Over the past few decades, an exponential increase in percutaneous coronary intervention (PCI) has led to a significant improvement in the clinical outcomes of coronary artery disease (CAD) patients. PCI has also been widely adopted as part of the standard treatment for CAD. However, in-stent restenosis (ISR) has become one of the main problems affecting the prognosis of patients after PCI, especially for complex diseases such as chronic occlusive disease or calcification or in patients with diabetes mellitus and chronic renal insufficiency [
The inclusion and exclusion criteria were in accordance with the Cochrane Handbook for Systematic Reviews manual [
The inclusion criteria for this study are as follows:
The exclusion criteria for this study are as follows:
Non-Chinese and non-English literature Duplicate published articles or earlier reports of the same outcome in the same study Conference abstracts, letters, case reports, editorials, or expert opinions Data, incomplete data, or documents that cannot be extracted
The two authors (Wen-Juan Xiu and Hai-Tao Yang) conducted systematic literature searches using PUBMED, MEDLINE, EMBASE, Cochrane Database, ClinicalTrials.gov, and Wanfang to collect data on RCTs and observational studies, as well as the retrieval time of the DEB and second-generation DES in coronary ISR until June 2017. The keywords used were (“Drug-eluting balloon,” OR “DEB,” OR “Drug-coated balloon,” OR “DCB”) AND (“Drug eluting stent,” OR “DES,” OR “everolimus eluting stent,” OR “EES,” OR “Xience,” OR “Promus,” OR “Zotarolimus eluting stent,” OR “ZES,” OR “Resolute”) AND (“in stent restenosis,” OR “ISR”).
Quality assessment of the retrieved literature was evaluated by the two authors (Wen-Juan Xiu and Hai-Tao Yang) based on preestablished assessment criteria. The data of the published articles were then summarized. Randomized controlled trials were extracted in a standardized format, and the details of the observational studies were taken and transformed into a standardized scale. In the event of a dispute, the authors assisted one another in coming to an agreement through mutual discussion or referral by a third author (Xiang Xie).
The two authors (Wen-Juan Xiu and Hai-Tao Yang) extracted the tables based on predesigned data. The authors then independently extracted and cross-checked the data, and in cases of a dispute, they assisted one another in coming to an agreement through mutual discussion or third parties (Xiang Xie). Data extraction included (1) the basic information included in the study, including the research topics, year of publication, first author, specific model of the DEB and DES, dual antiplatelet therapy (DAPT), MACEs, and end event; (2) the baseline characteristics of the study population, including the age, gender, and risk factors; and (3) the results of the outcome measures and indicators.
The primary endpoint was target lesion revascularization (TLR) at long-term follow-up. The secondary endpoints included major cardiovascular adverse events (MACEs), target vessel revascularization (TVR), myocardial infarction (MI), all-cause mortality (ACM), and cardiac death. The results of the angiography were minimum luminal diameter (MLD), late luminal loss (LLL), percent diameter stenosis (DS%), and stent restenosis (IR). When there were multiple follow-up time points when the outcome of the case was reported, the longest follow-up of the outcome of the incident situation analysis was used.
Meta-analysis was performed using RevMan 5.3 software. On comparing the outcomes of patients with coronary artery ISR treated with the DEB versus second-generation DES, the risk ratio (RR) and its 95% confidence interval (CI) were used to assess the incidence of TLR, TVR, MI, all-cause mortality, and MACEs. The mean (M), tandard deviation (SD), and 95% confidence interval (CI) were used to assess the incidence of MLD and DS% rate and LLL. Heterogeneity testing between studies was conducted using the Cochran
A total of 230 articles were screened in the first screening. The articles were then screened out in layers, excluding review articles, duplicated literature, and those in which the authors failed to obtain the full text. A total of 12 articles were included in the final meta-analysis [
Flow diagram of the literature search and study selection.
Four RCTs comparing the DEB versus second-generation DES [
Characteristics of the included studies.
Trial (year) | Treatment and no. of patients ( |
BMS- or DES-ISR | Type of the device | Study type | DAPT protocol | CAG F/U | Clinical F/U | MACE definition | Endpoint | ||
---|---|---|---|---|---|---|---|---|---|---|---|
DEB | DES | ||||||||||
Marquis-Gravel et al. [ |
100 | 102 | Canadian all comers | Paclitaxel | 2nd generation | Observational | NR | NR | 15 months | Death (all), nonfatal MI, TLR | Restenosis, MACE, stroke/TIA |
Adriaenssens et al. [ |
25 | 25 | Belgium BMS | Paclitaxel | Everolimus | RCT | 3 months for DEB | 9 months | 12 months | Death (all), MI, TVR | % of struts uncovered, DS%, LLL, MLD, MACE |
12 months for DES | |||||||||||
Alfonso et al. [ |
95 | 94 | Spain BMS | Paclitaxel | Everolimus | RCT | 3 months for DEB | 9 months | 12 months | CD, MI, TVR | Death (all), TLR, MACE |
12 months for DES | |||||||||||
Almalla et al. [ |
46 | 40 | Germany DES | Paclitaxel | Everolimus | Observational | NR | NR | DEB: 25 months | Death (all), MI, TVR | MACE, TLR, ST, MACE rate |
DES: 22 months | |||||||||||
Naganuma et al. [ |
73 | 85 | Italy bifurcation ISR | Paclitaxel | Everolimus/zotarolimus | Observational | NR | NR | 23 months | CD, MI, TVR | TLR, MACE |
Kubo et al. [ |
37 | 52 | Japan recurrent ISR after DEB | Paclitaxel | Everolimus | Observational | 3 months for PCB | 6–8 months | 24 months | NR | ACM, CD, nonfatal MI, ST, TLR, MLD |
12 months for DES | |||||||||||
Alfonso et al. [ |
154 | 155 | Spain DES-ISR | Paclitaxel | Everolimus | RCT | 3 months for DEB | 6–9 months | 12 months | CD, MI, TVR | MLD, MACE |
12 months for DES | |||||||||||
Kang et al. [ |
182 | 56 | DES | SeQuent Please | Everolimus | Observational | 1 month for DCB | NR | 24 months | CD, nonfatal MI, TVR | MACE |
12 months for DES | |||||||||||
Basavarajaiah et al. [ |
81 | 166 | DES | Paclitaxel | 2nd generation | Observational | 1 month for DCB | NR | 12 months | CD, MI, TVR | Death (all), TLR, ST, MACE |
12 months for DES | |||||||||||
Kawamoto et al. [ |
65 | 68 | BMS- or DES-ISR | In.Pact Falcon | 2nd generation | Observational | 1 month for DEB | NR | 12–24 months | ACM, MI, TLR | ST, MACE |
Pantera Lux | 12 months for DES | ||||||||||
Pleva et al. [ |
68 | 68 | BMS | Paclitaxel | Everolimus | RCT | 3 months for DEB | 12 months (±2 months) | 6 months, 12 months | ACM, any MI, AR | LLL, BR, ST, MACE |
6–12 months for DES | |||||||||||
Cui et al. [ |
74 | 109 | DES | SeQuent Please | 2nd generation | Observational | 3 months for DEB | NR | 12 months | CD, nonfatal MI, TVR | MACE, no-event survival rate, ACM, TLR |
12 months for DES |
DEB: drug-eluting balloon; DES: drug-eluting stent; BMS: bare-metal stent; ISR: in-stent restenosis; RCT: randomized controlled trial; DAPT: dual antiplatelet therapy; CAG: coronary angiography; F/U: follow-up; N/A: not applicable; MACE: major adverse cardiac event; CD: cardiac death; ACM: all-cause mortality; MI: myocardial infarction; ST: stent thrombosis; TVR: target vessel revascularization; TLR: target lesion revascularization; MLD: minimum luminal diameter; LLL: late lumen loss; PCB: paclitaxel-coated balloon.
Study | Demographics | Risk factors ( |
Indications ( |
||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Cohort | Age | Male ( |
HTN | DM | Smoke | Dyslipidaemia | Previous MI | Previous CABG | UAP | SAP | NSTEMI | Silent ischaemia | |
Marquis-Gravel et al. [ |
Overall | 65 | 145 | 65 | 145 | NR | 91 | NR | NR | NR | NR | 145 | NR |
Adriaenssens et al. [ |
DEB | 67.6 ± 7.7 | 18 | 16 | 6 | 5 | 24 | 12 | NR | 5 | 13 | 1 | 6 |
DES | 64.2 ± 11 | 25 | 15 | 1 | 3 | 24 | 10 | NR | 5 | 17 | 1 | 2 | |
Alfonso et al. [ |
DEB | 67 ± 11 | 82 | 68 | 30 | 56 | 69 | 57 | 4 | 38 | 43 | NR | 14 |
DES | 64 ± 12 | 82 | 68 | 19 | 70 | 62 | 56 | 7 | 42 | 41 | NR | 11 | |
Almalla et al. [ |
DEB | 69.6 ± 9.6 | 38 | 37 | 18 | 14 | NR | 17 | 10 | NR | NR | NR | NR |
DES | 67.7 ± 10.8 | 28 | 34 | 14 | 21 | NR | 21 | 4 | NR | NR | NR | NR | |
Naganuma et al. [ |
DEB | 67.2 ± 10.4 | 67 | 52 | 29 | 5 | 54 | 34 | 14 | 17 | 56 (including silent ischaemia and SAP) | NR | NR |
DES | 65.2 ± 10.1 | 74 | 61 | 32 | 6 | 69 | 45 | 17 | 14 | 71 (including silent ischaemia and SAP) | NR | NR | |
Kubo et al. [ |
DEB | 69.7 ± 9.7 | 32 | 30 | 18 | 28 | 24 | 19 | 6 | NR | NR | NR | NR |
DES | 71.3 ± 8.8 | 41 | 41 | 26 | 36 | 37 | 28 | 6 | NR | NR | NR | NR | |
Alfonso et al. [ |
DEB | 66 ± 10 | 127 | 110 | 75 | 89 | 110 | 73 | 16 | 80 | 74 (including silent ischaemia) | NR | NR |
DES | 66 ± 10 | 130 | 121 | 66 | 87 | 121 | 77 | 17 | 79 | 79 (including silent ischaemia) | NR | NR | |
Kang et al. [ |
DEB | 63.1 ± 9.8 | 125 | 132 | 80 | 85 | 165 | NR | NR | 60 | NR | NR | NR |
DES | 59.5 ± 11.0 | 36 | 39 | 16 | 26 | 46 | NR | NR | 24 | NR | NR | NR | |
Basavarajaiah et al. [ |
DEB | 66.8 ± 9.0 | 73 | 58 | 38 | 7 | 59 | 30 | 25 | NR | NR | NR | NR |
DES | 65.7 ± 9.6 | 143 | 119 | 55 | 12 | 127 | 85 | 56 | NR | NR | NR | NR | |
Kawamoto et al. [ |
DEB | 64.9 ± 9.1 | 57 | 51 | 28 | 6 | 51 | 36 | 17 | NR | NR | NR | NR |
DES | 67.2 ± 8.9 | 63 | 54 | 28 | 9 | 54 | 42 | 27 | NR | NR | NR | NR | |
Pleva et al. [ |
DEB | 65.6 ± 10.9 | 43 | NR | 17 | NR | NR | 43 | 3 | NR | 23 (including STEMI) | 24 | 3 |
DES | 65.5 ± 10.6 | 46 | NR | 18 | NR | NR | 41 | 6 | NR | 18 (including STEMI) | 25 | 10 | |
Cui et al. [ |
DEB | 61.9 ± 9.0 | 56 | 56 | 39 | 35 | 38 | 25 | 6 | 7 | NR | NR | NR |
DES | 61.5 ± 9.5 | 82 | 68 | 43 | 50 | 47 | 32 | 2 | 11 | NR | NR | NR |
HTN: hypertension; DM: diabetes mellitus; MI: myocardial infarction; CABG: coronary artery bypass graft; UAP: unstable angina pectoris; SAP: stable angina pectoris; NSTEMI: non-ST elevation myocardial infarction.
Baseline angiographic characteristics.
Study | Pre-MLD | Pre-DS% | Lesion length (mm) | Post-MLD | Post-DS% | |||||
---|---|---|---|---|---|---|---|---|---|---|
DEB | DES | DEB | DES | DEB | DES | DEB | DES | DEB | DES | |
Adriaenssens [ |
0.98 ± 0.60 | 0.57 ± 0.37 | 67.7 ± 18.4 | 79.4 ± 13.5 | NR | NR | 2.13 ± 0.45 | 2.12 ± 0.51 | 26.6 ± 13 | 25.9 ± 16.8 |
Alfonso et al. [ |
1.02 ± 0.40 | 0.93 ± 0.4 | 61 ± 14 | 65 ± 13 | 13.7 ± 7 | 13.8 ± 6 | 2.16 ± 0.5 | 2.38 ± 0.5 | 19 ± 11 | 11 ± 11 |
Almalla et al. [ |
0.57 ± 0.30 | 0.51 ± 0.41 | NR | NR | 9 ± 5.2 | 12.3 ± 11 | 2.42 ± 0.36 | 2.5 ± 0.5 | NR | NR |
Kubo et al. [ |
0.96 ± 0.45 | 0.80 ± 0.47 | 67 ± 14.9 | 72.2 ± 15.1 | 16.7 ± 12.9 | 15.7 ± 8.2 | 2.02 ± 0.4 4 | 2.56 ± 0.54 | 31.8 ± 10.3 | 16.2 ± 7.4 |
Alfonso et al. [ |
0.79 ± 0.40 | 0.75 ± 0.40 | 69 ± 17 | 72 ± 15 | 10.4 ± 5.6 | 10.7 ± 5.4 | 2.1 ± 0.4 | 2.22 ± 0.5 | 18 ± 10 | 13 ± 11 |
Kang et al. [ |
0.80 ± 0.40 | 0.80 ± 0.60 | 71.7 ± 5.2 | 74.6 ± 9.2 | 19.5 ± 8.9 | 21.3 ± 11.8 | 2.2 ± 0.4 | 2.7 ± 0.4 | 20.6 ± 11.9 | 13.6 ± 10.5 |
Kawamoto et al. [ |
0.74 ± 0.49 | 0.66 ± 0.43 | 74.8 ± 15.8 | 81.2 ± 14.4 | 18.7 ± 14.6 | 16.1 ± 9.6 | 2.34 ± 0.54 | 2.65 ± 0.48 | 18.2 ± 8.6 | 13.8 ± 7.6 |
Pleva et al. [ |
0.92 ± 0.45 | 0.79 ± 0.48 | 71.8 ± 13.9 | 78 ± 13.4 | NR | NR | 2.18 ± 0.39 | 2.51 ± 0.38 | 19.5 ± 7.4 | 16.3 ± 8.9 |
MLD: minimum luminal diameter; DS%: percent diameter stenosis; LLL: late lumen loss.
Document quality evaluation.
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Clinical outcomes between the DEB group and DES group: (a) TLR; (b) TVR; (c) MI; (d) ACM.
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Cardiac death (a) and MACEs (b) between the DEB group and DES group.
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Coronary angiography outcomes between the DEB group and DES group: (a) MLD; (b) late loss; (c) binary restenosis; (d) DS%.
The meta-analysis results suggested that, in DES-IRS but not in BMS-IRS, the difference in the MLD was significant. However, the incidence of TLR, TVR, MI, ACM, CD, MACEs, late loss, binary restenosis, and DS% was not significantly different between the DES group and DEB group (data not shown).
We performed a sensitivity analysis to examine the influence of each study on the pooled RRs by removing each study one at a time. The pooled RRs showed no significant change, suggesting the results are stable.
To avoid some of the confounders present in the observational studies, we also excluded the observational studies and only analyzed the results of the RCTs. These results also showed no significant change, suggesting the results are stable.
In the present study, we utilized funnel plots to evaluate the publication bias of all of the included studies. We did not find publication biases in this meta-analysis (data not shown).
In this study, we performed a meta-analysis to compare the efficacy of the DEB to DES in the treatment of ISR. The present study suggests that, during 6–25 months of follow-up, the clinical outcomes are similar between the DEB group and DES group. This result suggests that the DEB is not inferior to the DES in the treatment of ISR.
In clinical practice, many treatment strategies have been developed for ISR patients after PCI, including POBA, cutting balloons, rotational atherectomy, and intravascular brachytherapy. However, most of these techniques have been replaced by the DES due to its side effect of inhibiting neointimal formation. Therefore, the DES has become the standard treatment for ISR. In addition, although there appears to be no evidence that the second-generation DES is superior to the first-generation DES [
The literature published to date demonstrates that DEB treatment for BMS-ISR is very effective but is not as effective for the treatment of DES-ISR; in fact, the pathophysiology may be different. The metal in the stent stimulates the proliferation of blood vessels, and the polymer carrier on the surface of the drug stent also inhibits the repair of the vascular endothelium, resulting in the formation of a late thrombus. The drug-eluting balloon releases antiproliferative drugs locally to the vessel wall of coronary arteries, thereby achieving the effect of inhibiting intimal hyperplasia of the blood vessels and avoiding the need for additional stents and stent overlap, which also eliminates the increase of the intracoronary metal load. However, there are potential complications associated with the DEB. Compared with the DES, the DEB has no polymer matrix and no residual metal skeleton, which can reduce intimal inflammation and greatly reduce the risk of thrombosis, shortening the time for dual antiplatelet therapy (only 1 to 3 months after DCB). However, DCB treatment avoids the introduction of foreign bodies, which can result in follow-up treatment. The drug-eluting balloon is also less likely to compromise the ISR’s involvement of the bifurcation’s collaterals and may be more suitable for complex anatomies where stent implantation may not be ideal for drug delivery, such as curved or calcified blood vessels.
Persistent metal skeletons may remain the basis for stent thrombosis and restenosis. In recent years, endovascular neovascularization found in endoluminal imaging has confirmed this concept. In addition, the perpetuating metal skeleton has a risk of fracture, leading to adverse events, and the permanent influence of the metal skeleton on the normal vasomotion function of the stent at stent implantation is also an important factor that can lead to long-term adverse events.
Although the DEB can effectively inhibit the intimal hyperplasia of blood vessels, it cannot overcome the elastic retraction of blood vessels, which plays an important role in restenosis. Therefore, the DEB cannot completely replace the DES, and additional clinical data are still needed. The BRS supports diseased blood vessels early after implantation and is completely degraded after the negative remodeling of blood vessels is completed. After degradation, the BRS can restore the normal physiological and vasomotor function of the blood vessels, reduce inflammation of the blood vessel wall, and remove its influence on side branch vessels. Following repeated interventional treatment of the same lesion, the BRS can also be compatible with magnetic resonance imaging. In addition, at long-term follow-up, the BRS can result in late lumen enlargement.
At present, the materials used to make the BRS are primarily polymers (PLA) and metals (magnesium and iron). The BRS constructed from polymers has a relatively mature manufacturing process, while the BRS made from metals is difficult to use in clinical applications due to problems such as its degradation rate and inflammatory reaction. The only degradable PLA scaffold that has undergone large-scale clinical research and has been CE-approved is Abbott’s Absorb BVS. Since the clinical study was conducted in 2007, the ABSORB series of studies and various small-scale real-world registration studies have demonstrated good clinical efficacy and safety in regard to both clinical and angiographic results during an early follow-up period of 1 to 2 years.
However, the three-year results of the ABSORB II [
In our meta-analysis, we did not find a significant difference in clinical outcomes between the DEB group and DES group. The clinical endpoints observed in our analysis may only indicate short-term follow-up results. Clinical outcomes, such as MI, TLR, all-cause mortality, cardiac death, and TVR, may change significantly over time. Therefore, the present results require a large register or more elaborate RCTs with an appropriate long-term follow-up for validation.
First, in the present study, only the Chinese literature and English literature were included. Due to differences in the ISR types and specific interventions (DES type and DAPT time) among the study populations, there was a certain level of heterogeneity between the included studies. Second, the shorter follow-up period included in the study and smaller sample size can only increase the reliability of the evaluation results to a certain extent. Finally, the inclusion of studies that failed to consistently report results (TLR, TVR, MI, ACM, CD, and angiographic findings) limited our scope of analysis.
The authors declare that they have no conflicts of interest.