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Abstract
Background Flow diverters (FDs) are effective in the treatment of carotid aneurysms. Compared with carotid aneurysms, the treatment of distal intracranial aneurysms with FDs has been associated with a relatively high incidence of complications. Low thrombogenic modified-surface FDs may reduce ischemic complications and allow for the use of a single antiplatelet medication. The aim of this study was to assess the safety and efficacy of the p48 MW HPC Flow Modulation Device (Phenox GmbH, Bochum, Germany) to treat distal intracranial aneurysms used in combination with prasugrel monotherapy.
Methods This was a single-center, prospective, pivotal, open, single-arm study. Patients were included in this study from December 2019 to September 2020. The primary endpoints were the incidence of any neurologic deficit after treatment until 1 month of follow-up, defined as National Institutes of Health Stroke Scale (NIHSS) ≥1, and the incidence of acute ischemic lesions in magnetic resonance imagin (MRI) images 48 hours after treatment. The secondary endpoint was the rate of complete occlusion of the aneurysms at the 1-month follow-up.
Results Twenty-one patients harboring 27 distal aneurysms of the anterior circulation were included. Mean age was 57.8 (SD 9.7) years, and 16 patients were female (80%). No patient had neurologic symptoms at the 1-month follow-up. Four patients (20%) had asymptomatic acute brain ischemic lesions on MRI. Complete aneurysm occlusion occurred in 9/27 (33.3%) aneurysms at the 1-month follow-up.
Conclusion In this pilot safety trial, treatment of distal intracranial aneurysms with p48 MW HPC under monotherapy with prasugrel appeared to be safe.
- aneurysm
- flow diverter
Data availability statement
Unpublished or unprocessed data, protocols and images are available upon request from the corresponding author.
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Introduction
Flow diverter devices (FDs) have revolutionized the treatment of carotid aneurysms.1 However, the results of FDs observed in carotid aneurysms have not been translated to distal intracranial aneurysms. Although the treatment of distal intracranial aneurysms with FDs results in high occlusion rates, relatively high complication rates have been reported compared with carotid aneurysms.2–12 Focusing on reducing the complications of FD, scientific boundaries on safety have been explored. FDs with modified surfaces have low thrombogenic features, which may reduce ischemic complications and allow for the use of a single antiplatelet medication.13–21 In parallel, the antiplatelets prasugrel and ticagrelor have emerged as promising drugs in the context of FD treatments.22–27
The aim of the present pilot trial was to assess the safety and efficacy of the p48 MW HPC Flow Modulation Device (Phenox GmbH, Bochum, Germany) in the treatment of unruptured distal intracranial aneurysms used in combination with prasugrel monotherapy.
Methods
This was a single-center, prospective, pivotal, open, single-arm study. This article was prepared accordingly to recommendations in 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). Twenty-one consecutive patients presenting with unruptured intracranial aneurysms were enrolled in this study from December 2019 to September 2020 in a single University Hospital.
Before enrollment in this study, all patients were first evaluated in a multidisciplinary meeting when endovascular treatment was indicated. All patients read and signed informed consent before inclusion and treatment. The inclusion criteria were aged between 18 and 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) ≤3; and patient signed the informed consent form. 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 <1 00 000 cell/mm3; past adverse reaction to prasugrel or heparin; known contrast allergy; pregnancy or breastfeeding; kidney disease (creatinine >2.5 mg/dL); baseline mRS ≥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 prasugrel 5 mg or 10 mg/daily for 7 days before the treatment until 6 months after treatment. Prasugrel 5 mg/daily was indicated for patients presenting aged >75 years, body weight <60 kg, or any previous stroke. Patients who, for any reason, could not initiate prasugrel 7 days before the treatment received a dose of prasugrel 30 mg before the procedure, and the Platelet Reaction Units (PRU) test was done after 2 hours. On the day of the procedure, all patients were tested using the PRU test by the VerifyNow System (Accriva Diagnostics, CA, USA). A PRU test ≤180 was considered the therapeutic goal for prasugrel. If a patient had a PRU test ≥180, a dose of prasugrel 30 mg was indicated before the procedure, and the PRU test was repeated after 2 hours. Patients who had a PRU test ≥180 and necessitated a prasugrel attack after the procedure had their prasugrel doses increased to 10 mg for those patients who had taken 5 mg before the test, or 15 mg for those patients who had taken 10 mg before the test.
All patients underwent general anesthesia. The femoral or radial artery was punctured using 6F short sheaths, and after puncture, an intravenous unfractionated heparin bolus of 80–100 UI/kg was infused to maintain an activated clotting time >250 s. A 6F guiding catheter was used to catheterize the target vessel. Digital-subtracted angiography (DSA) with 3D acquisition was performed before and after the procedure. A 0.021-inch microcatheter (Rebar-Medtronic) was used with a 0.014-inch wire (Avigo-Medtronic). A flow diverter p48 MW HPC (Phenox) 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. As a routine safety protocol, a new DSA acquisition was performed 15 min after treatment to check for the occurrence of potential acute thrombus formation inside the devices. All patients were monitored for 96 hours (4 days) in the intensive care unit (ICU). 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 computed tomography (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 intravenous for 3 min, followed by 0.15 µg/kg/min for 5 hours) and aspirin 500 mg (single dose) followed by 100 mg/day for 6 months. If no arterial flow in the territory of the parent artery harboring the aneurysm was observed on CTA, the patient was immediately referred to the angiosuite for a potential thrombectomy.
Magnetic resonance imaging (MRI) was performed in the first 48 hours after treatment to assess ischemic events and vessel patency. After discharge, all patients were monitored by telephone for any adverse events. The patients returned to the hospital after 1 month for a neurologic examination and DSA. Complete aneurysm occlusion was defined as grade D on the O'Kelly–Marotta grading scale. DSA was assessed by two interventional neuroradiologists.
Endpoints
The primary (safety) endpoints were the absence of any new neurologic symptoms after treatment until the 1-month follow-up and the absence of any acute ischemic lesion on MRI after treatment. The secondary (efficacy) endpoint was the incidence of complete occlusion of aneurysms 1 month after treatment.
Data collection and monitoring, sample size and statistical analysis
All clinical, laboratory, and imaging data were registered by two collaborators. All image data, including DSA, MRI, and follow-up DSA, were anonymized and kept in the electronic database. A pilot sample of 20 patients was chosen to test primary safety endpoints. The upper prespecified limit for the primary endpoint of any neurologic symptom (NIHSS ≥1) was one case (<5%) of new neurologic symptoms after treatment. The upper prespecified limit for the primary endpoint of new ischemic brain lesions on MRI was 50% (10 patients). Categorical variables were described as percentages, and continuous variables were described as the means, range, SD, median, range, and IQR. STATA/IC version 16.1 (StataCorp, College Station TX, USA) was used for statistical analysis, and P values <0.05 were considered significant.
Results
A total of 22 consecutive patients presenting distal intracranial aneurysms were evaluated to be included in this study. One patient was excluded because he had a fusiform aneurysm associated with a tortuous P2 segment of a right posterior cerebral artery that prevented catheterization with a 0.021 microcatheter. A total of 21 patients harboring 27 distal aneurysms of the anterior circulation were included.
The primary safety endpoint of the absence of any neurologic symptoms from the treatment to the 1-month follow-up was achieved in all 21 patients (100%). One patient refused to undergo MRI posttreatment. Therefore, among 20 patients, 16 (80%) had no ischemic lesions by MRI 48 hours after treatment, while four patients (20%) had asymptomatic ischemic lesions. A binary logistic regression analysis was performed to find any baseline variables associated with the primary endpoint. Age was the only predictor of ischemic lesions on MRI after treatment (OR 1.44, 95% CI 0.99 to 2.09, P=0.051). Each year of age increased the risk of silent ischemic lesions on MRI by 1.44 times after treatment.
The secondary endpoint of complete aneurysm occlusion at the 1-month follow-up was observed in 9/27 aneurysms (33.3%). The logistic regression analysis showed that only adjunctive coiling was a predictor for complete occlusion of the aneurysm at the 1-month follow-up (OR 13.6, 95% CI 1.22 to 151.0, P=0.034). Performing coiling in addition to FD implantation increased the chance of complete aneurysm occlusion by 13.6 times after 1 month.
Tables 1–3 summarize the clinical, imaging, procedure, in-hospital, and 1-month follow-up data, respectively. There was no need of balloon angioplasty to assist p48 deployment, no case of p48 twist, no thrombus into the p48, no need of intravenous antiplatelet infusion, or thrombectomy. No patient had a new neurologic symptom, or serious adverse events after treatment, at discharge, or during the 30 days of follow-up. Most of the patients included in this study had both a baseline NIHSS and mRS 0, that remained unchanged until 30 days after treatment. However, three patients had a baseline mRS 1 or 2 (patients 6, 8, and 10), that also remained unchanged during the follow-up.
Patients’ baseline clinical data (n=21 patients, 27 aneurysms)
Baseline imaging data (n=21 patients, 27 aneurysms)
Treatment data and follow-up (n=21 patients, 27 aneurysms)
Online supplemental tables 4–10 summarize all individual data collected in this study. Figures 1 and 2 exemplify four cases treated and included in this study of aneurysms located in the anterior communicating artery, anterior cerebral artery, M1 segment of the middle cerebral artery (MCA), and bifurcation of the MCA.
Supplemental material
(A) Digital-subtracted angiography (DSA) of previously coiled and recanalized anterior communicating artery aneurysm, (B) X-ray showing the p48 MW HPC device implanted from A1 to A2 segment, and (C) a non-subtracted angiography after treatment. (D) DSA of a pericallosal aneurysm, (E) X-ray showing a smooth cast of coils in the aneurysm and a p48 MW HPC device implanted in the pericallosal artery, and (F) a non-subtracted angiography after treatment.
(A) Digital-subtracted angiography (DSA showing an aneurysm in the M1 segment of the middle cerebral artery (MCA), (B) X-ray showing the p48 MW HPC device implanted in the M1, and (C) a non-subtracted angiography after treatment. (D) DSA showing an aneurysm located in the MCA bifurcation, (E) X-ray showing a p48 MW HPC device implanted in the M1-M2 transition, and (F) a non-subtracted angiography after treatment.
Discussion
In this single-arm trial, the results on the safety of flow diversion in the treatment of unruptured distal intracranial aneurysms used in combination with prasugrel monotherapy were very encouraging. Aiming to increase the sensitivity of the methods assessing the safety endpoints, the incidence of any neurologic symptoms, defined by NIHSS ≥1, or the incidence of any acute ischemic brain lesions by MRI were applied as clinical and imaging tools, respectively. The primary safety endpoints showed that 100% of patients had no neurologic symptoms, which was in accordance with the upper prespecified limit for neurologic symptoms after treatment of one case (<5%). In addition, the second primary safety endpoint showed an incidence of 20% of silent ischemic lesions on MRI, which was in accordance with the upper prespecified limit of 50% of acute ischemic lesions.
The literature on FDs in the treatment of distal intracranial aneurysms was recently reviewed by Cagnazzo et al in a meta-analysis that showed a rate of complete aneurysm occlusion of 83% within 1 year of follow-up.11 12 However, this high occlusion rate was accompanied by a high complication rate of 12.5%. Of these complications, 6.7% were reported as transient and 5.4% as permanent. The mortality rate was 2.2%, and the rate of good neurologic outcome was 97%. Among complications, 5.9% were early complications, while 6.5% were delayed complications. Regarding ischemic or hemorrhagic complications, the rates were 9.9% and 2.6%, respectively. The most common complication was ischemia, and two variables were found to be independent predictors of ischemic complications after FD in the treatment of distal intracranial aneurysms. The middle cerebral artery (MCA) location (odds ratio (OR) = 1.8, P=0.02) and larger aneurysms (≥10 mm) (OR=2.2, P=0.03). Complications were observed in 14.6% of MCA aneurysms.11 12
Although the first generations of FDs were effective, significantly high complication rates were observed in the distal circulation, especially with larger aneurysms or in aneurysms located in the MCA bifurcations. The new FDs designed to be used in small intracranial arteries may overcome the complication risks of previous generations of FD. The FD evaluated in the present study, p48 MW HPC (Phenox), is a low-profile FD capable of being used with 0.021-inch catheters, with a hydrophilic polymer coating (HPC), a glycan-based multilayer polymer with low thrombogenic properties.13–21 Small case series reported results of p48 MW HPC under prasugrel monotherapy in the treatment of intracranial aneurysms. In a series of eight ruptured aneurysms treated with p48 MW HPC, six patients were treated with aspirin, while two patients were treated with prasugrel monotherapy. Of the five patients receiving aspirin, three received double antiplatelet therapy (DAPT) after treatment. The two patients prescribed prasugrel did not change to DAPT after treatment. The authors reported no case of rebleeding but observed thrombus formation inside the FD in 50% of the cases.17 Another retrospective study assessed p48 and p64 HPC devices in the treatment of seven patients with acute ruptured aneurysms. The authors used single antiplatelet therapy with aspirin, and they reported no rebleeding but an M2 acute occlusion that required thrombectomy.20 In another series including five unruptured distal intracranial aneurysms treated with p48 MW HPC under prasugrel monotherapy, the authors reported only one case (25%) of minor subarachnoid hemorrhage.21
Other studies have also investigated the use of single antiplatelet regimens during the treatment of diverse intracranial aneurysms with a Pipeline Embolization Device (PED).23 25 27 Most of the cases reported in these studies were ruptured aneurysms treated with PED under aspirin, prasugrel, or ticagrelor. In a small case series of nine patients presenting with ruptured blister-like aneurysms treated with PED under prasugrel monotherapy, the authors reported no complications indicating promising outcomes with prasugrel even for ruptured aneurysms.23 In another series of 14 patients presenting with ruptured aneurysms treated with PED under aspirin monotherapy, the authors reported an incidence of treatment-related morbimortality of 14.2% (2/14 patients). Interestingly, a significant incidence of hemorrhagic complications occurred when heparin was associated with aspirin.27 Another study assessed the outcomes of 24 patients with both ruptured or unruptured aneurysms treated with PED using ticagrelor.25 The authors reported an incidence of 8.3% of in-stent thrombosis and 4.2% of aneurysm rebleeding. Three patients (12.5%) did not tolerate the use of ticagrelor after treatment because of the side effects of the drug. The majority of previous studies assessed outcomes of FD in the treatment of ruptured carotid aneurysms under the use of a single antiplatelet regimen, which was different from the present trial.
The incidence of acute silent brain lesions by MRI has been assessed as a surrogate safety endpoint for diverse neurointerventional procedures. The incidence of ischemic brain lesions has been reported to be 9% to 23% after diagnostic digital angiography,28–30 37% after carotid angioplasty stenting,31 45% after aneurysm simple coiling, 44% after balloon-assisted coiling, 43% after stent-assisted coiling, and 67% after flow diversion.32 Recent studies assessing modified surface FDs in the treatment of intracranial aneurysms showed low rates of ischemic brain lesions on MRI compared with a previous meta-analysis.32–34 Pikis et al showed acute silent ischemic brain lesions on MRI in 6/33 (18.1%) patients who were treated with the PED shield.33 In another study assessing the p64 HPC device in the treatment of intracranial aneurysms, Petrov et al showed silent ischemic lesions in 4/29 (13.8%) patients.34 Despite the small samples analyzed,33 34 both studies resulted in rates at least three times lower than the previous 67% of ischemic lesions after the first generation of FDs reported in a systematic review.32 It is important to observe that unlike the present trial, the majority of previous studies assessing ischemic lesions on MRI after FD included aneurysms in the carotid axis and patients under double antiplatelet medications.32–34
The incidence of 20% of acute ischemic lesions after FD observed in the present trial was remarkable. First, because of the use of a single antiplatelet medication in contrast with the known safety standard double antiplatelet regimens. Second, FDs for distal aneurysms lead to a higher metal density over small caliber parent arteries but often cover perforators or cortical branches. Third, because 59% of the aneurysms treated in this trial were located in the MCA bifurcation, a type of aneurysm strongly associated with ischemic complications after treatment with FDs.11 12 Interestingly, in the present trial, 16/27 aneurysms (59%) were located in the MCA bifurcation, but only two cases (12.5%) had ischemic lesions.
The good safety outcomes obtained in the present trial may be explained by some factors, such as the known low thrombogenic property of the HPC,13–21 the low profile of the FD allowing for easy and fast delivery of FD that avoids time-consuming delivery maneuvers, and the efficacy of prasugrel itself, which is superior to aspirin or clopidogrel.26 In addition, the prasugrel effect was confirmed by a rapid platelet function test, in the concept of tailored medication. Most of the previous clinical studies on FDs indicated aspirin and clopidogrel without any platelet function test. However, whether different modified-surface FDs in combination with different antiplatelet regimens would result in similar or superior outcomes has to be demonstrated by future large and comparative trials.
Complete aneurysm occlusion, the secondary endpoint, was observed in one-third of cases (9/27 aneurysms), which was expected after a short-term angiographic follow-up and was in accordance with previous reports.1 11 12 An occlusion rate above 80% is expected after a long-term follow-up of 12 months.
This trial has the limitations of a small single-arm study without a comparative group. Although the data collected in this study were checked by two raters, the data were analyzed by local raters and not by an independent laboratory. As only distal intracranial aneurysms in the anterior circulation were included, the results of this study cannot be extrapolated to aneurysms located in the carotid axis or in the posterior circulation.
Conclusion
In this pilot safety trial, treatment of distal intracranial aneurysms with p48 MW HPC under monotherapy with prasugrel appeared to be safe. Large comparative studies are needed to confirm this finding and to compare prasugrel with standard double-antiplatelet regimens for the treatment of intracranial aneurysms.
Data availability statement
Unpublished or unprocessed data, protocols and images are available upon request from the corresponding author.
Ethics statements
References
Supplementary materials
Supplementary Data
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Footnotes
Twitter @GNakiri, @neuroabud
Contributors LHdC-A participated in study conception, and drafting and approval of the manuscript. GSN, TGA, LMM, RKF, RSdO, BOC, and ACdS participated in data acquisition, figure/table editing, revision of the manuscript, and final approval. DGA participated in study conception, data acquisition, critical revision of the manuscript, and approval of the final work.
Funding Regarding funding sources, the entire study was conducted in the context of clinical care practice of our Institution. The manufacturer phenox BmbH (Bochum-Germany) supported the study providing all devices p48 MW HPC, prasugrel and VerifyNow tests used in this study. However, the phenox BmbH did not participated in any data collection, management, analysis, interpretation or report results. The phenox did not have any authority regarding decision to publish the results obtained by the coordination center. The coordination center was the sole responsible for all data collection, register, analysis, interpretation and publication of the manuscript.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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