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 24th, 2013). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage.

Practice variation in the informed consent procedure for thrombolysis in acute ischemic stroke: a survey among neurologists and neurology residents.

BACKGROUND: Obtaining informed consent for intravenous thrombolysis in acute ischemic stroke can be challenging, and little is known about if and how the informed consent procedure is performed by neurologists in clinical practice. This study examines the procedure of informed consent for intravenous thrombolysis in acute ischemic stroke in high-volume stroke centers in the Netherlands. METHODS: In four high volume stroke centers, neurology residents and attending neurologists received an online questionnaire concerning informed consent for thrombolysis with tissue-type plasminogen activator (tPA). The respondents were asked to report their usual informed consent practice for tPA treatment and their considerations on whether informed consent should be obtained. RESULTS: From the 203 invited clinicians, 50% (n = 101) completed the questionnaire. One-third of the neurology residents (n = 21) and 21% of the neurologists (n = 8) reported that they always obtain informed consent for tPA treatment. If a patient is not capable of providing informed consent, 30% of the residents (n = 19) reported that they start tPA treatment without informed consent. In these circumstances, 53% of the neurologists (n = 20) reported that the resident under their supervision would start tPA treatment without informed consent. Most neurologists (n = 21; 55%) and neurology residents (n = 45; 72%) obtained informed consent within one minute. None of the respondents used more than five minutes for informed consent. Important themes regarding obtaining informed consent for treatment were patients' capacity, and medical, ethical and legal considerations. CONCLUSION: The current practice of informed consent for thrombolysis in acute ischemic stroke varies among neurologists and neurology residents. If informed consent is obtained, most clinicians stated to obtain informed consent within one minute. In the future, a shortened information provision process may be applied, making a shift from informed consent to informed refusal, while still considering the patient's capacity, stroke severity, and possible treatment delays.

Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial.

BACKGROUND: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months. METHODS: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812. FINDINGS: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups. INTERPRETATION: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale. FUNDING: Fonds NutsOhra.

Evaluation of the yield of 24-h close observation in patients with mild traumatic brain injury on anticoagulation therapy: a retrospective multicenter study and meta-analysis.

BACKGROUND/AIMS: Patients with mild traumatic brain injury (mTBI) on anticoagulants have an increased risk of intracranial hemorrhage (ICH). However, consensus is lacking on whether to admit them after normal initial cranial CT. We evaluated the yield of 24-h neurological observation. METHODS: Retrospective multicenter study including adult patients admitted over a 5-year period with mTBI on anticoagulation [therapeutic dose heparin, direct oral anticoagulant, or vitamin K antagonist (VKA) with international normalized ratio (INR) ≥ 1.7] and reportedly normal cranial CT obtained within 24 h after trauma. Primary endpoint was symptomatic ICH within 24 h of injury. Literature on delayed ICH in patients with mTBI and anticoagulation use was reviewed. RESULTS: Of 17.643 mTBI patients, 905 met the inclusion criteria (median age 82 years). 97% used VKA (median INR 2.9). None developed delayed ICH within 24 h. Nine patients deteriorated neurologically due to ICH, four within 24 h (0.4%, 95% CI 0.1-1.2) and five on day 2, 18, 22, 36 and 52, respectively. In six patients, including all four that developed symptoms within 24 h, ICH was found upon reevaluation of initial imaging. The meta-analysis comprised of 9 studies with data from 2885 patients. The estimated pooled proportion of symptomatic delayed ICH or delayed diagnosis of ICH within 24 h was 0.2% (95% CI 0.0-0.5). CONCLUSIONS: Delayed (diagnosis of) ICH within 24 h is very rare in mTBI patients on anticoagulants after reportedly normal initial CT. Routine hospitalization of these patients seems unwarranted when the initial cranial CT is scrupulously evaluated.

Variation in Organization of Transient Ischemic Attack Care in The Netherlands. A Nationwide Survey Study.

BACKGROUND: Previous research has shown the importance of urgent initiation of antiplatelet therapy after transient ischemic attack (TIA) to reduce the risk of stroke. Many hospitals in the Netherlands have therefore implemented rapid pathways for assessment of patients with TIA. Dutch stroke guidelines lack clear directives for organization of TIA assessment and thus allow for variation. The aim of this study was to investigate variation in organization of TIA assessment in Dutch hospitals. METHODS: One neurologist per hospital (of 88 Dutch hospitals) with special interest in stroke was invited to participate in a web-based survey addressing the organization, content, and timing of TIA assessment. RESULTS: Seventy (80%) neurologists completed the survey, all of whom reported performing TIA assessment in their hospital. There was considerable variation in the method of application and the location of assessment. In 10% of the hospitals, patients with TIA are always admitted to the ward. The content of diagnostics is fairly similar, but hospitals vary in the extent of cardiological workup. Almost all hospitals aim for a swift start of assessment as directed by guidelines, but access time differs. Eighty-six percent of respondents reported that antiplatelet therapy is usually initiated before assessment, based on history. CONCLUSIONS: This study showed variation in organization of TIA assessment in Dutch hospitals, especially regarding location within the hospital, time to assessment after announcement, and cardiological workup. Further research is needed to investigate implications of this variation for quality of care.

Medical Treatment for Spontaneous Anticoagulation-Related Intracerebral Hemorrhage in the Netherlands.

BACKGROUND: Spontaneous anticoagulation-related intracerebral hemorrhage accounts for up to a quarter of spontaneous intracerebral hemorrhage cases and is associated with higher hematoma volume and a worse outcome. Guidelines recommend rapid anticoagulant reversal but mode and timing are not specified and optimal strategy is uncertain. Variability in everyday practice is unknown. METHODS: An invitation to a web-based survey was sent to 85 Dutch stroke neurologists in different hospitals, with questions about importance, timing, and medical management of spontaneous anticoagulation-related intracerebral hemorrhage. RESULTS: In total, 61 (72%) neurologists completed the survey. Nearly all (97%) deemed rapid anticoagulant reversal important. A local guideline for management of anticoagulant reversal was used in 80% of the hospitals. Most neurologists (56%) estimated anticoagulant reversal in anticoagulation-related intracerebral hemorrhage to start later than intravenous thrombolysis in ischemic stroke. Few (5%) thought it was quicker. A minority (28%) of the hospitals started anticoagulation reversal without waiting for laboratory test results or consulting a specialist in hemostasis. Prothrombin complex concentrate was used by all neurologists for vitamin K antagonist reversal and by most (74%) for reversal of thrombin inhibitors and factor Xa inhibitors (72%). Anticoagulation reversal was initiated at the emergency department according to 89% of the respondents. CONCLUSION: Variability in logistics in acute management of spontaneous anticoagulation-related intracerebral hemorrhage was demonstrated. Anticoagulant reversal is deemed important, but is estimated to have a longer door-to-needle time than alteplase in thrombolysis for ischemic stroke by most neurologists. Several delaying factors were found. These factors might have an impact on outcome.

Association between i.v. thrombolysis volume and door-to-needle times in acute ischemic stroke.

Centralization of intravenous thrombolysis (IVT) for acute ischemic stroke in high-volume centers is believed to improve the door-to-needle times (DNT), but limited data support this assumption. We examined the association between DNT and IVT volume in a large Dutch province. We identified consecutive patients treated with IVT between January 2009 and 2013. Based on annualized IVT volume, hospitals were categorized as low-volume (≤ 24), medium-volume (25-49) or high-volume (≥ 50). In logistic regression analysis, low-volume hospitals were used as reference category. Of 17,332 stroke patients from 11 participating hospitals, 1962 received IVT (11.3 %). We excluded 140 patients because of unknown DNT (n = 86) or in-hospital stroke (n = 54). There were two low-volume (total 101 patients), five medium-volume (747 patients) and four high-volume hospitals (974 patients). Median DNT was shorter in high-volume hospitals (30 min) than in medium-volume (42 min, p < 0.001) and low-volume hospitals (38 min, p < 0.001). Patients admitted to high-volume hospitals had a higher chance of DNT < 30 min (adjusted OR 3.13, 95 % CI 1.70-5.75), lower risk of symptomatic intracerebral hemorrhage (adjusted OR 0.39, 95 % CI 0.16-0.92), and a lower mortality risk (adjusted OR 0.45, 95 % CI 0.21-1.01), compared to low-volume centers. There was no difference in DNT between low- and medium-volume hospitals. Onset-to-needle times (ONT) did not differ between the groups. Hospitals in this Dutch province generally achieved short DNTs. Despite this overall good performance, higher IVT volumes were associated with shorter DNTs and lower complication risks. The ONT was not associated with IVT volume.

Quetiapine in the treatment of psychotic adolescents: a case series of 23 patients with severe early onset psychosis.

Clinical efficacy, safety and tolerability of quetiapine in the treatment of 23 hospitalized psychotic adolescents were evaluated retrospectively. Twelve patients were changed to quetiapine from another antipsychotic medication during their hospital stay. In these patients, CGI-S improved from 4.75+/-0.87 to 2.92+/-0.67 (observation period 3.7+/-1.6 months). The most common adverse events were transient tachycardia and sedation. Mild EPS occurred only in one patient under quetiapine monotherapy. Transaminase increases more than threefold above norm were observed in two patients. fT4 values were slightly below the norm in 67% of the cases. In 11 patients, quetiapine was initiated using a rapid titration schedule with high dosages in the acute phase. Receiving a mean maximum daily dose of 927+/-300 mg, CGI-S improved from 6.00+/-0.63 to 3.18+/-1.25 (observation period 2.9+/-1.8 months). Severe adverse events did not occur. Besides applying lorazepam temporarily in nine of the 11 patients, antipsychotic co-medication was not necessary in this group. In line with other studies, quetiapine may be considered as an effective treatment for adolescents with a severe psychotic disorder showing a favourable side-effect profile. Our preliminary data suggest that a rapid initiation with high doses could be a promising approach in acute psychotic adolescents.