External Ventricular Drain and Hemorrhage in Aneurysmal Subarachnoid Hemorrhage Patients on Dual Antiplatelet Therapy: A Retrospective Cohort Study

External Ventricular Drain and Hemorrhage in Aneurysmal Subarachnoid Hemorrhage Patients on Dual... Abstract BACKGROUND Stenting and flow diversion for aneurysmal sub arachnoid hemorrhage (aSAH) require the use of dual antiplatelet therapy (DAPT). OBJECTIVE To investigate whether DAPT is associated with hemorrhagic complication following placement of external ventricular drains (EVD) in patients with aSAH. METHODS Rates of radiographically identified hemorrhage associated with EVD placement were compared between patients who received DAPT for stenting or flow diversion, and patients who underwent microsurgical clipping or coiling and did not receive DAPT by way of a backward stepwise multivariate analysis. RESULTS Four hundred forty-three patients were admitted for aSAH management. Two hundred ninety-eight patients required placement of an EVD. One hundred twenty patients (40%) were treated with stent-assisted coiling or flow diversion and required DAPT, while 178 patients (60%) were treated with coiling without stents or microsurgical clipping and did not receive DAPT. Forty-two (14%) cases of new hemorrhage along the EVD catheter were identified radiographically. Thirty-two of these hemorrhages occurred in patients on DAPT, while 10 occurred in patients without DAPT. After multivariate analysis, DAPT was significantly associated with radiographic hemorrhage [odds ratio: 4.92, 95% confidence interval: 2.45-9.91, P = .0001]. We did not observe an increased proportion of symptomatic hemorrhage in patients receiving DAPT (10 of 32 [31%]) vs those without (5 of 10 [50%]; P = .4508). CONCLUSION Patients with aSAH who receive stent-assisted coiling or flow diversion are at higher risk for radiographic hemorrhage associated with EVD placement. The timing between EVD placement and DAPT initiation does not appear to be of clinical significance. Stenting and flow diversion remain viable options for aSAH patients. Aspirin, Clopidogrel, Dual antiplatlet therapy, Endovascular, External ventricular drain, Subarachnoid haemorrhage ABBREVIATIONS ABBREVIATIONS ASA acetylsalicylic acid aSAH aneurysmal subarachnoid haemorrhage CI confidence interval CT computed tomography EVD external ventricular drain DAPT dual antiplatelet therapy OR odds ratio VP Ventriculoperitoneal Aneurysmal subarachnoid hemorrhage (aSAH) affects up to 30 000 individuals per year in the United States.1 Although advances in endovascular repair of ruptured aneurysms and expedited management have improved overall outcomes, it remains a devastating disease with a mortality rate approaching 25%.2-4 As most patients with aSAH present with hydrocephalus, emergent placement of an external ventricular drain (EVD) is frequently required. Historically, EVD placement has been associated with a low risk of clinically significant hemorrhage.5 Considerable advances in endovascular stenting and flow diversion have allowed for aneurysms with wide necks and complex morphologies to be treated without open microsurgery. As a result, these techniques are being used with increasing frequency for treatment of aSAH. However, acute stenting and flow diversion requires perioperative dual antiplatelet therapy (DAPT) to mitigate the risk of in-stent thrombosis. This creates a therapeutic trade off, requiring the neurointerventional surgeon to balance the widening applicability of these techniques against the risk of hemorrhagic complication in patients who may require additional neurosurgical interventions. There is an overall lack of published data regarding the risk of hemorrhagic complication associated with placement of EVDs in the setting of SAH and DAPT for endovascular stenting or flow diversion.6,7 Our group has conducted a number of smaller retrospective studies that examine this risk, ultimately concluding that an elevated risk of radiographic hemorrhage exists in patients receiving DAPT.7-9 Despite this increased risk, the majority of these hemorrhages appear to be asymptomatic. In this study, involving a larger cohort of patients collected over 6 and a half years from a high-volume quaternary center, we sought to evaluate the risk of hemorrhage associated with EVD placement in patients on DAPT required for intracranial stenting or flow diverters in patients with aSAH. Secondarily, we sought to determine if the time between EVD placement and DAPT initiation was related to the occurrence of EVD-associated hemorrhages or their clinical significance. METHODS Study Design, Setting, and Participants Study design and manuscript organization were guided by the STROBE statement on cohort studies. The study was approved by the Institutional Review Board. Informed consent was not obtained. Data were entered prospectively into a quality control database for patients presenting between July 2009 and November 2016 with aSAH. All patients in our database were considered eligible and included in the study. Patients from our 2011 analysis were not included. All medical records and imaging studies for all patients receiving EVD placement during this time period were retrospectively reviewed. Procedural Technique The standard techniques for EVD placement at our institution have been previously described.7 Briefly, EVDs were placed by using a standard ventriculostomy catheter through Kocher's point to a depth of 5 to 6 cm in all patients with radiographically observed hydrocephalus on admission. The Ghajar guide was used in all cases unless there was a significant shift of midline brain structures. No bedside ventriculostomies were performed. Ventricular drains were not changed unless they became obstructed or an infection related to the ventriculostomy occurred. Patients who underwent stent-assisted coiling or flow diversion received 600 mg clopidogrel and 325 mg of acetylsalicylic acid (ASA) at the time of stent deployment, followed by 75 mg clopidogrel daily and 325 mg ASA daily postoperatively. Aggrastat was given IV for 2 h at 0.15 mcg/kg/min immediately following deployment a stent or flow diverter. DAPT was not discontinued during the perioperative period. EVD was placed before DAPT initiation in 116 patients. Only 4 received DAPT prior to EVD placement. Demographics, Hemorrhage Risk Factors, and Baseline Characteristics The baseline characteristics for the study population were collected at the time of admission and are summarized in Table 1. TABLE 1. Demographic Characteristics of Patients Who Underwent Endovascular Treatment and EVD Placement. Characteristic  No DAPT  DAPT    n = 178  n = 120  Age in years       Mean ± SD  57.8 ± 13.1  55.7 ± 13.2   Range  20-86  20-91  Sex (F/M)  128/50  76/44  Antiplatelets prior to hospitalization (%)  28 (15.7)  20 (16.7)  Approach for EVD (R/L)  141/37  96/24  H&H grade (%)       I  13 (7.3)  5 (4.2)   II  40 (22.5)  34 (28.3)   III  49 (27.5)  44 (36.7)   IV  37 (20.8)  26 (21.7)   V  39 (21.9)  11 (9.2)   Mean  3.3 ± 1.2  3.0 ± 1.0  Fisher scale (%)       Grade 1  3 (1.7)  1 (0.8)   Grade 2  26 (14.6)  25 (20.8)   Grade 3  36 (20.2)  24 (20)   Grade 4  113 (63.5)  70 (58.3)   Mean  3.5 ± 0.8  3.4 ± 0.8  WFNS scale (%)       Grade 1  42 (23.6)  37 (30.8)   Grade 2  37 (20.8)  27 (22.5)   Grade 3  11 (6.2)  6 (5)   Grade 4  36 (20.2)  29 (24.1)   Grade 5  52 (29.2)  21 (17.5)   Mean  3.1 ± 1.6  2.7 ± 1.5  LOS (d)  17.4 ± 10.5  18.5 ± 10.4  Median number of CTs per patient  4  4  Characteristic  No DAPT  DAPT    n = 178  n = 120  Age in years       Mean ± SD  57.8 ± 13.1  55.7 ± 13.2   Range  20-86  20-91  Sex (F/M)  128/50  76/44  Antiplatelets prior to hospitalization (%)  28 (15.7)  20 (16.7)  Approach for EVD (R/L)  141/37  96/24  H&H grade (%)       I  13 (7.3)  5 (4.2)   II  40 (22.5)  34 (28.3)   III  49 (27.5)  44 (36.7)   IV  37 (20.8)  26 (21.7)   V  39 (21.9)  11 (9.2)   Mean  3.3 ± 1.2  3.0 ± 1.0  Fisher scale (%)       Grade 1  3 (1.7)  1 (0.8)   Grade 2  26 (14.6)  25 (20.8)   Grade 3  36 (20.2)  24 (20)   Grade 4  113 (63.5)  70 (58.3)   Mean  3.5 ± 0.8  3.4 ± 0.8  WFNS scale (%)       Grade 1  42 (23.6)  37 (30.8)   Grade 2  37 (20.8)  27 (22.5)   Grade 3  11 (6.2)  6 (5)   Grade 4  36 (20.2)  29 (24.1)   Grade 5  52 (29.2)  21 (17.5)   Mean  3.1 ± 1.6  2.7 ± 1.5  LOS (d)  17.4 ± 10.5  18.5 ± 10.4  Median number of CTs per patient  4  4  DAPT, dual antiplatelet therapy; SD, standard deviation; F, female; M, male; EVD, external ventricular drain (right or left); H&H, Hunt–Hess grade; WFNS, World Federation of Neurosurgical Societies; LOS, length of stay Standard deviations are calculated for mean values. View Large TABLE 1. Demographic Characteristics of Patients Who Underwent Endovascular Treatment and EVD Placement. Characteristic  No DAPT  DAPT    n = 178  n = 120  Age in years       Mean ± SD  57.8 ± 13.1  55.7 ± 13.2   Range  20-86  20-91  Sex (F/M)  128/50  76/44  Antiplatelets prior to hospitalization (%)  28 (15.7)  20 (16.7)  Approach for EVD (R/L)  141/37  96/24  H&H grade (%)       I  13 (7.3)  5 (4.2)   II  40 (22.5)  34 (28.3)   III  49 (27.5)  44 (36.7)   IV  37 (20.8)  26 (21.7)   V  39 (21.9)  11 (9.2)   Mean  3.3 ± 1.2  3.0 ± 1.0  Fisher scale (%)       Grade 1  3 (1.7)  1 (0.8)   Grade 2  26 (14.6)  25 (20.8)   Grade 3  36 (20.2)  24 (20)   Grade 4  113 (63.5)  70 (58.3)   Mean  3.5 ± 0.8  3.4 ± 0.8  WFNS scale (%)       Grade 1  42 (23.6)  37 (30.8)   Grade 2  37 (20.8)  27 (22.5)   Grade 3  11 (6.2)  6 (5)   Grade 4  36 (20.2)  29 (24.1)   Grade 5  52 (29.2)  21 (17.5)   Mean  3.1 ± 1.6  2.7 ± 1.5  LOS (d)  17.4 ± 10.5  18.5 ± 10.4  Median number of CTs per patient  4  4  Characteristic  No DAPT  DAPT    n = 178  n = 120  Age in years       Mean ± SD  57.8 ± 13.1  55.7 ± 13.2   Range  20-86  20-91  Sex (F/M)  128/50  76/44  Antiplatelets prior to hospitalization (%)  28 (15.7)  20 (16.7)  Approach for EVD (R/L)  141/37  96/24  H&H grade (%)       I  13 (7.3)  5 (4.2)   II  40 (22.5)  34 (28.3)   III  49 (27.5)  44 (36.7)   IV  37 (20.8)  26 (21.7)   V  39 (21.9)  11 (9.2)   Mean  3.3 ± 1.2  3.0 ± 1.0  Fisher scale (%)       Grade 1  3 (1.7)  1 (0.8)   Grade 2  26 (14.6)  25 (20.8)   Grade 3  36 (20.2)  24 (20)   Grade 4  113 (63.5)  70 (58.3)   Mean  3.5 ± 0.8  3.4 ± 0.8  WFNS scale (%)       Grade 1  42 (23.6)  37 (30.8)   Grade 2  37 (20.8)  27 (22.5)   Grade 3  11 (6.2)  6 (5)   Grade 4  36 (20.2)  29 (24.1)   Grade 5  52 (29.2)  21 (17.5)   Mean  3.1 ± 1.6  2.7 ± 1.5  LOS (d)  17.4 ± 10.5  18.5 ± 10.4  Median number of CTs per patient  4  4  DAPT, dual antiplatelet therapy; SD, standard deviation; F, female; M, male; EVD, external ventricular drain (right or left); H&H, Hunt–Hess grade; WFNS, World Federation of Neurosurgical Societies; LOS, length of stay Standard deviations are calculated for mean values. View Large Determination of EVD-Related Hemorrhage All postoperative computed tomography (CT) scans obtained during the index hospitalization were first reviewed by an attending neuroradiologist blinded to the clinical outcome. All patients underwent, at a minimum, a same day postoperative CT scan following EVD placement. Two blinded attending neurosurgeons then further reviewed identified CT scans to confirm hemorrhage extent and location. If discrepancy between interpretations existed, the neurosurgical interpretation took precedence. A hemorrhage was deemed EVD-related if it occurred along the ventricular catheter tract. A hemorrhage was classified as symptomatic if it required further surgical intervention, was associated with any temporally related deterioration in daily serial neurological examination, or caused seizures. If identified hemorrhages were not classified as symptomatic, they were categorized as purely radiographic. Statistical Analysis and Variables Demographic and clinical variables including: age, sex, EVD approach, antiplatelet therapy prior to admission (any dosage or combination of AP medications), presenting Hunt and Hess grade of the aSAH, presenting Fischer grade, and presenting World Federation of Neurosurgical Societies grade were compared between groups. All significant variables associated with hemorrhage (P < .35) were included in a backward, stepwise, multivariate analysis. Identified symptomatic hemorrhages were analyzed with respect to DAPT with the use of Fisher's exact test. Hemorrhage size (defined as largest linear dimension) was compared with respect to DAPT with the use of an unpaired 2-tailed Student's t-test. Mean times between DAPT initiation and EVD placement were compared with the use of an unpaired 2-tailed Student's t-test. RESULTS Clinical Characteristics Four hundred forty-three patients were admitted for management of aSAH. Of these patients, 298 underwent EVD placement. The demographic and clinical characteristics of these patients are summarized in Table 1. Of the patients receiving an EVD, 178 patients (60%) underwent coiling without a stent or microsurgical clipping and did not require DAPT. The remaining 120 patients (40%) underwent stent-assisted coiling or flow diversion and required DAPT. Main Results A total of 1309 postoperative head CT scans following EVD placement, or both EVD placement and DAPT initiation, were reviewed. Forty-two new cases (14%) of new intracranial hemorrhage were observed along the EVD tract. Thirty-two (26.7%) of these hemorrhages occurred in patients on DAPT. Ten (5.6%) hemorrhages occurred in patients who underwent microsurgical clipping or endovascular coiling and were not on DAPT. No identified hemorrhage occurred during or after EVD removal. The results of our analysis are summarized in (Table 2). After multivariate analysis, DAPT was significantly associated with hemorrhage (odds ratio [OR]: 4.92, 95% confidence interval [CI]: 2.45-9.91, P = .0001; Table 3). Fischer grades on presentation were significantly associated with EVD-associated hemorrhage after multivariate analysis (OR: 1.67, 95% CI: 1.03-2.70, P = .03; Table 3). Of the patients not receiving DAPT, 5 hemorrhages were judged to be clinically significant (5 of 10 [50%]). Among these patients, 2 required EVD revision due to hemorrhage-associated blockage, 1 developed new onset left-sided weakness, 1 patient developed left-sided pronator drift and confusion, and 1 patient developed left-sided focal deficits. Of the patients receiving DAPT, 10 hemorrhages were judged to be clinically significant (10 of 32 [31%]). Of these patients, 4 needed EVD revision. Temporally related deficits attributed to EVD-associated hemorrhage among the other 6 patients included new onset minimal reactivity, inability to follow commands in both left upper and lower extremities, weakness in extremities, headache, confusion, and drowsiness. DAPT was not significantly associated with increased numbers of symptomatic hemorrhage (P = .4508; Table 2). The size of the observed hematomas was not statistically different between the 2 groups (Table 2). In the 120 patients receiving DAPT and an EVD, imaging revealed 7 (6%) clinically silent infarcts. Seven (6%) additional patients were identified as having symptomatic transient ischemic attack or radiographically observed clinically significant infarct. During long-term follow-up of the 40 patients who did not receive an EVD but were on DAPT for stent-assisted coiling or flow diversion, we observed 4 (10%) transient ischemic complications. TABLE 2. Hemorrhages Observed in Patients Receiving or Not Receiving DAPT Parameter  No DAPT  DAPT  P-value  Radiographic hemorrhages (%)  10 (5.6)  32 (26.7)    Symptomatic hemorrhages (%)  5 (2.8)  10 (8.3)  P = .4508a  Size of hematoma (mm ± SEM)  15.3 ± 3.2  14.6 ± 1.64  P = .8335b  Size of asymptomatic hematoma (mm ± SEM)  11.52 ± 1.39  12.7 ± 1.55  P = .7126b  Size of symptomatic hematoma (mm ± SEM)  20.4 ± 5.91  18.7 ± 3.46  P = .7967b  Parameter  No DAPT  DAPT  P-value  Radiographic hemorrhages (%)  10 (5.6)  32 (26.7)    Symptomatic hemorrhages (%)  5 (2.8)  10 (8.3)  P = .4508a  Size of hematoma (mm ± SEM)  15.3 ± 3.2  14.6 ± 1.64  P = .8335b  Size of asymptomatic hematoma (mm ± SEM)  11.52 ± 1.39  12.7 ± 1.55  P = .7126b  Size of symptomatic hematoma (mm ± SEM)  20.4 ± 5.91  18.7 ± 3.46  P = .7967b  aFischer exact test. bTwo-tailed unpaired Student's t-test, SEM—standard error of the mean. View Large TABLE 2. Hemorrhages Observed in Patients Receiving or Not Receiving DAPT Parameter  No DAPT  DAPT  P-value  Radiographic hemorrhages (%)  10 (5.6)  32 (26.7)    Symptomatic hemorrhages (%)  5 (2.8)  10 (8.3)  P = .4508a  Size of hematoma (mm ± SEM)  15.3 ± 3.2  14.6 ± 1.64  P = .8335b  Size of asymptomatic hematoma (mm ± SEM)  11.52 ± 1.39  12.7 ± 1.55  P = .7126b  Size of symptomatic hematoma (mm ± SEM)  20.4 ± 5.91  18.7 ± 3.46  P = .7967b  Parameter  No DAPT  DAPT  P-value  Radiographic hemorrhages (%)  10 (5.6)  32 (26.7)    Symptomatic hemorrhages (%)  5 (2.8)  10 (8.3)  P = .4508a  Size of hematoma (mm ± SEM)  15.3 ± 3.2  14.6 ± 1.64  P = .8335b  Size of asymptomatic hematoma (mm ± SEM)  11.52 ± 1.39  12.7 ± 1.55  P = .7126b  Size of symptomatic hematoma (mm ± SEM)  20.4 ± 5.91  18.7 ± 3.46  P = .7967b  aFischer exact test. bTwo-tailed unpaired Student's t-test, SEM—standard error of the mean. View Large TABLE 3. Univariate and Multivariate Predictors of EVD-Associated Radiographic Hemorrhage   Univariate  Multivariate  Variables  OR  95% CI  P-value  OR  95% CI  P-value  Age  1.01  0.99-1.05  .16  –  –  –  Sex (female)  0.8  0.39-1.66  .55  –  –  –  Approach for EVD (right)  1.51  0.40-5.66  .53  –  –  –  DAPT  4.58  2.25-9.34  <.001  4.92  2.45-9.91  <.001  H&H grade  0.51  0.28-0.91  .023  0.52  0.29-0.91  .023  Fisher grade  1.62  0.97-2.68  .06  1.67  1.03-2.70  .03  WFNS score  1.43  0.94-2.17  .09  1.42  0.94-2.12  .09  Antiplatelets prior to admission  1.6  0.66-3.87  .31  1.83  0.82-4.12  .15    Univariate  Multivariate  Variables  OR  95% CI  P-value  OR  95% CI  P-value  Age  1.01  0.99-1.05  .16  –  –  –  Sex (female)  0.8  0.39-1.66  .55  –  –  –  Approach for EVD (right)  1.51  0.40-5.66  .53  –  –  –  DAPT  4.58  2.25-9.34  <.001  4.92  2.45-9.91  <.001  H&H grade  0.51  0.28-0.91  .023  0.52  0.29-0.91  .023  Fisher grade  1.62  0.97-2.68  .06  1.67  1.03-2.70  .03  WFNS score  1.43  0.94-2.17  .09  1.42  0.94-2.12  .09  Antiplatelets prior to admission  1.6  0.66-3.87  .31  1.83  0.82-4.12  .15  View Large TABLE 3. Univariate and Multivariate Predictors of EVD-Associated Radiographic Hemorrhage   Univariate  Multivariate  Variables  OR  95% CI  P-value  OR  95% CI  P-value  Age  1.01  0.99-1.05  .16  –  –  –  Sex (female)  0.8  0.39-1.66  .55  –  –  –  Approach for EVD (right)  1.51  0.40-5.66  .53  –  –  –  DAPT  4.58  2.25-9.34  <.001  4.92  2.45-9.91  <.001  H&H grade  0.51  0.28-0.91  .023  0.52  0.29-0.91  .023  Fisher grade  1.62  0.97-2.68  .06  1.67  1.03-2.70  .03  WFNS score  1.43  0.94-2.17  .09  1.42  0.94-2.12  .09  Antiplatelets prior to admission  1.6  0.66-3.87  .31  1.83  0.82-4.12  .15    Univariate  Multivariate  Variables  OR  95% CI  P-value  OR  95% CI  P-value  Age  1.01  0.99-1.05  .16  –  –  –  Sex (female)  0.8  0.39-1.66  .55  –  –  –  Approach for EVD (right)  1.51  0.40-5.66  .53  –  –  –  DAPT  4.58  2.25-9.34  <.001  4.92  2.45-9.91  <.001  H&H grade  0.51  0.28-0.91  .023  0.52  0.29-0.91  .023  Fisher grade  1.62  0.97-2.68  .06  1.67  1.03-2.70  .03  WFNS score  1.43  0.94-2.17  .09  1.42  0.94-2.12  .09  Antiplatelets prior to admission  1.6  0.66-3.87  .31  1.83  0.82-4.12  .15  View Large In nearly all patients, DAPT therapy was initiated within 24 h of EVD placement. Median time to DAPT for the 116 patients who underwent EVD placement first was 11.5 h. The mean number of hours between EVD and DAPT therapy initiation (endovascular treatment) was not statistically different between symptomatic EVD-associated hemorrhages and those that were classified as asymptomatic (10.88 ± 3.4 vs 18.15 ± 4.6, P = .2795). There was no significant difference between mean hours to DAPT initiation between those patients with radiographically identified hemorrhages and those without (15.24 ± 3.0 vs 15.18 ± 4.8, P = .9937). There was no significant difference in hours to DAPT between asymptomatic cases (no hemorrhage and radiographic hemorrhage) and symptomatic hemorrhage cases (15.69 ± 3.9 vs 10.5 ± 3.7, P = .6692). DISCUSSION When intracranial stents and flow diverters are used in the setting of aSAH, perioperative DAPT is required to avoid in-stent thrombosis. DAPT may theoretically complicate the patient's subsequent neurosurgical management, ultimately leading to a reluctance to treat patients with these minimally invasive modalities. Despite this hesitancy, a number of recent studies suggest that stents and flow diverters may be used effectively in aSAH patients when alternative treatment modalities are less clinically attractive.10-12 Our group previously performed a small single institution retrospective analysis of 131 patients with aSAH who underwent intracranial catheter placement (Ventriculoperitoneal (VP) shunt/EVD) in the setting of aSAH.7 We observed an increased rate of radiographically identified hemorrhage in patients on DAPT for stent-assisted coiling (P = .02). Additionally, we observed a statistically significant increase in the number of these radiographically identified hemorrhages that were classified as symptomatic in patients on DAPT (4 of 50 [8%] vs 1 of 109 [1%]; P = .03). In our current analysis, we wished to reevaluate our findings in a much larger number of patients over an extended period of time. After multivariate analysis, we confirmed that the odds of radiographic hemorrhage are significantly higher in those patients treated with DAPT. Based on a recent meta-analysis, the rate of radiographically identified hemorrhage in patients who undergo EVD placement is approximately 5.7%, with less than 1% of these hemorrhages becoming symptomatic.5 These numbers are in relative agreement with the values we report (Table 2), although in comparison, it is clear that DAPT confers an elevated risk of radiographic hemorrhage. However, we do not see a statistically significant increase in those hemorrhages judged to be symptomatic. Indeed, this is in agreement with a recent study our group conducted evaluating the risk of hemorrhage in patients receiving VP shunts for post hemorrhagic hydrocephalus in the setting of long-term DAPT prophylaxis.9 We observed an increased rate of intracranial catheter-associated hemorrhage but no significant increase in number of symptomatic hemorrhages in patients on DAPT. Taken together, these data confirm the necessity of continuing DAPT during the perioperative period and further characterize the risk profile associated with stenting and flow diversion in the setting of aSAH. We secondarily quantified the time between DAPT initiation and EVD placement with respect to EVD-associated hemorrhage. Placing the EVD first before endovascular therapy and DAPT makes clinical sense given the increased risk of radiographic hemorrhage associated with DAPT. Indeed, this occurred for nearly all patients in our analysis. However, our data suggest that patients with aSAH may be candidates for stenting or endovascular coiling regardless of the time interval between EVD placement and the subsequent initiation of DAPT. Interestingly, our multivariate analysis revealed that AP prior to admission was not associated with increased identified radiographic hemorrhage. We postulate that since nearly all of these patients (47 of 48) were on low-dose aspirin or antiplatelet monotherapy prior to admission, the switch to high dosage DAPT during stenting/flow diversion provides a pathophysiological explanation for this observation. In our manuscript, we report a higher percentage of aneurysms treated with stenting or flow diversion overall (40%) than is standard practice within the United States. The decision to treat with these modalities was made only after weighing a variety of factors. Those factors advancing the clinical decision towards stenting/flow diversion in our cohort included: age greater than 70 yr old, presence of multiple comorbid diseases, wide neck and anatomic considerations, Hunt Hess grade 4, and other clinical circumstances making the risks associated with open surgery high. Despite the nonsignificant rate of symptomatic hemorrhage observed with stenting and flow diversion, we observed 32 total hemorrhages in DAPT patients, 10 of being were symptomatic. All associated risks, not limited to the significant thromboembolic, ischemic, and hemorrhagic complications of stent usage, should be considered prior to selecting a therapeutic modality in the acute setting. Recently, our group conducted an analysis revealing that the usage of DAPT was associated with reduced risk of clinical vasospasm and delayed cerebral ischemic changes.13 These data suggest antiplatelet treatment may be of protective significance following aSAH. Additionally, we have noted that the use of tirofiban, a IIb/IIIa inhibitor, may be associated with fewer detrimental effects in aSAH patients. As a result, we have recently begun a phase I/IIa clinical trial at our institution investigating the IV infusion of tirofiban during the first 10 d of admission for aSAH. As a result of its 90-min half-life, tirofiban can eliminated from the patient's system within 4 h. This may ultimately allow for safer manipulation of EVDs and VP shunts. Recent advancements in stent coating technology may allow for the discontinuation of perioperative DAPT altogether. In a recent case report, Chui et al14 describes the use of aspirin as the sole antiplatelet agent alongside a single loading dose of abciximab in the setting of a World Federation of Neurosurgical Societies grade 5 intradural vertebral artery dissecting aneurysm rupture treated with a pipeline embolization device with shield technology (Covidien-Medtronic, Dublin, Ireland).14 Technological advancements in antithrombotic stent coatings may ultimately eliminate the risk associated with perioperative DAPT. Finally, patients treated with DAPT for stenting or flow diversion may respond differently given 5% to 12% of patients are clopidogrel nonresponders.15 Although we did not test for platelet responsiveness in our study, refinement of this technique may allow for patient-specific dosing, reducing the risk of DAPT-associated complication. Limitations Our study's external validity is limited by its single institution scope. It is limited overall by its retrospective nature. Uniform identification of radiographic EVD-associated hemorrhage across all patients may have been limited by variation in the number of CTs patients received during their hospitalization for clinical purposes, ultimately leading to missed hemorrhages. However, patients on DAPT and those not on DAPT received similar numbers of head CTs (Table 1). At a minimum, all patients received a postoperative CT scan immediately following EVD placement. Nevertheless, it is likely that nondetection would be limited to purely radiographic hemorrhages, as symptomatic hemorrhages would have necessitated a CT scan for clinical purposes. CONCLUSION To the best of our knowledge, we provide the largest and most statistically comprehensive assessment to date regarding the risk of perioperative hemorrhage following DAPT therapy for stenting and flow diversion of ruptured intracranial aneurysms. Our analysis confirms that patients with aSAH who are candidates for stent-assisted coiling or flow diversion are at higher risk for hemorrhage associated with EVD placement. Despite this risk, the identified DAPT-associated hemorrhages do not appear to be of increased clinical significance. The timing between EVD placement and DAPT initiation does not appear to be of clinical significance. Stent-assisted coiling and flow diversion for aSAH remain options in an era of evolving endovascular therapeutics. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Connolly ES Jr, Rabinstein AA, Carhuapoma JR et al.   Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke  2012; 43( 6): 1711- 1737. Google Scholar CrossRef Search ADS PubMed  2. Ingall TJ, Whisnant JP, Wiebers DO, O’Fallon WM. Has there been a decline in subarachnoid hemorrhage mortality? Stroke . 1989; 20( 6): 718- 724. Google Scholar CrossRef Search ADS PubMed  3. Johnston SC, Selvin S, Gress DR. The burden, trends, and demographics of mortality from subarachnoid hemorrhage. Neurology . 1998; 50( 5): 1413- 1418. Google Scholar CrossRef Search ADS PubMed  4. Shea AM, Reed SD, Curtis LH, Alexander MJ, Villani JJ, Schulman KA. Characteristics of nontraumatic subarachnoid hemorrhage in the United States in 2003. Neurosurgery  2007; 61( 6): 1131- 1138. Google Scholar CrossRef Search ADS PubMed  5. Binz DD, Toussaint LG III, Friedman JA. Hemorrhagic complications of ventriculostomy placement: a meta-analysis. Neurocrit Care . 2009; 10( 2): 253- 256. Google Scholar CrossRef Search ADS PubMed  6. Tumialán LM, Zhang YJ, Cawley CM, Dion JE, Tong FC, Barrow DL. Intracranial hemorrhage associated with stent-assisted coil embolization of cerebral aneurysms: a cautionary report. J Neurosurg.  2008; 108( 6): 1122- 1129. Google Scholar CrossRef Search ADS PubMed  7. Kung DK, Policeni BA, Capuano AW et al.   Risk of ventriculostomy-related hemorrhage in patients with acutely ruptured aneurysms treated using stent-assisted coiling. J Neurosurg . 2011; 114( 4): 1021- 1027. Google Scholar CrossRef Search ADS PubMed  8. Mahaney KB, Chalouhi N, Viljoen S et al.   Risk of hemorrhagic complication associated with ventriculoperitoneal shunt placement in aneurysmal subarachnoid hemorrhage patients on dual antiplatelet therapy. J Neurosurg . 2013; 119( 4): 937- 942. Google Scholar CrossRef Search ADS PubMed  9. Hudson JS, Nagahama Y, Nakagawa D et al.   Hemorrhage associated with ventriculoperitoneal shunt placement in aneurysmal subarachnoid hemorrhage patients on a regimen of dual antiplatelet therapy: a retrospective analysis.. J Neurosurg . 2017. [Published online ahead of print]. 10. Amenta PS, Dalyai RT, Kung D et al.   Stent-assisted coiling of wide-necked aneurysms in the setting of acute subarachnoid hemorrhage: experience in 65 patients. Neurosurgery . 2012; 70( 6): 1415- 1429. Google Scholar CrossRef Search ADS PubMed  11. Bodily KD, Cloft HJ, Lanzio G, Fiorella DJ, White PM, Kallmes DF. Stent-Assisted coiling in acutely ruptured intracranial aneurysms: a qualitative, systematic review of the literature. Am J Neuroradiol . 2011; 32( 7): 1232- 1236. Google Scholar CrossRef Search ADS PubMed  12. Chalouhi N, Jabbour P, Singhal S et al.   Stent-Assisted coiling of intracranial aneurysms: predictors of complications, recanalization, and outcome in 508 cases. Stroke  2013; 44( 5): 1348- 1353. Google Scholar CrossRef Search ADS PubMed  13. Nagahama Y, Allan L, Nakagawa D et al.   Dual antiplatelet therapy in aneurysmal subarachnoid hemorrhage: association with reduced risk of clinical vasospasm and delayed cerebral ischemia. J Neurosurg . 2017. [Published online ahead of print]. 14. Chiu AH, Ramesh R, Wenderoth J, Davies M, Cheung A. Use of aspirin as sole oral antiplatelet therapy in acute flow diversion for ruptured dissecting aneurysms. BMJ Case Rep . 2016; 1- 9. 15. Corliss BM, Polifka AJ, Harris NS, Hoh BL, Fox WC. Laboratory assessments of therapeutic platelet inhibition in endovascular neurosurgery: comparing results of the VerifyNow P2Y12 assay to thromboelastography with platelet mapping. J Neurosurg . 2017. [Published online ahead of print]. Neurosurgery Speaks! Audio abstracts available for this article at www.neurosurgery-online.com. COMMENT The authors in this manuscript investigate the risk of hemorrhagic complication associated with external ventricular drainage placement in the setting of ruptured aneurysms treated with endovascular stenting that requires the use of dual antiplatelet therapy (DAPT). This work is a valuable addition to the current existing literature that proves an increased risk of bleeding for neurosurgical procedure in patients under prophylactic or therapeutic DAPT: the authors specifically address the risk of hemorrhagic complication post EVD placement, that is often required in the setting of aneurysmal subarachnoid hemorrhage (aSAH) and compare the outcome of patients with and without DAPT. In this report, there is an increased propensity to use of stents/flow diversion in 40% of patients with ruptured aneurysms; this is a very large percentage that does not reflect the current practice in many centers in the US, and might be associated with higher complications. An alternative to stenting would be to use balloon remodeling technique as an adjunct tool for coiling to avoid the use of DAPT in the acute phase and plan on placing stent or flow diversion in a later stage, post-discharge. This analysis indicates that the rate of EVD related bleeds are 32/120, and the symptomatic ones are 10/120. This is a high rate and should not be neglected. The manuscript does not present data on thromboembolic complications related to the stents/flow diversion, and it should also be kept in mind that the complications related to stents/flow diversion in the acute aSAH phase are not related only to EVD. The combination of the use of DAPT and the thromboembolic complications can potentially offset the advantage of endovascular treatment over surgical treatment, and should be very carefully considered in the acute phase. Denise Brunozzi Ali Alaraj Chicago, Illinois Neurosurgery Speaks (Audio Abstracts) Listen to audio translations of this paper's abstract into select languages by choosing from one of the selections below. Chinese: Junjie Wang, MD Department of Neurosurgery Beijing Hospital National Center of Gerontology Beijing, China Chinese: Junjie Wang, MD Department of Neurosurgery Beijing Hospital National Center of Gerontology Beijing, China Close English: Roberto Jose Diaz, MD, PhD Department of Neurology and Neurosurgery Faculty of Medicine McGill University Montreal, Canada English: Roberto Jose Diaz, MD, PhD Department of Neurology and Neurosurgery Faculty of Medicine McGill University Montreal, Canada Close French: Atef Ben Nsir, MD Neurosurgery Department Fattouma Bourguiba University Hospital University of Medicine of Monastir Monastir, Tunisia French: Atef Ben Nsir, MD Neurosurgery Department Fattouma Bourguiba University Hospital University of Medicine of Monastir Monastir, Tunisia Close Italian: Daniele Bongetta, MD Department of Neurosurgery Fondazione IRCCS Policlinico San Matteo Pavia, Italy Italian: Daniele Bongetta, MD Department of Neurosurgery Fondazione IRCCS Policlinico San Matteo Pavia, Italy Close Russian: Roman Kovalenko, MD Federal Almazov North-West Medical Research Centre St. Petersburg, Russian Federation Russian: Roman Kovalenko, MD Federal Almazov North-West Medical Research Centre St. Petersburg, Russian Federation Close Spanish: Igor Paredes Sansinenea, MD, PhD Department of Neurosurgery University Hospital “12 de Octubre” Madrid, Spain Spanish: Igor Paredes Sansinenea, MD, PhD Department of Neurosurgery University Hospital “12 de Octubre” Madrid, Spain Close Portuguese: Andrei Joaquim, MD, PhD Department of Neurology Division of Neurosurgery University of Campinas (UNICAMP) Campinas, Brazil Portuguese: Andrei Joaquim, MD, PhD Department of Neurology Division of Neurosurgery University of Campinas (UNICAMP) Campinas, Brazil Close Japanese: Soichi Oya, MD, PhD Department of Neurosurgery Saitama Medical Center/University Saitama, Japan Japanese: Soichi Oya, MD, PhD Department of Neurosurgery Saitama Medical Center/University Saitama, Japan Close Copyright © 2018 by the Congress of Neurological Surgeons http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

External Ventricular Drain and Hemorrhage in Aneurysmal Subarachnoid Hemorrhage Patients on Dual Antiplatelet Therapy: A Retrospective Cohort Study

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Oxford University Press
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Copyright © 2018 by the Congress of Neurological Surgeons
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0148-396X
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1524-4040
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10.1093/neuros/nyy127
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Abstract

Abstract BACKGROUND Stenting and flow diversion for aneurysmal sub arachnoid hemorrhage (aSAH) require the use of dual antiplatelet therapy (DAPT). OBJECTIVE To investigate whether DAPT is associated with hemorrhagic complication following placement of external ventricular drains (EVD) in patients with aSAH. METHODS Rates of radiographically identified hemorrhage associated with EVD placement were compared between patients who received DAPT for stenting or flow diversion, and patients who underwent microsurgical clipping or coiling and did not receive DAPT by way of a backward stepwise multivariate analysis. RESULTS Four hundred forty-three patients were admitted for aSAH management. Two hundred ninety-eight patients required placement of an EVD. One hundred twenty patients (40%) were treated with stent-assisted coiling or flow diversion and required DAPT, while 178 patients (60%) were treated with coiling without stents or microsurgical clipping and did not receive DAPT. Forty-two (14%) cases of new hemorrhage along the EVD catheter were identified radiographically. Thirty-two of these hemorrhages occurred in patients on DAPT, while 10 occurred in patients without DAPT. After multivariate analysis, DAPT was significantly associated with radiographic hemorrhage [odds ratio: 4.92, 95% confidence interval: 2.45-9.91, P = .0001]. We did not observe an increased proportion of symptomatic hemorrhage in patients receiving DAPT (10 of 32 [31%]) vs those without (5 of 10 [50%]; P = .4508). CONCLUSION Patients with aSAH who receive stent-assisted coiling or flow diversion are at higher risk for radiographic hemorrhage associated with EVD placement. The timing between EVD placement and DAPT initiation does not appear to be of clinical significance. Stenting and flow diversion remain viable options for aSAH patients. Aspirin, Clopidogrel, Dual antiplatlet therapy, Endovascular, External ventricular drain, Subarachnoid haemorrhage ABBREVIATIONS ABBREVIATIONS ASA acetylsalicylic acid aSAH aneurysmal subarachnoid haemorrhage CI confidence interval CT computed tomography EVD external ventricular drain DAPT dual antiplatelet therapy OR odds ratio VP Ventriculoperitoneal Aneurysmal subarachnoid hemorrhage (aSAH) affects up to 30 000 individuals per year in the United States.1 Although advances in endovascular repair of ruptured aneurysms and expedited management have improved overall outcomes, it remains a devastating disease with a mortality rate approaching 25%.2-4 As most patients with aSAH present with hydrocephalus, emergent placement of an external ventricular drain (EVD) is frequently required. Historically, EVD placement has been associated with a low risk of clinically significant hemorrhage.5 Considerable advances in endovascular stenting and flow diversion have allowed for aneurysms with wide necks and complex morphologies to be treated without open microsurgery. As a result, these techniques are being used with increasing frequency for treatment of aSAH. However, acute stenting and flow diversion requires perioperative dual antiplatelet therapy (DAPT) to mitigate the risk of in-stent thrombosis. This creates a therapeutic trade off, requiring the neurointerventional surgeon to balance the widening applicability of these techniques against the risk of hemorrhagic complication in patients who may require additional neurosurgical interventions. There is an overall lack of published data regarding the risk of hemorrhagic complication associated with placement of EVDs in the setting of SAH and DAPT for endovascular stenting or flow diversion.6,7 Our group has conducted a number of smaller retrospective studies that examine this risk, ultimately concluding that an elevated risk of radiographic hemorrhage exists in patients receiving DAPT.7-9 Despite this increased risk, the majority of these hemorrhages appear to be asymptomatic. In this study, involving a larger cohort of patients collected over 6 and a half years from a high-volume quaternary center, we sought to evaluate the risk of hemorrhage associated with EVD placement in patients on DAPT required for intracranial stenting or flow diverters in patients with aSAH. Secondarily, we sought to determine if the time between EVD placement and DAPT initiation was related to the occurrence of EVD-associated hemorrhages or their clinical significance. METHODS Study Design, Setting, and Participants Study design and manuscript organization were guided by the STROBE statement on cohort studies. The study was approved by the Institutional Review Board. Informed consent was not obtained. Data were entered prospectively into a quality control database for patients presenting between July 2009 and November 2016 with aSAH. All patients in our database were considered eligible and included in the study. Patients from our 2011 analysis were not included. All medical records and imaging studies for all patients receiving EVD placement during this time period were retrospectively reviewed. Procedural Technique The standard techniques for EVD placement at our institution have been previously described.7 Briefly, EVDs were placed by using a standard ventriculostomy catheter through Kocher's point to a depth of 5 to 6 cm in all patients with radiographically observed hydrocephalus on admission. The Ghajar guide was used in all cases unless there was a significant shift of midline brain structures. No bedside ventriculostomies were performed. Ventricular drains were not changed unless they became obstructed or an infection related to the ventriculostomy occurred. Patients who underwent stent-assisted coiling or flow diversion received 600 mg clopidogrel and 325 mg of acetylsalicylic acid (ASA) at the time of stent deployment, followed by 75 mg clopidogrel daily and 325 mg ASA daily postoperatively. Aggrastat was given IV for 2 h at 0.15 mcg/kg/min immediately following deployment a stent or flow diverter. DAPT was not discontinued during the perioperative period. EVD was placed before DAPT initiation in 116 patients. Only 4 received DAPT prior to EVD placement. Demographics, Hemorrhage Risk Factors, and Baseline Characteristics The baseline characteristics for the study population were collected at the time of admission and are summarized in Table 1. TABLE 1. Demographic Characteristics of Patients Who Underwent Endovascular Treatment and EVD Placement. Characteristic  No DAPT  DAPT    n = 178  n = 120  Age in years       Mean ± SD  57.8 ± 13.1  55.7 ± 13.2   Range  20-86  20-91  Sex (F/M)  128/50  76/44  Antiplatelets prior to hospitalization (%)  28 (15.7)  20 (16.7)  Approach for EVD (R/L)  141/37  96/24  H&H grade (%)       I  13 (7.3)  5 (4.2)   II  40 (22.5)  34 (28.3)   III  49 (27.5)  44 (36.7)   IV  37 (20.8)  26 (21.7)   V  39 (21.9)  11 (9.2)   Mean  3.3 ± 1.2  3.0 ± 1.0  Fisher scale (%)       Grade 1  3 (1.7)  1 (0.8)   Grade 2  26 (14.6)  25 (20.8)   Grade 3  36 (20.2)  24 (20)   Grade 4  113 (63.5)  70 (58.3)   Mean  3.5 ± 0.8  3.4 ± 0.8  WFNS scale (%)       Grade 1  42 (23.6)  37 (30.8)   Grade 2  37 (20.8)  27 (22.5)   Grade 3  11 (6.2)  6 (5)   Grade 4  36 (20.2)  29 (24.1)   Grade 5  52 (29.2)  21 (17.5)   Mean  3.1 ± 1.6  2.7 ± 1.5  LOS (d)  17.4 ± 10.5  18.5 ± 10.4  Median number of CTs per patient  4  4  Characteristic  No DAPT  DAPT    n = 178  n = 120  Age in years       Mean ± SD  57.8 ± 13.1  55.7 ± 13.2   Range  20-86  20-91  Sex (F/M)  128/50  76/44  Antiplatelets prior to hospitalization (%)  28 (15.7)  20 (16.7)  Approach for EVD (R/L)  141/37  96/24  H&H grade (%)       I  13 (7.3)  5 (4.2)   II  40 (22.5)  34 (28.3)   III  49 (27.5)  44 (36.7)   IV  37 (20.8)  26 (21.7)   V  39 (21.9)  11 (9.2)   Mean  3.3 ± 1.2  3.0 ± 1.0  Fisher scale (%)       Grade 1  3 (1.7)  1 (0.8)   Grade 2  26 (14.6)  25 (20.8)   Grade 3  36 (20.2)  24 (20)   Grade 4  113 (63.5)  70 (58.3)   Mean  3.5 ± 0.8  3.4 ± 0.8  WFNS scale (%)       Grade 1  42 (23.6)  37 (30.8)   Grade 2  37 (20.8)  27 (22.5)   Grade 3  11 (6.2)  6 (5)   Grade 4  36 (20.2)  29 (24.1)   Grade 5  52 (29.2)  21 (17.5)   Mean  3.1 ± 1.6  2.7 ± 1.5  LOS (d)  17.4 ± 10.5  18.5 ± 10.4  Median number of CTs per patient  4  4  DAPT, dual antiplatelet therapy; SD, standard deviation; F, female; M, male; EVD, external ventricular drain (right or left); H&H, Hunt–Hess grade; WFNS, World Federation of Neurosurgical Societies; LOS, length of stay Standard deviations are calculated for mean values. View Large TABLE 1. Demographic Characteristics of Patients Who Underwent Endovascular Treatment and EVD Placement. Characteristic  No DAPT  DAPT    n = 178  n = 120  Age in years       Mean ± SD  57.8 ± 13.1  55.7 ± 13.2   Range  20-86  20-91  Sex (F/M)  128/50  76/44  Antiplatelets prior to hospitalization (%)  28 (15.7)  20 (16.7)  Approach for EVD (R/L)  141/37  96/24  H&H grade (%)       I  13 (7.3)  5 (4.2)   II  40 (22.5)  34 (28.3)   III  49 (27.5)  44 (36.7)   IV  37 (20.8)  26 (21.7)   V  39 (21.9)  11 (9.2)   Mean  3.3 ± 1.2  3.0 ± 1.0  Fisher scale (%)       Grade 1  3 (1.7)  1 (0.8)   Grade 2  26 (14.6)  25 (20.8)   Grade 3  36 (20.2)  24 (20)   Grade 4  113 (63.5)  70 (58.3)   Mean  3.5 ± 0.8  3.4 ± 0.8  WFNS scale (%)       Grade 1  42 (23.6)  37 (30.8)   Grade 2  37 (20.8)  27 (22.5)   Grade 3  11 (6.2)  6 (5)   Grade 4  36 (20.2)  29 (24.1)   Grade 5  52 (29.2)  21 (17.5)   Mean  3.1 ± 1.6  2.7 ± 1.5  LOS (d)  17.4 ± 10.5  18.5 ± 10.4  Median number of CTs per patient  4  4  Characteristic  No DAPT  DAPT    n = 178  n = 120  Age in years       Mean ± SD  57.8 ± 13.1  55.7 ± 13.2   Range  20-86  20-91  Sex (F/M)  128/50  76/44  Antiplatelets prior to hospitalization (%)  28 (15.7)  20 (16.7)  Approach for EVD (R/L)  141/37  96/24  H&H grade (%)       I  13 (7.3)  5 (4.2)   II  40 (22.5)  34 (28.3)   III  49 (27.5)  44 (36.7)   IV  37 (20.8)  26 (21.7)   V  39 (21.9)  11 (9.2)   Mean  3.3 ± 1.2  3.0 ± 1.0  Fisher scale (%)       Grade 1  3 (1.7)  1 (0.8)   Grade 2  26 (14.6)  25 (20.8)   Grade 3  36 (20.2)  24 (20)   Grade 4  113 (63.5)  70 (58.3)   Mean  3.5 ± 0.8  3.4 ± 0.8  WFNS scale (%)       Grade 1  42 (23.6)  37 (30.8)   Grade 2  37 (20.8)  27 (22.5)   Grade 3  11 (6.2)  6 (5)   Grade 4  36 (20.2)  29 (24.1)   Grade 5  52 (29.2)  21 (17.5)   Mean  3.1 ± 1.6  2.7 ± 1.5  LOS (d)  17.4 ± 10.5  18.5 ± 10.4  Median number of CTs per patient  4  4  DAPT, dual antiplatelet therapy; SD, standard deviation; F, female; M, male; EVD, external ventricular drain (right or left); H&H, Hunt–Hess grade; WFNS, World Federation of Neurosurgical Societies; LOS, length of stay Standard deviations are calculated for mean values. View Large Determination of EVD-Related Hemorrhage All postoperative computed tomography (CT) scans obtained during the index hospitalization were first reviewed by an attending neuroradiologist blinded to the clinical outcome. All patients underwent, at a minimum, a same day postoperative CT scan following EVD placement. Two blinded attending neurosurgeons then further reviewed identified CT scans to confirm hemorrhage extent and location. If discrepancy between interpretations existed, the neurosurgical interpretation took precedence. A hemorrhage was deemed EVD-related if it occurred along the ventricular catheter tract. A hemorrhage was classified as symptomatic if it required further surgical intervention, was associated with any temporally related deterioration in daily serial neurological examination, or caused seizures. If identified hemorrhages were not classified as symptomatic, they were categorized as purely radiographic. Statistical Analysis and Variables Demographic and clinical variables including: age, sex, EVD approach, antiplatelet therapy prior to admission (any dosage or combination of AP medications), presenting Hunt and Hess grade of the aSAH, presenting Fischer grade, and presenting World Federation of Neurosurgical Societies grade were compared between groups. All significant variables associated with hemorrhage (P < .35) were included in a backward, stepwise, multivariate analysis. Identified symptomatic hemorrhages were analyzed with respect to DAPT with the use of Fisher's exact test. Hemorrhage size (defined as largest linear dimension) was compared with respect to DAPT with the use of an unpaired 2-tailed Student's t-test. Mean times between DAPT initiation and EVD placement were compared with the use of an unpaired 2-tailed Student's t-test. RESULTS Clinical Characteristics Four hundred forty-three patients were admitted for management of aSAH. Of these patients, 298 underwent EVD placement. The demographic and clinical characteristics of these patients are summarized in Table 1. Of the patients receiving an EVD, 178 patients (60%) underwent coiling without a stent or microsurgical clipping and did not require DAPT. The remaining 120 patients (40%) underwent stent-assisted coiling or flow diversion and required DAPT. Main Results A total of 1309 postoperative head CT scans following EVD placement, or both EVD placement and DAPT initiation, were reviewed. Forty-two new cases (14%) of new intracranial hemorrhage were observed along the EVD tract. Thirty-two (26.7%) of these hemorrhages occurred in patients on DAPT. Ten (5.6%) hemorrhages occurred in patients who underwent microsurgical clipping or endovascular coiling and were not on DAPT. No identified hemorrhage occurred during or after EVD removal. The results of our analysis are summarized in (Table 2). After multivariate analysis, DAPT was significantly associated with hemorrhage (odds ratio [OR]: 4.92, 95% confidence interval [CI]: 2.45-9.91, P = .0001; Table 3). Fischer grades on presentation were significantly associated with EVD-associated hemorrhage after multivariate analysis (OR: 1.67, 95% CI: 1.03-2.70, P = .03; Table 3). Of the patients not receiving DAPT, 5 hemorrhages were judged to be clinically significant (5 of 10 [50%]). Among these patients, 2 required EVD revision due to hemorrhage-associated blockage, 1 developed new onset left-sided weakness, 1 patient developed left-sided pronator drift and confusion, and 1 patient developed left-sided focal deficits. Of the patients receiving DAPT, 10 hemorrhages were judged to be clinically significant (10 of 32 [31%]). Of these patients, 4 needed EVD revision. Temporally related deficits attributed to EVD-associated hemorrhage among the other 6 patients included new onset minimal reactivity, inability to follow commands in both left upper and lower extremities, weakness in extremities, headache, confusion, and drowsiness. DAPT was not significantly associated with increased numbers of symptomatic hemorrhage (P = .4508; Table 2). The size of the observed hematomas was not statistically different between the 2 groups (Table 2). In the 120 patients receiving DAPT and an EVD, imaging revealed 7 (6%) clinically silent infarcts. Seven (6%) additional patients were identified as having symptomatic transient ischemic attack or radiographically observed clinically significant infarct. During long-term follow-up of the 40 patients who did not receive an EVD but were on DAPT for stent-assisted coiling or flow diversion, we observed 4 (10%) transient ischemic complications. TABLE 2. Hemorrhages Observed in Patients Receiving or Not Receiving DAPT Parameter  No DAPT  DAPT  P-value  Radiographic hemorrhages (%)  10 (5.6)  32 (26.7)    Symptomatic hemorrhages (%)  5 (2.8)  10 (8.3)  P = .4508a  Size of hematoma (mm ± SEM)  15.3 ± 3.2  14.6 ± 1.64  P = .8335b  Size of asymptomatic hematoma (mm ± SEM)  11.52 ± 1.39  12.7 ± 1.55  P = .7126b  Size of symptomatic hematoma (mm ± SEM)  20.4 ± 5.91  18.7 ± 3.46  P = .7967b  Parameter  No DAPT  DAPT  P-value  Radiographic hemorrhages (%)  10 (5.6)  32 (26.7)    Symptomatic hemorrhages (%)  5 (2.8)  10 (8.3)  P = .4508a  Size of hematoma (mm ± SEM)  15.3 ± 3.2  14.6 ± 1.64  P = .8335b  Size of asymptomatic hematoma (mm ± SEM)  11.52 ± 1.39  12.7 ± 1.55  P = .7126b  Size of symptomatic hematoma (mm ± SEM)  20.4 ± 5.91  18.7 ± 3.46  P = .7967b  aFischer exact test. bTwo-tailed unpaired Student's t-test, SEM—standard error of the mean. View Large TABLE 2. Hemorrhages Observed in Patients Receiving or Not Receiving DAPT Parameter  No DAPT  DAPT  P-value  Radiographic hemorrhages (%)  10 (5.6)  32 (26.7)    Symptomatic hemorrhages (%)  5 (2.8)  10 (8.3)  P = .4508a  Size of hematoma (mm ± SEM)  15.3 ± 3.2  14.6 ± 1.64  P = .8335b  Size of asymptomatic hematoma (mm ± SEM)  11.52 ± 1.39  12.7 ± 1.55  P = .7126b  Size of symptomatic hematoma (mm ± SEM)  20.4 ± 5.91  18.7 ± 3.46  P = .7967b  Parameter  No DAPT  DAPT  P-value  Radiographic hemorrhages (%)  10 (5.6)  32 (26.7)    Symptomatic hemorrhages (%)  5 (2.8)  10 (8.3)  P = .4508a  Size of hematoma (mm ± SEM)  15.3 ± 3.2  14.6 ± 1.64  P = .8335b  Size of asymptomatic hematoma (mm ± SEM)  11.52 ± 1.39  12.7 ± 1.55  P = .7126b  Size of symptomatic hematoma (mm ± SEM)  20.4 ± 5.91  18.7 ± 3.46  P = .7967b  aFischer exact test. bTwo-tailed unpaired Student's t-test, SEM—standard error of the mean. View Large TABLE 3. Univariate and Multivariate Predictors of EVD-Associated Radiographic Hemorrhage   Univariate  Multivariate  Variables  OR  95% CI  P-value  OR  95% CI  P-value  Age  1.01  0.99-1.05  .16  –  –  –  Sex (female)  0.8  0.39-1.66  .55  –  –  –  Approach for EVD (right)  1.51  0.40-5.66  .53  –  –  –  DAPT  4.58  2.25-9.34  <.001  4.92  2.45-9.91  <.001  H&H grade  0.51  0.28-0.91  .023  0.52  0.29-0.91  .023  Fisher grade  1.62  0.97-2.68  .06  1.67  1.03-2.70  .03  WFNS score  1.43  0.94-2.17  .09  1.42  0.94-2.12  .09  Antiplatelets prior to admission  1.6  0.66-3.87  .31  1.83  0.82-4.12  .15    Univariate  Multivariate  Variables  OR  95% CI  P-value  OR  95% CI  P-value  Age  1.01  0.99-1.05  .16  –  –  –  Sex (female)  0.8  0.39-1.66  .55  –  –  –  Approach for EVD (right)  1.51  0.40-5.66  .53  –  –  –  DAPT  4.58  2.25-9.34  <.001  4.92  2.45-9.91  <.001  H&H grade  0.51  0.28-0.91  .023  0.52  0.29-0.91  .023  Fisher grade  1.62  0.97-2.68  .06  1.67  1.03-2.70  .03  WFNS score  1.43  0.94-2.17  .09  1.42  0.94-2.12  .09  Antiplatelets prior to admission  1.6  0.66-3.87  .31  1.83  0.82-4.12  .15  View Large TABLE 3. Univariate and Multivariate Predictors of EVD-Associated Radiographic Hemorrhage   Univariate  Multivariate  Variables  OR  95% CI  P-value  OR  95% CI  P-value  Age  1.01  0.99-1.05  .16  –  –  –  Sex (female)  0.8  0.39-1.66  .55  –  –  –  Approach for EVD (right)  1.51  0.40-5.66  .53  –  –  –  DAPT  4.58  2.25-9.34  <.001  4.92  2.45-9.91  <.001  H&H grade  0.51  0.28-0.91  .023  0.52  0.29-0.91  .023  Fisher grade  1.62  0.97-2.68  .06  1.67  1.03-2.70  .03  WFNS score  1.43  0.94-2.17  .09  1.42  0.94-2.12  .09  Antiplatelets prior to admission  1.6  0.66-3.87  .31  1.83  0.82-4.12  .15    Univariate  Multivariate  Variables  OR  95% CI  P-value  OR  95% CI  P-value  Age  1.01  0.99-1.05  .16  –  –  –  Sex (female)  0.8  0.39-1.66  .55  –  –  –  Approach for EVD (right)  1.51  0.40-5.66  .53  –  –  –  DAPT  4.58  2.25-9.34  <.001  4.92  2.45-9.91  <.001  H&H grade  0.51  0.28-0.91  .023  0.52  0.29-0.91  .023  Fisher grade  1.62  0.97-2.68  .06  1.67  1.03-2.70  .03  WFNS score  1.43  0.94-2.17  .09  1.42  0.94-2.12  .09  Antiplatelets prior to admission  1.6  0.66-3.87  .31  1.83  0.82-4.12  .15  View Large In nearly all patients, DAPT therapy was initiated within 24 h of EVD placement. Median time to DAPT for the 116 patients who underwent EVD placement first was 11.5 h. The mean number of hours between EVD and DAPT therapy initiation (endovascular treatment) was not statistically different between symptomatic EVD-associated hemorrhages and those that were classified as asymptomatic (10.88 ± 3.4 vs 18.15 ± 4.6, P = .2795). There was no significant difference between mean hours to DAPT initiation between those patients with radiographically identified hemorrhages and those without (15.24 ± 3.0 vs 15.18 ± 4.8, P = .9937). There was no significant difference in hours to DAPT between asymptomatic cases (no hemorrhage and radiographic hemorrhage) and symptomatic hemorrhage cases (15.69 ± 3.9 vs 10.5 ± 3.7, P = .6692). DISCUSSION When intracranial stents and flow diverters are used in the setting of aSAH, perioperative DAPT is required to avoid in-stent thrombosis. DAPT may theoretically complicate the patient's subsequent neurosurgical management, ultimately leading to a reluctance to treat patients with these minimally invasive modalities. Despite this hesitancy, a number of recent studies suggest that stents and flow diverters may be used effectively in aSAH patients when alternative treatment modalities are less clinically attractive.10-12 Our group previously performed a small single institution retrospective analysis of 131 patients with aSAH who underwent intracranial catheter placement (Ventriculoperitoneal (VP) shunt/EVD) in the setting of aSAH.7 We observed an increased rate of radiographically identified hemorrhage in patients on DAPT for stent-assisted coiling (P = .02). Additionally, we observed a statistically significant increase in the number of these radiographically identified hemorrhages that were classified as symptomatic in patients on DAPT (4 of 50 [8%] vs 1 of 109 [1%]; P = .03). In our current analysis, we wished to reevaluate our findings in a much larger number of patients over an extended period of time. After multivariate analysis, we confirmed that the odds of radiographic hemorrhage are significantly higher in those patients treated with DAPT. Based on a recent meta-analysis, the rate of radiographically identified hemorrhage in patients who undergo EVD placement is approximately 5.7%, with less than 1% of these hemorrhages becoming symptomatic.5 These numbers are in relative agreement with the values we report (Table 2), although in comparison, it is clear that DAPT confers an elevated risk of radiographic hemorrhage. However, we do not see a statistically significant increase in those hemorrhages judged to be symptomatic. Indeed, this is in agreement with a recent study our group conducted evaluating the risk of hemorrhage in patients receiving VP shunts for post hemorrhagic hydrocephalus in the setting of long-term DAPT prophylaxis.9 We observed an increased rate of intracranial catheter-associated hemorrhage but no significant increase in number of symptomatic hemorrhages in patients on DAPT. Taken together, these data confirm the necessity of continuing DAPT during the perioperative period and further characterize the risk profile associated with stenting and flow diversion in the setting of aSAH. We secondarily quantified the time between DAPT initiation and EVD placement with respect to EVD-associated hemorrhage. Placing the EVD first before endovascular therapy and DAPT makes clinical sense given the increased risk of radiographic hemorrhage associated with DAPT. Indeed, this occurred for nearly all patients in our analysis. However, our data suggest that patients with aSAH may be candidates for stenting or endovascular coiling regardless of the time interval between EVD placement and the subsequent initiation of DAPT. Interestingly, our multivariate analysis revealed that AP prior to admission was not associated with increased identified radiographic hemorrhage. We postulate that since nearly all of these patients (47 of 48) were on low-dose aspirin or antiplatelet monotherapy prior to admission, the switch to high dosage DAPT during stenting/flow diversion provides a pathophysiological explanation for this observation. In our manuscript, we report a higher percentage of aneurysms treated with stenting or flow diversion overall (40%) than is standard practice within the United States. The decision to treat with these modalities was made only after weighing a variety of factors. Those factors advancing the clinical decision towards stenting/flow diversion in our cohort included: age greater than 70 yr old, presence of multiple comorbid diseases, wide neck and anatomic considerations, Hunt Hess grade 4, and other clinical circumstances making the risks associated with open surgery high. Despite the nonsignificant rate of symptomatic hemorrhage observed with stenting and flow diversion, we observed 32 total hemorrhages in DAPT patients, 10 of being were symptomatic. All associated risks, not limited to the significant thromboembolic, ischemic, and hemorrhagic complications of stent usage, should be considered prior to selecting a therapeutic modality in the acute setting. Recently, our group conducted an analysis revealing that the usage of DAPT was associated with reduced risk of clinical vasospasm and delayed cerebral ischemic changes.13 These data suggest antiplatelet treatment may be of protective significance following aSAH. Additionally, we have noted that the use of tirofiban, a IIb/IIIa inhibitor, may be associated with fewer detrimental effects in aSAH patients. As a result, we have recently begun a phase I/IIa clinical trial at our institution investigating the IV infusion of tirofiban during the first 10 d of admission for aSAH. As a result of its 90-min half-life, tirofiban can eliminated from the patient's system within 4 h. This may ultimately allow for safer manipulation of EVDs and VP shunts. Recent advancements in stent coating technology may allow for the discontinuation of perioperative DAPT altogether. In a recent case report, Chui et al14 describes the use of aspirin as the sole antiplatelet agent alongside a single loading dose of abciximab in the setting of a World Federation of Neurosurgical Societies grade 5 intradural vertebral artery dissecting aneurysm rupture treated with a pipeline embolization device with shield technology (Covidien-Medtronic, Dublin, Ireland).14 Technological advancements in antithrombotic stent coatings may ultimately eliminate the risk associated with perioperative DAPT. Finally, patients treated with DAPT for stenting or flow diversion may respond differently given 5% to 12% of patients are clopidogrel nonresponders.15 Although we did not test for platelet responsiveness in our study, refinement of this technique may allow for patient-specific dosing, reducing the risk of DAPT-associated complication. Limitations Our study's external validity is limited by its single institution scope. It is limited overall by its retrospective nature. Uniform identification of radiographic EVD-associated hemorrhage across all patients may have been limited by variation in the number of CTs patients received during their hospitalization for clinical purposes, ultimately leading to missed hemorrhages. However, patients on DAPT and those not on DAPT received similar numbers of head CTs (Table 1). At a minimum, all patients received a postoperative CT scan immediately following EVD placement. Nevertheless, it is likely that nondetection would be limited to purely radiographic hemorrhages, as symptomatic hemorrhages would have necessitated a CT scan for clinical purposes. CONCLUSION To the best of our knowledge, we provide the largest and most statistically comprehensive assessment to date regarding the risk of perioperative hemorrhage following DAPT therapy for stenting and flow diversion of ruptured intracranial aneurysms. Our analysis confirms that patients with aSAH who are candidates for stent-assisted coiling or flow diversion are at higher risk for hemorrhage associated with EVD placement. Despite this risk, the identified DAPT-associated hemorrhages do not appear to be of increased clinical significance. The timing between EVD placement and DAPT initiation does not appear to be of clinical significance. Stent-assisted coiling and flow diversion for aSAH remain options in an era of evolving endovascular therapeutics. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Connolly ES Jr, Rabinstein AA, Carhuapoma JR et al.   Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke  2012; 43( 6): 1711- 1737. Google Scholar CrossRef Search ADS PubMed  2. Ingall TJ, Whisnant JP, Wiebers DO, O’Fallon WM. Has there been a decline in subarachnoid hemorrhage mortality? Stroke . 1989; 20( 6): 718- 724. Google Scholar CrossRef Search ADS PubMed  3. Johnston SC, Selvin S, Gress DR. The burden, trends, and demographics of mortality from subarachnoid hemorrhage. Neurology . 1998; 50( 5): 1413- 1418. Google Scholar CrossRef Search ADS PubMed  4. Shea AM, Reed SD, Curtis LH, Alexander MJ, Villani JJ, Schulman KA. Characteristics of nontraumatic subarachnoid hemorrhage in the United States in 2003. Neurosurgery  2007; 61( 6): 1131- 1138. Google Scholar CrossRef Search ADS PubMed  5. Binz DD, Toussaint LG III, Friedman JA. Hemorrhagic complications of ventriculostomy placement: a meta-analysis. Neurocrit Care . 2009; 10( 2): 253- 256. Google Scholar CrossRef Search ADS PubMed  6. Tumialán LM, Zhang YJ, Cawley CM, Dion JE, Tong FC, Barrow DL. Intracranial hemorrhage associated with stent-assisted coil embolization of cerebral aneurysms: a cautionary report. J Neurosurg.  2008; 108( 6): 1122- 1129. Google Scholar CrossRef Search ADS PubMed  7. Kung DK, Policeni BA, Capuano AW et al.   Risk of ventriculostomy-related hemorrhage in patients with acutely ruptured aneurysms treated using stent-assisted coiling. J Neurosurg . 2011; 114( 4): 1021- 1027. Google Scholar CrossRef Search ADS PubMed  8. Mahaney KB, Chalouhi N, Viljoen S et al.   Risk of hemorrhagic complication associated with ventriculoperitoneal shunt placement in aneurysmal subarachnoid hemorrhage patients on dual antiplatelet therapy. J Neurosurg . 2013; 119( 4): 937- 942. Google Scholar CrossRef Search ADS PubMed  9. Hudson JS, Nagahama Y, Nakagawa D et al.   Hemorrhage associated with ventriculoperitoneal shunt placement in aneurysmal subarachnoid hemorrhage patients on a regimen of dual antiplatelet therapy: a retrospective analysis.. J Neurosurg . 2017. [Published online ahead of print]. 10. Amenta PS, Dalyai RT, Kung D et al.   Stent-assisted coiling of wide-necked aneurysms in the setting of acute subarachnoid hemorrhage: experience in 65 patients. Neurosurgery . 2012; 70( 6): 1415- 1429. Google Scholar CrossRef Search ADS PubMed  11. Bodily KD, Cloft HJ, Lanzio G, Fiorella DJ, White PM, Kallmes DF. Stent-Assisted coiling in acutely ruptured intracranial aneurysms: a qualitative, systematic review of the literature. Am J Neuroradiol . 2011; 32( 7): 1232- 1236. Google Scholar CrossRef Search ADS PubMed  12. Chalouhi N, Jabbour P, Singhal S et al.   Stent-Assisted coiling of intracranial aneurysms: predictors of complications, recanalization, and outcome in 508 cases. Stroke  2013; 44( 5): 1348- 1353. Google Scholar CrossRef Search ADS PubMed  13. Nagahama Y, Allan L, Nakagawa D et al.   Dual antiplatelet therapy in aneurysmal subarachnoid hemorrhage: association with reduced risk of clinical vasospasm and delayed cerebral ischemia. J Neurosurg . 2017. [Published online ahead of print]. 14. Chiu AH, Ramesh R, Wenderoth J, Davies M, Cheung A. Use of aspirin as sole oral antiplatelet therapy in acute flow diversion for ruptured dissecting aneurysms. BMJ Case Rep . 2016; 1- 9. 15. Corliss BM, Polifka AJ, Harris NS, Hoh BL, Fox WC. Laboratory assessments of therapeutic platelet inhibition in endovascular neurosurgery: comparing results of the VerifyNow P2Y12 assay to thromboelastography with platelet mapping. J Neurosurg . 2017. [Published online ahead of print]. Neurosurgery Speaks! Audio abstracts available for this article at www.neurosurgery-online.com. COMMENT The authors in this manuscript investigate the risk of hemorrhagic complication associated with external ventricular drainage placement in the setting of ruptured aneurysms treated with endovascular stenting that requires the use of dual antiplatelet therapy (DAPT). This work is a valuable addition to the current existing literature that proves an increased risk of bleeding for neurosurgical procedure in patients under prophylactic or therapeutic DAPT: the authors specifically address the risk of hemorrhagic complication post EVD placement, that is often required in the setting of aneurysmal subarachnoid hemorrhage (aSAH) and compare the outcome of patients with and without DAPT. In this report, there is an increased propensity to use of stents/flow diversion in 40% of patients with ruptured aneurysms; this is a very large percentage that does not reflect the current practice in many centers in the US, and might be associated with higher complications. An alternative to stenting would be to use balloon remodeling technique as an adjunct tool for coiling to avoid the use of DAPT in the acute phase and plan on placing stent or flow diversion in a later stage, post-discharge. This analysis indicates that the rate of EVD related bleeds are 32/120, and the symptomatic ones are 10/120. This is a high rate and should not be neglected. The manuscript does not present data on thromboembolic complications related to the stents/flow diversion, and it should also be kept in mind that the complications related to stents/flow diversion in the acute aSAH phase are not related only to EVD. The combination of the use of DAPT and the thromboembolic complications can potentially offset the advantage of endovascular treatment over surgical treatment, and should be very carefully considered in the acute phase. Denise Brunozzi Ali Alaraj Chicago, Illinois Neurosurgery Speaks (Audio Abstracts) Listen to audio translations of this paper's abstract into select languages by choosing from one of the selections below. Chinese: Junjie Wang, MD Department of Neurosurgery Beijing Hospital National Center of Gerontology Beijing, China Chinese: Junjie Wang, MD Department of Neurosurgery Beijing Hospital National Center of Gerontology Beijing, China Close English: Roberto Jose Diaz, MD, PhD Department of Neurology and Neurosurgery Faculty of Medicine McGill University Montreal, Canada English: Roberto Jose Diaz, MD, PhD Department of Neurology and Neurosurgery Faculty of Medicine McGill University Montreal, Canada Close French: Atef Ben Nsir, MD Neurosurgery Department Fattouma Bourguiba University Hospital University of Medicine of Monastir Monastir, Tunisia French: Atef Ben Nsir, MD Neurosurgery Department Fattouma Bourguiba University Hospital University of Medicine of Monastir Monastir, Tunisia Close Italian: Daniele Bongetta, MD Department of Neurosurgery Fondazione IRCCS Policlinico San Matteo Pavia, Italy Italian: Daniele Bongetta, MD Department of Neurosurgery Fondazione IRCCS Policlinico San Matteo Pavia, Italy Close Russian: Roman Kovalenko, MD Federal Almazov North-West Medical Research Centre St. Petersburg, Russian Federation Russian: Roman Kovalenko, MD Federal Almazov North-West Medical Research Centre St. Petersburg, Russian Federation Close Spanish: Igor Paredes Sansinenea, MD, PhD Department of Neurosurgery University Hospital “12 de Octubre” Madrid, Spain Spanish: Igor Paredes Sansinenea, MD, PhD Department of Neurosurgery University Hospital “12 de Octubre” Madrid, Spain Close Portuguese: Andrei Joaquim, MD, PhD Department of Neurology Division of Neurosurgery University of Campinas (UNICAMP) Campinas, Brazil Portuguese: Andrei Joaquim, MD, PhD Department of Neurology Division of Neurosurgery University of Campinas (UNICAMP) Campinas, Brazil Close Japanese: Soichi Oya, MD, PhD Department of Neurosurgery Saitama Medical Center/University Saitama, Japan Japanese: Soichi Oya, MD, PhD Department of Neurosurgery Saitama Medical Center/University Saitama, Japan Close Copyright © 2018 by the Congress of Neurological Surgeons

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NeurosurgeryOxford University Press

Published: Apr 11, 2018

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