Abstract
Background
Emergent neuroendovascular stenting presents challenges for the utilization of antiplatelet agents.
Methods
This was a multicenter, retrospective cohort of patients who underwent emergent neuroendovascular stenting. The primary endpoints were thrombotic and bleeding events in relation to the timing of antiplatelet administration, route of administration, and choice of intravenous (IV) agent and the study investigated practice variability in antiplatelet utilization.
Results
Five-hundred and seventy patients were screened across 12 sites. Of those, 167 were included for data analysis. For patients who presented with ischemic stroke, artery dissection and emergent internal carotid artery (ICA) stenting who received an antiplatelet agent prior to or during the procedure, 57% were given an IV antiplatelet agent; for patients who were given an antiplatelet agent after the procedure, 96% were given an oral agent. For patients who presented for aneurysm repair and received an antiplatelet agent prior to or during the procedure, 74% were given an IV agent; patients who were given an antiplatelet agent after the completion of the procedure were given an oral antiplatelet agent 90% of the time. In patients who presented with ischemic stroke, artery dissection and emergent ICA stenting who received oral antiplatelet agents post-procedure were more likely to have thrombotic events compared to those who received oral antiplatelet agents prior to or during the procedure (29% vs 9%; p = 0.04). There were no differences in the primary outcomes observed when comparing other antiplatelet treatment strategies.
Conclusion
The optimal timing of antiplatelet administration in relation to stent placement and route of administration of antiplatelet agents is unclear. Timing and route of administration of antiplatelet agents may have an effect on thrombosis in emergent neuroendovascular stenting. Significant practice variation exists in antiplatelet agent utilization in emergent neuroendovascular stenting.
Keywords: Ischemic stroke, aneurysm, platelet aggregation inhibitors
Background
The use of antiplatelet therapy in emergent neuroendovascular stenting is widespread. Despite the consensus that antiplatelet agents should be utilized to maintain stent patency and reduce the risk of thrombus formation in neuroendovascular stenting, practice variation is significant. Furthermore, no standard exists for which agent(s) to use, whether intravenous (IV) or oral administration is preferred, or what dosing strategy should be utilized. Investigation of optimal timing of antiplatelet administration in relation to stent placement and the appropriate route of administration in emergent neuroendovascular stenting is limited. 1 Consensus statements have been published that address antiplatelet management in various neuroendovascular stenting procedures, but lack of data to guide recommendations and the need to rely on expert opinion limit their utility.2,3
The aims of this study were twofold. First, this study aimed to assess the effect of timing of antiplatelet agent administration in relation to stent placement, route of administration (oral vs. IV), and IV antiplatelet agent choice (cangrelor vs. glycoprotein IIb/IIIa inhibitors) on patient outcomes. Second, this study aimed to investigate the practice variation in route and timing of administration of antiplatelet agents in relation to stent placement.
Methods
Study design
Our study group has completed a multicenter, retrospective observational cohort study evaluating patients who received antiplatelet agents during neuroendovascular stenting procedures. The results presented here are from a preplanned analysis of patients who underwent emergent neuroendovascular stenting procedures and received antiplatelet agents prior to, during or after the procedure. Representatives from the Neurocritical Care Society Pharmacy Study Group and the primary site, University of Kentucky, coordinated the study. The cohort of patients in this analysis comprised data from 12 comprehensive stroke centers that participated on a voluntary basis, as no funding was utilized for the study. Participating centers are outlined in the Supplementary Appendix (Table 1 and Table 7). Institutional Review Boards at each institution approved the retrospective collection of de-identified patient data, and informed consent was not required. Data were primarily collected by neurocritical care pharmacists at each site and recorded using Research Electronic Data Capture (REDCap) electronic data capture tools hosted at University of Kentucky HealthCare. REDCap is a secure, web-based software platform designed to support data capture for research studies, providing (1) an intuitive interface for validated data capture; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for data integration and interoperability with external sources.4–6
Patients were included if they were between the ages of 18 and 85 years and underwent an emergent neuroendovascular stenting procedure, necessitating antiplatelet therapy between July 1, 2017, and October 31, 2020. Patients were identified based on receipt of antiplatelet agents and procedure type. Patients were included in a reverse chronological manner with a goal of including at least 40 patients per center, or until they exhausted their list. Patients were excluded if they were prisoners, pregnant, had another/preexisting indication for dual antiplatelet therapy or underwent an elective or planned neuroendovascular stenting procedure.
Data points collected included demographic information and medical history, antiplatelet therapy utilized prior to, during, and after the stenting procedure, neuroendovascular procedure details and intraprocedure and post-procedure thrombotic and bleeding complications.
Study endpoints
The primary endpoints were thrombotic and bleeding events in relation to the timing of antiplatelet administration (prior to or during the procedure vs. post-procedure), route of administration (IV vs. oral), and choice of IV agent when utilized (cangrelor vs. glycoprotein IIb/IIIa inhibitors). Intraprocedural thrombotic complications were defined as thrombosis documented during the procedure or use of a rescue agent due to acute thrombosis on digital subtraction angiography imaging. Immediate post-procedure thrombotic complications were defined as the presence of thrombus on computed tomography angiography, magnetic resonance imaging, or other imaging studies or signs of clinical stoke documented in the medical record within 48 h following the procedure. Outcomes of major and minor bleeding were defined by the International Society on Thrombosis and Haemostasis. 7 Major bleeding was defined as fatal bleeding, symptomatic bleeding in a critical area or organ, and/or bleeding causing a fall in hemoglobin level of 2 g/dL or more or leading to a transfusion of two or more units of whole blood or packed red blood cells. Minor bleeding was defined as any bleeding that did not meet the definition of major bleeding.
Due to differences in the risk of complications, patients were analyzed in two separate groups. The first group included patients with ischemic stroke, artery dissection, or emergent internal carotid artery (ICA) stenting. The second group included patients requiring aneurysm repair. Primary endpoint analysis was only performed in the first group due to a low number of patients who underwent aneurysm repair. Timing of antiplatelet administration was categorized into two groups: (1) prior to or during the stenting procedure or (2) post-procedure. This was done because intraprocedural documentation of the specific timing of stent placement in relation to antiplatelet drug administration is often not available, so the most robust time point to separate the groups was prior to or during the procedure or after the completion of the procedure.
Practice patterns of antiplatelet utilization are presented as an analysis of antiplatelet agents, the timing of administration, route of administration, and dose. All neuroendovascular procedures were conducted in accordance with guidelines, standards of care, and local practice patterns. Antiplatelet agent regimens were selected at the discretion of the neuroendovascular operator/provider.
Statistical analysis
Continuous data were analyzed using the Student's t test and nominal data were analyzed using the chi-squared test or Fisher's exact test. Two-tailed statistical tests were utilized with p < 0.05 determining statistical significance in the univariate analysis; SPSS was used for data analysis (IBM SPSS Statistics, Version 26 [SPSS Inc., Chicago, IL]).
Results
A total of 570 patients who underwent neuroendovascular stenting and received antiplatelet therapy were screened for eligibility. A total of 403 patients were excluded, leaving 167 patients to be included in the analysis (Figure 1). Baseline characteristics and procedure details are presented in Tables 1–3. Details of study site patient enrollment and patient-specific details of thrombotic and bleeding complications are presented in Supplemental Appendix (Tables 2–6). Information regarding the utilization of intra-arterial administration of antiplatelet agents for rescue post intraprocedure thrombosis was collected as part of the study but is not reported due to the small number of patients.
Figure 1.
Flow diagram of included patients.
Table 1.
Characteristics of patients at baseline and procedure indications*.
| Characteristic | Value (n = 167) |
|---|---|
| Age—year | 66 (19) |
| Gender—female | 69 (41) |
| Weight (kg) | 81.5 (25) |
| BMI (kg/m2) | 27.7 (8) |
| Race | |
| Caucasian | 124 (74) |
| African American | 22 (13) |
| Asian | 1 (0.5) |
| Latino | 6 (3.5) |
| Other | 1 (0.5) |
| Unknown | 13 (8) |
| Past medical history | |
| Hypertension | 120 (72) |
| Hyperlipidemia | 67 (40) |
| Diabetes | 49 (29) |
| Current Smoker | 45 (27) |
| Previous transient ischemic attach | 37 (22) |
| Prothrombotic disease | 1 (0.5) |
| Malignancy | 18 (11) |
| Unknown | 8 (5) |
| Procedure indication | |
| Ruptured aneurysm | 33 (20) |
| Unruptured aneurysm | 4 (2.5) |
| Artery dissection | 5 (3) |
| Thrombectomy and emergent stent placement | 87 (52) |
| Emergent ICA stent | 33 (20) |
| Other | 5 (3) |
ICA: internal carotid artery.
*All data are described as median (IQR) or number (percent).
Table 3.
Ischemic stroke/artery dissection/emergent ICA stent procedure details (n = 130)*.
| Procedure details | Number |
|---|---|
| Anatomic location of procedure | |
| ICA | 88 (68) |
| MCA | 26 (20) |
| ACA | 2 (1.5) |
| Basilar | 5 (4) |
| Vertebral | 8 (6) |
| Other | 1 (1) |
| Stroke scores | |
| NIHSS score | 13 (13) |
| mTICI score | |
| 0 | 2 (1.5) |
| 1 | 0 |
| 2a | 2 (1.5) |
| 2b | 34 (26) |
| 3 | 28 (22) |
| Not reported | 64 (49) |
| Procedural antithrombotic/thrombolytics | |
| Heparin administration | 88 (68) |
| Thrombolytic prior to procedure | 23 (18) |
ICA: internal carotid artery; MCA: middle cerebral artery; ACA: anterior communicating artery; NIHSS: National Institutes of Health Stroke Scale; mTICI: modified treatment in cerebral ischemia.
*All data are presented as number (percentage) or median (IQR) unless otherwise specified.
Table 2.
Aneurysm repair procedure details.
| Neuroendovascular procedure | |
| Ruptured aneurysm repair (n = 33) | |
| Anatomic location | |
| ICA | 5 (15) |
| MCA | 4 (12) |
| ACA | 7 (21) |
| Basilar | 2 (6) |
| ACOMM | 6 (18) |
| PCOMM | 4 (12) |
| PICA | 3 (9) |
| Other | |
| Device | |
| Stent-assisted coiling | 20 (60) |
| Flow-diverting stent | 8 (24) |
| WEB | 1 (3) |
| Other | 4 (12) |
| Hunt-Hess grade | |
| 0 | 0 |
| 1–2 | 17 (52) |
| 3–4 | 7 (21) |
| 5 | 2 (6) |
| Not reported/unknown | 7 (21) |
| Number of stents placed | |
| One | 28 (85) |
| Two | 5 (15) |
| Heparin administration | 23 (70) |
| Unruptured aneurysm repair (n = 4) | |
| Anatomic location | |
| ICA | 2 (50) |
| MCA | 2 (50) |
| Device | |
| Stent-assisted coiling | 1 (25) |
| Flow-diverting stent | 2 (50) |
| Other | 1 (25) |
ICA: internal carotid artery; MCA: middle cerebral artery; ACA: anterior cerebral artery; ACOMM: anterior communicating artery; PCOMM: posterior communicating artery; PICA: posterior inferior cerebellar artery; WEB: Woven EndoBridge.
Table 6.
Thrombotic and bleeding outcomes.
| Thrombotic outcomes | |
| Ischemic stroke/artery dissection/emergent ICA stent (n = 130) | |
| Intraprocedural thrombus | 8 (6) |
| Post-procedure thrombus (within 48 hours) | 8 (6) |
| Aneurysm repair (n = 37) | |
| Intraprocedural thrombus | 3 (8) |
| Post-procedure thrombus (within 48 hours) | 1 (3) |
| Bleeding outcomes | |
| Ischemic stroke/artery dissection/emergent ICA stent (n = 130) | |
| Major bleeding | 17 (13) |
| Minor bleeding | 6 (5) |
| Aneurysm repair (n = 37) | |
| Major bleeding | 2 (5) |
| Minor bleeding | 1 (3) |
ICA: internal carotid artery.
Data are presented as number (percent).
Practice pattern variation
Patients presenting with ischemic stroke, artery dissection, and emergent ICA stent
A total of 130 patients presented with ischemic stroke, artery dissection, and emergent ICA stenting. Most patients were administered an antiplatelet agent prior to or during the stenting procedure (Table 4).
Table 4.
Antiplatelet regimen details for ischemic stroke/artery dissection/emergent ICA stent patients (n = 130).
| Antiplatelet regimen timing | |
| Pre-procedure or intraprocedural | 105 |
| Post-procedure | 25 |
| Pre-procedure or intraprocedural route | |
| Intravenous | 60 |
| Eptifibatide bolus only | 25 |
| Eptifibatide infusion | 5 |
| Cangrelor infusion | 30 |
| Oral | 45 |
| Clopidogrel + aspirin | 36 |
| Ticagrelor + aspirin | 3 |
| Unsure | 6 |
| Post-procedure route | |
| Intravenous | 1 |
| Cangrelor infusion | 1 |
| Oral | 24 |
| Clopidogrel + aspirin | 15 |
| Ticagrelor + aspirin | 1 |
| Unsure | 8 |
Preprocedure/intraprocedural IV antiplatelet regimens
For the patients that received an antiplatelet agent prior to or during stent placement, 57% were given an IV antiplatelet agent (Table 4). The majority of patients, 79%, who underwent emergent thrombectomy with stent placement were given an IV antiplatelet agent, whereas IV antiplatelet agents were rarely (13%) utilized in patients who underwent emergent ICA stent placement. In patients who received an IV antiplatelet agent prior to or during stent placement, cangrelor was used 50% of the time and eptifibatide was used 50% of the time. Eptifibatide was utilized as a single bolus in 83% of patients, with the dose ranging from 52 mcg/kg to 170 mcg/kg. Continuous infusion eptifibatide was rarely used (n = 5) and when used was dosed at 2 mcg/kg/min in all patients except one (1 mcg/kg/min was used) with a median duration of 44 h (range 41 h). Four out of the five patients administered an eptifibatide continuous infusion were given an eptifibatide bolus prior to initiation of the infusion and in these patients eptifibatide bolus doses ranged from 90 to 135 mcg/kg. Cangrelor was always used as a continuous infusion. A loading dose was administered in 87% of patients prior to cangrelor infusion initiation; loading doses ranged from 5 to 15 mcg/kg. Dosing for continuous infusions of cangrelor ranged from 0.75 mcg/kg/min to 2 mcg/kg/min. The median duration of cangrelor infusion was 17 h (range 40 h). The median duration of overlap between the administration of an oral antiplatelet agent and discontinuation of the continuous infusion for eptifibatide was 3.7 h (range 2 h) and for cangrelor was 1 h (range 1 h).
Preprocedure/intraprocedural oral antiplatelet regimens
Aspirin plus clopidogrel was the oral regimen utilized in 80% of the patients if an oral agent was administered prior to or during the stenting procedure. Patients who received clopidogrel received a loading dose 78% of the time (16 were given 300 mg and 12 were given 600 mg). Three patients were administered ticagrelor; two out of the three were given a loading dose of 180 mg.
Post-procedure antiplatelet regimens
Patients given antiplatelet agents post-procedure were given an oral agent 96% of the time. The median time between the completion of the procedure and administration of an antiplatelet agent was 2.8 h (range 38 h). Cangrelor at a dose of 2 mcg/kg/min (15 mcg/kg load) was used in one patient.
Patients presenting for emergent aneurysm repair
A total of 37 patients presented for emergent aneurysm repair, and 73% were given an antiplatelet agent prior to or during the stent procedure (Table 5).
Table 5.
Antiplatelet regimen details for patients presenting for aneurysm repair (n = 37).
| Antiplatelet regimen timing | |
| Pre-procedure or intraprocedural | 27 |
| Post-procedure | 10 |
| Pre-procedure or intraprocedural route | |
| Intravenous | 20 |
| Eptifibatide bolus only | 10 |
| Eptifibatide infusion | 3 |
| Cangrelor infusion | 7 |
| Intra-arterial | |
| Eptifibatide | 1 |
| Oral | 6 |
| Clopidogrel | 5 |
| Ticagrelor | 1 |
| Post-procedure route | |
| Intravenous | 1 |
| Cangrelor infusion | 1 |
| Oral | 9 |
| Clopidogrel + aspirin | 8 |
| Ticagrelor + aspirin | 1 |
Preprocedure/intraprocedural IV antiplatelet regimens
For the patients that received an antiplatelet agent prior to or during aneurysm repair/stent placement, 74% were given an IV antiplatelet agent. Eptifibatide was utilized in 65% of patients and was given as a single bolus in 77% of patients. Eptifibatide bolus doses ranged from 55 mcg/kg to 180 mcg/kg in patients who received bolus-only administration. Three patients were administered a continuous infusion of eptifibatide; doses ranged from 0.5 mcg/kg/min to 2 mcg/kg/min and loading doses in these patients ranged from 90 mcg/kg to 180 mcg/kg. The median duration of an eptifibatide infusion was 219 h (range 505 h). Seven patients were given cangrelor infusions; loading doses ranged from 5 to 10 mcg/kg and infusion doses ranged from 0.75 mcg/kg/min to 2 mcg/kg/min. The median duration of cangrelor infusion was 21 h (range 24 h). The median duration of overlap between the administration of an oral antiplatelet agent and discontinuation of the continuous infusion for eptifibatide was 3.3 h (range 11.5 h) and for cangrelor was one hour (range 1 h).
Preprocedure/intraprocedural oral antiplatelet regimens
Six patients were given an oral antiplatelet agent prior to or during the aneurysm repair/stenting procedure. Clopidogrel was administered to five patients; in these patients, a loading dose of 300 mg was given to four patients and 600 mg was given to one patient. Ticagrelor was administered to one patient; a loading dose of 180 mg was used.
Post-procedure antiplatelet regimens
Most patients (90%) administered an antiplatelet agent after the completion of the stenting procedure were given an oral antiplatelet agent. Cangrelor at a dose of 2 mcg/kg/min (15 mcg/kg load) was used in one patient. The median time between the completion of the procedure and administration of an antiplatelet agent was 1.9 h (range 24 h).
Clinical outcomes and primary endpoint analysis
Patients presenting with ischemic stroke, artery dissection, or emergent ICA stenting
Thrombotic complications
Intraprocedural thrombotic complications occurred in eight patients (Table 6). An antiplatelet agent was administered after completion of the procedure in five of the patients and prior to or during the procedure in three of the patients. Post-procedure thrombotic complications (within 48 h post-procedure) occurred in eight patients. An antiplatelet agent was administered after completion of the procedure in three of the patients and prior to or during the procedure in five of the patients. Four patients who experienced intraprocedural thrombus also reported a post-procedure thrombus (three of the four were not given a rescue agent and all reported no thrombus resolution).
Bleeding complications
Major bleeding complications occurred in 17 patients and minor bleeding occurred in six patients (Table 6). No patients with bleeding complications were administered a rescue agent for intraprocedural thrombus.
Patients presenting for aneurysm repair
Thrombotic complications
Intraprocedural thrombotic complications occurred in three patients during aneurysm repair/stent deployment. An antiplatelet agent was administered after completion of the procedure in two of the patients and prior to or during the procedure in one of the patients. Post-procedure thrombotic complications (within 48 h post-procedure) occurred in one patient.
Bleeding complication
Major bleeding complications occurred in two patients treated for aneurysm repair and minor bleeding occurred in one patient. No patients with bleeding complications were administered a rescue agent for intraprocedural thrombus.
Primary endpoint analysis
More patients who received an oral antiplatelet agent after the completion of the procedure compared to prior to or during the procedure had thrombotic complications (7 [29%] vs. 4 [9%], p = 0.04) (Table 7). There were no differences in other comparisons of antiplatelet treatment strategy in relation to thrombotic complications. There was no difference in the rate of thrombotic complications in patients who received cangrelor versus eptifibatide. There was no difference in bleeding outcomes in any comparisons of antiplatelet treatment strategies (Table 8).
Table 7.
Thrombotic complications comparison based on antiplatelet regimen variables for patients presenting with ischemic stroke/artery dissection/emergent ICA stent.
| Subgroup analysis: thrombotic events | ||
|---|---|---|
| Antiplatelet administration timing | ||
| Oral antiplatelet prior to or during procedure (n = 45) | Oral antiplatelet post-procedure (n = 24) | p value |
| 4 (9) | 7 (29) | 0.040 |
| IV antiplatelet prior to or during procedure (n = 60) | IV antiplatelet post-procedure (n = 1) | |
| 5 (8) | 0 | 1.0 |
| Oral vs intravenous antiplatelet agent prior to procedure | ||
| Oral antiplatelet (n = 45) | Intravenous antiplatelet (n = 60) | |
| 4 (9) | 5 (8) | 1.0 |
| IV antiplatelet agents comparison | ||
| Eptifibatide (n = 30) | Cangrelor (n = 30) | |
| 4 (13) | 1 (3) | 0.353 |
ICA: internal carotid artery.
Data are presented as number (percent).
Table 8.
Bleeding complications (major and minor) comparison based on antiplatelet regimen variables for patients presenting with ischemic stroke/artery dissection/emergent ICA stent.
| Subgroup analysis: Bleeding events | ||
|---|---|---|
| Antiplatelet administration timing | ||
| Oral antiplatelet prior to or during procedure (n = 45) | Oral antiplatelet post-procedure (n = 24) | p value |
| 8 (18) | 7 (29) | 0.360 |
| IV antiplatelet prior to or during procedure (n = 60) | IV antiplatelet post-procedure (n = 1) | |
| 8 (13) | 0 | 1.0 |
| Oral vs intravenous antiplatelet agent prior to procedure | ||
| Oral antiplatelet (n = 45) | Intravenous antiplatelet (n = 60) | |
| 8 (18) | 8 (13) | 0.590 |
| IV antiplatelet agents comparison | ||
| Eptifibatide (n = 30) | Cangrelor (n = 30) | |
| 4 (13) | 4 (13) | 1 |
ICA: internal carotid artery.
Data are presented as number (percent).
Discussion
Our analysis shows that significant variability exists in antiplatelet agent utilization in emergent neuroendovascular stenting, specifically related to practical decisions of use such as when the medication is administered, what route is utilized, and which medication is utilized. This analysis suggests that in patients who undergo emergent stenting due to stroke or artery dissection or undergo emergent ICA stent placement, in whom an oral antiplatelet regimen is utilized, administration prior to the procedure as compared to after the procedure potentially leads to lower thrombotic complications.
Mechanical thrombectomy for acute ischemic stroke shows improved outcomes compared to thrombolysis alone or no intervention. Despite this improvement, failed mechanical thrombectomy procedures are not infrequent, largely due to underlying atherosclerosis and vessels stenosis leading to rapid reocclusion or inability to extract preformed clot.8,9 In addition, tandem occlusions of the intracranial vessels and extracranial internal carotid vessels are challenging to treat, as is isolated extracranial carotid artery occlusion with no associated intracranial lesion. The utilization of intracranial rescue stenting after failed thrombectomy and extracranial carotid stenting in tandem and nontandem occlusions shows improved outcomes in these situations.8,10 Although the literature continues to expand in relation to the best interventional approach to take in these scenarios, less attention has been focused on periprocedural antiplatelet management in these situations. Consensus guidelines have been published but are limited by a lack of data and the inability of panel members to reach consensus on many questions. 2 Both IV and oral agents have been used, and there is no little published information to guide decisions about when to administer antiplatelet agents in relation to when the stent is placed. 11
Studies have been published that report experience with a specific antiplatelet regimen and/or strategy, and some studies have aggregated data from multiple centers.10,12–14 These studies suggest that periprocedural antiplatelet utilization improves short- and long-term outcomes. What is lacking is comparative data about which antiplatelet strategy is optimal, specifically related to route of antiplatelet agent administration and appropriate time of administration in relation to stenting. One study compared three IV antiplatelet regimens, IV aspirin, abciximab, and cangrelor. The study showed that IV aspirin and cangrelor had superior outcomes in comparison to abciximab, which showed a high rate of intracranial hemorrhage (ICH). 15 Additional complexity is added in relation to deciding when to administer antiplatelet agents in patients who have received thrombolytics for acute stroke but require emergent stenting for either thrombectomy failure or due to tandem occlusions.13,16
In patients with ruptured aneurysms that are not amenable to traditional coiling, stent-assisted coiling and flow diversion are frequently utilized. These implants are highly thrombogenic, and because of this, patients with recent aneurysm rupture and ICH must be placed on antiplatelet agents. Literature describing antiplatelet treatment strategies in ruptured aneurysm repair is mostly observational with significant variation. Meta-analyses have attempted to combine studies to assess the merit of specific strategies but the quality of studies is low and the number of patients is small.1,17,18 Traditionally, oral antiplatelet agents have been utilized in the emergent treatment of ruptured aneurysms but IV antiplatelet agents are being used more often.19–21 Meta-analyses have shown that oral versus IV administration of antiplatelets have mostly similar outcomes but some differences were shown, specifically a potential for more bleeding complications with oral antiplatelet administration.1,18
With the rise in the use of IV antiplatelet agents in emergent neuroendovascular stenting, several practical considerations are important and require further study. Significant variation exists in the doses utilized for glycoprotein IIb/IIIa inhibitors and cangrelor. Limited literature on the use of cangrelor suggests that higher doses may have a higher rate of hemorrhage but further study is required. 22 Furthermore, the early use of tirofiban in percutaneous coronary intervention showed inferior outcomes due to the utilization of suboptimal dosing; thus, the influence of proper dosing should not be discounted in the neuroendovascular realm. 23 Currently, there is no consensus about which dose is appropriate for IV antiplatelet agents in neuroendovascular stenting and more study in this area is of paramount importance. In addition, the practical issue of transitioning from IV antiplatelet agents to oral antiplatelet agents in a patient with a recent neuroendovascular stent placed is of significant importance. Our study documented significant variation between centers in how patients were transitioned between IV and oral antiplatelet agents. An example of the practical importance of proper transition between IV and oral antiplatelets is the loss of platelet inhibition if patients are transitioned improperly from cangrelor to clopidogrel or prasugrel.24,25 The optimal time frame and method for transitioning between IV and oral antiplatelet agents is unclear and deserves further study as loss of platelet inhibition during the transition period increases the risk of thromboembolic complications.
Our study has several limitations that merit discussion. The analysis of patient outcomes in relation to time of antiplatelet administration and route of administration in the group that presented with ischemic stroke, artery dissection, or emergent ICA is limited by heterogeneity of the patient population in terms of bleeding and thrombosis risk. Furthermore, data were collected retrospectively, and patient outcomes were taken from chart review which is inherently limited compared to prospective data collection. Some variables that may have contributed to the bleeding or thrombosis rates (heparin utilization during the procedure and thrombolytic use prior to thrombectomy) were collected but the number of patients was too low for those variables to be incorporated into the analysis. Our study showed statistical differences in some patient outcomes comparisons but not others and it is likely that our study was underpowered to assess some patient outcomes. Due to the retrospective nature of the study and the small number of patients, the statistical difference seen in outcomes in relation to timing of antiplatelet administration are hypothesis generating and should be verified in larger, prospective studies.
Conclusion
Significant practice variation exists in antiplatelet agent utilization in emergent neuroendovascular stenting. The optimal timing of administration in relation to stent placement and route of administration of antiplatelet agents is unclear. Timing and route of administration of antiplatelet agents may have an effect on thrombosis and bleeding outcomes in emergent neuroendovascular stenting.
Supplemental Material
Supplemental material, sj-docx-1-ine-10.1177_15910199231180003 for Multicenter comparison of antiplatelet treatment strategies for urgent/emergent neuroendovascular stenting by Devin Holden, Casey C. May, Blake T. Robbins, Aaron M. Cook, the Neurocritical Care Pharmacy Section Research Group: Sara Jung, Keaton S. Smetana, Christina Roels, Sara Schuman Harlan, Shaun Keegan, Gretchen Brophy, Sulaiman Al Mohaish, Melissa Sandler, Samantha Spetz, Kevin Wohlfarth, Jocelyn Owusu-Guha, Pamela Buschur, Elizabeth Hetrick, Keith Dombrowski, Jennifer Glover, Melissa Levesque, Spencer Dingman, Mohammed Hussain in Interventional Neuroradiology
Acknowledgements
Collaboraters
Neurocritical Care Pharmacy Section Research Group Sara: Jung, PharmD, MS, BCCCP (Wellstar Kennestone Hospital); Keaton S. Smetana, PharmD, MBA, BCCCP (The Ohio State Wexner Medical Center); Christina Roels, PharmD, CPP, BCPS, BCCCP Novant Health Forsyth Medical Center; Sara Schuman Harlan, PharmD, BCCCP (University of Cincinnati Medical Center); Shaun Keegan, PharmD, BCPS (University of Cincinnati Medical Center); Gretchen Brophy, PharmD, BCPS, FCCP, FCCM, FNCS, MCCM (Virginia Commonwealth University); Sulaiman Al Mohaish, PharmD, BCPS (Virginia Commonwealth University); Melissa Sandler, PharmD, BCCCP (Virginia Commonwealth University); Samantha Spetz, PharmD, BCCCP (ProMedica Toledo Hospital); Kevin Wohlfarth, PharmD, BCPS, BCCCP, BCCP (ProMedica Toledo Hospital); Jocelyn Owusu-Guha, PharmD (OhioHealth Riverside Methodist Hospital); Pamela Buschur, PharmD, BCPS (OhioHealth Riverside Methodist Hospital); Elizabeth Hetrick, PharmD, BCPS, BCCCP (Tacoma General Hospital MultiCare Health System); Keith Dombrowski, MD (University of South Florida/Tampa General Hospital); Jennifer Glover, MD, FACS (University of South Florida/Tampa General Hospital); Melissa Levesque, PharmD, BCPS, BCCCP (University of South Florida/Tampa General Hospital); Spencer Dingman, PharmD, BCCCP (Wesley Medical Center); Mohammed Hussain, MD (Wesley Medical Center)
Footnotes
Author contribution(s): DH: Conceptualization, methodology, data curation, formal analysis, and writing—original draft.
CCM: Methodology, data curation, and writing—review and editing.
BTR: Methodology, data curation, and writing—review and editing.
AMC: Conceptualization, methodology, formal analysis, and writing— review and editing.
The Neurocritical Care Society Pharmacy Study Group: Data curation and writing—review and editing. All authors have reviewed and approved the final manuscript.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Devin Holden https://orcid.org/0000-0003-0847-3227
Blake T. Robbins https://orcid.org/0000-0002-1675-403X
References
- 1.Ryu CW, Park S, Shin HS, et al. Complications in stent-assisted endovascular therapy of ruptured intracranial aneurysms and relevance to antiplatelet administration: a systematic review. AJNR Am J Neuroradiol 2015; 36: 1682–1688. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Goyal M, Orlov K, Jensen ME, et al. A DELPHI consensus statement on antiplatelet management for intracranial stenting due to underlying atherosclerosis in the setting of mechanical thrombectomy. Neuroradiology 2021; 63: 627–632. [DOI] [PubMed] [Google Scholar]
- 3.Ospel JM, Brouwer P, Dorn F, et al. Antiplatelet management for stent-assisted coiling and flow diversion of ruptured intracranial aneurysms: a DELPHI consensus statement. AJNR Am J Neuroradiol 2020; 41: 1856–1862. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform 2019; 95: 103208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42: 377–381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Obeid JS, McGraw CA, Minor BL, et al. Procurement of shared data instruments for research electronic data capture (REDCap). J Biomed Inform 2013; 46: 259–265. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemostasis 2005; 3: 692–694. [DOI] [PubMed] [Google Scholar]
- 8.Chang Y, Kim BM, Bang OY, et al. Rescue stenting for failed mechanical thrombectomy in acute ischemic stroke: a multicenter experience. Stroke 2018; 49: 958–964. [DOI] [PubMed] [Google Scholar]
- 9.Fiehler J. Failed thrombectomy in acute ischemic stroke: return of the stent? Stroke 2018; 49: 811–812. [DOI] [PubMed] [Google Scholar]
- 10.Zhu F, Anadani M, Labreuche J, et al. Impact of antiplatelet therapy during endovascular therapy for tandem occlusions: a collaborative pooled analysis. Stroke 2020; 51: 1522–1529. [DOI] [PubMed] [Google Scholar]
- 11.Wareham J, Flood R, Phan K, et al. A systematic review and meta-analysis of observational evidence for the use of bailout self-expandable stents following failed anterior circulation stroke thrombectomy. J Neurointerv Surg 2019; 11: 675–682. [DOI] [PubMed] [Google Scholar]
- 12.Pop R, Severac F, Hasiu A, et al. (2022) Conservative versus aggressive antiplatelet strategy for emergent carotid stenting during stroke thrombectomy. Interv Neuroradiol 15910199221083112. Online ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Osteraas ND, Crowley RW, Panos N, et al. Eptifibatide use following emergent carotid stenting in acute anterior circulation ischemic stroke with tandem occlusion. J Stroke Cerebrovasc Dis 2020; 29: 105021. [DOI] [PubMed] [Google Scholar]
- 14.Marnat G, Finistis S, Delvoye F, et al. Safety and efficacy of cangrelor in acute stroke treated with mechanical thrombectomy: endovascular treatment of ischemic stroke registry and meta-analysis. AJNR Am J Neuroradiol 2022; 43: 410–415. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Delvoye F, Maier B, Escalard S, et al. Antiplatelet therapy during emergent extracranial internal carotid artery stenting: comparison of three intravenous antiplatelet perioperative strategies. J Stroke Cerebrovasc Dis 2021; 30: 105521. [DOI] [PubMed] [Google Scholar]
- 16.Smetana KS, Zakeri A, Dolia J, et al. Management of tandem occlusions in patients who receive rtPA. J Thromb Thrombolysis 2021; 52: 1182–1186. [DOI] [PubMed] [Google Scholar]
- 17.Caroff J, Aubert L, Lavenu-Bombled C, et al. Antithrombotic therapies for neurointerventional surgery: a 2021 French comprehensive national survey. J Neurointerv Surg 2023; 15: 402–407. [DOI] [PubMed] [Google Scholar]
- 18.Bilgin C, Ghozy S, Shehata M, et al. The prophylactic use of glycoprotein 2b/3a inhibitors in the endovascular treatment of intracranial aneurysms: a systematic review and meta-analysis. World Neurosurg 2022; 168: e50–e66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Chalouhi N, Jabbour P, Daou B, et al. A new protocol for anticoagulation with tirofiban during flow diversion. Neurosurgery 2016; 78: 670–674. [DOI] [PubMed] [Google Scholar]
- 20.Limaye K, Zanaty M, Hudson J, et al. The safety and efficacy of continuous tirofiban as a monoantiplatelet therapy in the management of ruptured aneurysms treated using stent-assisted coiling or flow diversion and requiring ventricular drainage. Neurosurgery 2019; 85: E1037–e1042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Entezami P, Dalfino JC, Boulos AS, et al. Use of intravenous cangrelor in the treatment of ruptured and unruptured cerebral aneurysms: an updated single-center analysis and pooled analysis of current studies. J Neurointerv Surg 2022. Online ahead of print. [DOI] [PubMed] [Google Scholar]
- 22.Boulos AS, Holden DN, Entezami P, et al. With regard to “the use of cangrelor in neurovascular interventions: a multicenter experience”. Neuroradiology 2021; 63: 829–831. [DOI] [PubMed] [Google Scholar]
- 23.King S, Short M, Harmon C. Glycoprotein IIb/IIIa inhibitors: the resurgence of tirofiban. Vascul Pharmacol 2016; 78: 10–16. [DOI] [PubMed] [Google Scholar]
- 24.Steinhubl SR, Oh JJ, Oestreich JH, et al. Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb Res 2008; 121: 527–534. [DOI] [PubMed] [Google Scholar]
- 25.Dovlatova NL, Jakubowski JA, Sugidachi A, et al. The reversible P2Y antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function. J Thromb Haemost 2008; 6: 1153–1159. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material, sj-docx-1-ine-10.1177_15910199231180003 for Multicenter comparison of antiplatelet treatment strategies for urgent/emergent neuroendovascular stenting by Devin Holden, Casey C. May, Blake T. Robbins, Aaron M. Cook, the Neurocritical Care Pharmacy Section Research Group: Sara Jung, Keaton S. Smetana, Christina Roels, Sara Schuman Harlan, Shaun Keegan, Gretchen Brophy, Sulaiman Al Mohaish, Melissa Sandler, Samantha Spetz, Kevin Wohlfarth, Jocelyn Owusu-Guha, Pamela Buschur, Elizabeth Hetrick, Keith Dombrowski, Jennifer Glover, Melissa Levesque, Spencer Dingman, Mohammed Hussain in Interventional Neuroradiology