In-stent restenosis (ISR) is the gradual narrowing of the stented coronary segment, presenting as angina or leading to an acute myocardial infarction. Although its incidence has decreased with the use of newer drug-eluting stents (DES), it still carries significant mortality and morbidity risks. We compared the 2 most common interventions for managing DES-related ISR: drug-coated balloons (DCBs) and DES. Electronic databases were searched to identify all randomized controlled trials comparing DCB with DES in patients with DES-ISR. The Mantel–Haenszel method with a random-effects model was used to calculate pooled risk ratios. Five trials comprising 1,100 patients (577 in DCB and 523 in DES group) were included in the final study. The mean follow-up was 42 months. DCB was found to have a higher risk for target lesion revascularization (risk ratio 1.41, p = 0.02) compared with DES. No difference was observed in all-cause mortality, target vessel revascularization, myocardial infarction, or stroke between the 2 intervention arms. In conclusion, management of DES-ISR with DCB has a higher risk of target lesion revascularization compared with re-stenting with DES. The 2 therapeutic interventions are comparable in terms of efficacy and safety profile.
Percutaneous coronary intervention (PCI) has been shown to have a significant impact on the treatment of obstructive coronary artery disease by improving the quality of life in patients with stable angina and reducing mortality in patients with acute coronary syndrome. However, the ongoing risk for in-stent restenosis (ISR) remains a clinical challenge in contemporary clinical practice that has a negative impact on the patient’s well-being. ISR refers to the gradual re-narrowing of the stented segment after PCI, attributed to arterial damage and subsequent neointimal tissue proliferation, typically occurring between 3 and 12 months. According to a 2020 report from the National Cardiovascular Data Registry, ISR represented 10.6% of all PCI procedures in the United States and is primarily managed with another stent. The incidence of restenosis differs according to the type of stent used and the complexity of the stented lesions. Patients who underwent PCI for ISR have similar in-hospital outcomes to those having PCI for the first time, with no significant differences in complications or hospital stay length. The introduction of drug-eluting stents (DES) has significantly reduced the rates of restenosis and target lesion revascularization (TLR) after PCI, with an ISR rate of 3% to 20%. The ISR rate after placement of DES depends on the duration of follow-up and the complexity of the lesions in which the stents were placed, and usually results in recurrent angina in some patients and acute coronary syndrome in others. Drug-coated balloons (DCBs) are notable for their success in treating prolonged and small-vessel ISR lesions, with lower rates of nonfatal myocardial infarction (MI) at 1 year and reduced bleeding rates at 2 years compared with DES. In the Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent (RIBS V) trial, both DES and DCBs effectively addressed bare-metal stent (BMS)-ISR over 3 years, with similar safety outcomes. DES had a lower TLR rate compared with DCB. Given that BMS are not commonly used in contemporary practice, our comparison of the 2 interventions is focused on DES-ISR, which is more relevant to current clinical practice. This study conducted a comprehensive meta-analysis to provide insights for clinical decisions and better patient outcomes.
Methods
We conducted a systematic review and meta-analysis using 5 randomized controlled trials (RCTs). We excluded studies such as case reports, clinical spotlights, review articles, and observational studies. Our meta-analysis search strategy has been reported in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews-2) guidelines. , The checklists of these guidelines are shown in Supplementary Table 1 and Supplementary Figure 1 , respectively.
The inclusion criteria for this meta-analysis were defined to select studies that focused on (1) patients aged ≥18 years, (2) patients with ISR related to DES, and (3) patients treated with DCB or DES. We excluded studies with participants having BMS-related ISR only or with combined DES and BMS-ISR with no subgroup analysis. In studies with both DES and BMS-related ISR participants, only subgroup analysis of DES-ISR was included. A literature search was conducted on Embase and PubMed for trials meeting the previously mentioned inclusion criteria from inception until April 2024, using a systematic search strategy and adhering to the PRISMA guidelines. We used Medical Subject Headings (MeSH) terms and keywords with Boolean operators “OR” and “AND” for terms including “coronary artery disease,” “drug-coated balloons,” “drug-eluting stents,” and “in-stent restenosis.” A “NOT” function was used to exclude “case reports” ( Supplementary Table 2 ).
RCTs that met our inclusion criteria were selected. Two authors (MK and NK) independently screened the articles. Full-text articles that met the screening criteria were reviewed as part of a second phase of screening to evaluate the outcomes of interest. We also performed backward snowballing by reviewing the reference sections of articles that may have outcomes of interest to identify additional studies to be included in the meta-analysis. Another author (YS) independently reviewed the data screening process.
Data on patient characteristics on admission comprised age, gender, stroke, previous PCI, previous coronary artery bypass graft (CABG), previous MI, smoking status, and left ventricular ejection fraction. All co-morbidities, including diabetes, hypertension, and dyslipidemia, were also taken into consideration.
The goal of the study is to evaluate the difference in outcomes between DES and DCB in patients with DES-ISR. The outcomes were divided into (1) primary outcomes, which include all-cause mortality, TLR, and target vessel revascularization (TVR), and (2) secondary outcomes, which include cardiac death, noncardiac death, MI, target vessel MI, target lesion thrombosis, stroke, and CABG.
Data from the chosen studies were transferred to Microsoft Excel (Microsoft Corporation, Redmond, Washington) and organized according to binary outcomes for categorical variables and continuous outcomes for numerical variables. We used RevMan 5.4 software (Cochrane, London, United Kingdom) to determine the pooled effect sizes. The Mantel–Haenszel random-effects model was used to obtain the pooled risk ratios (RRs), establishing statistical significance at p <0.05. To evaluate statistical heterogeneity, we calculated Higgins I-squared (I²) values: values ≤50% denoted low heterogeneity, 50% to 75% moderate heterogeneity, and ≥75% high heterogeneity. The articles selected underwent a quality review using the Cochrane risk-of-bias tool for randomized studies (RoB 2) ( Supplementary Figure 2 ).
Results
Our systematic search yielded 975 articles. After eliminating the duplicates (n = 432), 543 records were screened in the first phase; 524 articles were excluded because they did not meet the inclusion criteria. In the second phase, 543 articles were screened with a full-text review. Of the total studies, 19 were deemed eligible initially, but only 5 RCTs met the criteria and were included in the final analysis ( Figure 1 ).
Within our final analysis, a total of 1,100 patients were studied, with 573 in the DCB and 523 in the DES group. The most common co-morbidities among the included patients were hypertension, diabetes mellitus, dyslipidemia, stroke, previous MI, previous PCI, and previous CABG. The baseline characteristics of the included studies and the patients are shown in detail in Table 1 .
| Last Author Name (Trial name) | Wong et al (Restore) | Alfonso et al (RIBS IV) | Xu et al (PEPCAD China ISR) | Giacoppo et al (ISAR DESIRE 3) | Jensen et al (BIOLUX) |
|---|---|---|---|---|---|
| Study Year | 2018 | 2018 | 2016 | 2023 | 2018 |
| Country | South Korea | Spain | China | Germany | Germany/Latvia |
| Number of patients DCB/DES | 86/ 86 | 154/ 155 | 109/ 106 | 137/ 131 | 157/72 |
| Men (%) DCB/DES | 61 (70.9%)/ 62 (72.1%) | 127(82%) / 130(84%) | 88(80.7%)/ 86(81.1%) | 105(77%)/ 88(67%) | 122(77.7%)/ 49(68.05%) |
| Women (%)DCB/DES | 25 (29.1%) / 24 (27.9%) | 27 (18%) / 25 (16%) | 21 (19.3%) / 20 (18.9%) | 32 (23%) / 43 (33%) | 35 (22.3%) / 23 (31.9%) |
| Mean Age (± SD)DCB/DES (years) | 67 (10) / 66 (9) | 66 (10) / 66 (10) | 61.8 (9.3) / 62.1 (9.3) | 67.7 (10.4)/ 68.8 (10) | 67.2 (9.9) / 69.4 (8.8) |
| Diabetes (%) DCB/DES | 43 (50%) / 38 (44.2%) | 75 (49%) / 66 (43%) | 44 (40.4%) / 35 (33%) | 56 (41%) / 61 (47%) | 48 (3036%) / 24 (33.3%) |
| Insulin Requiring (%) DCB/DES | -/- | -/- | 14 (12.8%) / 9 (8.5%) | 21 (15%) / 27 (21%) | -/- |
| Hypertension (%)DCB/DES | 60 (69.8%) / 65 (75.6%) | 110 (71%)/ 121 (78%) | 78 (71.6%) / 69 (65.1%) | 105 (77%) / 101 (77%) | 144 (91.7%) / 70 (97.2%) |
| Hyperlipidemia (%)DCB/DES | 49 (57%) / 53 (61.6%) | 110 (71%) / 121 (78%) | 38 (34.9%) / 35 (33%) | 108 (79%) / 103 (79%) | 134 (85.4%) / 62 (86.1%) |
| Current or past smoker (%) DCB/DES | 40 (46.5%) / 37 (43%) | 89 (58%) / 87 (56%) | 23 (21.1%) / 27 (25.5%) | 19 (14%) / 15 (11%) | 104 (66.2%)/ 42 (58.3%) |
| Previous MI (%) DCB/DES | 26 (30.2%) / 22 (25.6%) | -/- | 53 (48.6%) / 37 (34.9%) | 53 (39%) / 50 (38%) | 93 (59.2%) / 35 (48.6%) |
| Previous CABG (%) DCB/DES | -/- | -/- | 3 (2.8) / 0 (0) | 15 (11%) / 32 (24%) | -/- |
| Silent Ischemia/Stable Angina (%) DCB/DES | 36 (41.8%) / 39 (45.4%) | 74 (48%) / 76 (49%) | 21 (19.3%) / 31 (29.2%) | -/- | -/- |
| Unstable Angina (%) DCB/DES | 39 (45.3%) / 33 (38.4%) | 80 (52%) / 79 (51%) | 70 (64.2%) / 61 (57.5%) | -/- | -/- |
| NSTEMI (%) DCB/DES | 5 (5.8%) / 7 (8.1%) | -/- | -/- | -/- | -/- |
| STEMI (%) DCB/DES | -/- | -/- | -/- | -/- | -/- |
| LVEF (SD) DCB/DES | 59.4 (8.4%) / 59.9 (7.8%) | -/- | 61.7 (8.5%) / 62.3 (8.6%) | 53.6 (9.8%) / 54.5 (9.9%) | -/- |
| Multivessel disease (%) DCB/DES | 22 (25.6%) / 18 (20.9%) | -/- | -/- | 129 (94%) / 124 (93%) | 95 (60.5%) / 39 (54.2%) |
| LAD involvement (%) DCB/DES | 48 (55.8%) / 52 (60.5%) | 77 (50%) / 71 (46%) | 47 (41.6%) / 61 (56.5%) | 59 (34%) / 50 (30%) | -/- |
| RCA involvement (%) DCB/DES | 24 (27.9%) / 21 (24.4%) | 43 (28%) / 45 (29%) | 45 (39.8%) / 34 (31.5%) | 59 (34%) / 56 (33%) | -/- |
| LCx involvement (%) DCB/DES | 13 (15.1%) / 11 (12.8%) | 27 (18%) / 34 (22%) | 21 (18.6%) / 13 (12%) | 54 (31%) / 61 (36%) | -/- |
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