Article Text
Abstract
Background This study reports a multicenter experience of using hydrophilic polymer-coated (HPC) flow diverters with prasugrel single antiplatelet therapy to treat ruptured aneurysms with subarachnoid hemorrhage (SAH).
Methods Patients treated for intracranial aneurysms within 30 days after SAH with a p64/p48 MW HPC flow diverter were prospectively identified. Clinical presentation and outcomes, periprocedural and postprocedural complications, and degree of occlusion at follow-up were evaluated.
Results A total of 84 patients were treated in 88 sessions (54.5% women; mean age 53.3 years). Four patients (4.7%) experienced flow diverter-dependent complications. No cases of aneurysm re-rupture or hemorrhagic complications related to antiplatelet therapy were recorded. Immediate complete occlusion was achieved in 27.4% of cases (23/84). The rate of complete occlusion among survivors was 83% in early follow-up, 90.2% in mid-term follow-up, and 92.3% in the latest possible follow-up.
Conclusion p64/p48 MW HPC flow diverters with prasugrel single antiplatelet therapy were associated with safety from aneurysm re-rupture and high occlusion rates at medium- and long-term follow-up in managing ruptured aneurysms. Adequate management of single antiplatelet therapy with prasugrel is crucial, particularly with higher doses than usual, to avoid both ischemic and hemorrhagic complications.
- Aneurysm
- Flow Diverter
- Hemorrhage
- Subarachnoid
Data availability statement
Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Flow diverter implantation to treat ruptured aneurysms in the acute phase remains debated, particularly given the requirement for dual antiplatelet therapy. Hydrophilic polymer-coated (HPC) flow diverters with prasugrel single antiplatelet therapy is a safe and efficient treatment for unruptured aneurysms.
WHAT THIS STUDY ADDS
This study shows the safe and effective use of HPC flow diverters under single antiplatelet therapy with prasugrel in the treatment of ruptured aneurysms.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Implantation of HPC flow diverters with prasugrel single antiplatelet therapy is an attractive alternative strategy for treating acutely ruptured and particularly complicated aneurysms to avoid complicated interventional treatments.
Introduction
Subarachnoid hemorrhage (SAH) from a ruptured intracranial aneurysm has an incidence of 10 per 100 000 in Europe and the USA,1 and 40% and 35% of cases show significant morbidity and mortality, respectively.2 The incidence of rebleeding in the first 72 hours is 8–23%,3 therefore early elimination of the ruptured aneurysm is the treatment goal. Both microsurgical and endovascular treatment (EVT) of ruptured aneurysms, particularly with clipping and coiling, have considerably improved in the past 30 years.4–6 Nonetheless, treatment of part of the ruptured aneurysm remains complex and associated with substantial complications. Treatment of aneurysms with complicated morphology, such as giant, dissecting, fusiform, blister or wide-neck aneurysms and pseudoaneurysms or aneurysms in difficult-to-reach locations, with classical treatment methods is limited and carries risks of periprocedural complications.
Flow diversion has substantially broadened the range of intracranial aneurysms that can be treated endovascularly.7 Compared with classical methods of treatment of aneurysms after SAH, flow diversion offers many advantages such as high device flexibility (particularly at curves), the ability to reconstruct vessels without primary contact with the highly fragile ruptured aneurysm wall, and high surface coverage for complete sealing of giant and wide-neck aneurysms.
Several flow diverters (FDs) with antithrombotic surfaces are used to treat cerebral aneurysms.7 However, successful experiences with single antiplatelet therapy (SAPT) have been reported only with p64 and p48 MW hydrophilic polymer-coated (HPC) devices.8 9
To date, only a few publications with small datasets have reported the use of surface-modified FDs in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) with SAPT, using different antiplatelet therapies. The aim of this study was to present our multicenter experience in using p48/64 MW HPC devices under prasugrel SAPT for ruptured aneurysms.
Methods
Patient population
We conducted a retrospective analysis of all patients with SAH caused by ruptured aneurysms who were treated with either p48 MW HPC or p64 MW HPC implantation under prasugrel SAPT within 30 days after the hemorrhage. Cases were included, even if the procedure was separate from the initial treatment procedure. However, patients who underwent staged flow diversion of aneurysm remnants after 30 days were excluded.
Seven German centers (Stuttgart, Erfurt, Marburg, Koblenz, Tübingen, Halle, and Regensburg) and two international centers (Sofia and Jerusalem) participated in this study. All these centers are equipped to handle all types of neuroendovascular emergencies, with a particular focus on ischemic stroke and SAH. All centers have experience with the use of HPC-FDs in elective aneurysm cases and are familiar with the use of these devices in ruptured aneurysms, considering both endovascular and medical management.
We recorded demographics, aneurysm morphology and, location, FD type and size, platelet function test results, intraprocedural and postprocedural complications, clinical outcomes, and radiological follow-up data.
Endovascular treatment
All centers performed procedures for ruptured aneurysms with a biplane angiography system in patients under general anesthesia. Arterial access was obtained via a 6–8 F sheath, typically in the right groin, and a standard 6–8 F guiding catheter. The insertion of an intermediate catheter was at the discretion of the physicians at each center, according to the condition of the cervical vessels. All FDs were deployed over a 0.021-inch microcatheter. The FD diameter and length were chosen according to two- or three-dimensional measurements of the parent artery diameter.
Antiplatelet medication
Two medical strategies were applied, as follows.
Strategy 1
After angiographic detection of a ruptured aneurysm and a decision made to use flow diversion for treatment, patients were admitted to the intensive care unit under general anesthesia. A loading dose of 30–60 mg prasugrel (Efient, Daiichi Sankyo, Munich, Germany) was administered orally via a gastric tube as SAPT. In patients in whom effective platelet aggregation inhibition was measured, inhibition was tested 3 hours later with multiplate (MP) (Roche Diagnostics, Mannheim, Germany), VerifyNow (VN) (Accriva, San Diego, California, USA) or platelet function assays.
If patients did not respond to the antiplatelet agents, a second loading dose of 30 prasugrel was administered and the efficacy of the antiplatelet regimen was tested 2–3 hours later. After effective antiplatelet therapy was confirmed, patients were immediately taken to the angiography suite for FD implantation.
Figure 1 shows an example of a ruptured aneurysm treated with flow diversion using strategy 1.
Strategy 2
FD implantation was performed in the first session after confirmation of a ruptured aneurysm. Before FD implantation a body weight-adjusted bolus of eptifibatide (Integrilin; GlaxoSmithKline, Munich, Germany), cangrelor (Kengrexal; Chiesi Farmaceutici, Parma, Italy), or tirofiban (Aggrastat; Carrevio, Vancouver, Canada) was administered IV.
After flow diversion treatment, a loading dose of 30–60 mg was administered with an overlapping, body weight-adjusted continuous IV infusion of eptifibatide or cangrelor.
Figure 2 shows an example of a ruptured aneurysm treated with flow diversion using strategy 2.
The daily post-procedural dose of prasugrel ranged from 1×10 mg to 2×20 mg orally. The dosage was optimized according to MP and VN platelet aggregation inhibition results.
Follow-up
Planned angiographic examinations were conducted at the following time points: early (3–6 months), mid-term (9–18 months), and long-term follow-up (>19 months). Aneurysm occlusion was evaluated with the O’Kelly–Marotta (OKM) scale,10 with adequate occlusion defined as OKM C or OKM D. Neurological examinations were conducted at admission, at and after discharge during early follow-up and long-term follow-up. Outcomes were measured with the modified Rankin Scale (mRS).11
Results
Patients and aneurysm characteristics
Between December 2017 and July 2023, 84 patients underwent 88 treatments with one or more p48MW/p64MW HPC stents within 30 days after aSAH. A total of 89 aneurysms were treated with EVT. The average patient age at presentation was 53.3 years. The saccular aneurysms had a mean maximum diameter of 5 mm. Demographic data, aneurysms, and FD characteristics are summarized in table 1.
A decision was made to use flow diversion as a secondary treatment to complete previous EVT in 4/84 (4.7%) of the included patients: three (3.6%) after coiling and one (1.2%) with balloon-assisted coiling after FD. In 13 (15.5%) cases, EVT involved FD-assisted coiling. However, the aneurysms were not tightly coiled. Four (4.5%) of the 88 EVTs were retreatments after FD implantation in the first 30 days after SAH.
Technical difficulties
In four (4.5%) cases the FD was not fully expanded after implantation. In three EVT cases, a stent retriever was used for several seconds to improve wall adaptation (two Solitaire-AB 3/20 mm Ev3 and one pRESET 5/40 mm WallabyPhenox). In one case this procedure was not sufficient and additional balloon dilatation was required. In the fourth case, balloon dilatation was performed first. In two cases the FDs were shortened during or soon after implantation, resulting in inadequate aneurysm coverage. Consequently, a second FD was implanted with the telescoping technique to ensure adequate coverage of the aneurysm neck. Although some challenges were encountered, all planned treatments were technically successful. In addition, all ruptured aneurysms were adequately covered with one or more FDs and all FDs were well adapted to the parent vessel.
Peri- and post-procedural complications related to flow diversion treatment or SAPT
All treated aneurysms remained stable and no cases of rupture or intracerebral hemorrhage related to SAPT were observed within the first 30 days at any center.
One patient presented to one center with prepontine SAH. DSA on the first day revealed a blister-like aneurysm on the dorsal wall of the basilar artery with a direct border to the SAH. A confident decision was made to cover the aneurysm with a FD and a loading dose of 60 mg prasugrel was administered the next day. Treatment effectiveness was confirmed 4 hours later with MP (ADP 8U, ASPI 33U) and VN (P2Y12 2/27; 99%, ARU 444). The FD implantation was successfully performed immediately afterwards. Because of severe pneumonia and impaired lung function, the patient initially remained intubated and sedated. After the pulmonary condition improved, the patient was extubated 5 days later. Subsequently, the patient exhibited motor aphasia and right hemiparesis which worsened several hours later with a decrease in vigilance and tetraplegia. An immediate DSA examination was conducted to investigate suspected cerebral vasospasm (CVS); the findings revealed no vascular occlusion, in-stent stenosis or thrombosis or spastic vessels. However, MP and VN tests confirmed hyporesponsiveness to SAPT (10 mg prasugrel daily) ADP 31U, ASPI 58U by MP and P2Y12 186/236; 21% by VN. Additionally, despite switching to double antiplatelet therapy (DAPT) and the use of cangrelor perfusor, the severe neurological deficits persisted and the patient left hospital with an mRS score of 4.
During the treatment of a ruptured AcomA aneurysm with SAH (Hunt & Hess (HH) grade 3 and Fisher grade 3), two coils and two p48 HPC FDs were used under IV tirofiban administration. However, an intraprocedural clot formation was found in a spastic anterior cerebral artery segment, which was removed with an aspiration catheter. Fortunately, no territorial ischemia occurred in the supply area of the occluded vessel.
On day eight after treatment of a ruptured aneurysm of the right middle cerebral artery with p48 HPC implantation, a patient experienced left hemiparesis. Angiography revealed a low-grade vasospasm with a thrombus in the distal part of the FD. The clot was dissolved through systemic lysis and DAPT with aspirin and prasugrel was initiated. The patient’s symptoms resolved completely and the mRS score was 1 at discharge.
Nine patients experienced CVS and were treated medically and/or mechanically. One of these patients developed CVS primarily in the middle cerebral artery and posterior communicating artery (PcomA) after rupture of an intradural dissection aneurysm of the ICA. It was unavoidable to cover the PcomA with the FD that had been implanted to cover the aneurysm. Notably, because this patient had aplasia of the ipsilateral P1 segment, the posterior supply area was supplied exclusively by the PcomA. As a result of delayed EVT of the CVS, the patient showed cerebral infarcts in the posterior and medial supply areas. The possibility that the FD coverage might have contributed to the development of cerebral ischemia in the posterior flow area, in addition to the primary cause (CVS), could not be ruled out. Notably, the patient demonstrated a sufficient effect of SAPT in the MP and VN tests.
Clinical follow-up
Nine patients died during the clinical period. In all cases, flow diversion treatment was not a contributing factor.
One patient died because of progressive generalized cerebral edema and one died because of massive and generalized CVS. In both cases, severe brain damage was the primary cause of death. Five other patients experienced severe brain damage after massive SAH (Fisher grade 4) and never recovered from the coma. Two patients died as a result of their conditions: one experienced systemic inflammation and secondary organ dysfunction while the other had severe pneumonia.
Three patients discharged with an mRS score of 5 died within the first 6 months after SAH. One patient died from metastatic ovarian carcinoma while another patient had multiple brain ischemias in all brain regions, probably because of atrial fibrillation. The third patient had a massive SAH and did not recover despite successful treatment. All three patients left the hospital in poor condition. The flow diversion treatment did not cause the poor condition during hospitalization or the fatal outcome after discharge. The clinical status of the patients at admission, discharge, and early follow-up represented by the HH score and mRS is shown in figure 3.
A comparison of the patients’ mRS scores between the pre-hemorrhage phase and discharge as well as the follow-up after 3–6 months showed that a deterioration in mRS of >2 was recorded in approximately 28.2% and 14.7% of patients, respectively. The clinical outcomes in terms of the mRS scores at each follow-up are shown in table 2.
Angiographic follow-up
Immediate complete occlusion was achieved in 23 (27.4%) patients. Regular follow-up examinations could not be conducted in all cases because of variations in centers and patients’ clinical conditions after discharge and the duration of rehabilitation phases after SAH.
Seven in-hospital deaths occurred before discharge and three deaths occurred in the first 6 months after discharge and were not related to flow diversion treatment. Angiographic follow-up was not possible for these 10 patients. Additionally, three patients continued to show severe neurological deficits after discharge: one due to severe CVS, one due to severe SAH, and one due to severe post-FD cerebral ischemia; these three patients did not receive a follow-up DSA.
Notably, four patients declined a DSA follow-up examination. Follow-up angiographic examinations were possible and performed in 67 of 74 surviving patients (90.5%).
Early follow-up (FU1, 3–6 months) was performed at a median of 6 months post-procedure in 65 patients (97%). Complete aneurysm occlusion (OKM D) was observed in 54 (83%) cases in early follow-up. Neck remnants (OKM C) were detected in four (6.1%) aneurysms, five cases (7.7%) exhibited subtotal aneurysmal filling (OKM B) and two (3.1%) cases remained unchanged (OKM A).
Mid-term follow-up DSA revealed OKM D in 37 of 41 (90.2%) patients. In four patients the aneurysms changed to OKM D from OKM B and in two patients the aneurysms changed from OKM A to OKM C, thus resulting in four patients (9.7%) having this grade.
At the latest possible follow-up examination (mean 12.8 months; median 12 months), DSA indicated OKM D in 62 of 67 patients (92.5%) and OKM C in 3/67 (4.5%) patients. No patients had OKM A.
The changes in OKM grades at each follow-up visit are summarized in table 3.
Discussion
The use of FDs in elective treatment has revolutionized the neurointerventional management of cerebral aneurysms. FDs have enabled much more simple elimination of many aneurysms that were previously impossible or very difficult to treat, including blister aneurysms and dissection aneurysms. The newly developed software and algorithm, which have been specifically designed to improve the accuracy of the device selection process, may facilitate the implementation of FD treatments and the implantation of devices in a more straightforward and secure manner.12 13 However, the use of flow diversion for treating ruptured aneurysms is not yet standardized, mainly because of hesitancy to administer DAPT in the presence of aSAH.
The few published trials and meta-analyses of flow diversion treatment after aSAH have reported approximately 9% and 8% rates of hemorrhagic and thromboembolic complications, respectively.14 15 The introduction of low-thrombogenic neurovascular implants prompted expectations that coated FDs would play a major role in treating ruptured aneurysms. However, initial experience showed modest results, as demonstrated by Meaning et al.16 In that study, 14 patients with aSAH due to a ruptured aneurysm were treated with PED Shield under SAPT, but no benefit was reported compared with known meta-analyses.
HPC is a hydrophilic glycan-based multilayer polymer coating that can be applied to nitinol surfaces. This low-thrombogenic coating is currently the only type indicated for use with SAPT. Hellstern et al8 reported no intraprocedural or periprocedural thromboembolic or hemorrhagic complications in the treatment of 132 unruptured intracranial aneurysms with p64 MW HPC under prasugrel SAPT.
To date, three studies have reported treatment of ruptured aneurysms with FD with HPC coating under SAPT. Aguilar-Perez et al17 described eight patients treated with one or more p48MW HPC FDs within 30 days after SAH. Four patients (50%) experienced transient intraprocedural thrombus formation and stent thrombosis was observed in one patient (12.5%) on day 3 which recanalized spontaneously after switching to DAPT. All patients initially received SAPT with aspirin. Lobsien et al18 studied the treatment of aneurysms in acute SAH with p64/p48 HPC under SAPT in 10 patients at three centers. After 24 hours, thrombus formation was observed in one patient in the overstented branch. The patient was receiving aspirin medication. The thrombus was resolved with a tiofibran bolus and infusion, and the medication was switched to DAPT. In a study of seven patients, Guzzardi et al19 reported intraprocedural thromboembolic occlusion in one patient (14%) during the implantation of a p64 HPC FD for the treatment of a ruptured aneurysm during SAPT with aspirin. All documented thromboembolic complications occurred in patients receiving aspirin treatment. No complications were observed with prasugrel in these studies, and no rebleeding or hemorrhagic complications from SAPT were reported during or after flow diversion treatment following aSAH.
SAPT with prasugrel has been shown to be both safe and effective in treating saccular non-ruptured aneurysms with HPC-coated FDs.8 Furthermore, patients treated with prasugrel SAPT have a low incidence of hemorrhagic complications during and after surgical procedures.20 We therefore chose to use SAPT with prasugrel for safe EVT to maintain the option of performing surgical interventions without interrupting the antiplatelet medication. In particular, patients with SAH may experience a complex clinical course and prolonged hospitalization.
The early DSA follow-up examination was performed 3–6 months after the initial procedure in 65/67 patients (of the 84 patients, 10 died before discharge or during the first 6 months, 3 were in poor clinical condition, and 4 refused follow-up). The aneurysm occlusion rate (OCM D) was 83% (54/67) and an additional 6.1% of these lesions showed neck remnants (OCM C).
Within the first 18 months (median 12 months) 60 of the 67 patients (89.6%) achieved complete occlusion of the aneurysm (OKM D), four of the 67 patients had remnants of the aneurysm neck (OKM C) and two patients had OKM B. One patient was not followed up with DSA during this period. Our study results are similar to those of Taschner et al21 and Hanel et al22 who reported complete aneurysm occlusion rates of 82% and 81.9%, respectively, with the Derivo embolization device and the Pipeline device for aneurysm treatment. Pierot et al23 reported a complete occlusion rate of 73.3% at 12 months with FRED. The high rate of adequate occlusion in our study (95.5% OKM C+D in the first 18 months) with respect to that reported by Hellstern et al (72.7% after treatment of unruptured anterior circulation aneurysms with p64 MW FD HPC under SAPT with prasugrel) was probably due to the high number of blister aneurysms, given the simultaneous onset of coils or the use of multiple FDs for maximum flow reduction in the aneurysms.
In the last possible DSA follow-up of these 67 patients we observed a complete aneurysm occlusion rate of 92.5% (OKM D) while 4.5% showed only neck remnants (OKM C).
FD implantation for the treatment of ruptured and unruptured blister, dissection, and fusiform aneurysms has been well established in recent years. However, the treatment of ruptured saccular aneurysms can be challenging because of the elongated vessels, difficult anatomy, and distal location and width of the aneurysm neck. These challenges can lead to difficult access, prolonged procedure times, and use of additional devices such as remodeling balloons, second microcatheters and others, thus increasing the risk of iatrogenic aneurysm re-rupture or intraprocedural thrombus formation. Flow diversion treatment does not require wire and/or catheter manipulation within the aneurysm sac, and the shortened treatment duration decreases the risk of rupture or thrombus formation.
The initial experience from our study and prior studies17–19 shows a good safety profile of FDs in the treatment of acutely ruptured aneurysms as an adjunct device or as a standalone treatment because no aneurysm rupture was documented in the in-hospital phase. In our study, no re-rupture was observed after discharge. Other hemorrhagic complications such as ICH, abdominal hemorrhage, femoral hemorrhage, or intraoperative hemorrhage, for example, during shunt placement were also not documented in our study, suggesting a good safety profile of SAPT with prasugrel.
We observed only four patients (4.8%) with ischemic complications. In the first patient the primary cause was CVS in a PcomA covered by the FD and, as always, the recommendation of early detection and treatment of CVS to avoid ischemic and fatal outcomes applies. The second and third patients had CVS events accompanied by clot formation in the FD and distal vascular segments. The first event occurred during the procedure and was treated with tirofiban before prasugrel administration. The second event occurred 8 days after the procedure and was treated with a daily dose of 10 mg prasugrel. Whether any hyporesponsiveness to SAPT occurred is unclear because no testing was performed. In both of these cases the clots were successfully resolved and no territorial infarcts were found in the territory supplied by these occluded vessels. The fourth patient experienced brain stem ischemia after treatment for a basilar artery blister aneurysm. The patient’s hyporesponsiveness to SAPT under 10 mg prasugrel was confirmed by MP and VN tests. At the center where this complication occurred, the hospital intensified its strategy after the event, thus resulting in daily monitoring of the efficacy of prasugrel SAPT with MP and VN tests. If the results were unsatisfactory, a platelet function assay was performed. Experience at this center has shown that patients with SAH often do not respond to a daily dose of 10 mg of prasugrel. Therefore, at this center the starting dose was standardized to 2×20 mg prasugrel daily and the dose was subsequently adjusted according to daily MP and VN tests. In some cases, 3×30 mg prasugrel daily was required to confirm adequate SAPT efficacy. This strategy did not result in any documented hemorrhagic or ischemic complications at this center.
Limitations
A substantial limitation of this study is its retrospective single-arm design. The results are applicable to only the two FD devices (p64/p48 MW HPC) implanted and cannot be generalized to other FDs or FD-associated procedures. Assessment of clinical outcomes of the SAH is complicated and the true effects of device-associated complications on the final clinical outcome are difficult to determine.
Conclusion
The use of p64/p48 MW HPC FDs with prasugrel SAPT for ruptured aneurysms with SAH were associated in our collective study with safety from re-rupture of the aneurysm and high occlusion rates at medium- and long-term follow-up. Despite the low rate of immediate complete occlusion and the use of prasugrel, no rebleeding or hemorrhagic complications occurred. Appropriate management of prasugrel SAPT during and after the procedure is essential to avoid both ischemic and hemorrhagic complications. Regular doses of prasugrel SAPT may often be insufficient to achieve adequate efficacy. In our case series, ischemic complications were more prevalent than hemorrhagic complications. Use of HPC FDs with prasugrel SAPT achieved a high rate of complete angiographic occlusion at mid- and long-term follow-up, with a good safety profile.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
The responsible ethics committee approved this retrospective study (Ethik-Kommission der Landesärztekammer Baden-Württemberg, Reference No: F-2018-080). Participants or their legal representatives gave informed consent to participate in the study before taking part.
References
Footnotes
X @AlexanderSirak1
Contributors Design of the work: AK and HH. Acquisition of data: AK, AS, MA, M-SS, DP, TB, KH. Analysis and interpretation of data: AK, DL, AS, FH, JEC. Drafting the work: AK. Revising of the work: HH, OG, HB, SF, SS, AK, SS, JK and MF. Final approval of the version to be published: all authors. Agreement 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: AK and HH. Guarantee for the overall content responsible for the work and the data: AK and HH
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 HH: Consulting and proctoring for Wallaby Phenox GmbH, co-owner of CONTARA GmbH.
Provenance and peer review Not commissioned; externally peer reviewed.