Drug-Coated Balloon versus Drug-Eluting Stent in Patients with Small-Vessel Coronary Artery Disease: A Meta-Analysis of Randomized Controlled Trials

Background Percutaneous coronary intervention (PCI) with drug-eluting stents (DES) of small-vessel coronary artery disease (SVD) is related to an increased risk of in-stent restenosis (ISR) and stent thrombosis (ST). The application of the drug-coated balloon (DCB) for patients with SVD remains controversial. Objectives Assess the outcomes of DCB in the treatment of SVD compared with DES in patients with SVD. Methods A meta-analysis of randomized controlled trials (RCTs) published up to June 2020, reporting the outcomes of DCB versus DES in the treatment of SVD, was performed. Results Four RCTs with 1227 patients were included. The results indicated that DCB was associated with the decreased risk for myocardial infarction (MI) compared with the DES, but the difference showed no significance (OR 0.50, 95% CI 0.24–1.03, P=0.06). And, there was no significant difference in death (OR 0.76, 95% CI 0.17–3.43, P=0.72), cardiac death (OR 1.92, 95% CI 0.74–4.98, P=0.18), target vessel revascularization (TVR) (OR 0.81, 95% CI 0.51–1.28, P=0.36), target lesion revascularization (TLR) (OR 1.29, 95% CI 0.66–2.52, P=0.46), and major adverse cardiac events (MACE) (OR 0.92, 95% CI 0.61–1.38, P=0.69) between the DCB group and DES group. Conclusion Compared with DES, DCB was associated with a decreased risk of MI among patients with SVD, but the difference showed no significance. The application of DCB in SVD is associated with comparable outcomes of death, TVR, and MACE when compared with DES.


Introduction
Drug-eluting stents (DES) were normative of care for severe coronary artery disease (CAD). However, the efficacy of DES was limited by stent thrombosis (ST) and in-stent restenosis (ISR) [1]. e drug-coated balloon (DCB) delivers the antiproliferative drug into the vessel wall without implanting a stent. e DCB was a novel therapeutic strategy to overcome the ISR of bare-metal stents (BMS) and DES and recommended in the European Society of Cardiology guidelines (class I, level of evidence A) [2,3]. But the application of DCB for patients with SVD remains controversial because different studies have obtained conflicting conclusions. In recent studies, SVD has been identified as an angiographic reference vessel diameter of less than 3 mm as the most appropriate cutoff [4]. SVD is common among the patients who underwent PCI [5,6], which also remains an independent predictor of major adverse cardiac events (MACE) [7]. We conducted a meta-analysis of RCTs directly to compare DCB and DES on several outcomes in patients with SVD in the hope of providing a better choice for clinical treatment.

Search Strategy.
It was searched for PubMed, Embase, and Cochrane Library up to June 2020 to identify randomized controlled trials (RCTs). Searches were conducted without any language restrictions using the keywords "drugeluting balloon," "drug-coated balloon," "drug-eluting stent," "drug-coated stent," "small coronary artery disease," "small coronary vessel," "small vessel coronary artery disease," and "small vessel disease." e electronic search strategy was complemented by a manual review of the reference list of each included article. e report of the methods in this meta-analysis was in accord with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [8]. All analyses were based on published RCTs; therefore, no ethical approval or patient consent was required.

Study Selection.
e inclusion criteria in this metaanalysis were (1) all patients with SVD, (2) complete reporting of clinical outcomes such as myocardial infarction (MI), death, cardiac death, target vessel revascularization (TVR), target lesion revascularization (TLR), and major adverse cardiac events (MACE), (3) comparison of the DCB and DES strategies, and (4) randomized controlled trials (RCTs). Studies lack comparison or control groups, in which data concerning the above outcomes were excluded.

Data Extraction and Quality
Assessment. Data extraction was performed by two authors using a standardized data collection form, and disagreements were resolved by discussion. Patient characteristics, study quality, and clinical outcomes, including MI, death, cardiac death, TVR, TLR, and MACE, were analyzed in both the DCB group and DES group. e eligible studies' risk of bias was assessed using the Cochrane collaboration's tool for randomized controlled trials [9]. e tool consists of 7 points: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Trials with >2 high-risk components were considered a moderate risk of bias, and trials with >4 high-risk components were considered a high risk of bias.

Statistical Analysis.
e statistical analyses were performed using the Review Manager (RevMan) software version 5.3. Count data were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Statistical heterogeneity tested was performed using the value of P and I 2 when the heterogeneity test showed P ≥ 0.1, and I 2 ≤ 50% was considered to have homogeneity; a fixed-effects model was selected. Otherwise, when the heterogeneity test showed P < 0.1, I 2 > 50% was considered to have substantial heterogeneity, and a random-effects model was used.

Study Characteristics.
e baseline characteristics of the included RCTs are presented in Table 1. Four RCTs containing 1227 patients with SVD were eligible for inclusion in  Table 2.

Quality Assessment and Risk of Bias.
e quality of most RCTs was higher, according to the Cochrane quality assessment criteria (Figures 2 and 3). e whole four RCTs revealed a high risk of bias at the blinding of participants and personnel. e BASKET-SMALL2 study and PICCOLETO study showed a high risk of bias at blinding outcome assessment and allocation concealment.

Discussion
Currently, PCI with DES has been widely promoted for patients with CAD. Given the limitations of DES in terms of ISR and ST, DCB angioplasty has shown to be a new strategy for the treatment of de novo stenosis in SVD. Only a few RCTs compared DCB angioplasty with DES in SVD. In this meta-analysis, the efficacy of DCB and DES in patients with SVD was compared.
e results indicated that the DCB strategy was associated with decreased risk for MI compared with the DES strategy, but there was no significant difference. And there were no statistical differences in the other clinical outcomes such as all-cause death, cardiac death, TVR, TLR, and MACE, which were consistent with the conclusion of the earlier study reported by Li et al. [16].
PCI aims to improve the minimum lumen diameter in a given target coronary segment, which has a specific reference vessel diameter [17]. us, the minimum lumen diameter increases after the procedure but decreases at follow-up, mainly because of hyperplasia phenomena and recoil. DES implantation results in arterial injury, initiating a vascularproliferative cascade with smooth muscle cell proliferation and migration, resulting in neointimal hyperplasia. us, the amount of neointimal hyperplasia is mainly independent of vessel size. Small vessels were easier to restenosis than larger vessels [18,19]. DCB delivers the antiproliferative drug into the vessel wall without implanting a stent that can play a suppression role of the intimal hyperplasia after it contacts the vessel wall, thereby reducing the inflammation of the intima.
e study was terminated early after the inclusion of 57 patients based on an interim analysis which showed a higher rate of target lesion     stenosis after six months (DCB 44% vs. DES 24%, P � 0.029) and a higher risk of MACE (36% in the DCB group vs. 14% in the DES group, P � 0.054). e principal investigator of the PICCOLETO trial hypothesized these findings were based on a lack of efficacy of the DIOR paclitaxel-coated balloon, which they used, which was later replaced by newer generation DCBs [20].
Balloon predilatation is essential, which can be seen in the BELLO trial; balloon predilatation was performed in 96.8% of interventions, while 25% in the PICCOLETO study [1]. In the following BASKET-SMALL2 and RESTORE SVD China studies, after successful balloon predilatation, DCB indicated not inferior to new generation DES on cardiac death, MI, and TVR in 1-2 years follow-up [13][14][15].
If the data of the PICCOLETO study were excluded from this meta-analysis, it would be found that the DCB strategy was associated with a significant reduction in the clinical outcomes of MI (OR 0.44, 95% CI 0.21-0.94, P � 0.03), and the heterogeneity of TLR and MACE would be improved ( Figure 5). Tailored DCB device selection and sufficient balloon predilatation were helpful to the outcomes of PCI with DCB in patients with SVD.
Furthermore, we speculate no difference in outcome between the two strategies, which may be related to the multiple pathophysiological pathways involved in ischemic heart disease and restenosis after PCI. Mechanisms of ischemic heart disease are complicated, including microvascular dysfunction, inflammatory response, atherosclerotic plaque rupture, and vasospasm [21]. And multiple factors, such as biological, genetic, mechanical, and technical, may contribute to DES restenosis [22]. Compared with DES, DCB was associated with a decreased risk of stent under expansion, stent fracture, polymer damage, and stent gap. But inflammation, neoatherosclerosis, and genetic factors might also play a critical role in DCB as well as DES restenosis.
Some limitations of this meta-analysis should also be mentioned. First, the duration of the follow up of included RCTs was short. Second, the lack of extensive RCTs limits the power to detect differences between the outcomes of the compared groups. Finally, only paclitaxel-coated balloons were used in the included RCTs. Current, sirolimus-coated balloons are available and may have promising results [23].  Total (95% CI) Total events Heterogeneity: chi 2 = 1.95, df = 1 (P = 0.16); I 2 = 49% Test for overall effect: Z = 1.12 (P = 0.26) Figure 5: Forest plots comparing DCB with DES in MI, TLR, and MACE (excluded PICCOLETO trial). MACE, major adverse cardiac events; MI, myocardial infarction; TLR, target lesion revascularization.

Conclusions
In summary, this meta-analysis found that DCB was associated with decreased risk for MI compared with DES among patients with SVD, but the difference showed no significance. e application of DCB in SVD is associated with comparable outcomes of death, cardiac death, TVR, TLR, and MACE when compared with DES.