Venous Thromboembolism After Intraventricular Hemorrhage: Results From the CLEAR III Trial

Venous Thromboembolism After Intraventricular Hemorrhage: Results From the CLEAR III Trial Abstract BACKGROUND Venous thromboembolism (VTE) after intracerebral hemorrhage is well studied, but data on patients with spontaneous intraventricular hemorrhage (IVH) are limited. OBJECTIVE To study the factors associated with VTE, association between VTE and clinical outcomes in IVH, and safety of VTE chemoprophylaxis in IVH treated with intraventricular catheters and thrombolysis. METHODS Retrospective cohort study of patients enrolled in the CLEAR III trial, a multicenter, randomized trial comparing external ventricular drainage, with administration of intraventricular alteplase vs placebo, for obstructive IVH. Predictor variable was incident VTE in the first 30 d. Outcome measures were factors associated with VTE, and death/severe disability (modified Rankin Score 4-6) at 6 mo. RESULTS Of the 500 patients with IVH, VTE occurred in 59 patients (11.8%) within the first 30 d. VTE chemoprophylaxis was initiated in 412 (82.4%) patients, but before VTE diagnosis in only 401 (80.2%) at median of 4 d (interquartile range, 1-8) from IVH onset, and was not associated with intracranial bleeding or catheter tract hemorrhage. In the multivariate logistic regression analysis, infection within 30 d (odds ratio, 1.80; confidence interval, 1.03-3.17) was significantly associated with higher odds of VTE occurrence. Starting VTE chemoprophylaxis after 72 h was additionally associated with VTE occurrence after the first week. CONCLUSION Infection and delay in timely initiation of VTE chemoprophylaxis were associated with VTE occurrence. VTE chemoprophylaxis in IVH appears safe and should not be delayed beyond standard care policies for ICH including when intraventricular catheter placement and thrombolytic therapy are performed. Deep vein thrombosis, Intracerebral hemorrhage, Intraventricular hemorrhage, Pulmonary embolism, Venous thromboembolism ABBREVIATIONS ABBREVIATIONS CI confidence interval CT computed tomography EVD external ventricular drain ICH intracerebral hemorrhage IQR interquartile range IVH intraventricular hemorrhage GCS Glasgow Coma Scale mRS modified Rankin score NIHSS National Institute of Health Stroke Scale OR odds ratio VTE venous thromboembolism Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality.1 About 40% of patients with ICH have intraventricular hemorrhage (IVH), which represents a critically ill subpopulation.2 Rates of venous thromboembolism (VTE) after ICH are reported to range from 0.5% to 40%.3-6 Factors identified in models evaluating association between VTE and ICH include female gender, African-American race, obesity, prolonged immobilization greater than 72 h, lower extremity paralysis, National Institute of Health Stroke Scale (NIHSS) score ≥12, presence of indwelling central venous catheter, infection, and elevated admission D-dimer levels.6-9 Prior studies are largely convenience samples without protocolized monitoring with the exception of 1 clinical trial of a prothrombotic therapy where VTE was a likely complication.3 Furthermore, previous studies have evaluated VTE in patients with predominantly parenchymal hematomas accompanied by varying amounts of intraventricular extension. There is, hence, a paucity of data regarding factors influencing VTE among patients primarily with IVH despite the expected strong influence of IVH on VTE risk due to altered level of consciousness. No studies have evaluated VTE prophylaxis and bleeding risk in ICH/IVH patients receiving external ventricular drainage (EVD) with addition of intraventricular thrombolysis. Our aim was 2-fold: first, to study predictors of VTE among patients with primary IVH, and the relationship between VTE occurrence and IVH outcomes using data from a large randomized clinical trial; and second, to evaluate the timing and safety of ICH management guidelines for VTE prophylaxis in an aggressively managed IVH population with rigorous monitoring of bleeding complications. METHODS Study Design and Patients We performed a retrospective cohort study using patients enrolled in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III trial. CLEAR III was a multicenter, randomized, double-blinded, placebo-controlled trial conducted to determine if pragmatically employed EVD plus intraventricular alteplase improved outcome by removing IVH and controlling intracranial pressure, in comparison to EVD plus saline.10 The main inclusion criteria were (1) adult patients, ages 18 to 80 yr, (2) spontaneous (hypertensive) ICH with hematoma volume <30 mL with IVH or primary IVH, (3) obstruction of the third and/or fourth ventricles, (4) presentation within 24 h of symptom onset, and (5) stability of ICH, IVH and any EVD tract hemorrhage prior to 72 h from diagnostic noncontrast computed tomography (CT) scan. The trial randomized patients to receive up to 12 doses of alteplase or 0.9% saline every 8 h via the EVD until third and fourth ventricles were radiographically open, IVH mass effect relieved, or 80% of clot was removed.11 Measurements Patient demographics and comorbidities were recorded at the time of enrollment and included the following baseline characteristics: age, gender, stroke comorbidities, medication history particularly antithrombotics, and admission severity variables such as NIHSS and Glasgow Coma Scale (GCS). Noncontrast CT scans were obtained on admission and at 12-h intervals until stability. Subsequently, CT scans were performed once daily after randomization, until after the last dose of study agent. CT scans were assessed daily for radiographic opening of the third and fourth ventricles. Hematoma volumes were calculated using semiautomated planimetry and read centrally by a single neuroradiologist blinded to treatments and outcomes. ICH and IVH volumes were calculated at diagnosis, stability (defined as no further evidence of hematoma expansion or new intracranial bleeding), and at the end of treatment (defined as 24 h after last dose of study agent). Our predictor variable was VTE, defined as a composite of deep vein thrombosis and pulmonary embolism that occurred in the first 30 d after symptom onset. Data on VTE were collected by the enrolling centers and were reported as adverse events. Decisions regarding triggers for evaluation of VTE, initiation of VTE chemoprophylaxis and choice of medication were at the discretion of the treating physicians. In this study, we only considered VTE chemoprophylaxis that was initiated prior to the diagnosis of VTE. We also collected data on any infection from randomization through day 30. Infections were captured through adverse event reporting and included site-reported pneumonia, urinary tract infection, bloodstream infection, and bacterial central nervous system infection. Only infections that preceded the diagnosis of VTE were included in the study since our aim was to study factors associated with the development of VTE. Outcomes Our primary outcome measures were factors associated with VTE, and blinded assessment of poor functional outcome defined as a modified Rankin score (mRS) of 4 to 6 at 6 mo. Secondary outcomes were mortality and severe disability (mRS 4-5) assessed separately, and intracranial bleeding complications of VTE chemoprophylaxis, categorized as symptomatic, asymptomatic bleeding, and catheter tract hemorrhage occurring after start of VTE chemoprophylaxis until 30 d from IVH onset. Symptomatic hemorrhage was defined as new or expansion of prior parenchymal bleed on CT scan by >5 mL in volume or >5 mm in diameter (EVD tract) or IVH expansion >2 mm increase in 2 out of 3 ventricular regions with sustained decrease in GCS motor scale >2 points over 8 h or other neurological signs and symptoms of similar severity. Asymptomatic bleeding was defined as ICH expansion ≤5 mm, IVH expansion ≤2 mm increase in 2 out of 3 ventricular regions, and catheter tract hemorrhage ≤5 mm in largest diameter without aforementioned clinical change. Additional Analyses The initial CLEAR III protocol recommended withholding initiation of VTE chemoprophylaxis until 72 h after the last dose of test article (approximately day 7 post ictus) due to perceived high risk of hemorrhage,12 which was later changed to allow standard of care policies to govern the use of fractionated and unfractionated heparin for VTE prophylaxis during the acute treatment and follow-up periods. We undertook additional analyses comparing the rates of VTE in the first 100 patients vs the remaining 400 patients, since this reflected the time point when the change in the CLEAR III VTE chemoprophylaxis policy was made. Additionally, given delays in the initiation of VTE chemoprophylaxis due to EVD placement, awaiting IVH/ICH stability, and change in the protocol for VTE prevention mentioned above, we performed an additional analysis including VTEs that occurred only between days 7 and 30 after admission in order to mitigate the effect of these inconsistencies in treatment in the first week. Finally, we also compared demographics and IVH severity characteristics in patients stratified by the timing of VTE chemoprophylaxis (≤72 h vs >72 h), to better understand reasons for delay in initiation of VTE chemoprophylaxis. Statistical Analysis Descriptive statistics were performed using Pearson's Chi-square test for categorical variables (Fisher exact test when appropriate). We used the Wilcoxon Rank Sum test or Student's t-test for continuous variables depending on the normality of data. Binary logistic regression was used to assess factors associated with VTE and the relationship between VTE and IVH outcomes. Covariates for the regression models were chosen based on bivariate logistic regression with a significance of P < .10. Based on these criteria, in the regression model that assessed predictors of VTE, we adjusted for infection in the first 30 d, and initiation of VTE prophylaxis within 72 h of IVH symptom onset. We also included hematoma severity variables such as stability IVH and ICH volumes, screening GCS, and age. Similarly, the regression models that studied the relationship between VTE and ICH outcomes were adjusted for age, stability IVH and ICH volumes, GCS score at screening, and withdrawal of active treatment. Statistical analyses were performed using Stata (version 14.0, College Station, Texas). All analyses were 2-tailed, and significance level was determined by P < .05. Standard Protocol Approvals, Registrations, and Patient Consents The CLEAR III trial was performed at 73 sites in Brazil, Canada, Germany, Hungary, Israel, Spain, the UK, and the USA, following local institutional review board and country ethics approval.10 This study is registered with ClinicalTrials.gov. Written informed consent for research was obtained from all participants (or legal representatives or surrogates when applicable) in the study. RESULTS There were 500 patients with IVH enrolled in the CLEAR III trial between September 2009 and January 2015. VTE occurred in 59 (11.8%) patients during the study follow-up period, of whom 52 (10%) had deep vein thrombosis, 13 (2.6%) had pulmonary embolism, and 6 (1.2%) had both. The 2 groups were similar in regards to demographics, comorbidities, and ICH severity characteristics (Table 1). Median time to VTE diagnosis was 15 d (interquartile range [IQR], 9-21 d) from IVH onset. There were 29 infections preceding VTE diagnosis within the first 30 d after IVH onset. Mean duration between infection and VTE detection was 6 d (range 1-24 d). Respiratory tract infections were most common (n = 20, 69%), followed by bacteremia (n = 3, 10%), urinary tract infection (n = 2, 7.9%), and meningitis (n = 2, 7.9%). FIGURE 1. View largeDownload slide Bleeding complications with VTE prophylaxis from the onset of prophylaxis to day 30, postadmission. FIGURE 1. View largeDownload slide Bleeding complications with VTE prophylaxis from the onset of prophylaxis to day 30, postadmission. TABLE 1. Baseline Demographics, Comorbidities and Clinical Severity Factors in Patients With Spontaneous IVH, Stratified by VTE VTE, n = 59 (%) No VTE, n = 441 (%) P value Demographic factors  Mean age (SD), yr 56.5 (12.5) 58.9 (11.1) .16  Female gender 21 (35.6) 201 (45.6) .09  Race   Caucasian 25 (42.4) 227 (51.5)   African American 24 (40.7) 146 (33.1) .61   Hispanic 7 (11.9) 46 (10.4)   Other 3 (5.0) 22 (5.0)  Hypertension 55 (93.2) 410 (93.0) .99  Hyperlipidemia 58 (98.3) 427 (96.8) .99  Obesity 5 (8.5) 37 (8.4) .98  Smoking 12 (220.3) 120 (27.0) .35  Coronary artery disease 4 (6.8) 25 (5.7) .73  Prior anticoagulant use 4 (6.8) 45 (10.2) .49  Prior antiplatelet use 12 (20.3) 116 (26.3) .43 Clinical severity factors  Glasgow Coma Scale at screeninga 10 (7-13) 10 (7-14) .91  NIHSS at screeninga 13.0 (10-26) 14 (8.0-24.0) .34  ICH location   Thalamus 34 (57.6) 259 (58.7) .89   Nonthalamic 25 (42.4) 182 (41.3)  Stability IVH volumea 21.9 (10.4-36.5) 21.6 (12.8-37.9) .78  Stability ICH volumea 8.8 (3.1-14.6) 7.9 (2.4-15.1) .86  End of treatment IVH volumea 8.8 (4.7-17.2) 8.6 (3.0-17.6) .80  End of treatment ICH volumea 7.2 (2.2-13.3) 6.6 (1.6-13.7) .73  Percentage of initial IVH volume removed (%)a 59.4 (33.4-76.9) 57.9 (35.3-77.1) .96  Day of clearing of 3rd and 4th ventriclesa 2 (2-4) 2 (2-4) .50  ICP elevation > 30 mm Hg 17 (29.3) 144 (33.0) .98  Intraventricular alteplase use 29 (49.2) 220 (49.9) .99  Withdrawal of active treatment 3 (5.1) 54 (12.2) .13 VTE, n = 59 (%) No VTE, n = 441 (%) P value Demographic factors  Mean age (SD), yr 56.5 (12.5) 58.9 (11.1) .16  Female gender 21 (35.6) 201 (45.6) .09  Race   Caucasian 25 (42.4) 227 (51.5)   African American 24 (40.7) 146 (33.1) .61   Hispanic 7 (11.9) 46 (10.4)   Other 3 (5.0) 22 (5.0)  Hypertension 55 (93.2) 410 (93.0) .99  Hyperlipidemia 58 (98.3) 427 (96.8) .99  Obesity 5 (8.5) 37 (8.4) .98  Smoking 12 (220.3) 120 (27.0) .35  Coronary artery disease 4 (6.8) 25 (5.7) .73  Prior anticoagulant use 4 (6.8) 45 (10.2) .49  Prior antiplatelet use 12 (20.3) 116 (26.3) .43 Clinical severity factors  Glasgow Coma Scale at screeninga 10 (7-13) 10 (7-14) .91  NIHSS at screeninga 13.0 (10-26) 14 (8.0-24.0) .34  ICH location   Thalamus 34 (57.6) 259 (58.7) .89   Nonthalamic 25 (42.4) 182 (41.3)  Stability IVH volumea 21.9 (10.4-36.5) 21.6 (12.8-37.9) .78  Stability ICH volumea 8.8 (3.1-14.6) 7.9 (2.4-15.1) .86  End of treatment IVH volumea 8.8 (4.7-17.2) 8.6 (3.0-17.6) .80  End of treatment ICH volumea 7.2 (2.2-13.3) 6.6 (1.6-13.7) .73  Percentage of initial IVH volume removed (%)a 59.4 (33.4-76.9) 57.9 (35.3-77.1) .96  Day of clearing of 3rd and 4th ventriclesa 2 (2-4) 2 (2-4) .50  ICP elevation > 30 mm Hg 17 (29.3) 144 (33.0) .98  Intraventricular alteplase use 29 (49.2) 220 (49.9) .99  Withdrawal of active treatment 3 (5.1) 54 (12.2) .13 Abbreviations: ICH, intracerebral hemorrhage; ICP, intracranial pressure; IVH, intraventricular hemorrhage; mL, milliliters; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). View Large TABLE 1. Baseline Demographics, Comorbidities and Clinical Severity Factors in Patients With Spontaneous IVH, Stratified by VTE VTE, n = 59 (%) No VTE, n = 441 (%) P value Demographic factors  Mean age (SD), yr 56.5 (12.5) 58.9 (11.1) .16  Female gender 21 (35.6) 201 (45.6) .09  Race   Caucasian 25 (42.4) 227 (51.5)   African American 24 (40.7) 146 (33.1) .61   Hispanic 7 (11.9) 46 (10.4)   Other 3 (5.0) 22 (5.0)  Hypertension 55 (93.2) 410 (93.0) .99  Hyperlipidemia 58 (98.3) 427 (96.8) .99  Obesity 5 (8.5) 37 (8.4) .98  Smoking 12 (220.3) 120 (27.0) .35  Coronary artery disease 4 (6.8) 25 (5.7) .73  Prior anticoagulant use 4 (6.8) 45 (10.2) .49  Prior antiplatelet use 12 (20.3) 116 (26.3) .43 Clinical severity factors  Glasgow Coma Scale at screeninga 10 (7-13) 10 (7-14) .91  NIHSS at screeninga 13.0 (10-26) 14 (8.0-24.0) .34  ICH location   Thalamus 34 (57.6) 259 (58.7) .89   Nonthalamic 25 (42.4) 182 (41.3)  Stability IVH volumea 21.9 (10.4-36.5) 21.6 (12.8-37.9) .78  Stability ICH volumea 8.8 (3.1-14.6) 7.9 (2.4-15.1) .86  End of treatment IVH volumea 8.8 (4.7-17.2) 8.6 (3.0-17.6) .80  End of treatment ICH volumea 7.2 (2.2-13.3) 6.6 (1.6-13.7) .73  Percentage of initial IVH volume removed (%)a 59.4 (33.4-76.9) 57.9 (35.3-77.1) .96  Day of clearing of 3rd and 4th ventriclesa 2 (2-4) 2 (2-4) .50  ICP elevation > 30 mm Hg 17 (29.3) 144 (33.0) .98  Intraventricular alteplase use 29 (49.2) 220 (49.9) .99  Withdrawal of active treatment 3 (5.1) 54 (12.2) .13 VTE, n = 59 (%) No VTE, n = 441 (%) P value Demographic factors  Mean age (SD), yr 56.5 (12.5) 58.9 (11.1) .16  Female gender 21 (35.6) 201 (45.6) .09  Race   Caucasian 25 (42.4) 227 (51.5)   African American 24 (40.7) 146 (33.1) .61   Hispanic 7 (11.9) 46 (10.4)   Other 3 (5.0) 22 (5.0)  Hypertension 55 (93.2) 410 (93.0) .99  Hyperlipidemia 58 (98.3) 427 (96.8) .99  Obesity 5 (8.5) 37 (8.4) .98  Smoking 12 (220.3) 120 (27.0) .35  Coronary artery disease 4 (6.8) 25 (5.7) .73  Prior anticoagulant use 4 (6.8) 45 (10.2) .49  Prior antiplatelet use 12 (20.3) 116 (26.3) .43 Clinical severity factors  Glasgow Coma Scale at screeninga 10 (7-13) 10 (7-14) .91  NIHSS at screeninga 13.0 (10-26) 14 (8.0-24.0) .34  ICH location   Thalamus 34 (57.6) 259 (58.7) .89   Nonthalamic 25 (42.4) 182 (41.3)  Stability IVH volumea 21.9 (10.4-36.5) 21.6 (12.8-37.9) .78  Stability ICH volumea 8.8 (3.1-14.6) 7.9 (2.4-15.1) .86  End of treatment IVH volumea 8.8 (4.7-17.2) 8.6 (3.0-17.6) .80  End of treatment ICH volumea 7.2 (2.2-13.3) 6.6 (1.6-13.7) .73  Percentage of initial IVH volume removed (%)a 59.4 (33.4-76.9) 57.9 (35.3-77.1) .96  Day of clearing of 3rd and 4th ventriclesa 2 (2-4) 2 (2-4) .50  ICP elevation > 30 mm Hg 17 (29.3) 144 (33.0) .98  Intraventricular alteplase use 29 (49.2) 220 (49.9) .99  Withdrawal of active treatment 3 (5.1) 54 (12.2) .13 Abbreviations: ICH, intracerebral hemorrhage; ICP, intracranial pressure; IVH, intraventricular hemorrhage; mL, milliliters; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). View Large Although a total of 412 patients received chemoprophylaxis for VTE, only 401 (80.2%) patients had chemoprophylaxis initiated prior to VTE diagnosis, at a median of 4 d (IQR, 1-8 d) from IVH onset. Patients who received VTE chemoprophylaxis were less likely to develop VTE as compared to those who did not receive chemoprophylaxis (33/401, 8.23% vs 22/99, 22.2%; P < .001). There was a trend towards fewer patients with VTE receiving chemoprophylaxis within 72 h of IVH symptom onset compared to those who did not develop VTE (22.0% vs 33.8%, P = .07; Table 2). Initiation of VTE chemoprophylaxis was not significantly associated with subsequent symptomatic or asymptomatic intracranial bleeding at 30 d, and rates of catheter tract hemorrhage were similar regardless of VTE chemoprophylaxis use (Figure 1). TABLE 2. Treatment Characteristics in Patients With Spontaneous IVH, Stratified by VTE. Variable VTE, n = 59 (%) No VTE, n = 441 (%) P value Duration of EVD, da 11.0 (9.0-15.0) 11.0 (8.0-14.0) .20 Permanent CSF shunt placement 10 (16.9) 80 (18.1) .99 Preceding infection (within first 30 d) 30 (50.8) 5 (1.1) < .001 Type of VTE prophylaxisb  Unfractionated heparin 36 (76.6) 256 (70.1) .39  Low molecular weight heparin 11 (23.4) 109 (29.9) Initiation of VTE prophylaxis before VTE detection 36 (61.0) 365 (82.8) .02 Initiation of VTE prophylaxis within 72 h of IVH symptom onset 13 (22.0) 149 (33.8) .07 Initiation of VTE prophylaxis within 7 d of IVH symptom onset 29 (49.1) 274 (62.1) .64 Variable VTE, n = 59 (%) No VTE, n = 441 (%) P value Duration of EVD, da 11.0 (9.0-15.0) 11.0 (8.0-14.0) .20 Permanent CSF shunt placement 10 (16.9) 80 (18.1) .99 Preceding infection (within first 30 d) 30 (50.8) 5 (1.1) < .001 Type of VTE prophylaxisb  Unfractionated heparin 36 (76.6) 256 (70.1) .39  Low molecular weight heparin 11 (23.4) 109 (29.9) Initiation of VTE prophylaxis before VTE detection 36 (61.0) 365 (82.8) .02 Initiation of VTE prophylaxis within 72 h of IVH symptom onset 13 (22.0) 149 (33.8) .07 Initiation of VTE prophylaxis within 7 d of IVH symptom onset 29 (49.1) 274 (62.1) .64 Abbreviations: CSF, cerebrospinal fluid; EVD, external ventriculostomy drain; IVH, intraventricular hemorrhage; SD, standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). bVTE chemoprophylaxis was started in 401 patients. Bold font represents statistical significance. View Large TABLE 2. Treatment Characteristics in Patients With Spontaneous IVH, Stratified by VTE. Variable VTE, n = 59 (%) No VTE, n = 441 (%) P value Duration of EVD, da 11.0 (9.0-15.0) 11.0 (8.0-14.0) .20 Permanent CSF shunt placement 10 (16.9) 80 (18.1) .99 Preceding infection (within first 30 d) 30 (50.8) 5 (1.1) < .001 Type of VTE prophylaxisb  Unfractionated heparin 36 (76.6) 256 (70.1) .39  Low molecular weight heparin 11 (23.4) 109 (29.9) Initiation of VTE prophylaxis before VTE detection 36 (61.0) 365 (82.8) .02 Initiation of VTE prophylaxis within 72 h of IVH symptom onset 13 (22.0) 149 (33.8) .07 Initiation of VTE prophylaxis within 7 d of IVH symptom onset 29 (49.1) 274 (62.1) .64 Variable VTE, n = 59 (%) No VTE, n = 441 (%) P value Duration of EVD, da 11.0 (9.0-15.0) 11.0 (8.0-14.0) .20 Permanent CSF shunt placement 10 (16.9) 80 (18.1) .99 Preceding infection (within first 30 d) 30 (50.8) 5 (1.1) < .001 Type of VTE prophylaxisb  Unfractionated heparin 36 (76.6) 256 (70.1) .39  Low molecular weight heparin 11 (23.4) 109 (29.9) Initiation of VTE prophylaxis before VTE detection 36 (61.0) 365 (82.8) .02 Initiation of VTE prophylaxis within 72 h of IVH symptom onset 13 (22.0) 149 (33.8) .07 Initiation of VTE prophylaxis within 7 d of IVH symptom onset 29 (49.1) 274 (62.1) .64 Abbreviations: CSF, cerebrospinal fluid; EVD, external ventriculostomy drain; IVH, intraventricular hemorrhage; SD, standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). bVTE chemoprophylaxis was started in 401 patients. Bold font represents statistical significance. View Large In the multivariate logistic regression analysis adjusted for confounders (Table 3), presence of prior infection within the first 30 d after IVH onset was significantly associated with higher odds of VTE occurrence (odds ratio [OR], 1.80; confidence interval [CI], 1.03-3.17). We found no relationship between VTE and ICH outcomes (mRS 4-6) in the logistic regression model adjusted for known predictors of ICH mortality (OR, 1.49; 95% CI, 0.74-3.00; Table 4). TABLE 3. Multivariable Logistic Regression of Factors Associated With VTE in First 30 d and From Day 7-30 in Patients With Spontaneous IVH VTE in the first 30 d VTE between days 7 and 30 Covariates OR (95% CI) P value OR (95% CI) P value Infection preceding VTE 1.80 (1.03-3.17) .04 1.81 (1.06-3.29) .04 Initiation of VTE prophylaxis within 72 h of IVH symptom onseta 0.56 (0.29-1.09) .09 0.46 (0.22-0.96) .04 Age 0.98 (0.95-1.01) .16 0.98 (0.95-1.05) .19 Stability IVH volume (per mL) 0.99 (0.98-1.102) .71 1.0 (0.98-1.02) .82 Stability ICH volume (per mL) 0.99 (0.96-1.03) .75 0.99 (0.95-1.04) .72 Glasgow Coma Scale at screening 1.01 (0.06-1.83) .21 0.98 (0.92-1.10) .96 VTE in the first 30 d VTE between days 7 and 30 Covariates OR (95% CI) P value OR (95% CI) P value Infection preceding VTE 1.80 (1.03-3.17) .04 1.81 (1.06-3.29) .04 Initiation of VTE prophylaxis within 72 h of IVH symptom onseta 0.56 (0.29-1.09) .09 0.46 (0.22-0.96) .04 Age 0.98 (0.95-1.01) .16 0.98 (0.95-1.05) .19 Stability IVH volume (per mL) 0.99 (0.98-1.102) .71 1.0 (0.98-1.02) .82 Stability ICH volume (per mL) 0.99 (0.96-1.03) .75 0.99 (0.95-1.04) .72 Glasgow Coma Scale at screening 1.01 (0.06-1.83) .21 0.98 (0.92-1.10) .96 Abbreviations: CI, Confidence interval; ICH, Intracerebral hemorrhage; IVH, Intraventricular hemorrhage; mL, milliliters; OR: Odds ratio; VTE, venous thromboembolism. aOnly cases where chemoprophylaxis was initiated prior to VTE diagnosis were considered. Bold font represents statistical significance. View Large TABLE 3. Multivariable Logistic Regression of Factors Associated With VTE in First 30 d and From Day 7-30 in Patients With Spontaneous IVH VTE in the first 30 d VTE between days 7 and 30 Covariates OR (95% CI) P value OR (95% CI) P value Infection preceding VTE 1.80 (1.03-3.17) .04 1.81 (1.06-3.29) .04 Initiation of VTE prophylaxis within 72 h of IVH symptom onseta 0.56 (0.29-1.09) .09 0.46 (0.22-0.96) .04 Age 0.98 (0.95-1.01) .16 0.98 (0.95-1.05) .19 Stability IVH volume (per mL) 0.99 (0.98-1.102) .71 1.0 (0.98-1.02) .82 Stability ICH volume (per mL) 0.99 (0.96-1.03) .75 0.99 (0.95-1.04) .72 Glasgow Coma Scale at screening 1.01 (0.06-1.83) .21 0.98 (0.92-1.10) .96 VTE in the first 30 d VTE between days 7 and 30 Covariates OR (95% CI) P value OR (95% CI) P value Infection preceding VTE 1.80 (1.03-3.17) .04 1.81 (1.06-3.29) .04 Initiation of VTE prophylaxis within 72 h of IVH symptom onseta 0.56 (0.29-1.09) .09 0.46 (0.22-0.96) .04 Age 0.98 (0.95-1.01) .16 0.98 (0.95-1.05) .19 Stability IVH volume (per mL) 0.99 (0.98-1.102) .71 1.0 (0.98-1.02) .82 Stability ICH volume (per mL) 0.99 (0.96-1.03) .75 0.99 (0.95-1.04) .72 Glasgow Coma Scale at screening 1.01 (0.06-1.83) .21 0.98 (0.92-1.10) .96 Abbreviations: CI, Confidence interval; ICH, Intracerebral hemorrhage; IVH, Intraventricular hemorrhage; mL, milliliters; OR: Odds ratio; VTE, venous thromboembolism. aOnly cases where chemoprophylaxis was initiated prior to VTE diagnosis were considered. Bold font represents statistical significance. View Large TABLE 4. Logistic Regression Analyses Showing the Relationship Between VTE and Outcomes in Spontaneous Intraventricular Hemorrhage. Outcome VTE No VTE Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value Modified Rankin Score 4-6 at 6 mo 35 (59.3) 229 (53.0) 1.14 (0.64-2.02) .66 1.49 (0.74-3.00) .27 Mortality at 6 mo 14 (23.7) 105 (23.8) 1.05 (0.54-2.03) .89 1.63 (0.75-3.54) .22 Modified Rankin Score 4-5 at 6 mo 21 (46.7) 124 (37.9) 1.18 (0.61-2.30) .63 1.28 (0.58-2.82) .54 Outcome VTE No VTE Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value Modified Rankin Score 4-6 at 6 mo 35 (59.3) 229 (53.0) 1.14 (0.64-2.02) .66 1.49 (0.74-3.00) .27 Mortality at 6 mo 14 (23.7) 105 (23.8) 1.05 (0.54-2.03) .89 1.63 (0.75-3.54) .22 Modified Rankin Score 4-5 at 6 mo 21 (46.7) 124 (37.9) 1.18 (0.61-2.30) .63 1.28 (0.58-2.82) .54 Abbreviations: CI: confidence interval; OR: odds ratio. Each model was adjusted for age, stability intraventricular and intracerebral hemorrhage volume, Glasgow Coma Scale score at screening, and withdrawal of active treatment. View Large TABLE 4. Logistic Regression Analyses Showing the Relationship Between VTE and Outcomes in Spontaneous Intraventricular Hemorrhage. Outcome VTE No VTE Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value Modified Rankin Score 4-6 at 6 mo 35 (59.3) 229 (53.0) 1.14 (0.64-2.02) .66 1.49 (0.74-3.00) .27 Mortality at 6 mo 14 (23.7) 105 (23.8) 1.05 (0.54-2.03) .89 1.63 (0.75-3.54) .22 Modified Rankin Score 4-5 at 6 mo 21 (46.7) 124 (37.9) 1.18 (0.61-2.30) .63 1.28 (0.58-2.82) .54 Outcome VTE No VTE Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value Modified Rankin Score 4-6 at 6 mo 35 (59.3) 229 (53.0) 1.14 (0.64-2.02) .66 1.49 (0.74-3.00) .27 Mortality at 6 mo 14 (23.7) 105 (23.8) 1.05 (0.54-2.03) .89 1.63 (0.75-3.54) .22 Modified Rankin Score 4-5 at 6 mo 21 (46.7) 124 (37.9) 1.18 (0.61-2.30) .63 1.28 (0.58-2.82) .54 Abbreviations: CI: confidence interval; OR: odds ratio. Each model was adjusted for age, stability intraventricular and intracerebral hemorrhage volume, Glasgow Coma Scale score at screening, and withdrawal of active treatment. View Large Additional Analyses To account for the change in the protocol for VTE chemoprophylaxis, we first assessed VTEs that occurred after the first week in the full cohort. We observed that preceding infection (OR, 1.81; CI, 1.06-3.29) and delay in initiation of VTE chemoprophylaxis beyond 72 h of IVH onset (OR, 0.46; CI, 0.22-0.96) were associated with occurrence of VTE. We then excluded the first 100 patients and found similar results. Second, to understand reasons for delay in starting VTE chemoprophylaxis, we compared the characteristics of patients with initiation of VTE chemoprophylaxis before and after 72 h (Table 5). Patients with delayed initiation of VTE chemoprophylaxis (>72 h) were more likely to have lower NIHSS at screening (P = .004) and nonthalamic ICH (P = .01). TABLE 5. Baseline Demographics, Comorbidities and Clinical Severity Factors in Patients With Spontaneous IVH, Stratified by Timing of Initiation of VTE Prophylaxis Demographic factors VTE prophylaxis ≤ 72 h (n = 162) VTE prophylaxis > 72 h (n = 239) P value Mean age (SD), yr 59.3 (11.5) 58.3 (11.4) .46 Female gender 76 (46.9) 110 (46.0) .86 Glasgow coma scale at screeninga 10 (7-14) 10 (7-14) .59 NIHSS at screeninga 17 (4-29) 13 (4-24) .004 ICH location  Thalamus 107 (66.0) 126 (52.7) .01  Nonthalamic 55 (34.0) 113 (47.3) Stability IVH volumea 20.0 (12.5-30.5) 22.5 (12.7-39.9) .07 Stability ICH volumea 8.5 (3.6-15.7) 7.6 (2.6-14.3) .14 Intraventricular alteplase use 81 (50.0) 116 (48.5) .84 Withdrawal of active treatment 17 (10.5) 26 (10.9) .90 More than one EVD 61 (37.7) 89 (36.8) .86 Asymptomatic hemorrhage 40 (24.7) 48 (20.1) .32 Symptomatic hemorrhage 4 (2.5) 9 (3.8) .57 Catheter tract hemorrhage 34 (21.0) 43 (18.0) .39 First 100 patients 16 (9.9) 52 (21.8) .002 Remaining 400 patients 146 (90.1) 187 (78.2) Demographic factors VTE prophylaxis ≤ 72 h (n = 162) VTE prophylaxis > 72 h (n = 239) P value Mean age (SD), yr 59.3 (11.5) 58.3 (11.4) .46 Female gender 76 (46.9) 110 (46.0) .86 Glasgow coma scale at screeninga 10 (7-14) 10 (7-14) .59 NIHSS at screeninga 17 (4-29) 13 (4-24) .004 ICH location  Thalamus 107 (66.0) 126 (52.7) .01  Nonthalamic 55 (34.0) 113 (47.3) Stability IVH volumea 20.0 (12.5-30.5) 22.5 (12.7-39.9) .07 Stability ICH volumea 8.5 (3.6-15.7) 7.6 (2.6-14.3) .14 Intraventricular alteplase use 81 (50.0) 116 (48.5) .84 Withdrawal of active treatment 17 (10.5) 26 (10.9) .90 More than one EVD 61 (37.7) 89 (36.8) .86 Asymptomatic hemorrhage 40 (24.7) 48 (20.1) .32 Symptomatic hemorrhage 4 (2.5) 9 (3.8) .57 Catheter tract hemorrhage 34 (21.0) 43 (18.0) .39 First 100 patients 16 (9.9) 52 (21.8) .002 Remaining 400 patients 146 (90.1) 187 (78.2) Abbreviations: EVD, External ventriculostomy drain; ICH: Intracerebral hemorrhage; IVH: Intraventricular hemorrhage; mL: milliliters; SD: Standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). Bold font represents statistical significance. View Large TABLE 5. Baseline Demographics, Comorbidities and Clinical Severity Factors in Patients With Spontaneous IVH, Stratified by Timing of Initiation of VTE Prophylaxis Demographic factors VTE prophylaxis ≤ 72 h (n = 162) VTE prophylaxis > 72 h (n = 239) P value Mean age (SD), yr 59.3 (11.5) 58.3 (11.4) .46 Female gender 76 (46.9) 110 (46.0) .86 Glasgow coma scale at screeninga 10 (7-14) 10 (7-14) .59 NIHSS at screeninga 17 (4-29) 13 (4-24) .004 ICH location  Thalamus 107 (66.0) 126 (52.7) .01  Nonthalamic 55 (34.0) 113 (47.3) Stability IVH volumea 20.0 (12.5-30.5) 22.5 (12.7-39.9) .07 Stability ICH volumea 8.5 (3.6-15.7) 7.6 (2.6-14.3) .14 Intraventricular alteplase use 81 (50.0) 116 (48.5) .84 Withdrawal of active treatment 17 (10.5) 26 (10.9) .90 More than one EVD 61 (37.7) 89 (36.8) .86 Asymptomatic hemorrhage 40 (24.7) 48 (20.1) .32 Symptomatic hemorrhage 4 (2.5) 9 (3.8) .57 Catheter tract hemorrhage 34 (21.0) 43 (18.0) .39 First 100 patients 16 (9.9) 52 (21.8) .002 Remaining 400 patients 146 (90.1) 187 (78.2) Demographic factors VTE prophylaxis ≤ 72 h (n = 162) VTE prophylaxis > 72 h (n = 239) P value Mean age (SD), yr 59.3 (11.5) 58.3 (11.4) .46 Female gender 76 (46.9) 110 (46.0) .86 Glasgow coma scale at screeninga 10 (7-14) 10 (7-14) .59 NIHSS at screeninga 17 (4-29) 13 (4-24) .004 ICH location  Thalamus 107 (66.0) 126 (52.7) .01  Nonthalamic 55 (34.0) 113 (47.3) Stability IVH volumea 20.0 (12.5-30.5) 22.5 (12.7-39.9) .07 Stability ICH volumea 8.5 (3.6-15.7) 7.6 (2.6-14.3) .14 Intraventricular alteplase use 81 (50.0) 116 (48.5) .84 Withdrawal of active treatment 17 (10.5) 26 (10.9) .90 More than one EVD 61 (37.7) 89 (36.8) .86 Asymptomatic hemorrhage 40 (24.7) 48 (20.1) .32 Symptomatic hemorrhage 4 (2.5) 9 (3.8) .57 Catheter tract hemorrhage 34 (21.0) 43 (18.0) .39 First 100 patients 16 (9.9) 52 (21.8) .002 Remaining 400 patients 146 (90.1) 187 (78.2) Abbreviations: EVD, External ventriculostomy drain; ICH: Intracerebral hemorrhage; IVH: Intraventricular hemorrhage; mL: milliliters; SD: Standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). Bold font represents statistical significance. View Large DISCUSSION In a large, multicenter, retrospective cohort study of patients with primary IVH, we found that preceding infection within the first 30 d was independently associated with VTE. Initiation of VTE chemoprophylaxis after 72 h was also associated with VTE, but only for VTE between days 7 and 30 (vs the full 30 d), which may reflect a lack of statistical power for this secondary outcome from the trial. Rates of VTE did not differ by treatment group (intraventricular alteplase or saline), and VTE chemoprophylaxis was found to be safe from the standpoint of risk for intracranial bleeding and catheter tract hemorrhage. Occurrence of VTE was not associated with mortality or poor functional outcome in this population. The significant relationship between presence of infection within the first 30 d and occurrence of VTE corroborates the results of prior studies, which have reported higher rates of infections with VTE. In fact, infection was identified as the most frequent trigger of hospitalization for VTE, in a large population-based study.13 Although the underlying pathophysiology remains to be elucidated, inflammation accompanying an infection is purported to result in the activation of the coagulation cascade in turn causing thromboembolic complications.14,15 Additionally, prolonged hospital stay occurring as a consequence of infection may also predispose these patients to develop VTE. While these factors may promote or hasten the development of VTE, our study was not designed to assess a causal association between incident infection and new VTE, which therefore, requires further study. We also observed that VTE was not associated with mortality in our study, which mirrors the results of prior literature.3 However, VTE has been shown to increase the cost of medical care significantly16 and, therefore, warrants early aggressive prevention strategies. Timing of initiation of chemoprophylaxis was also an independent predictor of delayed VTE in the CLEAR III trial. We calculated that the number needed to prevent a VTE event by initiating chemoprophylaxis within 72 h (vs after 72 h) was 13. We observed that lower clinical severity (NIHSS) and nonthalamic location of ICH were associated with delay in starting VTE chemoprophylaxis. Delays in initiation of prophylaxis may have stemmed from concerns over concurrent use of intraventricular alteplase or EVD insertion and removal. We found no differences in rates of intracranial bleeding and catheter tract hemorrhage irrespective of VTE chemoprophylaxis use. Furthermore, intraventricular alteplase has been shown to have no effect on systemic coagulation.17 The current guideline statements by the American Heart Association and Neurocritical Care Society recommend commencement of VTE chemoprophylaxis within 4 d of symptom onset, after ascertainment of hematoma stability,18,19 but these do not specifically include patients receiving EVDs and intraventricular thrombolysis. Our results support a favorable risk-benefit profile of initiation of VTE prophylaxis in the presence of an EVD and concomitant use of intraventricular alteplase as early as 72 h after IVH symptom onset providing that all hematoma locations are stable (ICH, IVH, and catheter tract hemorrhage) as was required for trial enrollment.11 Strengths and Limitations The strengths of this study include analyzing the largest cohort of IVH patients studied, well-defined inclusion criteria, protocolized frequent neuroimaging to monitor for complications, and protocolized safety event reporting of VTE occurrence and VTE chemoprophylaxis use. There are, however, several important limitations. First, the inclusion of a selective cohort of IVH patients with small hematoma volumes and obstructive IVH, and rigid screening and monitoring performed in the setting of a trial, introduce selection bias and limit generalizability of the results. Second, triggers for assessment of VTE, whether symptom-based or routine surveillance, were not standardized and hence, results could represent an overestimation of clinically evident VTE. Third, all decisions regarding initiation of VTE chemoprophylaxis and type of pharmacological agent chosen were made at the discretion of the treating physicians at the different participating institutions. Thus, we captured a range of prophylaxis timing practices. Although VTE rates did not differ by enrollment site or geographical location, residual confounding is still a possibility given that there were 73 different participating centers. Fourth, we assessed the impact of relevant physiological variables that predict development of VTE, but data on other typical risk factors such as prior history of VTE, extremity paralysis, and history of lower extremity varices were not available. Lastly, although this is the largest cohort of IVH patients, the study may not have been powered to evaluate risk factors or outcomes in patients developing VTE. CONCLUSION Patients with spontaneous IVH are at high-risk for developing VTE. Presence of infection and timing of chemoprophylaxis are independently associated with occurrence of VTE. Chemoprophylaxis for VTE appears to be safe in this population, even when used concomitantly with EVD and intraventricular alteplase and should not be delayed beyond standard of care policies for ICH patients. Disclosures Dr Murthy is supported by the American Academy of Neurology, American Brain Foundation, and the Leon Levy Neuroscience Foundation. Drs Awad, Hanley and Ziai have received significant research support through grant numbers 5U01NS062851 for Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage III and for Minimally Invasive Surgery Plus r-tPA for Intracerebral Hemorrhage Evacuation III 1U01NS08082. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Notes Oral platform presentation at the International Stroke Conference (American Heart Association/American Stroke Association), February 2016, Los Angeles, California REFERENCES 1. van Asch CJ , Luitse MJ , Rinkel GJ , van der Tweel I , Algra A , Klijn CJ . Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis . Lancet Neurol . 2010 ; 9 ( 2 ): 167 - 176 . Google Scholar CrossRef Search ADS PubMed 2. Qureshi AI , Tuhrim S , Broderick JP , Batjer HH , Hondo H , Hanley DF . Spontaneous intracerebral hemorrhage . N Engl J Med . 2001 ; 344 ( 19 ): 1450 - 1460 . Google Scholar CrossRef Search ADS PubMed 3. Diringer MN , Skolnick BE , Mayer SA et al. Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial . Stroke . 2010 ; 41 ( 1 ): 48 - 53 . Google Scholar CrossRef Search ADS PubMed 4. Skaf E , Stein PD , Beemath A , Sanchez J , Bustamante MA , Olson RE . Venous thromboembolism in patients with ischemic and hemorrhagic stroke . Am J Cardiol . 2005 ; 96 ( 12 ): 1731 - 1733 . Google Scholar CrossRef Search ADS PubMed 5. Goldstein JN , Fazen LE , Wendell L et al. Risk of thromboembolism following acute intracerebral hemorrhage . Neurocrit Care . 2009 ; 10 ( 1 ): 28 - 34 . Google Scholar CrossRef Search ADS PubMed 6. Ogata T , Yasaka M , Wakugawa Y , Inoue T , Ibayashi S , Okada Y . Deep venous thrombosis after acute intracerebral hemorrhage . J Neuroll Sci . 2008 ; 272 ( 1-2 ): 83 - 86 . Google Scholar CrossRef Search ADS 7. Christensen MC , Dawson J , Vincent C . Risk of thromboembolic complications after intracerebral hemorrhage according to ethnicity . Adv Ther . 2008 ; 25 ( 9 ): 831 - 841 . Google Scholar CrossRef Search ADS PubMed 8. Kawase K , Okazaki S , Toyoda K et al. Sex difference in the prevalence of deep-vein thrombosis in Japanese patients with acute intracerebral hemorrhage . Cerebrovasc Dis . 2009 ; 27 ( 4 ): 313 - 319 . Google Scholar CrossRef Search ADS PubMed 9. Kim KS , Brophy GM . Symptomatic venous thromboembolism: incidence and risk factors in patients with spontaneous or traumatic intracranial hemorrhage . Neurocrit Care . 2009 ; 11 ( 1 ): 28 - 33 . Google Scholar CrossRef Search ADS PubMed 10. Hanley DF , Lane K , McBee N et al. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial . Lancet . 2017 ; 389 ( 10069 ): 603 - 611 Google Scholar CrossRef Search ADS PubMed 11. Ziai WC , Tuhrim S , Lane K et al. A multicenter, randomized, double-blinded, placebo-controlled phase iii study of clot lysis evaluation of accelerated resolution of intraventricular hemorrhage (clear iii) . Int J Stroke . 2014 ; 9 ( 4 ): 536 - 542 Google Scholar CrossRef Search ADS PubMed 12. Naff N , Williams MA , Keyl PM et al. Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial . Stroke . 2011 ; 42 ( 11 ): 3009 - 3016 . Google Scholar CrossRef Search ADS PubMed 13. Rogers MA , Levine DA , Blumberg N , Flanders SA , Chopra V , Langa KM . Triggers of hospitalization for venous thromboembolism . Circulation . 2012 ; 125 ( 17 ): 2092 - 2099 . Google Scholar CrossRef Search ADS PubMed 14. van der Poll T , de Boer JD , Levi M . The effect of inflammation on coagulation and vice versa . Curr Opin Infect Dis . 2011 ; 24 ( 3 ): 273 - 278 . Google Scholar CrossRef Search ADS PubMed 15. Esmon CT . The impact of the inflammatory response on coagulation . Thromb Res . 2004 ; 114 ( 5-6 ): 321 - 327 . Google Scholar CrossRef Search ADS PubMed 16. Otite FO , Khandelwal P , Malik AM , Chaturvedi S , Sacco RL , Romano JG . Ten-year temporal trends in medical complications after acute intracerebral hemorrhage in the United States . Stroke . 2017 ; 48 ( 3 ): 596 - 603 . Google Scholar CrossRef Search ADS PubMed 17. Herrick D , Ziai WC , Thompson C , Lane K , McBee NA , Hanley DF . Systemic hematologic status following intraventricular recombinant tissue-type plasminogen activator for intraventricular hemorrhage . Stroke 2011 ; 42 ( 12 ): 3631 - 3633 . Google Scholar CrossRef Search ADS PubMed 18. Hemphill JC 3rd , Greenberg SM , Anderson CS et al. Guidelines for the management of spontaneous intracerebral hemorrhage . Stroke . 2015 ; 46 ( 7 ): 2032 - 2060 . Google Scholar CrossRef Search ADS PubMed 19. Nyquist P , Bautista C , Jichici D et al. Prophylaxis of venous thrombosis in neurocritical care patients: an evidence-based guideline: a statement for healthcare professionals from the neurocritical care society . Neurocrit Care . 2016 ; 24 ( 1 ): 47 - 60 . Google Scholar CrossRef Search ADS PubMed Neurosurgery Speaks! Audio abstracts available for this article at www.neurosurgery-online.com. COMMENTS Using the CLEAR III randomized controlled trial database examining the utility of locally instilled tissue plasminogen activator for intraventricular hemorrhage, the authors present a retrospective cohort analysis with a focus on associations and outcomes related to venous thromboembolism (VTE). This study represents Level 2b evidence and it provides the strongest information to date for guidance of this common scenario for an uncommon disease. The authors did not identify adverse complications related to starting VTE prophylaxis after initial hematoma stabilization, thus perhaps allaying some concerns for inadvertently augmenting hemorrhage in patients receiving ventricular thrombolytic medication. However, this study did not provide specific guidance as to the optimal method of prevention (eg, heparin and dosing, anti-embolism stockings, etc) as the trial left such medical management decisions wholly to the discretion of participating physicians and future study will be needed. There were trends suggestive that early initiation of prophylaxis prevented VTE, and that infection may play a role in VTE causation although given the authors did not measure infection post-VTE diagnosis, it may be an association rather than etiological factor. This study directs attention to important issues encountered in the optimal medical management of hemorrhagic stroke patients. John H. Wong Calgary, Canada Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in critically-ill patients.1 The neurosurgical patient population, often with reduced level of consciousness and extended periods of immobility, are at particular risk.2 The use of VTE chemoprophylaxis and the timing of its use has been a source of much debate in the neurosurgical community due to concern of exacerbating the primary pathology such as intracerebral (ICH) and intraventricular hemorrhage (IVH), as well as interventions which potentially predispose to further bleeding complications (eg, tract hemorrhage following external ventricular drain).3,4 The authors present a retrospective study from the CLEAR III trial cohorts on the effect of VTE chemoprophylaxis in the setting of ICH and IVH, and randomized treatment with external ventricular drain with saline or alteplase.5 In this well-written and succinctly presented paper, VTE chemoprophylaxis and its initiation within the first 72 hours is associated with reduction of VTE events. Confirming prior studies, infection is associated with VTE. Early initiation of chemoprophylaxis does not result in increased in morbidity or mortality from hemorrhagic complications. In this study, the authors were able to take advantage of an RCT patient population and provided evidence that 1) VTE chemoprophylaxis significantly reduced VTE (8.2% vs 22.2%), 2) delayed initiation of chemoprophylaxis was associated with increased risk of VTE, and 3) infection almost doubled the risk of VTE (odds ratio 1.8). Importantly, from a safety standpoint, in these patients with recent brain hemorrhage who required neurosurgical intervention such as an EVD, as well as intraventricular alteplase infusion, VTE chemoprophylaxis could be commenced early, within 72-hours of ictus, without significant adverse events. The study falls short of providing conclusive Level 1 evidence. The decision to administer or hold VTE chemoprophylaxis was not protocolled and was left to clinician discretion at individual centers. Ninety-nine out of 500 patients (20%) did not receive VTE chemoprophylaxis at all. Therefore, it is not known whether VTE chemoprophylaxis would have led to significant complications in this group. Although the standard of care VTE protocols appeared safe, the threshold for safe and early VTE chemoprophylaxis administration remains difficult to define. The evaluation of VTE was not systemic and there may well be missed cases, although such cases were likely of limited clinical significance. Nevertheless, the present study supports the early use of VTE chemoprophylaxis to prevent clinically relevant VTE in an acute neurosurgical patient population. The current standard of care protocols for VTE chemoprophylaxis appears safe, although future studies including RCTs will help better define the threshold at which VTE may be administered, balancing safety and prevention of VTE events. Chris Young Louis Kim Seattle, Washington 1. Khaldi A Helo N Schneck MJ Origitano TC . Venous thromboembolism: deep venous thrombosis and pulmonary embolism in a neurosurgical population . J Neurosurg . 2011 ; 114 ( 1 ): 40 - 46 . Google Scholar CrossRef Search ADS PubMed 2. Rolston JD Han SJ Bloch O Parsa AT . What clinical factors predict the incidence of deep venous thrombosis and pulmonary embolism in neurosurgical patients ? J Neurosurg . 2014 ; 121 ( 4 ): 908 - 918 . Google Scholar CrossRef Search ADS PubMed 3. Browd SR Ragel BT Davis GE Scott AM Skalabrin EJ Couldwell WT . Prophylaxis for deep venous thrombosis in neurosurgery: a review of the literature . Neurosurg Focus . 2004 ; 17 ( 4 ): E1 . Google Scholar CrossRef Search ADS PubMed 4. Hoh BL Nogueira RG Ledezma CJ Pryor JC Ogilvy CS . Safety of heparinization for cerebral aneurysm coiling soon after external ventriculostomy drain placement . Neurosurgery . 2005 ; 57 ( 5 ): 845 - 849 . Google Scholar CrossRef Search ADS PubMed 5. Ziai WC Tuhrim S Lane K , et al . A multicenter, randomized, double-blinded, placebo-controlled phase III study of Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III) . Int J Stroke Off J Int Stroke Soc . 2014 ; 9 ( 4 ): 536 - 542 . Google Scholar CrossRef Search ADS 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: Xiang Huang, MD. Pacific Neuroscience Institute Los Angeles, California Chinese: Xiang Huang, MD. Pacific Neuroscience Institute Los Angeles, California Close French: Michael Bruneau, MD, PhD. Department of Neurosurgery Erasme Hospital Brussels, Belgium French: Michael Bruneau, MD, PhD. Department of Neurosurgery Erasme Hospital Brussels, Belgium Close English: Oluwakemi Aderonke Badejo, MBBS, FWACS. Department of Surgery College of Medicine University of Ibadan Ibadan, Nigeria English: Oluwakemi Aderonke Badejo, MBBS, FWACS. Department of Surgery College of Medicine University of Ibadan Ibadan, Nigeria Close Italian: Danilo De Paulis, MD. Department of Neurosurgery San Sebastiano & San Annae City Hospital Caserta, Italy Italian: Danilo De Paulis, MD. Department of Neurosurgery San Sebastiano & San Annae City Hospital Caserta, Italy Close Spanish: Carlos Alarcon, MD. Department of Neurosurgery Hospital Universitari Mutua de Terrassa Barcelona, Spain Spanish: Carlos Alarcon, MD. Department of Neurosurgery Hospital Universitari Mutua de Terrassa Barcelona, Spain Close Portuguese: Andre Luiz Beer-Furlan, MD. Department of Neurological Surgery Rush University Medical Center Chicago, Illinois Portuguese: Andre Luiz Beer-Furlan, MD. Department of Neurological Surgery Rush University Medical Center Chicago, Illinois Close Japanese: Toshiaki Hayashi, MD, PhD. Department of Neurosurgery Sendai City Hospital Sendai, Japan Japanese: Toshiaki Hayashi, MD, PhD. Department of Neurosurgery Sendai City Hospital Sendai, Japan Close Korean: Keun Young Park, MD. Department of Neurosurgery Yonsei University College of Medicine Seoul, Republic of Korea Korean: Keun Young Park, MD. Department of Neurosurgery Yonsei University College of Medicine Seoul, Republic of Korea Close Russian: Mikhail Gelfenbeyn, MD, PhD. Department of Neurological Surgery University of Washington Seattle, Washington Russian: Mikhail Gelfenbeyn, MD, PhD. Department of Neurological Surgery University of Washington Seattle, Washington Close Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Venous Thromboembolism After Intraventricular Hemorrhage: Results From the CLEAR III Trial

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Congress of Neurological Surgeons
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Copyright © 2018 by the Congress of Neurological Surgeons
ISSN
0148-396X
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1524-4040
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10.1093/neuros/nyy189
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Abstract

Abstract BACKGROUND Venous thromboembolism (VTE) after intracerebral hemorrhage is well studied, but data on patients with spontaneous intraventricular hemorrhage (IVH) are limited. OBJECTIVE To study the factors associated with VTE, association between VTE and clinical outcomes in IVH, and safety of VTE chemoprophylaxis in IVH treated with intraventricular catheters and thrombolysis. METHODS Retrospective cohort study of patients enrolled in the CLEAR III trial, a multicenter, randomized trial comparing external ventricular drainage, with administration of intraventricular alteplase vs placebo, for obstructive IVH. Predictor variable was incident VTE in the first 30 d. Outcome measures were factors associated with VTE, and death/severe disability (modified Rankin Score 4-6) at 6 mo. RESULTS Of the 500 patients with IVH, VTE occurred in 59 patients (11.8%) within the first 30 d. VTE chemoprophylaxis was initiated in 412 (82.4%) patients, but before VTE diagnosis in only 401 (80.2%) at median of 4 d (interquartile range, 1-8) from IVH onset, and was not associated with intracranial bleeding or catheter tract hemorrhage. In the multivariate logistic regression analysis, infection within 30 d (odds ratio, 1.80; confidence interval, 1.03-3.17) was significantly associated with higher odds of VTE occurrence. Starting VTE chemoprophylaxis after 72 h was additionally associated with VTE occurrence after the first week. CONCLUSION Infection and delay in timely initiation of VTE chemoprophylaxis were associated with VTE occurrence. VTE chemoprophylaxis in IVH appears safe and should not be delayed beyond standard care policies for ICH including when intraventricular catheter placement and thrombolytic therapy are performed. Deep vein thrombosis, Intracerebral hemorrhage, Intraventricular hemorrhage, Pulmonary embolism, Venous thromboembolism ABBREVIATIONS ABBREVIATIONS CI confidence interval CT computed tomography EVD external ventricular drain ICH intracerebral hemorrhage IQR interquartile range IVH intraventricular hemorrhage GCS Glasgow Coma Scale mRS modified Rankin score NIHSS National Institute of Health Stroke Scale OR odds ratio VTE venous thromboembolism Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality.1 About 40% of patients with ICH have intraventricular hemorrhage (IVH), which represents a critically ill subpopulation.2 Rates of venous thromboembolism (VTE) after ICH are reported to range from 0.5% to 40%.3-6 Factors identified in models evaluating association between VTE and ICH include female gender, African-American race, obesity, prolonged immobilization greater than 72 h, lower extremity paralysis, National Institute of Health Stroke Scale (NIHSS) score ≥12, presence of indwelling central venous catheter, infection, and elevated admission D-dimer levels.6-9 Prior studies are largely convenience samples without protocolized monitoring with the exception of 1 clinical trial of a prothrombotic therapy where VTE was a likely complication.3 Furthermore, previous studies have evaluated VTE in patients with predominantly parenchymal hematomas accompanied by varying amounts of intraventricular extension. There is, hence, a paucity of data regarding factors influencing VTE among patients primarily with IVH despite the expected strong influence of IVH on VTE risk due to altered level of consciousness. No studies have evaluated VTE prophylaxis and bleeding risk in ICH/IVH patients receiving external ventricular drainage (EVD) with addition of intraventricular thrombolysis. Our aim was 2-fold: first, to study predictors of VTE among patients with primary IVH, and the relationship between VTE occurrence and IVH outcomes using data from a large randomized clinical trial; and second, to evaluate the timing and safety of ICH management guidelines for VTE prophylaxis in an aggressively managed IVH population with rigorous monitoring of bleeding complications. METHODS Study Design and Patients We performed a retrospective cohort study using patients enrolled in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III trial. CLEAR III was a multicenter, randomized, double-blinded, placebo-controlled trial conducted to determine if pragmatically employed EVD plus intraventricular alteplase improved outcome by removing IVH and controlling intracranial pressure, in comparison to EVD plus saline.10 The main inclusion criteria were (1) adult patients, ages 18 to 80 yr, (2) spontaneous (hypertensive) ICH with hematoma volume <30 mL with IVH or primary IVH, (3) obstruction of the third and/or fourth ventricles, (4) presentation within 24 h of symptom onset, and (5) stability of ICH, IVH and any EVD tract hemorrhage prior to 72 h from diagnostic noncontrast computed tomography (CT) scan. The trial randomized patients to receive up to 12 doses of alteplase or 0.9% saline every 8 h via the EVD until third and fourth ventricles were radiographically open, IVH mass effect relieved, or 80% of clot was removed.11 Measurements Patient demographics and comorbidities were recorded at the time of enrollment and included the following baseline characteristics: age, gender, stroke comorbidities, medication history particularly antithrombotics, and admission severity variables such as NIHSS and Glasgow Coma Scale (GCS). Noncontrast CT scans were obtained on admission and at 12-h intervals until stability. Subsequently, CT scans were performed once daily after randomization, until after the last dose of study agent. CT scans were assessed daily for radiographic opening of the third and fourth ventricles. Hematoma volumes were calculated using semiautomated planimetry and read centrally by a single neuroradiologist blinded to treatments and outcomes. ICH and IVH volumes were calculated at diagnosis, stability (defined as no further evidence of hematoma expansion or new intracranial bleeding), and at the end of treatment (defined as 24 h after last dose of study agent). Our predictor variable was VTE, defined as a composite of deep vein thrombosis and pulmonary embolism that occurred in the first 30 d after symptom onset. Data on VTE were collected by the enrolling centers and were reported as adverse events. Decisions regarding triggers for evaluation of VTE, initiation of VTE chemoprophylaxis and choice of medication were at the discretion of the treating physicians. In this study, we only considered VTE chemoprophylaxis that was initiated prior to the diagnosis of VTE. We also collected data on any infection from randomization through day 30. Infections were captured through adverse event reporting and included site-reported pneumonia, urinary tract infection, bloodstream infection, and bacterial central nervous system infection. Only infections that preceded the diagnosis of VTE were included in the study since our aim was to study factors associated with the development of VTE. Outcomes Our primary outcome measures were factors associated with VTE, and blinded assessment of poor functional outcome defined as a modified Rankin score (mRS) of 4 to 6 at 6 mo. Secondary outcomes were mortality and severe disability (mRS 4-5) assessed separately, and intracranial bleeding complications of VTE chemoprophylaxis, categorized as symptomatic, asymptomatic bleeding, and catheter tract hemorrhage occurring after start of VTE chemoprophylaxis until 30 d from IVH onset. Symptomatic hemorrhage was defined as new or expansion of prior parenchymal bleed on CT scan by >5 mL in volume or >5 mm in diameter (EVD tract) or IVH expansion >2 mm increase in 2 out of 3 ventricular regions with sustained decrease in GCS motor scale >2 points over 8 h or other neurological signs and symptoms of similar severity. Asymptomatic bleeding was defined as ICH expansion ≤5 mm, IVH expansion ≤2 mm increase in 2 out of 3 ventricular regions, and catheter tract hemorrhage ≤5 mm in largest diameter without aforementioned clinical change. Additional Analyses The initial CLEAR III protocol recommended withholding initiation of VTE chemoprophylaxis until 72 h after the last dose of test article (approximately day 7 post ictus) due to perceived high risk of hemorrhage,12 which was later changed to allow standard of care policies to govern the use of fractionated and unfractionated heparin for VTE prophylaxis during the acute treatment and follow-up periods. We undertook additional analyses comparing the rates of VTE in the first 100 patients vs the remaining 400 patients, since this reflected the time point when the change in the CLEAR III VTE chemoprophylaxis policy was made. Additionally, given delays in the initiation of VTE chemoprophylaxis due to EVD placement, awaiting IVH/ICH stability, and change in the protocol for VTE prevention mentioned above, we performed an additional analysis including VTEs that occurred only between days 7 and 30 after admission in order to mitigate the effect of these inconsistencies in treatment in the first week. Finally, we also compared demographics and IVH severity characteristics in patients stratified by the timing of VTE chemoprophylaxis (≤72 h vs >72 h), to better understand reasons for delay in initiation of VTE chemoprophylaxis. Statistical Analysis Descriptive statistics were performed using Pearson's Chi-square test for categorical variables (Fisher exact test when appropriate). We used the Wilcoxon Rank Sum test or Student's t-test for continuous variables depending on the normality of data. Binary logistic regression was used to assess factors associated with VTE and the relationship between VTE and IVH outcomes. Covariates for the regression models were chosen based on bivariate logistic regression with a significance of P < .10. Based on these criteria, in the regression model that assessed predictors of VTE, we adjusted for infection in the first 30 d, and initiation of VTE prophylaxis within 72 h of IVH symptom onset. We also included hematoma severity variables such as stability IVH and ICH volumes, screening GCS, and age. Similarly, the regression models that studied the relationship between VTE and ICH outcomes were adjusted for age, stability IVH and ICH volumes, GCS score at screening, and withdrawal of active treatment. Statistical analyses were performed using Stata (version 14.0, College Station, Texas). All analyses were 2-tailed, and significance level was determined by P < .05. Standard Protocol Approvals, Registrations, and Patient Consents The CLEAR III trial was performed at 73 sites in Brazil, Canada, Germany, Hungary, Israel, Spain, the UK, and the USA, following local institutional review board and country ethics approval.10 This study is registered with ClinicalTrials.gov. Written informed consent for research was obtained from all participants (or legal representatives or surrogates when applicable) in the study. RESULTS There were 500 patients with IVH enrolled in the CLEAR III trial between September 2009 and January 2015. VTE occurred in 59 (11.8%) patients during the study follow-up period, of whom 52 (10%) had deep vein thrombosis, 13 (2.6%) had pulmonary embolism, and 6 (1.2%) had both. The 2 groups were similar in regards to demographics, comorbidities, and ICH severity characteristics (Table 1). Median time to VTE diagnosis was 15 d (interquartile range [IQR], 9-21 d) from IVH onset. There were 29 infections preceding VTE diagnosis within the first 30 d after IVH onset. Mean duration between infection and VTE detection was 6 d (range 1-24 d). Respiratory tract infections were most common (n = 20, 69%), followed by bacteremia (n = 3, 10%), urinary tract infection (n = 2, 7.9%), and meningitis (n = 2, 7.9%). FIGURE 1. View largeDownload slide Bleeding complications with VTE prophylaxis from the onset of prophylaxis to day 30, postadmission. FIGURE 1. View largeDownload slide Bleeding complications with VTE prophylaxis from the onset of prophylaxis to day 30, postadmission. TABLE 1. Baseline Demographics, Comorbidities and Clinical Severity Factors in Patients With Spontaneous IVH, Stratified by VTE VTE, n = 59 (%) No VTE, n = 441 (%) P value Demographic factors  Mean age (SD), yr 56.5 (12.5) 58.9 (11.1) .16  Female gender 21 (35.6) 201 (45.6) .09  Race   Caucasian 25 (42.4) 227 (51.5)   African American 24 (40.7) 146 (33.1) .61   Hispanic 7 (11.9) 46 (10.4)   Other 3 (5.0) 22 (5.0)  Hypertension 55 (93.2) 410 (93.0) .99  Hyperlipidemia 58 (98.3) 427 (96.8) .99  Obesity 5 (8.5) 37 (8.4) .98  Smoking 12 (220.3) 120 (27.0) .35  Coronary artery disease 4 (6.8) 25 (5.7) .73  Prior anticoagulant use 4 (6.8) 45 (10.2) .49  Prior antiplatelet use 12 (20.3) 116 (26.3) .43 Clinical severity factors  Glasgow Coma Scale at screeninga 10 (7-13) 10 (7-14) .91  NIHSS at screeninga 13.0 (10-26) 14 (8.0-24.0) .34  ICH location   Thalamus 34 (57.6) 259 (58.7) .89   Nonthalamic 25 (42.4) 182 (41.3)  Stability IVH volumea 21.9 (10.4-36.5) 21.6 (12.8-37.9) .78  Stability ICH volumea 8.8 (3.1-14.6) 7.9 (2.4-15.1) .86  End of treatment IVH volumea 8.8 (4.7-17.2) 8.6 (3.0-17.6) .80  End of treatment ICH volumea 7.2 (2.2-13.3) 6.6 (1.6-13.7) .73  Percentage of initial IVH volume removed (%)a 59.4 (33.4-76.9) 57.9 (35.3-77.1) .96  Day of clearing of 3rd and 4th ventriclesa 2 (2-4) 2 (2-4) .50  ICP elevation > 30 mm Hg 17 (29.3) 144 (33.0) .98  Intraventricular alteplase use 29 (49.2) 220 (49.9) .99  Withdrawal of active treatment 3 (5.1) 54 (12.2) .13 VTE, n = 59 (%) No VTE, n = 441 (%) P value Demographic factors  Mean age (SD), yr 56.5 (12.5) 58.9 (11.1) .16  Female gender 21 (35.6) 201 (45.6) .09  Race   Caucasian 25 (42.4) 227 (51.5)   African American 24 (40.7) 146 (33.1) .61   Hispanic 7 (11.9) 46 (10.4)   Other 3 (5.0) 22 (5.0)  Hypertension 55 (93.2) 410 (93.0) .99  Hyperlipidemia 58 (98.3) 427 (96.8) .99  Obesity 5 (8.5) 37 (8.4) .98  Smoking 12 (220.3) 120 (27.0) .35  Coronary artery disease 4 (6.8) 25 (5.7) .73  Prior anticoagulant use 4 (6.8) 45 (10.2) .49  Prior antiplatelet use 12 (20.3) 116 (26.3) .43 Clinical severity factors  Glasgow Coma Scale at screeninga 10 (7-13) 10 (7-14) .91  NIHSS at screeninga 13.0 (10-26) 14 (8.0-24.0) .34  ICH location   Thalamus 34 (57.6) 259 (58.7) .89   Nonthalamic 25 (42.4) 182 (41.3)  Stability IVH volumea 21.9 (10.4-36.5) 21.6 (12.8-37.9) .78  Stability ICH volumea 8.8 (3.1-14.6) 7.9 (2.4-15.1) .86  End of treatment IVH volumea 8.8 (4.7-17.2) 8.6 (3.0-17.6) .80  End of treatment ICH volumea 7.2 (2.2-13.3) 6.6 (1.6-13.7) .73  Percentage of initial IVH volume removed (%)a 59.4 (33.4-76.9) 57.9 (35.3-77.1) .96  Day of clearing of 3rd and 4th ventriclesa 2 (2-4) 2 (2-4) .50  ICP elevation > 30 mm Hg 17 (29.3) 144 (33.0) .98  Intraventricular alteplase use 29 (49.2) 220 (49.9) .99  Withdrawal of active treatment 3 (5.1) 54 (12.2) .13 Abbreviations: ICH, intracerebral hemorrhage; ICP, intracranial pressure; IVH, intraventricular hemorrhage; mL, milliliters; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). View Large TABLE 1. Baseline Demographics, Comorbidities and Clinical Severity Factors in Patients With Spontaneous IVH, Stratified by VTE VTE, n = 59 (%) No VTE, n = 441 (%) P value Demographic factors  Mean age (SD), yr 56.5 (12.5) 58.9 (11.1) .16  Female gender 21 (35.6) 201 (45.6) .09  Race   Caucasian 25 (42.4) 227 (51.5)   African American 24 (40.7) 146 (33.1) .61   Hispanic 7 (11.9) 46 (10.4)   Other 3 (5.0) 22 (5.0)  Hypertension 55 (93.2) 410 (93.0) .99  Hyperlipidemia 58 (98.3) 427 (96.8) .99  Obesity 5 (8.5) 37 (8.4) .98  Smoking 12 (220.3) 120 (27.0) .35  Coronary artery disease 4 (6.8) 25 (5.7) .73  Prior anticoagulant use 4 (6.8) 45 (10.2) .49  Prior antiplatelet use 12 (20.3) 116 (26.3) .43 Clinical severity factors  Glasgow Coma Scale at screeninga 10 (7-13) 10 (7-14) .91  NIHSS at screeninga 13.0 (10-26) 14 (8.0-24.0) .34  ICH location   Thalamus 34 (57.6) 259 (58.7) .89   Nonthalamic 25 (42.4) 182 (41.3)  Stability IVH volumea 21.9 (10.4-36.5) 21.6 (12.8-37.9) .78  Stability ICH volumea 8.8 (3.1-14.6) 7.9 (2.4-15.1) .86  End of treatment IVH volumea 8.8 (4.7-17.2) 8.6 (3.0-17.6) .80  End of treatment ICH volumea 7.2 (2.2-13.3) 6.6 (1.6-13.7) .73  Percentage of initial IVH volume removed (%)a 59.4 (33.4-76.9) 57.9 (35.3-77.1) .96  Day of clearing of 3rd and 4th ventriclesa 2 (2-4) 2 (2-4) .50  ICP elevation > 30 mm Hg 17 (29.3) 144 (33.0) .98  Intraventricular alteplase use 29 (49.2) 220 (49.9) .99  Withdrawal of active treatment 3 (5.1) 54 (12.2) .13 VTE, n = 59 (%) No VTE, n = 441 (%) P value Demographic factors  Mean age (SD), yr 56.5 (12.5) 58.9 (11.1) .16  Female gender 21 (35.6) 201 (45.6) .09  Race   Caucasian 25 (42.4) 227 (51.5)   African American 24 (40.7) 146 (33.1) .61   Hispanic 7 (11.9) 46 (10.4)   Other 3 (5.0) 22 (5.0)  Hypertension 55 (93.2) 410 (93.0) .99  Hyperlipidemia 58 (98.3) 427 (96.8) .99  Obesity 5 (8.5) 37 (8.4) .98  Smoking 12 (220.3) 120 (27.0) .35  Coronary artery disease 4 (6.8) 25 (5.7) .73  Prior anticoagulant use 4 (6.8) 45 (10.2) .49  Prior antiplatelet use 12 (20.3) 116 (26.3) .43 Clinical severity factors  Glasgow Coma Scale at screeninga 10 (7-13) 10 (7-14) .91  NIHSS at screeninga 13.0 (10-26) 14 (8.0-24.0) .34  ICH location   Thalamus 34 (57.6) 259 (58.7) .89   Nonthalamic 25 (42.4) 182 (41.3)  Stability IVH volumea 21.9 (10.4-36.5) 21.6 (12.8-37.9) .78  Stability ICH volumea 8.8 (3.1-14.6) 7.9 (2.4-15.1) .86  End of treatment IVH volumea 8.8 (4.7-17.2) 8.6 (3.0-17.6) .80  End of treatment ICH volumea 7.2 (2.2-13.3) 6.6 (1.6-13.7) .73  Percentage of initial IVH volume removed (%)a 59.4 (33.4-76.9) 57.9 (35.3-77.1) .96  Day of clearing of 3rd and 4th ventriclesa 2 (2-4) 2 (2-4) .50  ICP elevation > 30 mm Hg 17 (29.3) 144 (33.0) .98  Intraventricular alteplase use 29 (49.2) 220 (49.9) .99  Withdrawal of active treatment 3 (5.1) 54 (12.2) .13 Abbreviations: ICH, intracerebral hemorrhage; ICP, intracranial pressure; IVH, intraventricular hemorrhage; mL, milliliters; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). View Large Although a total of 412 patients received chemoprophylaxis for VTE, only 401 (80.2%) patients had chemoprophylaxis initiated prior to VTE diagnosis, at a median of 4 d (IQR, 1-8 d) from IVH onset. Patients who received VTE chemoprophylaxis were less likely to develop VTE as compared to those who did not receive chemoprophylaxis (33/401, 8.23% vs 22/99, 22.2%; P < .001). There was a trend towards fewer patients with VTE receiving chemoprophylaxis within 72 h of IVH symptom onset compared to those who did not develop VTE (22.0% vs 33.8%, P = .07; Table 2). Initiation of VTE chemoprophylaxis was not significantly associated with subsequent symptomatic or asymptomatic intracranial bleeding at 30 d, and rates of catheter tract hemorrhage were similar regardless of VTE chemoprophylaxis use (Figure 1). TABLE 2. Treatment Characteristics in Patients With Spontaneous IVH, Stratified by VTE. Variable VTE, n = 59 (%) No VTE, n = 441 (%) P value Duration of EVD, da 11.0 (9.0-15.0) 11.0 (8.0-14.0) .20 Permanent CSF shunt placement 10 (16.9) 80 (18.1) .99 Preceding infection (within first 30 d) 30 (50.8) 5 (1.1) < .001 Type of VTE prophylaxisb  Unfractionated heparin 36 (76.6) 256 (70.1) .39  Low molecular weight heparin 11 (23.4) 109 (29.9) Initiation of VTE prophylaxis before VTE detection 36 (61.0) 365 (82.8) .02 Initiation of VTE prophylaxis within 72 h of IVH symptom onset 13 (22.0) 149 (33.8) .07 Initiation of VTE prophylaxis within 7 d of IVH symptom onset 29 (49.1) 274 (62.1) .64 Variable VTE, n = 59 (%) No VTE, n = 441 (%) P value Duration of EVD, da 11.0 (9.0-15.0) 11.0 (8.0-14.0) .20 Permanent CSF shunt placement 10 (16.9) 80 (18.1) .99 Preceding infection (within first 30 d) 30 (50.8) 5 (1.1) < .001 Type of VTE prophylaxisb  Unfractionated heparin 36 (76.6) 256 (70.1) .39  Low molecular weight heparin 11 (23.4) 109 (29.9) Initiation of VTE prophylaxis before VTE detection 36 (61.0) 365 (82.8) .02 Initiation of VTE prophylaxis within 72 h of IVH symptom onset 13 (22.0) 149 (33.8) .07 Initiation of VTE prophylaxis within 7 d of IVH symptom onset 29 (49.1) 274 (62.1) .64 Abbreviations: CSF, cerebrospinal fluid; EVD, external ventriculostomy drain; IVH, intraventricular hemorrhage; SD, standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). bVTE chemoprophylaxis was started in 401 patients. Bold font represents statistical significance. View Large TABLE 2. Treatment Characteristics in Patients With Spontaneous IVH, Stratified by VTE. Variable VTE, n = 59 (%) No VTE, n = 441 (%) P value Duration of EVD, da 11.0 (9.0-15.0) 11.0 (8.0-14.0) .20 Permanent CSF shunt placement 10 (16.9) 80 (18.1) .99 Preceding infection (within first 30 d) 30 (50.8) 5 (1.1) < .001 Type of VTE prophylaxisb  Unfractionated heparin 36 (76.6) 256 (70.1) .39  Low molecular weight heparin 11 (23.4) 109 (29.9) Initiation of VTE prophylaxis before VTE detection 36 (61.0) 365 (82.8) .02 Initiation of VTE prophylaxis within 72 h of IVH symptom onset 13 (22.0) 149 (33.8) .07 Initiation of VTE prophylaxis within 7 d of IVH symptom onset 29 (49.1) 274 (62.1) .64 Variable VTE, n = 59 (%) No VTE, n = 441 (%) P value Duration of EVD, da 11.0 (9.0-15.0) 11.0 (8.0-14.0) .20 Permanent CSF shunt placement 10 (16.9) 80 (18.1) .99 Preceding infection (within first 30 d) 30 (50.8) 5 (1.1) < .001 Type of VTE prophylaxisb  Unfractionated heparin 36 (76.6) 256 (70.1) .39  Low molecular weight heparin 11 (23.4) 109 (29.9) Initiation of VTE prophylaxis before VTE detection 36 (61.0) 365 (82.8) .02 Initiation of VTE prophylaxis within 72 h of IVH symptom onset 13 (22.0) 149 (33.8) .07 Initiation of VTE prophylaxis within 7 d of IVH symptom onset 29 (49.1) 274 (62.1) .64 Abbreviations: CSF, cerebrospinal fluid; EVD, external ventriculostomy drain; IVH, intraventricular hemorrhage; SD, standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). bVTE chemoprophylaxis was started in 401 patients. Bold font represents statistical significance. View Large In the multivariate logistic regression analysis adjusted for confounders (Table 3), presence of prior infection within the first 30 d after IVH onset was significantly associated with higher odds of VTE occurrence (odds ratio [OR], 1.80; confidence interval [CI], 1.03-3.17). We found no relationship between VTE and ICH outcomes (mRS 4-6) in the logistic regression model adjusted for known predictors of ICH mortality (OR, 1.49; 95% CI, 0.74-3.00; Table 4). TABLE 3. Multivariable Logistic Regression of Factors Associated With VTE in First 30 d and From Day 7-30 in Patients With Spontaneous IVH VTE in the first 30 d VTE between days 7 and 30 Covariates OR (95% CI) P value OR (95% CI) P value Infection preceding VTE 1.80 (1.03-3.17) .04 1.81 (1.06-3.29) .04 Initiation of VTE prophylaxis within 72 h of IVH symptom onseta 0.56 (0.29-1.09) .09 0.46 (0.22-0.96) .04 Age 0.98 (0.95-1.01) .16 0.98 (0.95-1.05) .19 Stability IVH volume (per mL) 0.99 (0.98-1.102) .71 1.0 (0.98-1.02) .82 Stability ICH volume (per mL) 0.99 (0.96-1.03) .75 0.99 (0.95-1.04) .72 Glasgow Coma Scale at screening 1.01 (0.06-1.83) .21 0.98 (0.92-1.10) .96 VTE in the first 30 d VTE between days 7 and 30 Covariates OR (95% CI) P value OR (95% CI) P value Infection preceding VTE 1.80 (1.03-3.17) .04 1.81 (1.06-3.29) .04 Initiation of VTE prophylaxis within 72 h of IVH symptom onseta 0.56 (0.29-1.09) .09 0.46 (0.22-0.96) .04 Age 0.98 (0.95-1.01) .16 0.98 (0.95-1.05) .19 Stability IVH volume (per mL) 0.99 (0.98-1.102) .71 1.0 (0.98-1.02) .82 Stability ICH volume (per mL) 0.99 (0.96-1.03) .75 0.99 (0.95-1.04) .72 Glasgow Coma Scale at screening 1.01 (0.06-1.83) .21 0.98 (0.92-1.10) .96 Abbreviations: CI, Confidence interval; ICH, Intracerebral hemorrhage; IVH, Intraventricular hemorrhage; mL, milliliters; OR: Odds ratio; VTE, venous thromboembolism. aOnly cases where chemoprophylaxis was initiated prior to VTE diagnosis were considered. Bold font represents statistical significance. View Large TABLE 3. Multivariable Logistic Regression of Factors Associated With VTE in First 30 d and From Day 7-30 in Patients With Spontaneous IVH VTE in the first 30 d VTE between days 7 and 30 Covariates OR (95% CI) P value OR (95% CI) P value Infection preceding VTE 1.80 (1.03-3.17) .04 1.81 (1.06-3.29) .04 Initiation of VTE prophylaxis within 72 h of IVH symptom onseta 0.56 (0.29-1.09) .09 0.46 (0.22-0.96) .04 Age 0.98 (0.95-1.01) .16 0.98 (0.95-1.05) .19 Stability IVH volume (per mL) 0.99 (0.98-1.102) .71 1.0 (0.98-1.02) .82 Stability ICH volume (per mL) 0.99 (0.96-1.03) .75 0.99 (0.95-1.04) .72 Glasgow Coma Scale at screening 1.01 (0.06-1.83) .21 0.98 (0.92-1.10) .96 VTE in the first 30 d VTE between days 7 and 30 Covariates OR (95% CI) P value OR (95% CI) P value Infection preceding VTE 1.80 (1.03-3.17) .04 1.81 (1.06-3.29) .04 Initiation of VTE prophylaxis within 72 h of IVH symptom onseta 0.56 (0.29-1.09) .09 0.46 (0.22-0.96) .04 Age 0.98 (0.95-1.01) .16 0.98 (0.95-1.05) .19 Stability IVH volume (per mL) 0.99 (0.98-1.102) .71 1.0 (0.98-1.02) .82 Stability ICH volume (per mL) 0.99 (0.96-1.03) .75 0.99 (0.95-1.04) .72 Glasgow Coma Scale at screening 1.01 (0.06-1.83) .21 0.98 (0.92-1.10) .96 Abbreviations: CI, Confidence interval; ICH, Intracerebral hemorrhage; IVH, Intraventricular hemorrhage; mL, milliliters; OR: Odds ratio; VTE, venous thromboembolism. aOnly cases where chemoprophylaxis was initiated prior to VTE diagnosis were considered. Bold font represents statistical significance. View Large TABLE 4. Logistic Regression Analyses Showing the Relationship Between VTE and Outcomes in Spontaneous Intraventricular Hemorrhage. Outcome VTE No VTE Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value Modified Rankin Score 4-6 at 6 mo 35 (59.3) 229 (53.0) 1.14 (0.64-2.02) .66 1.49 (0.74-3.00) .27 Mortality at 6 mo 14 (23.7) 105 (23.8) 1.05 (0.54-2.03) .89 1.63 (0.75-3.54) .22 Modified Rankin Score 4-5 at 6 mo 21 (46.7) 124 (37.9) 1.18 (0.61-2.30) .63 1.28 (0.58-2.82) .54 Outcome VTE No VTE Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value Modified Rankin Score 4-6 at 6 mo 35 (59.3) 229 (53.0) 1.14 (0.64-2.02) .66 1.49 (0.74-3.00) .27 Mortality at 6 mo 14 (23.7) 105 (23.8) 1.05 (0.54-2.03) .89 1.63 (0.75-3.54) .22 Modified Rankin Score 4-5 at 6 mo 21 (46.7) 124 (37.9) 1.18 (0.61-2.30) .63 1.28 (0.58-2.82) .54 Abbreviations: CI: confidence interval; OR: odds ratio. Each model was adjusted for age, stability intraventricular and intracerebral hemorrhage volume, Glasgow Coma Scale score at screening, and withdrawal of active treatment. View Large TABLE 4. Logistic Regression Analyses Showing the Relationship Between VTE and Outcomes in Spontaneous Intraventricular Hemorrhage. Outcome VTE No VTE Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value Modified Rankin Score 4-6 at 6 mo 35 (59.3) 229 (53.0) 1.14 (0.64-2.02) .66 1.49 (0.74-3.00) .27 Mortality at 6 mo 14 (23.7) 105 (23.8) 1.05 (0.54-2.03) .89 1.63 (0.75-3.54) .22 Modified Rankin Score 4-5 at 6 mo 21 (46.7) 124 (37.9) 1.18 (0.61-2.30) .63 1.28 (0.58-2.82) .54 Outcome VTE No VTE Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value Modified Rankin Score 4-6 at 6 mo 35 (59.3) 229 (53.0) 1.14 (0.64-2.02) .66 1.49 (0.74-3.00) .27 Mortality at 6 mo 14 (23.7) 105 (23.8) 1.05 (0.54-2.03) .89 1.63 (0.75-3.54) .22 Modified Rankin Score 4-5 at 6 mo 21 (46.7) 124 (37.9) 1.18 (0.61-2.30) .63 1.28 (0.58-2.82) .54 Abbreviations: CI: confidence interval; OR: odds ratio. Each model was adjusted for age, stability intraventricular and intracerebral hemorrhage volume, Glasgow Coma Scale score at screening, and withdrawal of active treatment. View Large Additional Analyses To account for the change in the protocol for VTE chemoprophylaxis, we first assessed VTEs that occurred after the first week in the full cohort. We observed that preceding infection (OR, 1.81; CI, 1.06-3.29) and delay in initiation of VTE chemoprophylaxis beyond 72 h of IVH onset (OR, 0.46; CI, 0.22-0.96) were associated with occurrence of VTE. We then excluded the first 100 patients and found similar results. Second, to understand reasons for delay in starting VTE chemoprophylaxis, we compared the characteristics of patients with initiation of VTE chemoprophylaxis before and after 72 h (Table 5). Patients with delayed initiation of VTE chemoprophylaxis (>72 h) were more likely to have lower NIHSS at screening (P = .004) and nonthalamic ICH (P = .01). TABLE 5. Baseline Demographics, Comorbidities and Clinical Severity Factors in Patients With Spontaneous IVH, Stratified by Timing of Initiation of VTE Prophylaxis Demographic factors VTE prophylaxis ≤ 72 h (n = 162) VTE prophylaxis > 72 h (n = 239) P value Mean age (SD), yr 59.3 (11.5) 58.3 (11.4) .46 Female gender 76 (46.9) 110 (46.0) .86 Glasgow coma scale at screeninga 10 (7-14) 10 (7-14) .59 NIHSS at screeninga 17 (4-29) 13 (4-24) .004 ICH location  Thalamus 107 (66.0) 126 (52.7) .01  Nonthalamic 55 (34.0) 113 (47.3) Stability IVH volumea 20.0 (12.5-30.5) 22.5 (12.7-39.9) .07 Stability ICH volumea 8.5 (3.6-15.7) 7.6 (2.6-14.3) .14 Intraventricular alteplase use 81 (50.0) 116 (48.5) .84 Withdrawal of active treatment 17 (10.5) 26 (10.9) .90 More than one EVD 61 (37.7) 89 (36.8) .86 Asymptomatic hemorrhage 40 (24.7) 48 (20.1) .32 Symptomatic hemorrhage 4 (2.5) 9 (3.8) .57 Catheter tract hemorrhage 34 (21.0) 43 (18.0) .39 First 100 patients 16 (9.9) 52 (21.8) .002 Remaining 400 patients 146 (90.1) 187 (78.2) Demographic factors VTE prophylaxis ≤ 72 h (n = 162) VTE prophylaxis > 72 h (n = 239) P value Mean age (SD), yr 59.3 (11.5) 58.3 (11.4) .46 Female gender 76 (46.9) 110 (46.0) .86 Glasgow coma scale at screeninga 10 (7-14) 10 (7-14) .59 NIHSS at screeninga 17 (4-29) 13 (4-24) .004 ICH location  Thalamus 107 (66.0) 126 (52.7) .01  Nonthalamic 55 (34.0) 113 (47.3) Stability IVH volumea 20.0 (12.5-30.5) 22.5 (12.7-39.9) .07 Stability ICH volumea 8.5 (3.6-15.7) 7.6 (2.6-14.3) .14 Intraventricular alteplase use 81 (50.0) 116 (48.5) .84 Withdrawal of active treatment 17 (10.5) 26 (10.9) .90 More than one EVD 61 (37.7) 89 (36.8) .86 Asymptomatic hemorrhage 40 (24.7) 48 (20.1) .32 Symptomatic hemorrhage 4 (2.5) 9 (3.8) .57 Catheter tract hemorrhage 34 (21.0) 43 (18.0) .39 First 100 patients 16 (9.9) 52 (21.8) .002 Remaining 400 patients 146 (90.1) 187 (78.2) Abbreviations: EVD, External ventriculostomy drain; ICH: Intracerebral hemorrhage; IVH: Intraventricular hemorrhage; mL: milliliters; SD: Standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). Bold font represents statistical significance. View Large TABLE 5. Baseline Demographics, Comorbidities and Clinical Severity Factors in Patients With Spontaneous IVH, Stratified by Timing of Initiation of VTE Prophylaxis Demographic factors VTE prophylaxis ≤ 72 h (n = 162) VTE prophylaxis > 72 h (n = 239) P value Mean age (SD), yr 59.3 (11.5) 58.3 (11.4) .46 Female gender 76 (46.9) 110 (46.0) .86 Glasgow coma scale at screeninga 10 (7-14) 10 (7-14) .59 NIHSS at screeninga 17 (4-29) 13 (4-24) .004 ICH location  Thalamus 107 (66.0) 126 (52.7) .01  Nonthalamic 55 (34.0) 113 (47.3) Stability IVH volumea 20.0 (12.5-30.5) 22.5 (12.7-39.9) .07 Stability ICH volumea 8.5 (3.6-15.7) 7.6 (2.6-14.3) .14 Intraventricular alteplase use 81 (50.0) 116 (48.5) .84 Withdrawal of active treatment 17 (10.5) 26 (10.9) .90 More than one EVD 61 (37.7) 89 (36.8) .86 Asymptomatic hemorrhage 40 (24.7) 48 (20.1) .32 Symptomatic hemorrhage 4 (2.5) 9 (3.8) .57 Catheter tract hemorrhage 34 (21.0) 43 (18.0) .39 First 100 patients 16 (9.9) 52 (21.8) .002 Remaining 400 patients 146 (90.1) 187 (78.2) Demographic factors VTE prophylaxis ≤ 72 h (n = 162) VTE prophylaxis > 72 h (n = 239) P value Mean age (SD), yr 59.3 (11.5) 58.3 (11.4) .46 Female gender 76 (46.9) 110 (46.0) .86 Glasgow coma scale at screeninga 10 (7-14) 10 (7-14) .59 NIHSS at screeninga 17 (4-29) 13 (4-24) .004 ICH location  Thalamus 107 (66.0) 126 (52.7) .01  Nonthalamic 55 (34.0) 113 (47.3) Stability IVH volumea 20.0 (12.5-30.5) 22.5 (12.7-39.9) .07 Stability ICH volumea 8.5 (3.6-15.7) 7.6 (2.6-14.3) .14 Intraventricular alteplase use 81 (50.0) 116 (48.5) .84 Withdrawal of active treatment 17 (10.5) 26 (10.9) .90 More than one EVD 61 (37.7) 89 (36.8) .86 Asymptomatic hemorrhage 40 (24.7) 48 (20.1) .32 Symptomatic hemorrhage 4 (2.5) 9 (3.8) .57 Catheter tract hemorrhage 34 (21.0) 43 (18.0) .39 First 100 patients 16 (9.9) 52 (21.8) .002 Remaining 400 patients 146 (90.1) 187 (78.2) Abbreviations: EVD, External ventriculostomy drain; ICH: Intracerebral hemorrhage; IVH: Intraventricular hemorrhage; mL: milliliters; SD: Standard deviation; VTE, venous thromboembolism. aindicates values represented as median (interquartile range). Bold font represents statistical significance. View Large DISCUSSION In a large, multicenter, retrospective cohort study of patients with primary IVH, we found that preceding infection within the first 30 d was independently associated with VTE. Initiation of VTE chemoprophylaxis after 72 h was also associated with VTE, but only for VTE between days 7 and 30 (vs the full 30 d), which may reflect a lack of statistical power for this secondary outcome from the trial. Rates of VTE did not differ by treatment group (intraventricular alteplase or saline), and VTE chemoprophylaxis was found to be safe from the standpoint of risk for intracranial bleeding and catheter tract hemorrhage. Occurrence of VTE was not associated with mortality or poor functional outcome in this population. The significant relationship between presence of infection within the first 30 d and occurrence of VTE corroborates the results of prior studies, which have reported higher rates of infections with VTE. In fact, infection was identified as the most frequent trigger of hospitalization for VTE, in a large population-based study.13 Although the underlying pathophysiology remains to be elucidated, inflammation accompanying an infection is purported to result in the activation of the coagulation cascade in turn causing thromboembolic complications.14,15 Additionally, prolonged hospital stay occurring as a consequence of infection may also predispose these patients to develop VTE. While these factors may promote or hasten the development of VTE, our study was not designed to assess a causal association between incident infection and new VTE, which therefore, requires further study. We also observed that VTE was not associated with mortality in our study, which mirrors the results of prior literature.3 However, VTE has been shown to increase the cost of medical care significantly16 and, therefore, warrants early aggressive prevention strategies. Timing of initiation of chemoprophylaxis was also an independent predictor of delayed VTE in the CLEAR III trial. We calculated that the number needed to prevent a VTE event by initiating chemoprophylaxis within 72 h (vs after 72 h) was 13. We observed that lower clinical severity (NIHSS) and nonthalamic location of ICH were associated with delay in starting VTE chemoprophylaxis. Delays in initiation of prophylaxis may have stemmed from concerns over concurrent use of intraventricular alteplase or EVD insertion and removal. We found no differences in rates of intracranial bleeding and catheter tract hemorrhage irrespective of VTE chemoprophylaxis use. Furthermore, intraventricular alteplase has been shown to have no effect on systemic coagulation.17 The current guideline statements by the American Heart Association and Neurocritical Care Society recommend commencement of VTE chemoprophylaxis within 4 d of symptom onset, after ascertainment of hematoma stability,18,19 but these do not specifically include patients receiving EVDs and intraventricular thrombolysis. Our results support a favorable risk-benefit profile of initiation of VTE prophylaxis in the presence of an EVD and concomitant use of intraventricular alteplase as early as 72 h after IVH symptom onset providing that all hematoma locations are stable (ICH, IVH, and catheter tract hemorrhage) as was required for trial enrollment.11 Strengths and Limitations The strengths of this study include analyzing the largest cohort of IVH patients studied, well-defined inclusion criteria, protocolized frequent neuroimaging to monitor for complications, and protocolized safety event reporting of VTE occurrence and VTE chemoprophylaxis use. There are, however, several important limitations. First, the inclusion of a selective cohort of IVH patients with small hematoma volumes and obstructive IVH, and rigid screening and monitoring performed in the setting of a trial, introduce selection bias and limit generalizability of the results. Second, triggers for assessment of VTE, whether symptom-based or routine surveillance, were not standardized and hence, results could represent an overestimation of clinically evident VTE. Third, all decisions regarding initiation of VTE chemoprophylaxis and type of pharmacological agent chosen were made at the discretion of the treating physicians at the different participating institutions. Thus, we captured a range of prophylaxis timing practices. Although VTE rates did not differ by enrollment site or geographical location, residual confounding is still a possibility given that there were 73 different participating centers. Fourth, we assessed the impact of relevant physiological variables that predict development of VTE, but data on other typical risk factors such as prior history of VTE, extremity paralysis, and history of lower extremity varices were not available. Lastly, although this is the largest cohort of IVH patients, the study may not have been powered to evaluate risk factors or outcomes in patients developing VTE. CONCLUSION Patients with spontaneous IVH are at high-risk for developing VTE. Presence of infection and timing of chemoprophylaxis are independently associated with occurrence of VTE. Chemoprophylaxis for VTE appears to be safe in this population, even when used concomitantly with EVD and intraventricular alteplase and should not be delayed beyond standard of care policies for ICH patients. Disclosures Dr Murthy is supported by the American Academy of Neurology, American Brain Foundation, and the Leon Levy Neuroscience Foundation. Drs Awad, Hanley and Ziai have received significant research support through grant numbers 5U01NS062851 for Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage III and for Minimally Invasive Surgery Plus r-tPA for Intracerebral Hemorrhage Evacuation III 1U01NS08082. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Notes Oral platform presentation at the International Stroke Conference (American Heart Association/American Stroke Association), February 2016, Los Angeles, California REFERENCES 1. van Asch CJ , Luitse MJ , Rinkel GJ , van der Tweel I , Algra A , Klijn CJ . Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis . Lancet Neurol . 2010 ; 9 ( 2 ): 167 - 176 . Google Scholar CrossRef Search ADS PubMed 2. Qureshi AI , Tuhrim S , Broderick JP , Batjer HH , Hondo H , Hanley DF . Spontaneous intracerebral hemorrhage . N Engl J Med . 2001 ; 344 ( 19 ): 1450 - 1460 . Google Scholar CrossRef Search ADS PubMed 3. Diringer MN , Skolnick BE , Mayer SA et al. Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial . Stroke . 2010 ; 41 ( 1 ): 48 - 53 . Google Scholar CrossRef Search ADS PubMed 4. Skaf E , Stein PD , Beemath A , Sanchez J , Bustamante MA , Olson RE . Venous thromboembolism in patients with ischemic and hemorrhagic stroke . Am J Cardiol . 2005 ; 96 ( 12 ): 1731 - 1733 . Google Scholar CrossRef Search ADS PubMed 5. Goldstein JN , Fazen LE , Wendell L et al. Risk of thromboembolism following acute intracerebral hemorrhage . Neurocrit Care . 2009 ; 10 ( 1 ): 28 - 34 . Google Scholar CrossRef Search ADS PubMed 6. Ogata T , Yasaka M , Wakugawa Y , Inoue T , Ibayashi S , Okada Y . Deep venous thrombosis after acute intracerebral hemorrhage . J Neuroll Sci . 2008 ; 272 ( 1-2 ): 83 - 86 . Google Scholar CrossRef Search ADS 7. Christensen MC , Dawson J , Vincent C . Risk of thromboembolic complications after intracerebral hemorrhage according to ethnicity . Adv Ther . 2008 ; 25 ( 9 ): 831 - 841 . Google Scholar CrossRef Search ADS PubMed 8. Kawase K , Okazaki S , Toyoda K et al. Sex difference in the prevalence of deep-vein thrombosis in Japanese patients with acute intracerebral hemorrhage . Cerebrovasc Dis . 2009 ; 27 ( 4 ): 313 - 319 . Google Scholar CrossRef Search ADS PubMed 9. Kim KS , Brophy GM . Symptomatic venous thromboembolism: incidence and risk factors in patients with spontaneous or traumatic intracranial hemorrhage . Neurocrit Care . 2009 ; 11 ( 1 ): 28 - 33 . Google Scholar CrossRef Search ADS PubMed 10. Hanley DF , Lane K , McBee N et al. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial . Lancet . 2017 ; 389 ( 10069 ): 603 - 611 Google Scholar CrossRef Search ADS PubMed 11. Ziai WC , Tuhrim S , Lane K et al. A multicenter, randomized, double-blinded, placebo-controlled phase iii study of clot lysis evaluation of accelerated resolution of intraventricular hemorrhage (clear iii) . Int J Stroke . 2014 ; 9 ( 4 ): 536 - 542 Google Scholar CrossRef Search ADS PubMed 12. Naff N , Williams MA , Keyl PM et al. Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial . Stroke . 2011 ; 42 ( 11 ): 3009 - 3016 . Google Scholar CrossRef Search ADS PubMed 13. Rogers MA , Levine DA , Blumberg N , Flanders SA , Chopra V , Langa KM . Triggers of hospitalization for venous thromboembolism . Circulation . 2012 ; 125 ( 17 ): 2092 - 2099 . Google Scholar CrossRef Search ADS PubMed 14. van der Poll T , de Boer JD , Levi M . The effect of inflammation on coagulation and vice versa . Curr Opin Infect Dis . 2011 ; 24 ( 3 ): 273 - 278 . Google Scholar CrossRef Search ADS PubMed 15. Esmon CT . The impact of the inflammatory response on coagulation . Thromb Res . 2004 ; 114 ( 5-6 ): 321 - 327 . Google Scholar CrossRef Search ADS PubMed 16. Otite FO , Khandelwal P , Malik AM , Chaturvedi S , Sacco RL , Romano JG . Ten-year temporal trends in medical complications after acute intracerebral hemorrhage in the United States . Stroke . 2017 ; 48 ( 3 ): 596 - 603 . Google Scholar CrossRef Search ADS PubMed 17. Herrick D , Ziai WC , Thompson C , Lane K , McBee NA , Hanley DF . Systemic hematologic status following intraventricular recombinant tissue-type plasminogen activator for intraventricular hemorrhage . Stroke 2011 ; 42 ( 12 ): 3631 - 3633 . Google Scholar CrossRef Search ADS PubMed 18. Hemphill JC 3rd , Greenberg SM , Anderson CS et al. Guidelines for the management of spontaneous intracerebral hemorrhage . Stroke . 2015 ; 46 ( 7 ): 2032 - 2060 . Google Scholar CrossRef Search ADS PubMed 19. Nyquist P , Bautista C , Jichici D et al. Prophylaxis of venous thrombosis in neurocritical care patients: an evidence-based guideline: a statement for healthcare professionals from the neurocritical care society . Neurocrit Care . 2016 ; 24 ( 1 ): 47 - 60 . Google Scholar CrossRef Search ADS PubMed Neurosurgery Speaks! Audio abstracts available for this article at www.neurosurgery-online.com. COMMENTS Using the CLEAR III randomized controlled trial database examining the utility of locally instilled tissue plasminogen activator for intraventricular hemorrhage, the authors present a retrospective cohort analysis with a focus on associations and outcomes related to venous thromboembolism (VTE). This study represents Level 2b evidence and it provides the strongest information to date for guidance of this common scenario for an uncommon disease. The authors did not identify adverse complications related to starting VTE prophylaxis after initial hematoma stabilization, thus perhaps allaying some concerns for inadvertently augmenting hemorrhage in patients receiving ventricular thrombolytic medication. However, this study did not provide specific guidance as to the optimal method of prevention (eg, heparin and dosing, anti-embolism stockings, etc) as the trial left such medical management decisions wholly to the discretion of participating physicians and future study will be needed. There were trends suggestive that early initiation of prophylaxis prevented VTE, and that infection may play a role in VTE causation although given the authors did not measure infection post-VTE diagnosis, it may be an association rather than etiological factor. This study directs attention to important issues encountered in the optimal medical management of hemorrhagic stroke patients. John H. Wong Calgary, Canada Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in critically-ill patients.1 The neurosurgical patient population, often with reduced level of consciousness and extended periods of immobility, are at particular risk.2 The use of VTE chemoprophylaxis and the timing of its use has been a source of much debate in the neurosurgical community due to concern of exacerbating the primary pathology such as intracerebral (ICH) and intraventricular hemorrhage (IVH), as well as interventions which potentially predispose to further bleeding complications (eg, tract hemorrhage following external ventricular drain).3,4 The authors present a retrospective study from the CLEAR III trial cohorts on the effect of VTE chemoprophylaxis in the setting of ICH and IVH, and randomized treatment with external ventricular drain with saline or alteplase.5 In this well-written and succinctly presented paper, VTE chemoprophylaxis and its initiation within the first 72 hours is associated with reduction of VTE events. Confirming prior studies, infection is associated with VTE. Early initiation of chemoprophylaxis does not result in increased in morbidity or mortality from hemorrhagic complications. In this study, the authors were able to take advantage of an RCT patient population and provided evidence that 1) VTE chemoprophylaxis significantly reduced VTE (8.2% vs 22.2%), 2) delayed initiation of chemoprophylaxis was associated with increased risk of VTE, and 3) infection almost doubled the risk of VTE (odds ratio 1.8). Importantly, from a safety standpoint, in these patients with recent brain hemorrhage who required neurosurgical intervention such as an EVD, as well as intraventricular alteplase infusion, VTE chemoprophylaxis could be commenced early, within 72-hours of ictus, without significant adverse events. The study falls short of providing conclusive Level 1 evidence. The decision to administer or hold VTE chemoprophylaxis was not protocolled and was left to clinician discretion at individual centers. Ninety-nine out of 500 patients (20%) did not receive VTE chemoprophylaxis at all. Therefore, it is not known whether VTE chemoprophylaxis would have led to significant complications in this group. Although the standard of care VTE protocols appeared safe, the threshold for safe and early VTE chemoprophylaxis administration remains difficult to define. The evaluation of VTE was not systemic and there may well be missed cases, although such cases were likely of limited clinical significance. Nevertheless, the present study supports the early use of VTE chemoprophylaxis to prevent clinically relevant VTE in an acute neurosurgical patient population. The current standard of care protocols for VTE chemoprophylaxis appears safe, although future studies including RCTs will help better define the threshold at which VTE may be administered, balancing safety and prevention of VTE events. Chris Young Louis Kim Seattle, Washington 1. Khaldi A Helo N Schneck MJ Origitano TC . Venous thromboembolism: deep venous thrombosis and pulmonary embolism in a neurosurgical population . J Neurosurg . 2011 ; 114 ( 1 ): 40 - 46 . Google Scholar CrossRef Search ADS PubMed 2. Rolston JD Han SJ Bloch O Parsa AT . What clinical factors predict the incidence of deep venous thrombosis and pulmonary embolism in neurosurgical patients ? J Neurosurg . 2014 ; 121 ( 4 ): 908 - 918 . Google Scholar CrossRef Search ADS PubMed 3. Browd SR Ragel BT Davis GE Scott AM Skalabrin EJ Couldwell WT . Prophylaxis for deep venous thrombosis in neurosurgery: a review of the literature . Neurosurg Focus . 2004 ; 17 ( 4 ): E1 . Google Scholar CrossRef Search ADS PubMed 4. Hoh BL Nogueira RG Ledezma CJ Pryor JC Ogilvy CS . Safety of heparinization for cerebral aneurysm coiling soon after external ventriculostomy drain placement . Neurosurgery . 2005 ; 57 ( 5 ): 845 - 849 . Google Scholar CrossRef Search ADS PubMed 5. Ziai WC Tuhrim S Lane K , et al . A multicenter, randomized, double-blinded, placebo-controlled phase III study of Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III) . Int J Stroke Off J Int Stroke Soc . 2014 ; 9 ( 4 ): 536 - 542 . Google Scholar CrossRef Search ADS 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: Xiang Huang, MD. Pacific Neuroscience Institute Los Angeles, California Chinese: Xiang Huang, MD. Pacific Neuroscience Institute Los Angeles, California Close French: Michael Bruneau, MD, PhD. Department of Neurosurgery Erasme Hospital Brussels, Belgium French: Michael Bruneau, MD, PhD. Department of Neurosurgery Erasme Hospital Brussels, Belgium Close English: Oluwakemi Aderonke Badejo, MBBS, FWACS. Department of Surgery College of Medicine University of Ibadan Ibadan, Nigeria English: Oluwakemi Aderonke Badejo, MBBS, FWACS. Department of Surgery College of Medicine University of Ibadan Ibadan, Nigeria Close Italian: Danilo De Paulis, MD. Department of Neurosurgery San Sebastiano & San Annae City Hospital Caserta, Italy Italian: Danilo De Paulis, MD. Department of Neurosurgery San Sebastiano & San Annae City Hospital Caserta, Italy Close Spanish: Carlos Alarcon, MD. Department of Neurosurgery Hospital Universitari Mutua de Terrassa Barcelona, Spain Spanish: Carlos Alarcon, MD. Department of Neurosurgery Hospital Universitari Mutua de Terrassa Barcelona, Spain Close Portuguese: Andre Luiz Beer-Furlan, MD. Department of Neurological Surgery Rush University Medical Center Chicago, Illinois Portuguese: Andre Luiz Beer-Furlan, MD. Department of Neurological Surgery Rush University Medical Center Chicago, Illinois Close Japanese: Toshiaki Hayashi, MD, PhD. Department of Neurosurgery Sendai City Hospital Sendai, Japan Japanese: Toshiaki Hayashi, MD, PhD. Department of Neurosurgery Sendai City Hospital Sendai, Japan Close Korean: Keun Young Park, MD. Department of Neurosurgery Yonsei University College of Medicine Seoul, Republic of Korea Korean: Keun Young Park, MD. Department of Neurosurgery Yonsei University College of Medicine Seoul, Republic of Korea Close Russian: Mikhail Gelfenbeyn, MD, PhD. Department of Neurological Surgery University of Washington Seattle, Washington Russian: Mikhail Gelfenbeyn, MD, PhD. Department of Neurological Surgery University of Washington Seattle, Washington Close Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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NeurosurgeryOxford University Press

Published: May 21, 2018

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