Drug-coated balloon angioplasty for symptomatic intracranial atherosclerotic stenosis

To the Editor: Stroke remains the second leading cause of death and disability worldwide and is associated with high rates of disability, mortality, and recurrence.^[1] Symptomatic intracranial atherosclerotic stenosis (sICAS), characterized by clinical symptoms caused by cerebral hypoperfusion due to the narrowing of intracranial arteries, is a major contributor to ischemic stroke. The primary treatment strategies for sICAS include conventional medical therapy (CMT) and endovascular treatment (ET). The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial demonstrated that ET was associated with a higher risk of stroke or death within 30 days compared to CMT (14.7% vs. 5.8%).^[2] However, beyond the 30-day window, the rate of ischemic events was significantly higher in the CMT group (6.2%) than in the ET group (2.2%).^[2] These findings suggest that treatment outcomes vary across specific timeframes. Common ET approaches for sICAS include stenting and balloon angioplasty. Both techniques aim to reduce the degree of stenosis; however, stent placement requires dual antiplatelet therapy (DAPT), which is linked to an increased risk of serious bleeding complications.

Drug-coated balloons (DCBs) serve as drug-delivery device that release antiproliferative agents directly into the vessel wall during balloon expansion at the lesion site. This approach not only reduces stenosis but also inhibits neointimal hyperplasia. Potential benefits of DCBs include a reduced duration of DAPT, which may lower the risk of bleeding, and the elimination of the need for permanent implantable devices. Given the current state of research, this study aims to conduct an evaluation of the clinical evidence surrounding DCB in the treatment of sICAS, using systematic review and meta-analysis to inform clinical practice. This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study protocol was registered with the National Institute for Health and Care Research (NIHR) PROSPERO database (No. CRD42023431194).

Two independent investigators conducted a comprehensive search of literature published up to April 8, 2024, regarding DCB treatment for intracranial artery stenosis. Searches were performed across PubMed, EMBASE, Web of Science (all fields), and the Cochrane Library (titles, abstracts, and keywords) [Supplementary Figure 1, http://links.lww.com/CM9/C730]. The retrieved records were imported into EndNote 21 (Clarivate, Philadelphia, PA, USA) for deduplication and further screening. Two reviewers independently screened the titles and abstracts of 1184 articles. After excluding irrelevant studies, the full texts of potentially eligible articles were reviewed based on predefined inclusion and exclusion criteria [Supplementary Materials, http://links.lww.com/CM9/C730]. Data extraction was performed independently, capturing the first author, publication year, and primary and secondary outcome measures. Any disagreements during screening or data extraction were resolved through discussion. If consensus could not be reached, a neurointerventional specialist with over 10 years of clinical experience made the final decision.

The primary safety outcome was the incidence of perioperative complications and any stroke or death occurring within 30 days of the procedure. The primary efficacy outcome was restenosis within 6 months post-procedure, defined as ≥50% stenosis on angiography within the treated segment or within 5 mm of the adjacent segments. Secondary outcomes included: Any stroke or death occurring between 30 days and 1 year post-procedure, transient ischemic attack (TIA), and bailout stent.

Meta-analysis and forest plot generation were conducted using STATA 17.0 (Stata-Corp LP, College Station, TX, USA) with the metan package. Pooled event rates for both primary and secondary outcomes were calculated using the double arcsine transformation. The choice between fixed- and random-effects models was based on heterogeneity testing (fixed-effects for I² <50%; random-effects otherwise). Risk of bias was assessed using the Newcastle–Ottawa Scale (NOS) for comparative studies and the Center for Evidence-Based Medicine (CEBM) Prognostic Study Quality Assessment Checklist for single-arm studies.

After deduplication, title/abstract screening, and full-text assessment of 1184 records, eight single-center studies (one in Chinese and seven in English) were included [Supplementary Figure 2, http://links.lww.com/CM9/C730]. These consisted of six retrospective and two prospective investigations: Three were dual-arm studies comparing DCB to stenting, conventional balloon angioplasty, or CMT; five were single-arm studies evaluating DCB alone. Study locations included multiple centers in China (six studies) and a single center in Switzerland (two studies). Device usage varied: Five studies employed the SeQuent Please paclitaxel-coated balloon (B. Braun, Melsungen, Germany), one used the Neuro Elutax SV paclitaxel-coated balloon (Aachen Resonance, Aachen, Germany), one used the Ranger rapamycin-coated balloon (Boston Scientific, Marlborough, United States), and one used an unspecified novel rapamycin-coated balloon. In total, 311 patients with sICAS treated with DCB were included; among them, 23 required bailout stents following DCB angioplasty, with the specific characteristics of the patients shown in Supplementary Table 1, http://links.lww.com/CM9/C730. Risk of bias was assessed using the NOS for dual-arm studies, with all three scoring ≥7, indicating low risk of bias [Supplementary Table 2, http://links.lww.com/CM9/C730]. The five single-arm studies were evaluated using the CEBM and were also deemed to have a low risk of bias [Supplementary Table 3, http://links.lww.com/CM9/C730]. Sensitivity analysis was conducted for the primary efficacy outcome [Supplementary Table 4, http://links.lww.com/CM9/C730].

Meta-analysis of the eight studies yielded the following pooled estimates for DCB treatment in sICAS: Restenosis (ES = 0.07, 95% confidence interval [CI, 0.04, 0.10], I² = 27.15%, 8 studies, n = 311) [Supplementary Figure 3, http://links.lww.com/CM9/C730], perioperative complications (ES = 0.08, 95% CI [0.04, 0.13], I² = 5.87%, 4 studies, n = 201) [Supplementary Figure 4, http://links.lww.com/CM9/C730], 30-day stroke or death (ES = 0.06, 95% CI [0.02, 0.10], I² = 0.00%, 4 studies, n = 180) [Supplementary Figure 5, http://links.lww.com/CM9/C730], 30-day to 1-year stroke or death (ES = 0.00, 95% CI [0.00, 0.03], I² = 12.31%, 6 studies, n = 213) [Supplementary Figure 6, http://links.lww.com/CM9/C730], TIA (ES = 0.05, 95% CI [0.00, 0.18], I² = 80.60%, 6 studies, n = 213) [Supplementary Figure 7, http://links.lww.com/CM9/C730], and bailout stent (ES = 0.14, 95% CI [0.02, 0.33], I² = 86.73%, 4 studies, n = 181) [Supplementary Figure 8, http://links.lww.com/CM9/C730].

To account for potential coating-related bias, subgroup analyses were performed comparing paclitaxel- and rapamycin-coated DCBs. Due to limited data in the rapamycin subgroup (2 studies, n = 140), only restenosis (ES = 0.10, 95% CI [0.05, 0.16], I² = 0.00%, P = 0.018) [Supplementary Figure 9, http://links.lww.com/CM9/C730], and 30-day stroke or death (ES = 0.08, 95% CI [0.03, 0.13], I² = 0.00%, P = 0.341) [Supplementary Figure 10, http://links.lww.com/CM9/C730] could be analyzed. In the paclitaxel subgroup (6 studies, n = 171), analyses included restenosis (ES = 0.05, 95% CI [0.02, 0.10], I² = 0.00%) [Supplementary Figure 11, http://links.lww.com/CM9/C730] and 30-day stroke or death (ES = 0.03, 95% CI [0.00, 0.14], I² = 0.00%, P = 0.416; 2 studies, n = 40) [Supplementary Figure 12, http://links.lww.com/CM9/C730].

DCB may offer significant clinical value by avoiding permanent device implantation and delivering localized drug therapy, potentially allowing for shorter DAPT duration and reduced risk of restenosis. However, substantial evidence gaps remain regarding their efficacy and safety in intracranial vascular disease. Endothelial injury and platelet activation following stent implantation are key contributors to restenosis. DCB aims to mitigate these mechanisms through the direct delivery of antiproliferative agents to the vessel wall. In this meta-analysis, the pooled restenosis rate for DCB in sICAS was 7%. For comparison, the restenosis rate associated with the Wingspan stent system in the SAMMPRIS trial was 9.6%.^[2] Although this appears favorable, the data do not provide strong evidence of a significant advantage for DCB over stents in reducing restenosis. Furthermore, differences in device generations and study timelines complicate direct comparisons and preclude definitive conclusions regarding DCB superiority.

Unlike coronary arteries, intracranial vessels lack an external elastic lamina, making them more prone to dissection, rupture, or elastic recoil during angioplasty due to their fragility and reduced wall support. While minor dissections may be manageable, severe cases can result in significant disability or mortality, necessitating a bailout stent.

This meta-analysis showed a perioperative complication rate of 8% and bailout stent rate of 14%. These findings underscore the importance of carefully evaluating the risks of DCB treatment. It should also be noted that only four studies (n = 201) reported on perioperative complications and only four studies (n = 181) on bailout stent. The high heterogeneity in the latter outcome (I² = 86.73%) further limits interpretability.

Recurrent adverse events, such as TIA, stroke, or death, significantly affect the quality of life in sICAS patients. The 30-day stroke or death rate in the DCB group was 6.0%, lower than the 14.7% reported in the SAMMPRIS ET group and comparable to the 5.7% rate in the CMT group.^[2] Between 30 days and 1 year post-procedure, the stroke or death rate in the DCB group was remarkably low at 1%, compared to 5.3% in the ET group and 6.5% in the CMT group.^[2] These findings suggest that DCB may offer advantages over ET in reducing the 1-year stroke or death risk and may also outperform CMT in the longer term. The 1-year TIA rate was 2%. However, due to high heterogeneity in both TIA (I² = 80.60%) and bailout stent analyses, random-effects models were used, and the reliability of these outcomes requires further investigation in high-quality studies.

The efficacy of DCB is closely tied to the properties of the antiproliferative coating. While paclitaxel-coated balloons are more commonly used, interest in rapamycin-coated alternatives is growing. Although the two drugs differ in pharmacological mechanisms, their goal is shared: Inhibition of neointimal hyperplasia. In this study’s subgroup analysis, paclitaxel-coated DCB demonstrated a 5% restenosis rate and a 3% 30-day stroke or death rate. Rapamycin-coated DCB showed a 10% restenosis rate and an 8% 30-day stroke or death rate. Although paclitaxel appeared to show more favorable outcomes, the small number of studies and limited sample sizes make it difficult to determine if one coating is definitively superior in the treatment of sICAS.

This study has several limitations. Of the eight included studies, six were retrospective and only two were prospective; no randomized controlled trials (RCTs) were available. Most studies had relatively small sample sizes, and heterogeneity was present in both outcome definitions and the types of DCBs used.

Based on the available evidence, DCB treatment for sICAS demonstrates acceptable safety and efficacy. The results suggest potential benefits in reducing perioperative complications and short-term adverse events, such as stroke and TIA. However, these conclusions are primarily derived from retrospective, single-center studies with limited sample sizes. To better establish the role of DCB in the management of sICAS, future high-quality, multicenter, RCTs are essential.

Funding

This work was supported by grants from the Henan Medical Science and Technology Research Plan Provincial and Ministerial Youth Project (No. SBGJ202303001), Henan Province Key Research and Development & Promotion Special (Science and Technology) Foundation (Nos. 222102310378 and 232102231042), National Health Commission Capacity Building and Continuing Education Project (No. GWJJ2023100101), and Key Research and Development Project of Henan Province (No. 241111313200).

Conflicts of interest

None.

Supplementary Material

cm9-139-2496-s001.pdf ^{(759.8KB, pdf)}