Abstract
Background
Intracranial atherosclerotic disease (ICAD) is a leading cause of ischemic stroke. The Medtronic Resolute Onyx Zotarolimus-eluting stents (RO-ZES) are promising in preventing stroke recurrence compared with medical management (MM) and percutaneous angioplasty and stenting (PTAS) at both 30-day and one-year follow-ups. We evaluated long-term outcomes for patients treated with RO-ZES, PTAS, or MM.
Methods
A retrospective multicenter study was conducted including patients who underwent RO-ZES stenting for symptomatic ICAD between March 2018 and May 2023, with follow-up through October 2024. Propensity score-matched control groups, representing MM and PTAS, were derived from the SAMMPRIS trial. Primary outcomes included recurrence rates of transient ischemic attack, stroke, intracerebral hemorrhage (ICH), and mortality. Time-to-event after intervention was evaluated.
Results
Patients who underwent stenting with RO-ZES and two propensity-matched cohorts from the SAMMPRIS trial who underwent MM and PTAS were included. Mean follow-up was 27.9 ± 17.0 months. The RO-ZES group demonstrated significantly fewer recurrent strokes (11.3%) compared with MM (27.0%) and PTAS (27.8%) (p = .003). The MM group experienced the lowest recurrence rate of ICH (0.9%) (p = .018). Multivariable regression revealed that RO-ZES experienced lower odds of recurrent strokes (OR = .40, 95% CI [0.17–0.92], p = .031) than PTAS throughout follow-up. Multivariable Cox regression demonstrated that RO-ZES stenting lowered the hazard of recurrent strokes compared with PTAS (hazard ratio = .36, 95% CI [0.16–0.80], p = .012).
Conclusion
Treatment of severe, symptomatic ICAD using RO-ZES was associated with lower odds of recurrent strokes compared with PTAS in this long-term follow-up study. Further prospective trials comparing MM with novel stent technologies are necessary.
Keywords: Drug-eluting stent, bare metal stent, intracranial atherosclerotic disease, stroke prevention
Introduction
Intracranial atherosclerotic disease (ICAD) is a major cause of ischemic stroke globally. Symptomatic ICAD is associated with a greater risk of recurrent strokes and leads to impaired distal perfusion and early neurological deterioration. 1 Aggressive medical management (MM) and endovascular interventions have not consistently reduced the recurrence of stroke in patients with ICAD. 2 The Stenting Versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial and several other key clinical trials comparing stenting with MM have demonstrated that stenting offers no significant reduction in stroke risk and, in many cases, is associated with higher rates of adverse outcomes, including higher stroke incidence and mortality.3–6
The failure of stenting compared with MM in the SAMMPRIS trial can be attributed to several key limitations including the absence of perfusion-based patient selection, the inclusion of a substantial proportion of patients with perforator occlusions—who may have been particularly vulnerable to procedural risks—and delays in treatment initiation relative to the qualifying ischemic event.7,8 Additionally, technical and procedural factors played a significant role. The outcomes may have been influenced by the interventionalists’ varying levels of expertise, as well as the performance characteristics of the Wingspan system. 9 This self-expanding device, which uses bare metal stents, requires a system exchange process that could introduce procedural complexity and elevate the risk of complications.7,9 Recent technological advancements have led to the development of stenting systems with enhanced mounting properties and longer-lasting effects through drug coatings, making it essential to reassess this topic. However, to accurately evaluate the performance of these next-generation devices, it is essential to address the methodological limitations of previous trials.
One of the newly designed stents offering enhanced functionality is the resolute Onyx Zotarolimus-eluting stent (RO-ZES), used off-label to treat severe symptomatic ICAD (Medtronic, Minneapolis, MN, USA).10,11 It uses the new balloon-mounted design which has been associated with better outcomes compared with self-expandable stents, and does not need the system exchange that was required with Wingspan stents.12–14 Additionally, its drug-eluting coating helps suppress neointimal hyperplasia, reducing the risk of in-stent restenosis compared with bare metal stents.15–17 Several studies have reported superior clinical outcomes with RO-ZES compared with Wingspan stents and MM at both 30-day and one-year follow-ups.18,19
This study assessed the overall long-term outcomes (mean follow-up of over two years) of patients with symptomatic ICAD treated with RO-ZES, and evaluated the recurrence of stroke, transient ischemic attack (TIA), intracerebral hemorrhage (ICH), and mortality. These outcomes were compared with the historical clinical outcomes of patients who underwent Wingspan stenting or MM during the SAMMPRIS trial.
Methods
Study design
This multiinstitutional retrospective study was conducted across six centers and included patients treated with RO-ZES for symptomatic, severe ICAD between 1 March 2018 and 31 May 2023. Institutional Review Board approval was obtained at each participating center.
Patient population
A retrospective review was conducted using data collected from patients who underwent endovascular intervention with RO-ZES for treatment of symptomatic ICAD, with follow-up extending through October 2024. Inclusion criteria consisted of adult patients (≥18 years) presenting with recurrent stroke or TIA, intracranial artery stenosis of 70–99%, and at least one ischemic event after best MM. Best MM was defined as dual antiplatelet therapy combined with the treatment of primary risk factors (i.e. elevated systolic blood pressure and elevated low-density lipoprotein levels) and secondary risk factors (i.e. diabetes, smoking, and excessive weight). 5 Patients who underwent balloon angioplasty alone after unsuccessful stent implantation were excluded, and 6% of subjects in the RO-ZES arm were lost to follow-up. Further analysis confirmed that the data of patients lost to follow-up were missing completely at random (MCAR), and Little's MCAR test showed no significant deviation from randomness (p = .693). Therefore, the missing data are unlikely to bias the analysis outcomes. The last follow-up date was recorded as either the patient's date of death or the last available clinical follow-up.
Propensity matching
The data from the SAMMPRIS trial were used to establish control arms for comparing the outcomes of patients who underwent stenting with RO-ZES. From this cohort, 224 patients who received aggressive MM and 207 patients who underwent percutaneous angioplasty and stenting (PTAS) using the Wingspan system were identified using the inclusion criteria, and their data were extracted for analysis. A 1:1 propensity score matching was conducted to account for potential confounding variables, including age, sex, race, hypertension, diabetes, hyperlipidemia, smoking status, affected artery, lesion length, and stenosis ratio. This process resulted in 115 matched cases for each group.
Exposure variables
The exposure variables included demographics (age, sex, and race), comorbidities (history of hypertension, diabetes, and hyperlipidemia), smoking status, the qualifying cerebrovascular event (recurrent TIA or stroke), lesion characteristics (affected artery, stenosis length, and percentage of stenosis), and the treatment type (RO-ZES, PTAS, and MM).
Outcome variable
The primary outcomes were the recurrence of cerebrovascular events, including TIA, stroke, and ICH, including the time-to-event after the intervention and mortality during the follow-up period. The outcome variables reflect the number of patients that experienced recurrent events, not the total number of events in the population, because some patients had multiple recurrences during follow-up. Notably, in the SAMMPRIS trial, patients that experienced a recurrence of cerebrovascular events were often excluded from the trial afterward. For these cases, the date of the recurrence was recorded as the last day of follow-up. In some instances, this last day occurred only a few days after the primary procedure, resulting in a recorded follow-up duration of 0 months for those patients.
Statistical analysis
Descriptive statistics were presented as mean ± standard deviation for continuous variables and as frequencies with a percentage for categorical variables. The Shapiro–Wilk test was used to assess the normality of continuous data, and Levene's test was used to evaluate the homogeneity of variances. Parametric data with equal variance were compared using a two-tailed Student's t-test, and a Welch's t-test was applied for data with unequal variance. Categorical variables were compared using either the Chi-square test or Fisher's exact test, depending on the expected cell frequencies in the contingency table.
Survival outcomes between groups were analyzed using Kaplan–Meier survival curves, with comparisons performed via the log-rank test. Univariable and multivariable binary logistic regression models, controlling for potential confounders including age, sex, race, hypertension, diabetes, hyperlipidemia, smoking status, affected artery, qualifying cerebrovascular event, and stenosis ratio, were used to assess the association between stent type and the incidence of recurrent cerebrovascular events. Model performance was evaluated using receiver operating characteristic curve analysis, and area under the curve (AUC) was calculated to quantify discriminatory ability. Additionally, time-to-event outcomes were analyzed using univariable and multivariable Cox proportional hazards models, adjusting for the same covariables. A p-value < .05 was considered statistically significant for all tests. Statistical analyses were performed using R (version 4.4.1) and IBM SPSS Statistics 30.
Results
Patient demographics
A total of 115 patients who underwent RO-ZES placement for treatment of symptomatic ICAD were included in this study, with a mean follow-up period of 27.0 ± 19.2 months (Table 1). The mean age at the time of intervention was 64.4 ± 12.5 years, and 39 patients (33.9%) were female. The cohort comprised 8 (7.0%) African American patients, 54 (47.0%) Hispanic patients, 52 (45.2%) white patients, and one (0.9%) patient labeled as other/unknown. Recurrent stroke was the qualifying cerebrovascular event for 76 patients (66.1%), and 38 patients (33.0%) experienced recurrent TIA.
Table 1.
Demographics, baseline and lesion characteristics and 72-h postoperative outcomes in patients treated with resolute Onyx Zotarolimus-eluting stent versus propensity-matched patients treated with bare metal stents or medical management.
| Patient demographics | Total, n = 345 | RO-ZES, n = 115 | MM, n = 115 | PTAS, n = 115 | p-value* |
|---|---|---|---|---|---|
| Length of follow-up (months), mean ± SD | 27.9 ± 17.0 | 27.0 ± 19.2 | 29.2 ± 14.8 | 27.5 ± 16.7 | .587 |
| Age, mean ± SD | 63.4 ± 11.5 | 64.4 ± 12.5 | 63.0 ± 11.6 | 62.9 ± 10.4 | .529 |
| Sex | |||||
| Female, n (%) | 127 (36.8) | 39 (33.9) | 43 (37.4) | 45 (39.1) | .705 |
| Race | |||||
| African American, n (%) | 45 (13.0) | 8 (7.0) | 19 (16.5) | 18 (15.7) | <.001 |
| Hispanic, n (%) | 84 (24.3) | 54 (47.0) | 13 (11.3) | 17 (14.8) | |
| White, n (%) | 208 (60.8) | 52 (45.2) | 78 (67.8) | 78 (67.8) | |
| Other, n (%) | 8 (2.3) | 1 (0.9) | 5 (4.3) | 2 (1.7) | |
| Hypertension, n (%) | 287 (83.2) | 92 (80.0) | 97 (84.3) | 98 (85.2) | .526 |
| Diabetes mellitus, n (%) | 167 (48.4) | 62 (53.9) | 56 (48.7) | 49 (42.6) | .229 |
| Hyperlipidemia, n (%) | 260 (75.4) | 74 (64.3) | 92 (80.0) | 94 (81.7) | .003 |
| Smoking | |||||
| Current, n (%) | 122 (35.4) | 27 (23.5) | 47 (40.9) | 48 (41.7) | .008 |
| Prior, n (%) | 34 (9.9) | 9 (7.8) | 13 (11.3) | 12 (10.4) | |
| Qualifying cerebrovascular event | |||||
| Recurrent stroke, n (%) | 236 (68.4) | 76 (66.1) | 83 (72.2) | 77 (67.0) | .553 |
| Recurrent TIA, n (%) | 108 (31.3) | 38 (33.0) | 32 (27.8) | 38 (33.0) | |
| Lesion characteristics | |||||
| Stenosis location | |||||
| Anterior circulation, n (%) | 216 (62.6) | 66 (57.4) | 84 (73.0) | 66 (57.4) | .014 |
| Posterior circulation, n (%) | 130 (37.7) | 50 (43.5) | 31 (27.0) | 49 (42.6) | |
| Involved artery | |||||
| Petrous-ICA, n (%) | 21 (6.1) | 14 (12.2) | 4 (3.5) | 3 (2.6) | .004 |
| Cavernous-ICA, n (%) | 26 (7.5) | 8 (7.0) | 9 (7.8) | 9 (7.8) | |
| Supraclinoid-ICA, n (%) | 39 (11.3) | 10 (8.7) | 15 (13.0) | 14 (12.2) | |
| M1-segment, n (%) | 111 (48.3) | 31 (26.9) | 46 (40.0) | 34 (29.6) | |
| M2-segment, n (%) | 19 (5.5) | 3 (2.6) | 10 (8.7) | 6 (5.2) | |
| Vertebral artery, n (%) | 93 (27.0) | 41 (35.7) | 21 (18.3) | 31 (27.0) | |
| Basilar artery, n (%) | 35 (10.1) | 7 (6.1) | 10 (8.7) | 18 (15.7) | |
| Posterior cerebral artery, n (%) | 2 (0.9) | 2 (1.7) | 0 (0.0) | 0 (0.0) | |
| Side: left circulation, n (%) | 175 (56.1) | 66 (60.0) | 56 (53.3) | 53 (54.6) | .580 |
| Length of stenosis, n (%) | N/A | ||||
| <5 mm | 95 (41.3) | 65 (56.5) | 30 (26.1) | <.001 | |
| 5–10 mm | 91 (39.6) | 33 (28.7) | 58 (50.4) | ||
| >10 mm | 44 (19.1) | 17 (14.8) | 27 (23.5) | ||
| Preprocedure stenosis ratio (%), mean ± SD | 78.1 ± 9.8 | 81.2 ± 11.7 | 76.9 ± 8.3 | 76.4 ± 8.3 | <.001 |
| 72-h postoperative outcomes | |||||
| ICH at 72 h, n (%) | 8 (3.5) | 3 (2.6) | 0 (0.0) | 5 (4.3) | .088 |
| Stroke at 72 h, n (%) | 19 (5.5) | 4 (3.5) | 5 (4.3) | 10 (8.7) | .178 |
Abbreviations: RO-ZES: resolute Onyx Zotarolimus-eluting stent; MM: medical management; PTAS: percutaneous angioplasty and stenting; n: number of cases; ICA: internal carotid artery; SD: standard deviation; TIA: transient ischemic attack; ICH: intracerebral hemorrhage; N/A: not applicable.
Two propensity-matched groups, each consisting of 115 patients who underwent MM or Wingspan stenting (PTAS) for ICAD treatment, were extracted from the SAMMPRIS trial database. The mean follow-up periods were 29.2 ± 14.8 months for the MM group and 27.5 ± 16.7 months for the PTAS group. Significant differences among patients in the RO-ZES, MM, and PTAS groups were observed in racial composition (p < .001) and prevalence of hyperlipidemia (64.3% RO-ZES, 80.0% MM, and 81.7% PTAS; p = .003). Current smokers comprised 23.5% of the RO-ZES group, 40.9% of the MM group, and 41.7% of the PTAS group, and past smokers represented 7.8% of the RO-ZES group, 11.3% of the MM group, and 10.4% of the PTAS group (p = .008). All other demographic and stroke-related risk factors were evenly distributed across the three groups.
Lesion characteristics
Among the patients who underwent RO-ZES placement, 66 (57.4%) had stenosis in the anterior circulation (Table 1). Of these, 32 (27.9%) had lesions in the internal carotid artery (ICA), and 34 (29.5%) had lesions in the middle cerebral artery (MCA). The mean preprocedure stenosis ratio for this group was 81.2 ± 11.7%, and most patients (n = 65, 56.5%) had stenosis lengths under 5 mm.
Among the propensity-matched patients undergoing MM, 84 (73.0%) had involvement in the anterior circulation, with 28 (24.3%) cases of ICA and 56 (48.7%) cases of MCA involvement. In the PTAS group, 66 patients (57.4%) had their lesion in the anterior circulation, consisting of 26 (22.6%) in the ICA and 40 (34.8%) in the MCA. The distribution of frequencies differed significantly among the RO-ZES, MM, and PTAS groups based on anterior/posterior circulation location (p = .014) and the specific artery involved (p = .004). A detailed comparison of these and other lesion characteristics is provided in Table 1. The preprocedure stenosis ratio was significantly lower in the MM and PTAS groups compared with the RO-ZES group (p < .001). The PTAS group had a higher proportion of patients with lesion lengths of 5–10 mm (n = 58, 50.4%; p < .001) compared with patients in the RO-ZES group. Lesion length data for the MM group were not reported in the SAMMPRIS trial, so this group was excluded from the comparison.
Overall long-term clinical outcomes
TIA, stroke, and ICH recurrences were tracked in the same arterial region where the stent was implanted from the first day after the procedure through the entire follow-up period (Table 2). There were no differences in the incidence of recurrent TIA among groups (p = .300). Recurrent strokes occurred in 13 (11.3%) patients in the RO-ZES group, significantly fewer than the 31 (27.0%) patients in the MM group and the 32 (27.8%) patients in the PTAS group (p = .003). There were five cases (4.3%) of recurrent ICH in the RO-ZES group and 1 (0.9%) case in the MM group, compared with 10 (8.7%) cases in the PTAS group (p = .018). Post hoc power analysis showed sufficient power (>80%) to compare stroke rates among the three groups (RO-ZES vs PTAS: 1 − β = 0.889; RO-ZES vs MM: 1 − β = 0.862). However, analyses involving TIA and ICH were underpowered (<80%).
Table 2.
Recurrence of cerebrovascular events in the same arterial region and mortality rates in cases with resolute Onyx Zotarolimus-eluting stent versus propensity-matched bare metal stent and medical management throughout the entire follow-up period.
| Outcome variables | Total, n = 345 | RO-ZES, n = 115 | MM, n = 115 | PTAS, n = 115 | p-value* |
|---|---|---|---|---|---|
| TIA, n (%) | 28 (8.1) | 13 (11.3) | 7 (6.1) | 8 (7.0) | .300 |
| Stroke, n (%) | 76 (22.0) | 13 (11.3) | 31 (27.0) | 32 (27.8) | .003 |
| ICH, n (%) | 16 (4.6) | 5 (4.3) | 1 (0.9) | 10 (8.7) | .018 |
| Death, n (%) | 26 (7.5) | 13 (11.3) | 6 (5.2) | 7 (6.1) | .167 |
Abbreviations: RO-ZES: resolute Onyx Zotarolimus-eluting stent; MM: medical management; PTAS: percutaneous angioplasty and stenting; TIA: transient ischemic attack; ICH: intracerebral hemorrhage.
*Bold value indicates statistical significance (p-value < .05).
Univariable and multivariable binary logistic regression analyses were conducted to assess the association between RO-ZES implantation (as an independent variable) and other potential predictors with the recurrence of TIA, stroke, and ICH during the follow-up period. Univariable analysis revealed that RO-ZES use was associated with a lower stroke recurrence compared with MM (odds ratio (OR) = .34, 95% confidence interval (CI) [0.17–0.70]; p = .003) and PTAS (OR = .33, CI [0.16–0.67]; p = .002), but no significant association was found in TIA or ICH recurrence rates (Table 3).
Table 3.
Univariable and multivariable regression analyses comparing the recurrence of cerebrovascular events in the same arterial region and mortality rates throughout the entire follow-up period.
| Outcome variable | Independent variable | Univariable | Multivariable | ||
|---|---|---|---|---|---|
| OR/β [95% CI] | p-value* | OR/β (95% CI) | p-value* | ||
| TIA | RO-ZES vs MM | 1.96 [0.75–5.13] | .166 | 1.21 [0.35–4.22] | .767 |
| RO-ZES vs PTAS | 1.70 [0.68–4.28] | .257 | 1.07 [0.33–3.44] | .910 | |
| Stroke | RO-ZES vs MM | 0.34 [0.17–0.70] | .003 | 0.44 [0.19–1.04] | .063 |
| RO-ZES vs PTAS | 0.33 [0.16–0.67] | .002 | 0.40 [0.17–0.92] | .031 | |
| ICH | RO-ZES vs MM | 5.18 [0.60–45.45] | .136 | 3.18 [0.28–35.71] | .348 |
| RO-ZES vs PTAS | 0.48 [0.16–1.44] | .190 | 0.25 [0.05–1.19] | .082 | |
| Mortality | RO-ZES vs MM | 2.31 [0.85–6.33] | .101 | 1.13 [0.28–4.54] | .862 |
| RO-ZES vs PTAS | 1.97 [0.75–5.12] | .166 | 0.75 [0.21–2.62] | .650 | |
Abbreviations: OR: odds ratio; CI: confidence interval; TIA: transient ischemic attack; ICH: intracerebral hemorrhage; RO-ZES: resolute Onyx Zotarolimus-eluting stent; MM: medical management; PTAS: percutaneous angioplasty and stenting.
*Bold value indicates statistical significance (p-value < .05).
Multivariable analysis is adjusted for age, sex, race, hypertension, diabetes, hyperlipidemia, smoking, affected artery, qualifying cerebrovascular event, and arterial stenosis ratio.
In the multivariable regression model, which was adjusted for age, sex, race, hypertension, diabetes, hyperlipidemia, smoking, affected artery, qualifying cerebrovascular event, and arterial stenosis ratio, RO-ZES use was significantly associated with lower stroke recurrence (OR = .40, 95%CI [0.17–0.92]; p = .031) compared with the PTAS group; however, the multivariable model did not show any association between the use of RO-ZES and fewer stroke recurrences when compared with the MM group (OR = .44, 95%CI [0.19–1.04]; p = .063). Figure 1 illustrates the receiver operating characteristic curves, demonstrating the performance of the multivariable regression models in predicting stroke (AUC = .744; p < .001) and ICH (AUC = .836; p < .001).
Figure 1.
Receiver operating characteristic curves illustrating the performance of the multivariable regression model in predicting the recurrence of (A) stroke and (B) intracerebral hemorrhage throughout the entire follow-up period. Each model incorporated stent type, age, sex, race, hypertension, diabetes, hyperlipidemia, smoking status, affected artery, qualifying cerebrovascular event, and stenosis ratio as covariates.
Overall long-term mortality
Throughout the follow-up period, 13 deaths (11.3%) occurred in the RO-ZES group compared with six deaths (5.2%) in the MM group and seven deaths (6.1%) in the PTAS group (p = .167) (Table 2). There was no significant association between the use of RO-ZES and patient mortality rate compared with the use of MM or PTAS on univariable (p = .101; p = .166) and multivariable (p = .862; p = .650) regression analyses (Table 3). Kaplan–Meier survival analysis further demonstrated no significant differences in overall survival outcomes between patients treated with RO-ZES, PTAS, and MM (log-rank test, p = .180). Figure 2 presents the Kaplan–Meier survival curves for the three groups of patients.
Figure 2.
Kaplan–Meier plot demonstrating survival probability among patients who received resolute Onyx Zotarolimus-eluting stents (green) compared with those who received Wingspan system stents (red) and medical management (blue). The plot shows no significant difference in long-term outcomes between the three groups (p = .18).
PTAS: percutaneous angioplasty and stenting; RO-ZES: resolute Onyx Zotarolimus-eluting stent; MM: medical management.
Time-to-event analysis overview
Univariable Cox regression indicated that the use of RO-ZES was associated with a lower hazard ratio (HR) of recurrent stroke compared with MM (HR = .34, 95% CI [0.17–0.71]; p = .004) (Table 4); however, this finding was not confirmed in multivariable Cox regression analysis. Univariable and multivariable Cox regression analyses, adjusted for age, sex, race, hypertension, diabetes, hyperlipidemia, smoking status, affected artery, qualifying cerebrovascular event, and stenosis ratio, revealed that the use of RO-ZES was associated with a significantly lower HR of recurrent strokes compared with PTAS (univariable: HR = .30, 95% CI [0.15–0.60]; p = .001; multivariable: HR = .36, 95% CI [0.16–0.80]; p = .012) during follow-up. There was no significant association between RO-ZES use and the HR of TIA, ICH, or mortality. Figure 3 illustrates the hazard plot from the multivariable Cox regression for recurrent stroke and TIA events.
Table 4.
Cox regression analysis of recurrence of cerebrovascular events, comparing resolute Onyx Zotarolimus-eluting stent versus propensity-matched bare metal stent and medical management.
| Outcome variable | Independent variable | Univariable regression | Multivariable regression | ||
|---|---|---|---|---|---|
| HR/β [95% CI] | p-value* | HR/β [95% CI] | p-value* | ||
| TIA | RO-ZES vs MM | 1.44 [0.55–3.77] | .460 | 0.93 [ 0.27–3.11] | .900 |
| RO-ZES vs PTAS | 1.29 [0.49–3.39] | .607 | 0.74 [0.23–2.34] | .607 | |
| Stroke | RO-ZES vs MM | 0.34 [0.17–0.71] | .004 | 0.46 [0.20–1.03] | .058 |
| RO-ZES vs PTAS | 0.30 [0.15–0.60] | .001 | 0.36 [0.16–0.80] | .012 | |
| ICH | RO-ZES vs MM | 5.05 [0.59–43.48] | .140 | 3.38 [0.31–37.04] | .320 |
| RO-ZES vs PTAS | 0.54 [0.18–1.62] | .273 | 0.34 [0.07–1.53] | .160 | |
| Mortality | RO-ZES vs MM | 2.52 [0.85–5.92] | .101 | 1.22 [0.33–4.57] | .763 |
| RO-ZES vs PTAS | 1.82 [0.73–4.57] | .201 | 0.79 [0.24–2.59] | .700 | |
Abbreviations: HR: hazard ratio; CI: confidence interval; TIA: transient ischemic attack; RO-ZES: resolute Onyx Zotarolimus-eluting stent; MM: medical management; PTAS: percutaneous angioplasty and stenting; ICH: intracerebral hemorrhage.
*Bold value indicates statistical significance (p-value < .05).
Multivariate regression was controlled for age, sex, race, history of hypertension, diabetes, hyperlipidemia, smoking, affected artery, qualifying cerebrovascular event, and arterial stenosis ratio.
Figure 3.
Hazard plot demonstrating the outcomes of multivariable Cox regression analysis on the recurrence of stroke in patients who received resolute Onyx Zotarolimus-eluting stents (blue) versus Wingspan system stents (red) and medical management (green), adjusted for age, sex, race, hypertension, diabetes, hyperlipidemia, smoking status, affected artery, qualifying cerebrovascular event, and stenosis ratio.
RO-ZES: resolute Onyx Zotarolimus-eluting stent; PTAS: percutaneous angioplasty and stenting: MM: medical management; OR: odds ratio; CI: confidence interval.
Periprocedural clinical outcomes
Three separate subanalyses were performed to assess the frequency of recurrent strokes within short time frames at 72 h, seven days, and 30 days after the procedure. No significant difference was observed in stroke rates among the three groups at 72 h after intervention (Table 1). However, stroke incidence within seven days varied significantly among the groups, with patients in the RO-ZES group having the lowest rate (3.5%), followed by MM (4.3%) and PTAS (13.9%) (p = .003; Figure 4(a)). The cumulative stroke frequencies beyond seven days, shown in Figure 4(a), indicate that RO-ZES maintained superior performance compared with both MM and PTAS (p = .010). Stroke rates within the first 30 days after the procedure were also significant: the RO-ZES group had the lowest rate (3.5%), followed by MM (7.0%) and PTAS (13.9%) (p = .013; Figure 4(b)). The cumulative stroke rates beyond 30 days, presented in Figure 4(b), indicate that the RO-ZES group continued to have better clinical outcomes than the MM and PTAS groups (p = .037).
Figure 4.
Periprocedural recurrent stroke rates up to (a) seven days and (b) 30 days, along with cumulative stroke rates beyond these time points for each group.
RO-ZES: resolute Onyx Zotarolimus-eluting stent; PTAS: percutaneous angioplasty and stenting: MM: medical management.
Discussion
Off-label use of RO-ZES for treatment of symptomatic ICAD has shown promise in limited patient series. An initial study involving a small cohort of 13 patients indicated that only 7.7% experienced recurrent TIAs within a six-month follow-up period. 11 Another study involving 58 patients undergoing RO-ZES stenting showed fewer incidents of stroke or death within the first 72 h after the procedure compared with patients treated with PTAS with the Wingspan system (1.7% vs 6.3%). 20 Additionally, the RO-ZES group exhibited significantly lower rates of TIA (4.9% vs 22.8%) and stroke (0 vs 8.9%) over six months compared with the PTAS group.
Subsequent multicenter studies have investigated radiologic and clinical outcomes of patients with symptomatic ICAD treated with RO-ZES, comparing these results with the MM and PTAS arms of the SAMMPRIS trial. A study evaluating 30-day outcomes in 132 patients reported stroke and/or death rates of 3.03% after intervention with RO-ZES, compared with 6.6% in the MM arm and 15.6% in the PTAS arm of the SAMMPRIS trial. 18 Furthermore, a recent study assessing one-year outcomes in 104 patients treated with RO-ZES, propensity-matched against the PTAS arm of the SAMMPRIS trial, found significantly lower rates of stroke, ICH, and/or death at 11.5% in the RO-ZES group compared with 28.1% in the PTAS arm. 19 Notably, the SAMMPRIS trial included patients experiencing their first symptomatic ICAD event, 5 whereas studies evaluating RO-ZES performance, including this one, focused on patients with recurrent cerebrovascular ischemic events refractory to medical treatment who are inherently at higher risk for further recurrences. Despite this, evidence to date has demonstrated the superior performance of RO-ZES.
In this study, we extended the follow-up period for patients who received RO-ZES stents and compared their outcomes with propensity-matched patients from the MM and PTAS arms of the SAMMPRIS trial. The results indicated that the RO-ZES group experienced lower rates of strokes (11.3%) in the same arterial region during the follow-up period. Post hoc power analysis confirmed sufficient power for this comparison. These findings were further supported by a multivariable regression model, which showed that RO-ZES was associated with a 0.40 OR for stroke recurrence compared with PTAS (95% CI [0.17–0.92]; p = .031). It is essential to highlight that the multivariable model controlled for differences in the distribution of predictor variables, such as hyperlipidemia, smoking, and the involved artery. Finally, a time-to-event Cox regression analysis revealed a significantly lower HR for stroke recurrence in the RO-ZES group compared with the PTAS arm over the long-term follow-up period (HR = .36, 95% CI [0.16–0.80], p = .012). The graph in Figure 3(a) highlights that RO-ZES and MM initially exhibit similar HRs and lower stroke rates compared with PTAS. Over time, however, patients treated with MM experience a steeper increase in stroke incidence, reaching rates similar to PTAS by 12–18 months. In contrast, RO-ZES maintains a relatively stable stroke rate until approximately the third year of the follow-up period, after which it begins to rise gradually. The subanalyses presented in Figure 4 further confirmed that RO-ZES provides superior clinical outcomes in stroke incidence during both the first seven and 30 days after the procedure and also maintains a lower cumulative stroke rate beyond these time points.
The recurrence rates of TIAs (11.3% vs 6.1% and 7.0%) and mortality (11.3% vs 5.2% and 6.1%) were not statistically significant when comparing the RO-ZES group with the MM and PTAS groups. Multivariable regression analysis found no association between these outcomes and the use of RO-ZES, Wingspan, or MM. The Cox regression time-to-event analysis, presented in Figure 3(b), indicates that TIA recurrences began after the first month and progressed at a similar pace across all three groups throughout the follow-up. The analysis found no significant association between treatment methods and the overall hazard of TIA recurrence. Additionally, patients in the RO-ZES (4.3%) and MM (0.9%) groups had significantly lower ICH recurrence rates compared with the PTAS group (8.7%). Notably, about half of the ICH events in the RO-ZES and PTAS groups occurred within the first 72 h after the procedure. Finally, the Kaplan–Meier survival analysis in Figure 2 shows that patients treated with PTAS had the highest early mortality rate, followed by those treated with RO-ZES. Over time, MM gradually approached the other two groups; however, mortality rates across all three groups did not differ significantly throughout the follow-up period.
Several studies assessing the safety of Wingspan stents versus aggressive MM in treating ICAD were halted because of adverse outcomes in the stenting groups.6,21,22 These findings have led to the current guidelines recommending against the routine use of stents for ICAD treatment23,24; however, advancements are being made in stent technology. It is essential to determine whether newer stents can improve short- and long-term outcomes for patients with ICAD.
The latest generation of DES, including the RO-ZES, offers significant enhancements over the Wingspan system used in earlier trials. The Wingspan system demanded the use of the Gateway angioplasty balloon for initial angioplasty, followed by its removal, after which, the stenting system had to navigate back through the stenotic lesion to place the stent, which required several exchanges to finalize the procedure. Additionally, the polyolefin tip of the stent delivery system complicated delivery in tightly angled junctions. 14 The RO-ZES offers enhanced navigational abilities and faster deployment times because of its balloon-mounted design. 11 The bare metal stents used in the Wingspan system are also associated with higher rates of ISR compared with the newer DES, further highlighting the advantages of the RO-ZES. 25
The current study reaffirms earlier findings that RO-ZES implantation demonstrates significantly lower stroke rates compared with the Wingspan system. Because the difference in stroke recurrence rates between RO-ZES and MM was only marginally insignificant, we recommend further large-scale prospective trials to enhance statistical power and potentially confirm the long-term benefits of RO-ZES over aggressive MM.
Limitations
To our knowledge, this study represents the largest and longest-term investigation into the use of RO-ZES for treating ICAD, but it is essential to acknowledge certain study limitations. First, the data were retrospectively extracted and analyzed from a prospectively collected registry, making the study subject to the inherent limitations of a retrospective design. Because this was not a controlled trial, there was no standardized protocol for clinical or imaging follow-up, which may have resulted in delays in reporting data relative to the actual events. Additionally, it is important to highlight that the imaging data were self-adjudicated. Individual centers participating in this unblinded multicenter study may have been biased toward underreporting complication rates. Patients who underwent PTAS in the SAMMPRIS trial and experienced a recurrent stroke or ICH requiring further intervention were excluded from subsequent follow-up and data collection. As a result, a number of patients in the PTAS group had shorter follow-up periods, reducing the cohort's mean follow-up duration. This limitation did not affect this study's outcome analysis because cerebrovascular recurrences and their dates were documented and included in the registry used.
Conclusion
Our findings suggest that RO-ZES placement for the treatment of symptomatic ICAD is associated with lower odds of recurrent strokes and ICHs compared with PTAS during an extended follow-up period. Use of RO-ZES was also associated with delayed stroke recurrence. These findings suggest that RO-ZES may provide notable long-term benefits—potentially because of its drug-eluting properties, improved implantation techniques, and newer design. Larger, prospective studies using this technology may enhance the significance of our findings.
Acknowledgments
We thank Cortlynd Olsen and Kristin Kraus for editorial assistance.
Footnotes
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical approval: The databases used adhered to institutional review board requirements and ethical guidelines from each participating center at the time of initial data collection. Institutional Review Board approval was obtained at each participating center under the supervision of the University of Utah Institutional Review Board (103968).
Disclosures—conflicts of interest: The authors declare the following potential conflicts of interest:
OS: no relevant relationships; RG: consulting fees from Medtronic Neurovascular, Balt Neurovascular, Stryker, Rapid Medical and Cerenovus; SM: no relevant relationships; JR: no relevant relationships; VJ: no relevant relationships; BM: no relevant relationships; OT: no relevant relationships; JKB: consulting fees from Q`Apel Medical, Stryker, Medtronic, Cerenovous, and MicroVention; PMJ: consultant for Medtronic, MicroVention, Balt and Cerus Endovascular; AHS: financial interest/investor/stock options/ownership: Adona Medical, Inc., Basecamp Vascular SAS, Bend IT Technologies, Ltd, BlinkTBI, Inc, Borvo Medical, Inc., CerebrovaKP, Code Zero Medical, Inc., Cognition Medical, Collavidence, Inc., Contego Medical, Inc., CVAID Ltd, E8, Inc., Endostream Medical, Ltd, FreeOx Biotech, SL, Galaxy Therapeutics, Inc., Hyperion Surgical, Inc., Imperative Care, Inc., InspireMD, Ltd, Instylla, Inc., IRRAS AB, Launch NY, Inc., Neurolutions, Inc., Neurovascular Diagnostics, Inc., NeXtGen Biologics, Peijia Medical, PerFlow Medical, Ltd, Physician X, LLC, Piraeus Medical, Inc., Prometheus Therapeutics, Inc., Q’Apel Medical, Inc., QAS.ai, Inc., Radical Catheter Technologies, Inc., Rist Neurovascular, Inc. (Purchased 2020 by Medtronic), Sense Diagnostics, Inc., Serenity Medical, Inc., Silk Road Medical, Sim & Cure, Spinnaker Medical, Inc., StimMed, LLC, Synchron, Inc., T.G. Medical, Inc., Tulavi Therapeutics, Inc., Vastrax, LLC, Viseon, Inc., Viz.ai, Whisper Medical, Inc., Willow Medtech, Inc. Consultant/Advisory Board: Asahi Intecc Co. Ltd, Canon Medical Systems USA, Inc., CerebrovaKP, Cerenovus, Contego Medical, Inc., Cordis, Endostream Medical, Ltd, FreeOx Biotech, SL, Hyperfine Operations, Inc., Imperative Care, InspireMD, Ltd, IRRAS AB, Medtronic, MicroVention (now Terumo Neuro), Minnetronix Neuro, Inc., Peijia Medical, Perflow Medical, Ltd, Piraeus Medical, Inc., Prometheus Therapeutics, Inc., Q’Apel Medical, Inc., Serenity Medical, Inc., Shockwave Medical, Inc., StimMed, LLC, Stryker Neurovascular., Synchron Australia Pty Ltd, T.G. Medical, Inc., Vastrax, LLC, Vesalio, Viz.ai, Inc., WL Gore. National PI/steering committees: Cerenovus EXCELLENT and ARISE II Trial; Medtronic SWIFT PRIME, VANTAGE, EMBOLISE and SWIFT DIRECT Trials; MicroVention (now Terumo Neuro) FRED Trial & CONFIDENCE Study; MUSC POSITIVE Trial; Penumbra 3D Separator Trial, COMPASS Trial, INVEST Trial, MIVI neuroscience EVAQ Trial; Rapid Medical SUCCESS Trial; InspireMD C-GUARDIANS IDE Pivotal Trial; Patents: Patent No. US 11,464,528 B2, Date: October 11, 2022, CLOT RETRIEVAL SYSTEM FOR REMOVING OCCLUSIVE CLOT FROM A BLOOD VESSEL, Applicant and Assignee: Neuravi Limited (Galway); role: coinventor; FS: no relevant relationships; AEH: consultant/speaker: Medtronic, Microvention, Stryker, Penumbra, Cerenovus, Genentech, GE Healthcare, Scientia, Balt, Viz.ai, Insera therapeutics, Proximie, NeuroVasc, NovaSignal, Vesalio, Rapid Medical, Imperative Care, Galaxy Therapeutics, Route 92, Perfuze, CorTech, Shockwave, Toro and Xcath; principal investigator: COMPLETE study—Penumbra, LVO SYNCHRONISE—Viz.ai, MARRS—Perfuze, RESCUE—ICAD—Medtronic. Steering committee/publication committee member: SELECT, DAWN, SELECT 2, EXPEDITE II, EMBOLISE, CLEAR, ENVI, DELPHI, DISTALS, Rapid Pulse. DSMB—COMAND trial. Supported by grants from: Asahi, Balt, Scientia, Valley baptist, GE Healthcare, and Viz.ai
Data availability: Data are available upon reasonable request to the corresponding author.
Author contributions: Conceptualization: Ramesh Grandhi and Omid Shoraka; data collection: Omid Shoraka, Ramesh Grandhi, Samantha Miller, Joanna Roy, Vinay Jaikumar, Basel Musmar, Omar Tanweer, Jan-Karl Burkhardt, Pascal M Jabbour, Adnan H Siddiqui, Farhan Siddiq, and Ameer E Hassan; data analysis: Omid Shoraka and Ramesh Grandhi; methodology development: Omid Shoraka and Ramesh Grandhi; writing-original draft: Omid Shoraka and Ramesh Grandhi; writing-review and editing: Omid Shoraka, Ramesh Grandhi, Omar Tanweer, Jan-Karl Burkhardt, Pascal M Jabbour, Adnan H Siddiqui, Farhan Siddiq, and Ameer E Hassan; supervision: Ramesh Grandhi and Ameer E Hassan.
ORCID iDs: Omid Shoraka https://orcid.org/0000-0003-1387-3866
Ramesh Grandhi https://orcid.org/0000-0001-9000-6083
Samantha Miller https://orcid.org/0000-0001-9851-8622
Vinay Jaikumar https://orcid.org/0000-0002-6677-1858
Pascal M Jabbour https://orcid.org/0000-0002-8965-2413
Adnan H Siddiqui https://orcid.org/0000-0002-9519-0059
Farhan Siddiq https://orcid.org/0000-0001-8568-1543
Ameer E Hassan https://orcid.org/0000-0002-7148-7616
Basel Musmar https://orcid.org/0009-0000-4910-6090
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