- Email: [email protected]
Predictors of Clinical Outcome After Treatment of Intracranial Aneurysms with the Pipeline Embolization Device
Original Article
Predictors of Clinical Outcome After Treatment of Intracranial Aneurysms with the Pipeline Embolization Device Andrew Griffin1, Vanessa Reese1, Zeynep Hu¨seyinoglu1, Donna Niedzwiecki2, Lexie Yang2, Andrew Cutler1, L. Fernando Gonzalez1, Ali Zomorodi1, Tony Smith1, Erik F. Hauck1
BACKGROUND: Flow-diverting stents have revolutionized the endovascular treatment of intracranial aneurysms. The purpose of this study is to identify predictors of adverse outcomes associated with the pipeline embolization device (PED).
-
METHODS: A retrospective analysis of all patients treated with PED at a single high-volume center from January 2014 to September 2018. Patient outcomes, neurologic morbidity/mortality, and other clinical variables were analyzed.
patient baseline, wider aneurysm neck or larger size, and rupture predict an increased risk of an unfavorable outcome.
-
RESULTS: We treated 204 aneurysms in 170 patients with PED. Mean length of follow-up was 11 months. Most (181) aneurysms (89%) were located in the anterior circulation, and 23 (11%) were found in the posterior circulation. Most aneurysms were saccular (82%), followed by fusiform (11%), blister (4%), and dissecting pseudoaneurysms (3%). Mean aneurysm size was 8.2 D 5.7 mm with 145 (71%) small aneurysms (£10 mm), 53 (26%) large aneurysms (between 10 and 25 mm), and 6 (3%) giant aneurysms (‡25 mm). Ninety-two percent of aneurysms were unruptured, and 8% were ruptured. The overall major neurologic morbidity/mortality was 4.7% and 1.8%, respectively. The all-cause mortality was 2.9%. Predictors of neurologic morbidity/mortality included the baseline modified Rankin Scale (P [ 0.001), aneurysm neck size (P [ 0.003), aneurysm size (P [ 0.006), anterior versus posterior location (P [ 0.02), and rupture at presentation (0.006). The P2Y12 Reactivity Unit, parent vessel diameter, and patient age did not correlate with adverse events.
-
CONCLUSIONS: The PED has a satisfactory safety profile in both on- and off-label indications. A poor clinical
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Key words - Aneurysm - Pipeline embolization device - Stent Abbreviations and Acronyms IPH: Intraparenchymal hemorrhage PED: Pipeline Embolization Device PRU: P2Y12 Reactivity Unit
INTRODUCTION
T
he Pipeline Embolization Device (PED; Medtronic Neurovascular, Irvine, California, USA) is the most commonly used flow diverter for the treatment of intracranial aneurysms. The PED received initial U.S. Food and Drug Administration (FDA) premarket approval in 2011 for large or giant wide-necked internal carotid artery aneurysms from the petrous to the superior hypophyseal segment. More recently, the FDA expanded the indication including smaller internal carotid artery aneurysms up to the carotid bifurcation. Numerous prior studies have demonstrated the safety of the device with low complication rates of 3%7%.1-4 However, most of these studies were multicenter studies and/or focused on the on-label indications of the device. The purpose of this study is to report on the safety of the PED in a current “real-world setting” population and to identify predictors of neurologic morbidity/mortality. METHODS Patient Population and Aneurysms We conducted a retrospective review of all consecutive patients undergoing PED placement for ruptured and unruptured intracranial aneurysms at a quaternary care center in the United States between January 1, 2014 and September 30, 2018. The electronic medical records were used to obtain relevant clinical and demographic information. Aneurysms were classified as small (10 mm), large (between 10 and 25 mm), and giant (25 mm).5 The largest aneurysm diameter and the aneurysm neck were
From the Departments of 1Neurosurgery and 2Biostatistics, Duke University Medical Center, Durham, North Carolina, USA To whom correspondence should be addressed: Andrew Griffin, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.06.185 Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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ORIGINAL ARTICLE ANDREW GRIFFIN ET AL.
PED OUTCOME PREDICTORS FOR IC ANEURYSM
measured, as well as the parent vessel diameter. The study was approved by the Institutional Review Board and was compliant with the Health Insurance Portability and Accountability Act. Individual patient consent was waived per standard retrospective protocol.
Table 1. Patient Demographics Variable Number of patients Age (years)
Outcomes The primary outcome of this study is major neurologic morbidity and mortality. Any neurologic deficit resolved within fewer than 7 days was considered minor.5 Any neurologic deficit lasting 7 days or longer was considered major.5 Neurologic morbidity was defined as any new neurologic deficit caused by intraparenchymal hemorrhage (IPH), stroke, coil prolapse, in-stent thrombosis, cranial neuropathy, or vessel perforation with creation of a fistula. Neurologic mortality was defined as death due to IPH, stroke, or aneurysm rupture. Endovascular Procedure Patients were started on dual antiplatelet therapy (aspirin 81 mg and clopidogrel 75 mg daily) 1 week before the procedure. A P2Y12 receptor inhibition test was obtained on the day of the procedure, and the P2Y12 Reactivity Unit (PRU) was recorded. PED placement was performed under general anesthesia. Postoperatively, patients were admitted to the neurocritical care unit for observation overnight. Most patients were discharged the following day and maintained on clopidogrel for 3 months and aspirin 81 mg daily for life. Statistical Analyses Continuous variables are summarized with means and standard deviations. Categorical variables are summarized with frequency counts and percentages. Univariate analyses for association with neurologic morbidity/mortality and complications were conducted on variables including baseline modified Rankin Scale (mRS), parent vessel diameter, aneurysm neck size, aneurysm location, PRU, sex, aneurysm side, aneurysm size, aneurysm type, prior treatment, and rupture. Statistical significance was assessed using an alpha level of 0.004 after Bonferroni adjustment for multiple testing. Multivariable logistic regression models were fit on complication as a function of baseline mRS and aneurysm size with either the location variable or the on/off label use variable. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, USA). RESULTS Baseline Patient Characteristics We identified 170 patients with 204 aneurysms for the analysis, and no patients were excluded (Table 1). The mean age was 56.3 13.8 years. Most patients (169) were adults (18 years), and 1 patient was 13 years of age. The majority of the patients were female (80%). Regarding race, 65.3% of them were Caucasian and 27.6% were African American. The remaining patients were other ethnicities including Asian, Hispanic, and Native American. Most patients (89.3%) had a good baseline functional status (mRS 0e2).
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Number 170 56.3 13.8
Sex Male
34 (20%)
Female
136 (80%)
Race African American Asian Caucasian
47 (27.6%) 5 (2.9%) 111 (65.3%)
Hispanic
4 (2.4%)
Native American
3 (1.8%)
PRU (mean þSD, procedure day)
137.3 þ 74.7
Baseline mRS 0
58 (34.1%)
1
81 (47.6%)
2
13 (7.6%)
3
2 (1.2%)
4
8 (4.7%)
5
8 (4.7%)
Length of follow-up (months)
11 10
PRU, P2Y12 reactivity unit; SD, standard deviation; mRS, modified Rankin Scale.
Baseline Aneurysm Characteristics The mean aneurysm size was 8.5 5.7 mm and the mean aneurysm neck size measured 5.0 2.9 mm (Table 2). The majority of aneurysms were located in the internal carotid artery (83.5%). 89% were located in the anterior circulation and 11% were in the posterior circulation. The majority of aneurysms were saccular (82.4%), followed by fusiform (11.3%), blister (3.9%) and dissecting pseudoaneurysm (2.5%). 48 (24%) aneurysms were used off-label and 156 (76%) were used on-label according to expanded indications based on the recent PREMIER trial.6 Mean parent vessel diameter was 4.0 0.7 mm. 92% were unruptured compared to 8% ruptured. The mean PRU on the day of the procedure was 137.3 74.7. PRU was tested in 92% of cases. Outcomes The overall complication rate was 13.5% (Table 3). These complications included stroke (5, 2.9%); IPH (3, 1.8%); groin hematoma (3, 1.8%); retroperitoneal hematoma (2, 1.2%); health careassociated pneumonia (2, 1.2%); in-stent thrombosis (2, 1.2%); vessel perforation (2, 1.2%); retinal artery occlusion (1, 0.6%); seizure (1, 0.6%); groin pseudoaneurysm (1, 0.6%); and aneurysm rupture (1, 0.6%). The major neurologic morbidity rate was 4.7% (8 patients), and the neurologic mortality rate was 1.8%
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ORIGINAL ARTICLE ANDREW GRIFFIN ET AL.
PED OUTCOME PREDICTORS FOR IC ANEURYSM
Table 2. Aneurysm Characteristics Variable
Number
Table 3. Safety Outcomes of Pipeline Embolization Device Placement Complications
Number (%)
All complications
23 (13.5%)
Side Left Right Midline
93 (45.6%) 6 (3%) 105 (51.5%)
Location ACA
3 (1.5%)
AChA
1 (0.5%)
BA
5 (2.5%)
Cavernous
35 (17.2%)
Clinoid
3 (1.5%)
MCA
2 (1.0%)
Ophthalmic
94 (46.1%)
PCA
3 (1.5%)
PICA
3 (1.5%)
Pcom
29 (14.2%)
Superior hypophyseal
11 (5.4%)
Terminus
3 (1.5%)
VA
12 (5.9%)
Anterior
181 (89%)
Posterior
23 (11%)
Aneurysm type Blister Dissecting pseudoaneurysm
8 (3.9%) 5 (2.5%)
Fusiform
23 (11.3%)
Saccular
168 (82.4%)
Aneurysm size
8.2 5.7
Small (10 mm)
145 (71.1%)
Large (>10 and <25 mm)
53 (26.0%)
Giant (25 mm)
6 (2.9%)
Aneurysm neck [mm] (mean SD)
5.0 2.9
Parent vessel diameter [mm] (mean SD)
4.0 0.7
Rupture status Ruptured Unruptured
16 (7.8%) 188 (92.2%)
Prior clipping or coiling No
153 (75%)
Yes
51 (25%)
ACA, anterior circulation artery; AChA, anterior choroidal artery; BA, basilar artery; MCA, middle cerebral artery; PCA, posterior communicating artery; PICA, posterior inferior communicating artery; Pcom, posterior communicating artery; VA, vertebral artery; SD, standard deviation.
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Major neurologic morbidity
8 (4.7%)
Neurologic mortality
3 (1.8%)
All-cause mortality
5 (2.9%)
(3 patients) with deaths due to stroke, IPH, or aneurysm rupture. The all-cause mortality was 2.9% (5 patients). On-label and off-label use was not significantly associated with neurologic morbidity (P ¼ 0.3588) or mortality (P ¼ 0.1386) in univariate analysis. The complication rate was 7.7% for on-label cases and 20.8% for off-label cases (P ¼ 0.016); however, after adjusting for baseline mRS and aneurysm size in multivariate analysis, on/off label use was not significantly associated with complications (P ¼ 0.1488). A univariate analysis on neurologic morbidity and mortality was performed after Bonferroni correction for multiple testing (significance at 0.004 level; Table 4). Significant predictors of major neurologic morbidity/mortality included the baseline mRS (P ¼ 0.001) and aneurysm neck size (P ¼ 0.003). The results of the univariate analysis on all complications are summarized in Table 5. After Bonferroni correction for multiple testing (significance at 0.004 level), predictors reaching significance were baseline mRS (P ¼ 0.004), aneurysm size (P ¼ 0.004), and rupture at presentation (0.004). Posterior location was associated with a trend toward adverse events but did not reach significance level. PRU, parent vessel diameter, and patient age did not correlate with neurologic morbidity and mortality in either analysis.
DISCUSSION This study demonstrates the PED is safe for both on-label and offlabel treatment of intracranial aneurysms in a real-world setting. The major neurologic morbidity and mortality rates for all aneurysms, including both ruptured and unruptured aneurysms, were 4.7% and 1.8%, respectively, for a combined rate of 6.5%. This is in line with other prior large studies that have reported combined morbidity and mortality rates ranging from 5%8%.1,2,5,7 Major complications that occurred were hemorrhagic or thrombotic and included stroke (2.9%), intraparenchymal hemorrhage (1.8%), and groin hematoma (1.8%). Significant predictors of neurologic morbidity/mortality and overall complications included baseline mRS, aneurysm size, neck width, and rupture at presentation. Giant aneurysms have a poor natural history and can be challenging to treat. Prior work has shown that flow diversion is a viable treatment option for these aneurysms,1,7-9 but it is associated with increased complication rates.2,5 Our findings support these data and suggest that patients undergoing PED of giant aneurysms are at higher risk for neurologic morbidity and mortality—higher than what other recent studies regarding pipeline suggest such as the PREMIER data.6
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PED OUTCOME PREDICTORS FOR IC ANEURYSM
Table 4. Predictors of Neurologic Morbidity and Mortality*
Table 5. Predictors of Any Complication*
Neurologic Morbidity and Mortality
Complications Yes (N [ 23)
No (N [ 181)
P Value
Baseline mRS
1.8 1.6
1.0 1.2
0.004
Parent vessel diameter
4.1 0.7
4.0 0.7
0.671
Aneurysm neck size
7.5 4.8
4.6 2.4
Variable Yes (N [ 11)
No (N [ 193)
P Value
Baseline mRS
2.6 1.9
1.0 1.1
0.001
Parent vessel (mm)
4.1 0.7
4.0 0.7
0.669
Aneurysm neck size
8.9 5.5
4.7 2.5
0.003
Anterior
7 (63.6%)
174 (90.2%)
Posterior
4 (36.4%)
19 (9.8%)
156.8 76.8
136.1 74.7
Variable
Anterior/posterior
PRU
0.024
Sex 2 (18.2%)
38 (19.7%)
Female
9 (81.8%)
155 (80.3%)
Aneurysm size Small
4 (36.4%)
141 (73.1%)
Medium
5 (45.5%)
48 (24.9%)
Large
2 (18.2%)
4 (2.1%)
Aneurysm type 0 (0.0%)
8 (4.1%)
Dissecting pseudoaneurysm
1 (9.1%)
4 (2.1%)
Fusiform
2 (18.2%)
21 (10.9%)
Saccular
8 (72.7%)
160 (82.9%)
Rupture status 4 (36.4%)
12 (6.2%)
Unruptured
7 (63.6%)
181 (93.8%)
This must be carefully considered when discussing treatment options with patients and their families. Posterior circulation aneurysms can be treacherous lesions to treat either surgically or endovascularly as the posterior circulation anatomy supplies the highly critical and sensitive brainstem structures. Multiple studies have demonstrated higher complication rates in patients with posterior circulation aneurysms treated with flow diversion compared with anterior circulation aneurysms.10,11 Griessenauer reviewed 131 posterior circulation aneurysms treated with Pipeline and reported an overall complication rate of 24.8%.12 Bender et al13 reported an overall complication rate of 15% among 59 posterior circulation aneurysms treated with Pipeline. Our cohort with posterior circulation aneurysms trended toward a higher overall complication rate with 30% compared with only 8.8% in patients with anterior circulation aneurysms. It may relate to the higher incidence of ruptured cases in the posterior circulation (30%) compared with the anterior circulation (4%).
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144.6 73.6
136.3 75
Male
5 (21.7%)
35 (19.3%)
Female
18 (78.3%)
146 (80.7%)
Sex
0.437 0.783
0.004
Small
11 (47.8%)
134 (74.0%)
Medium
9 (39.1%)
44 (24.3%)
3 (13%)
3 (1.7%)
Blister
1 (4.3%)
7 (3.9%)
Dissecting pseudoaneurysm
1 (4.3%)
4 (2.2%)
0.053
Fusiform
6 (26.1%)
17 (9.4%)
Saccular
15 (65.2%)
153 (84.5%)
Rupture status
mRS, modified Rankin Scale; PRU, P2Y12 reactivity unit. *Multiple variable testing after Bonferroni correction (significance level at P ¼ 0.004).
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16 (8.8%)
Aneurysm type
0.006
Ruptured
165 (91.2%)
7 (30.4%)
Large 0.237
Blister
16 (69.6%)
Posterior
Aneurysm size 0.006
0.002 0.007
Anterior
PRU 0.264 1.000
Male
Anterior/posterior
0.004
Ruptured
6 (26.1%)
10 (5.5%)
Unruptured
17 (73.9%)
171 (94.5%)
mRS, modified Rankin Scale; PRU, P2Y12 reactivity unit. *Multiple variable testing after Bonferroni correction (significance level at P ¼ 0.004).
The baseline mRS and rupture status may be interrelated variables. It is intuitive that patients with a poor baseline functional status and/or rupture will have a higher rate of morbidity/mortality. The PUFS and ASPIRe studies only evaluated unruptured aneurysms, and the IntrePED data did not compare complication rates of ruptured to unruptured aneurysms. Smaller case series focusing only on ruptured aneurysms treated with PED have shown complication rates ranging from 5%19%.14,15 Patients with ruptured intracranial aneurysms have additional limitations regarding flow diversion. Starting dual antiplatelet therapy and heparin before securing a ruptured aneurysm in preparation for flow diversion may be associated with an increased risk of rupture in itself, even though we did not encounter this complication in this series. After stent placement, the aneurysm may not be fully secured if flow diversion was chosen as stand-alone treatment. In one case of a ruptured blister aneurysm, we observed aneurysm growth after treatment with only 1 PED. The aneurysm subsequently thrombosed after treatment with a second device 2 days
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ORIGINAL ARTICLE ANDREW GRIFFIN ET AL.
PED OUTCOME PREDICTORS FOR IC ANEURYSM
later. Furthermore, the potential need for cerebrospinal fluid diversion is complicated by dual antiplatelet therapy. Generally, we recommend management of cerebrospinal fluid shunting before flow diversion if possible. On-label and off-label use was not significantly associated with the overall complication rate, neurologic morbidity, or neurologic mortality. This is in line with other recent studies in the literature.16,17 Zammar et al16 examined the outcomes of off-label aneurysms treated with PED at 4 different centers based on FDA-approved guidelines from 2011e2015. They reported an overall complication rate of 8.3%, which is lower than our overall complication rate for off-label cases of 20.8%. The complication rate in this study may be higher because our on-label and off-label indications were based on the most recent FDA guidelines, so many of the aneurysms in the Zammar et al16 cohort would now be considered on-label. Thrombotic and hemorrhagic complications are the most common and serious complications associated with PED placement. Interventionalists have tried to mitigate these risks with platelet function testing to identify hyporesponders and hyperresponders to antiplatelet therapy. However, platelet function
REFERENCES 1. Becske T, Kallmes DF, Saatci I, et al. Pipeline for uncoilable or failed aneurysms: results from a multicenter clinical trial. Radiology. 2013;267: 858-868. 2. Kallmes DF, Brinjikji W, Boccardi E, et al. Aneurysm study of pipeline in an observational Registry (ASPIRe). Intervent Neurol. 2016;5:89-99. 3. Park MS, Kilburg C, Taussky P, et al. Pipeline embolization device with or without adjunctive coil embolization: analysis of complications from the IntrePED Registry. AJNR Am J Neuroradiol. 2016; 37:1127-1131. 4. Kallmes DF, Brinjikji W, Cekirge S, et al. Safety and efficacy of the Pipeline embolization device for treatment of intracranial aneurysms: a pooled analysis of 3 large studies. J Neurosurg. 2017;127: 775-780. 5. 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;36:108-115. 6. Hanel R. Prospective, multi-center study of flow diversion for small and medium-sized aneurysms: results of the Premier trial. Paper presented at International Stroke Conference. February 22-24, 2017. Houston, TX. 7. Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D. The pipeline embolization device for the intracranial treatment of aneurysms trial. AJNR Am J Neuroradiol. 2011;32:34-40.
testing before PED placement remains controversial.18-22 Some authors have found that preoperative P2Y12 values predict complications,20,21,23 while others have found that P2Y12 levels do not influence the risk of complications22,24 or may even increase risk of complications.25 PRU did not correlate with clinical outcomes for patients treated with PED in our cohort. CONCLUSIONS The major neurologic morbidity/mortality associated with PED in both on- and off-label situations is low in this large single-center review and in line with other published data. Nevertheless, in offlabel situations including larger, ruptured aneurysms at any location, the chance of an adverse outcome is increased. The current study identifies individual, significant risk factors associated with morbidity/mortality or complications. These factors should be considered carefully when choosing treatment with PED and counseling patients and their families. Risk factors include a poor clinical baseline, a wider neck or larger size aneurysm, and rupture at presentation. Posterior location is another potential factor to be considered.
8. Adeeb N, Griessenauer CJ, Shallwani H, et al. Pipeline embolization device in treatment of 50 unruptured large and giant aneurysms. World Neurosurg. 2017;105:232-237. 9. Miyachi S, Hiramatsu R, Ohnishi H, Yagi R, Kuroiwa T. Usefulness of the pipeline embolic device for large and giant carotid cavernous aneurysms. Neurointervention. 2017;12:83-90. 10. Brinjikji W, Murad MH, Lanzino G, Cloft HJ, Kallmes DF. Endovascular treatment of intracranial aneurysms with flow diverters: a meta-analysis. Stroke. 2013;44:442-447. 11. Lopes DK, Jang DK, Cekirge S, et al. Morbidity and mortality in patients with posterior circulation aneurysms treated with the pipeline embolization device: a subgroup analysis of the International Retrospective Study of the pipeline embolization device. Neurosurgery. 2018;83:488-500. 12. Griessenauer CJ, Ogilvy CS, Adeeb N, et al. Pipeline embolization of posterior circulation aneurysms: a multicenter study of 131 aneurysms. J Neurosurg. 2018:1-13. 13. Bender MT, Colby GP, Jiang B, et al. Flow diversion of posterior circulation cerebral aneurysms: a single-institution series of 59 cases. Neurosurgery. 2019;84:206-216. 14. Lin N, Brouillard AM, Keigher KM, et al. Utilization of pipeline embolization device for treatment of ruptured intracranial aneurysms: US multicenter experience. J Neurointerv Surg. 2015;7: 808-815. 15. Chalouhi N, Zanaty M, Whiting A, et al. Treatment of ruptured intracranial aneurysms with the
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pipeline embolization device. Neurosurgery. 2015; 76:165-172. 16. 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. 17. 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:E4. 18. Adeeb N, Griessenauer CJ, Foreman PM, et al. Use of platelet function testing before Pipeline embolization device placement: a multicenter cohort study. Stroke. 2017;48:1322-1330. 19. Taylor LI, Dickerson JC, Dambrino RJ, et al. Platelet testing in flow diversion: a review of the evidence. Neurosurg Focus. 2017;42:E5. 20. Delgado Almandoz JE, Crandall BM, Scholz JM, et al. Last-recorded P2Y12 reaction units value is strongly associated with thromboembolic and hemorrhagic complications occurring up to 6 months after treatment in patients with cerebral aneurysms treated with the pipeline embolization device. AJNR Am J Neuroradiol. 2014;35:128-135. 21. Tan LA, Keigher KM, Munich SA, Moftakhar R, Lopes DK. Thromboembolic complications with pipeline embolization device placement: impact of procedure time, number of stents and preprocedure P2Y12 reaction unit (PRU) value. J Neurointerv Surg. 2015;7:217-221. 22. Bender MT, Lin LM, Colby GP, et al. P2Y12 hyporesponse (PRU>200) is not associated with increased thromboembolic complications in
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anterior circulation Pipeline. J Neurointerv Surg. 2017;9:978-981.
pipeline embolization device: a review and metaanalysis. J Neurointerv Surg. 2016;8:58-65.
23. Almandoz JED, Crandall BM, Scholz JM, et al. Preprocedure P2Y12 reaction units value predicts perioperative thromboembolic and hemorrhagic complications in patients with cerebral aneurysms treated with the pipeline embolization device. J Neurointerv Surg. 2013;5(suppl 3):iii3-iii10.
25. Brinjikji W, Lanzino G, Cloft HJ, Siddiqui AH, Hanel RA, Kallmes DF. Platelet testing is associated with worse clinical outcomes for patients treated with the pipeline embolization device. AJNR Am J Neuroradiol. 2015;36:2090-2095.
commercial or financial relationships that could be construed as a potential conflict of interest. Received 9 May 2019; accepted 24 June 2019 Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.06.185 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com
24. Skukalek SL, Winkler AM, Kang J, et al. Effect of antiplatelet therapy and platelet function testing on hemorrhagic and thrombotic complications in patients with cerebral aneurysms treated with the
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any
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Predictors of Clinical Outcome After Treatment of Intracranial Aneurysms with the Pipeline Embolization Device Andrew Griffin1, Vanessa Reese1, Zeynep Hu¨seyinoglu1, Donna Niedzwiecki2, Lexie Yang2, Andrew Cutler1, L. Fernando Gonzalez1, Ali Zomorodi1, Tony Smith1, Erik F. Hauck1
BACKGROUND: Flow-diverting stents have revolutionized the endovascular treatment of intracranial aneurysms. The purpose of this study is to identify predictors of adverse outcomes associated with the pipeline embolization device (PED).
-
METHODS: A retrospective analysis of all patients treated with PED at a single high-volume center from January 2014 to September 2018. Patient outcomes, neurologic morbidity/mortality, and other clinical variables were analyzed.
patient baseline, wider aneurysm neck or larger size, and rupture predict an increased risk of an unfavorable outcome.
-
RESULTS: We treated 204 aneurysms in 170 patients with PED. Mean length of follow-up was 11 months. Most (181) aneurysms (89%) were located in the anterior circulation, and 23 (11%) were found in the posterior circulation. Most aneurysms were saccular (82%), followed by fusiform (11%), blister (4%), and dissecting pseudoaneurysms (3%). Mean aneurysm size was 8.2 D 5.7 mm with 145 (71%) small aneurysms (£10 mm), 53 (26%) large aneurysms (between 10 and 25 mm), and 6 (3%) giant aneurysms (‡25 mm). Ninety-two percent of aneurysms were unruptured, and 8% were ruptured. The overall major neurologic morbidity/mortality was 4.7% and 1.8%, respectively. The all-cause mortality was 2.9%. Predictors of neurologic morbidity/mortality included the baseline modified Rankin Scale (P [ 0.001), aneurysm neck size (P [ 0.003), aneurysm size (P [ 0.006), anterior versus posterior location (P [ 0.02), and rupture at presentation (0.006). The P2Y12 Reactivity Unit, parent vessel diameter, and patient age did not correlate with adverse events.
-
CONCLUSIONS: The PED has a satisfactory safety profile in both on- and off-label indications. A poor clinical
-
Key words - Aneurysm - Pipeline embolization device - Stent Abbreviations and Acronyms IPH: Intraparenchymal hemorrhage PED: Pipeline Embolization Device PRU: P2Y12 Reactivity Unit
INTRODUCTION
T
he Pipeline Embolization Device (PED; Medtronic Neurovascular, Irvine, California, USA) is the most commonly used flow diverter for the treatment of intracranial aneurysms. The PED received initial U.S. Food and Drug Administration (FDA) premarket approval in 2011 for large or giant wide-necked internal carotid artery aneurysms from the petrous to the superior hypophyseal segment. More recently, the FDA expanded the indication including smaller internal carotid artery aneurysms up to the carotid bifurcation. Numerous prior studies have demonstrated the safety of the device with low complication rates of 3%7%.1-4 However, most of these studies were multicenter studies and/or focused on the on-label indications of the device. The purpose of this study is to report on the safety of the PED in a current “real-world setting” population and to identify predictors of neurologic morbidity/mortality. METHODS Patient Population and Aneurysms We conducted a retrospective review of all consecutive patients undergoing PED placement for ruptured and unruptured intracranial aneurysms at a quaternary care center in the United States between January 1, 2014 and September 30, 2018. The electronic medical records were used to obtain relevant clinical and demographic information. Aneurysms were classified as small (10 mm), large (between 10 and 25 mm), and giant (25 mm).5 The largest aneurysm diameter and the aneurysm neck were
From the Departments of 1Neurosurgery and 2Biostatistics, Duke University Medical Center, Durham, North Carolina, USA To whom correspondence should be addressed: Andrew Griffin, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.06.185 Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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measured, as well as the parent vessel diameter. The study was approved by the Institutional Review Board and was compliant with the Health Insurance Portability and Accountability Act. Individual patient consent was waived per standard retrospective protocol.
Table 1. Patient Demographics Variable Number of patients Age (years)
Outcomes The primary outcome of this study is major neurologic morbidity and mortality. Any neurologic deficit resolved within fewer than 7 days was considered minor.5 Any neurologic deficit lasting 7 days or longer was considered major.5 Neurologic morbidity was defined as any new neurologic deficit caused by intraparenchymal hemorrhage (IPH), stroke, coil prolapse, in-stent thrombosis, cranial neuropathy, or vessel perforation with creation of a fistula. Neurologic mortality was defined as death due to IPH, stroke, or aneurysm rupture. Endovascular Procedure Patients were started on dual antiplatelet therapy (aspirin 81 mg and clopidogrel 75 mg daily) 1 week before the procedure. A P2Y12 receptor inhibition test was obtained on the day of the procedure, and the P2Y12 Reactivity Unit (PRU) was recorded. PED placement was performed under general anesthesia. Postoperatively, patients were admitted to the neurocritical care unit for observation overnight. Most patients were discharged the following day and maintained on clopidogrel for 3 months and aspirin 81 mg daily for life. Statistical Analyses Continuous variables are summarized with means and standard deviations. Categorical variables are summarized with frequency counts and percentages. Univariate analyses for association with neurologic morbidity/mortality and complications were conducted on variables including baseline modified Rankin Scale (mRS), parent vessel diameter, aneurysm neck size, aneurysm location, PRU, sex, aneurysm side, aneurysm size, aneurysm type, prior treatment, and rupture. Statistical significance was assessed using an alpha level of 0.004 after Bonferroni adjustment for multiple testing. Multivariable logistic regression models were fit on complication as a function of baseline mRS and aneurysm size with either the location variable or the on/off label use variable. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, USA). RESULTS Baseline Patient Characteristics We identified 170 patients with 204 aneurysms for the analysis, and no patients were excluded (Table 1). The mean age was 56.3 13.8 years. Most patients (169) were adults (18 years), and 1 patient was 13 years of age. The majority of the patients were female (80%). Regarding race, 65.3% of them were Caucasian and 27.6% were African American. The remaining patients were other ethnicities including Asian, Hispanic, and Native American. Most patients (89.3%) had a good baseline functional status (mRS 0e2).
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Number 170 56.3 13.8
Sex Male
34 (20%)
Female
136 (80%)
Race African American Asian Caucasian
47 (27.6%) 5 (2.9%) 111 (65.3%)
Hispanic
4 (2.4%)
Native American
3 (1.8%)
PRU (mean þSD, procedure day)
137.3 þ 74.7
Baseline mRS 0
58 (34.1%)
1
81 (47.6%)
2
13 (7.6%)
3
2 (1.2%)
4
8 (4.7%)
5
8 (4.7%)
Length of follow-up (months)
11 10
PRU, P2Y12 reactivity unit; SD, standard deviation; mRS, modified Rankin Scale.
Baseline Aneurysm Characteristics The mean aneurysm size was 8.5 5.7 mm and the mean aneurysm neck size measured 5.0 2.9 mm (Table 2). The majority of aneurysms were located in the internal carotid artery (83.5%). 89% were located in the anterior circulation and 11% were in the posterior circulation. The majority of aneurysms were saccular (82.4%), followed by fusiform (11.3%), blister (3.9%) and dissecting pseudoaneurysm (2.5%). 48 (24%) aneurysms were used off-label and 156 (76%) were used on-label according to expanded indications based on the recent PREMIER trial.6 Mean parent vessel diameter was 4.0 0.7 mm. 92% were unruptured compared to 8% ruptured. The mean PRU on the day of the procedure was 137.3 74.7. PRU was tested in 92% of cases. Outcomes The overall complication rate was 13.5% (Table 3). These complications included stroke (5, 2.9%); IPH (3, 1.8%); groin hematoma (3, 1.8%); retroperitoneal hematoma (2, 1.2%); health careassociated pneumonia (2, 1.2%); in-stent thrombosis (2, 1.2%); vessel perforation (2, 1.2%); retinal artery occlusion (1, 0.6%); seizure (1, 0.6%); groin pseudoaneurysm (1, 0.6%); and aneurysm rupture (1, 0.6%). The major neurologic morbidity rate was 4.7% (8 patients), and the neurologic mortality rate was 1.8%
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PED OUTCOME PREDICTORS FOR IC ANEURYSM
Table 2. Aneurysm Characteristics Variable
Number
Table 3. Safety Outcomes of Pipeline Embolization Device Placement Complications
Number (%)
All complications
23 (13.5%)
Side Left Right Midline
93 (45.6%) 6 (3%) 105 (51.5%)
Location ACA
3 (1.5%)
AChA
1 (0.5%)
BA
5 (2.5%)
Cavernous
35 (17.2%)
Clinoid
3 (1.5%)
MCA
2 (1.0%)
Ophthalmic
94 (46.1%)
PCA
3 (1.5%)
PICA
3 (1.5%)
Pcom
29 (14.2%)
Superior hypophyseal
11 (5.4%)
Terminus
3 (1.5%)
VA
12 (5.9%)
Anterior
181 (89%)
Posterior
23 (11%)
Aneurysm type Blister Dissecting pseudoaneurysm
8 (3.9%) 5 (2.5%)
Fusiform
23 (11.3%)
Saccular
168 (82.4%)
Aneurysm size
8.2 5.7
Small (10 mm)
145 (71.1%)
Large (>10 and <25 mm)
53 (26.0%)
Giant (25 mm)
6 (2.9%)
Aneurysm neck [mm] (mean SD)
5.0 2.9
Parent vessel diameter [mm] (mean SD)
4.0 0.7
Rupture status Ruptured Unruptured
16 (7.8%) 188 (92.2%)
Prior clipping or coiling No
153 (75%)
Yes
51 (25%)
ACA, anterior circulation artery; AChA, anterior choroidal artery; BA, basilar artery; MCA, middle cerebral artery; PCA, posterior communicating artery; PICA, posterior inferior communicating artery; Pcom, posterior communicating artery; VA, vertebral artery; SD, standard deviation.
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Major neurologic morbidity
8 (4.7%)
Neurologic mortality
3 (1.8%)
All-cause mortality
5 (2.9%)
(3 patients) with deaths due to stroke, IPH, or aneurysm rupture. The all-cause mortality was 2.9% (5 patients). On-label and off-label use was not significantly associated with neurologic morbidity (P ¼ 0.3588) or mortality (P ¼ 0.1386) in univariate analysis. The complication rate was 7.7% for on-label cases and 20.8% for off-label cases (P ¼ 0.016); however, after adjusting for baseline mRS and aneurysm size in multivariate analysis, on/off label use was not significantly associated with complications (P ¼ 0.1488). A univariate analysis on neurologic morbidity and mortality was performed after Bonferroni correction for multiple testing (significance at 0.004 level; Table 4). Significant predictors of major neurologic morbidity/mortality included the baseline mRS (P ¼ 0.001) and aneurysm neck size (P ¼ 0.003). The results of the univariate analysis on all complications are summarized in Table 5. After Bonferroni correction for multiple testing (significance at 0.004 level), predictors reaching significance were baseline mRS (P ¼ 0.004), aneurysm size (P ¼ 0.004), and rupture at presentation (0.004). Posterior location was associated with a trend toward adverse events but did not reach significance level. PRU, parent vessel diameter, and patient age did not correlate with neurologic morbidity and mortality in either analysis.
DISCUSSION This study demonstrates the PED is safe for both on-label and offlabel treatment of intracranial aneurysms in a real-world setting. The major neurologic morbidity and mortality rates for all aneurysms, including both ruptured and unruptured aneurysms, were 4.7% and 1.8%, respectively, for a combined rate of 6.5%. This is in line with other prior large studies that have reported combined morbidity and mortality rates ranging from 5%8%.1,2,5,7 Major complications that occurred were hemorrhagic or thrombotic and included stroke (2.9%), intraparenchymal hemorrhage (1.8%), and groin hematoma (1.8%). Significant predictors of neurologic morbidity/mortality and overall complications included baseline mRS, aneurysm size, neck width, and rupture at presentation. Giant aneurysms have a poor natural history and can be challenging to treat. Prior work has shown that flow diversion is a viable treatment option for these aneurysms,1,7-9 but it is associated with increased complication rates.2,5 Our findings support these data and suggest that patients undergoing PED of giant aneurysms are at higher risk for neurologic morbidity and mortality—higher than what other recent studies regarding pipeline suggest such as the PREMIER data.6
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PED OUTCOME PREDICTORS FOR IC ANEURYSM
Table 4. Predictors of Neurologic Morbidity and Mortality*
Table 5. Predictors of Any Complication*
Neurologic Morbidity and Mortality
Complications Yes (N [ 23)
No (N [ 181)
P Value
Baseline mRS
1.8 1.6
1.0 1.2
0.004
Parent vessel diameter
4.1 0.7
4.0 0.7
0.671
Aneurysm neck size
7.5 4.8
4.6 2.4
Variable Yes (N [ 11)
No (N [ 193)
P Value
Baseline mRS
2.6 1.9
1.0 1.1
0.001
Parent vessel (mm)
4.1 0.7
4.0 0.7
0.669
Aneurysm neck size
8.9 5.5
4.7 2.5
0.003
Anterior
7 (63.6%)
174 (90.2%)
Posterior
4 (36.4%)
19 (9.8%)
156.8 76.8
136.1 74.7
Variable
Anterior/posterior
PRU
0.024
Sex 2 (18.2%)
38 (19.7%)
Female
9 (81.8%)
155 (80.3%)
Aneurysm size Small
4 (36.4%)
141 (73.1%)
Medium
5 (45.5%)
48 (24.9%)
Large
2 (18.2%)
4 (2.1%)
Aneurysm type 0 (0.0%)
8 (4.1%)
Dissecting pseudoaneurysm
1 (9.1%)
4 (2.1%)
Fusiform
2 (18.2%)
21 (10.9%)
Saccular
8 (72.7%)
160 (82.9%)
Rupture status 4 (36.4%)
12 (6.2%)
Unruptured
7 (63.6%)
181 (93.8%)
This must be carefully considered when discussing treatment options with patients and their families. Posterior circulation aneurysms can be treacherous lesions to treat either surgically or endovascularly as the posterior circulation anatomy supplies the highly critical and sensitive brainstem structures. Multiple studies have demonstrated higher complication rates in patients with posterior circulation aneurysms treated with flow diversion compared with anterior circulation aneurysms.10,11 Griessenauer reviewed 131 posterior circulation aneurysms treated with Pipeline and reported an overall complication rate of 24.8%.12 Bender et al13 reported an overall complication rate of 15% among 59 posterior circulation aneurysms treated with Pipeline. Our cohort with posterior circulation aneurysms trended toward a higher overall complication rate with 30% compared with only 8.8% in patients with anterior circulation aneurysms. It may relate to the higher incidence of ruptured cases in the posterior circulation (30%) compared with the anterior circulation (4%).
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144.6 73.6
136.3 75
Male
5 (21.7%)
35 (19.3%)
Female
18 (78.3%)
146 (80.7%)
Sex
0.437 0.783
0.004
Small
11 (47.8%)
134 (74.0%)
Medium
9 (39.1%)
44 (24.3%)
3 (13%)
3 (1.7%)
Blister
1 (4.3%)
7 (3.9%)
Dissecting pseudoaneurysm
1 (4.3%)
4 (2.2%)
0.053
Fusiform
6 (26.1%)
17 (9.4%)
Saccular
15 (65.2%)
153 (84.5%)
Rupture status
mRS, modified Rankin Scale; PRU, P2Y12 reactivity unit. *Multiple variable testing after Bonferroni correction (significance level at P ¼ 0.004).
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16 (8.8%)
Aneurysm type
0.006
Ruptured
165 (91.2%)
7 (30.4%)
Large 0.237
Blister
16 (69.6%)
Posterior
Aneurysm size 0.006
0.002 0.007
Anterior
PRU 0.264 1.000
Male
Anterior/posterior
0.004
Ruptured
6 (26.1%)
10 (5.5%)
Unruptured
17 (73.9%)
171 (94.5%)
mRS, modified Rankin Scale; PRU, P2Y12 reactivity unit. *Multiple variable testing after Bonferroni correction (significance level at P ¼ 0.004).
The baseline mRS and rupture status may be interrelated variables. It is intuitive that patients with a poor baseline functional status and/or rupture will have a higher rate of morbidity/mortality. The PUFS and ASPIRe studies only evaluated unruptured aneurysms, and the IntrePED data did not compare complication rates of ruptured to unruptured aneurysms. Smaller case series focusing only on ruptured aneurysms treated with PED have shown complication rates ranging from 5%19%.14,15 Patients with ruptured intracranial aneurysms have additional limitations regarding flow diversion. Starting dual antiplatelet therapy and heparin before securing a ruptured aneurysm in preparation for flow diversion may be associated with an increased risk of rupture in itself, even though we did not encounter this complication in this series. After stent placement, the aneurysm may not be fully secured if flow diversion was chosen as stand-alone treatment. In one case of a ruptured blister aneurysm, we observed aneurysm growth after treatment with only 1 PED. The aneurysm subsequently thrombosed after treatment with a second device 2 days
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PED OUTCOME PREDICTORS FOR IC ANEURYSM
later. Furthermore, the potential need for cerebrospinal fluid diversion is complicated by dual antiplatelet therapy. Generally, we recommend management of cerebrospinal fluid shunting before flow diversion if possible. On-label and off-label use was not significantly associated with the overall complication rate, neurologic morbidity, or neurologic mortality. This is in line with other recent studies in the literature.16,17 Zammar et al16 examined the outcomes of off-label aneurysms treated with PED at 4 different centers based on FDA-approved guidelines from 2011e2015. They reported an overall complication rate of 8.3%, which is lower than our overall complication rate for off-label cases of 20.8%. The complication rate in this study may be higher because our on-label and off-label indications were based on the most recent FDA guidelines, so many of the aneurysms in the Zammar et al16 cohort would now be considered on-label. Thrombotic and hemorrhagic complications are the most common and serious complications associated with PED placement. Interventionalists have tried to mitigate these risks with platelet function testing to identify hyporesponders and hyperresponders to antiplatelet therapy. However, platelet function
REFERENCES 1. Becske T, Kallmes DF, Saatci I, et al. Pipeline for uncoilable or failed aneurysms: results from a multicenter clinical trial. Radiology. 2013;267: 858-868. 2. Kallmes DF, Brinjikji W, Boccardi E, et al. Aneurysm study of pipeline in an observational Registry (ASPIRe). Intervent Neurol. 2016;5:89-99. 3. Park MS, Kilburg C, Taussky P, et al. Pipeline embolization device with or without adjunctive coil embolization: analysis of complications from the IntrePED Registry. AJNR Am J Neuroradiol. 2016; 37:1127-1131. 4. Kallmes DF, Brinjikji W, Cekirge S, et al. Safety and efficacy of the Pipeline embolization device for treatment of intracranial aneurysms: a pooled analysis of 3 large studies. J Neurosurg. 2017;127: 775-780. 5. 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;36:108-115. 6. Hanel R. Prospective, multi-center study of flow diversion for small and medium-sized aneurysms: results of the Premier trial. Paper presented at International Stroke Conference. February 22-24, 2017. Houston, TX. 7. Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D. The pipeline embolization device for the intracranial treatment of aneurysms trial. AJNR Am J Neuroradiol. 2011;32:34-40.
testing before PED placement remains controversial.18-22 Some authors have found that preoperative P2Y12 values predict complications,20,21,23 while others have found that P2Y12 levels do not influence the risk of complications22,24 or may even increase risk of complications.25 PRU did not correlate with clinical outcomes for patients treated with PED in our cohort. CONCLUSIONS The major neurologic morbidity/mortality associated with PED in both on- and off-label situations is low in this large single-center review and in line with other published data. Nevertheless, in offlabel situations including larger, ruptured aneurysms at any location, the chance of an adverse outcome is increased. The current study identifies individual, significant risk factors associated with morbidity/mortality or complications. These factors should be considered carefully when choosing treatment with PED and counseling patients and their families. Risk factors include a poor clinical baseline, a wider neck or larger size aneurysm, and rupture at presentation. Posterior location is another potential factor to be considered.
8. Adeeb N, Griessenauer CJ, Shallwani H, et al. Pipeline embolization device in treatment of 50 unruptured large and giant aneurysms. World Neurosurg. 2017;105:232-237. 9. Miyachi S, Hiramatsu R, Ohnishi H, Yagi R, Kuroiwa T. Usefulness of the pipeline embolic device for large and giant carotid cavernous aneurysms. Neurointervention. 2017;12:83-90. 10. Brinjikji W, Murad MH, Lanzino G, Cloft HJ, Kallmes DF. Endovascular treatment of intracranial aneurysms with flow diverters: a meta-analysis. Stroke. 2013;44:442-447. 11. Lopes DK, Jang DK, Cekirge S, et al. Morbidity and mortality in patients with posterior circulation aneurysms treated with the pipeline embolization device: a subgroup analysis of the International Retrospective Study of the pipeline embolization device. Neurosurgery. 2018;83:488-500. 12. Griessenauer CJ, Ogilvy CS, Adeeb N, et al. Pipeline embolization of posterior circulation aneurysms: a multicenter study of 131 aneurysms. J Neurosurg. 2018:1-13. 13. Bender MT, Colby GP, Jiang B, et al. Flow diversion of posterior circulation cerebral aneurysms: a single-institution series of 59 cases. Neurosurgery. 2019;84:206-216. 14. Lin N, Brouillard AM, Keigher KM, et al. Utilization of pipeline embolization device for treatment of ruptured intracranial aneurysms: US multicenter experience. J Neurointerv Surg. 2015;7: 808-815. 15. Chalouhi N, Zanaty M, Whiting A, et al. Treatment of ruptured intracranial aneurysms with the
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pipeline embolization device. Neurosurgery. 2015; 76:165-172. 16. 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. 17. 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:E4. 18. Adeeb N, Griessenauer CJ, Foreman PM, et al. Use of platelet function testing before Pipeline embolization device placement: a multicenter cohort study. Stroke. 2017;48:1322-1330. 19. Taylor LI, Dickerson JC, Dambrino RJ, et al. Platelet testing in flow diversion: a review of the evidence. Neurosurg Focus. 2017;42:E5. 20. Delgado Almandoz JE, Crandall BM, Scholz JM, et al. Last-recorded P2Y12 reaction units value is strongly associated with thromboembolic and hemorrhagic complications occurring up to 6 months after treatment in patients with cerebral aneurysms treated with the pipeline embolization device. AJNR Am J Neuroradiol. 2014;35:128-135. 21. Tan LA, Keigher KM, Munich SA, Moftakhar R, Lopes DK. Thromboembolic complications with pipeline embolization device placement: impact of procedure time, number of stents and preprocedure P2Y12 reaction unit (PRU) value. J Neurointerv Surg. 2015;7:217-221. 22. Bender MT, Lin LM, Colby GP, et al. P2Y12 hyporesponse (PRU>200) is not associated with increased thromboembolic complications in
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anterior circulation Pipeline. J Neurointerv Surg. 2017;9:978-981.
pipeline embolization device: a review and metaanalysis. J Neurointerv Surg. 2016;8:58-65.
23. Almandoz JED, Crandall BM, Scholz JM, et al. Preprocedure P2Y12 reaction units value predicts perioperative thromboembolic and hemorrhagic complications in patients with cerebral aneurysms treated with the pipeline embolization device. J Neurointerv Surg. 2013;5(suppl 3):iii3-iii10.
25. Brinjikji W, Lanzino G, Cloft HJ, Siddiqui AH, Hanel RA, Kallmes DF. Platelet testing is associated with worse clinical outcomes for patients treated with the pipeline embolization device. AJNR Am J Neuroradiol. 2015;36:2090-2095.
commercial or financial relationships that could be construed as a potential conflict of interest. Received 9 May 2019; accepted 24 June 2019 Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.06.185 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com
24. Skukalek SL, Winkler AM, Kang J, et al. Effect of antiplatelet therapy and platelet function testing on hemorrhagic and thrombotic complications in patients with cerebral aneurysms treated with the
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any
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