The use of FD-HPC in Ruptured and Unruptured Aneurysms, the Italian Dataset (RUAID): Preliminary results on feasibility and safety

Abstract

Background

The introduction of flow diverters (FDs) has revolutionized the treatment of complex intracranial aneurysms; subsequent surface modifications have extended their indications to ruptured, bifurcation, and distal aneurysms. The aim of this study is to assess the real-world feasibility and safety of HPC surface-modified devices in the treatment of ruptured and unruptured aneurysms.

Methods

This independent, multicenter, prospective observational study evaluated the outcomes of patients treated with implanted Phenox p64 or p48 MW-HPC-FDs between 2020 and 2022. The sub-analysis of the procedures, complications (clinical and technical), and additional treatment requirements assessed the devices’ feasibility and safety in the peri-procedural period.

Results

One hundred and forty aneurysms (35% ruptured and 65% unruptured) were treated in 140 patients (37 females and 103 males) using 153 HPC-FDs (111 p64 and 42 p48): 100 aneurysms were saccular (71%), 22 dissecting (16%), 13 fusiform (9%), and five blister-like (3.6%). The successful deployment rate was 97.9%. The overall peri-procedural mortality rate was 9%, including three device-related deaths (2.2%); the overall morbidity rate was 12.1% (6.4% severe, 3.6% mild, and 2.1% asymptomatic adverse events); 4.4% of the clinical adverse events were certainly device related, and 2.2% were probably device related.

Conclusions

The use of p64 and p48 HPC-FDs is highly feasible and acceptably safe, although further data are needed to assess the impact of the coating on safety in emergency and elective procedures.

Introduction

Flow diverters (FDs) have transformed neurovascular interventions by offering a viable treatment option for complex intracranial aneurysms.^1,2 Originally intended for large or giant, wide-necked aneurysms of the internal carotid artery (ICA), recent advances have extended their use to ruptured, bifurcation, and distal ones. ³

However, the first-generation FDs were associated with a higher rate of technical and clinical complications than standard treatments such as coiling,^4,5 and their optimal deployment required significant expertise.^1,2 Furthermore, the antiplatelet therapy necessary to prevent thromboembolic complications added the further limitations of prolonged bleeding in case of complications (especially in patients at high risk for concurrent disease or those who had experienced a recent intracranial hemorrhage), and the crucial need for long-term patient compliance in order to avoid the risk of subsequent thromboembolic events.

To overcome these limitations, various technological improvements have been made, including the introduction of devices with modified surfaces and lower profiles^6,7 resulting in reduced platelet activation, adhesion and clot formation. These devices currently include the Pipeline Flex Embolisation Device with Shield Technology (SPED; Medtronic, Dublin, Ireland), the Derivo Embolisation Device (DED; Acandis GmbH & Co, KG, Pforzheim, Germany), and the p64 and p48 microwire (MW)-hydrophilic polymer-coated (HPC) flow modulation devices (HPC-FD; Phenox, Bochum, Germany). Indeed, animal studies and in vitro tests have confirmed that these surface modifications reduce platelet aggregation.^8,9 Furthermore, retrospective studies have demonstrated that the use of HPC-FD p64 in dual antiplatelet therapy (DAPT) results in low rates of procedural complications. ¹⁰ However, there is still a lack of real-world feasibility, safety and efficacy data.

Our article describes the preliminary results of the analysis of data from the independent Italian registry RUAID (Ruptured and Unruptured Aneurysm Italian Dataset), regarding the 30-day peri-procedural feasibility and safety of p64 and p48 HPC-FDs in the treatment of cerebral aneurysms.

Material and methods

Ethical aspects

This study was carried out as part of the ONIRIC (Outcomes in Neurointerventional Radiology Indications and Complications) research project in accordance with the principles laid down in the Declaration of Helsinki, approved by our Ethics Committee (Lombardy Region, section Fondazione IRCCS Istituto Neurologico Carlo Besta), the STROBE cohort reporting guidelines ¹¹ and supported by the Italian Ministry of Health (RC 2024).

Study design

Between January 2020 and December 2022 all the consecutive patients carrying an intracranial aneurysm who underwent HPC-FD implantation, were enrolled in this independent, multicenter, prospective observational post-marketing study, involving 18 Italian Neurointerventional Centers expert in the use of cerebral FD (minimum experience: ≥10 cases per year). The intracranial aneurysm could have been saccular, fusiform or dissecting, ruptured (RIA), unruptured (UIA), or even recanalized.

Extracranial aneurysms or fistula-AVM related aneurysms were excluded. RIAs treated within 30 days of a subarachnoid hemorrhage (SAH) were considered emergencies; aneurysms treated after 30 days were considered unruptured. ¹²

The collected baseline data were age, sex and ethnicity, medical history (co-morbidities and family history of SAH), clinical data (symptoms and modified Rankin score, mRS), aneurysm data (side, location, segment, diameter, neck dimension, morphology, thrombosis, previous treatment), and anti-platelet medication. The collected procedural data were vessels measurement modality, FD type (p64 or p48) and size, deployment technique, additional coiling, pre- and post-procedural imaging, complications (clinical and technical), and any additional treatment required. Upon discharge, the mRS and adverse events were recorded.

The patients were followed up after 3, 6, and 12 months in accordance with the standard practice at each center. Follow-up imaging data included all techniques used to visualize the aneurysm sac and parent vessel (digital subtraction angiography, DSA; computed tomography angiography, CTA; magnetic resonance angiography, MRA). Follow-up clinical data included changes in clinical status, from baseline to discharge (mRS), and pharmacological treatment, clinical complications, and any additional notes.

Devices: p64 and p48 Mw-HPC flow diverters

HPC-FDs are self-expanding, low-porosity stents with a <12-nm glycan-based multilayer hydrophilic polymer coating simulating features of the glycocalyx (thus reducing thrombogenicity) whose endovascular implantation allows the reconstruction of extra- and intra-cranial arteries. They respectively consist of 64 and 48 platinum-filled microwires made of nitinol micro-tubing. The thinness of the coating does not affect the mechanical properties of the strands or the devices.

The devices are inserted into the cranio-cervical vasculature via a microcatheter (internal diameter 0.021 inches) and, before being fully deployed, can be retracted to allow their repositioning or removal. ⁸ Both devices have a central, independently movable nitinol-wire with an atraumatic distal tip, and the p48 is specifically designed to treat small-diameter (1.75–3 mm) distal vessels. ³

Study endpoints

The study assessed the peri-procedural (0–30 days) feasibility and safety of the FDs. Feasibility was determined by evaluating the rates of successful and sub-optimal deployment (incorrect positioning or inadequate vessel apposition) at the end of the procedure; any additional maneuver required to optimize device opening was recorded.

Safety was assessed by evaluating clinical complication and mortality rates during the procedure and over the following 0–30 days. Adverse events were classified as serious (SAEs: events leading to permanent neurological deficits), mild (MAEs: events leading to temporary neurological deficits), or asymptomatic (AEs: without clinical significance); furtherly they were classified as certainly or probably device/procedure-related or unrelated.

The level of patient independence (changes in the mRS) was recorded at the time of discharge and during follow-up.

Data collection and analysis

The study data were recorded and stored in a protected website database allowing only encrypted access. Each center, using a unique password, was able to upload pseudo-anonymized data and images of their patients, which were centrally reanalyzed by two blinded interventional neuroradiologists with extensive experience in neurointerventional procedures (MP, AV). Each case was independently evaluated by both, who separately completed a data form; any disagreement in their analyses were resolved by means of discussion and consensus. Technical failures and misdeployments were excluded from the imaging follow-up analysis but included in the clinical follow-up analysis.

Statistical analysis

Categorical variables are descriptively presented as counts and were compared using Chi-squared tests with contingency tables; subgroup analyses were made of ruptured and unruptured aneurysms. All the analyses were made using Jamovi software for Windows. ¹³

Results

Patient population

One hundred and forty aneurysms were treated in 140 patients (103 females, 73.6%, and 37 males, 26.4%) using a total of 153 HPC-FDs (111 p64 and 42 p48; a second FD was added in 13 cases) (Table 4); 116 procedures (82.9%) were ex novo and 24 (17.1%) were retreatments after previous coiling (Tables 1 and 2).

Table 4.

Pharmacological therapy.

Antiplatelet test
No	121/140		86.4%
Yes	19/140		13.6%
Pre-intervention antiplatelet therapy
Single antiplatelet	69/140		49.3%
Loading dose*/interprocedural dose**
Aspirin 500*	33/70		47.1%
Aspirin 1000*	5/70		7.1%
Aspirin 100	1/70		1.4%
Clopidogrel (Plavix) 300 II Aspirin 500*	2/70		2.9%
Clopidogrel (Plavix) 600 II Aspirin 500*	3/70		4.3%
Clopidogrel (Plavix) 300*	11/70		15.7%
Clopidogrel (Plavix) 600 II Tirofiban (Aggrastat)*	1/70		1.4%
Tirofiban (Aggrastat) II Aspirin 500*	3/70		4.3%
Tirofiban (Aggrastat) II maintain 12 h**	1/70		1.4%
Cangrelor**	1/70		1.4%
Flectadol 250**	3/70		4.3%
Flectadol 500**	3/70		4.3%
Flectadol 500 at start II Aggrastat at stent release**	2/70		2.9%
Flectadol 500 II Aspirin**	1/70		1.4%
Dual antiplatelet	71 / 140		50 . 7%
Clopidogrel (Plavix) 75 || Aspirin 100	67/71		94.4%
Ticlopidine (Tiklid) 250 || Aspirin 100	4/71		5.6%
Post-intervention Antiplatelet therapy
DAPT	107/140		76.4%
DAPT 12 months	7/140		5%
DAPT 6 months	22/140		15.7%
DAPT 3 months	78/140		55.7%
SAPT	33/140		23.6%
SAPT for life	7/140		5%
SAPT 12 months	3/140		2.1%
SAPT 6 months	10/140		7.1%
SAPT 3 months	13/140		9.3%
Medications antiplatelet therapy
SAPT
Aspirin 100	23	Aspirin 30	70.6%	81.2%
Aspirin 300/375	7		20.6%
Tiacagrelor 90 (Brilique)	1		2.9%
Seleparin 0.4 × 2 II ASA 100	1		2.9%
ASA 100 II OAT	1		2.9%
DAPT
Clopidogrel (Plavix) 75 II Aspirin 100	100		93.5%
Ticlopidine (Tiklid)250 II Aspirin 100	7		6.5%

Table 1.

Population data.

Characteristics	Value (n)	Percentage %
Sample population	n = 140
Male	37	26.4%
Female	103	73.6%
Age population (years)
18–35	1	0.7%
35–50	23	16.4%
50–65	67	47.9%
>65	49	35.0%
Ethnicity
Caucasian	136	97.1%
Non-Caucasian	4	2.9%
Family history of SAH
First grade relative with SAH	9	6.4%
Comorbidities
None	57	40.7%
Diabetes	2	1.4%
Hypertension	46	32.9%
Cardiovascular disease	14	10.0%
Others (mixed)	21	15.0%
Centers = 18	No. of patients for center
H. Cardarelli	26	18.6%
H. Brotzu	20	14.3%
Istituto Besta	15	10.7%
Humanitas	14	10.0%
H. Maggiore Novara	14	10.0%
H. Cuneo	11	7.9%
H. SGB Torino	9	6.4%
H. Lecce	8	5.7%
H. Monza	4	2.9%
Policlinico Bari	4	2.9%
H. Niguarda	3	2.1%
H. Papa Giovanni Bergamo	2	1.4%
H. Alessandria	2	1.4%
H. Aosta	2	1.4%
H. del Mare di Napoli	2	1.4%
H. Caserta	1	0.7%
H. Varese	1	0.7%
H. Borgo Trento Verona	1	0.7%

Table 2.

Baseline aneurysm data.

Characteristics	Value (n)		Percentage %
Aneurysm position
Anterior circulation	107		76.4%
Posterior circulation	33		23.6%
Aneurysm side
Right	70		50.0%
Left	60		42.9%
Midline	10		7.1%
Aneurysm location
ACA	18		12.9%
A1	1		3.5%
A2	6		4.3%
A3	7		1.4%
AComA	4		3.5%
ICA	58		41.4%
ICA tip	6		4.3%
ICA cavernous	11		7.9%
ICA ophthalmic	16		11.4%
ICA para-ophthalmic	23		16.4%
ICA petrous	2		1.4%
MCA	19		13.6%
M1	13		9.3%
M2	4		2.9%
M3	2		1.4%
PCA	19		13.6%
P2	4		2.9%
P3	2		1.4%
PComA	13		9.3%
BA	26		18.6%
BA	9		6.4%
PICA	3		2.1%
SCA	4		2.9%
V3	4		2.9%
V4	6		4.3%
Aneurysm size
<5 mm	32		22.9%
5–8 mm	52		37.1%
8–10 mm	23		16.4%
10–15 mm	16		11.4%
15–20 mm	17		12.1%
Neck (dome-to-neck ratio)
<50% diameter	47		33.6%
>50% diameter	93		66.4%
Aneurysm morphology
Saccular	100		71.4%
Fusiform	13		9.3%
Dissecting	22		15.7%
Blister	5		3.6%
Aneurysm status
Ruptured (RIA)	49		35%
Unruptured (UIA)	91		65%
Symptoms in UIA (28/91–30.7%)
Cranial nerves	7/28	29%	Neurological deficits 15/28 (53.6%)
Vision decline	6/28	25%
Hyposthenia	1/28	4.2%
Vertigo	1/28	4.2%
Headache	13/28	46.4%
Thrombosed
No	124		88.6%
Partially	16		11.4%
Coiling re-treatment
No	116		82.9%
Yes	24		17.1%

Sixty-seven patients (47.9%) were aged 50–65 years, 49 (35.0%) > 65 years, 23 (16.4%) 35–50 years, and just one (0.7%) 18–35 years. The most prevalent comorbidity was hypertension (46 patients, 32.9%), followed by cardiovascular diseases (14, 10.0%), diabetes (2, 1.4%), and other diseases (21, 25.0%); 57 patients (40.7%) had no comorbidity (Table 1).

Forty-nine patients (35.0%) underwent emergency treatment for SAH in RIA; the remaining 91 (65.0%) were UIA patients, 28 of whom (30.7%) were symptomatic. Symptoms of UIA patients were headache in 13 cases (46.4%) and neurological deficits in 15 (53.6%: cranial nerves, 7; visual decline, 6; hyposthenia and vertigo, 2) (Table 2). Ninety/91 UIA patients had mRS ≤2 (76 = 0; 13 = 1; 1 = 2); the remaining case (SAH recanalized 2 months post-coiling) had mRS=4.

Before their SAH, 47 of the 49 RIA patients (95.9%) had mRS ≤2 (46 = 0; 1 = 1) and two (4.1%) had mRS >2 (2 = 3).

Baseline aneurysm data

The aneurysms were saccular in 100 cases (71.4%), fusiform in 13 (9.3%), dissecting in 22 (15.7%), and blister-like in five (3.6%). Most (75, 53.5%) were 5–10 mm in diameter, 33 (23.5%) were 10–20 mm, and 32 (22.9%) were <5 mm, of which 23 were RIAs according to the UCAS classification. ¹³ Sixteen aneurysms (11.4%) were partially thrombosed. The aneurysm neck was large (dome to neck ratio >50%) in 93 cases (66.4%). One hundred and seven aneurysms (76.4%) were in the anterior circulation, while 33 (23.6%) in the posterior; 50.0% right and 42.9% left sided (Tables 2 and 3).

Table 3.

Aneurysms; RIA versus UIA.

Morphology	Dome to neck ratio <50%	Dome to neck ratio >50%	Not thrombosed	Partially thrombosed
Blister like		5/140 (3.6%)	4/140 (2.9%)	1/140 (0.7%)
RIA	–	4/49 (8.2%)	4/49 (8.2%)	–
UIA	–	1/91(10.1%)	–	1/91(10.1%)
Dissecant	5/140 (3.6%)	17/140 (12.1%)	21/140 (15%)	1/140 (0.7%)
RIA	2/49 (4.1%)	10/49 (20.4%)	12/49 (24.5%)	–
UIA	3/91 (3.3%)	7/91 (7.7%)	9/91 (9.9%)	1/91(10.1%)
Fusiform	1/140 (0.7%)	12/140 (8.6%)	11/140 (7.6%)	2/140 (1.4%)
RIA	–	5/49 (10.2%)	5/49 (10.2%)	–
UIA	1/91(10.1%)	7/91 (7.7%)	6/91 (6.6%)	2/91 (2.2%)
Saccular	41/140 (29.3%)	59/140 (42.1%)	88/140 (62.3%)	12/140 (8.6%)
RIA	14/49 (28.6%)	14/49 (28.6%)	23/49 (47%)	5/49 (10.2%)
UIA	27/91 (29.7%)	45/91 (49.5%)	65/91 (71.4%)	7/91 (7.7%)

The involved artery was ICA in 58 cases (41.4%), BA in 26 (18.6%), MCA in 19 (13.6%), PCA in 19 (13.6%), and ACA in 18 (12.9%). The most frequent location was ICA para-ophthalmic segment (23 cases, 16.4%).

Anti-platelet regimen

Sixty-nine patients (49.3%) received single antiplatelet therapy (SAPT) with an intra-procedural loading dose (33 continued SAPT post-procedure; 36 switched to DAPT). The other 71 (50.7%) received DAPT starting 3–7 days before the procedure depending on the standard practice of the individual centers: most (67/71, 94.4%) clopidogrel 75 mg and aspirin 100 mg, but four (5.6%) ticlopidine 250 mg and aspirin 100 mg (Tables 4 and 5).

Table 5.

Pharmacological therapy RIA versus UIA.

	RIA n (%)	UIA n (%)
Pre-intervention antiplatelet therapy
Single antiplatelet 69/140	45/49 (91.8%)	24/91 (26.1%)
Loading dose (mg)/interprocedural dose (mg)
Aspirin 500	26/45 (56.5%)	7/24 (29.2%)
Aspirin 1000	5/45 (11.2%)	–
Aspirin 100	–	1/24 (4.2%)
Clopidogrel (Plavix) 300 II Aspirin 500	–	2/24 (8.3%)
Clopidogrel (Plavix) 600 II Aspirin 500	1/45 (2.2%)	2/24 (8.3%)
Clopidogrel (Plavix) 300	1/45 (2.2%)	10/24 (41.7%)
Clopidogrel (Plavix) 600 II Tirofiban (Aggrastat)	1/45 (2.2%)	–
Tirofiban (Aggrastat) II Aspirin 500	3/45 (6.6%)	–
Tirofiban (Aggrastat) maintained 12 h	1/45 (2.2%)	–
Cangrelor	1/45 (2.2%)	–
Flectadol 250	1/45 (2.2%)	1/24 (4.2%)
Flectadol 500	3/45 (6.6%)	–
Flectadol 500, and Aggrastat at release	2/45 (4.2%)	–
Flectadol 500 II Aspirin	–	1/24 (4.2%)
Double antiplatelet 71/140	4/49 (8.2%)	67/91 (73.9%)
Clopidogrel (Plavix) 75 || Aspirin 100	4/4 (100%)	63/67 (94.1%)
Ticlopidine (Tiklid) 250 || Aspirin 100	–	4/67 (5.9 %)
Post-intervention Antiplatelet therapy
DAPT 107/140 (76.4%)	22/49 (44.9%)	85/91 (93.5%)
SAPT 33/140 (23.1%)	27/49 (55.1%)	6/91 (6.5%)
Medications antiplatelet therapy	RIA	UIA
SAPT
Aspirin 100	21/27	2/6 (33.3%)
Aspirin 300/375	4/27	3/6 (50%)
Tiacagrelor 90 (Brilique)	1/27	–
Seleparin 0.4 × 2 II ASA 100	1/27	–
ASA 100 II TAO	–	1/6 (16.7%)
DAPT
Clopidogrel (Plavix) 75 II Aspirina 100	22/22	78/85 (91.9%)
Ticlopidine (Tiklid) 250 II Aspirina 100	–	7/85 (8.1%)

Table 4 shows anti-platelet treatment sub-groups: 45/49 RIA patients (91.8%) initially received SAPT, with a loading (37/49) or intra-procedural dose (8/49); 4/49 DAPT (8.2%), 1/4 was previously on DAPT, 3/4 were treated few days post-rupture. Eighteen of the patients initially receiving SAPT (40.0%) were switched to DAPT immediately after the procedure, and 27 (60%) continued SAPT, although one of these was switched to DAPT 4-day post-procedure for severe vasospasm.

Sixty-seven of the UIA patients (73.9%) received DAPT as the standard practice of their center, and 24 (26.1%) received SAPT before the procedure with a loading (22) or intra-procedural dose (2), five of whom continued SAPT after the procedure. Only nineteen patients (13.6%) underwent platelet response tests before the procedure.

Endovascular procedures

All 140 procedures were performed under general anesthesia, using a femoral triaxial access in 90 cases (64.3%), a femoral biaxial in 43 (30.5%), a radial biaxial in six (4.3%), and a radial triaxial in one (0.7%) (Table 6).

Table 6.

Procedure data.

	Value	Percentage %
Technique of access
Femoral biaxial	43	30.5%
Femoral triaxle	90	64.3%
Radial biaxial	6	4.3%
Radial triaxle	1	0.7%
Measurement
Manual measurement	126	90%
Software simulation	14	10%
Antiplatelet test
Yes	121	86.4%
No	19	13.6%
Total FD used 153, total FD implanted 149/153
Type of first FD	Used 140/153 Implanted 137/140
p64	Used 99/140; Implanted 96/99	72%; 97%
p48	Used 41/140; Implanted 41/41	29.3%; 100%
Type of second FD	Used 13/153 Implanted 12/13
p64	Used 12/13; Implanted 11/13	92.3%; 84.6%
p48	Used 1/13; Implanted 1/13	7.7%; 7.7%
FD Deployment
Optimal	135	88.2%
Suboptimal	14	9.2%
Failure	4	2.6%
1. Instability of triaxle system due to carotid vascular axis tortuosity; release of braided stent.
2. Stent not released due to instability, switch to coiling assisted with Atlas Neuroform stent
3. Attempt failed to implant two different HPC-FD, solved with placement of FRED-FD
Causes of Suboptimal FD placement
1. Non-optimal proximal apposition
2. Proximal shortening
3. Distal fish mouth and intermediate tract narrowing
4. Slight set back from desired position
5. Need for placement of second stent to optimize coverage of aneurysmal neck
6. Incorrect stent opening in proximal landing zone, PTA required
7. Incorrect sealing with the parent vessel
8. Incorrect sealing of stent necessitating THA
9. Non-optimal midline apposition
10. Partial twisting of the imbricated stents
11. FD more caudal than desired position
12. Little imbrication between the 2 stents but complete coverage of the neck
13. Narrowing intermediate tract, suboptimal placement of intermediate tract, PTA performed
14. Failure to open for probable twisting not possible stent retrieval, carotid thrombosis with contralateral compensation
Additional Coiling
No	117	83.6%
Yes	23	16.4%
Complications (*failure)
Technical complications	n = 18/140	12.8%
None	122	87.1%
FD not opened	6*	4.3%
FD twisted	3	2.1%
Proximal Fish Mouthing	4	2.9%
Distal Fish Mouthing	2**	1.4%
FD instability	1*	0.7%
Micro replaced	1	0.7%
Shortening and disimbrication	1	0.7%
Clinical complications	n = 14/140	10%
None	125	89.3%
Inguinal Hematoma	1	0.7%
Thromboembolism	4	2.9%
Femoral artery pseudo aneurysm	1	0.7%
Parent vessel occlusion	8	5.7%
SAH-ICH	1	0.7%
Sub-occlusion artery	2	1.4%
Additional treatment	n = 29/140	20.7%
None	111	79.3%
Pharmacological	18	12.9%
Flectadol 300 at stent release	2/18	11.1%
Flectadol 500 at stent release	4/18	22.2%
Tirofiban	4/18	22.2%
Tirofiban and Stentretriver	2/18	11.1%
Soldesan	2/18	11.1%
Aggrastat for thrombosis intrastent	1/18	5.6%
Nimopidina	1/18	5.6%
Corticosteroids	1/18	5.6%
Clopidogrel 1 day with loading dose after procedure for fillings defects in FD lumen	1/18	5.6%
Mechanical	11	7.9%
PTA	7/11	63.6%
Others	4/11	36.4%
Aspiration of thrombi in two M2 branches of the right ACM
Placement of second FD to resolve fish mouthing
Cangrelor and thrombectomy with CatchView Mini stentriever
Not specified*

Feasibility and technical complications

As there were four technical failures in deploying p64 FDs during three procedures (2.1%), 149 FDs were implanted in 137 patients. Two of the failures were related to triaxial system instability due to severe carotid tortuosity: in one case, the FD was replaced by stent-assisted coiling; in the other, after two failed attempts at implantation, the procedure was halted and rescheduled. During the third procedure, two unsuccessful attempts at deploying a p64 FD were followed by the release of a p48 FD.

FD placement was considered optimal in 135 cases (88.2%), and sub-optimal in 14 (9.2%): these latter cases were due to inadequate wall apposition (7), partial twisting (3), or proximal or distal fish mouthing (4). Six cases of sub-optimal opening required further endovascular maneuvers (percutaneous transluminal angioplasty [PTA] in four, and a second FD in two), and three were managed pharmacologically to prevent thromboembolism; the remaining five required no further action as there was no flow impairment (illustrative case in Figure 1).

Figure 1.

Illustrative case. DSA images during placement of a p64-HPC for treatment of an unruptured p-com aneurysm of the right ICA. DSA left images are unsubtracted, right images are subtracted. Top row DSA LL views, bottom bottom row DSA AP views. (Figure B) Final DSA images showing caudal shift of the p64, compared to Figure A (arrow). DSA left images are unsubtracted, right images are subtracted. Top row DSA LL views, bottom row DSA AP views.

Sub-optimal FD opening led to thromboembolic complications in four cases (three clinical adverse events and one asymptomatic case): one case of FD twisting led to death due to acute parent artery occlusion (PAO) despite multiple attempts at PTA; a second case of twisting led to death due to post-procedural stent occlusion; and a case of FD shortening with proximal fish mouthing leading to acute PAO, successfully treated with tirofiban but followed by post-discharge cerebral ischemia despite DAPT. In the asymptomatic case, the ICA occluded after several unsuccessful attempts to untwist/retrieve the device, but the situation was rescued by optimal contralateral compensation.

Technical complication p64 versus p48

The 14 cases of sub-optimal deployment involved 13 p64 FDs and 1 p48 FDs. As p64 FDs were used in 99 patients, the technical complication rate was 15.15% (13/99), whereas regarding p48 FDs was 7.3% (1/41) (Table 6).

Safety

Mortality

Overall mortality was 9.3% (13/140 patients) (Tables 7 and 8).

Table 7.

Morbi-mortality relation with the device.

Variable	Overall	HPC-FD related	Probably related to HPC-FD
Mortality	13/140 (9.3%)	3/137 (2.2%)	–
p64	7	2	–
p48	6	1	–
Morbidity (SAE + MAE)	14/140 (10%)	6/137 (4.4%)	3/137 (2.2%)
p64	6	2	1
p48	8	4	2
SAE	9/140 (6.4%)	3/137 (2.2%)	2/137 (1.5%)
p64		-	1
p48		3	1
MAE	5/140 (3.6%)	3/137 (2.2%)	1/137 (0.7%)
p64		2	–
p48		1	1

Table 8.

Morbi-mortality outcomes SAPT versus DAPT in RIA and UIA cases.

Morbi-mortality	Percentage	RIA	UIA
Mortality	13/140 (9.3%)	11/140 (7.9%)	2/140 (1.4%)
SAPT	6/33 (18.2%)	4/33 (12.1%)	2/33 (6.1%)
DAPT	7/107 (6.5%)	7/107 (6.5%)	–
Morbidity (SAE + MAE)	14/140 (10%)	8/140 (5.7%)	6/140 (4.3%)
SAPT	5/33 (15.1%)	4/33 (12.1%)	1/33 (3%)
DAPT	9/107 (8.4%)	4/107 (3.7%)	5/107 (4.7%)
SAE	9/140 (6.4%)	6/140 (4.3%)	3/140 (2.1%)
SAPT	4/33 (12.1%)	4/33 (12.1%)	–
DAPT	5/107 (4.7%)	2/107 (1.9%)	3/107 (2.8%)
MAE	5/140 (3.6%)	2/140 (1.4%)	3/140 (2.1%)
SAPT	1/33 (3%)	–	1/33 (3%)
DAPT	4/107 (3.7%)	2/107 (1.9%)	2/107 (1.9%)

There were three FD-related deaths (3/137, 2.2%) due to peri-procedural PAO, all in emergency-treated RIA patients. Two were related to sub-optimal FD opening (described above); the third involved a patient in their 80s with a Fisher 4 SAH and small A2–A3 bifurcation aneurysm receiving SAPT whose p48 FD occluded 24-hour post-procedure despite mechanical thrombectomy and a second anti-platelet drug (illustrative case in Figure 2). FD-unrelated mortality was 7.1% (10/140): 8 RIA patients (7 because of complications due to SAH, including vasospasm, 1 because of pulmonary complications related to prolonged bedrest) and 2 UIA patients (1 because of multi-organ insufficiency and 1 because of septic complications due to prolonged bedrest from a prior different RIA-SAH occurred 2-month before resulting mRS 4).

Figure 2.

Illustrative case. The basal CT shows severe SAH (A). The CTA shows a small dissecting right A2 ruptured aneurysm (arrow in B), confirmed by DSA (arrow in C), treated by p48-HPC FD (arrows in D) under single aggregation. After clinical deterioration the perfusional CT demonstrated hypoperfusion in the right parasagittal territory (in E), due to parent artery occlusion at the FD level (white arrow in F), partially recanalized after mechanical thrombolisis (white arrow in G). Unfortunately the patient did not survive.

Morbidity

Overall, 30-day morbidity was 10% (14/140): nine serious (6.4%) and five mild adverse events (3.6%). There were also three clinically irrelevant adverse events (2.1%).

Serious adverse events (SAEs)

The 9 clinically relevant adverse events requiring hospitalization/prolonging hospitalization/life-threatening and leading to disability/incapacity after 30 days ¹⁴ occurred in 6 RIA and 3 UIA patients, with 3/9 certainly and 2/9 probably device-related. The first certainly device-related SAE was an intra-stent thrombosis occurring in DAPT after 24 hours, resistant to rescue maneuvers (tirofiban, stent retrieval, deployment of a closed-stent); the patient remained hemiplegic due to a deep MCA stroke (RIA, discharge mRS 4). The second case was caused by intra-stent platelet aggregation 10-day after the procedure with stent sub-occlusion (UIA, discharge mRS 3). The third ischemic thromboembolic lesions occurred in the left hemisphere causing mild aphasia and right hemiparesis the day after the procedure in a DAPT patient. DSA revealed an intra-stent thrombosis that was not present at the end of the procedure (UIA, discharge mRS 2).

The 2 probably device-related SAEs were a thromboembolic event in the territory of the ACA probably due to a transient thromboembolism in a SAPT patient (RIA, discharge mRS 4), and a case of left hemiparesis occurring after right hemisphere multi-embolic ischemia in a DAPT patient (UIA, discharge mRS 3).

The 4 SAEs unrelated to the device or procedure were 2 cases of ischemia due to vasospasm in two RIA patients (discharge mRS respectively 4 and 5), one case of pulmonary complications (RIA, discharge mRS 3), and one case of thromboembolic complications during coiling of a mirror aneurysm (RIA, discharge mRS 3).

Mild adverse events (MAEs)

The 5 (3.6%) clinically relevant but transient adverse events ¹⁴ occurred in 3 UIA and 2 RIA patients; 4 were considered device-related (three certainly and one probably), and 1 device-unrelated. The first certainly device-related MAE was an intra-procedural carotid occlusion due to stent twisting that led to transient aphasia and visual deficit recovered in few hours, thanks to good collateral supply (RIA, discharge mRS 0); the second was a case of mild motor hemi-syndrome with right homonymous inferior quadrantopsia due to a distal thromboembolism in M2, that resolved after mechanical thrombectomy (UIA, discharge mRS 1). In the third one, on DAPT, PTA was necessary to open correctly the FD, unfortunately the day after he developed SAH and ICH (UIA, discharge mRS 1).

The probably device-related MAE was a case of transient right arm hyposthenia that occurred the day after the procedure (UIA patient on DAPT) resolved within a week.

The device- and procedure-unrelated MAE was a minor stroke due to an uncontrolled hypotensive episode during the hospitalization (RIA, discharge mRS 2).

Clinically irrelevant adverse events (AEs)

The 3 procedure-related but clinically irrelevant events, ¹⁴ occurred in three RIA patients (2.1%): 2 inguinal hematomas and 1 femoral pseudoaneurysm.

Adverse event rates p64 versus p48 FDs

The 9 device-related adverse events were: 3 deaths, 3 SAEs, and 3 MAEs. The deaths occurred in 2 patients with p64 and in 1 with p48. The clinically relevant events occurred in 2 patients with p64 and 4 with p48. As the p64 was used in 99 patients and the p48 in 41, the adverse event rates were respectively 4.0% and 12.2% (Table 7).

Discussion

RUAID is the first nationwide registry recording the real-world outcomes of the p64 and p48 HPC-FD treatment of ruptured and unruptured cerebral aneurysms. Its heterogeneous population sample of 140 consecutive patients treated at 18 centers includes 49 RIA who underwent emergency treatment. The anti-platelet therapeutic protocols used vary depending on the best clinical practice of each center, with SAPT being used for 49% of the procedures and DAPT for 51%.

The revolutionary impact of the FD treatment in brain aneurysms over the last 15 years is comparable with that of the use of detachable coils in the 1990s.^15,16 FDs promote the formation of a thrombus within the aneurysmal sac and stimulate endothelial cell growth along struts over the aneurysmal neck, thus allowing the aneurysm to be excluded from the circulation. ¹⁷ However, although their high-mesh density promotes occlusion, it also increases the risk of platelet activation and thromboembolic complications.

FDs were originally approved for the treatment of unruptured large, giant or wide-necked aneurysms of the ICA, but the recent introduction of surface-modified, lower-profiled devices has allowed them to be used to treat bifurcation, distal, and even acutely ruptured aneurysms. ³

Feasibility

Our data indicate an overall device placement success rate of 88.2%; a deployment failure rate of 2.6%, and a sub-optimal opening rate of 9.2%. The intra-procedural problems included inadequate wall apposition, device twisting and fish mouthing, successfully resolved by balloon angioplasty or positioning of a second FD in 5% of cases.

There were differences in the viability of the p64 and p48, with the former being responsible for all deployment failures, and the latter giving rise to fewer technical complications (15.1% vs. 7.3%).

These findings are similar to those of a recent meta-analysis ¹⁸ indicating a 4% intra-procedural technical event rate, with balloon-assisted angioplasty required in 2% of cases, although another meta-analysis of outcomes in patients treated with other surface-modified FDs (DEDs and SPEDs) reported a 99.6% successful deployment rate, with balloon angioplasty or other techniques being necessary in only 1% of cases. ⁴ The Italian FRED registry found that deployment was impossible in 2/163 cases (1.2%), and that misdeployment occurred in a further four cases (2.5%). ¹⁹ The Italian Derivo Registry has indicated a sub-optimal opening rate of 10.2% but, as these mainly involved early cases, they were probably due to initial inexperience. ¹⁵ To avoid or correct suboptimal FD deployment several strategies have been suggested in the literature, some of them utilized in the series described. ²⁰

However, it is worth noting that our comparable multicenter real-world data refer to a wide range of ruptured and unruptured aneurysms of different nature, size, and location, and provide specific information concerning the apposition and deliverability of HPC-FDs. ²⁰

Safety

We recorded a device-related mortality rate of 2.2%, an overall (certainly and probably) device-related morbidity rate of 6.6% (SAEs 3.7% and MAEs 2.9%), and a certainly device-related event rate (SAEs and MAEs) of 4.4%. All these events were due to thromboembolic and non-hemorrhagic cerebral complications, even considering the RIA subgroup, which remained on antiplatelet therapy during the vasospasm period. The mortality rate is higher than the 1% reported by Li et al. in their meta-analysis of Acandis’ DEDs and Medtronic's SPEDs, with no significant difference between the two FDs; however, all of their aneurysms were unruptured and treated electively in combination with DAPT. ¹⁸ The meta-analysis of p64- and p48-treated aneurysms by Suarez et al. indicated mortality rates of respectively 0.49% and 2%, ²¹ although most of these aneurysms were also unruptured and only a minority of patients received SAPT. A systematic review of complications associated with uncoated FDs by Zhou et al. reported a mortality rate of 2.8%, ²² and Brinjikji et al. found an even higher rate of 4% during the early years of FDs. ²³

Our findings compare well with previously published data and suggest that surface-modified FDs lower overall mortality rates.

In comparison with our finding of 6.6% of certainly and probably device-related SAEs and MAEs, Suarez et al. reported that the complication rates associated with p64 and p48 were respectively 4% and 3%; however, only 7.2% of their aneurysms were ruptured, which is considerably lower than our 35%. Furthermore, Li et al. reported an overall pooled morbidity rate of 6.0%, mainly due to ischemic events. ¹⁸

The difference in the adverse event rates associated with the p48 (12.2%) and p64 (4%) is possibly because the higher percentage of aneurysms located beyond the circle of Willis and the consequently smaller caliber of their parent vessels.

However, the relatively high rate of complications may also be explained by the generally higher percentage of ruptured aneurysms in comparison with other cohorts. Indeed, SAH can contribute to a hyper-thrombotic state that may be exacerbated by the type of anti-platelet therapy. ²¹ This is supported by the finding of a 28.3% (95% CI, 12.4–52.5) overall risk of complications (thromboembolic 23.9%; hemorrhagic complications 9.4%) in a recent systematic review of the safety and efficacy of coated FDs in RIA patients receiving SAPT. ²⁴ Advances in FD technology have greatly improved the feasibility and safety of endovascular procedures, but we are still a long way from developing a device that requires less intensive or even no anti-platelet therapy. ²⁵ A recently published multicenter case series of ruptured aneurysm treated with P64/48 under single prasugrel regimen showed only 4.7% ²⁶ flow diverter-dependent complications. Differently from our cases in SAPT, all their patients were tested as good responders before the procedure and some of them were pretreated with eptifibatide (Integrilin; GlaxoSmithKline, Munich, Germany), cangrelor (Kengrexal; Chiesi Farmaceutici, Parma, Italy), or tirofiban (Aggrastat; Carrevio, Vancouver, Canada) IV before switching to prasugrel. Additionally, prasugrel is still not widely available in Italy for cerebral endovascular procedures.

The limitations of our study include the multicenter nature and the heterogeneity of the study population. Differences in the anti-platelet regimens and in the experience of the investigators in deploying the p64 or p48 may have increased the complication rate, affecting the results. However, it is important to note that our dataset reflects the real-world use of FDs in Italy.

Conclusions

Our preliminary real-world data concerning a heterogeneous population of patients with ruptured and unruptured brain aneurysms receiving SAPT or DAPT demonstrate that the p64 and p48 have a generally good feasibility and safety profile, especially in the case of unruptured aneurysms. The p48 seems to be easier to deploy than the p64, but seems to be associated with higher rate of complications. Further studies are required to evaluate the safety of the devices in acute settings and in combination with SAPT.