In-stent restenosis remains the primary cause of PCI failure, though the development of DESs generations has improved anti-restenosis performance (18). A recent report showed that approximately 20% of patients required target lesion revascularization (TLR) at the 10-year follow-up (19). Several therapies for ISR of BMS or DES have been tested in clinical trials (20), and DCB and repeated stenting with DES have become the most effective therapeutic options, which have been recommended as class IA by guidance (5). A recent meta-analysis of 10 RCTs showed that DCB and DES were similarly effective and safe in the treatment of BMS-ISR, whereas DES had higher efficacy than DCB in the treatment of DES-ISR (21).

As the first trial demonstrated that paclitaxel-DCB angioplasty was superior to plain old balloon angioplasty (POBA) alone in BMS-ISR, the PACCOCATH ISR trial recommended DAPT for 1 month followed by treatment with aspirin alone (2). At 6 months, the primary endpoint late lumen loss (LLL) in-segment was lower in the DCB group than in the POBA group (0.03 ± 0.48 mm vs. 0.74 ± 0.86 mm, P = 0.002). Restenosis occurred in 10 of 23 patients (43%) in the POBA group, compared to only 1 of 22 patients (5%) in the DCB group (P = 0.002). Patents who required TLR were significantly fewer in the DCB group than in the POBA group (0 vs. 6%, P = 0.02). At 5 years, TLR rates were still significantly lower in the DCB group than in the POBA group (38.9 vs. 9.3%, P = 0.004) (22). No stent thrombosis was found during the entire follower-up trial, which suggests that short-term DAPT may be feasible and safe for patients who undergo DCB angioplasty.

In most trials on BMS-ISR treatment, DAPT with aspirin 100 mg per day and clopidogrel was recommended for 3 months (23–26) (Table 2). Among these trials, only two cases of stent thrombosis were found during the follow-up (24, 25). It is worth mentioning that one patient in the DCB group experienced stent thrombosis due to clopidogrel discontinuation before late angiography in the RIBS V trial. The PEPCAD II ISR study showed that 19 of 66 (28.8%) patients in the DCB group and 42 of 65 (64.4%) patients in the DES group were still using clopidogrel (P < 0.0001) at 6 months, whereas after 12 months, the usage declined to 12 of 66 (18.1%) and 27 of 65 (41.5%), respective (P < 0.01) (23). However, there was no significance difference between the treatment groups with DAPT at 1 and 3 years (P = 0.80 and 0.47, respectively) (35).

However, the duration of DAPT varied from 3 to 12 months in trials for DES-ISR treatment (Table 2). In the RIBS IV randomized clinical trial, which showed DCB had lower efficacy compared to EES in patients presenting with DES-ISR, DAPT was prescribed for only 3 months after DCB angioplasty, and then aspirin monotherapy was maintained (30, 36). The TLR rates were significantly reduced in the EES group both at 1-year (4.5 vs. 13.0%, P = 0.007) and 3-years (7.1 vs. 15.6%, P = 0.015) follow-up, but the need for “late” (>1 year) TLR (2.6 vs. 4%) was similar in the two groups. Stent thrombosis (both definitive and probable) occurred in three patients (two in the DCB group and one in the EES group) at 1 year and after that another two cases of stent thrombosis occurred in the DCB group at 3 years (36). However, during the actual follow-up for the trial, 84% of patients in the DCB group were still receiving DAPT at 9 months, and 64% were still receiving DAPT at 1 year, of which 52% suffered from unstable angina at the time of recruitment. For most trials, DAPT was administered for 6 months after DCB dilatation (27, 28, 31, 32). In these trials, DCB showed higher efficacy than POBA with DES-ISR treatment, which showed similar efficacy to DES. Two stent thrombosis cases were found in the DCB group during the follow-up, one in the PEPCAD-DES trial (37) and another in the ISAR-DESIRE trial (28). The PEPCAD China ISR trial also demonstrated that angioplasty with DCB was non-inferior to PES implantation when used to treat DES-ISR (29, 38). In this trial, all patients, irrespective of treatment allocation, were prescribed DAPT for 12 months. There was one late stent thrombosis occurred in the DCB group and two in the PES group at the 1-year follow-up, and another very late stent thrombosis occurred in the PES group at the 2-year follow-up (38).

It remains challenging to treat coronary small-vessel disease, which is usually defined as lesions in vessels <3.0 or ≤ 2.75 mm, because it is significantly and directly associated with an increased risk of clinical events (39). Though DES has been found to be equally effective in small and large vessels, the resulting LLL occupies a higher percentage of the respective vessel diameter, leading to a higher incidence of ISR and other clinical events (40). Drug-coated balloon angioplasty has the theoretical advantage of providing immediate and homogenous drug uptake, leaving no metal in the coronary artery and respecting the vessel anatomy, thus forming a “leave nothing behind” strategy in the treatment of do novo CAD (41). Many notable RCTs involving small vessel disease have used this strategy and all studies have shown the benefits of DCB except the PICCOLETO (42) (Table 3), which may be explained as the limitations of the first-generation Dior DCB (49). A recent meta-analysis showed that the use of DCB in the treatment of do novo CAD was associated with comparable clinical outcomes regardless of the indication or comparator device (50). However, there is still no clear conclusion regarding the duration of DAPT against small-vessel disease treated by DCB.

At present, the widely used postoperative DAPT strategy from clinical trials for the DCB treatment of small-vessel disease is the following: (1) DAPT duration in stable patients using DCB is 4 weeks; (2) DAPT duration in stable patients using DES is 6 months; (3) DAPT duration in patients with ACS is 12 months; and (4) DAPT duration in patients treated with a combination of DCB and BMS is 3 months, and in patients with DCB and DES is 6 months. Notable trials that used this strategy include PICCOLETO (42), BELLO (43), BASKET-SMALL 2 (45), and PICCOLETO II (48). Among these trials, the binary restenosis rates and TLR rates were comparable between the DCB and DES groups and were all low-probability events. It is important to acknowledge that patients treated with DCB and without stenting did not experience any thrombotic events in these trials, whereas only two stent thrombosis events were found in the BASKET-SMALL 2 trial during the 3-year follow-up (45). These results suggest that DCB may provide significant advantages over DES in treating small vessel disease, such as a lower risk of stent thrombosis, a shorter duration and less dependence on DAPT (43).

The RESTORE SVD China trial also demonstrated that the Restore DCB was non-inferior to the second-generation RESOLUTE Integrity DES (47, 51). However, DAPT was prescribed for at least 6 months after discharge from the hospital. During the 12-month follow-up, no significant difference was observed in the comparison of DAPT duration between the DCB and DES groups (91.4 vs. 94.7%), which was partly due to the high proportion of unstable angina in this study and the high incidence of MACE in small vessels.

Many interventional cardiologists had doubts about the safety of DCB alone for large vessel de novo CAD because large coronary arteries have more smooth muscle fibers than small vessel arteries and are more prone to recoil and dissection, which may lead to acute occlusion or restenosis of blood vessels (52). Although randomized data for comparing DCB and DES in the treatment of large vessels are still lacking, there are variable proportions of large vessels that were treated using the DCB-only approach in studies, which creates growing evidence for the safety and efficacy of the DCB-only strategy for the treatment of large coronary arteries. The durations of DAPT in these trials ranged from 1 to 12 months (Table 4).

A recent prospective large-scale multicenter trial demonstrated that DCB as a stand-alone-therapy showed similar efficacy on large and small vessels (60, 61). In this trial, standard DAPT duration was recommended for 1 month in DCB-only treatment and a minimum of 6 months when additional stents were implanted. During the follow-up, in the large vessel group, the DAPT duration was 2.7 ± 1.6 months, whereas in the small vessel group, the DAPT duration was 2.8 ± 1.6 months (p = 0.583). Meanwhile, this trial observed that around half of each group had a recommendation for 4 weeks of DAPT (>2.75 mm: 53.3% vs. ≤ 2.75 mm: 48.1%, p = ns). Only one case of stent thrombosis occurred in each group. The DEBUT trial which showed DCB-only coronary intervention was superior to BMS in patients at bleeding risk, was also administered 1-month of DAPT for all patients (9). In patients assigned to DCB, 64% were treated with a DCB that was 3 mm or larger diameter, and stent thrombosis occurred in none of them. A short duration of DAPT after DCB angioplasty was recommended in the other three trials without any stent thrombosis found and low risk rates of clinical events (56–58). These results indicate that short-term DAPT may be feasible and safe. On the contrary, some trials recommended DAPT for 6 months or longer, and they also did not find stent thrombosis during follow-up (53–55). These trials chose a longer DAPT duration because most patients in these trials were admitted to the hospital for ACS.

Although receiving second-generation DES is the most common option for the treatment of patients with ACS and is generally considered the optimal strategy (65), some small sample size clinical trials have attempted to use the DCB-only strategy in primary percutaneous coronary intervention (PPCI) (54, 55, 66–68). Nicola et al. conducted the first study of a DCB-only strategy in the setting of PPCI, and DPAT was scheduled to be continued for 12 months (66). This study showed good 1-year clinical results with only five MACEs occurring, including three TLR and one acute stent thrombosis, but additional stenting was performed in half of the patients. Recently, the REVELATION study shown that DCB was non-inferior to the second-generation DES in the treatment of ST-segment elevated myocardial infarction patients (55). All patients were on DAPT and/or combined with oral anticoagulation for at least 1 year. Up to the 9-month follow-up, only three patients required TLR (one in the DES group and two in the DCB group) and only one thrombotic event was found in the DCB group. The 1-year duration of DAPT seemed to be a reasonable option based on the guideline recommendations and the results of existing clinical trials.

However, it remains a question whether DAPT duration for ACS patients is worth reducing or prolonging. A recent meta-analysis of the duration of DAPT after PCI with DES demonstrated that short-term DAPT presented similar efficacy and safety to standard-term DAPT for patients with ACS (69). In the DEBUT trial, 46% of patients treated with DCB only were diagnosed with ACS (9). All patients in this trial were recommended to undergo only a 1-month duration of DAPT, and the results showed low MACE rates with no TLR event at 9 months. Meanwhile, no stent thrombosis event occurred during the follow-up. In another retrospective study which contained 55% of ACS patients showed a 12% MACE rate and 2.8% TLR rate at 12 months (64). The median and mean durations of DAPT were 1 and 3.3 months in the ACS population. Of note, half of the patients had at least one risk factor for bleeding. Furthermore, about 4% of patients did not receive any ADP receptor blockers at all during or after PCI due to a contraindication for DAPT. Meanwhile, the European Society of Cardiology Guidelines also suggest that patients at high or moderate ischemic risk who have well-tolerated DAPT within the first year after myocardial infarction may benefit from more intense antithrombotic therapy beyond 12 months from the acute event (70). For this kind of patients (e.g., age ≥65 years and multivessel coronary disease), aspirin 75–100 mg with ticagrelor 60 mg twice daily or rivaroxaban 2.5 mg twice daily may be administered, which would reduce the ischemic risk with no major bleeding events and infrequent minor/minimal bleeding (71, 72). Whether prolonging or reducing the duration of DAPT, it is important to tailor the treatment to each patient to get the best benefits of DAPT.

Thus far, paclitaxel, as a cytotoxic agent, is the preferred drug for balloon coating and has been widely cited in cardiovascular interventional therapies. With the growing clinical research evidence of sirolimus-coated balloon (SCB), their clinical feasibility and safety are being increasingly recognized. The SABRE trial showed excellent procedural success for the Virtue sirolimus-eluting angioplasty balloon in the treatment of ISR (73). In this trial, DAPT was continued for at least 3 months and the MACE rate was 14.3% at 12 months, with a 12.2% TLR rate. Soon after that, an RCT that compared a crystalline coating SCB with paclitaxel-coated balloon (PCB) demonstrated similar angiographic outcomes in the treatment of coronary DES-ISR (74). Interestingly, DAPT was recommended for 1 months in stable patients and 12 months in cases of ACS. The MACE and TLR rates were similar between the two groups, and only one stent thrombosis occurred in the PCB group. Two other large prospective trials that enrolled a real-world, all-comer patient population also showed the safety and efficacy of SCB, both in patients with ISR or de novo lesions (75, 76). The Nanolutè study evaluated the clinical performance of a novel SCB (Concept Medical Research Private Limited, India) for the treatment of ISR and de novo coronary lesions. Dual antiplatelet therapy was recommended for 3–12 months in this trial (75). The MACE rate was 4.2% with 3.2% TLR at 2 years. The EASTBOURNE registry also evaluated this kind of SCB and obtained similar results as the Nanolutè study (76). In this trial, DAPT duration was prescribed for a minimum of 1 and 6 months in the case of additional stent implantation. As for ACS patients, DAPT duration was prescribed according to the current guidelines.