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Abstract
Background Drug-coated balloon (DCB) angioplasty has been studied for reducing the occurrence of restenosis after treatment for intracranial atherosclerotic stenosis (ICAS), but no comparison has been published of the use of drug-coated and non-coated balloons in angioplasty for ICAS. We aim to compare the safety and efficacy of DCB angioplasty with conventional balloon (CB) angioplasty for the treatment of symptomatic ICAS.
Methods One hundred cases with symptomatic ICAS treated with DCB (n=49) and CB (n=51) angioplasty were retrospectively analyzed. 1:1 propensity score matching (PSM) was completed to eliminate bias in the patients selected for further analysis. The periprocedural events and follow-up outcomes between the two groups were compared.
Results There were 32 cases in each group after PSM. Technical success (<50% residual stenosis) was achieved in 30 cases (93.8%) in the DCB group and in 28 cases (87.5%) in the CB group. The rates of stroke or mortality within 30 days were 3.1% in the DCB group and 6.3% in the CB group (p=1). The incidence of restenosis in the DCB group (6.3%) was significantly lower than that in the CB group (31.3%) (p=0.01).
Conclusions Compared with CB angioplasty, DCB angioplasty can effectively reduce the incidence of restenosis. Further studies are needed to validate the role of DCB angioplasty in the management of symptomatic ICAS.
- Angioplasty
- Atherosclerosis
- Stenosis
- Stroke
- Balloon
Data availability statement
Data are available upon reasonable request. Data are available from the corresponding author upon reasonable request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke, as well as being a significant risk factor for stroke recurrence. As an important treatment for ICAS, endovascular therapy is limited by perioperative complications and restenosis. Drug-coated balloon (DCB) angioplasty is a new interventional technique which may reduce the risk of restenosis for ICAS. However, there are few comparisons between DCB angioplasty and conventional treatment methods.
WHAT THIS STUDY ADDS
To the best of our knowledge, this is the first study to compare the efficacy and safety of DCB angioplasty with conventional balloon angioplasty in the treatment of patients with symptomatic ICAS. The effects of DCB angioplasty in reducing restenosis were impressive.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY
The results suggest that further study of the safety and efficacy of DCB angioplasty for stroke treatment and prevention is warranted for patients with ICAS.
Introduction
Ischemic stroke is a major cause of death and disability in the Chinese population, accounting for about 80% of all strokes.1 Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke, as well as being a significant risk factor for stroke recurrence.2 The current guidelines recommend intensive drug therapy for ICAS.3 However, for some patients with hypoperfusion stroke, drug therapy is not effective.4 A previous study reported that the annual rate of stroke or mortality in patients with ICAS receiving aggressive medical therapy was as high as 20%.5 Endovascular therapy was considered to be an important complementary treatment for patients with a poor response to drug therapy.6 7 The main limitations of endovascular treatment are a high perioperative complication rate and a high restenosis rate. Two clinical trials were terminated prematurely due to the high incidence of perioperative stroke or death, which reached 14.7% in the SAMMPRIS trial and 24.1% in the VISSIT trial.8 9 Restenosis limits surgical benefits for patients. The in-stent restenosis rate has been reported to be 23–30% for bare metal stents.7 10 11 The incidence of restenosis was 18.4% after undergoing conventional balloon (CB) angioplasty.12 Compared with the two classical methods, CB angioplasty is associated with lower risks of surgery.13
Drug-coated balloon (DCB) angioplasty is a new interventional technique. Anti-cell proliferation drugs are coated on the surface of the balloon and delivered to the lesion through a catheter. The balloon is dilated to release the drugs into the vessel wall to inhibit intimal hyperplasia and prevent restenosis. Previous studies using DCB angioplasty for the treatment of ICAS have indicated its potential to reduce the recurrence of stroke.14 However, there are no publications comparing the efficacy of DCB and CB for angioplasty to treat symptomatic ICAS. In this study, we analyzed the clinical data of patients with symptomatic ICAS who were treated with DCB or CB angioplasty and compared the safety and efficacy between these two methods.
Methods
Study population
This study was approved by the ethics committee at our hospital. Clinical and imaging data of 100 patients with symptomatic ICAS who received endovascular treatment with DCB or CB from January 2019 to August 2021 were retrospectively analyzed. The patients were divided into two groups (DCB and CB).
The inclusion criteria were as follows: (1) patients who experienced a transient ischemic attack (TIA) or non-disabling ischemic stroke caused by ICAS due to hypoperfusion with poor collateral flow; (2) patients who received at least one antithrombotic drug and/or one drug for the treatment of risk factors such as hypertension and diabetes; (3) patients with 70–99% stenosis confirmed by DSA according to the warfarin-aspirin symptomatic intracranial disease (WASID) method15; (4) patients who had a target artery diameter of ≥2 mm with a lesion <15 mm long; and (5) patients in whom the target vessels included C4–C7 of the internal carotid artery, M1 and M2 segments of the middle cerebral artery, V4 segment of the vertebral artery and basilar artery.
Hypoperfusion with poor collaterals was determined by the following three methods16: (1) ASITN/SIR score 0–2; (2) decrease of >30% in the cerebral blood flow in the territory distal to the target lesion by CT perfusion; (3) a diagnosis of hemodynamic ischemic lesions by MRI or CT. Major exclusion criteria were: (1) >70% stenosis of large intracranial vessels outside the responsible vessel or >50% stenosis of the main blood supply artery of the responsible vessel; (2) CT or angiographic evidence of severe calcification at the target lesion; and (3) a history of undergoing angioplasty or stenting in the target lesion.
Surgical procedures
All procedures were performed under general anesthesia. Patients were treated with oral aspirin (100 mg/day) and clopidogrel (75 mg/day) and continued for 3–5 days before operation. It is recommended to perform thromboelastography, aspirin, and clopidogrel genetic testing to detect whether the antiplatelet therapy reaches the target; in patients who do not meet the target, the medication time can be appropriately prolonged or the dose adjusted.
All interventional operations were performed by neurointerventional neurosurgeons with more than 10 years of clinical experience. A right femoral access with an 8F sheath was used. Unfractionated heparin 70 units/kg was injected intravenously and increased by 1000 units every hour. Using a loach guidewire and an angiographic catheter, the tip of the 6F long sheath was placed at the level of the extracranial segment of the internal carotid artery or the intervertebral foramen of the vertebral artery. A 5F intermediate catheter was sent to the proximal end of the lesion through the 6F sheath. Using the best working angle, a microcatheter was delivered to the distal end of the lesion using a 200 cm micro guidewire. A 300 cm micro guidewire with small pig tail plastic was exchanged. A pre-expanded balloon was inserted, the diameter of which was 80% of the diameter of the normal blood vessels and the length completely covered both ends of the lesion. Under fluoroscopy, the pre-expanded balloon was inflated slowly to the nominal pressure and remained at that level for 60 s, then the balloon was slowly emptied. The DCB system (SeQuent Please NEO, B. Braun, Germany) was delivered to the stenotic segment along with the micro guidewire. This type of DCB is compatible with 5F guiding catheters as well as 0.014 inch guidewires. It has a full range of sizes (balloon diameter 2.0–4.0 mm, length 10–40 mm) and longer working length (145 cm),17 which is suitable for intracranial lesions. The diameter of the DCB was at least as large as that of the pre-dilation, and the length was 2–3 mm longer than the stenotic lesion. The DCB was rapidly inflated to 3 atm, slowly expanded to the nominal pressure, and kept inflated for 60 s. The balloon was then emptied for the angiography to rule out vascular dissection, perforation, and distal embolism. After removing the balloon, monitoring was continued for 30 min to confirm that there were no complications and the surgery was finished. In the CB group, similar surgical procedures were performed, and the target vessel was dilated by the intracranial non-coated balloon (SacSpeed Balloon, Achieva Medical, Peijia Company). Technical success was defined as a residual stenosis of the target vessel ≤50% after angioplasty. A salvage stent was placed in case of severe vessel dissection during angioplasty.
Follow-up and data collection
Patients received dual antiplatelet therapy (aspirin 100 mg and clopidogrel 75 mg per day) for at least 90 days, and a longer treatment time was required for implanting stents. Administration of aspirin or clopidogrel alone was adjusted according to the patient’s condition during follow-up. Patients were followed up for 30 days, 90 days, 6 months, 1 year, and yearly thereafter by telephone or face-to-face interview. It was recommended to perform DSA at the time interval of 6 months (±1 month) after the surgery to clarify the lesions. CT angiography (CTA) was alternatively performed in patients who did not undergo DSA. The demographic, clinical, radiological, and surgical records of the patients as well as follow-up data were collected and analyzed.
Outcomes
The primary safety endpoint was any causes of stroke or death within 30 days such as vascular injury, subarachnoid hemorrhage, parenchymal hemorrhage, acute thrombosis, and cerebral infarction. The primary efficacy endpoint was restenosis within 6 months after the procedure. Restenosis was defined as angiographic evidence of >50% stenosis within or immediately adjacent (within 5 mm) to the treated segment. Secondary endpoints included technical success rate, recurrent ischemic events, symptomatic restenosis, stenosis degree at follow-up, and modified Rankin Scale (mRS) score at 1 year. Recurrent ischemic events were defined as any focal neurological symptoms related to the corresponding vascular territory. Symptomatic restenosis was defined as the recurrence of previously treated artery stenosis over time with ischemic symptoms. The imaging and clinical outcomes were reviewed by two investigators. Disagreements were resolved by consensus.
Statistical analysis
The statistical analysis was performed using SPSS 26.0 software (IBM, Armonk, New York, USA). The Shapiro–Wilk test was used to analyze the data for normality. Normally distributed continuous variables were expressed as mean±SD and inter-group comparisons were conducted using the independent samples t-test. Abnormally distributed continuous variables were expressed as median (IQR), and inter-group comparisons were carried out using the Wilcoxon rank-sum test. Categorical variables were expressed as frequency and constituent ratio and compared using the χ2 test or the Fisher exact test.
Propensity score matching (PSM) was used to match patients in the DCB group and the CB group to eliminate differences in baseline data with age and pre-intervention stenosis as covariates, and nearest-neighbor matching with a caliper value of 0.02 for 1: 1 match. The primary safety end point was assessed by the Kaplan–Meier method, and the log-rank test was used to test for differences between groups. p<0.05 was considered statistically significant.
Results
From January 2019 to August 2021, a total of 100 patients with symptomatic ICAS received balloon angioplasty, including 49 patients in the DCB group and 51 patients in the CB group. After 1:1 PSM, a total of 64 patients were included in the analysis, 32 of whom were treated with DCB and 32 with CB.
Key results before PSM
Of the 100 patients with ICAS, there were 74 men and 26 women, with an average age of 56.4±9.0 years (range 30–80). Fifty-eight patients presented with cerebral infarction and 42 with TIA. Hypertension was the most common risk factor in both groups (n=80, 80.0%). There was a significant difference between the two groups in age and degree of stenosis before treatment (p<0.05), but there was no difference in gender, proportion of risk factors, preoperative mRS score, lesion location, and stenosis length. The technical success rate of the DCB group was 91.8% (45/49), the perioperative ischemic stroke rate was 2.0% (1/49), and no TIA, death or hemorrhagic stroke events were observed. All patients received clinical follow-up. The median follow-up time was 12 months (range 8–37). There were two (4.1%, 2/49) recurrent stroke events in the target vessel area; 38 cases were imaging followed in the DCB group with a median of 6 months (range 3–12) and the restenosis rate was 2.5%. The degree of stenosis in the DCB and CB groups was not significantly different (20% vs 30%, p<0.001). The incidence of restenosis in the DCB group was significantly lower than that of the CB group (5.3% vs 27.9%, p=0.015). There was no significant difference between the two groups in the incidence of perioperative stroke or death, stroke recurrence rate, and symptomatic restenosis rate (p>0.05). The baseline data, perioperative period, and follow-up results of the two groups before matching are shown in online supplemental file 1.
Supplemental material
Key results after PSM
After 1:1 PSM there were 32 patients in each group. The baseline characteristics between the two groups were unified, and there was no significant difference in age, gender, proportion of risk factors, and mRS score. Table 1 shows specific baseline data. During the operation, all balloons were successfully delivered to the lesion location and expanded, and there was no failure to reach the position. In the DCB group, one patient had acute thrombosis during the operation. The vessel was reopened and there were no symptoms after local tirofiban treatment. No vascular rupture, perforation, or vasospasm was seen. Two cases of subarachnoid hemorrhage caused by vascular perforation were observed in the CB group; one patient eventually died and the other had no symptoms. There was no difference in lesion characteristics and degree of vascular stenosis between the two groups before and after treatment. The degree of vascular stenosis in the DCB group decreased from 80.0% to 21.5% after operation (z=−6.894, p<0.001), and the degree of vascular stenosis in the CB group decreased from 84.5% to 20.0% after operation (z=−6.886, p<0.001). The degrees of stenosis before and after treatment in the two groups are shown in online supplemental file 2.
Supplemental material
Baseline characteristics of the study population after propensity score matching
Safety endpoints
The safety endpoint results are shown in table 2. The rates of any causes of stroke or death within 30 days in the DCB and CB groups were not significantly different (3.1% (1/32) vs 6.3% (2/32), p=1). One patient with hemorrhagic stroke in the CB group eventually died. No significant differences in other safety endpoints were found between the two groups. Kaplan–Meier survival analysis showed that the cumulative probability of stroke and death within 30 days and recurrent stroke related to the corresponding vascular territory beyond 30 days to 1-yearin the DCB and CB groups were 5.6% and 18.7%, respectively (figure 1). There was no significant difference between the two groups (p=0.412).
Kaplan–Meier curves for the cumulative probability of stroke and death within 30 days and recurrent stroke related to the corresponding vascular territory beyond 30 days.
Safety and efficacy endpoints
Efficacy endpoints
The results of efficacy endpoints are shown in table 2. The median stenosis degree in the DCB group was lower than that of the CB group in a median follow-up time of 6 months (range 3–12)(figure 2). The incidence of restenosis was significantly lower in the DCB group (6.3%) than in the CB group (31.3%) (p=0.01). The occurrence of symptomatic restenosis in the CB group (12.5%) was higher than that of the DCB group (3.1%), but the difference between the two groups was not significant (p=0.352). There was no significant difference regarding the technical success between the two groups (93.8% vs 87.5%, p=0.668) .
Angiographic outcome of one drug-coated balloon (DCB) dilation for intracranial atherosclerotic stenosis. (A) Left internal carotid artery severe stenosis. (B) Pre-dilation with a pre-expanded balloon. (C) Angiographic result after pre-dilation. (D) DCB dilation. (E) Angiographic result after DCB dilation. (F) Angiographic outcome at 6-month follow-up.
Discussion
This study indicates that the use of DCB angioplasty could reduce the incidence of restenosis at the 6-month follow-up for the treatment of symptomatic ICAS. Meanwhile, DCB did not increase the risk of perioperative stroke or death and stroke recurrence in comparison with CB in the target vascular territory beyond 30 days. This is the first study to compare the efficacy and safety of DCB with CB in the treatment of patients with symptomatic ICAS.
There are several publications related to DCB in ICAS. Gruber et al 14 first reported on DCB angioplasty in patients with high-grade ICAS. Compared with stents, DCB showed a significantly lower rate of ischemic re-events or restenosis. Then, another of their studies suggested that SeQuent Please NEO DCB (the same as we used in our study) was feasible and safe without perioperative complications and death at a median follow-up of 3 months.18 Remonda et al 19 showed that 6% of patients had perioperative complications. Wang et al 20 reported 5.7% perioperative complications. In a recent large cohort study with 245 procedures,21 Qiao et al reported 16 major and 12 minor complications (6.5% and 4.9%, respectively). Eight lesions (4.8%, 8/167) were restenotic during the follow-up period. These results are similar to ours.
Although there is potential risk to using DCB for angioplasty, our current study did not show any increase in complications because of DCB. The possible reasons are, first, that we selected the appropriate size of DCB, which was similar to the pre-dilated balloon. The drug from the coating could be diffused into the blood vessel wall without severe vessel damage because of a lack of vessel overdilation. Second, by using the intermediate catheter, the balloon catheter can reach the lesion location quickly and safely, which was helpful in avoiding the loss of coating materials and reducing vessel injury during the catheter delivery.
The degree of stenosis was very similar in both groups in the immediate post-treatment period, although it was lower in the DCB group than in the CB group at the 6-month follow-up. This suggests that DCB might have a positive remodeling effect on the vascular lumen, which could be related to the improvement in the proliferation and distribution of smooth muscle cells. Additionally, although the incidence of restenosis was higher in the CB group, the incidence of symptomatic restenosis was similar in the two groups, which might be attributed to the role of standard medical treatment and strict control of risk factors in preventing recurrent stroke. Therefore, a larger randomized controlled trial comparing DCB angioplasty with other treatment approaches should be conducted in the future. A recent study showed that drug-eluting stents can reduce the risks of restenosis and recurrence of ischemic stroke in patients with symptomatic high-grade ICAS.22 Currently, there are no comparable studies of DCB and drug-eluting stent angioplasty for symptomatic ICAS. Theoretically, DCB has better compliance, passage ability, and drug distribution in the vessel wall than drug-eluting stents. With the same efficacy, DCB angioplasty does not require additional stents and long-term double antiplatelet therapy, which is an advantage for some high-risk patients with ICAS.
The present study has some limitations. First, the study was not randomized, which might have caused selection bias. Second, three different tests were used to determine patients with hypoperfusion, which could have made it difficult to assess heterogeneity in the subgroup of patients. Finally, the follow-up time point was 6 months, and the long-term risk of DCB angioplasty and the occurrence of restenosis after the angioplasty procedure remains unknown.
Conclusions
DCB angioplasty appears to be effective and safe in the treatment of patients with symptomatic ICAS. Compared with CB angioplasty, DCB angioplasty could effectively decrease the incidence of restenosis. DCB angioplasty is a potential treatment for symptomatic ICAS, but randomized controlled trials are needed for further validation.
Supplemental material
Data availability statement
Data are available upon reasonable request. Data are available from the corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the Medical Ethics Committee of Zhengzhou University People's Hospital (2020-1-155). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors are grateful to Professor Yonghong Ding at the Mayo Clinic for his English editing assistance.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors Contributors: YT drafted and revised the paper, conceived and designed the study, acquired and analyzed the data. TL provided study ideas and resources and revised the manuscript critically. WL acquired data, applied software and statistics. YH acquired, monitored and validated data. LZ undertook the study of patients and supervised the whole study. Z-LW undertook the study of patients and supervised the whole study. YH formulated the overarching research goals and aims, designed the study, wrote the statistical analysis plan, and drafted and revised the paper. YH is responsible for the overall content as guarantor.
Funding (1) Henan Province Key Research and Development & Promotion Special (Science and Technology) Foundation (202102310037). (2) Key Scientific Research Projects of Colleges and Universities in Henan Province (21A320002). (3) Henan Young and Middle-Aged Health Science and Technology Innovation Talent Training Project (YXKC2020041). (4) Henan Medical Science and Technology Research Plan Provincial and Ministerial Youth Project (SBGJ202003004).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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