Combined use of drug-coated balloon (DCB) and cutting balloon angioplasty (CBA) in the treatment of acute coronary syndrome

Purpose: To determine the effectiveness and safety of combined use of drug-coated balloon (DCB) and cutting balloon angioplasty (CBA) in patients with acute coronary syndrome (ACS). Methods: One hundred and fifty-six patients with ACS undergoing DCB or CBA from January 2019 to January 2021 served as subjects in this study. There were 30 in-stent re-stenosis (ISR) patients in group A, 31 ISR patients in group B, 61 de novo patients in group C, and 34 de novo patients in group D. Baseline characteristics, high-risk factors, biochemical indices, incidence of intervention-related complications, and major adverse cardiovascular events (MACE) were compared amongst the groups, before and after operation. Results: Group B had a higher immediate minimum lumen diameter (MLD) after operation than group A, and group D had higher immediate MLD after operation than group C. Group B produced higher acute gain after intervention than group A, but post-intervention acute gain was greater in group D than in group C. There were significant differences in late luminal loss (LLL) amongst the groups (p = 0.013), but LLL was comparable in groups A and B (p = 0.411), and in groups C and D (p = 0.434). During the follow-up period, the incidence of MACE in group A was significantly greater than in group B, but MACE in group C was comparable to that in group D. Conclusion: Combined treatment with CBA and DCB significantly improves postoperative immediate MLD and acute gain after intervention in patients with ISR lesions or de novo lesions, without reducing long-term effectiveness and safety. Multi-center trials involving larger number of patients will be required to validate the results from this study.


INTRODUCTION
Coronary heart disease (CHD) is associated with high morbidity and mortality, and it is the leading cause of death worldwide [1].Percutaneous coronary intervention (PCI) has become an important strategy for the treatment of ACS [2].Minimum lumen diameter (MLD) usually increases remarkably after PCI, but decreases during follow-up, leading to late lumen loss (LLL) mainly due to vascular elastic retraction and intimal hyperplasia [3].In-stent restenosis (ISR) is the main cause of stent failure after PCI.Research has found that the incidence of ISR after bare metal stent implantation is about 16 -44 %, while that after drug-eluting stent (DES) implantation is about 5 -15 % [4][5][6][7].Drug-coated balloon (DCB) is a novel strategy for the treatment of ACS [8], and it represents an effective treatment for patients with re-stenosis after stent implantation [9][10][11][12].Cutting balloon angioplasty (CBA) enables uniform tearing of atherosclerotic plaques, thereby reducing the occurrence of acute vascular occlusion and reducing mortality [13].A retrospective study demonstrated that CBA applied after rotational resection of moderately-to-severely calcified lesions resulted in good lumen gain, and reduced the risk of ISR [14].
However, only a few clinical studies have compared the efficacy of DCB alone versus combined use of DCB and CBA in the treatment of ACS.This research evaluated the effect of the combination of DCB and CBA on ACS patients (ISR and de novo lesions).

Study population and ethical considerations
This study involved 156 patients with ACS (ISR and de novo) who were treated with DCB or CBA at Tianjin Medical University Clinical Cardiovascular Institute from January 2019 to 2021.The study received approval from the Ethics Committee of Tianjin Medical University (approval no.PJ-KS-KY-2022-299), and it met the criteria in the Declaration of Helsinki [15].The subjects were divided into four groups: 30 ISR patients with DCB treatment (group A), 31 ISR patients with DCB + CBA treatment (group B), 61 patients with de novo lesions treated only with DCB (group C), and 34 patients with de novo lesions treated with DCB + CBA (group D).

Exclusion criteria
Patients in the following categories were excluded: those aged below 18 or over 80 years; women planning to have children within 1 year; patients with contraindications to surgery; those with intraoperative cardiac arrest or cardiogenic shock; patients unable to receive dual antiplatelet therapy; those whose conditions were complicated with malignant tumors, and patients with severe dysfunction of important organs.

Study design and treatments
All patients received oral dose of clopidogrel (300 mg) or ticagrelor (180 mg) 24 h before operation.During operation, intravenous injection of unfractionated heparin was used for anticoagulation.After operation, all patients were given standard double antiplatelet therapy, namely 100 mg of aspirin in combination with 75 mg of clopidogrel, once a day for 1 year.The femoral artery was cannulated according to standard methods.It was pre-dilatated using a plain balloon or CBA (Boston Scientific Corporation, USA), and then implanted with a DCB (paclitaxel-coated balloon; B. Braun, Berlin, Germany).

Follow-up
Patients were followed up via telephone and outpatient service for at least 1 year.All patients were encouraged to undergo coronary angiography (CAG) at 6 and/or 12 months after operation, to measure the degree of stenosis and reference diameter.

Study end-points
The main end points were major adverse cardiovascular events (MACE) and all-cause death.

Baseline indicators
Baseline data of patients were collected after admission.The data comprised sex, age, BMI, smoking history, history of myocardial infarction, diabetes, hyperlipidemia and hypertension, and history of coronary artery bypass grafting (CABG).After complete examination, the levels of fasting blood glucose, glycosylated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), serum creatinine, high sensitivity C-reactive protein (CRP), B-type brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF) and vascular lesions were recorded.The MLD-and PCI-related complications (coronary artery rupture, dissection, pericardial effusion and myocardial infarction) were recorded after operation.

Statistical analysis
The SPSS version 22 software was used for statistical processing of data.Categorical data are presented as numbers and percentages, and Chi-squared test was employed for comparison of baseline characteristics and clinical characteristics amongst the groups.Continuous variables are expressed as mean ± standard deviation (SD).Paired t-test was used for comparison between preoperative and postoperative data.Two-group comparison was done with unpaired t-test, while one-way ANOVA was used for multi-group comparisons.Values of p < 0.05 indicated statistical differences.

Baseline profile of patients
Table 1 shows that in group A, 30 patients (86.67 %) aged 65.67 ± 7.83 years, were males.In group B, 31 patients (90.32 %) with mean age of 64.74 ± 9.79 years, were males.In group C, 30 subjects (68.85 %) with mean age of 62.47 ± 14.62 years, were males.There were 30 male subjects (76.47 %) in D, with mean age of 59.58 ± 13.44 years.There was no significant difference in baseline characteristics (age, sex and BMI); high risk factors (previous smoking history, myocardial infarction history, CABG history, diabetes history, hyperlipidemia history, and hypertension history); blood glucose, blood lipid, serum creatinine, CRP, BNP and LVEF, among all the groups of patients (p ˃ 0.05).

Coronary angiography in patients
Table 2 shows that ACS types were comparable amongst the four groups (p = 0.079).The main locations of diseased vessels were right coronary artery (RCA), left circumflex branch (LCX) and left anterior descending branch (LAD).The locations of vessel lesions were comparable in the four groups (p = 0.622).The number and length of lesioned vessels were comparable in all groups.Length of diseased vessels was comparable in groups A and B (15.76 ± 6.39 mm vs 17.26 ± 6.97 mm, p = 0.215), and in C and D (14.19 ± 5.06 mm vs 13.41 ± 5.40 mm, p = 0.484).In addition, in groups A -D, the length, diameter, filling pressure and dilation time of DCB used during operation were similar.

DISCUSSION
Drug-coated balloon (DCB) was loaded with an anti-proliferative drug (paclitaxel).Paclitaxel is quickly absorbed by the vascular intima when the balloon is inflated against the vessel wall, thereby effectively blocking early cell proliferation and inhibiting coronary restenosis.Moreover, DCB inhibits the migration of smooth muscle cells and attenuates the proliferative inflammatory response in the intima, thereby significantly reducing LLL [16].Currently, DCB, a new choice for the treatment of coronary ISR, may compensate for many disadvantages of DES.Numerous clinical studies have confirmed that DCB plays a role in reducing ISR [17,18].
However, there are also some problems with DCB, such as the possibility of acute vessel occlusion, as well as dissection and vessel rupture caused by excessive dilation [19].The CBA reduces vessel dissection and rupture by slowly and evenly cutting the intima longitudinally, rather than causing uncontrolled destruction of atherosclerotic plaques [20].Studies have shown that immediate post-PCI MLD is closely linked to the incidence of ISR after stent implantation [21].Pre-dilation of the target vessels by CBA increases the lumen diameter, thereby improving the efficacy of ISR treatment by DCB.In addition, CBA dilates blood vessels with less tension, a situation which may reduce vascular proliferative response and neointimal hyperplasia, resulting in reduction in occurrence of ISR [22].Extant investigations have shown that pretreatment of coronary lesions with CBA reduced TLR and ISR [23].However, few clinical studies have compared the clinical effect of combined use of DCB with CBA versus DCB alone in the treatment of ISR.In addition, there is a paucity of comparative data on treatment of de novo lesions with DCB alone versus combined use of DCB and CBA.
In this study, the types of coronary heart disease were UA, NSTEMI and STEMI, and the main sites of diseased vessels were RCA, LCX and LAD.The incidence of poly-vascular disease was high in each group.Peng et al have shown that, compared with patients with ISR lesions treated with DCB alone, the MLD in the CBA+DCB group was larger [24].We found that for patients with both ISR and de novo, the immediate post-PCI MLD and acute gain after PCI were greater in the DCB+CBA group than in DCB-alone group, revealing that the use of CBA may effectively improve the benefits of DCB in patients with ISR and de novo stenosis.Interestingly, the combined use of DCB and CBA still showed a good therapeutic effect in patients with de novo stenosis.There were significant differences in LLL among the four groups, but the LLL of patients treated with DCB alone was similar to that of those treated with DCB in combination with CBA, indicating that the use of CBA did not reduce the long-term effect on patients.The reason for this may be that CBA pretreatment increased the acute benefit of lumen diameter before DCB implantation, while a little intimal rupture caused by CBA enhanced drug transport between intima and media, and increased the uptake of antiproliferative drugs in the vascular wall, thereby improving the efficacy of DCB [25].
At the same time, we observed that one patient each in groups A and C had pericardial effusion, but there was no significant difference in PCIrelated complications among the four groups, indicating that the application of CBA did not cause additional intervention-related complications, and also showing that DCB in combination with CBA treatment was safe.The incidences of TVR, angina-related hospitalization, non-fatal myocardial infarction, heart failure-related hospitalization, non-target vascular reconstruction and all-cause death, were similar in DCB+CBA group and DCB group.These results suggest that CBA did not increase the incidence of TVR, heart failure-related hospitalization, and all-cause death in ISR and de novo lesion patients.This is consistent with the finding in a previous study [24].However, the incidence of MACE was lower in ISR patients given DCB plus CBA treatment during follow-up.For patients with de novo lesions, the incidence of MACE during follow-up was similar, regardless of whether or not CBA was used.The reason for this may be that the pretreatment of ISR with cutting balloon reduced the occurrence of severe dissection, rupture and elastic retraction of blood vessels, thereby decreasing the long-term restenosis rate of target lesions [24].

Limitations of this study
Potential bias may exist considering the apparently small number of ACS patients that were observed.

CONCLUSION
This study demonstrates that the combined use of DCB and CBA for re-stenosis and de novo lesions significantly improves the immediate post-PCI MLD and acute gain after PCI, without reducing long-term outcomes and safety.Multicenter trials involving a larger number of patients should be conducted to validate the results obtained from this study.

Table 3 :
Angiographic follow-up results in the four groups MLD: minimum lumen diameter; LLL: late luminal loss

Table 3
than in group C (2.11 ± 0.51 mm vs 1.86 ± 0.42 mm, p = 0.011).There was no significant difference amongst the different groups (A vs. B, p = 0.411; C vs. D, p = 0.434).Only one patient in each group (A and C) had pericardial effusion.

Table 4 :
Comparison of clinical follow-up results in the four groups