1-Year outcomes of Resolute Onyx Zotarolimus-Eluting Stent for symptomatic intracranial atherosclerotic disease: A multicenter propensity score–matched comparison with stenting versus aggressive medical management for preventing recurrent stroke in intracranial stenosis trial

Abstract

Background

Intracranial atherosclerotic disease (ICAD) is one of the most prevalent causes of stroke across the world. Endovascular treatment has gained prominence but remains a challenge with unfavorable results. Recent literature has demonstrated that the Resolute Onyx Zotarolimus-Eluting Stent (RO-ZES) is a technically safe option with low complication rates along with 30-day outcomes associated with intracranial stent placement for ICAD with RO-ZES compared to results from the Stenting Versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial. Here, we aim to compare outcomes at one year with the SAMMPRIS trial with a multicenter longitudinal study.

Materials and methods

Prospectively maintained databases across seven stroke centers were analyzed for adult patients undergoing RO-ZES placement for ICAD between January 2019 and May 2023. The primary endpoint was composite of one-year stroke, ICH, and/or death. These data were propensity score matched using age, sex, hypertension, diabetes mellitus, smoking status, and impacted vessel for comparison between RO-ZES and the SAMMPRIS percutaneous angioplasty and stenting groups (S-PTAS).

Results

A total of 104 patients were included, mean age ± SD: 64.9 ± 10.9 years, 25.5% female. Propensity score match analysis of the 104 patients with S-PTAS demonstrated one-year stroke, ICH, and/or death rate of 11.5% in the RO-ZES group and 28.1% in the S-PTAS group (odds ratio 4.17, 95% CI 2.06–8.96, p = 0.001).

Conclusion

The RO-ZES system demonstrates strong potential to reduce long-term complications at one year compared with the S-PTAS group. Further prospective multicenter studies are needed to corroborate and build upon these findings.

Introduction

Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke globally, carrying a plethora of clinical consequences for patients in addition to significant pressure on healthcare systems. Treatment of ICAD remains controversial, yet critical, due to a high risk of recurrent stroke in the territory of the stenotic artery, estimated at up to 23% at one year. ¹ Endovascular treatment (ET) for ICAD has gained prominence, but remains a challenge with unfavorable results due to trials such as Stenting Versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) and the Vitesse Intracranial Stent Study for Ischemic Stroke Therapy (VISSIT).^1,2 Both trials were halted due to high rate of stroke and/or death at 30 days. However, studies such as the Wingspan Stent System Post Market Surveillance Study (WEAVE) indicated lower periprocedural event rates of stroke, as compared to previous studies, yet still demonstrated high recurrent stroke rates during follow-up. ³

The proposed mechanism behind recurrent stenosis in traditional bare-metal stents such as the Wingspan system is neointimal hyperplasia occurring within the stent. ⁴ Drug-eluting stents (DES) mitigate this process via the elution of an antiproliferative agent that prevents the development of neointimal hyperplasia, thereby reducing in-stent restenosis. ⁵ Recent literature has shown favorable results highlighting the Resolute Onyx Zotarolimus-Eluting stent (RO-ZES) as a technically feasible option with low reported rates of procedural complications, recurrent stroke, and death compared to traditional bare-metal stents.^4,6–9 A recently published multicenter study reported favorable 30-day outcomes associated with RO-ZES for ICAD in comparison to SAMMPRIS. ⁷ However, the scope of this study was limited in the longitudinal assessment of outcomes and complication rates. We aim to report one-year outcomes of a large multicenter cohort of ICAD patients undergoing treatment with RO-ZES to further evaluate the efficacy of RO-ZES for ICAD.

Methods

Prospectively maintained databases across seven stroke centers were reviewed to identify adult patients undergoing RO-ZES placement for treatment of ICAD between January 2019 and May 2023. The primary endpoint was composite of one-year stroke, ICH, and/or death. The secondary endpoint included in-stent restenosis (ISR) rates. ISR was defined as >50% stenosis within or adjacent (within 5 mm) of the implanted stent.^10,11 The inclusion criteria for the study only included patients that presented with either recurrent stroke or transient ischemic attack (TIA), with intracranial stenosis of 70–99% and with at least one ischemic event on best medical management. Best medical management was defined as per SAMMPRIS, with dual antiplatelet therapy along with management of primary (elevated systolic blood pressure and elevated low-density lipoprotein [LDL] levels) and secondary risk factors (diabetes, smoking, excessive weight). ¹ Patients who did not meet this criterion were excluded from the study. Institutional review board approval was obtained at each individual participating center, and all patients underwent an informed consent process.

Data collection

Age, sex, race, stroke risk factors (hypertension, diabetes mellitus, hyperlipidemia, smoking status), qualifying event, time from qualifying event, stenosis location, preprocedural and postprocedural stenosis rates, postprocedure stroke, TIA, ICH, and death at 30 days and one year were recorded. Notably, all sites had primary operators with at least three years of experience performing intracranial stenting to ensure adequate procedure-specific expertise. In the SAMMPRIS trial, percutaneous transluminal angioplasty and stenting (PTAS) was performed by neurointerventionalists who were selected by a committee of experienced neurointerventionalists on basis of review procedure notes and outcomes for the 20 most recent consecutive cases of intracranial stenting or angioplasty, but there was no delineation with number of years of experience as in our present study. Clinical and radiographic data were also assessed for residual stenosis and the development of in-stent restenosis (ISR) at up to one year. A stroke event was considered as any symptomatic new neurological deficit that caused increased in baseline National Institute of Health stroke score (NIHSS) with corresponding ischemic changes on magnetic resonance imaging (MRI) or computed tomography (CT).

Statistical analysis

Comparison of patient characteristics between RO-ZES treated patients and SAMMPRIS percutaneous angioplasty and stenting groups (S-PTAS) intervention arm was conducted using Wilcoxon rank-sum tests and Fisher's exact tests. This univariate comparison demonstrated key similarities and differences between these two patient cohorts. To correct for these baseline demographic differences between the two groups, 1:1 propensity-score matching was conducted using age, sex, hypertension, diabetes mellitus, smoking status, and stenotic vessel as covariates to allow for comparison between RO-ZES and S-PTAS. These covariates were used in alignment with the previous 30-day outcome study as well, to maintain consistency as well. ⁷ Age was defined as a continuous variable, while smoking status, sex, hypertension, diabetes mellitus, and stenotic vessel were defined as categorical variables. All patients who had undergone RO-ZES intervention were monitored with routine follow-up care and visits, with maintenance of records at least one year after treatment date were studied. After matching of the groups using the aforementioned covariates, primary endpoints between the two groups were compared with Fisher's exact test. Statistical significance was defined as p < 0.05, with all p-values reported being two-sided. Statistical analysis was done using SPSS (version 26.0; IBM) and R statistical software (version 3.4.0; R Foundation for Statistical Computing).

Results

Demographics

A total of 104 patients deemed eligible to meet our inclusion criteria (mean age ± SD: 64.9 ± 10.9 years), with 26 female patients (25.5%). The group consisted of 56 white patients (54.9%), 34 Hispanic patients (29.4%), 8 African American patients (7.8%), and 1 Asian patient (1.05). The remainder of patient demographics include stroke risk factors is summarized in Table 1. Qualifying events included recurrent stroke in 66 patients (4.7%), and recurrent TIA in 36 patients (35.3%). The mean (±SD) preprocedural severity of stenosis was 82.7 ± 9.1, with lesion location and characteristics further described in Table 1.

Table 1.

Demographics, risk factors, and lesions characteristics in patients treated with RO-ZES who were deemed eligible for study and had regular care documented till at least one-year follow-up after the procedure.

Characteristics of all patients, n (%)	n = 104
Age (years) mean ± SD	64.9 ± 10.9
Time from qualifying event median [IQR]	6.5 [2–30]
Female	26 (25.5)
Race
African American	8 (7.8)
Asian	1 (1.0)
Hispanic	34 (29.4)
White	56 (54.9)
Hypertension	86 (84.3)
Diabetes mellitus	55 (49.1)
Hyperlipidemia	73 (71.6)
Current or prior cigarette smoking	46 (45.1)
Qualifying event
Recurrent stroke	66 (64.7)
Recurrent TIA	36 (35.3)

SD: standard deviation; IQR: interquartile range; TIA: transient ischemic attack; ICA: internal carotid artery; ICH: intracerebral hemorrhage.

Thirty-day stroke and/or death in RO-ZES

At 30 days, for the patients treated with RO-ZES, a total of 6 (6.4%) TIAs and/or deaths were reported. There were no strokes or ICH within 30 days (0%). The mean postprocedural residual stenosis (mean ± SD) was 8.9 ± 13.9. No access site complications were reported. These data are summarized in Table 2, which displays outcomes in the RO-ZES group for 30 days, one year, including ISR and the type of one-year angiographic follow-up that was performed.

Table 2.

Primary and secondary outcomes at 30-days and one-year in RO-ZES group.

30-day outcomes, n (%)	n = 91
Recurrent stroke	0
Recurrent TIA	4 (4.4)
ICH	0
Death	2 (2.2)

TIA: transient ischemic attack; ICH: intracerebral hemorrhage; DSA: digital subtraction angiography; MRA: magnetic resonance imaging; ISR: In-stent.

Secondary outcomes at one year in RO-ZES

Table 2 also highlights additional outcome measures and follow-up data. Eighty-one patients had angiographic follow-up at one year, with CTA in 25 patients (30.9%), MRA in 14 patients (17.3%), DSA in 31 patients (38.3%), and carotid Doppler in 11 patients (13.6%). Of these patients, ISR occurred in eight patients (9.9%) at one year. Patients who were lost to follow-up were not included in this composite outcome. In the one-year period, no ICH or deaths were reported, and three strokes (3.3%) and nine TIAs (9.7%) occurred.

Propensity score–matched group analysis for one-year outcomes

Subsequently, a one-to-one propensity score–matched groups for age, sex, hypertension, diabetes mellitus, smoking status, and impacted vessel were created for the two groups with the intention of controlling these differences in populations. A total of 104 patients were matched in the RO-ZES and S-PTAS groups with characteristics as depicted in Table 3. Propensity score match analysis of the 104 patients with S-PTAS demonstrated one-year stroke, ICH, and/or death rate of 11.5% in the RO-ZES group and 28.1% in the S-PTAS group (odds ratio [OR] 4.17, 95% CI 2.06–8.96, p = 0.001), which is summarized in Table 4.

Table 3.

Propensity score–matched comparison: population characteristics of RO-ZES and SAMMPRIS S-PTA cohorts.

Characteristics	RO-ZES (104)	SAMMPRIS PTAS (104)	p-value
Age (mean (SD)	62.63 (11.81)	63.48 (9.81)	0.575
Gender = Male (%)	71 (68.3)	71 (68.3)	1.000
Race (%)			0.001
Asian	0 (0.0)	2 (1.9)
Black	51 (49.0)	24 (23.1)
White	51 (49.0)	76 (73.1)
Other
Hypertension (%)	83 (79.8)	88 (84.6)	0.468
Diabetes mellitus (%)	57 (54.8)	55 (52.9)	0.889
Hyperlipidemia (%)	71 (68.3)	79 (76.0)	0.279
Smoking (%)	43 (41.3)	61 (58.6)	0.002
Symptomatic artery (%)	7 (6.7)	5 (4.8)	0.461
Basilar	28 (26.9)	37 (35.6)
ICA MCA	31 (29.8)	33 (31.7)
PCA	1 (1.0)	0 (0.0)
Vertebral	37 (35.6)	29 (27.9)

SD: standard deviation; ICA: internal carotid artery; MCA: middle cerebral artery; PCA: posterior cerebral artery.

Table 4.

Propensity score–matched comparison between primary endpoints of RO-ZES and SAMMPRIS S-PTA cohorts at one year.

Primary endpoint	RO-ZES	S-PTAS
Stroke/ICH (%)	10 (9.6)	38 (36.5)	p value < 0.001
Death (%)	2 (1.9)	0 (0.0)
Composite (%)	12 (11.5)	38 (35.6)	p value 0.001 OR 4.17 95% CI 2.06–8.96

RO-ZES: Resolute Onyx Zotarolimus-Eluting Stent; S-PTAS: SAMMPRIS percutaneous angioplasty and stenting.

Discussion

The current study represents the largest multicenter scale study to investigate long-term outcomes of the RO-ZES stent. In prior preliminary data for RO-ZES at 30 days, short-term outcomes were addressed and compared outcomes of employing the RO-ZES in ICAD patients, with the propensity matched SAMMPRIS trial medical management and SAMMPRIS percutaneous angioplasty and stenting groups (PTAS). ⁷ In this study, with n = 132, 3.03% of patients experienced stroke and/or death in the RO-ZES group, compared to 6.6% in the SAMMPRIS medical management group (OR 2.26, 95% confidence interval [CI] 0.7–9.56, p = 0.22), and 15.6% in the S-PTAS group (OR 5.9, 95% CI 2.04–23.4, p < 0.001). After propensity score matching of 104 patients in each group, the 30-day stroke and/or death rate was 2.6% in the RO-ZES group and 15.6% in the S-PTAS group (OR 6.88, 95% CI 1.92–37.54, p < 0.001), demonstrating the superiority of the RO-ZES system. In this study, we determined that the one-year stroke and/or death was significantly lower using RO-ZES as compared to the SMMPRIS stenting arm, when propensity score matching was performed. In addition, even in comparison with other studies such as VISSIT, raw complication rates with RO-ZES appear to be lower as well. ² Our study marks a milestone in utilization of the RO-ZES stent for ICAD patients, suggesting that long-term efficacy and outcomes remain consistent extending beyond 30 days of intervention with further confirmation necessary via multicenter randomized controlled trial.

As previously discussed, ICAD is one of the most prevalent causes of strokes with a high mortality and morbidity rate, with high recurrent stroke rates as well. Our work highlights the possibility that perhaps patients with high-grade stenosis and recurrent ischemic events with strong predisposing risk factors would benefit from early thorough radiographic and clinical screening even at first ischemic event to determine as early as possible if the patient would be a candidate for ET to prevent future events, rather than defaulting to medical management as the traditional practice. While medical management is certainly vital, these discussions also require an understanding of the clinical significance of stenting, especially in the advent of new generation DES such as RO-ZES that demonstrate low complications rates and long-term efficacious outcomes. These discussions require a multidisciplinary approach among primary care providers who play a key role in a patient's long-term overall health monitoring and management, stroke neurologists who provide acute care management of ischemic events and post-event follow-up, and neurointerventionalists who perform ETs and assess the longitudinal outcomes of these therapies.

There are several potential proposed mechanisms that may contribute to the significant outcomes seen with the RO-ZES as compared to initial studies with unfavorable results, some of which have been addressed in the prior 30-day preliminary data study and require additional emphasis here. ¹² Operator experience is an extremely crucial component of the periprocedural complications and later outcomes. The initial studies such as VISSIT and SAMMPRIS indicate that perhaps the newer Wingspan technology at the time did not allow for a large enough pool of operators that were experienced in the modality, with the VISSIT directly commenting on operator experience miscalculation as a potential contributing factor on outcomes.^1,2 The subsequent trials such as WEAVE did reveal that the periprocedural complication rate was substantially lower at 2.6% with experienced operators. ³ As such in the current study with average time of nine years of experience in operators, we continue to believe that this factor contributes a significant impact on favorability of periprocedural and overall outcomes.

Furthermore, another key imperative factor is the stenting system itself. As previously described, the prior studies were primarily conducted with the bare-metal Wingspan stenting system. The advantages of the DES are both mechanistic and technical in nature, with the mechanism of drug-elution impeding neointimal hyperplasia, while technically providing greater favorability for use from the operator's standpoint, as will be further discussed below. ⁴

Resolute Onyx Stent

Data for using the RO-ZES stent for ICAD patients have been established, as it provides much greater overall safety and lower endpoints than the preexisting bare-metal stents. However, it is imperative to explore features and mechanistic details of this stenting system itself that may facilitate these outcomes. Resolute Onyx Zotarolimus-Eluting Stent (Medtronic) is a single-wire with composition of 90% platinum-10% iridium core alloy along with cobalt alloy. The thickness of the strut is 18 um, with a larger strut width-to-thickness ratio than older generation stents improving operator navigation and reducing procedural steps overall. ¹¹ The RO-ZES system not only allows for reduced procedural steps and decreased fluoroscopy time but provides protection in locations such as middle cerebral artery and basilar artery, against perforator occlusion. ¹² Previous generation drug-eluting stents with sirolimus and paclitxel have thought to cause delayed endothelization, which in turn raises late-stent thrombosis rates. ¹³ Consequently, zotarolimus in the RO-ZES system allows for early endotheliazation, which decreases late-stent thrombosis concerns with the prior generation DES. ¹⁴ Some of the other data demonstrating positive outcomes of using drug-eluting stents have been highlighted above. Several studies have established favorable evidence for DES in terms of safety and efficacy, with more recent data also demonstrating similar findings for RO-ZES.^8–11

A study comparing NOVA (sirolimus-eluting stent, SINOMED) with a bare-metal stent (APOLLO) displayed superior primary outcomes in the drug eluting stent group, compared to the bare-metal stent group in terms stroke/death rates and lower rate of recurrent stroke.⁴ Furthermore, in a single center study, Hassan et al. revealed a significantly lower stroke/death rate within 72 h of the RO-ZES stenting procedure along with lower recurrent stroke and significant in-stent restenosis rates at six months follow-up. ¹⁴ Likewise, multiple other studies have also yielded positive results.^8,9

Ultimately, the aggregate outcomes and data from these prior studies indicate that in general the RO-ZES system when compared to bare-metal stents such as Wingspan demonstrates a significantly lower rate of symptomatic in-stent restenosis along with overall improved outcomes and decreased periprocedural complications.^11,14

Limitations

This study does have some limitations that require further discussion. In line with its retrospective nature, and because only patients who underwent successful implementation of RO-ZES procedure, the effect of sleection bias cannot be adequately determined. Also, due to the retrospective nature of the study, the possibility that our selected patients are not fully representative of the general population cannot be dismissed. Some of the patients included in the preceding data to the current study were not able to complete follow up to a full year. ¹⁰ Furthermore, individual centers in a multicenter unblinded investigation may be biased to underreport complication rates. In regard to the data analysis itself, assessment of ISR rates between propensity-matched groups was not studied, though it was generally outlined in the primary RO-ZES group. In addition, we did not include patients that were lost to general follow-up or imaging follow-up at one year in the composite outcome. Thus in comparison with the SAMMPRIS stenting arm, we are unable to have a true comparison of ISR rates. And lastly, though our sample size is relatively large compared to most previous studies, the significance of the results can benefit from increased power with an even larger sample size.

Conclusions

The RO-ZES system demonstrates potential to reduce long-term complications at one year compared with the S-PTAS group, extending beyond the 30-day period. In the setting of limited data on RO-ZES for ICAD, our work serves as a landmark in establishing long-term favorable outcomes. Further prospective multicenter studies along with randomized trials are needed to corroborate and expand upon these findings and compare RO-ZES directly with other stents.