evidence is emerging for the use of DCB angioplasty in a wide range of coronary diseases, and the indications are expanding internationally. Based on the latest research from China and elsewhere, the Expert Writing Committee of the Chinese Expert Consensus on Clinical Applications of Drug-Coated Balloon has updated the previous DCB consensus after evidence-based discussions and meetings in terms of adequate preparation of in-stent restenosis lesions, expansion of the indications for coronary de novo lesions, and precise guidance of DCB treatment by intravascular imaging and functional evaluation.

With the development of percutanronary intervention (PCI), there has been dramatic progress in the treatment of coronary heart disease (CHD). Intracoronary stenting has become a major therapeutic choice for the treatment of CHD. However, in-stent restenosis (ISR) and in-stent thrombogenesis bring great challenges to the long-term effects after coronary stenting. With the evolution of coronary stents [from the original bare-metal stents (BMSs)], the latest generation of drug-eluting stents (DESs) has brought the restenosis rates down to < 10%.^[1] However, the likelihood of DES restenosis increases over time, which is still a challenge in clinical practice. Additionally, stent thrombosis also needs to be addressed.

As a novel therapeutic option for CHD, drug-coated balloons (DCBs) can deliver antiproliferative drugs rapidly and uniformly to the blood vessel wall without permanent implantation. The DCB has been effective in dealing with ISR and de novo small vessel diseases (SVDs) of the coronary artery. Growing evidence supports the application of DCBs in various kinds of CHDs, accompanied by expanded indications overseas. Based on the latest research from China and elsewhere, the Expert Writing Committee of the 2016 Chinese Expert Consensus on Clinical Applications of Drug-Coated Balloon^[2] has updated this consensus after Chinese expert discussions. The latest version of the consensus renewed several aspects during DCB application, including the perspectives of sufficient pretreatment for ISR, indication extension of de novo coronary artery lesions, and DCB treatment under the precise guidance of intravascular imaging and functional information.

1. MECHANISM OF ACTION OF DCB AND ITS RESEARCH PROGRESS

A DCB is created by coating a traditional balloon with a single layer of antiproliferative drugs whose pharmaceutical ingredients can rapidly infiltrate the blood vessel wall during a single balloon dilatation and inhibit smooth muscle cell proliferation and migration to disrupt the corresponding restenosis process. Considering its mechanism of action, the antiproliferative drugs carried by a DCB should have a higher transport rate and longer retention time within the blood vessel wall while being released and infiltrating the blood vessel wall. Paclitaxel, a highly lipophilic drug, can be rapidly and uniformly absorbed into the blood vessel wall, leading to persistent suppression of smooth muscle cell proliferation. In this case, paclitaxel is the main medicinal option of DCBs. In comparison with paclitaxel, sirolimus and its derivatives might be safer because of their lower cytotoxicity. However, their binding with the sirolimus receptor is reversible to some extent due to poor lipophilicity. In addition, sirolimus and its derivatives have shorter retention times in local tissues. The above shortcoming imposes certain limitations on their applications in DCBs. With new drug delivery techniques, such as nanotechnology, biodegradable polymeric microspheres and balloon micropore technology, the latest generation of sirolimus-coated DCBs has overcome these shortcomings of sirolimus. With these new technologies, sirolimus can also be released under control, offering a new therapeutic option. Currently, dozens of DCB products have been launched all over the world, as listed in Table 1.^[3] Notably, different DCBs have different compositions and coating techniques, resulting in significant differences in their pharmacokinetic characteristics. There is still no evidence that different DCBs have a “class effect” according to the existing clinical research.^[4]

Table 1. Commercial drug-coated balloons in China and abroad.

Name	Manufacturer	Drug-coated	Excipient
SeQuent Please/SeQuent Please Neo	B.Braun	Paclitaxel	Iopromide
Dior I and II	Eurocor	Paclitaxel	Shellac/Dimethyl sulfate
Biostream	Biosensors International Group	Paclitaxel	Shellac
Agent	Boston Scientific	Paclitaxel	Citric easter
Essential	iVascular	Paclitaxel	Organic ester
IN.PACT Falcon	Medtronic	Paclitaxel	Carbonyldiamide
Pantera Lux	Biotronik	Paclitaxel	Trihexylo-butyrylcitrate
Elutax	Aachen Resonance	Paclitaxel	Glucan
Danubio	Minvasys	Paclitaxel	Trihexylo-butyrylcitrate
RESTORE	Cardionovum	Paclitaxel	Lac amine salt
Protégé	Blue Medical	Paclitaxel	Trihexylo-butyrylcitrate
Bingo	Yinyi Biotech	Paclitaxel	Iohexol
Orchid & Dhalia	Acotec	Paclitaxel	–
Stellarex	Covidien	Paclitaxel	–
Virtue	Caliber Therapeutics	Sirolimus	Micropore balloon
Selution	Med Alliance	Sirolimus	Cell attachment
SeQuent Please SCB	B.Braun	Sirolimus	Butylated hydroxytoluene (BHT)
Magictouch	Concept Medical Research	Sirolimus	Phospholipid
Baiteng	Jiwei Medical	Biolimus A9™	Polyethylene oxide

2. INDICATIONS FOR DCB AND EVIDENCE

2.1. Indications for DCB Angioplasty based on Angiographic Characteristics

2.1.1. ISR

As stent technology has progressed, inhibiting the ISR process is particularly important. There are differences in clinical manifestations, plaque morphology, pathological progress and responses to therapies for BMS-ISR and DES-ISR after stenting. Excessive neointimal hyperplasia is a major cause of BMS-ISR, which manifests as homogeneous hyperplasia under optical coherence tomography (OCT).^[5] The drugs that are used to coat a DES can inhibit intimal hyperplasia. However, polymer carriers of the drugs may also induce an inflammatory response owing to localized stimulation, leading to delayed endothelial healing. This condition mainly manifests as the development of atherosclerotic plaques in the advanced stage, and heterogeneous or laminar hyperplasia may be observed under OCT.^[1] Based on research on the plaque pathology of ISR, some researchers believe that for both BMSs and DESs, the ultimate in-stent pathological change is the development of atherosclerotic plaques over time.^[6] Therefore, distinguishing the histological type of ISR is essential for management, which also raises several concerns regarding intravascular imaging-guided DCB treatment.

The definite efficacy of DCB in ISR treatment has been confirmed by many clinical trials comparing DCB with conventional therapies in recent decades (Table 2). As DCB technology has developed, DCBs of various types and brands have been brought to market. In addition to paclitaxel-coated DCBs, sirolimus and its derivative DCB have also been explored,^[7] revealing similar safety and efficacy. Although paclitaxel-coated DCBs have been successfully applied clinically, different coating formulas and techniques produce various vascular reactions due to differential interactions between specific pharmaceutical preparations, doses or pharmacokinetics and the lesion. To date, no class effect has been revealed to exist among various DCBs. According to a recent meta-analysis, DCBs and DESs were similar in their efficacy and safety for BMS-ISR treatment, while the efficacy of DCBs was inferior to repeated DES implantation during DES-ISR treatment, despite similar safety.^[8] Another meta-analysis included 10 randomized clinical trials (RCTs) comparing DCBs and DESs for ISR treatment. During a 3-year follow-up, it was found that the target lesion revascularization rate was higher in patients receiving DCBs than the new generation of DESs. However, no significant differences were found in all-cause mortality or the incidence of myocardial infarction (MI) or target lesion thrombus formation between the two groups.^[9] Furthermore, as reported by the recent large-scale, multicenter, real-world study in China, the target vessel revascularization rate of DCBs used in DES-ISR treatment was higher than that in the treatment of de novo lesions.^[10] Nevertheless, the DCB has the advantage of being implant-free, a big advantage over the DES. In particular, for patients with a previous history of multilayer stenting and bifurcation extending from the ISR segment or for patients who can clinically benefit from short-term dual antiplatelet therapy (DAPT), a DCB is still a good therapeutic strategy. Accordingly, DCBs are recommended for the treatment of various ISR lesions (recommended classification: I; level of evidence: A) in the 2016 Chinese Guidelines for Percutaneous Coronary Intervention^[11] and 2018 ESC/EACTS Guidelines on Myocardial Revascularization^[4].

Table 2. Randomized controlled trials of ISR treatment with DCBs.

Authors/Literature (time)	Research design	Types of ISR	Follow-up		Key results
			Imaging	Clinical
BMS: bare-metal stent; BP-SES: biodegradable polymer-coated sirolimus eluting stent; BTHC: trihexylo-butyrylcitrate; DCB: drug-coated balloon; DES: drug-eluting stent; ISR: in-stent restenosis; LLL: late lumen loss; MACE: major adverse cardiac events; MLD: minimum lumen diameter; OCT: optical coherence tomography; TLF: target lesion failure; TLR: target lesion revascularization.
PACCOCATH ISR I (2006)[15]	PACCOCATH (26 cases)/Plain balloon (26 cases)	BMS-ISR	6 months; 12 months	6 months; 12 months	6-month LLL: 0.03 ± 0.48 mm vs. 0. 74 ± 0.86 mm (P < 0.002) 6-month restenosis rate: 5% vs. 43% (P < 0.002) 12-month MACE: 4% vs. 31% (P = 0.02)
PACCOCATH ISR II (2008)[16]	PACCOCATH (54 cases)/Plain balloon (54 cases)	BMS-ISR & DES-ISR	6 months	12 months; 24 months	6-month LLL: 0.11 ± 0.44 mm vs. 0.8 ± 0.79 mm (P < 0.001) 6-month restenosis rate: 6% vs. 51% (P < 0.001) 24-month MACE: 11% vs. 46% (P < 0.001)
PACCOCATH ISR II 5-year follow-up (2012)[17]	PACCOCATH (54 cases)/Plain balloon (54 cases)	BMS-ISR & DES-ISR		5 years	5-year TLR: 9.3% vs. 38.9% (P = 0.004) 5-year MACE: 27.8% vs. 59.3% (P = 0.009)
PEPCAD II (2009)[18]	SeQuent Please (66 cases)/TAXUS stents (65 cases)	BMS-ISR	6 months	12 months	6-month LLL: 0.17 ± 0. 42 mm vs. 0.38 ± 0.61 mm (P = 0.03) 6-month restenosis rate: 7% vs. 20% (P = 0. 06) 12-month MACE: 9% vs. 22% (P = 0.08)
PEPCAD II 3-year follow-up (2015)[19]	SeQuent Please (66 cases)/TAXUS stents (65 cases)	BMS-ISR		3 years	3-year TLR: 6.2% vs. 15.4% (P = 0.10) 3-year MACE: 7.6% vs. 16.9% (P = 0.11)
PEPCAD DES (2012)[20]	SeQuent Please (65 cases)/Plain balloon (38 cases)	DES-ISR	6 months	6 months	6-month LLL: 0.43 ± 0.61 mm vs. 1.03 ± 0.77 mm (P < 0.001) 6-month MACE: 16.7% vs. 50.0% (P < 0.001) 6-month restenosis rate: 17.2% vs. 58.1% (P < 0.001)
PEPCAD DES 3-year follow-up[21]	SeQuent Please (72 cases)/Plain balloon (38 cases)	DES-ISR		3 years	3-year TLR: 19.4% vs. 36.8% (P = 0.046)
Habara, et al. (2011)[22]	SeQuent Please (25 cases)/Plain balloon (25 cases)	DES-ISR	6 months	6 months	6-month LLL: 0.18 ± 0.45 mm vs. 0.72 ± 0.55 mm (P = 0.001) 6-month restenosis rate: 8.7% vs. 62.5% (P = 0.0001) 6-month TLR: 4.3% vs. 42% (P = 0. 003) 6-month MACE: 96% vs. 60% (P = 0. 005)
Habara, et al. (2013)[23]	SeQuent Please (137 cases)/Plain balloon (71 cases)	BMS-ISR & DES-ISR	6 months	1 month; 3 months; 6 months	6-month LLL: 0.11 ± 0.33 mm vs. 0.49 ± 0.50 mm (P < 0.001) 6-month MACE: 6.6% vs. 31% (P < 0.001)
ISAR-DESIRE III (2013)[24]	SeQuent Please (137 cases)/TAXUS stents (131 cases)/Plain balloon (134 cases)	DES-ISR	6–8 months	12 months	6-month restenosis rate: 39 cases/34 cases/72 cases 12-month TLR: 22.1% vs. 13.5% vs. 43.5% No differences in 12-month MI and mortality among three groups
ISAR-DESIRE III 3-year follow-up (2015)[25]	SeQuent Please (137 cases)/TAXUS stents (131 cases)/Plain balloon (134 cases)	DES-ISR		3 years on average	TLR in 3 years: 33.3% vs. 24.2% vs. 50.8% MI and mortality in 3 years: 10.4% vs. 18.3% vs. 10.9%
SEDUCE (2014)[26]	SeQuent Please (20 cases)/Xience stents (20 cases)	BMS-ISR	9 months (OCT)	12 months	9-month MLD: 2.13 mm vs. 2.54 mm (P = 0.006) 9-month LLL: 0.28 mm vs. 0.07 mm (P = 0.1) No differences in in-stent thrombosis, TLR or mortality in 1 year
PEPCAD China (2014)[27]	SeQuent Please (110 cases)/TAXUS stents (110 cases)	DES-ISR	9 months	9 months; 12 months	9-month LLL: 0.46 ± 0.51 mm vs. 0.55 ± 0.61 mm (Pnon-inferiority = 0.0005) 12-month TLR: 14.5% vs. 13.6% (P = 0.84)
PEPCAD China 2-year follow-up (2016)[28]	SeQuent Please (110 cases)/TAXUS stents (110 cases)	DES-ISR		24 months	24-month TLR: 15.9% vs. 13.7% (P = 0.66)
RIBS V (2014)[29]	SeQuent Please (95 cases)/Xience stents (94 cases)	BMS-ISR	6 months; 9 months	12 months	9-month MLD: 2.01 ± 0.6 mm vs. 2.36 ± 0.6 mm (P < 0.001) 9-month LLL: 0.14 ± 0.5 mm vs. 0.04 ± 0.5 mm No obvious differences in 12-month MACE
RIBS V 3-year follow-up (2016)[30]	SeQuent Please (95 cases)/Xience stents (94 cases)	BMS-ISR		3 years	3-year TLR: 8% vs. 2% (P = 0.04)
RIBS IV (2015)[31]	SeQuent Please (154 cases)/Xience stents (155 cases)	DES-ISR	6–9 months	6–9 months; 1 year	6–9-month min. lumen diameter: 1.80 ± 0.6 mm vs. 2.03 ± 0.7 mm (P < 0.01) 6–9-month restenosis rates: 19% vs. 11% (P = 0.06) 1-year MACE: 18% vs. 10% (P = 0.04)
TIS (2016)[32]	SeQuent Please (68 cases)/Promus stents (68 cases)	BMS-ISR	12 months (± 2 months)	6 months; 12 months	12-month LLL: 0.09 ± 0.44 mm vs. 0.44 ± 0.73 (P = 0.0004) 12-month restenosis rates: 8.7% vs. 19.12% (P = 0.078) 12-month MACE: 10.29% vs. 19.12% (P = 0.213)
ISAR DESIRE IV (2017)[33]	Scoring balloon + Pantera Lux drug balloon (125 cases)/Pantera Lux drug balloon (127 cases)	DES-ISR	6–8 months	12 months	6-8-month LLL: 0.31 ± 59 mm vs. 0.41 ± 0.74 mm (P = 0.27) 12-month MACE: 18.4% vs. 23.3% (P = 0.35) 12-month TLR: 16.2% vs. 21.8% (P = 0.26)
RESTORE (2018)[34]	SeQuent Please (86 cases)/Xience stents (86 cases)	DES-ISR	9 months	12 months	9-month LLL: 0.15 ± 0.49 mm vs. 0.19 ± 0.41 mm (P = 0.54) 12-month MACE: 7% vs. 4.7% (P = 0.51) 12-month TLR: 5.8% vs. 1.2% (P = 0.1)
BIOLUX (2018)[35]	BTHC-based DCB (157 cases)/BP-SES (72 cases)	MIXED-ISR	6 months	12 months	6-month LLL: 0.03 ± 0.40 mm vs. 0.20 ± 0.70 mm (P = 0.40) 12-month TLF: 16.9% vs. 14.2% (P = 0.65) 12-month TLR: 12.5% vs. 10.1% (P = 0.82)
DARE (2018)[36]	SeQuent Please (141 cases)/Xience stents (137 cases)	MIXED-ISR	6 months	12 months	6-month MLD: 1.71 ± 0.51 mm vs. 1.74 ± 0.61 mm (Pnon-inferiority < 0.0001) 12-month TLR: 8.8% vs. 7.1% (P = 0.65)
RESTORE ISR China (2018)[37]	SeQuent Please (120 cases)/Restore DCB (120 cases)	MIXED-ISR	9 months	12 months	9-month LLL: 0.35 ± 0.47 mm vs. 0.38 ± 0.50 mm 12-month TLF: 12.6% vs. 13.3% (P = 0.87)
FIM LIMUS DCB (2019)[7]	Sequent SCB (25 cases)/SeQuent Please Neo (25 cases)	DES-ISR	6 months	12 months	6-month LLL: 0.17 ± 0.55 mm vs. 0.21 ± 0.54 mm (P = 0.794) No differences in 12-month clinical events
Zhu, et al. (2021)[38]	SeQuent Please (108 cases)/Swide (108 cases)	MIXED-ISR	9 months	12 months	9-month LLL: 0.30 ± 0.46 mm vs. 0.29 ± 0.43 mm (P = 0.002) 12-month TLF: 15.09% vs. 10.91% (P = 0.42)

As increasingly supported by evidence-based medicine, intravascular imaging has begun to play a more important role in guiding DCBs for ISR treatment. Undoubtedly, intravascular imaging is beneficial for identifying ISR pathogenesis, including biological (e.g., neointima and newly developed atherosclerotic plaques) and mechanical factors (e.g., excessively small stent diameters, incomplete stent expansion, stent dislodgement and stent fracture). Eventually, it may benefit the selection of an appropriate pretreatment strategy. In addition, intravascular imaging can provide accurate evidence for selecting DCB dimensions.^[12] Available data indicate that in the treatment of ISR with DCBs, the effect of pretreatment is closely associated with long-term efficacy.^[13] According to the EAPCI 2018 Expert Consensus Document on Clinical Use of intravascular imaging, intravascular imaging is strongly recommended for use in evaluating ISR pathogenesis.^[14] Concerning the selection of intravascular imaging tools, intravascular ultrasound (IVUS) has a lower resolution than OCT; in addition, complex tissue structures detected by IVUS cannot be used as histopathological imaging evidence. Consequently, operators prefer to use OCT to guide ISR treatment in clinical practice, and the application of OCT in ISR treatment has been highly evaluated by clinical researchers.

2.1.2. SVDs of the coronary artery

SVD of the coronary artery is generally defined as vasculopathy with a diameter no greater than 2.75 mm. A PEPCAD China SVD multicenter RCT showed that the late lumen loss (LLL) within the segment at 9 months after the procedure with DCB reached an end-point of optimal efficiency compared with plain old balloon angioplasty for SVD treatment.^[39] The results of the BIO-RISE CHINA multicenter RCT showed that the novel limus (Biolimus A9, BA9) DCB was more effective for the treatment of SVD than plain balloon dilatation therapy.^[40] In previous practice of SVD treatment with stenting, there was a larger proportion of postoperative LLL events of small vessels, leading to a higher incidence of ISR and clinical events.^[41] Therefore, more importance is attached to the therapeutic schedule of implant-free treatment with DCBs. An early meta-analysis suggested that DES outperformed DCB, but without considering the “no class effect” of DCB.^[42] A recent large-scale BASKET-SMALL 2 trial compared the efficacy of DCB coated with a mixed matrix of paclitaxel and iopromide with DES in treating SVD patients, and a 3-year follow-up revealed the noninferiority of DCB vs. DES.^[43] The recent PICCOLETO II international multicenter RCT and another meta-analysis that incorporated 5 RCTs comparing the efficacy of DCB and DES for SVDs both concluded that DCB outperformed DES in terms of LLL both at 6 months and 1 year after the procedure, without obvious differences in the incidence of major adverse cardiac event, etc.^[44,45] The clinical efficacy of DCB in SVD treatment has also been confirmed through 3-year follow-up visits in multiple Chinese and overseas trials.^[46–50] Therefore, DCBs show noninferiority to DES implantation, confirming that DCBs can be used for the treatment of de novo SVD (2.0–2.75 mm) coronary artery lesions^{[39,40,43,45–48,51]} (Table 3). For small vessel lesions 2.0–2.25 mm in diameter, the clinical effect of DCBs remains to be determined.

Table 3. Randomized control trials of DCBs in treating primary small vessel diseases of the coronary artery.

Authors/Studies (time)	Research design	Follow-up	Key results
DCB: drug-coated balloon; LLL: late lumen loss; MACE: major adverse cardiac events; MLD: minimum lumen diameter; SVD: small vessel disease; TLF: target lesion failure; TLR: target lesion revascularization.
PICCOLETO (2010)[51]	Dior I drug balloon (28 cases)/Taxus stents (29 cases)	6 months; 9 months	6-month MLD: 1.11 ± 0.65 mm vs. 1.94 ± 0.72 mm (P = 0.0002) 9-month MACE: 35.7% vs. 13.8% (P = 0.054) 9-month TLR: 32.1% vs. 10.3% (P = 0.15)
BELLO (2015)[47,48]	IN.PACT Falcondrug balloon (90 cases)/Taxusstent (92 cases)	6 months; 12 months; 3 years	6-month TLR: 4.4% vs. 7.6% (P = 0.37) 6-month LLL: 0.08 ± 0.38 mm vs. 0.29 ± 0.44 mm (P = 0.001) 12-month MACE: 10% vs. 16.3% (P = 0.21) 3-year MACE: 14.4% vs. 30.4% (P = 0.015)
RESTORE SVD (2018)[46]	RESTORE drug balloon (116 cases)/Resolute Integrity stent (114 cases)	9–12 months	9–12-month LLL: 0.26 ± 0.42 mm vs. 0.30 ± 0.35 mm (P = 0.41) 12-month TLR: 4.4% vs. 2.6% (P = 0.72)
BASKET-SMALL 2 (2020)[43]	SeQuent Please drug balloon (382 cases)/TAXUS and Xience stents (376 cases)	36 months	6-month LLL: 0.13 (-0.14 to 0.57) mm vs. 0.10 (-0.16 to 0.34) mm (P = 0.72) 36-month MACE: 15% vs. 15% (P = 0.95) 36-month target vessel revascularization: 9% vs. 9% (P = 0.83)
PICCOLETO II (2020)[45]	Elutax SV (118 cases)/Xience EES (114 cases)	6 months	6-month LLL: 0.04 mm vs. 0.17 mm (Pnon-inferiority = 0.001, Psuperiority = 0.03) 12-month MACE: 5.6% vs. 7.5% (P = 0.55)
BIO-RISE CHINA (2021)[40]	Biolimus drug balloon (106 cases)/POBA (103 cases)	9 months	9-month LLL: 0.16 ± 0.29 mm vs. 0.30 ± 0.35 mm (P = 0.001)
PEPCAD China SVD (2023)[39]	SeQuent Please drug balloon (181 cases)/POBA (89 cases)	9 months; 12 months	9-month LLL: 0.10 ± 0.33 mm vs. 0.25 ± 0.38 mm (P = 0.0027), Psuperiority = 0.0068 12-month MACE: 13.8% vs. 19.5% (P = 0.234) 12-month TLF: 5.0% vs. 9.2% (P = 0.196) Cardiac death caused by myocardial infarction in 12 months: 0 vs. 0

2.1.3. Bifurcation lesions

Bifurcation lesions have special anatomical characteristics that bring challenges to the corresponding interventional treatment, despite the continuous development of therapeutic techniques. Both single-stent and double-stent strategies may give rise to a high restenosis rate. Their treatment with DCBs can improve therapeutic outcomes by reducing carina shift and preventing uneven local drug distribution and local metal accumulation.^[3,52] Different therapeutic strategies can be undertaken based on the types of bifurcation lesions and their pretreatment results. DCB-only strategies are generally selected for pseudobifurcation lesions. However, in terms of true bifurcation lesions, a DES for the main branch and a DCB for the side branch are the most commonly used strategies.

The procedure sequence may have an impact on the clinical outcome for bifurcation lesion intervention. It is recommended to apply a DCB after main branch stenting and bifurcation lesion pretreatment, followed by final kissing balloon inflation and proximal optimization.^[53] To ensure a smooth delivery of DCB through stent struts, noncompliant balloons equal to the branch vessel size (balloon to reference vessel diameter ratio 1:1) are generally used for sufficient expansion at the ostium of the bifurcation. Treatment with DCBs can be performed in cases of relatively smaller side branches or relatively larger bifurcation angles, making it difficult to deliver guide wires or DCBs. With the application of a DCB in the side branch followed by a DES in the main branch, there may be a risk of stenosis at the ostium of the bifurcation owing to plaque or carina shifting at the bifurcation site. In this case, when the side branch must be rewired, there may be a higher incidence of complications resulting from the wires entering the subintimal because of possible dissections. Additionally, repeated manipulations after treatment with a DCB may have an impact on the long-term efficacy of local drugs delivered. Once a dissection of type B or above presents at the bifurcation after DCB treatment, a DES can be adopted for rescue spot stent implantation at sites of severe dissections distal to the bifurcation to reduce the use of double stents, which may improve the long-term prognosis. When a DCB alone is utilized for treating bifurcation lesions, appropriate DCBs of the main branch are generally selected according to the size of the distal vessels. The DCB is inflated in the side branch and then the main branch. In most cases, kissing balloon inflation should be avoided because it can damage the proximal main branch. The ostium of the side branch can be expanded in the late stage after treatment of the main branch with a DCB.^[54] Moreover, for the treatment of bifurcation lesions, the application of a DCB has the advantages of both alleviating restenosis and simplifying procedures, which has been supported by an increasing body of evidence.^[55,56]

2.1.4. Large coronary artery lesion

Based on experience with SVD treatment, a DCB is also gradually applied in large coronary arteries (reference blood vessel diameter > 2.75 mm, as generally defined). The large coronary artery commonly involves the main branch or a large side branch that supplies a larger territory of myocardium. Therefore, these vessels should be treated with DCBs cautiously. In addition, larger vessels have more rich smooth muscle layers and elastic fibers than small vessels, suggesting a greater likelihood of elastic recoil and hence a higher requirement for more adequate preparations for these lesions. Accordingly, special balloons (e.g., cutting balloon, dual-wire balloon, nonslip element balloon and noncompliant balloon) are more frequently used to achieve better lesion preparation and prevent serious dissection. In case of failure to identify dissection severity and residual lumen area, intravascular imaging tools (e.g., IVUS and OCT) should be used through coronary angiography. A DES should be implanted in cases of obvious intramural hematoma or dissection involving media via intravascular imaging. Recent research has demonstrated that fractional flow reserve (FFR) is safe and effective in guiding the treatment of large coronary artery lesions (including acute coronary syndrome) with DCBs. The postprocedure acute luminal gain can also be maintained during the follow-up, as documented by OCT.^[57,58] Moreover, it is suggested that a 5–15-minute observation between balloon predilatation and DCB implementation^[59] is necessary to determine whether there is a change in residual lumen restenosis and progress in the dissection. An obvious postprocedure decrease in FFR or instantaneous wave-free ratio within 15 min after the procedure indicates dissection progression, in which case rescue stenting should be performed.^[59] As shown by multiple Chinese studies^{[49,60,61,63,65–70]} (Table 4), DCBs alone are both effective and safe in the treatment of large coronary arteries,^[60–62] and similar results have been found in some studies elsewhere.^[63] However, the safety and efficacy of DCBs in large vessels should be further verified by large-scale multicenter trials. At present, only a few studies support the possible noninferiority of DCBs versus DESs in the treatment of large coronary artery lesions,^[64,65] and there has been no head-to-head comparative RCTs of DCBs versus DESs.

Table 4. Clinical studies on DCBs in the treatment of large coronary artery lesions.

Authors/Studies (time)	Research design	Inclusion criteria	Rescue stenting	Follow-up	Key results
DCB: drug-coated balloon; DES: drug-eluting stent; LLL: late lumen loss; MACE: major adverse cardiac events; TLF: target lesion failure; TLR: target lesion revascularization.
Venetsanos, et al. (2018)[49]	DCB (221 lesions)	2.51–3.00 mm (151 lesions) ≥ 3.00 mm (70 lesions)	–	12 months	12-month TLR: 3%
Yu, et al. (2019)[60]	SeQuent Please (222 lesions)	> 2.8 mm	1 case (0.5%)	10 months on average	10-month MACE: 0 10-month TLR: 0
Lu, et al. (2019)[67]	SeQuent Please (92 cases)	> 2.75 mm	6 cases (6.4%)	9 months; 12 months	9-month LLL: -0.02 ± 0.49 mm 12-month MACE: 4.3% 12-month TLR: 4.3%
Liu, et al. (2019)[61]	SeQuent Please (120 cases)	> 3.0 mm	2 cases (1.6%)	12 months	12-month TLF: 3.4%
Rosenberg, et al. (2019)[63]	SeQuent Please (134 cases)	≥ 2.75	7%	9 months	9-month MACE: 6.1% 9-month TLR: 1.0%
DEBUT (2019)[70]	SeQuent Please (102 cases)/Integrity bare stent (106 cases)	2.5–4.0 mm	3 cases (2%)	9 months	9-month MACE: 1% vs. 14% (Pnon-inferiority < 0.00001)
Yu, et al. (2022)[65]	SeQuent Please (85 cases)/New-generation DES of Resolute Integrity, Xience Xpedition, SYNERGY and Firehawk (85 cases)	2.25–4.0 mm	2 cases (2.4%)	9 months; 12 months	9-month LLL: −0.19 ± 0.49 mm vs. 0.03 ± 0.64 mm (P = 0.019) 9-month restenosis rate: 8.9% vs. 9.6% (P = 0.877) 12-month MACE: 2.4% vs. 6.3% (P = 0.226)

2.1.5. Chronic total occlusion and other coronary lesions

Chronic total occlusion (CTO) of the coronary artery remains one of the most challenging lesion subsets in interventional cardiology. Despite advancements in device technology and operative techniques, there is still unsatisfactory long-term safety and efficacy in the treatment of CTO. Owing to the vascular occlusion, distal vessels of the CTO may develop negative remodeling. It may take weeks and even months for the vessels to return to their normal sizes after recanalization. In this context, measurement immediately after recanalization of blood vessels usually underestimates the true diameter of the vessel. Therefore, DCBs have a great advantage in CTO treatment, as no passive stent malapposition occurs when the target vessels of the CTO are restored to their original sizes. A small study supported the feasibility of applying a DCB alone in CTO treatment to a certain extent.^[71] Another study showed the noninferiority of DCB + BMS compared with DES treatment for CTO after recanalization of the occluded vessels.^[72] However, there are scant clinical data concerning the application of DCBs in CTO treatment. Large-scale clinical trials should test whether DCBs are effective for intervention against CTO.

It is also challenging to apply PCI to treat the other de novo lesions of the coronary artery, such as diffuse long lesions, heavily calcified lesions and ostial lesions.^[73–75] Strategies of DCB alone and hybrid therapy (i.e., DCB + DES) are being explored and applied to treat some of these lesions, and some data support the application of DCB in these scenarios.^[76–81] It is expected that future large-scale prospective RCTs will provide more evidence for or against applying DCBs to treat complex lesions of the coronary artery. For now, the application and treatment with DCBs are still recommended to be used with caution.

2.2. Clinical Indications for DCB Angioplasty

2.2.1. Acute myocardial infarction (AMI)

There are a few reports of DCBs as a primary PCI therapy for AMI. The presence of thrombi may affect local drug delivery with DCBs. For this reason, adequate pretreatment is required when applying DCBs in vessels containing lesions in AMI to reduce the thrombus burden and restore blood flow. When necessary, a staged intervention could be performed.^[82] For patients whose lumen diameter cannot be easily determined, DCBs have natural advantages, offering a possible treatment strategy of using DCBs in AMI. In a recent PEPCAD NSTEMI study, DCB alone was demonstrated to be noninferior to stenting in the treatment of non-ST-segment elevation MI.^[83] According to the REVELATION study targeted at ST-segment elevation MI, there was no significant difference in the therapeutic effect of DCB versus stenting.^[84] Overall, the available data show that DCB alone may serve as an alternative to primary PCI for AMI, which is especially applicable to patients with high bleeding risk.

2.2.2. Diabetes mellitus

Diabetes mellitus (DM) is a crucial risk factor for CHD, and cardiovascular diseases are the main cause of death in this population. Approximately one-quarter of patients with acute coronary syndrome have DM.^[85] However, vascular lesions of diabetic patients mostly develop in small vessels, which are characterized by limited vasodilatation reserves, as well as complex and diffuse lesions.^[86] Traditional DES treatment leads to maldistribution of the coated drugs and stent fracture, leading to higher risks of thrombogenesis and restenosis and thus a rather poor prognosis in most cases.^[87] A DCB does not have these defects because it involves no implant and has an effective administration route. Undeniably, DCB is a favorable treatment method. A few large-scale clinical registries compared DCBs with BMSs or the efficacy of DCBs combined with BMSs. Data in these studies support the use of DCBs in patients with DM.^[88] Through a 3-year follow-up, a cohort analysis of patients with DM in a BASKET-SMALL 2 study strongly confirmed that DCBs outperformed DESs in treating CHD patients with DM.^[89] It is hoped that more clinical studies will be carried out to explore the applications of DCBs in patients with DM.

2.2.3. High bleeding risk

Advanced age, concomitant oral administration of anticoagulants, malignant tumors and scheduled surgical procedures are all high-risk factors for bleeding. DAPT after PCI dramatically increases the bleeding risk in patients who already have high bleeding risk. Under this background, a short-term DAPT scheme after DCB (i.e., 4 weeks) shows its advantages.^[48,70] According to relevant clinical data, single antiplatelet therapy after DCB is sufficient for patients whose bleeding risk is particularly high.^[69] In a DEBUT study, DCB treatment was deemed a preferred scheme for intervening in de novo lesions of the coronary artery in patients with high bleeding risk. Moreover, additional clinical data revealed that the short-term DAPT scheme after DCB insertion did not raise the occurrence rate of postoperative thrombotic events.^[90,91] In general, a DCB alone should be the first choice of interventional therapy for CHD patients with high bleeding risk. For some patients whose bleeding risk is especially high (e.g., oral administration of anticoagulants, recent bleeding events and scheduled surgical procedures), a P2Y₁₂ inhibitor alone may be considered for antiplatelet therapy after the procedure.

3. CLINICAL PROCEDURES AND PRECAUTIONS FOR DCBs

3.1. Clinical Procedures (Figure 1)

Figure 1.

Flow of DCB treatment.

ACS: acute coronary syndrome; BMS: bare-metal stent; DAPT: dual antiplatelet therapy; DCB: drug-coated balloon; DES: drug-eluting stent; FFR: fractional flow reserve; ISR: in-stent restenosis; SAPT: single antiplatelet therapy; TIMI: Thrombolysis in Myocardial Infarction; 1 atm = 101.325 kPa.

3.1.1. Lesion preparation^[92]

For compliant/semicompliant balloons, the ratio of the balloon diameter to the reference vessel diameter should be 0.8–1.0. To avoid inadequate predilatation, special balloons such as noncompliant balloons, cutting balloons or scoring balloons could be used for predilatation. Intravascular imaging tools, such as OCT and IVUS, are useful tools for guidance. FFR testing may also provide important information.

Prior to lesion preparation, ISR patients must be carefully examined to discern the pathogenesis. It is strongly recommended to use intravascular imaging tools to clarify the cause of stenting failure and prepare the lesion accordingly. For example, high-pressure predilatation is a countermeasure to ISR incurred by poor stent dilatation. When using DCB for ISR treatment, good lesion pretreatment can reduce the incidence of postoperative events.^[13] The independent predictive factors of target lesion failure after DCB for the treatment of DES-ISR are residual restenosis after pretreatment, diameter ratios of DCBs and DESs, and dilation duration of DCBs.^[92] In comparison with de novo lesions, ISR requires more active pretreatment. Less residual lumen restenosis after pretreatment may be beneficial for long-term prognosis. To improve the long-term efficacy of DCBs, it is suggested that the residual restenosis be below 20% after pretreatment. Intravascular imaging tools are recommended in cases of unsatisfactory conventional predilation. Considering different ISR pathogenesis, plaque volume reduction for ISR can be realized by means of intracoronary shock wave lithotripsy, rotational atherectomy, excimer laser atherectomy, etc.

The pretreatment of de novo lesions of the coronary artery should balance ideal lumen acquisition against the risk of severe dissection. In some studies, de novo lesion pretreatment using balloons with a larger balloon diameter/vessel diameter ratio was accompanied by a high incidence of dissection, which might increase the risk of implant-free strategy failure.^[93]

3.1.2. Evaluation of lesion preparation results

After sufficient predilatation, there is a need to evaluate whether the vessel is suitable for DCB treatment based on relevant predilatation results. A DCB is deemed appropriate if the following three conditions are all satisfied: (1) type B or lower dissection; (2) Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow; and (3) residual restenosis ≤ 30%. Other interventional therapies are suggested if any of the above three conditions cannot be met after adequate predilatation.

3.1.3. DCB treatment

DCBs should be delivered to the target region rapidly (< 2 min, as recommended), and the dilatation time should be long enough (i.e., ≥ 30 s). If the target lesion is at the distal end, with tortuous blood vessels or severe calcification, this may have a negative impact on DCB delivery or may lead to implantation failure. To avoid this outcome, it is recommended to use a dual wire or an extension catheter. Additionally, it should be noted that a DCB is just a tool for delivering drugs and cannot be used to alleviate restenosis at the target site. To prevent a “geographic miss” between the DCB and the segment targeted for pretreatment/stenting, the DCB should cover the entire pretreated segment and exceed both edges by 2–3 mm.

3.1.4. Post-PCI DAPT

When the DCB-alone strategy is used in patients with stable conditions, postoperative DAPT should last for 1–3 months. If DAPT is adopted in combination with stenting, the medication should be administered in accordance with the DAPT requirement of the selected stent. In cases of acute coronary syndrome, postoperative DAPT should continue for at least 12 months. For patients with the high bleeding risk, it is feasible to shorten the duration of DAPT or even replace DAPT with single antiplatelet therapy.

3.2. Treatment with DCB Under Physiological Guidance

Coronary arteriography fails to provide information about the functional significance of stenosis. Consequently, the evaluation criteria of DCB implantation under angiography guidance after balloon dilatation alone have encountered some challenges in lesion pretreatment. In the current literature, FFR-guided PCI outperformed coronary arteriography-guided PCI in terms of prognosis. After lesion pretreatment, coronary arteriography results were highly inconsistent with functional characteristics when a threshold of FFR = 0.75 was established to define functionally significant lesions.^[94] As recommended in the 2019 Asian-Pacific Expert Panel Consensus^[95], DCB implantation can be assessed according to physiological indicators (TIMI grade 3 flow and FFR ≥ 0.75) and DCB implantation criteria after pretreatment (TIMI grade 3 flow, type C and lower dissections, and residual restenosis ≤ 30%) in the 2016 Chinese Expert Consensus on Clinical Applications of Drug-Coated Balloon^[2]. In the case of FFR < 0.75, further pretreatment or stenting can be performed; in the case of FFR ≥ 0.75, a DCB can be implanted. In the 2020 International DCB Consensus^[55], it was recommended that the threshold of FFR be set to 0.80. Given the above results, this expert consensus suggests that not all coronary artery diseases require physiological guidance. Physiological guidance (e.g., consideration of the FFR) is necessary when the distal vessel of the target lesion supplies an extensive amount of myocardium (e.g., proximal lesions of the left anterior descending, proximal lesions of the dominant right coronary artery, and proximal lesions of the donor left circumflex artery), in which case the FFR threshold should be set at 0.80.

In addition, a new algorithm combining three-dimensional quantitative coronary angiography with computational fluid mechanics has been adopted by multiple Chinese scholars to rapidly determine the FFR of the target vessel, that is, the quantitative flow ratio. The role of this algorithm in guiding ISR and SVD treatment has been reported in multiple large-scale randomized clinical registries.^[96,97] As an alternative measure that is adenosine independent, the instantaneous wave-free ratio has recently been used to guide the treatment of in situ lesions of the coronary artery.^[98] It is still safe and effective when its threshold is set at 0.86, but this approach requires more evidence.

3.3. Treatment with DCB Guided by Intravascular Imaging

When applying a DCB, intravascular imaging can help evaluate the nature of preoperative lesions to guide pretreatment strategy selection, precise measurement of the vascular diameter and lesion length to assist in determining DCB size, and identification of dissection severity after pretreatment to predict DCB safety. It is also valuable in postoperative follow-up after treatment with a DCB and can be considered an important supplementary means for DCB treatment. Moreover, IVUS/OCT can provide a reference for operators to determine an appropriate pretreatment strategy based on the different natures and severities of the lesion, which may reduce the incidence of residual restenosis and severe dissections simultaneously. For lipid-rich plaques, no-reflow and slow-flow may occur frequently. After treatment with a DCB, patients with this type of plaque have a higher risk of dissection and vascular occlusion than patients with other plaques. In this event, excessive pressure should be avoided during balloon expansion. For fibrous and calcified plaques, the dilatation effect may be poor with conventional balloons. Special balloons, such as scoring balloons or cutting balloons, can be applied to achieve adequate predilatation. For ISR caused by inadequate stent expansion or severe calcification, it is recommended to adopt debulking techniques (e.g., coronary rotational atherectomy, excimer laser atherectomy, shock wave lithotripsy, etc.) for lesion pretreatment. At present, coronary artery dissection classification is mainly based on the coronary angiography criteria. Intravascular imaging is effective in accurately interpreting severe dissections and intramural hematoma and predicting DCB safety. Severe dissections observed under IVUS/OCT are primarily characterized by high residual plaque burden at a site where dissection occurs, horizontal expansion > 60°, vertical depth > 2 mm, and dissections involving the media/adventitia and located at the distal end of the stent. Intramural hematomas are barely observed by a conventional coronary angiogram. However, they are a major cause of coronary blood flow deterioration after treatment with a DCB. Accordingly, the IVUS/OCT-assisted identification of intramural hematomas seems to be particularly important, but there are still no standardized treatment criteria supported by evidence. Therefore, for intramural hematomas observed after DCB treatment, especially those that have caused lumen compression or affected blood flows, it is suggested that distal cutting balloons or rescue spot stent implantation should be applied as early as possible to prevent further hematoma progression.

Intravascular imaging has been recommended for the treatment of various ISR cases according to the 2016 Chinese Guidelines for Percutaneous Coronary Intervention^[11] and 2018 ESC/EACTS Guidelines on Myocardial Revascularization^[4] (recommended classification: I; level of evidence: A; refer to Section 2.1.1 for details). The present expert consensus recommends the use of intravascular imaging tools (OCT and IVUS primarily) to guide DCB treatment of ISR, clarify the reasons for failure of previous implantations and correct the current procedure.

3.4. Additional Precautions for the Use of DCB

(1) Do not touch the DCB directly with the hands, and do not soak the balloon with normal saline or other liquids, to avoid drug loss; (2) Do not use a DCB more than once. A DCB is a disposable device, and the coated drugs are almost totally released and delivered to the diseased region after balloon dilatation. Repeated use does not deliver any more drugs; (3) For lesions with a high DCB delivery failure rate (e.g., distal lesions, severe calcification, etc.), auxiliary devices, such as extension catheters, could be used; and (4) In the case of severe dissections after treatment with a DCB, there is a need for rescue stent implantation using a DES, and it should also be ensured that the DCB covers the entire region and extends beyond all edges of the DES by 2–3 mm to prevent a “geographic miss” between the stent site and the DCB.

4. SAFETY

Sirolimus-coated DESs are a major concern in the clinical application of DESs. Their safety and efficacy have both been recognized based on the accumulation of massive clinical data. There are relatively few studies on paclitaxel-coated DESs. A recent meta-analysis reported that paclitaxel-coated DESs and DCBs might raise the mortality risk of patients with femoral-popliteal artery diseases in the lower extremity, which has attracted extensive attention.^[99] In contrast, another meta-analysis revealed that a paclitaxel-coated DCB was safer in the treatment of coronary artery lesions during a 3-year follow-up period in terms of all-cause mortality, MI incidence and stent thrombosis of the target lesion.^[100]

5. UNSOLVED PROBLEMS AND FUTURE PROSPECTS

As the concept of “leave nothing behind” prevails, there is a continuous extension of the application of DCBs in coronary interventions. Paclitaxel-coated DCBs still hold a dominant position at present. As the new-generation sirolimus-coated DCBs emerge, their efficacy remains to be clarified by more clinical data. Lesion pretreatment is a key factor for DCB efficacy. Various imaging modalities, such as OCT and IVUS, show advantages in determining the nature and characteristics of lesions and are expected to become important tools to optimize interventional decisions. Physiological guidance may also play a certain assisting role. In terms of indications, in addition to the recommended ISR, a DCB may become an important measure for interventional treatment of de novo SVDs, as indicated by multiple clinical data. Evidence is accumulating that DCB angioplasty is appropriate for bifurcation lesions, de novo macrovascular lesions and other de novo lesions of the coronary artery, such as CTO. For the treatment of patients with AMI, DM or high bleeding risk, the applicability of DCBs is expected to be confirmed by more clinical data in the future.