Aneurysm treatment within 6 h versus 6-24 h after rupture in patients with subarachnoid hemorrhage

BACKGROUND The risk of rebleeding after aneurysmal subarachnoid hemorrhage (aSAH) is the highest during the initial hours after rupture. Emergency aneurysm treatment may decrease this risk, but is a logistic challenge and economic burden. We aimed to investigate whether aneurysm treatment <6 h after rupture is associated with a decreased risk of poor functional outcome compared to aneurysm treatment 6-24 h after rupture. METHODS We used data of patients included in the ULTRA trial (NCT02684812). All patients in ULTRA were admitted within 24 h after aneurysm rupture. For the current study, we excluded patients in whom the aneurysm was not treated <24 h after rupture. We calculated crude and adjusted risk ratios (aRR) with 95% confidence intervals using Poisson regression analyses for poor functional outcome (death or dependency, assessed by the modified Rankin Scale) after aneurysm treatment <6 h versus 6-24 h after rupture. Adjustments were made for age, sex, clinical condition on admission (WFNS scale), amount of extravasated blood (Fisher score), aneurysm location, tranexamic acid treatment, and aneurysm treatment modality. RESULTS We included 497 patients. Poor outcome occurred in 63/110 (57%) patients treated within 6 h compared to 145/387 (37%) patients treated 6-24 h after rupture (crude RR: 1.53, 95% CI: 1.24-1.88; adjusted RR: 1.36, 95% CI: 1.11-1.66). CONCLUSION Aneurysm treatment <6 h is not associated with better functional outcome than aneurysm treatment 6-24 h after rupture. Our results do not support a strategy aiming to treat every patient with a ruptured aneurysm <6 h after rupture

Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial

BACKGROUND AND OBJECTIVES The ULTRA-trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at six months. An expected proportion of the included patients had non-aneurysmal subarachnoid hemorrhage In this post-hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at six months. METHODS The ULTRA-trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013 and January 20, 2020. After confirmation of subarachnoid hemorrhage on non-contrast computer tomography, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care, or usual care only. In this post-hoc analysis, we included all ULTRA-participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. The primary endpoint was clinical outcome at six months, assessed by the modified Rankin Scale, dichotomized into good (0-3) and poor (4-6) outcome. RESULTS Of the 813 ULTRA-trial patients who had an aneurysmal subarachnoid hemorrhage, 409 (50%) were assigned to the tranexamic acid group and 404 (50%) to the control group. In the intention-to-treat analysis, 233 of 405 (58%) patients in the tranexamic acid group and 238 of 399 (60%) patients in the control group had a good clinical outcome (adjusted odds ratio (aOR) 0·92; 95% confidence interval (C.I.) 0·69 to 1·24). None of the secondary outcomes showed significant differences between the treatment groups: excellent clinical outcome (mRS 0-2) aOR 0.76, 95% C.I. 0.57-1.03, all-cause mortality at 30 days aOR 0.91, 95% C.I. 0.65-1.28), all-cause mortality at six months aOR 1.10 (95% C.I. 0.80-1.52). DISCUSSION Ultra-early and short-term tranexamic acid treatment did not improve clinical outcome at six months in patients with aneurysmal subarachnoid hemorrhage and therefore, cannot be recommended. TRIAL REGISTRATION ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24$^{th}$, 2013). CLASSIFICATION OF EVIDENCE This study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage

A Systematic Review of Viscoelastic Testing in Patients with Subarachnoid Hemorrhage

Objective: Bleeding and thromboembolic complications frequently occur after subarachnoid hemorrhage (SAH) and substantially contribute to poor outcome. Viscoelastic testing could be used for detection of coagulopathies after SAH. This review summarizes literature on the usefulness of viscoelastic testing to detect coagulopathy in patients with SAH and explores whether viscoelastic parameters are associated with SAH-related complications and clinical outcome. Methods: PubMed, Embase, and Google Scholar were systematically searched on August 18, 2022. Two authors independently selected studies that reported viscoelastic testing in patients with SAH and assessed the quality of studies using the Newcastle-Ottawa Scale or a previously reported framework for quality assessment. Data were meta-analyzed if methodologically possible. Results: The search yielded 19 studies (1160 patients with SAH). Pooling of data including all relevant studies was not possible for any of the outcome measurements because of methodological differences. Thirteen of 19 studies evaluated the association of coagulation profiles and SAH, of which 11 studies showed a hypercoagulable profile. Rebleeding was associated with platelet dysfunction, deep venous thrombosis was associated with faster clot initiation, and both delayed cerebral ischemia and poor outcome were associated with increased clot strength. Conclusions: This explorative review shows that patients with SAH frequently have a hypercoagulable profile. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) parameters are associated with rebleeding, delayed cerebral ischemia, deep venous thrombosis, and poor clinical outcome after SAH; however, more research on the subject is needed. Future studies should focus on determining the optimal time frame and cutoff values for TEG or ROTEM to predict these complications

Prehemorrhage antiplatelet use in aneurysmal subarachnoid hemorrhage and impact on clinical outcome

BACKGROUND Literature is inconclusive regarding the association between antiplatelet agents use and outcome after aneurysmal subarachnoid hemorrhage. AIMS To investigate the association between clinical outcome and prehemorrhage use in aneurysmal subarachnoid hemorrhage patients as well as the impact of thrombocyte transfusion on rebleed and clinical outcome. METHODS Data were collected from prospective databases of two European tertiary reference centers for aneurysmal subarachnoid hemorrhage patients. Patients were divided into "antiplatelet-user" and "non-user" according to the use of acetylsalicylic acid prior to the hemorrhage. Primary outcome was poor clinical outcome at six months (Glasgow Outcome Scale score 1-3). Secondary outcomes were in-hospital mortality and impact of thrombocyte transfusion. RESULTS Of the 1033 patients, 161 (15.6%) were antiplatelet users. The antiplatelet users were older with higher incidence of cardiovascular risk factors. Antiplatelet use was associated with poor outcome and in-hospital mortality. After correction for age, sex, World Federation of Neurosurgical Societies score, infarction and heart disorder, pre-hemorrhage acetylsalicylic acid use was only associated with poor clinical outcome at six months (adjusted OR 1.80, 95% CI 1.08-3.02). Thrombocyte transfusion was not associated with a reduction in rebleed or poor clinical outcome. CONCLUSION In this multicenter study, the prehemorrhage acetylsalicylic acid use in aneurysmal subarachnoid hemorrhage patients was independently associated with poor clinical outcome at six months. Thrombocyte transfusion was not associated with the rebleed rate or poor clinical outcome at six months

Impact of time to start of tranexamic acid treatment on rebleed risk and outcome in aneurysmal subarachnoid hemorrhage

INTRODUCTION: The ULTRA-trial investigated effectiveness of ultra-early administration of tranexamic acid (TXA) in subarachnoid hemorrhage (SAH) and showed that TXA reduces the risk of rebleeding without concurrent improvement in clinical outcome. Previous trials in bleeding conditions, distinct from SAH, have shown that time to start of antifibrinolytic treatment influences outcome. This post-hoc analysis of the ULTRA-trial investigates whether the interval between hemorrhage and start of TXA impacts the effect of TXA on rebleeding and functional outcome following aneurysmal SAH. PATIENTS AND METHODS: A post-hoc comparative analysis was conducted between aneurysmal SAH patients of the ULTRA-trial, receiving TXA and usual care to those receiving usual care only. We assessed confounders, hazard ratio (HR) of rebleeding and odds ratio (OR) of good outcome (modified Rankin Scale 0-3) at 6 months, and investigated the impact of time between hemorrhage and start of TXA on the treatment effect, stratified into time categories (0-3, 3-6 and >6 h). RESULTS: Sixty-four of 394 patients (16.2%) in the TXA group experienced a rebleeding, compared to 83 of 413 patients (19.9%) with usual care only (HR 0.86, 95% confidence interval (CI): 0.62-1.19). Time to start of TXA modifies the effect of TXA on rebleeding rate (p < 0.001), with a clinically non-relevant reduction observed only when TXA was initiated after 6 h (absolute rate reduction 1.4%). Tranexamic acid treatment showed no effect on good outcome (OR 0.96, 95% CI: 0.72-1.27) with no evidence of effect modification on the time to start of TXA (p = 0.53). DISCUSSION AND CONCLUSIONS: This study suggests that the effect of TXA on rebleeding is modified by time to treatment, providing a protective, albeit clinically non-relevant, effect only when started after 6 h. No difference in functional outcome was seen. Routine TXA treatment in the aneurysmal SAH population, even within a specified time frame, is not recommended to improve functional outcome

Large practice variations in diagnosis and treatment of delayed cerebral ischemia after subarachnoid hemorrhage

Background: Delayed cerebral ischemia (DCI) contributes to poor outcomes after subarachnoid hemorrhage (SAH). The pathophysiology of DCI is not fully understood, which has hindered the adoption of a uniform definition. Furthermore, a reliable diagnostic test and an effective evidence-based treatment are lacking. This could lead to variations in care. Methods: A web-based survey on the variations in the definition, diagnosis, and treatment of DCI was designed and sent to 314 intensivists, neurologists, and neurosurgeons of all 9 hospitals in the Netherlands who care for patients with SAH. The responders were categorized into physicians responsible for the coordination of SAH care and those who were not. For questions on the definition and diagnosis, only the responses from the coordinating physicians were evaluated. For the treatment questions, all the responses were evaluated. Results: The response rate was 34% (106 of 314). All 9 hospitals were represented. Of the responses, 27 did not provide answers for the definition, diagnosis, or treatment questions; 79 responses were used for analysis. Signs of vasospasm were required by 21 of the 47 coordinating physicians (44%) when considering DCI. Of the 47 coordinating physicians, 24 (51%) did not use a diagnostic test results for a positive diagnosis of DCI. When patients were discharged within 21 days, 33 of the 73 responders (45%) did not provide a prescription for nimodipine continuation. Finally, all but one hospital had treated DCI with hypertension induction. Conclusions: We found large variations in the definition, diagnosis, and treatment of DCI in the Netherlands. In the absence of evidence-based treatment, standardization of management seems warranted in an effort to optimize DCI care

Clinical response following hypertension induction for clinical delayed cerebral ischemia following subarachnoid hemorrhage: A retrospective, multicenter, cohort study

Background: Hypertension induction (HTI) is often used for treating delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH); however, high-quality studies on its efficacy are lacking. We studied immediate and 3−/6-month clinical efficacy of HTI in aSAH patients with clinical DCI. Methods: A retrospective, multicenter, comparative, observational cohort study in aSAH patients with clinical deterioration due to DCI, admitted to three tertiary referral hospitals in the Netherlands from 2015 to 2019. Two hospitals used a strategy of HTI (HTI group) and one hospital had no such strategy (control group). We calculated adjusted relative risks (aRR) using Poisson regression analyses for the two primary (clinical improvement of DCI symptoms at days 1 and 5 after DCI onset) and secondary outcomes (DCI-related cerebral infarction, in-hospital mortality, and poor clinical outcome [modified Rankin Scale 4–6] assessed at 3 or 6 months), using the intention-to-treat principle. We also performed as-treated and per-protocol analyses. Results: The aRR for clinical improvement on day 1 after DCI in the HTI group was 1.63 (95% CI 1.17–2.27) and at day 5 after DCI 1.04 (95% CI 0.84–1.29). Secondary outcomes were comparable between the groups. The as-treated and per-protocol analyses yielded similar results. Conclusions: No clinical benefit of HTI is observed 5 days after DCI due to spontaneous reversal of DCI symptoms in patients treated without HTI. The 3−/6-month clinical outcome was similar for both groups. Therefore, these data suggest that one may consider to not apply HTI in aSAH patients with clinical DCI

Tumor-Educated Platelet RNA for the Detection and (Pseudo)progression Monitoring of Glioblastoma

Tumor-educated platelets (TEPs) are potential biomarkers for cancer diagnostics. We employ TEP-derived RNA panels, determined by swarm intelligence, to detect and monitor glioblastoma. We assessed specificity by comparing the spliced RNA profile of TEPs from glioblastoma patients with multiple sclerosis and brain metastasis patients (validation series, n = 157; accuracy, 80%; AUC, 0.81 [95% CI, 0.74–0.89; p < 0.001]). Second, analysis of patients with glioblastoma versus asymptomatic healthy controls in an independent validation series (n = 347) provided a detection accuracy of 95% and AUC of 0.97 (95% CI, 0.95–0.99; p < 0.001). Finally, we developed the digitalSWARM algorithm to improve monitoring of glioblastoma progression and demonstrate that the TEP tumor scores of individual glioblastoma patients represent tumor behavior and could be used to distinguish false positive progression from true progression (validation series, n = 20; accuracy, 85%; AUC, 0.86 [95% CI, 0.70–1.00; p < 0.012]). In conclusion, TEPs have potential as a minimally invasive biosource for blood-based diagnostics and monitoring of glioblastoma patients

Tumor-Educated Platelet RNA for the Detection and (Pseudo)progression Monitoring of Glioblastoma

Tumor-educated platelets (TEPs) are potential biomarkers for cancer diagnostics. We employ TEP-derived RNA panels, determined by swarm intelligence, to detect and monitor glioblastoma. We assessed specificity by comparing the spliced RNA profile of TEPs from glioblastoma patients with multiple sclerosis and brain metastasis patients (validation series, n = 157; accuracy, 80%; AUC, 0.81 [95% CI, 0.74-0.89; p &lt; 0.001]). Second, analysis of patients with glioblastoma versus asymptomatic healthy controls in an independent validation series (n = 347) provided a detection accuracy of 95% and AUC of 0.97 (95% CI, 0.95-0.99; p &lt; 0.001). Finally, we developed the digitalSWARM algorithm to improve monitoring of glioblastoma progression and demonstrate that the TEP tumor scores of individual glioblastoma patients represent tumor behavior and could be used to distinguish false positive progression from true progression (validation series, n = 20; accuracy, 85%; AUC, 0.86 [95% CI, 0.70-1.00; p &lt; 0.012]). In conclusion, TEPs have potential as a minimally invasive biosource for blood-based diagnostics and monitoring of glioblastoma patients

Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial

Background and ObjectivesThe ULTRA trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at 6 months. An expected proportion of the included patients experienced nonaneurysmal subarachnoid hemorrhage. In this post hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at 6 months.MethodsThe ULTRA trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013, and January 20, 2020. After confirmation of subarachnoid hemorrhage on noncontrast CT, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care or usual care only. In this post hoc analysis, we included all ULTRA participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin scale (mRS), dichotomized into good (0-3) and poor (4-6) outcomes.ResultsOf the 813 ULTRA trial patients who experienced an aneurysmal subarachnoid hemorrhage, 409 (50%) were assigned to the tranexamic acid group and 404 (50%) to the control group. In the intention-to-treat analysis, 233 of 405 (58%) patients in the tranexamic acid group and 238 of 399 (60%) patients in the control group had a good clinical outcome (adjusted odds ratio [aOR] 0.92; 95% CI 0.69-1.24). None of the secondary outcomes showed significant differences between the treatment groups: excellent clinical outcome (mRS 0-2) (aOR 0.76; 95% CI 0.57-1.03), all-cause mortality at 30 days (aOR 0.91; 95% CI 0.65-1.28), and all-cause mortality at 6 months (aOR 1.10; 95% CI 0.80-1.52).DiscussionUltra-early and short-term tranexamic acid treatment did not improve clinical outcomes at 6 months in patients with aneurysmal subarachnoid hemorrhage and therefore cannot be recommended.Trial Registration InformationClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24, 2013).Classification of EvidenceThis study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage