The Pipeline embolization device (PED) (Medtronic Neurovascular) is commonly used to treat brain aneurysms via flow diversion. The approved indications for PED use in the United States were originally defined in 2011 on the basis of the Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial and included adult patients with unruptured, large or giant, wide-necked intracranial aneurysms from the petrous to superior hypophyseal segments of the internal carotid artery (ICA).1 Based on the results of the Prospective Study on Embolization of Intracranial Aneurysms With the Pipeline Embolization Device (PREMIER), these indications were expanded in 2018 to include fusiform aneurysms and saccular aneurysms with a neck greater than 4 mm up to the ICA terminus.2–4 In these on-label applications, PED is known to have high rates of safety and efficacy.2,3,5
Given the potential utility of flow diversion in off-label clinical scenarios, PEDs are often considered for treatment of aneurysms beyond on-label indications.6–13 Although different off-label uses may carry unique risks,7,12–15 it is unknown if the spectrum of off-label uses in actual practice compares favorably to on-label use and thus reflects a reasonable exercise of physician judgment. In this work, we compared the safety and efficacy of off-label versus on-label use of PED in real-world practice at an experienced center.
Methods
Patient Selection
Institutional review board approval was obtained for this study. Consecutive patients who underwent endovascular aneurysm treatment with PED at a single, urban, high-volume neurovascular center from July 2011 to November 2020 were identified from a prospectively maintained neurointerventional database and included in this study.
Embolization Procedure
Informed consent for each procedure was obtained from all patients, per clinical routine. Before treatment, patients were administered dual antiplatelet therapy that generally consisted of aspirin plus clopidogrel, prasugrel, or ticagrelor with dose titration based on the results of the VerifyNow assay (Instrumentation Laboratory).16 Patients in the supine position underwent embolization via a transfemoral or transradial route in a biplane neurointerventional suite. Intraprocedural systemic heparinization was titrated to achieve an activated clotting time approximately 2.5 times greater than at baseline and was usually reversed at the end of the procedure. Postprocedural care including use of closure devices and access site monitoring was performed, per clinical routine. Initial angiographic follow-up was typically performed approximately 6 months after treatment. Dual antiplatelet therapy was usually continued for 6–12 months, followed by indefinite aspirin monotherapy.
Data Acquisition and Classification
Patient characteristics (e.g., age, sex, major comorbidities, pretreatment functional status), aneurysm characteristics (location, size, morphology, rupture status), periprocedural details (pretreatment platelet reactivity), treatment details (retreatment status, immediate procedural complications), and angiographic (aneurysm occlusion, in-stent stenosis) and clinical (posttreatment functional status, ischemic or hemorrhagic complications) follow-up data were collected.
The assessed comorbidities included hypertension, diabetes mellitus, hyperlipidemia, recent smoking history, cardiovascular disease, ischemic stroke or transient ischemic attack, and intracranial hemorrhage. Patients who quit smoking more than 6 months prior to PED placement did not have smoking counted as a comorbidity. Aneurysm size was defined as the largest aneurysm dimension recorded prior to PED implantation. Aneurysms were considered recently ruptured if there was clinical or radiological evidence of aneurysm rupture within the previous 60 days. Platelet reactivity was reported in platelet reactivity units (PRU), as measured with the VerifyNow assay. Procedural complications included thrombus formation, vasospasm, device malfunction, arterial dissection, access site complications such as hematoma formation or prolonged bleeding, and anesthesia-related complications such as arrhythmia or prolonged hypotension. Total duration of follow-up was calculated as the time from PED placement to the most recent catheter angiography or clinical evaluation. Aneurysm occlusion was graded using the O’Kelly-Marotta scale.17 PED constructs were classified as demonstrating in-stent stenosis if there was a 10% or greater reduction in luminal diameter at the site of PED deployment, or they were classified as demonstrating occlusion if there was arrest of antegrade flow through the PED. A 10% threshold for stenosis was employed to avoid misclassification of normal posttreatment intimal hyperplasia as in-stent stenosis, but this threshold was deliberately conservative. Ischemic complications were defined as transient ischemic attack or stroke ipsilateral to the site of PED deployment at any point in the postoperative or follow-up period. Early ischemic complications were defined as ischemic complications that occurred within 1 week of treatment. Preprocedural and postprocedural functional status was classified with the modified Rankin Scale (mRS).18
Aneurysm treatment was systematically classified as on-label if it met the most recent United States Food and Drug Administration (FDA) criteria: patient age 22 years or older; aneurysm location in the ICA up to the terminus; fusiform or saccular morphology; neck width greater than 4 mm or a dome-to-neck ratio < 2; parent vessel diameter 2–5 mm; aneurysm not acutely ruptured; and no preexisting stent (such as from stent-assisted coiling) at the site of PED deployment.4 All other aneurysm treatments were classified as off-label and further subclassified on the basis of the reason for off-label classification. For patients with multiple aneurysms, treatment was classified as off-label if any of the treated aneurysms did not meet the currently approved indications, but each individual aneurysm maintained its original on-label or off-label classification. Aneurysm treatments were classified as previously off-label if they were on-label according to current criteria but off-label according to the original 2011 FDA-approved criteria of patient age 22 years or older, aneurysm location in the ICA from the petrous to the superior hypophyseal segments, and large or giant (> 10 mm) aneurysm dome with a wide neck.1,2
Data Analysis
Rates of aneurysm occlusion were reported on a per-aneurysm basis, whereas ischemic and hemorrhagic complications were reported on a per-patient basis. The in-stent stenosis rate was calculated per PED construct, and the procedural complication rate was calculated on a per-treatment basis. Patients who did not present for follow-up were included in the analysis to capture relevant periprocedural data. More specifically, if a procedure was aborted for any reason, periprocedural data were nonetheless included in this analysis on the basis of the intention to treat. Groups were compared using the 2-tailed Fisher exact test for count data and the 2-tailed Mann-Whitney U-test for continuous data. The distributions of the mRS scores were also compared with the 2-tailed Mann-Whitney U-test. The threshold of statistical significance was 0.05.
Results
Patient and Aneurysm Characteristics
In total, 416 aneurysms in 330 patients were treated with PED at our center during the study period. Of these, 256 aneurysms in 190 patients received on-label treatments and 160 aneurysms in 140 patients received off-label treatments. Patient characteristics were comparable between the on-label and off-label groups (Table 1). The median (interquartile range [IQR]) aneurysm size was 5.1 (3.2–9.2) mm for on-label aneurysms and 7.1 (4.2–12.0) mm for off-label aneurysms. The reasons for off-label classification were location in 52.5% of aneurysms (84/160), neck size in 26.9% (43/160), parent vessel size in 9.4% (15/160), morphology in 12.5% (20/160), recent rupture in 20.6% (33/160), patient age less than 22 years in 6.9% (11/160), and prior stent placement at the site of PED deployment in 1.3% (2/160). In total, 23.1% (37/160) of aneurysms were off-label for multiple reasons, and 32.0% (133/416) of aneurysms were previously off-label but considered on-label in current practice.
Patient and aneurysm characteristics
| Characteristic | On-Label | Off-Label |
|---|---|---|
| Total no. of patients | 190 | 140 |
| Demographic | ||
| Age, yrs | 56.0 (47.0–65.0) | 57.5 (48.0–67.3) |
| Female sex | 166 (87.4) | 103 (73.6) |
| Comorbidities | ||
| Diabetes | 20 (10.5) | 16 (11.4) |
| Hypertension | 104 (54.7) | 76 (54.3) |
| Hyperlipidemia | 51 (26.8) | 47 (33.6) |
| Smoking | 60 (31.6) | 46 (32.9) |
| Cardiovascular disease | 33 (17.4) | 40 (28.6) |
| Intracerebral hemorrhage | 48 (25.3) | 39 (27.9) |
| Transient ischemic attack/stroke | 38 (20.0) | 29 (20.7) |
| Preprocedural PRU* | 134.7 ± 60.8 | 135.3 ± 57.3 |
| Preprocedural mRS score | ||
| 0 | 151 (79.5) | 94 (67.1) |
| 1 | 22 (11.6) | 25 (17.9) |
| 2 | 15 (7.9) | 13 (9.3) |
| 3 | 1 (0.5) | 3 (2.1) |
| 4 | 1 (0.5) | 2 (1.4) |
| 5 | 0 (0.0) | 3 (2.1) |
| 6 | 0 (0.0) | 0 (0.0) |
| Aneurysm characteristics | ||
| Total no. of aneurysms | 256 | 160 |
| Size, mm | 5.1 (3.2–9.2) | 7.1 (4.2–12.0) |
| Location | ||
| Anterior circulation | ||
| ICA | 256 (100) | 76 (47.5) |
| Extracranial | 1 (0.4) | 7 (4.4) |
| Cavernous | 38 (14.8) | 13 (8.1) |
| Intracranial | 217 (84.8) | 56 (35.0) |
| Middle cerebral artery | 0 (0.0) | 17 (10.6) |
| Anterior cerebral artery | 0 (0.0) | 19 (11.9) |
| Posterior circulation | ||
| Vertebral artery | 0 (0.0) | 20 (12.5) |
| Posterior inferior cerebellar artery | 0 (0.0) | 5 (3.1) |
| Basilar artery | 0 (0.0) | 18 (11.3) |
| Posterior cerebral artery | 0 (0.0) | 5 (3.1) |
| Morphology | ||
| Saccular | 246 (96.1) | 105 (65.6) |
| Fusiform | 10 (3.9) | 35 (21.9) |
| Other | 0 (0.0) | 20 (12.5) |
| Recent rupture | 0 (0.0) | 33 (20.6) |
| Prior treatment | 46 (18.0) | 31 (19.4) |
Values are shown as n (%) or median (IQR) unless otherwise indicated.
Mean ± SD.
Angiographic Outcomes
Angiographic follow-up data were available for 89.5% (229/256) of on-label aneurysms and 81.9% (131/160) of off-label aneurysms (Table 2). Of the aneurysms without angiographic follow-up, 55.2% (16/29) of on-label aneurysms and 29.6% (8/27) of off-label aneurysms had not undergone regularly scheduled follow-up at the time of data collection; the remainder were lost to follow-up. The median (IQR) duration of angiographic follow-up was 17.7 (8.2–29.7) months for on-label aneurysms and 14.9 (6.7–46.6) months for off-label aneurysms (p = 0.090).
Angiographic outcomes, clinical outcomes, and complication rates
| Characteristic* | On-Label | Off-Label | p Value |
|---|---|---|---|
| Angiographic outcomes | |||
| Total no. of aneurysms w/ follow-up | 229 | 131 | |
| Angiographic follow-up duration, mos | 17.7 (8.2–29.7) | 14.9 (6.7–46.6) | 0.090 |
| Complete aneurysm occlusion | 175/229 (76.4) | 99/131 (75.6) | 0.898 |
| In-stent stenosis or occlusion† | 12/187 (6.4) | 11/108 (10.2) | 0.265 |
| Procedural complications | |||
| Total no. of procedures | 209 | 138 | |
| Any complication | 20/209 (9.6) | 20/138 (14.5) | 0.172 |
| Thrombus formation | 5/209 (2.4) | 8/138 (5.8) | 0.147 |
| Vasospasm | 3/209 (1.4) | 6/138 (4.3) | 0.164 |
| Device malfunction | 1/209 (0.5) | 3/138 (2.2) | 0.305 |
| Dissection | 4/209 (1.9) | 3/138 (2.2) | 1.000 |
| Access site related | 3/209 (1.4) | 0/138 (0.0) | 0.279 |
| Anesthesia related | 2/209 (1.0) | 0/138 (0.0) | 0.520 |
| Clinical outcomes | |||
| Total no. of patients w/ follow-up | 144 | 105 | |
| Clinical follow-up duration, mos | 14.6 (6.4–36.3) | 13.7 (6.7–28.1) | 0.585 |
| Ischemic event | 6/144 (4.2) | 16/105 (15.2) | 0.003‡ |
| w/ increased mRS score | 2/144 (1.4) | 8/105 (7.6) | 0.020‡ |
| Intracranial hemorrhage | 4/144 (2.8) | 6/105 (5.7) | 0.330 |
| Postprocedural mRS score | 0.325 | ||
| 0 | 104/144 (72.2) | 63/105 (60.0) | |
| 1 | 21/144 (14.6) | 25/105 (23.8) | |
| 2 | 14/144 (9.7) | 9/105 (8.6) | |
| 3 | 1/144 (0.7) | 4/105 (3.8) | |
| 4 | 1/144 (0.7) | 0/105 (0.0) | |
| 5 | 0/144 (0.0) | 0/105 (0.0) | |
| 6 | 3/144 (2.1) | 4/105 (3.8) |
Values are shown as n/N (%) or median (IQR) unless otherwise indicated.
Aneurysm outcomes are reported per aneurysm with imaging follow-up, procedural outcomes are reported per procedure, and clinical outcomes are reported per patient with clinical follow-up, except where noted.
Reported on a per–PED construct basis.
Statistically significant (p < 0.05).
Complete aneurysm occlusion was achieved in 76.4% (175/229) of on-label aneurysms and 75.6% (99/131) of off-label aneurysms (p = 0.898) (Fig. 1). Among off-label aneurysms, the rate of complete aneurysm occlusion was 67.2% (45/67) for aneurysms that were off-label due to location, 82.1% (32/39) for aneurysms off-label due to neck size, 75.0% (9/12) for aneurysms off-label due to parent vessel size, 50.0% (8/16) for aneurysms off-label due to morphology, 72.0% (18/25) for aneurysms off-label due to recent rupture, 88.9% (8/9) for aneurysms in patients under age 22 years, 100% (2/2) for aneurysms off-label due to prior stent placement, and 63.6% (21/33) for aneurysms off-label for multiple reasons. Among on-label aneurysms, the rate of complete occlusion was 85.7% (108/126) for aneurysms that were previously off-label. The median (IQR) time to complete aneurysm occlusion was 6.7 (5.9–8.2) months for on-label aneurysms and 6.6 (6.6–7.6) months for off-label aneurysms (p = 0.387).
Rates of complete aneurysm occlusion, in-stent stenosis, and assorted clinical outcomes for on-label and off-label use of PED. Error bars represent 95% CIs.
In-stent stenosis was observed in 6.4% (12/187) of on-label PED constructs and 10.2% (11/108) of off-label PED constructs (p = 0.265). Of the off-label constructs that developed stenosis, 54.5% (6/11) were off-label due to location, 27.3% (3/11) due to recent rupture, 18.2% (2/11) due to neck size, 27.3% (3/11) due to morphology, 9.1% (1/11) due to parent vessel diameter, 9.1% (1/11) due to patient age, 0.0% (0/11) due to a prior stent, and 36.4% (4/11) due to multiple criteria.
Clinical Outcomes and Complications
Clinical follow-up data were available for 75.8% (144/190) of on-label patients and 75.0% (105/140) of off-label patients. The median (IQR) duration of clinical follow-up was 14.6 (6.4–36.3) months for on-label patients and 13.7 (6.7–28.1) months for off-label patients (p = 0.585).
The per-procedure incidence of procedural complications was 9.6% (20/209) for on-label procedures and 14.5% (20/138) for off-label procedures (p = 0.172). The per-patient risk of ischemic complications was 4.2% (6/144) for on-label patients compared with 15.2% (16/105) for off-label patients (p = 0.003). Among patients with ischemic complications, 40.9% (9/22) had early ischemic complications, and 22.2% (2/9) of early ischemic complications occurred after on-label treatments and 77.8% (7/9) occurred after off-label treatments. The per-patient risk of stroke resulting in increased mRS score was 1.4% (2/144) for on-label patients and 7.6% (8/105) for off-label patients (p = 0.020). Among the patients who experienced ischemic complications after on-label treatment, 83.3% (5/6) received previously off-label treatment. Among the patients who experienced ischemic complications after off-label treatment, aneurysms were considered off-label due to location in 68.8% (11/16), neck size in 18.8% (3/16), parent vessel size in 12.5% (2/16), morphology in 12.5% (2/16), recent rupture in 12.5% (2/16), patient age in 6.3% (1/16), a prior stent in 0.0% (0/16), and multiple off-label criteria in 12.5% (2/16). Of the 11 aneurysms that were considered off-label due to location, 8 were in the posterior circulation. Intracranial hemorrhage occurred in 2.8% (4/144) of on-label patients and 5.7% (6/105) of off-label patients (p = 0.330). Postprocedural mRS scores, including those indicative of death, did not differ significantly between on-label and off-label patients (p = 0.325).
Discussion
In this study, we comprehensively compared the safety and efficacy of on-label and off-label PED use in a large cohort of patients to assess the degree and reasonableness of off-label utilization in real-world practice. There was a higher overall risk of ischemic complications in patients who received off-label treatment, particularly in posterior circulation, but other metrics of safety and efficacy were comparable between the on-label and off-label groups. These findings suggest that current off-label use of PED can provide comparable performance to formally approved on-label uses, and secondarily, that there may be future opportunity to expand the currently approved indications for use.
Initial approval of PED use in the United States was based on studies that focused primarily on unruptured, medium-sized ICA aneurysms.2 Since then, several studies have investigated the safety and efficacy of PED use in other situations and assessed the impact of aneurysm size,9–11 location,12,13,19 or rupture status10,20–22 on outcomes after PED treatment. Due to the nature of the device approval pathway, much of the knowledge gathered from these and other studies is not incorporated into the approved indications for PED.23 As a result, there is a disparity between formally recognized, on-label uses and what expert clinicians may regard as reasonable off-label uses.
Not all off-label uses of PED have the same safety and efficacy. For instance, our data suggest that off-label treatment of aneurysms with a small neck size may achieve complete aneurysm occlusion after PED placement at a higher rate than on-label aneurysms, which is in line with the results of previous studies.11 Conversely, our data comport with the findings of other studies by suggesting that aneurysms in off-label locations, particularly posterior circulation, may carry an increased risk of ischemic complications after PED placement.19 Accordingly, PED safety and efficacy under the broad umbrella of off-label use are heterogeneous, and classification of aneurysm treatment as on-label or off-label is not in itself sufficient to guide clinical decision-making. It is also important to note that the higher rate of ischemic complications seen with the use of flow diversion in posterior circulation may be reasonable compared with alternative treatments for posterior circulation aneurysms that may have high rates of perioperative complications.
Overall, our results suggest that expert judgment about reasonable PED use may allow for treatment of a greater range of aneurysms than would be allowed by the approved indications alone. Complete aneurysm occlusion after PED placement occurred in 76.4% of on-label aneurysms and 75.6% of off-label aneurysms, both of which are very similar to the occlusion rates demonstrated in the PUFS and PREMIER studies.2,3 Procedural complications and postprocedural functional status were also comparable between the on-label and off-label groups in most respects, with the notable exception of posterior circulation aneurysms. In fact, every category of off-label use in this cohort met or exceeded the preset safety and efficacy goals used in the PUFS trial (> 50% rate of aneurysm occlusion without parent vessel stenosis and < 20% rate of major ipsilateral stroke).2 These results expressly do not imply the appropriateness of PED use in all off-label settings. Rather, these data indicate that the clinical judgment and technical skill of experienced physicians can facilitate off-label PED use with similar performance as on-label applications, and there may be future opportunities to thoughtfully expand approved uses of PED. Some neurointerventionalists may consider this validation of off-label PED use as unnecessary given the already widespread utilization of these treatments. However, widespread utilization of seemingly obvious off-label treatments has not always resulted in clinical validation, including most memorably with stenting of intracranial atherosclerotic lesions.24 Therefore, even seemingly obvious off-label uses warrant clinical scrutiny to identify areas of concern and to highlight pathways for formal validation and approval.
There were several limitations to this study. First, heterogeneous follow-up duration may have impacted the documented rates of occlusion or complications. More specifically, aneurysm occlusion or clinical complications may have been undercounted in patients with short follow-up, whereas spurious clinical events may have been misclassified as PED-related complications in patients with extended follow-up. Second, there was potential for bias in patient selection. Although this bias may reflect the expert judgment that is the subject of this study, such as the selective prolongation of dual antiplatelet therapy beyond 6 months in patients with in-stent stenosis, there may have been subtle additional determinants of safety and efficacy that were not captured in our analysis. Third, expansion of the approved indications for PED use during the review period may have affected patient selection. Fourth, ruptured aneurysms, the treatment of which is considered off-label, represent a vastly different clinical situation than unruptured aneurysms and may confound comparisons of intrinsic characteristics such as size or location. Finally, conclusions drawn from an experienced, high-volume institution may be difficult to generalize to centers with less PED experience.
Conclusions
In real-world clinical practice, off-label use of PED is common and can achieve similar efficacy as on-label use, though with a higher rate of ischemic complications. With appropriate consideration of individual patient characteristics and understanding of the risk of ischemic complications, these results highlight the scale and general feasibility of off-label use in the hands of experts and the opportunity to expand the approved indications of PED with future clinical trials.
Disclosures
Dr. Osbun is a consultant for Medtronic, Terumo, and MicroVention. Dr. Moran is a consultant for Medtronic and Cerenovus. Dr. Kansagra is a consultant for MicroVention, Penumbra, and iSchemaView.
Author Contributions
Conception and design: Kansagra, Cler, Lauzier. Acquisition of data: Kansagra, Cler, Lauzier. Analysis and interpretation of data: Kansagra, Cler. Drafting the article: Kansagra, Cler. Critically revising the article: Kansagra, Cler, Lauzier. Reviewed submitted version of manuscript: all authors. Statistical analysis: Kansagra, Cler. Study supervision: Kansagra.
Supplemental Information
Previous Presentations
An abbreviated version of this work was presented as a live presentation at the 2021 Society of Neurointerventional Surgery Annual Meeting, Colorado Springs, CO, June 26–30, 2021.
References
- 1↑
US Food & Drug Administration. Premarket approval, Pipeline Flex embolization device. US Department of Health & Human Services. Accessed December 2, 2021. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P100018S015
- 2↑
Becske T, Kallmes DF, Saatci I, et al. Pipeline for uncoilable or failed aneurysms: results from a multicenter clinical trial. Radiology. 2013;267(3):858–868.
- 3↑
Hanel RA, Kallmes DF, Lopes DK, et al. Prospective study on embolization of intracranial aneurysms with the pipeline device: the PREMIER study 1 year results. J Neurointerv Surg. 2020;12(1):62–66.
- 4↑
US Food & Drug Administration. Label change, Premarket approval, Pipeline Flex embolization device. US Department of Health & Human Services. Accessed December 2, 2021. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P100018S015
- 5↑
Kallmes DF, Brinjikji W, Boccardi E, et al. Aneurysm Study of Pipeline in an Observational Registry (ASPIRe). Intervent Neurol. 2016;5(1-2):89–99.
- 6
Patel PD, Chalouhi N, Atallah E, et al. Off-label uses of the Pipeline embolization device: a review of the literature. Neurosurg Focus. 2017;42(6):E4.
- 7↑
Limbucci N, Leone G, Renieri L, et al. Expanding indications for flow diverters: distal aneurysms, bifurcation aneurysms, small aneurysms, previously coiled aneurysms and clipped aneurysms, and carotid cavernous fistulas. Neurosurgery. 2020;86(suppl 1):S85–S94.
- 8
Zammar SG, Buell TJ, Chen CJ, et al. Outcomes after off-label use of the Pipeline embolization device for intracranial aneurysms: a multicenter cohort study. World Neurosurg. 2018;115:e200–e205.
- 9
Griessenauer CJ, Ogilvy CS, Foreman PM, et al. Pipeline Embolization Device for small intracranial aneurysms: evaluation of safety and efficacy in a multicenter cohort. Neurosurgery. 2017;80(4):579–587.
- 10↑
Chalouhi N, Zanaty M, Whiting A, et al. Safety and efficacy of the Pipeline Embolization Device in 100 small intracranial aneurysms. J Neurosurg. 2015;122(6):1498–1502.
- 11↑
Kole MJ, Miller TR, Cannarsa G, et al. Pipeline embolization device diameter is an important factor determining the efficacy of flow diversion treatment of small intracranial saccular aneurysms. J Neurointerv Surg. 2019;11(10):1004–1008.
- 12↑
Primiani CT, Ren Z, Kan P, et al. A2, M2, P2 aneurysms and beyond: results of treatment with pipeline embolization device in 65 patients. J Neurointerv Surg. 2019;11(9):903–907.
- 13↑
Lin N, Lanzino G, Lopes DK, et al. Treatment of distal anterior circulation aneurysms with the Pipeline embolization device: a US multicenter experience. Neurosurgery. 2016;79(1):14–22.
- 14
Cagnazzo F, Mantilla D, Lefevre PH, Dargazanli C, Gascou G, Costalat V. Treatment of middle cerebral artery aneurysms with flow-diverter stents: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2017;38(12):2289–2294.
- 15
Brinjikji W, Murad MH, Lanzino G, Cloft HJ, Kallmes DF. Endovascular treatment of intracranial aneurysms with flow diverters: a meta-analysis. Stroke. 2013;44(2):442–447.
- 16↑
Sambu N, Curzen N. Monitoring the effectiveness of antiplatelet therapy: opportunities and limitations. Br J Clin Pharmacol. 2011;72(4):683–696.
- 17↑
O’kelly CJ, Krings T, Fiorella D, Marotta TR. A novel grading scale for the angiographic assessment of intracranial aneurysms treated using flow diverting stents. Interv Neuroradiol. 2010;16(2):133–137.
- 18↑
Rankin J. Cerebral vascular accidents in patients over the age of 60. III. Diagnosis and treatment. Scott Med J. 1957;2(6):254–268.
- 19↑
Cagnazzo F, Perrini P, Dargazanli C, et al. Treatment of unruptured distal anterior circulation aneurysms with flow-diverter stents: a meta-analysis. AJNR Am J Neuroradiol. 2019;40(4):687–693.
- 20
Cagnazzo F, di Carlo DT, Cappucci M, Lefevre PH, Costalat V, Perrini P. Acutely ruptured intracranial aneurysms treated with flow-diverter stents: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2018;39(9):1669–1675.
- 21
Chan RS, Mak CH, Wong AK, Chan KY, Leung KM. Use of the Pipeline embolization device to treat recently ruptured dissecting cerebral aneurysms. Interv Neuroradiol. 2014;20(4):436–441.
- 22
Madaelil TP, Moran CJ, Cross DT III, Kansagra AP. Flow diversion in ruptured intracranial aneurysms: a meta-analysis. AJNR Am J Neuroradiol. 2017;38(3):590–595.
- 23↑
Kallmes DF, Hanel R, Lopes D, et al. International retrospective study of the Pipeline Embolization Device: a multicenter aneurysm treatment study. AJNR Am J Neuroradiol. 2015;36(1):108–115.
- 24↑
Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365(11):993–1003.
