Resolute onyx stent more effective than wingspan stent at preventing procedural complications and long-term restenosis

Abstract

Background and Purpose

Angioplasty and stenting is a treatment option for patients with medically refractory symptomatic intracranial atherosclerotic disease (sICAD). Currently the Wingspan Stent System (WSS) is the only FDA approved device for this indication. We find the Resolute (R) Onyx Stent, a drug-eluting balloon mounted stent (DES), a better alternative to the WSS for treatment of sICAD. Herein, we present our findings comparing the two stents based on our single center experience.

Methods

A prospectively maintained neuro-endovascular databased was queried for patients between January 2013 to June 2021. Inclusion criteria for patients included sICAD with failed medical management, and intracranial stenting with either R-Onyx DES or WSS, including patients treated within 7 days of their last stroke. Primary outcomes were assessed via the occurrence of ischemic or hemorrhagic stroke or death within 72 h of the procedure. Secondary outcomes consisted of recurrent stroke or significant in-stent restenosis evaluated by a clinical or angiographic follow-up at 6 months.

Results

A total of 184 patients, average age 61.26 (SD = 12.53) (44% women), were eligible for analysis with 58 having R-onyx DES and 126 having WSS. Within 72 h, the primary outcome was observed in 1.7% (n = 1) of patients in the R-onyx DES group and 6.3% (n = 8) of patients in the WSS group (p = 0.089). Among 41 angiographic and clinical follow-ups in the R-onyx DES group, none had a recurrent stroke, while among 101 patients who had follow-up in the WSS group, 8.9% (n = 9) had a stroke (p = 0.024). At a 6-month angiographic follow-up, there was a significantly lower rate of symptomatic in-stent restenosis among the R-onyx DES group with 1.7% (n = 1) compared with 21.4% (n = 27) in the WSS group (p = 0.0003).

Conclusion

R-onyx DES is more effective than WSS in treating sICAD with low rates of periprocedural complications and long-term strokes and symptomatic in-stent restenosis. Future prospective randomized multicenter trials are needed.

Introduction

Angioplasty and stenting is a common treatment modality for medically refractory symptomatic intracranial atherosclerotic disease (sICAD), a common cause of stroke. Currently, the only FDA-approved stent for this specific indication is the Wingspan Stent System (WSS) which was used in the FDA-mandated Wingspan Stent System Post Market Surveillance ¹ (WEAVE) trial. Primary analysis of WEAVE consisted of periprocedural complications within 72 h of the procedures to evaluate the safety of the stent. Recently, a research group has shown that the Resolute (R) Onyx Stent, a drug-eluting balloon mounted stent (DES) can be used as an alternative to safely treat sICAD with high technical success rate.^2,3 Herein, we compare the safety and efficacy of the two stents in similar patient populations.

Methods

This study has been approved by the local Institutional Review Board. A prospectively maintained neuro-endovascular databased was retrospectively queried for patients treated with intracranial angioplasty and stenting between January 2013 and June 2021. Inclusion criteria for patients included sICAD (≥70% stenosis) with a recurrent transient ischemic attack (TIA) or stroke despite maximal medical management (MMM) consisting of treatment with dual antiplatelet and statin therapy, having intracranial stenting with either the R-onyx DES or WSS, and treatment within or after 7 days of the qualifying ischemic event. The first R-Onyx DES was placed in October 2019 as part of a consecutive 18 patient study to determine the feasibility of using R-Onyx DES intracranially. After promising results, all stenting procedures were conducted using R-Onyx DES except in the case of target arteries that contained differently sized terminal ends, where WSS would be used. Patients treated after 7 days were also included in a secondary analysis with more WEAVE-like criteria for comparison between the two stents. Each intervention was done after a multidisciplinary consultation among vascular neurologists and neuro-interventionalists and the operator decided on the location of arterial access. All patients received heparin to achieve an activated clotting time from 250 to 300 s during the procedure. The neuro-interventionalist determined the stent size based on the digital subtraction angiography (DSA) measurements. The degree of percent stenosis was calculated using the following equation: Percent Stenosis = [(1-( $D_{\mathrm{stenosis}}/D_{\mathrm{normal}}$ )] × 100, where $D_{\mathrm{stenosis}}$ is the diameter of the artery where stenosis is most severe and $D_{\mathrm{normal}}$ is the diameter of the proximal normal artery. Using a road map, a microwire was inserted into the vessel distal to the stenosis then the desired stent system, chosen based on the timeline outlined above, was advanced distally to and positioned across the stenotic segment typically with the assistance of a distal access support catheter, and the stent was deployed. At the operator's discretion, a pre-dilation with a balloon was sometimes performed before being exchanged for the desired stent system and navigated to the desired lesion. A final digital subtraction angiographic image was generated following withdrawal of the balloon catheter to verify proper stent deployment. Post-procedure therapy included dual-antiplatelet therapy with aspirin and either ticagrelor or clopidogrel.

Data collected on eligible patients included age, sex, ethnicity, risk factors (hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking), indication for procedure (TIA or stroke), number of days from qualifying event to treatment, degree of percent stenosis before the procedure, degree of residual stenosis after the procedure. In addition to baseline characteristics, primary outcomes including the occurrence of ischemic or hemorrhagic stroke or mortality within 72 h of the procedure were recorded, similar to the WEAVE study outcome measurements. A stroke was defined by sudden neurological deterioration and confirmed by the combination of the clinical assessment of an independent vascular neurologist and a head CT scan and brain MRI with positive diffuse weighted imaging (DWI) for hemorrhagic and ischemic strokes respectively.

Secondary outcomes consisting of stroke and TIA beyond 72 h post-procedure, and in-stent restenosis (≥50% stenosis) at a 3 to 12-month angiographic follow-up were recorded. Furthermore, in-stent restenosis at these follow-ups were categorized to be either asymptomatic, with no associated stroke or TIA symptoms due to the restenosis, or symptomatic, with associated stroke or TIA symptoms due to the restenosis. All information that was not recorded was presumed to be absent.

Outcomes between the two groups were compared using the z-test for two population proportions after no significant difference was established between the two groups for age, gender, ethnicity, and risk factors for stroke. Continuous variables were compared using the Mann-Whitney U-test while categorical variables were compared using the z- test for two population proportions (for gender and risk factors) and the chi-squared categorical test (for ethnicity). Tests to determine no significant difference in baseline characteristics between the R-onyx DES and WSS groups were two-sided while tests to determine the difference in outcome between those two groups were one-sided with the null hypothesis being that R-onyx DES would yield statistically significant fewer adverse outcomes than WSS. Statistical analyses were performed using SPSS 28.0 software (IBM® Armonk, NY, USA) and Microsoft Excel (Microsoft Corporation 2018).

Results

A total of 184 patients, average age 61.26 years (SD = 12.53 years) with 44.0% (n = 81) women, 10.9% (n = 20) were White, 88.6% (n = 163) were Hispanic, and 0.5% (n = 1) of them were Asian and eligible for analysis. The indication for stenting was stroke for 65.8% (n = 121) of the patients and TIA for 34.2% (n = 63). Of the 184 patients, 31.5% (n = 58) were treated with the R-onyx DES and 68.5% (n = 126) were treated with WSS. The median degree of percent stenosis before the procedure was 90% [IQR = 10%] and the median residual stenosis after the procedure was 0% [IQR = 20%]. There was no significant difference in age, gender, ethnicity, or premorbid risk factors between the two groups as detailed on Table 1.

Table 1.

Demographic and clinical characteristics for all patients based on stent type.

	Resolute Patients N = 58	Wingspan Patients N = 126	P value
Demographic and clinical characteristics n (%)
Age	63.66 ± 13.05	60.16 ± 12.78	0.117
Male	37 (63.8)	66 (52.4)	0.147
Ethnic background
White	4 (6.9)	16 (12.7)
Hispanic	54 (93.1)	109 (86.5)	0.390
Asian	0 (0%)	1 (0.8)
Hypertension	55 (94.8)	112 (88.9)	0.197
Diabetes mellitus	44 (75.9)	78 (61.9)	0.063
Hyperlipidemia	39 (67.2)	78 (61.9)	0.484
Current cigarette smoking	6 (10.3)	11 (8.7)	0.726
Time from the last event to stenting, days median [IQR]	4 [2–8]	3.5 [2–9.25]	0.796
Degree of stenosis (%) median [IQR]	87.5 [78.8–90.0]	90 [80–90]	0.625
Residual stenosis post-stenting (%) median [IQR]	0 [0–0]	0 [0–20]	<0.001
Early outcome n (%)
Procedural complications	1	0	0.139
Stroke within 72 h of the procedure	1 (1.7)	8 (6.3)	0.089
Ischemic stroke	0	2 (1.6)
Hemorrhagic stroke	1 (1.7)	6 (4.8)
Death on discharge	2 (3.4)	5 (4.0)	>0.433
Late outcome n (%)
Clinical Follow up	N = 41	N = 101
TIA	2 (4.9)	23 (22.8)	0.006
Ischemic/hemorrhagic strokes	0	9 (8.9)	0.024
Follow up Imaging	N = 22	N = 59
In-stent stenosis	1 (4.5)	40 (67.9)	<0.001*
- Symptomatic:	1	27 (45.8)	<0.001*
Retreatment	1 (1 angioplasty)	23 (23 angioplasty)	0.001*
- Asymptomatic	0	13	0.006*

*proportion used in p-value calculation includes the whole stent group rather than just among follow-ups.

Within 72 h post-procedure, 1.7% (n = 1) of patients had a primary event of ischemic or hemorrhagic stroke or death in the R-onyx DES group while 6.3% (n = 8) of patients had those indications in the WSS group (p = 0.089). In the R-Onyx DES group, this complication was due to inadvertent wire perforation that ruptured a nearby posterior communication artery aneurysm. Among patients treated with WSS, 4 of the periprocedural complications associated with symptomatic intracranial hemorrhages resulted in death before discharge. Additionally, two patients treated with WSS had periprocedural ischemic strokes— one due to vasospasms after the procedure and the other due to an in-stent thrombus which was treated with intra-arterial thrombolysis. Beyond 72 h— and therefore not counted as a periprocedural complication according to WEAVE criteria— there was one additional in-hospital mortality in each group; one was due to a cardiac arrest and the other due to respiratory failure and end-stage renal disease.

Among 41 angiographic and clinical follow-ups in the R-onyx DES group, none had a stroke and 4.9% (n = 2) had a TIA, while among 101 of those follow-ups in the WSS group, 8.9% (n = 9) had a stroke (p = 0.024) and 22.8% (n = 23) had a TIA (p = 0.006). In terms of 6-month angiographic follow-ups, there was a significantly lower rate of symptomatic in-stent restenosis among the R-onyx DES group with 1.7% (n = 1) and 21.4% (n = 27) in the WSS group (p = 0.0003). For combined symptomatic and asymptomatic rates however, 1.7% (n = 1) of R-onyx DES group patients experienced long-term in-stent restenosis compared to 31.7% (n = 40) of the WSS group (p < 0.001). In line with operator notes, the WSS group had four patients who were below the 50% restenosis rate classified as having restenosis, two of whom were symptomatic but left untreated. Furthermore, another patient in the R-onyx DES group had a stent migration recorded on a 2-month follow-up angiogram due to a clinical TIA. There was, however, no in-stent restenosis, and although this event occurred at only 2-months following the procedure, the TIA was still included as a long-term event given the stent moved from its original deployment location following the TIA at 2-months.

A total of 43 patients (16 = R-onyx DES and 27 = WSS) were also eligible for analysis under the WEAVE trial inclusion criteria of treatment beyond 7 days. The average age of the WEAVE eligible group was 61.5 (SD = 12.93 years) with 37.2% (n = 16) being female. The median [IQR] time from the qualifying event to procedure was 28 days [11–68] and none of the patients experienced periprocedural complications or mortality within 72 h which is also the primary outcome assessed by the WEAVE trial. Among longer-term outcomes (beyond 72 h) of those treated 7 days beyond the initial event, there was also only one (3.7%) stroke and 5 (18.5%) TIAs in the WSS group while the R-Onyx DES group had 2 (12.5%) patients experiencing TIAs. Notably, there was still significantly less in-stent restenosis among this group of patients in the R-Onyx DES group (6.25% and n = 1) compared to the WSS group (37.0% and n = 10) (p = 0.013).

Discussion

In this study, we found the rate of periprocedural complications within 72 h post treatment markedly lower in patients treated with the R-onyx DES (1.7%) than those treated with WSS (6.3%) with a p-value of (p = 0.089). Moreover, we found statistically significantly lower rates of long-term stroke (p = 0.024) and TIA (p = 0.006) in patients treated with the R-onyx DES compared to those with WSS. Symptomatic in-stent restenosis rates were also statistically significantly lower in R-onyx DES patients than those in WSS group (p = 0.0003), and overall in-stent restenosis rates strongly followed that trend (p < 0.001).

Our findings are similar to those in a study that found another balloon mounted stent, the Apollo stent, ⁴ to be comparable to the WSS by contrasting stroke, mortality, and in-stent restenosis rates to the WEAVE and the Wingspan One-year Vascular Events and Neurologic Outcomes ⁵ (WOVEN) trials’ data. The WEAVE cohort included patients who underwent angioplasty and stenting beyond 7 days from the qualifying event, and it reported a 2.6% periprocedural complication rate within 72 h for WSS. Our study found a lower rate of these complications (1.7%) for R-onyx DES including patients who underwent stenting within 7 days, and both our study and the Apollo study found no complications (0%) in balloon mounted stents for patients who underwent stenting more than 7 days after the qualifying event.

The Vitesse Intracranial Stent Study for Ischemic Stroke Therapy (VISSIT) ⁶ and Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) ⁷ trials compared the Vitesse balloon-expandable stent and the WSS, respectively, to MMM. Although those trials concluded medical treatment was superior to the stents they used, both the VISSIT and SAMMPRIS trial had a higher rate of stroke and death within 30 days, (24.1%) and (14.7%) respectively, compared to our trial's R-onyx DES group rate of stroke and death within 30 days (3.4%) and to the Apollo stent's rate (2.5%). The high rates of primary events observed in the VISSIT and SAMMPRIS studies are due to periprocedural complications that account for a large number of recurrent strokes, and previous studies show that most recurrent strokes in angioplasty and stenting procedures occur within 30 days due to periprocedural complications. ⁸ Particularly for the VISSIT trial, this high rate of periprocedural complications could be due to an older and less flexible stent type compared to the R-onyx DES, which is also drug-eluting.

The VISSIT trial also reports much higher rates of stroke and TIA in late outcomes (36.2%) than the present trial's R-onyx DES group (4.9%) and similarly, much higher rates of in-stent restenosis (29.4%) compared to the present trial's R-onyx DES group (4.5%). This discrepancy of long-term stroke and in-stent restenosis rates cannot likely be explained solely through the longer follow-up period of the VISSIT trial (12 months) compared to the present study's follow-up period window (3–12 months). However, the difference between in-stent restenosis rates could be explained due to stent integration, while the difference between the long-term event rates could be explained with higher rates of in-stent restenosis subsequently contributing to increasing rates of long term recurrent stroke and TIA. ⁹

For balloon-mounted stents such as R-onyx DES, low in-stent restenosis rates are reported in many studies. For example, in a study where WSS was compared with different balloon-mounted coronary stents used intracranially, ¹⁰ WSS had much higher rates of in-stent restenosis (37%) than the balloon mounted coronary stents (9%). While the WSS restenosis rate reported by Tarlov et al. is similar to the WSS rate in our current study (31.7%), the in-stent restenosis rates of balloon mounted stents are relatively high (9%) compared to the present study (1.7%). Furthermore, Tarlov et al. reported the recurrent stroke rate for patients treated with WSS to be lower (15.7%) than those treated with the balloon mounted stents (22.7%), opposite to our findings of 0% for R-onyx DES and 8.9% for WSS. We believe the discrepancies across the different types of balloon mounted stents could be potentially explained by relative difficulty with trackability and the “increased associated risk” of the older balloon mounted stents used by Tarlov et al.

In theory, the lower rate of periprocedural complications in the R-onyx DES group is mainly due to avoidance of the “over-the-wire exchange after angioplasty” which could increase risk of strokes from a wire perforation or dissection. Previous studies provide evidence that DES decreases the risk of in-stent restenosis intracranially^11,12 and our study corroborates this assertion. Furthermore, the design of our study allowed us to directly compare the efficacy of R-onyx DES and WSS in the same population after a strict adoption of the R-Onyx DES instead of WSS, with the exception of vessels that have different terminal end diameters. This is contrary to comparing our balloon mounted stent efficacy to solely other studies where operators, patient demographics and other factors might differ. We further stratified our data to include WEAVE-like inclusion criteria in our analysis.

Our findings in this study add to the increasing body of evidence that suggests R-onyx DES could be a more effective treatment option in lowering the short-term and long-term adverse effects that are associated with treatment of sICAD compared to WSS. After analyzing procedures done after 7 days since the qualifying event, the present study also demonstrated a decreased rate of periprocedural complications for both stents. However, the present study contains the normal limitations of a single-center retrospective study, and although the stent system selection was solely R-Onyx DES after October 2019 (with the exceptions highlighted above) and solely WSS before that date, this doesn't constitute a true randomized trial. Regardless, the large sample sizes of both groups in this study provides ample data across many types of vessels to draw helpful conclusions based on the use of R-Onyx DES versus WSS.

Conclusion

R-onyx DES is superior in treating sICAD than WSS with lower observed rates of periprocedural complications, recurrent strokes and TIAs, and symptomatic in-stent restenosis. Future prospective randomized multicenter trials, with control for stenotic legions types and cost analysis, are warranted.