Statistical analysis plan for the multicenter, open, randomized controlled clinical trial to assess the efficacy and safety of intravenous tirofiban vs aspirin in acute ischemic stroke due to tandem lesion, undergoing recanalization therapy by endovascular treatment (ATILA trial).

RATIONALE: In-stent reocclusion after endovascular therapy has a negative impact on outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Optimal antiplatelet therapy approach in these patients to avoid in-stent reocclusion is yet to be elucidated. AIMS: To assess efficacy and safety of intravenous tirofiban versus intravenous aspirin in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. SAMPLE SIZE ESTIMATES: Two hundred forty patients will be enrolled, 120 in every treatment arm. METHODS AND DESIGN: A multicenter, prospective, randomized, controlled (aspirin group), assessor-blinded clinical trial will be conducted. Patients fulfilling the inclusion criteria will be randomized at MT onset to the experimental or control group (1:1). Intravenous aspirin will be administered at a 500-mg single dose and tirofiban at a 500-mcg bolus followed by a 200-mcg/h infusion during the first 24 h. All patients will be followed for up to 3 months. STUDY OUTCOMES: Primary efficacy outcome will be the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. Primary safety outcome will be the rate of symptomatic intracranial hemorrhage. DISCUSSION: This will be the first clinical trial to assess the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. TRIAL REGISTRATION: The trial is registered as NCT05225961. February, 7th, 2022.

Safety and efficacy of tirofiban in acute ischemic stroke due to tandem lesions undergoing mechanical thrombectomy: A multicenter randomized clinical trial (ATILA) protocol.

Background: In-stent thrombosis after mechanical thrombectomy (MT) worsen outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Although an optimal antiplatelet therapy is needed, the best approach to avoid in-stent thrombosis is yet to be elucidated. Hypothesis: Low-dose intravenous tirofiban is superior to intravenous aspirin in avoiding in-stent thrombosis in patients undergoing MT plus carotid stenting in the setting of AIS due to TL. Methods: The ATILA-trial is a multicenter, prospective, phase IV, randomized, controlled (aspirin group as control), assessor-blinded clinical trial. Patients fulfilling inclusion criteria (AIS due to TL, ASPECTS ⩾ 6, pre-stroke modified Rankin Scale ⩽2 and onset <24 h) will be randomized (1:1) at MT onset to experimental (intravenous tirofiban) or control group (intravenous aspirin). Intravenous aspirin will be administered at a 500 mg single dose and tirofiban at a 500 µg bolus followed by a 200 µg/h infusion during first 22 h. All patients will be followed up to 3 months. Sample size estimated is 240 patients. Outcomes: The primary efficacy outcome is the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. The primary safety outcome is the rate of symptomatic intracranial hemorrhage. Secondary outcomes include functional independence defined as modified Rankin Scale 0-2, proportion of patients undergoing rescue therapy due to in-stent aggregation during MT and carotid reocclusion at 30 days. Discussion: ATILA-trial will be the first clinical trial regarding the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL. Trial registration: NCT0522596.

RP11-362K2.2:RP11-767I20.1 Genetic Variation Is Associated with Post-Reperfusion Therapy Parenchymal Hematoma. A GWAS Meta-Analysis.

Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09, p-value 3.90 × 10-8) located in the RP11-362K2.2:RP11-767I20.1 gene and a suggestive variant (rs13297983: beta 0.07, p-value 6.10 × 10-8) located in PCSK5 associated with PH occurrence. The genetic correlation showed a shared genetic background of PH with Alzheimer's disease and white matter hyperintensities. In addition, genes containing the ten most significant associations have been related to aggregated amyloid-ß, tau protein, white matter microstructure, inflammation, and matrix metalloproteinases.

Time Trends in Intracerebral Hemorrhage Associated with Oral Anticoagulation and Its Risks Factors in Spain from 2008 to 2015.

BACKGROUND: Intracerebral hemorrhage (ICH) is 7- to 10-fold higher in anticoagulated patients. Given the more extended use of oral anticoagulants, an increase in the prevalence of ICH associated with oral anticoagulation (ICH-OAC) could be expected. However, there is no previous study that assesses the time trends of ICH-OAC in Spain. METHODS: We conducted a combined data analysis after creating a joint database of the 3 most important epidemiological studies on ICH-OAC of our country: the EPICES study (2008-2009), the TAC Registry (TR) study (2012-2013) and the TAC Registry 2 (TR2) study (2015). We finally included 65, 235, and 366 patients from the EPICES, TR, and TR2 studies, respectively. RESULTS: We have observed a 3.73-fold increase in the crude annual incidence of ICH-OAC throughout the period of study, with proportion of ICH-OAC out of total ICH increasing from 8.4% in 2008 to 18.2% in 2015. Age, dyslipidemia, and prior antiplatelet treatment increased during the study, but we found no statistically significant differences in other risk factors for ICH-OAC. CONCLUSIONS: The incidence of ICH-OAC is increasing in our country. It might at least be partly explained by aging of the population, with mean age at presentation being higher in the last years.

Symptomatic intracranial embolic foreign-body reactions after endovascular neurointerventional procedures: A retrospective study in a tertiary hospital.

INTRODUCTION: Polymer-coats may peel-off the surface of catheters and devices during endovascular procedures and might lead to brain inflammatory foreign-body reactions. METHODS: We conducted a retrospective, descriptive, single-centre study including all patients with symptomatic intracranial oedematous and contrast-enhancing lesions after any neurointerventional procedure performed in our hospital between 2013 and 2019. RESULTS: From a total of 7446 neurointerventional procedures, 11 cases were identified (9 female, 2 male, median age 47 year-old), with an incidence of 0.14 %. The procedures were therapeutic in all: ten aneurysm embolization/isolation, one acute ischaemic stroke recanalization. Intracranial coils, stent or both were placed in all. Symptoms appeared during the following one day to fourteen months (median of 4.2 weeks). Brain MRI showed oedematous, contrast-enhancing lesions scattered through the vascular territory of the canalized vessel. Brain biopsy confirmed the diagnosis in one case and was supportive in another one. Eight patients received immunosuppression. No treatment was started in two. After a median time of follow-up of 3.5 years, five patients are totally asymptomatic. One patient presents slight weakness. Four patients have remote symptomatic seizures, but they have comorbid lesions (previous stroke, intracranial haemorrhage, biopsy needle-track's gliosis). Follow-up MRI showed significant improvement in all the cases, with complete resolution in five. Non-symptomatic lesion fluctuation was observed in three cases. Two patients experienced symptomatic rebounds. CONCLUSION: Intracranial embolic foreign-body symptomatic reactions are uncommon complications of neurointerventional procedures. Diagnostic angiographies might have lower risk of polymer-embolization than therapeutic procedures. This entity's early recognition enables making proper diagnosis and treatment decisions.

Epidemiology of Intracranial Hemorrhage Associated with Oral Anticoagulants in Spain: Trends in Anticoagulation Complications Registry - The TAC 2 Study.

OBJECTIVE: Patients receiving treatment with oral anticoagulants (OACs) are at risk of intracranial hemorrhage (ICH). In this study, we describe the epidemiological and clinical characteristics of patients receiving OACs who experience ICH and compare those receiving vitamin K antagonists (ICH-VKAs) with those receiving direct OACs (ICH-DOACs). METHODS: We performed a national, multicenter, descriptive, observational, retrospective study of all adult patients receiving OACs who were admitted to the neurology department with ICH over a 1-year period. The study population was divided into 2 groups (ICH-VKAs and ICH-DOACs). Epidemiological, clinical, radiological, and therapy-related variables, as well as functional outcome, were compared at 3 months. A total of 366 cases were included (331 ICH-VKAs, 35 ICH- DOACs). RESULTS: The crude annual incidence of OAC-induced ICH was 3.8 (95% CI, 2.78-3.41) per 100,000 inhabitants/year. The mean (± SD) age was greater for ICH-DOACs (81.5 ± 8.3 vs. 77.7 ± 8.3 years; p = 0.012). The median (IQR) volume of the hemorrhage was lower for ICH-DOACs (11 [30.8] vs. 25 [50.7] mL; p = 0.03). The functional independence rate at 3 months (modified Rankin Scale, mRS < 3) was similar in both groups, although stroke-related mortality was greater in ICH-VKAs (40 vs. 72.7%; p = 0.02). The most frequently indicated poststroke antithrombotic therapy was DOACs (38.7%). CONCLUSION: We found that the incidence of OAC-induced ICH was greater than in previous studies. Hemorrhage volume and mortality were lower in ICH-DOACs than in ICH-VKAs. After stroke, DOACs were the most frequently indicated antithrombotic treatment.

Epidemiology of Intracranial Haemorrhages Associated with Vitamin K Antagonist Oral Anticoagulants in Spain: TAC Registry.

BACKGROUND: Vitamin K antagonist oral anticoagulants (VKA-OACs) are effective for primary and secondary prevention of embolic events. The rate of haemorrhagic neurological complications in patients admitted to neurology departments in Spain is not yet known. AIMS: We aimed to determine the clinical and epidemiological characteristics of patients with intracranial haemorrhage secondary to VKA-OACs as well as the incidence of this severe complication. METHODS: We conducted a retrospective, descriptive, multi-centre study using information from the medical records of all patients admitted to neurology departments, diagnosed with spontaneous intracranial haemorrhage, and treated with VKA-OACs within a 1-year period. We collected demographic and care data from centres, patients' medical records [demographic data, medical history, haemorrhage origin, vascular risk factors, concomitant treatment, and National Institutes of Health Stroke Scale (NIHSS) scores], and patients' outcome at 3 months [independence (modified Rankin Scale score <3) and mortality rate]. RESULTS: Twenty-one hospitals serving a population of 8,155,628 inhabitants participated in the study. The total number of cases was 235, the mean age was 78.2 (SD 9.4) years, and the baseline NIHSS score was 11.6 (SD 9.5; median 9; interquartile range 14). The VKA-OACs used were acenocoumarol in 95.3% (224 patients) and warfarin in 4.7% (11 patients). The haemorrhage origin was deep in 29.8%, lobar in 25.5%, intraventricular in 11.5%, extensive in 17.4% (>100 ml), cerebellar in 12.3%, and in the brainstem in 3.4%. The international normalised ratio was within therapeutic ranges at admission (according to indication) in 29.4% (69 patients). The global incidence (cases per 100,000 inhabitants per year) is 2.88. The in-hospital mortality rate was 40%, and 24.3% of the patients were independent at 3 months, while the mortality at 3 months was 42.6%. CONCLUSION: VKA-OAC treatment is associated with a large percentage of all cases of spontaneous intracranial haemorrhage, an event leading to high dependence and mortality rates.