Drug-Coated Balloon in Primary Percutaneous Coronary Intervention

According to the latest coronary interventional guidelines, a drug-eluting stent is the recommended reperfusion therapy in primary percutaneous coronary intervention (pPCI). However, deficiencies and defects, such as in-stent restenosis (ISR), incomplete stent apposition, stent thrombosis, reinfarction after stent implantation, long-term dual antiplatelet drug use, and adverse reactions of metal implants, plague clinicians and patients. Drug-coated balloon (DCB), which delivers antiproliferative agents into the vessel wall without stent implantation and leaves no implants behind after the procedure, is a novel option for percutaneous coronary intervention and has proven to be a promising strategy in cases of ISR, small vessel coronary artery disease, and bifurcation lesions. However, most of the available experience has been gained in elective percutaneous coronary intervention, and experience in pPCI is lacking. The current evidence for the use of DCB-only in pPCI was discussed and analyzed in this review.


Introduction
Although advances have been made in emergency treatment, acute myocardial infarction (AMI) remains the leading cause of death worldwide [1]. Primary percutaneous coronary intervention (pPCI) is the best treatment modality [2]. With the development of devices and advances in surgical techniques, drug-eluting stents (DESs) have become the preferred option for interventional procedures and were proven to be an efective and safe treatment for acute coronary syndrome (ACS) in pPCI [2]. DES was recommended as a Class I indication by guidelines for the management of ST-elevation myocardial infarction (STEMI) published by the European Society of Cardiology (ESC) in 2017 [3,4]. Until today, pPCI implantation of DES has been recommended because the technique shows excellent immediate revascularization results as well as good medium-to long-term clinical outcomes [5].
With the use of DESs and the development of long-term observational studies, many shortcomings of DES have come to the fore. In this context, the drug-coated balloon (DCB), a semicompliant balloon with drug coated around the outside, may ofer an attractive treatment modality as an emerging percutaneous coronary interventional device. Te main disadvantage of the stent strategy comes from the metal residue. Te DCB-only strategy without stenting is increasingly accepted by patients. However, evidence of efectiveness and safety is still lacking [6,7]. Tis review discussed the current studies using DCB-only in pPCI and provided a preliminary analysis of the results.

Challenges of DES
To prevent stent thrombosis in the early or late stages of implantation, we need to use long-term dual antiplatelet therapy, which increases the risk of bleeding [8,9]. Some bleeding events can lead to death, especially in older or low glomerular fltration rate populations with dual antiplatelet therapy [10]. Intrastent restenosis (ISR) causes recurrence of ACS and makes retreatment of coronary arteries more difcult, which is a troublesome problem with stents [11]. Highly calcifed lesions increase the risk of incomplete stent apposition (ISA). Several devices and equipment have been developed to improve the outcome of stents. For example, rotational atherectomy and intravascular lithotripsy have decreased the risk of ISA [12][13][14], and intravascular ultrasound (IVUS) and optical coherence tomography (OCT) have optimized stent implantation results [15][16][17]. However, the risks associated with stents cannot be ignored, especially in pPCI. For example, ISA is more frequent in DESs implanted during pPCI than in DESs implanted for stable/ unstable angina [18].

The Overview of DCB Technology
DCB allows delivery of antiproliferative topical agents directly into the coronary wall after a single balloon infation [19]. DCB-only strategy fulflls the concept of "implantfree," which prevents any potential problem caused by stents. A shorter duration of antiplatelet therapy was needed, which reduces the risk of bleeding [20,21] and avoids the increased risk of thrombosis associated with implants such as stents [22].
Paclitaxel and rapamycin are attached to the exterior of the balloon as inhibitors of vascular endothelial proliferation and have been shown to be successful in preventing vascular endothelial hyperplasia [23]. Most DCB surfaces use paclitaxel due to its high lipophilic characteristics that allow passive absorption through the cell membranes and a persistent efect inside the target vessel wall. However, that dominance is now being challenged. Some studies suggest possible risks of paclitaxel, such as the possibility of increased long-term mortality [24,25]. Sirolimus is being coated on the balloon surface as a new inhibitor and is being introduced into the interventional feld, and some evidence has been obtained in clinical trials [26][27][28]. However, only 3 sirolimus DCBs were approved for clinical use, and clinical data for sirolimus-coated balloons are still scarce compared to paclitaxel-coated balloons.

DCB-Only Strategy in pPCI
When DCB was the frst used to treat ISR, several randomized trials confrmed its efcacy and safety profle in small-vessel disease and high bleeding risk [29]. Subsequently, several emerging indications for DCBs were identifed, such as bifurcation lesions, large-vessel diseases, diabetes mellitus, and ACS [30][31][32]. Tis strategy using DCB-only without stenting is increasingly accepted by patients and has demonstrated its efectiveness and safety. Te main disadvantage of stents strategy comes from the metal residue, whereas the DCB-only strategy has the advantage of providing antiproliferative agents to the endothelium without leaving any implants.
Tere are studies on the use of DCB-only strategies in pPCI, including prospective studies or retrospective analyses evaluating the safety and efcacy of DCB-only strategies in pPCI and whether they are inferior to DESs (Table 1).
Vos et al. may have conducted the frst study to evaluate the safety and feasibility of using only DCB in STEMI patients undergoing pPCI [33]. In this prospective single-arm study, a total of 100 STEMI patients underwent pPCI, 59 of whom were treated with DCB-only, and 41 required additional stenting because they developed C-to-F coronary dissection or residual stenosis >50%. It was the frst study using a DCB-only angioplasty strategy in the setting of pPCI and showed good one-year clinical outcomes. Of the 98 who completed the 1-year follow-up, 5 had MACE, 2 had cardiac death, and 3 received target lesion revascularization (TLR).
Ho et al. also conducted a single-arm retrospective study of the clinical feasibility of using DCB-only in STEMI patients undergoing pPCI [34]. All 89 STEMI patients included received DCB during pPCI, and 4% of them received compensatory stenting. At the 30-day follow-up, there were four deaths. In this study, using DCB-only pPCI was feasible. It was necessary for better contact such as aspiration of visible thrombus prior to DCB angioplasty, adequate predilation, and extended balloon infation.
To compare the safety and diferences in late vascular lumen conditions in STEMI patients treated with DCB or DES, Gobić et al. conducted a prospective controlled study [35]. 75 patients with STEMI were randomized to the DES group (n � 37) and the DCB group (n � 38) and received 6month follow-up. In this study, DCB-only strategy was safe and feasible and showed good clinical and angiographic outcomes in a 6-month follow-up period. MACE occurred in 5.4% of patients in the DES group and none in the DCB group (P � 0.29). LLL was 0.10 ± 0.19 mm in the DES group and −0.09 ± 0.09 mm in the DCB group (P < 0.05).
Zhang et al. conducted a single-center clinical trial to compare the safety and clinical outcomes of the DCB strategy with the DES strategy in pPCI in patients with AMI [36]. 380 patients received a 3-month follow-up. Te incidence of MACE during hospitalization was similar in both groups (DCB group 3.3% (6/180) and DES group 1.0% (2/ 200), P � 0.15) which was mostly associated with delayed coronary artery dissection, and 1 death occurred in each group. In this study, the safety and efcacy of the DCB strategy were similar to DES. No MACE occurred in either group within 3 months after discharge, while the diference in the incidence of bleeding events was not statistically signifcant (P � 0.91). Te incidence of coronary artery dissection was signifcantly higher in the DCB group than in the DES group (8.3% (15/180) and 3.0% (6/200), P � 0.02), but most of them were type B or A dissections and did not need special treatment.
Hao et al. conducted a randomized controlled clinical trial to study late lumen loss after DCB treatment in pPCI among STEMI patients [37]. 80 patients, randomized to the DCB-treated group (n � 38) and the DES group (n � 42), were reviewed by coronary angiography for late lumen loss (LLL) in both groups at 1 year postoperatively, and their incidence of MACE at 1 month, 6 months, and 1 year postoperatively was recorded. Te results showed that DCB without stenting in pPCI for STEMI was safe and efective during the one-year follow-up period. Te DCB group had less target lesion LLL after 1 year compared to the DES group (−0.12 ± 0.46 mm vs 0.14 ± 0.37 mm, P < 0.05), while the incidence of MACE was not signifcantly diferent (11% (4/38) in the DCB group vs 12% (5/42) in the DES group).

Advantages and Disadvantages of the DCB-Only Strategy in pPCI
Considering the above studies, DCB-only may be a safe and efective option for pPCI. DCB-only is a possible treatment option for pPCI in patients with contraindications to DES or who are not suitable for immediate DES implantation. However, these studies also refect the shortcomings of the DCB strategy and provide some ideas for improving them. Tey are summarized in Figure 1. Residual thrombus in the coronary artery during pPCI can prevent adequate drug release into the vessel wall. Aspirating a visible thrombus prior to DCB angioplasty, performing adequate predilation, and prolonging balloon flling time were suggested to achieve better contact. Te incidence of coronary artery dissection after DCB was higher than that of DES, which may lead to remedial stent implantation for even more inhospital MI [33]. Experienced physicians, proper pretreatment, and the use of endovascular luminal aids can improve outcomes and reduce complications. For example, IVUS and OCT can provide proper protocol guidance to decrease the incidence of dissection or identify hidden dissections for remedial treatment [40]. Cutting the balloon can reduce postoperative elastic retraction of the vessel and lumen loss due to a lack of bracing [41,42]. Compared to conventional balloons, predilation with cutting balloon was proven to be able to reduce the incidence of severe dissections (types E and F) [43,44].

Conclusions
Although DES remains the standard reperfusion strategy in the cases of most AMI lesions, initial evidence, clinical practice, and theoretical evidence point towards DCB-only which appears to be a promising strategy in pPCI. While the clinical data supporting the use of DCB-only in pPCI are limited, research currently exists showing that the use of DCB can reduce the total number and length of stents and even avoid implantation in suitable patients, with undiminished efcacy, which represents a huge allure for patients, especially young people or patients who are reluctant or unable to undergo implantation for any reason.

Data Availability
No new data are applicable to this study.   Journal of Interventional Cardiology