Article Text
PDF
Abstract
Background Flow diversion (FD) is a common treatment modality for complex intracranial aneurysms. A major concern regarding the use of FD is thromboembolic events (TEE). There is debate surrounding the optimal antiplatelet regimen to prevent TEE. We aim to evaluate the safety and efficacy of ticagrelor as a single antiplatelet therapy (SAPT) for the prevention of TEE following FD for complex aneurysm treatment.
Methods A retrospective review of a prospectively maintained neuroendovascular database at three endovascular centers was performed. Patients were included if they had an intracranial aneurysm that was treated with FD between January 2018 and September 2019 and were treated with ticagrelor as SAPT. Primary outcomes included early (within 72 hours post-procedure) and late (within 6 months) ischemic events.
Results A total of 24 patients (mean age 47.7 years) with 36 aneurysms were eligible for analysis, including 15 (62.5%) females. 14 (58.3%) patients presented with subarachnoid hemorrhage. 35 aneurysms arose from the anterior circulation and 1 from the posterior circulation. 23 aneurysms had a saccular morphology, whereas 7 were fusiform and 6 were blister. For the treatment of all 36 aneurysms, 30 procedures were performed with 32 FD devices. Procedural in-stent thrombosis occurred in 2 cases and was treated with intra-arterial tirofiban without complications. Aneurysm re-bleeding was reported in 1 (4.2%) patient. There were no reported early or late TEE. Three patients discontinued ticagrelor due to systemic side effects.
Conclusion Ticagrelor is a safe and effective SAPT for the prevention of TEE after FD. Large multicenter prospective studies are warranted to validate our findings.
- flow diverter
- device
- hemorrhage
- drug
- platelets
Statistics from Altmetric.com
Introduction
Flow diversion (FD) is a new endovascular treatment approach for large and complex intracranial aneurysms.1 FD devices are self-expandable cylindrical stents composed of porous meshes that divert blood flow away from the aneurysm sac and lead to gradual thrombosis and healing of the sac, while providing a scaffold for endothelial growth across the aneurysm neck.2 Thromboembolic events (TEE) are the main concern following FD treatment. A dual antiplatelet therapy (DAPT) regimen with acetylsalicylic acid (ASA) and clopidogrel is commonly used for 3–12 months post-procedure, followed by ASA indefinitely to prevent TEE. However, there is no standardized dose or duration.3 DAPT increases the potential for hemorrhagic complications, which can be greater in patients with acutely ruptured aneurysms.4 5 In addition, resistance to both ASA and clopidogrel has been described, which is known to increase the risk of TEE. This is a significant concern in clinical practice, as clopidogrel resistance has been reported in 36.5% of patients.6 Our aim in this study is to evaluate the safety and efficacy of ticagrelor, a potent P2Y12 inhibitor with a high level of platelet inhibition and less resistance,7 as a single antiplatelet therapy (SAPT) for the prevention of TEE associated with FD for the treatment of intracranial aneurysms.
Methods
Patient selection
A retrospective review of a prospectively maintained neuroendovascular database at three endovascular centers was performed. Patients were included if they had an intracranial aneurysm treated with FD from January 2018 through September 2019 with ticagrelor as SAPT. Basic patient demographic data, aneurysm characteristics (size, morphology and location), procedural characteristics and outcomes were collected. The study was approved by the Institutional Review Board.
Endovascular procedure
All procedures were performed under general anesthesia and all patients underwent cerebral digital subtraction angiography (DSA), including three-dimensional rotational angiography to evaluate aneurysm size, shape and location to help with proper selection of FD device size and deployment. The Pipeline Embolization Device (PED; Medtronic Neurovascular, Irvine, California, USA) was used in all procedures.
Antiplatelet treatment and anticoagulation
During the procedure, an intravenous bolus dose of intravenous heparin 5000 units was administered. Patients who underwent elective FD received 3 days of ticagrelor 90 mg twice daily before the procedure followed by the same dose after the procedure. If stent placement was unplanned, an intravenous bolus of tirofiban (8.0 µg/kg) was administered for 3 min immediately before stent deployment, followed by a maintenance dose (0.10 µg/kg/min) for 24 hours. A single loading dose of ticagrelor 180 mg was then administered during the procedure after stent deployment or after the procedure 2 hours before tirofiban cessation. In case of in-stent thrombosis (IST) during the procedure, patients were given an intra-arterial bolus of tirofiban (0.5 mg diluted with 10 mL of normal saline, at a rate of 1 mL/min; the dose ranged from 0.5–1.0 mg). Ticagrelor 90 mg twice daily was continued after the loading dose as SAPT.
Outcome and follow up
The primary outcomes were the occurrence of early (within 72 hours post-procedure) and late (within 6 months) TEE following FD. Patients underwent clinical and angiographic follow-up at 6 month post-procedure to assess aneurysm occlusion.
Statistical analysis
Categorical variables were expressed as frequencies and percentages. After normality testing using Shapiro-Wilk, continuous variables were expressed as mean±SD and median for parametric and non-parametric variables, respectively. The analysis was performed using SPSS 26 software (IBM Armonk, NY, USA).
Results
A total of 24 patients were included in the study, including 15 (62.5%) females. The mean age was 47.7 years. Eight (33.3%) patients had hypertension, seven (29.2%) had diabetes mellitus, and eight (33.3%) were current smokers. All treated patients were symptomatic at presentation; 14 (58.3%) patients presented with subarachnoid hemorrhage (SAH) and 10 (41.7%) presented with mass effect from large aneurysm size. A total of 36 aneurysms were treated. Thirty-five (97.2%) aneurysms arose from the anterior circulation. Aneurysm morphology was saccular in 23 (63.9%) cases, fusiform in seven (19.4%) and blister in six (16.7%). Median (IQR) neck length and largest diameter were 5 (3–9) mm and 6 (3–24) mm, respectively (table 1).
Baseline characteristics of patients and aneurysms
Endovascular procedure
A total of 32 PEDs were deployed in 30 procedures. Twenty-three procedures were performed for primary FD (19 procedures with a single device, two procedures with adjuvant coiling, and two procedures with telescopic deployment of two PEDs). Six procedures were performed for neck remnant after coiling, and one procedure for subtotal aneurysm filling (grade B on O’Kelly-Marotta grading scale)8 after primary FD (figure 1). Bilateral FD was performed in five patients. One patient had bilateral complex aneurysms in both internal carotid arteries (ICAs); parent artery occlusion was performed on one side followed by PED implantation on the other ICA.
Patients flow chart. FD, flow diversion.
Median time from onset of SAH to treatment in cases of ruptured aneurysms was 30 days. Rescue intra-arterial tirofiban was reported in two procedures without any complications for the treatment of IST. Periprocedural loading of ticagrelor 180 mg was done in seven (23.3%) procedures.
Outcome and follow-up
There were no cases of reported intraprocedural bleeding. Aneurysm rebleeding occurred in one patient on the third day post-procedure and the patient died from hospital-acquired pneumonia. One patient experienced a transient ischemic attack (TIA) on the fourth day post-procedure and there were no ischemic lesions on brain MRI. Three patients stopped ticagrelor due to side effects; two patients developed shortness of breath and one patient developed subcutaneous bruising. All three patients transitioned to a regimen of ASA 150 mg and clopidogrel 75 mg daily.
The median length of follow-up was 12 (6–12) months. At 6 month follow-up, angiography showed complete occlusion in 31 (91.2%) aneurysms (figure 2) and subtotal filling in three (8.8%) aneurysms. One of these three aneurysms required retreatment at a 1 year follow-up with another PED, and the rest will be managed according to 1 year follow-up angiography as well. One patient was lost to follow-up (table 2).
Procedural characteristics and treatment outcome
Digital subtraction angiography (DSA)—lateral view (A), anterior-posterior view (B), and three-dimensional image (C)—showing a giant right posterior communicating artery aneurysm. Roadmap (D) shows the microcatheter over the microwire navigating through the aneurysm sac for stable positioning of the Pipeline Embolization Device (PED) delivery system across the aneurysm neck (E). DSA at 6 month follow-up shows complete aneurysm occlusion (F).
Discussion
The present study demonstrated the safety and efficacy of ticagrelor as SAPT in the prevention of TEE after FD using PED. DAPT with aspirin and clopidogrel is often utilized to prevent TEE in clinical practice, but in fact, cases of TEE persist. ASA acts through inhibition of platelet cyclooxygenase, leading to irreversible inhibition of platelet-dependent thromboxane.9 Clopidogrel is a pro‐drug metabolized by cytochrome P450 in the liver to produce the active metabolite, which irreversibly blocks the P2Y12receptor on the platelet surface.10 Aspirin may have an unpredictable antiplatelet response,11 while approximately 36% of patients taking clopidogrel exhibit antiplatelet resistance due to variable response in CYP2C19 heterozygotes.6
Hemorrhagic complications are common with FD for acutely ruptured intracranial aneurysms,12 particularly in cases where shunt placement may be necessary.4 5 As such, the increased bleeding risks associated with DAPT cannot be ignored. Moreover, several studies13 14 reported the effect of aspirin on delaying the rate of endothelial cell production. This issue is of particular concern as FD devices have a high metal density that increases the risk of TEE, and it has been described that early endothelialization over the intravascular stents reduces the risk of thrombus formation.15 Therefore, there may be practical benefits of a new antiplatelet drug without the aforementioned disadvantages. Several studies reported the efficacy and safety of the newer anti-aggregation drugs such as ticagrelor and prasugrel as an alternative to clopidogrel in combination with ASA in the prevention of TEE16 17; however, the addition of ASA to a potent P2Y12 receptor blocker such as ticagrelor has been reported to produce effects secondary to inhibition of cyclooxygenase at non-platelet sites, increasing side effects without providing additional antithrombotic activity.18 19
To the best of our knowledge, this is the first study to evaluate the safety and efficacy of ticagrelor as SAPT after deployment of the currently approved PED. Manning et al 20 reported the safety of ASA as SAPT in patients with acutely ruptured intracranial aneurysm treated with the off-label Pipeline Shield Device (Medtronic Neurovascular, Irvine, California, USA), which contains phosphorylcholine—a major constituent of red blood cell membranes—covalently bound to the braid wires and reducing platelet adhesion and activation21; they reported 7.1% treatment-related morbidity and 7.1% treatment-related death. The present study demonstrated the safety of ticagrelor as SAPT after PED treatment in acutely ruptured and symptomatic unruptured intracranial aneurysms, as well as the efficacy of tirofiban—a direct glycoprotein IIb/IIIa antagonist—in the prevention and treatment of acute IST after device deployment, which is in line with previously reported studies.22
TEE associated with FD is often related to fusiform aneurysm morphology and the deployment of multiple FD devices.23 24 Burrows et al 25 reported 28% perioperative clinical events, of which 6.5% were due to thromboembolism and access site complications. The International Retrospective Study of the Pipeline Embolization Device reported 4.5% TEE and 2.5% intraparenchymal hemorrhage.26 However, 91% of treated aneurysms were unruptured and treatment-related complications increased to 18% in cases of ruptured aneurysms.12 Our study found a low rate of IST (6.7%) despite including patients with variable aneurysm characteristics and patients requiring PED deployment in a telescopic fashion, and all cases of IST were successfully treated with rescue intra-arterial tirofiban. Furthermore, we reported a low complication rate with one (4.2%) patient experiencing aneurysmal rebleed.
Posterior circulation and middle cerebral artery aneurysms showed a higher incidence of TEE after FD than ICA aneurysms due to the risk of perforator infarction secondary to reduced flow and perforator occlusion.23 Moreover, a meta-analysis27 of outcomes after FD for posterior circulation non-saccular aneurysms reported TEE in 23% which caused the majority of all-cause morbidity. The low rate of TEE in our study might be related to the fact that 94.4% of the aneurysms arose from ICA with a low risk of perforator infarction.
SAPT with ticagrelor appears to be well tolerated in our study. Only three (12.5%) patients switched to another regimen; two patients reported dyspnea and one patient experienced subcutaneous bruising. Previous studies28 showed an 11.6% incidence of ticagrelor-related dyspnea leading to drug discontinuation, while others demonstrated that most of the ticagrelor-related dyspnea was mild. Improved education of patients and physicians is warranted to reduce the rate of drug withdrawal.29
The primary limitations of this study are the retrospective design and the relatively small sample size, with only 24 patients and 30 procedures included. Ticagrelor can be cost-prohibitive compared with alternative antiplatelet medications, which directly impacted patient inclusion at our study sites. An additional limitation of this study, which potentially affects the generalizability of the findings, is that the majority of aneurysms included in our analysis were located in the ICA with a lower chance of device deployment over a perforator. Furthermore, there was no follow-up MRI that could detect silent thromboembolic lesions.
Conclusion
Ticagrelor is a safe and effective SAPT for the prevention of TEE after FD device implantation for the treatment of complex intracranial aneurysms. Large multicenter prospective studies are warranted to validate our findings.
References
Footnotes
Contributors MHM: design of the work, acquisition of data, interpretation of data, drafting of the manuscript. SWE, CJS, EK, AS, AH: critical revision of the manuscript. AE: study conception, design of the work, acquisition of data, interpretation of data, drafting of the manuscript. All authors gave final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval IRB obtained through Aswan University, ASU44116.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. The unpublished data from this dataset is held by MHM/AE. Requests for data sharing would be required to be discussed with them directly.