Background Flow diverters (FDs) result in high occlusion rates of aneurysms located distally to the carotid artery. However, the complications reported are not negligible. New modified surface FDs have low thrombogenic properties that may reduce ischemic complications related to the treatment. In addition, a modified surface FD may allow for the use of a single antiplatelet medication to reduce hemorrhagic risk during the procedure. The aim of this study was to assess the safety and efficacy of the p48 MW HPC (phenox, Bochum, Germany) to treat distal intracranial aneurysms under the use of aspirin monotherapy.
Methods The primary endpoint was the incidence of any neurologic deficit after treatment after 6 months of follow-up. The secondary endpoint was the rate of the complete occlusion of the aneurysms at the 6-month follow-up. Enrollment of 20 patients was planned, but after inclusion of seven patients the study was stopped due to safety issues.
Results Seven patients with eight aneurysms were included. Among the seven patients, three (42.8%) had ischemic complications on the second day after FD deployment. Two patients experienced complete recovery at discharge (National Institutes of Health Stroke Scale (NIHSS) score=0), while one patient maintained mild dysarthria at discharge (NIHSS score=1) which improved after 6 months (NIHSS score=0). All three patients had no new symptoms during the 6-month follow-up. Complete aneurysm occlusion occurred in six (75%) of the eight aneurysms at the 6-month follow-up.
Conclusions Antiplatelet monotherapy with aspirin for the treatment of distal intracranial aneurysms with this modified surface FD resulted in a significant incidence of ischemic complications after treatment.
- intracranial aneurysm
- flow diverter
Data availability statement
Unpublished or unprocessed data, protocols, or images are available upon request from the corresponding author.
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Flow diverter devices (FDs) have revolutionized the treatment of intracranial aneurysms by applying the concept of remodeling the wall of parent arteries harboring aneurysms.1 2 As observed with aneurysms in the carotid axis, aneurysms located distally have high occlusion rates with FDs; however, the complications are not negligible.3–16 New flow diversion technologies have been developed following the principle of improving aneurysm occlusion rates while reducing complication rates. FDs with modified surface technologies have low thrombogenic properties, which may reduce ischemic complications related to the procedures.17–23 In addition, a modified surface FD may allow the use of a single antiplatelet medication to reduce the hemorrhagic risks of the procedures.24–27
The aim of the present pilot trial was to assess the safety and efficacy of the p48 MW HPC FD (phenox, Bochum, Germany) to treat distal intracranial aneurysms under the use of aspirin monotherapy.
This was a single-center, prospective, pivotal, open, single-arm study. This paper was prepared applying recommendations from the CONSORT statement. The study protocol was registered with the institutional ethics committee on February 15, 2018 (number CAAE 90940518.2.0000.5440), and a second version (February 14, 2019) of the study protocol was approved by the Institutional Review Board on February 18, 2019 (advice number 3.151.435). Enrollment of 20 patients presenting with unruptured intracranial aneurysms was planned. In November 2019, after inclusion of seven patients, the study was halted due to safety issues.
Before enrollment in this study, all patients were first evaluated in a multidisciplinary meeting when endovascular treatment was indicated. All patients read and signed the informed consent before inclusion and treatment. The inclusion criteria were age 18–80 years; unruptured aneurysms measuring ≥3 mm in diameter; neck diameter ≥3 mm or dome/neck ratio ≤2; aneurysm located in the anterior, middle or posterior cerebral arteries; baseline modified Rankin Scale (mRS) score ≤3; and signed informed consent. The exclusion criteria were any stroke in the last 3 months; ruptured aneurysm in the last 3 months; known irreversible bleeding disorder; use of anticoagulants; known platelet dysfunction or a platelet count of <100 000 cells/mm3; past adverse reaction to prasugrel or heparin; known contrast allergy; pregnancy or breastfeeding; kidney disease (creatinine >2.5 mg/dL); baseline mRS score ≥4; life expectancy <12 months; prior stent implanted in the target vessel; and/or the patient refused to sign the informed consent.
Patients were evaluated before and after treatment by means of the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) by a certified neurologist. All patients received aspirin 100 mg/day for 7 days before treatment. On the day of the procedure, all patients were tested using the ARU-Test by the VerifyNow System (Accriva Diagnostics, California, USA). An ARU-Test <550 was considered the therapeutic goal for aspirin. If a patient had an ARU-Test ≥550, a dose of aspirin 500 mg was indicated before the procedure and the ARU-Test was repeated after 2 hours.
All patients underwent general anesthesia. The femoral artery was punctured using 6F short sheaths and, after the puncture, an intravenous unfractionated heparin bolus of 80–100 IU/kg was infused to maintain an activated clotting time >250 s. A 6F guiding catheter was used to catheterize the target carotid. Digital subtraction angiography (DSA) with 3D acquisition was performed before and after the procedure. A 0.021 inch microcatheter (Rebar-Medtronic or Headway-Microvention) was used with a 0.014 inch wire (Avigo-Medtronic or Traxcess-Microvention). The p48 MW HPC FD was used for all cases. Adjunctive use of coiling was allowed. Balloon remodeling was allowed to assist coiling or to properly expand the p48 device, if necessary. Then, 15 min after implantation of the device, a new DSA acquisition was performed to check for the occurrence of potential thrombus formation inside the device. All patients were monitored for 96 hours (4 days) in the intensive care unit. A neurologic deficit was defined as any sudden deficit resulting in a NIHSS score ≥1.
The protocol for any new neurologic symptoms after the procedure included a prompt examination combining a CT scan of the brain and CT angiography (CTA). In the absence of hemorrhage, patients promptly received an intravenous antiplatelet drug (tirofiban 10 µg/kg IV for 3 min followed by 0.15 µg/kg/min for 5 hours) and prasugrel 30 mg (single dose) followed by 5–10 mg/day for 6 months. If no arterial flow in the territory of the parent artery harboring the aneurysm was observed on the CTA, the patient was immediately referred to the angiosuite for a potential thrombectomy by aspiration.
After discharge all patients were monitored by telephone for any adverse events. The patients returned to the hospital after 1 and 6 months for a neurologic examination and after 6 months for a DSA. Complete aneurysm occlusion was defined as grade D on the O'Kelly–Marotta grading scale. DSA was assessed by two interventional neurologists.
The primary (safety) endpoint was the incidence of any neurologic deficit after treatment during 6 months of follow-up. The secondary (efficacy) endpoint was the incidence of complete occlusion of aneurysms at the 6-month follow-up.
Seven patients with eight aneurysms were included. The mean (SD) age was 54.1 (10) years. Tables 1 and 2 summarize the baseline (Table 1) and treatment data (Table 2) and the results are summarized in table 3.
Among the seven patients, three (42.8%) developed ischemic complications during day 2 after FD deployment. Patient 3 presented 30 hours after treatment with left brachial paresis and dysarthria (NIHSS score=4) which resolved after 10 min. This patient received tirofiban and prasugrel. The patient had no new symptoms and was discharged 4 days after treatment. Patient 5 presented 29 hours after treatment with left hemiplegia, gaze deviation to the right, and dysarthria (NIHSS score=15) which spontaneously resolved after 30 min; tirofiban and prasugrel were indicated. This patient had no new symptoms and was discharged 4 days later. Despite a good neurologic recovery, patients 3 and 5 had ischemic lesions associated with the M1 perforators covered by the device on MRI (figure 1).
Patient 7 presented 29 hours after treatment with left hemiplegia, gaze deviation to the right, and severe dysarthria (NIHSS score=18). This patient had a normal CT and an occlusion of the right M1 on CTA. Tirofiban and prasugrel were indicated. The patient was promptly taken to the angiosuite. DSA showed complete recanalization of the right MCA and complete occlusion of the aneurysm and the frontal branch emerging from the aneurysm. Thrombectomy was not indicated. The patient had significant improvement of the deficits (NIHSS score=5 after 24 hours) and was discharged 4 days later with mild dysarthria (NIHSS score=1). However, the frontal M2 branch emerging from the aneurysm remained occluded and resulted in an insular-frontal infarction.
After the enrollment of seven patients in this study, three ischemic complications occurred. The other four patients who presented with no complications were contacted and received prasugrel in addition to aspirin.
Complete aneurysm occlusion occurred in six (75%) of the eight aneurysms at the 6-month follow-up.
Despite the impact of FD on the treatment of intracranial aneurysms during the last decade, FDs have a non-negligible rate of complications of approximately 4–7%.1 2 27 The main neurologic complications during the treatment of intracranial aneurysms with FDs are ischemic and/or hemorrhagic complications. Compared with hemorrhagic complications, ischemic complications after FDs usually result in less morbidity and mortality.1 2 27 In general, ischemic complication rates associated with FDs have been reported to be twice the rates of hemorrhagic complications (6.6% vs 3.0%).27
The present pilot study was designed as a proof-of-concept study aiming to reduce the complications of FDs in the treatment of distal aneurysms. The use of a hypothrombogenic surface FD (p48 MW HPC) would reduce ischemic complications while the use of aspirin monotherapy would reduce hemorrhagic complications. From a clinical point of view, an FD capable of being safely implanted under aspirin alone would reduce the risks of hemorrhage during treatment for diverse conditions such as ruptured aneurysms, dissecting aneurysms, unruptured aneurysms in old patients or in patients with a high risk of hemorrhage due to any cause.
However, in this pilot study, antiplatelet monotherapy with aspirin could not prevent thrombus formation inside the FDs in 42.8% of cases. Interestingly, it was observed that all three cases in whom complications developed had symptoms between 24 and 30 hours after FD implant placement, and two cases did not have complete occlusion of the FD but did have occlusion of M1 perforators by a thrombus lamina under the FD surface. Only one case had complete occlusion of the FD, and all three cases recanalized with tirofiban and did not require thromboaspiration using large-bore catheters. The delay in thrombus formation, as well as only partial occlusions of the FD, indicated the low thrombogenic property of the p48 MW HPC device, which is in accordance with previous studies on hydrophilic polymer coating (HPC) technology.17–23 The low thrombogenic properties of the HPC have previously been shown by in vitro19 and in vivo bench studies.17 18 20 However, it was not sufficient to prevent thrombosis under the use of aspirin alone.
Failure to prove the safety of the FD under aspirin monotherapy in this study was due to three main reasons. First, the HPC was not sufficient to prevent in-stent thrombosis under the use of aspirin alone, and improvements in the coating are needed for this purpose. Second, antiplatelet inhibition by aspirin based on ARU <550 cannot guarantee total protection against thrombosis of the p48 MW HPC device regardless of its proven low thrombogenic properties. Third, the device is designed for aneurysms distal to the carotid artery, where arteries are smaller in diameter. In addition, in distal arteries the FD will often cover perforators or cortical arterial branches, which may increase the risk of ischemic complications compared with FDs implanted in the carotid axis.
Regarding the aspirin protocol in this study, a low dose of 100 mg/day was indicated. Of the seven patients, six had favorable ARU tests (<550) and only one patient needed a 500 mg dose of aspirin followed by 300 mg/day to achieve an ARU <550. In this study, similar to previous studies, the aspirin effect was defined as a cut-off ARU <550. However, it is unlikely that higher aspirin doses and lower ARU values could reduce the thrombogenic complications. In a systematic review of FDs and antiplatelet therapies which included 28 studies and 1556 patients treated with FDs under dual antiplatelet therapy, the authors found no statistical association between thromboembolic events in patients who received low doses of aspirin (81–150 mg) and those who received high doses of aspirin (300–325 mg) (9.4% vs 8.1%, respectively; p=0.32). Moreover, patients who received low versus high doses of aspirin had a trend for fewer hemorrhagic events (0.7% vs 3.3%, respectively; p=0.053).27 In addition, previous studies on the antiplatelet effect of aspirin showed that even low doses of aspirin are effective and that aspirin resistance is more a laboratory finding than a clinical issue.28 29 Therefore, based on the data available, a study using higher doses of aspirin as a monotherapy during FD treatment would be expected to increase the general hemorrhagic risks rather than reduce the ischemic complications. Moreover, high doses of aspirin of 300–500 mg/day may not be tolerated by some of the patients. Discontinuation of aspirin after myocardial infarction has been reported by 35% of patients.30
This study has the limitations of a small case series without a control group. As only small intracranial aneurysms located in small distal intracranial arteries were included, the results of this study cannot be extrapolated to aneurysms located in the carotid or vertebral arteries.
Antiplatelet monotherapy with aspirin for the treatment of distal intracranial aneurysms with this modified surface FD resulted in a significant incidence of ischemic complications after treatment. During treatment of distal intracranial aneurysms, even when using this specific low thrombogenic modified surface FD, the use of aspirin as a single antiplatelet medication should be avoided.
Data availability statement
Unpublished or unprocessed data, protocols, or images are available upon request from the corresponding author.
Patient consent for publication
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Correction notice This article has been corrected since it first published. The provenance and peer review statement has been included.
Contributors LHdC-A: conception of the study, drafting and approval of the manuscript. GSN, TGA, LMM, and RKF: data acquisition, figures and tables, revision and final approval of the manuscript. DGA: conception of the study, data acquisition, critical revision of the manuscript and approval of the final work.
Funding The entire study was conducted in the context of the clinical care practice of our Institution. The manufacturer phenox GmbH (Bochum, Germany) supported the study by providing all p48 MW HPC devices, prasugrel and VerifyNow tests used in the study. However, phenox GmbH did not participate in any data collection, management, analysis, interpretation or reporting of results. phenox did not have any authority regarding the decision to publish the results obtained by the coordination center. The coordination center was solely responsible for all data collection, registration, analysis, interpretation and publication of the manuscript.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.