Management strategies of unanticipated intracranial stenosis during mechanical thrombectomy for acute stroke: A survey of academic neurointerventionalists

Abstract

Background

The optimal approach to the management of intracranial atherosclerotic disease (ICAD) at the time of mechanical thrombectomy (MT) for large vessel occlusion (LVO) remains controversial. The goal of this study is to characterize current practices concerning this challenging clinical situation in a survey of practicing neurointerventionalists.

Methods

An electronic questionnaire was sent to a cross-section of North American academic neurointerventionalists using publicly available contact information and departmental websites. Prior to analysis, responses were anonymized and categorized by region.

Results

A total of 136/360 responses were recorded from the U.S. and Canada. The mean number of years of practicing as a neurointerventionalist among the respondents was 10.5 (± 6.2 years). ICAD was perceived as a causative factor during MT for LVO in 5–10% of thrombectomy cases. The most common first-line treatment approach for significant ICAD, assuming a TICI 2b or better reperfusion, was medical therapy (77.9% of respondents), followed by angioplasty + stent placement (8.8% of respondents). There were no significant differences in the first line treatment of ICAD in LVO between geographical regions (p = 0.815).

Conclusion

The approach to underlying ICAD in LVO varies widely; however, the majority of neurointerventionalists prefer medical therapy with DAPT as a first-line treatment approach. The current survey highlights the need for studies that better define the optimal timing and modality of treatment, along with an evidence-based framework for balancing the risks associated with these treatment approaches.

Introduction

Intracranial atherosclerotic disease (ICAD) is a common cause of ischemic stroke, although its incidence likely varies significantly by population. ¹ For patients with large vessel occlusions (LVO), mechanical thrombectomy (MT) has become the standard of care due to the preponderance of high-quality evidence demonstrating improved survival and functional outcomes.^2–6 Underlying ICAD as an etiology is a relatively common finding during MT for patients presenting with LVO, and these cases are often refractory to stent retriever thrombectomy, requiring more passes for successful placement, and even after having higher rates of immediate and delayed re-occlusion.^7,8 After successful reperfusion, a wide range of treatment approaches may be taken for patients with underlying ICAD, including balloon angioplasty (without stenting), balloon angioplasty with intracranial stenting, intra-arterial infusion of antiplatelet medication, or systemic medical therapy.^9–18 A recent meta-analysis indicated that rescue angioplasty and/or stenting for emergent LVO with underlying ICAD may be safe, with no differences in mortality and incidence of symptomatic intracranial hemorrhage (ICH) in patients with underlying ICAD compared with those without. ¹⁹ However, in the setting of acute stroke due to occlusion with underlying ICAD, the optimal treatment approach remains unclear.

To better characterize the approach towards this challenging situation among the neurointerventional community, we conducted a survey of neurologists, neurointerventional radiologists, and neurosurgeons in academic institutions across North America. With this survey, we sought to identify differing approaches to the issue of ICAD in LVO and highlight the range of complexities in the decision-making process necessary to promote optimal outcomes.

Methods

Survey design

An electronic questionnaire was created using secure survey platform (Google Forms) and sent to a cross-sectional sample of physicians from North America whose practice included neurointerventional management of acute stroke (Supplemental figure 1). The sample was drawn from publicly available departmental websites from institutions with residency or fellowship training programmes involving neurosurgery, neurology or neurointerventional radiology. This was a voluntary online survey conducted using publicly available contact information, thus approval by the institutional review board was not required. No specific patient-identifying information was asked as part of participation of the survey.

Survey participants and outcome measures

The survey was sent to 360 physicians (neurologists, interventional neuroradiologists, and neurosurgeons) from academic practices in the U.S. and Canada. Participants were invited to provide basic demographic information including practice location, career stage, specialty, and years of neurointerventional experience. The survey included 25 questions and took approximately 10 min to complete. It included a mixture of multiple-choice questions regarding current practice, freeform questions, and brief narrative case scenarios. No incentive was offered for participation. The survey was initially sent in March 2021, and final responses received by August 2021. Prior to analysis, responses were anonymized and categorized by region (Northeast, Southeast, Midwest, Southwest, and West).

The primary goal of the survey was to understand respondents’ treatment paradigm for management of intracranial stenosis (ICAD) as an underlying cause for acute ischemic large vessel occlusion (LVO). Using different scenarios, we attempted to delineate respondents’ protocols for approach to management of ICAD, anticoagulation/antiplatelet administration, and responses to hemorrhagic complications. Respondents were asked to describe their management of ICAD in LVO with questions regarding: first-line treatment approach for ICAD after TICI 2b or better reperfusion, use of anticoagulation during stenting (e.g. systematic heparinization, ACT target in harpin titration, GPIIb/IIIa inhibitors, imaging before administration), and use of anticoagulation post-stenting. Questions and response results are presented in Table 2. Additionally, respondents were asked to estimate, using percentages, their perceived incidence of ICAD in LVAO in their practices. The goal of this question was to understand the perceived burden of this issue, as well as to gauge regional differences in experiences.

Table 2.

Treatment approach for ICAD in LVO Among survey respondents.

	N
Perceived incidence of significant ICAD* during MT (% of total annual LVO volume)
<5%	32 (23.9)
5–10%	58 (43.3)
10–15%	27 (20.1)
15–20%	15 (11.2)
>20%	2 (1.5)
First-line treatment approach for ICAD after TICI 3 reperfusion
No active treatment	3 (2.2)
Medical therapy	106 (77.9)
Angioplasty	9 (6.6)
Stent	6 (4.4)
Angioplasty + Stent	12 (8.8)
Use of systemic heparinization during stenting (n, %)
Yes	57 (41.9)
No	37 (27.2)
Depends on whether the patient received tPA	31 (22.8)
Depends on other factors	11 (8.1)
Use of ACT Target in heparin titration during stenting (n, %)	60 (60.0)
Use of GPIIb/IIIa inhibitors during stenting procedure (n, %)
Yes	79 (59.0)
No	20 (14.9)
Depends on other factors	35 (26.1)
Use of imaging prior to antiplatelet loading (n, %)	87 (64.9)
Consideration of IV P2Y12 inhibitor (cangrelor) use during stenting procedure (n, %)
Yes	95 (69.6)
No	8 (5.9)
Depends on other factors	33 (24.4)
Preferred antiplatelet regimen after stent placement for ICAD during MT
ASA + clopidogrel	88 (64.7)
ASA + ticagrelor	42 (30.9)
Ticagrelor alone	4 (2.9)
Other**	2 (1.5)

* Significant ICAD = >50% stenosis; ** ticagrelor or prasugrel, or no antiplatelet.

ASA = aspirin; ICAD = intracranial atherosclerotic disease; LVO = large vessel occlusion; MT = mechanical thrombectomy.

Statistical analysis

Descriptive statistics were used to analyse demographic characteristics of participants as well as their perception of the incidence of ICAD in the local population of patients undergoing thrombectomy for LVO. For statistical comparison of responses across North American regions, a Kruskal-Wallis test was used to compare categorical survey responses, performed using GraphPad Prism (San Diego, CA).

Results

A total of 136 completed surveys were included in the study, equating to a 37.8% respons rate (126/360). Demographic data of respondents are summarized in Table 1. Respondents practiced primarily at academic institutions with representation from all U.S.regions and one Canadian province. Fifty-two percent were in the mid-career stage with 5–15 years of practice. The mean number of years of practicing as a neurointerventionalist among the respondents was 10.5 (± 6.2 years). The majority of participants were neurosurgeons by training (65.4%), followed by interventional radiologists (20.6%) and neurologists (14.0%). The largest subgroup respondents reported performing approximately 20–40 thrombectomies for LVO per year (45.9%). Moreover, 120 respondents (90.3%) reported performing less than 10 cases of stent placement for ICAD per year, with 12 (9.0%) reporting performing 10–20 cases, and 1 reporting performing more than 20 cases per year (0.7%). In contrast, annual carotid stent volume was reported to be <10 cases per year in 22.8%, 10–20 cases in 45.6%, 20–40 cases in 22.1%, 40–60 cases in 4.4% and over 60 cases per year in 5.1%.

Table 1.

Respondent demographics.

Demographic Factor	N
Total respondents (n)	136
U.S. region of practice (n, %)
Northeast	47 (37.9)
Southeast	30 (24.2)
Midwest	16 (12.9)
Southwest	10 (8.1)
West	19 (15.3)
Canada	2 (1.6)
Career stage (n, %)
Junior (first 5 years of practice)	32 (23.5)
Mid-career (5–15 years of practice)	71 (52.2)
Senior (>15 years of practice)	33 (24.3)
Average neurointerventional experience (years, SD)	10.5 (6.2)
Primary specialty (n, %)
Interventional neuroradiology	28 (20.6)
Neurology	19 (14.0)
Neurosurgery	89 (65.4)
Personal annual LVO treatment volume (n, %)
<20	3 (2.2)
20–40	62 (45.9)
40–60	30 (22.2)
>60	40 (29.6)

LVO = large vessel occlusion.

The perceived incidence of, and treatment approaches for ICAD when encountered during MT for LVO is summarized in Table 2. Most participants reported a 5–10% incidence of ICAD during thrombectomy cases. Furthermore, the most common first-line treatment approach for significant ICAD, assuming a TICI 2b or better reperfusion, was medical therapy (77.9% of respondents), followed by angioplasty and stent placement (8.8% of respondents). A pictorial visualization of these results segmented by geographical region of North America is shown in Figure 1. There were no significant differences in the first line treatment of ICAD in LVO between geographical regions (p = 0.815).

Figure 1.

Respondents’ preferred first line treatment of ICAD when encountered during mechanical thrombectomy for LVO, by geographical region. There were no significant differences in the responses by region (p = 0.815). W = West; SW = Southwest; MW = Midwest; SE = Southeast; NE = Northeast.

Only a minority of respondents (28.7%) reported having a formalized institutional protocol for management of ICAD in MT. In cases requiring stent placement, systemic heparinization was reported to be used by 41.9% of respondents, whereas 22.8% of respondents would heparinize depending only if the patient had not received tPA, and 27.2% denied using systemic heparinization (Table 2). Among those who used heparin, the dose of heparin used was a standard bolus dose in 18.0%, weight-based dose in 22.0%, and an adjusted dose based on ACT in 45.0%. The majority of respondents (68.3%) would not wait for a desired ACT level prior to placing a stent. Among those who use GPIIb/IIIa inhibitors in this situation, 59.0% of respondents continue the medication as an infusion peri-procedurally. Given the recent availability of IV P2Y12 inhibitors (cangrelor) within the U.S., 69.6% of respondents would consider choosing this agent over a GPIIb/IIIa inhibitor intra-procedurally prior to stent deployment.

After placing a stent, most practitioners (64.9%) would obtain imaging prior to continuing antiplatelet loading; whereas 35.1% stated that they would proceed with antiplatelet loading without imaging confirmation of no ICH. The most preferred antiplatelet regimen was ASA + clopidogrel (64.7%), followed by ASA + ticagrelor (30.9%), and then ticagrelor alone (4.4%). After antiplatelet loading, the practice of P2Y12 level verification also varied, with 6.6% checking P2Y12 immediately, 26.5% checking 6 h after administration, 36.0% checking the following day, and 30.9% not checking P2Y12 levels at all. Aspirin levels were less commonly checked regardless of the timing (39.1% of respondents). Most commonly, practitioners stated that they would adjust medication doses based on P2Y12 only (42.5% of respondents), while 29.1% reported medication adjustments based on P2Y12 and ASA levels. Among respondents who initially use clopidogrel, the most common adjustment based on non-therapeutic P2Y12 levels was to switch to ticagrelor (85.7%) or prasugrel (9.5%); few responded that they would increase or double the clopidogrel dose (3.8%) or make no change to allow clopidogrel responsivity to accrue over time (1.0%).

Respondents were also asked about their practices regarding subarachnoid hemorrhage, contrast staining, or frank ICH on post-procedural imaging after placement of a stent for ICAD was also explored. A key strategy was to employ repeat imaging and intensive blood pressure control (37/136, 27.2% of respondents). Several participants mentioned performing a dual energy CT or MRI to differentiate between blood and contrast (8/136, 5.9%). Furthermore, attitudes towards antiplatelet reversal were highly variable. Only 6/136 (4.4%) responded that they would completely reverse antiplatelet therapy after ICH was detected, while and 2.2% would administer platelets for large volume ICH. In addition, 23/136 (16.9%) would pause or reduce antiplatelet dosages, 6/136 (4.4%) would continue antiplatelet medications with or without heparin infusion, 17/136 (12.5%) would narrow the antiplatelet regimen to aspirin only. In the section of the survey allowing open-ended responses, 8/136 (5.9%) participants stressed continuing DAPT, since the perceived risk of in-stent thrombosis is greater than the risk associated with ICH expansion. Five out of 136 respondents (3.7%) mentioned that their institutional protocol was variable and largely depended on the amount or symptomatology of the ICH.

Discussion

In this study, we surveyed neurointerventionalists across North America to better characterize the current management strategies of underlying ICAD after successful reperfusion following LVO. Overall, we found significant variability in reported management. Although most interventionalists noted that they prefer medical management of ICAD in LVO, practices regarding stent placement, post-procedure dual antiplatelet regimen, and post-procedure hemorrhage management were quite variable across different regions. Ultimately, this lack of uniformity in practice suggests a paucity of clear evidence in the literature to guide the management of ICAD in LVO.

The use of dual antiplatelet therapy for primary stroke prevention in severe ICAD has been well established since the SAMMPRIS trial. ²⁰ However, the medical management of ICAD in the setting of acute LVO remains unclear, although present in up to 29% patients after MT. ²¹ Furthermore, ICAD seen at the thrombectomy site is a predictor of re-occlusion within 48 h after MT and is associated with unfavorable neurologic outcomes^8,22Thus, several prospective studies have looked at stenting these patients to prevent these poor outcomes.^23,24 One meta-analysis by Maingard et al. suggests that rescue stenting with MT failure due to ICAD had significantly lower 90-day disability and death, without increasing the subsequent risk of ICH due to the addition of antiplatelet therapy. ²² However, randomized prospective data are currently lacking to corroborate these findings.

Among the surveyed neurointerventionalists who place stents for ICAD in LVO, protocols for antiplatelet loading and regimen varied; widely reflecting a lack of data regarding prevention of thromboembolic complications for this indication. While the rate of thromboembolic complications after stent placement for ICAD in LVO is unclear, stent placement for aneurysm embolization is about 5% within 90-days.^23,24 In addition, stents typically used for ICAD typically have lower metal coverage than other intracranial implants such as flow diverters and intrasaccular devices, so there may theoretically be a lower risk of thromboembolic complications in the current setting. Furthermore, some balloon-mounted cardiac stents incorporate a drug-eluting coating that may have some efficacy in reducing platelet adherence.^25,26 However, evidence specific to ICAD in MT is lacking. Based on pharmacologic evidence of optimal platelet inhibition, our institutional protocol for antiplatelet loading has been to administer a half loading dose of tirofiban, 180 mg ticagrelor (which can be administered via nasogastric tube), and 300 mg ASA (via rectal administration) followed by ticagrelor 90mg BID and aspirin 81mg daily starting the following day. ²⁷ However, another option may be to utilize a lower dose of aspirin, along with ticagrelor. One respondent reported employing a strategy of potentially slowing the antiplatelet effect of a clopidogrel load by breaking the loading dose over multiple applications every 6 h. Two respondents reported minimizing the antiplatelet effect of clopidogrel by adjusting dosing based on multiple P2Y12 levels. Intravenous cangrelor may offer a new option, as it has a predictable, rapid onset and metabolism; however, it is not yet available at many North American institutions.

A further complication to the assessment and management of ICAD during LVO is the risk and consequences of hemorrhage, related either to systemic thrombolytic therapy, MT itself, or antiplatelet agents performed for stent placement. Many respondents in our survey emphasized the utility of Dyna CT on the angiography table, which may be performed 1) prior to the decision to move forward with stent placement, 2) after stent placement and before antiplatelet loading, or 3) after completion of stent/antiplatelet load. Perhaps this is because Dyna CT may be helpful to appreciate the difference between contrast staining and frank ICH before and/or after stent placement. On the other hand, in the case of patients with ICH but also high-grade stenosis at high risk for re-occlusion, there may be a role for single agent antiplatelet medication (aspirin) until documentation of ICH stability, and then re-assessment for antiplatelet loading and/or stent placement. Importantly, due to the interference of GPIIb/IIIa inhibitors with the interpretation of P2Y12 levels, the stent may have to be delayed 72 h or longer to be certain of adequate antiplatelet effect prior to stent placement. This may be another reason respondent would prefer cangrelor to GPIIb/IIIa inhibitors; however, there is not sufficient evidence to support this practice.

One limitation of this study is the survey format of the study. As with any survey-based experiment, there is opportunity for recall bias to impact the results and the interpretation of practice patterns. Respondents with a lower volume of ICAD with LVO cases may not recollect their management techniques as clearly given the frequency with which they perform these studies. However, this study still successfully demonstrates a large variance in practice patterns regarding this pathology, which again indicates that there are not clear guidelines for how to endovascularly intervene on cases of LVO due to ICAD. Future work could involve pooling cases from multiple institutions, in the setting of institution-specific protocols, to see how these management techniques might differ in patient outcomes.

Conclusions

There is a wide range of approaches to the management of underlying ICAD after successful reperfusion following LVO among neurointerventionalists in modern practices. Despite a growing body of evidence regarding the safety of angioplasty and/or stenting, most physicians in our survey preferred medical therapy as a first line approach, presuming achievement of adequate reperfusion by the MT procedure. Peri-procedural management of patients after acute stent placement remains extremely varied, indicating that the balance of antiplatelet therapy and the risk of hemorrhagic complications remains a challenge. Further work will be necessary to better characterize the best approach, but instead of applying a rigid protocol, a nuanced balance of risks and benefits considering individual patient factors and comorbidities may lead to optimal outcomes.