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Brian M. Corliss, Rachel Freedman, Meghan M. Brennan, Jessica Smith, John D. Nerva, Neil S. Harris, Adam J. Polifka, Brian L. Hoh and W. Christopher Fox

OBJECTIVE

Inhibition of platelet aggregation is universally used to prevent thromboembolic complications related to stent placement in endovascular neurosurgery, but excessive inhibition potentiates hemorrhagic complications. Previously, the authors demonstrated that two different commercially available measures of adenosine diphosphate (ADP)–dependent platelet inhibition—the VerifyNow P2Y12 clopidogrel assay (measured in platelet reactivity units [PRU]) and maximal amplitude (MA) attributable to ADP activity (MA-ADP) derived from thromboelastography (TEG) with platelet mapping (PM)—yielded wildly different results. This study sought to analyze observed complications to quantify the ideal therapeutic windows for both tests.

METHODS

Ninety-one patients with simultaneous or near-simultaneous PRU and TEG-PM results who underwent craniocervical endovascular stenting at the authors’ institution between September 2015 and November 2017 were identified and retrospectively enrolled. From November 2017 until June 2019, 109 additional patients were prospectively enrolled. For this study, in-hospital thrombotic and hemorrhagic complications (both CNS and non-CNS) were tabulated, and receiver operating characteristic (ROC) curve analysis was used to identify threshold values of the PRU and MA-ADP for predicting each type of complication.

RESULTS

Of the 200 patients enrolled, 7 were excluded because of anemia or thrombocytopenia outside of the test manufacturer’s specified ranges and 1 was excluded because they did not have a TEG-PM result. Including complications of all severities, there were a total of 15 CNS thrombotic complications, 1 access-site thrombotic complication, 3 CNS hemorrhages, 8 access-site hemorrhagic complications, and 3 hemorrhagic complications not affecting either the CNS or the access site. ROC curve analysis yielded therapeutic threshold values of 118–144 PRU. The results demonstrated PRU has a significant dose-dependent effect on the rates of thrombosis and hemorrhage. Logistic regression models did not demonstrate statistically significant relationships between the MA-ADP and either thrombosis or hemorrhage. ROC analysis based on these models is of little value and did not identify significant threshold values for MA-ADP.

CONCLUSIONS

There continues to be poor correlation between the results of TEG-PM and PRU. PRU accurately predicted complications, with a relatively narrow ideal value range of 118–144. The MA-ADP alone does not appear able to accurately predict either hemorrhagic or thrombotic complications in this group.

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R. Loch Macdonald, Daniel Hänggi, Poul Strange, Hans Jakob Steiger, J Mocco, Michael Miller, Stephan A. Mayer, Brian L. Hoh, Herbert J. Faleck, Nima Etminan, Michael N. Diringer, Andrew P. Carlson, Francois Aldrich and the NEWTON Investigators

OBJECTIVE

The objective of this study was to measure the concentration of nimodipine in CSF and plasma after intraventricular injection of a sustained-release formulation of nimodipine (EG-1962) in patients with aneurysmal subarachnoid hemorrhage (SAH).

METHODS

Patients with SAH repaired by clip placement or coil embolization were randomized to EG-1962 or oral nimodipine. Patients were classified as grade 2–4 on the World Federation of Neurosurgical Societies grading scale for SAH and had an external ventricular drain inserted as part of their standard of care. Cohorts of 12 patients received 100–1200 mg of EG-1962 as a single intraventricular injection (9 per cohort) or they remained on oral nimodipine (3 per cohort). Plasma and CSF were collected from each patient for measurement of nimodipine concentrations and calculation of maximum plasma and CSF concentration, area under the concentration-time curve from day 0 to 14, and steady-state concentration.

RESULTS

Fifty-four patients in North America were randomized to EG-1962 and 18 to oral nimodipine. Plasma concentrations increased with escalating doses of EG-1962, remained stable for 14 to 21 days, and were detectable at day 30. Plasma concentrations in the oral nimodipine group were more variable than for EG-1962 and were approximately equal to those occurring at the EG-1962 800-mg dose. CSF concentrations of nimodipine in the EG-1962 groups were 2–3 orders of magnitude higher than in the oral nimodipine group, in which nimodipine was only detected at low concentrations in 10% (21/213) of samples. In the EG-1962 groups, CSF nimodipine concentrations were 1000 times higher than plasma concentrations.

CONCLUSIONS

Plasma concentrations of nimodipine similar to those achieved with oral nimodipine and lasting for 21 days could be achieved after a single intraventricular injection of EG-1962. The CSF concentrations from EG-1962, however, were at least 2 orders of magnitude higher than those with oral nimodipine. These results supported a phase 3 study that demonstrated a favorable safety profile for EG-1962 but yielded inconclusive efficacy results due to notable differences in clinical outcome based on baseline disease severity.

Clinical trial registration no.: NCT01893190 (ClinicalTrials.gov).

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Natasha Ironside, Brandon Christophe, Samuel Bruce, Amanda M. Carpenter, Trae Robison, Nina Yoh, Serge Cremers, Donald Landry, Hans-Peter Frey, Ching-Jen Chen, Brian L. Hoh, Louis J. Kim, Jan Claassen and Edward Sander Connolly Jr.

OBJECTIVE

Delayed cerebral ischemia (DCI) is a significant contributor to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). The neurotoxin 3-aminopropanal (3-AP) is upregulated in cerebral ischemia. This phase II clinical trial evaluated the efficacy of tiopronin in reducing CSF 3-AP levels in patients with aSAH.

METHODS

In this prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial, 60 patients were assigned to receive tiopronin or placebo in a 1:1 ratio. Treatment was commenced within 96 hours after aSAH onset, administered at a dose of 3 g daily, and continued until 14 days after aSAH or hospital discharge, whichever occurred earlier. The primary efficacy outcome was the CSF 3-AP level at 7 ± 1 days after aSAH.

RESULTS

Of the 60 enrolled patients, 29 (97%) and 27 (93%) in the tiopronin and placebo arms, respectively, received more than one dose of the study drug or placebo. At post-aSAH day 7 ± 1, CSF samples were available in 41% (n = 12/29) and 48% (n = 13/27) of patients in the tiopronin and placebo arms, respectively. No difference in CSF 3-AP levels at post-aSAH day 7 ± 1 was observed between the study arms (11 ± 12 nmol/mL vs 13 ± 18 nmol/mL; p = 0.766). Prespecified adverse events led to early treatment cessation for 4 patients in the tiopronin arm and 2 in the placebo arm.

CONCLUSIONS

The power of this study was affected by missing data. Therefore, the authors could not establish or refute an effect of tiopronin on CSF 3-AP levels. Additional observational studies investigating the role of 3-AP as a biomarker for DCI may be warranted prior to its use as a molecular target in future clinical trials.

Clinical trial registration no.: NCT01095731 (ClinicalTrials.gov)

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William C. Newman, Paul S. Kubilis and Brian L. Hoh

OBJECTIVE

Comorbidities have a significant effect on patient outcomes. Accounting for this effect is especially important in retrospective reviews of large databases; overpowered studies are at risk for finding significant results because of inaccurate patient risk stratification. The authors previously created a neurovascular comorbidities index (NCI) for patients with an unruptured intracranial aneurysm and found that the model’s ability to predict patient outcomes was statistically significantly improved over that of the routinely used Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI). In this study, the authors aimed to validate use of the NCI over that of the CCI and ECI for risk stratification of patients with other neurovascular diseases.

METHODS

The authors queried the National (Nationwide) Inpatient Sample database for the years 2002–2012 to compare the accuracy of the previously validated NCI with that of the CCI and ECI with respect to predicting outcomes for patients who had an arteriovenous malformation, a ruptured intracranial aneurysm, carotid artery stenosis, or dural arteriovenous fistula and who underwent surgical intervention.

RESULTS

For patients with an arteriovenous malformation, the NCI outperformed the CCI and ECI in predicting poor outcome, hospital length of stay (LOS), and total cost but was equivalent to the CCI in predicting death. For patients with a ruptured intracranial aneurysm, the NCI outperformed the ECI and CCI in predicting death, poor outcome, LOS, and total cost. For patients with carotid artery stenosis, the NCI outperformed the ECI and CCI in predicting LOS, but it was equivalent to the ECI in predicting death and total cost and inferior to the CCI in predicting poor outcome (p < 0.002 for all). An insufficient number of patients with dural arteriovenous fistula who underwent surgical intervention were available for analysis (n < 10), and they therefore were excluded from study. For 11 of 12 metrics, the NCI was the significantly more efficient model.

CONCLUSIONS

The NCI outperforms the CCI and ECI by providing more appropriate and efficient risk stratification of patients regarding death, outcome, LOS, and cost. Given this finding, the NCI should be used for retrospective reviews of patient outcomes instead of the CCI or ECI.

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Brian M. Corliss, Adam J. Polifka, Neil S. Harris, Brian L. Hoh and W. Christopher Fox

OBJECTIVE

Inhibition of platelet aggregation is vital to preventing thromboembolic complications related to stent placement in endovascular neurosurgery, but excessive inhibition potentiates hemorrhagic complications. Recent evidence suggests an ideal inhibition range of 70–150 P2Y12 response units (PRU) as measured on the VerifyNow assay, which relies on photometric measurements of platelet aggregation. Thromboelastography (TEG) with platelet mapping (PM) is an alternative assay that directly measures clot formation and mechanical strength. This study compares the results of PRU to TEG-PM.

METHODS

Patients with simultaneous or near-simultaneous PRU and TEG-PM results who underwent cervical carotid artery stenting, intracranial stent-assisted aneurysm coiling, or flow diversion at the authors’ institution between August 2015 and November 2016 were identified. PRU results were compared with the TEG maximal amplitude (MA) attributable to adenosine diphosphate (ADP) activity (MA-ADP) as measured by TEG-PM. Platelet inhibition was considered therapeutic for MA-ADP values < 50 mm or PRU < 194. The Pearson correlation coefficient was calculated, and the sensitivity and specificity of PRU were calculated assuming that the results of TEG-PM reflected the true degree of platelet inhibition.

RESULTS

Twenty-three patients were identified with a total of 37 matched sets of TEG-PM and PRU. Three of these pairs were excluded due to anemia outside of the PRU manufacturer’s recommended range. The Pearson correlation coefficient for these values was 0.50 (p = 0.0026). The prevalence of clopidogrel nonresponders determined by TEG-PM (9%) matched reported rates (5%–12%); PRU demonstrated much higher prevalence (39%). For detecting a therapeutic level of platelet inhibition, PRU demonstrated a sensitivity of 0.59, specificity of 0.50, positive predictive value of 0.95, and negative predictive value of 0.07. Ideal inhibition was concordant in only 25% of observations in which at least one of the results was ideal.

CONCLUSIONS

Agreement between TEG-PM and PRU regarding the degree of platelet inhibition is poor. PRU likely overestimates clopidogrel resistance, as 93% of patients with PRU > 194 demonstrate a therapeutic level of platelet inhibition on TEG.

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William C. Newman, Dan W. Neal and Brian L. Hoh

OBJECTIVE

Comorbidities have an impact on risk stratification for outcomes in analyses of large patient databases. Although the Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) are the most commonly used comorbidity indexes, these have not been validated for patients with unruptured cerebral aneurysms; therefore, the authors created a comorbidity index specific to these patients.

METHODS

The authors extracted all records involving unruptured cerebral aneurysms treated with clipping, coiling, or both from the Nationwide Inpatient Sample (2002–2010). They assessed the effect of 37 variables on poor outcome and used the results to create a risk score for these patients. The authors used a validation data set and bootstrapping to evaluate the new index and compared it to CCI and ECI in prediction of poor outcome, mortality, length of stay, and hospital charges.

RESULTS

The index assigns integer values (−2 to 7) to 20 comorbidities: neurological disorder, renal insufficiency, gastrointestinal bleeding, paralysis, acute myocardial infarction, electrolyte disorder, weight loss, metastatic cancer, drug abuse, arrhythmia, coagulopathy, cerebrovascular accident, psychosis, alcoholism, perivascular disease, valvular disease, tobacco use, hypothyroidism, depression, and hypercholesterolemia. Values are summed to determine a patient's risk score. The new index was better at predicting poor outcome than CCI or ECI (area under the receiver operating characteristic curve [AUC] 0.814 [95% CI 0.798–0.830], vs 0.694 and 0.712, respectively, for the other indices), and it was also better at predicting mortality (AUC 0.775 [95% CI 0.754–0.792], vs 0.635 and 0.657, respectively, for CCI and ECI).

CONCLUSIONS

This new comorbidity index outperforms the CCI and ECI in predicting poor outcome, mortality, length of stay, and total charges for patients with unruptured cerebral aneurysm. Reevaluation of other patient cohorts is warranted to determine the impact of more accurate patient stratification.

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Kyle M. Fargen, Brian L. Hoh, Dan Neal, Timothy O’connor, Marie Rivera-Zengotita and Gregory J. A. Murad

OBJECT

Ventriculostomy occlusion is a known complication after external ventricular drain (EVD) placement. There have been no prospective published series that primarily evaluate the incidence of and risk factors for EVD occlusion. These phenomena are investigated using a prospective database.

METHODS

An ongoing prospective study of all patients undergoing frontal EVD placement in the Neurosurgery Intensive Care Unit at the University of Florida was accessed for the purposes of this analysis. Demographic, procedural, and radiographic data were recorded prospectively and retrospectively. The need for catheter irrigation or replacement was meticulously documented. Univariate and multivariate regression analyses were performed.

RESULTS

Ninety-eight of 101 total enrolled patients had accessible data, amounting to 131 total catheters and 1076 total catheter days. Nineteen percent of patients required at least 1 replacement. Forty-one percent of catheters developed at least 1 temporary occlusion, with an average of 2.4 irrigations per patient. Intracranial hemorrhage occurred in 28% of patients after the first EVD placement (2% resulting in new neurological deficit) and in 62% of patients after 1 replacement. The cost of occlusion is estimated at $615 per enrolled patient. Therapeutic anticoagulation and use of small EVD catheters were statistically significant predictors of permanent occlusion (p = 0.01 and 0.04, respectively).

CONCLUSIONS

EVD occlusion is frequent and imparts a significant burden in terms of patient morbidity, physician upkeep, and cost. This study suggests that developing strategies or devices to prevent EVD occlusion, such as the preferential use of larger diameter catheters, may be beneficial in reducing the burden associated with ventriculostomy malfunction.

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Brian L. Hoh, Yan Gong, Caitrin W. McDonough, Michael F. Waters, Adrienne J. Royster, Tiffany O. Sheehan, Ben Burkley, Taimour Y. Langaee, J Mocco, Scott L. Zuckerman, Nishit Mummareddy, Marcus L. Stephens II, Christie Ingram, Christian M. Shaffer, Joshua C. Denny, Murray H. Brilliant, Terrie E. Kitchner, James G. Linneman, Dan M. Roden and Julie A. Johnson

OBJECT

Symptomatic intracranial atherosclerotic disease (ICAD) has a high risk of recurrent stroke. Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients, but have not been studied in ICAD. The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms (SNPs) in symptomatic ICAD patients.

METHODS

Genotype testing for CYP2C19*2, *3, *8, *17 and CES1 G143E was performed on 188 adult symptomatic ICAD patients from 3 medical centers who were medically managed with clopidogrel and aspirin. Testing was performed prospectively at 1 center, and retrospectively from a DNA sample biorepository at 2 centers. Multiple logistic regression and Cox regression analysis were performed to assess the association of these SNPs with the primary endpoint, which was a composite of transient ischemic attack (TIA), stroke, myocardial infarction, or death within 12 months.

RESULTS

The primary endpoint occurred in 14.9% of the 188 cases. In multiple logistic regression analysis, the presence of the CYP2C19 loss of function (LOF) alleles *2, *3, and *8 in the medically managed patients was associated with lower odds of primary endpoint compared with wild-type homozygotes (odds ratio [OR] 0.13, 95% CI 0.03–0.62, p = 0.0101). Cox regression analysis demonstrated the CYP2C19 LOF carriers had a lower risk for the primary endpoint, with hazard ratio (HR) of 0.27 (95% CI 0.08–0.95), p = 0.041. A sensitivity analysis of a secondary composite endpoint of TIA, stroke, or death demonstrated a significant trend in multiple logistic regression analysis of CYP2C19 variants, with lower odds of secondary endpoint in patients carrying at least 1 LOF allele (*2, *3, *8) than in wild-type homozygotes (OR 0.27, 95% CI 0.06–1.16, p = 0.078). Cox regression analysis demonstrated that the carriers of CYP2C19 LOF alleles had a lower risk forthe secondary composite endpoint (HR 0.22, 95% CI 0.05–1.04, p = 0.056).

CONCLUSIONS

This is the first study examining genetic variants and their effects in symptomatic ICAD. Variant alleles of CYP2C19 (*2, *3, *8) were associated with lower odds of the primary and secondary composite endpoints. However, the direction of the association was opposite of what is expected based on this SNP. This may reflect an incomplete understanding of this genetic variation and its effect in symptomatic ICAD and warrants further investigations.

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Matthew R. Reynolds, Robert T. Buckley, Santoshi S. Indrakanti, Ali H. Turkmani, Gerald Oh, Emanuela Crobeddu, Kyle M. Fargen, Tarek Y. El Ahmadieh, Andrew M. Naidech, Sepideh Amin-Hanjani, Giuseppe Lanzino, Brian L. Hoh, Bernard R. Bendok and Gregory J. Zipfel

OBJECT

Vasopressor-induced hypertension (VIH) is an established treatment for patients with aneurysmal subarachnoid hemorrhage (SAH) who develop vasospasm and delayed cerebral ischemia (DCI). However, the safety of VIH in patients with coincident, unruptured, unprotected intracranial aneurysms is uncertain.

METHODS

This retrospective multiinstitutional study identified 1) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who required VIH therapy (VIH group), and 2) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who did not require VIH therapy (non-VIH group). All patients had previously undergone surgical or endovascular treatment for the presumed ruptured aneurysm. Comparisons between the VIH and non-VIH patients were made in terms of the patient characteristics, clinical and radiographic severity of SAH, total number of aneurysms, number of ruptured/unruptured aneurysms, aneurysm location/size, number of unruptured and unprotected aneurysms during VIH, severity of vasospasm, degree of hypervolemia, and degree and duration of VIH therapy.

RESULTS

For the VIH group (n = 176), 484 aneurysms were diagnosed, 231 aneurysms were treated, and 253 unruptured aneurysms were left unprotected during 1293 total days of VIH therapy (5.12 total years of VIH therapy for unruptured, unprotected aneurysms). For the non-VIH group (n = 73), 207 aneurysms were diagnosed, 93 aneurysms were treated, and 114 unruptured aneurysms were left unprotected. For the VIH and non-VIH groups, the mean sizes of the ruptured (7.2 ± 0.3 vs 7.8 ± 0.6 mm, respectively; p = 0.27) and unruptured (3.4 ± 0.2 vs 3.2 ± 0.2 mm, respectively; p = 0.40) aneurysms did not differ. The authors observed 1 new SAH from a previously unruptured, unprotected aneurysm in each group (1 of 176 vs 1 of 73 patients; p = 0.50). Baseline patient characteristics and comorbidities were similar between groups. While the degree of hypervolemia was similar between the VIH and non-VIH patients (fluid balance over the first 10 days of therapy: 3146.2 ± 296.4 vs 2910.5 ± 450.7 ml, respectively; p = 0.67), VIH resulted in a significant increase in mean arterial pressure (mean increase over the first 10 days of therapy relative to baseline: 125.1% ± 1.0% vs 98.2% ± 1.2%, respectively; p < 0.01) and systolic blood pressure (125.6% ± 1.1% vs. 104.1% ± 5.2%, respectively; p < 0.01).

CONCLUSIONS

For small, unruptured, unprotected intracranial aneurysms in SAH patients, the frequency of aneurysm rupture during VIH therapy is rare. The authors do not recommend withholding VIH therapy from these patients.