Acute Noncardioembolic Stroke Research Articles

Hemorrhagic Transformation in Noncardioembolic Acute Ischemic Stroke: MRI Analysis From PACIFIC-STROKE.

In the phase 2 PACIFIC-STROKE trial (Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following Acute Noncardioembolic Stroke), asundexian, an oral factor XIa inhibitor, did not increase the risk of hemorrhagic transformation (HT). In this secondary analysis, we aimed to investigate the frequency, types, and risk factors of HT on brain magnetic resonance imaging (MRI). This was a secondary analysis of the PACIFIC-STROKE trial. Patients with mild-to-moderate acute noncardioembolic ischemic stroke were randomly assigned to asundexian or placebo plus guideline-based antiplatelet therapy. Brain MRIs were required at baseline (≤120 hours after stroke onset) and at 26 weeks or end-of-study. HT was defined using the Heidelberg classification and classified as early HT (identified on baseline MRI) or late HT (new HT by 26 weeks) based on iron-sensitive sequences. Multivariable logistic regression models were used to test factors that are associated with early HT and late HT, respectively. Of 1745 patients with adequate baseline brain MRI (mean age, 67 years; mean National Institutes of Health Stroke Scale score, 2.8), early HT at baseline was detected in 497 (28.4%). Most were hemorrhagic infarctions (hemorrhagic infarction type 1: 15.2%; HI2: 12.7%) while a few were parenchymal hematomas (parenchymal hematoma type 1: 0.4%; parenchymal hematoma type 2: 0.2%). Early HT was more frequent with longer symptom onset-to-MRI interval. Male sex, diabetes, higher National Institutes of Health Stroke Scale large (>15 mm) infarct size, cortical involvement by infarct, higher number of acute infarcts, presence of chronic brain infarct, cerebral microbleed, and chronic cortical superficial siderosis were independently associated with early HT in the multivariable logistic regression model. Of 1507 with follow-up MRI, HT was seen in 642 (42.6%) overall, including 361 patients (23.9%) with late HT (new HT: 306; increased grade of baseline HT: 55). Higher National Institutes of Health Stroke Scale, large infarct size, cortical involvement of infarct, and higher number of acute infarcts predicted late HT. About 28% of patients with noncardioembolic stroke had early HT, and 24% had late HT detectable by MRI. Given the high frequency of HT on MRI, more research is needed on how it influences treatment decisions and outcomes.

Effects of Tirofiban on Neurological Deterioration in Patients With Acute Ischemic Stroke

Evidence supports using antiplatelet therapy in patients with acute ischemic stroke. However, neurological deterioration remains common under the currently recommended antiplatelet regimen, leading to poor clinical outcomes. To determine whether intravenous tirofiban administered within 24 hours of stroke onset prevents early neurological deterioration in patients with acute noncardioembolic stroke compared with oral aspirin. This investigator-initiated, multicenter, open-label, randomized clinical trial with blinded end-point assessment was conducted at 10 comprehensive stroke centers in China between September 2020 and March 2023. Eligible patients were aged 18 to 80 years with acute noncardioembolic stroke within 24 hours of onset and had a National Institutes of Health Stroke Scale (NIHSS) score of 4 to 20. Patients were assigned randomly (1:1) to receive intravenous tirofiban or oral aspirin for 72 hours using a central, web-based, computer-generated randomization schedule; all patients then received oral aspirin. The primary efficacy outcome was early neurological deterioration (increase in NIHSS score ≥4 points) within 72 hours after randomization. The primary safety outcome was symptomatic intracerebral hemorrhage within 72 hours after randomization. A total of 425 patients were included in the intravenous tirofiban (n = 213) or oral aspirin (n = 212) groups. Median (IQR) age was 64.0 years (56.0-71.0); 124 patients (29.2%) were female, and 301 (70.8%) were male. Early neurological deterioration occurred in 9 patients (4.2%) in the tirofiban group and 28 patients (13.2%) in the aspirin group (adjusted relative risk, 0.32; 95% CI, 0.16-0.65; P = .002). No patients in the tirofiban group experienced intracerebral hemorrhage. At 90-day follow-up, 3 patients (1.3%) in the tirofiban group and 3 (1.5%) in the aspirin group died (adjusted RR, 1.15; 95% CI, 0.27-8.54; P = .63), and the median (IQR) modified Rankin scale scores were 1.0 (0-1.25) and 1.0 (0-2), respectively (adjusted odds ratio, 1.28; 95% CI, 0.90-1.83; P = .17). In patients with noncardioembolic stroke who were seen within 24 hours of symptom onset, tirofiban decreased the risk of early neurological deterioration but did not increase the risk of symptomatic intracerebral hemorrhage or systematic bleeding. ClinicalTrials.gov Identifier: NCT04491695.

The Body Mass Index as a Determinant of Acute Ischemic Location in Mild Non-cardioembolic Stroke Patients.

Objective Although the body mass index (BMI) is considered a meaningful parameter for evaluating obesity, the association between the BMI and acute non-cardioembolic stroke remains unclear. We investigated how the BMI was related to patients' background, type of infarction, and infarction location in patients with non-cardioembolic stroke using an acute dual study (ADS) cohort. Methods The ADS trial was conducted between May 2011 and June 2017 in Japan. The BMI classifications were those proposed by the World Health Organization classification: underweight, <18.5 kg/m2; normal weight, 18.5-24.9 kg/m2; overweight, 25-29.9 kg/m2; and obese, ≥30 kg/m2. Results Data from 1136 patients were analyzed. The median BMI was 23.6 kg/m2 (interquartile range: 21.6-25.8 kg/m2), with a BMI ≥30 kg/m2 in 63 patients (6%), 25-29.9 kg/m2 in 321 (28%), 18.5-24.9 kg/m2 in 692 (61%), and <18.5 kg/m2 in 60 (5%). The group with a BMI ≥30 kg/m2 was the youngest, and the group with a BMI <18.5 kg/m2 was the oldest (p<0.001). The proportion of patients with a history of hypertension (p<0.001), diabetes (p<0.001), dyslipidemia (p<0.001), and statin therapy (p=0.005) increased with increasing BMI. Pontine infarcts were frequent in the following order: obese, overweight, normal weight, and underweight (24%, 18%, 14%, and 13%, respectively; p=0.034). In contrast, cortical infarct were frequent in the order of underweight, normal weight, overweight, and obese at 20%, 19%, 14%, and 3%, respectively (p=0.007). Conclusion Acute stroke patients with a high BMI have more atherosclerosis-related factors in their backgrounds than those with lower BMIs. In addition, the BMI may be a determinant of infarct location in patients with acute stroke.

Cost-effectiveness of ticagrelor plus aspirin versus aspirin in acute ischaemic stroke or transient ischaemic attack: an economic evaluation of the THALES trial

ObjectiveTHALES demonstrated that ticagrelor plus aspirin reduced the risk of stroke or death but increased bleeding versus aspirin during the 30 days following a mild-to-moderate acute non-cardioembolic ischaemic stroke (AIS)...

Optimising the analysis of vascular prevention trials: Re-Assessment of the TARDIS trial, the first prevention trial to adopt an ordinal primary outcome measure

BackgroundOrdinalised vascular outcomes incorporating event severity are more informative than binary outcomes that just include event numbers. The TARDIS trial was the first vascular prevention study to use an ordinalised vascular outcome as its primary efficacy and safety measures and collected severity information for other vascular events. MethodsTARDIS was an international prospective randomised open-label blinded-endpoint trial assessing one month of intensive versus guideline antiplatelet therapy in patients with acute non-cardioembolic stroke or TIA. Vascular events and their severity were recorded up to final follow-up at 90 days post randomisation. For each outcome, statistical techniques compared ordinal/continuous (10 models) and dichotomous (5 models) analyses; results were then ranked with the smallest p-value being given the smallest rank. Outcomes were also assessed within the pre-defined subgroup of participants with mild stroke (NIHSS≤3), or TIA recruited within 24 h. ResultsOrdinal versions of vascular event outcomes were created in 3096 participants for stroke, myocardial infarction, major cardiac events, bleeding events, serious adverse events and venous thromboembolism (VTE), with 32 outcomes being created overall (29 in the subgroup population due to the absence of VTE events). Overall, the tests run on ordinal outcomes tended to rank higher than tests performed on binary outcomes. 764 (24.7%) participants were recruited within 24 h of a mild stroke/TIA; again, tests run on ordinal outcomes ranked higher. ConclusionsIn TARDIS, tests performed on ordinal vascular outcomes tended to attain a higher rank than those performed on binary outcomes. Trial registrationISRCTN47823388

Contemporary Antiplatelet and Anticoagulant Therapies for Secondary Stroke Prevention: A Narrative Review of Current Literature and Guidelines.

Stroke is a leading cause of death and disability worldwide. The annual incidence of new or recurrent stroke is approximately 795,000 cases per year in the United States, of which 87% are ischemic in nature. In addition to the management of modifiable high-risk factors to reduce the risk of recurrent stroke, antithrombotic agents (antiplatelets and anticoagulants) play an important role in secondary stroke prevention. This review will discuss the published literature on the use of antiplatelets and anticoagulants in secondary prevention of acute ischemic stroke and transient ischemic attack (TIA), including their pharmacology, efficacy, and adverse effects. We will also highlight the role of dual antiplatelet therapy (DAPT) in secondary stroke prevention, along with supporting literature. Single antiplatelet therapy (SAPT) with aspirin or clopidogrel reduces the risk of recurrent ischemic stroke in patients with non-cardioembolic ischemic stroke or TIA. However, as shown in recent trials, short-term DAPT with aspirin and clopidogrel or ticagrelor for 21-30days is more effective than SAPT in patients with minor acute non-cardioembolic stroke or high-risk TIA. Although short-term DAPT is highly effective in preventing recurrent stroke, a more prolonged course can increase bleeding risks without additional benefit. DAPT for 90days, followed by aspirin monotherapy for patients with large vessel intracranial atherosclerotic disease, is suitable for secondary stroke prevention. However, patients need to be monitored for both minor (e.g., bruising) and major (e.g., intracranial) bleeding complications. Conversely, oral warfarin and newer direct oral anticoagulant (DOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban are the agents of choice for secondary stroke prevention in patients with non-valvular cardioembolic strokes. DOACs may be preferred over warfarin due to decreased bleeding risks, including ICH, lack of need for international normalized ratio monitoring, no dietary restrictions, and limited drug-drug interactions. The choice between different antiplatelets and anticoagulants for prevention of ischemic stroke depends on the underlying stroke mechanism, cytochrome P450 2C19 polymorphisms, bleeding risk profile, compliance, drug tolerance, and drug resistance. Physicians must carefully weigh each patient's relative benefits and bleeding risks before initiating an antiplatelet/anticoagulant treatment regimen. Further studies are warranted to study the optimal duration of DAPT in symptomatic intracranial atherosclerosis since the benefit is most pronounced in the short term while the bleeding risk remains high during the extended duration of therapy.

Tachycardia Changes Increase Neurological Deterioration in Patients with Acute Non-Cardioembolic Stroke: An ADS Post-Hoc Analysis.

A previous randomized study showed that dual antiplatelet therapy (DAPT) with aspirin and cilostazol is not superior to aspirin monotherapy for patients with acute non-cardioembolic stroke; however, the reason for this remains uncertain. We focused on the unusual side effects of cilostazol, namely, tachycardia changes, and validated their influence on patients with acute non-cardioembolic stroke. This post-hoc study extracted data from the acute aspirin plus cilostazol dual therapy study (ADS) registry, a multicenter, prospective, randomized, open-label trial. Patients were randomly allocated to the dual group (aspirin plus cilostazol) and the aspirin monotherapy group (aspirin alone). Tachycardia changes were defined as ≥ 5% heart rate increase at 48 h after admission compared with that at admission. Baseline data and outcomes were validated with four divided groups: aspirin-non-tachycardia changes (AN), aspirin-tachycardia changes (AT), dual-non-tachycardia changes (DN), and dual-tachycardia changes (DT). Finally, 1,188 patients were analyzed in this ADS post-hoc analysis (aspirin monotherapy group, 594; dual group, 594). The proportion of change in tachycardia was 19.2% in the aspirin monotherapy group and 38.2% in the dual group (p＜0.001＊＊＊). Although the recurrences of symptomatic stroke and transient ischemic attack were not significantly different, the neurological deterioration was significantly different among the AN, AT, DN, and DT groups (p＜0.05＊). Tachycardia changes increase neurological deterioration even in patients with non-cardioembolic acute stroke. DAPT consisting of aspirin and cilostazol increases the proportion of tachycardia changes and is not superior to aspirin monotherapy.

Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial

Asundexian (Bayer AG, Leverkusen, Germany), an oral small molecule factor XIa (FXIa) inhibitor, might prevent thrombosis without increasing bleeding. Asundexian's effect for secondary prevention of recurrent stroke is unknown. In this randomised, double-blind, placebo-controlled, phase 2b dose-finding trial (PACIFIC-Stroke), patients with acute (within 48 h) non-cardioembolic ischaemic stroke were recruited from 196 hospitals in 23 countries. Patients were eligible if they were aged 45 years or older, to be treated with antiplatelet therapy, and able to have a baseline MRI (either before or within 72 h of randomisation). Eligible participants were randomly assigned (1:1:1:1), using an interactive web-based response system and stratified according to anticipated antiplatelet therapy (single vs dual), to once daily oral asundexian (BAY 2433334) 10 mg, 20 mg, or 50 mg, or placebo in addition to usual antiplatelet therapy, and were followed up during treatment for 26-52 weeks. Brain MRIs were obtained at study entry and at 26 weeks or as soon as possible after treatment discontinuation. The primary efficacy outcome was the dose-response effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after randomisation. The primary safety outcome was major or clinically relevant non-major bleeding as defined by International Society on Thrombosis and Haemostasis criteria. The efficacy outcome was assessed in all participants assigned to treatment, and the safety outcome was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04304508, and is now complete. Between June 15, 2020, and July 22, 2021, 1880 patients were screened and 1808 participants were randomly assigned to asundexian 10 mg (n=455), 20 mg (n=450), or 50 mg (n=447), or placebo (n=456). Mean age was 67 years (SD 10) and 615 (34%) participants were women, 1193 (66%) were men, 1505 (83%) were White, and 268 (15%) were Asian. The mean time from index stroke to randomisation was 36 h (SD 10) and median baseline National Institutes of Health Stroke Scale score was 2·0 (IQR 1·0-4·0). 783 (43%) participants received dual antiplatelet treatment for a mean duration of 70·1 days (SD 113·4) after randomisation. At 26 weeks, the primary efficacy outcome was observed in 87 (19%) of 456 participants in the placebo group versus 86 (19%) of 455 in the asundexian 10 mg group (crude incidence ratio 0·99 [90% CI 0·79-1·24]), 99 (22%) of 450 in the asundexian 20 mg group (1·15 [0·93-1·43]), and 90 (20%) of 447 in the asundexian 50 mg group (1·06 [0·85-1·32]; t statistic -0·68; p=0·80). The primary safety outcome was observed in 11 (2%) of 452 participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1·57 [90% CI 0·91-2·71]). In this phase 2b trial, FXIa inhibition with asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not increase the composite of major or clinically relevant non-major bleeding compared with placebo in patients with acute, non-cardioembolic ischaemic stroke. Bayer AG.

Association of Timing for Starting Dual Antiplatelet Treatment With Cilostazol and Recurrent Stroke

Background and ObjectivesLong-term treatment with the combination of cilostazol with aspirin or clopidogrel showed a lower risk of stroke recurrence compared to aspirin or clopidogrel alone after high-risk noncardioembolic ischemic stroke in a randomized trial. We aimed to determine whether the effect of the dual medication compared to monotherapy on risk of recurrent ischemic stroke differs according to timing of starting medication after stroke onset.MethodsIn a subanalysis of the randomized controlled trial, patients between 8 and 180 days after stroke onset were randomly assigned to receive aspirin or clopidogrel alone or a combination of cilostazol with aspirin or clopidogrel. They were divided into 3 groups according to the timing of starting trial treatment: between 8 and 14 days after stroke onset (8–14 days group), between 15 and 28 days after stroke onset (15–28 days group), and between 29 and 180 days after stroke onset (29–180 days group). The primary efficacy outcome was the first recurrence of ischemic stroke. Safety outcomes included severe or life-threatening bleeding.ResultsOf 1,879 patients, 498 belonged to the 8–14 days group, 467 to the 15–28 days group, and 914 to the 29–180 days group. There was a significant treatment-by-subgroup interaction for the recurrence of ischemic stroke between trial treatment and trichotomized groups. The recurrence of ischemic stroke was less common with dual therapy than with monotherapy in the 15–28 days group (annualized rate 1.5% vs 4.9%, respectively; adjusted hazard ratio 0.34 [95% CI 0.12–0.95]) and the 29–180 days group (1.9% vs 4.4%, respectively; 0.27 [0.12–0.63]) and similarly common in the 8–14 days group (4.5% for both; 1.02 [0.51–2.04]). Severe or life-threatening bleeding occurred similarly between patients on dual therapy and those on monotherapy in any of the trichotomized groups (crude hazard ratio 0.22 [95% CI 0.03–1.88] in the 8–14 days group, 1.07 [0.15–7.60] in the 15–28 days group, and 0.76 [0.24–2.39] in the 29–180 days group).DiscussionLong-term dual antiplatelet therapy using cilostazol starting 15–180 days after stroke onset, compared to therapy started 8–14 days after onset, was more effective for secondary stroke prevention than monotherapy without increasing hemorrhage risk.Trial Registration InformationClinicalTrials.gov NCT01995370; UMIN Clinical Trials Registry 000012180.Classification of EvidenceThis study provides Class II evidence that for patients with acute noncardioembolic stroke taking either aspirin or clopidogrel, the addition of cilostazol 15–180 days after stroke onset decreases the risk of recurrent ischemic stroke.

Variability of mean platelet volume in patients with ischemic stroke in the early recovery period depending on comorbidity

High platelet reactivity in patients with ischemic noncardioembolic stroke is associated with an increased risk of recurrent ischemic events. However, their determinants are still poorly understood. The aim of our study was to examine changes in mean platelet volume in patients with ischemic stroke in the early recovery period depending on comorbidity.Material and methods. Clinical and laboratory analysis of 90 patients with acute noncardioembolic stroke of the early recovery period. Among those surveyed were 49 men and 41 women aged (60.42 ± 6.8) years. Platelet count (PLT) and mean platelet volume (MPV) were determined on an Abacus 30 hematology analyzer.Results. Significantly more often, the highest mean platelet counts were observed in patients with atherothrombotic subtype of ischemic stroke with greater neurological deficit. Patients with the highest MPV rates had a higher prevalence of diabetes, an elevated body mass index, and a degree of cerebral atherosclerosis compared with patients with lower MPV levels.Conclusion. The increase in MPV in patients with ischemic stroke is observed in parallel with the increase in the influence of known factors in the development of cardiovascular diseases that cause the progression of vascular endothelial damage and atherothrombosis and indicates an increased risk of recurrent stroke.

Heart rate variability and delirium in acute non-cardioembolic stroke: a prospective, cross-sectional, cohort study

ObjectivesDelirium is an acute fluctuating disorder of attention and awareness. It is associated with autonomic dysfunction and increased mortality. The primary endpoint of our study was to measure autonomic activity in acute stroke patients, by means of heart rate variability analysis, in order to identify autonomic modifications that can predispose to delirium.MethodsPatients were consecutively enrolled from the stroke unit. Inclusion criteria were age ≥ 18 years and diagnosis of stroke with onset within the previous 72 h confirmed by neuroimaging. Exclusion criteria were atrial fibrillation, congestive heart failure, and conditions requiring intensive care unit. Patients were evaluated by means of Richmond Agitation Sedation Scale (RASS) and Confusion Assessment Method-Intensive Care Unit (CAM-ICU) at baseline, after 72 h, or when symptoms suggesting delirium occurred. For each patient, ECG was recorded at baseline assessment and HRV analysis was conducted on five consecutive minutes of artifact-free ECG traces.ResultsFifty-six ECGs were available for analysis. During the study period, 11 patients developed delirium. Patients with and without delirium did not differ for sex, age, severity of stroke, and comorbidities. The delirium group had greater standard deviation of the heart rate (DLR − :9.16 ± 8.28; DLR + : 14.36 ± 5.55; p = 0.026) and lower power spectral density of the HF component (DLR − : 38.23 ± 19.23 n.u.; DLR + : 25.75 ± 8.77 n.u.; p = 0.031).ConclusionsAcute non-cardioembolic stroke patients with increased variability of heart rate and decreased vagal control are at risk for delirium.

Early and long-term outcomes of argatroban use in patients with acute noncardioembolic stroke

BackgroundArgatroban in acute noncardioembolic stroke ineligible for intravenous thrombolysis (IVT) or endovascular treatment (EVT) remains unclear. This study aimed to evaluate whether argatroban improved early and long-term outcomes compared with antiplatelet treatment. MethodsThis retrospective observational study, using the prospective stroke database from our hospital, included all consecutive patients who hospitalized from January 1, 2017 to December 31, 2019, with a diagnosis of acute non-cardioembolic stroke within 48 hours of stroke onset but not receiving IVT and EVT. Patients were divided into 2 groups: the argatroban group and the control group without argatroban. Outcome assessment with early neurological deterioration (END), National Institutes of Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), bleeding complications, and mortality were compared between the 2 groups in all cases and different stroke subtypes. An ordinal logistic regression analysis evaluated the association between argatroban use and mRS score at 90 days. ResultsOf 1325 patients were enrolled, 519 patients in the argatroban group and 806 in the control. Baseline characteristics, hospital bleeding complications, and 90-day mortality were similar for the 2 groups. The argatroban group showed lower END, larger improvement of 7-day NIHSS score and higher percentage of a 90-day mRS score of 02. Similar results were found in subgroup analysis with large-artery atherosclerosis, anterior circulation infarction, and moderate stroke. Also, argatroban use was significantly associated with an excellent long-term stroke outcome (mRS ≤ 2). ConclusionThe current study suggested that argatroban was safe and effective for improving short and long-term outcomes in noncardioembolic stroke patients.

Cilostazol uncovers covert atrial fibrillation in non-cardioembolic stroke

BackgroundWe hypothesized that administration of cilostazol may clarify the occult atrial fibrillation (AF) during hospitalization in mild stroke patients, who has no history of AF. MethodsFrom our prospective non-cardioembolic stroke study, randomized to dual antiplatelet therapy using cilostazol and aspirin or aspirin alone trial (ADS), data on the presence or absence of AF were retrospectively analyzed. In the ADS, during hospitalization, as a routine examination, presence of AF was investigated using electrocardiogram (ECG), ECG monitoring and Holter ECG. Multivariate regression analysis was conducted to evaluate the independent parameters related to the AF. Clinical outcome at 3 months was evaluated using modified Rankin Scale (mRS) score. ResultsData on 1194 patients (793 [66%] men; median age [interquartile range] of 69 [61–77] years, National Institutes of Health Stroke Scale score 2 [1–4], onset-to-admission 10.8 [4.7–20.5] hours) were retrospectively analyzed. AF was newly detected in 41 (3%) patients (3 by ECG, 21 by the ECG monitoring and 17 by the Holter ECG) during hospitalization. Patients treated with combined cilostazol and aspirin therapy frequently had the AF than those took aspirin alone (5% vs. 2%, p = .007). Multivariate regression analysis showed that cilostazol administration was one of the independent factors for new-AF (odds ratio 2.672, 95%CI: 1.205–5.927, p = .016). The frequency of mRS 0-1 was 68% in the new-AF group and 67% in the non-AF group (p = 1.000). ConclusionCilostazol therapy may increase the detectability of AF in acute non-cardioembolic stroke, though the new-AF was not related to clinical outcome at 3 months.

Abstract WP256: Administration of Cilostazol Clarifies the Burden Atrial Fibrillation in Non-Cardioembolic Stroke

Introduction: The survey of atrial fibrillation (AF) is routinely recommended in acute stroke case, even in patients without AF on admission, because the AF leads to a sever stroke. Cilostazol is often used for stroke patients without AF in Japan; however, it has the adverse events of palpitation due to the vessels dilatation by increased nitric oxide. We hypothesized that administration of cilostazol may clarify the burden AF in stroke patients without AF. Methods: From our prospective randomized control study, (randomized to dual antiplatelet therapy using cilostazol and aspirin or aspirin alone targeted patients for non-cardioembolic stroke [ADS]), patients assessed the presence of AF were retrospectively analyzed. Presence of AF was detected using ECG monitoring and Holter ECG. All patients were divided into the AF group and the non-AF group and imaging and laboratory findings were compared between the 2 groups. Multivariate regression analysis was conducted to evaluate the independent factors related to new AF. Results: 1194 patients (793 [66%] men; median age [IQR] of 69 [61-77] years, NIHSS score 2 [1-4], onset-to-admission 10.8 [4.7-20.5] hours) patients were included. AF was newly detected in 41 patients (3 by ECG, 21 by the ECG monitoring and 17 by the Holter ECG) during hospitalization. Patients randomized to the combined cilostazol and aspirin therapy frequently had the AF than those to aspirin alone (29/596 [5%] vs. 12/598 [2%], p=0.007). AF group was older than the non-AF group (76 [72-82] vs. 68 [60-77] years, p&lt;0.001). NIHSS score was similar between AF and non-AF group (5 [3-12] vs. 4 [2-6] p=0.062). Serum brain natriuretic peptide (BNP) level was higher in AF group (65.9 [31.7-145.5] vs. 25.6 [13.1-52.5] ng/ml. p&lt;0.001). Regarding imaging findings, cardio-thoracic ratio (CTR) was elevated (p&lt;0.001), multiple infarcts was frequent (p=0.003) and the infarcts size was larger (&gt;1.5cm) (p&lt;0.001) in AF group. By multivariate regression analysis, cilostazol administration was the independent factor for new AF detection (odds ratio 2.81, 95%CI: 1.30-6.09, p=0.009) adjusting for age, infarct size and number, CTR, BNP, and NIHSS score. Conclusion: Administration of cilostazol increases the detectability of AF in acute non-cardioembolic stroke.

Dabigatran Treatment of Acute Non-Cardioembolic Ischaemic Stroke: A Randomised Controlled Trial

Background: Transient ischaemic attack (TIA) and minor ischaemic stroke patients are at high risk for recurrent events. Anticoagulants are associated with reduced recurrent ischemic stroke rates, but also increased risk of haemorrhagic transformation (HT). Dabigatran, a novel oral anticoagulant associated with reduced risk of intracranial bleeding compared with warfarin in atrial fibrillation patients, has not been assessed in acute brain ischemia. We hypothesised that HT rates are not increased by dabigatran relative to aspirin after acute ischaemic stroke/TIA. Methods: DAbigatran Treatment of Acute Stroke II (DATAS II) was a prospective, randomised open label, blinded endpoint trial of dabigatran versus aspirin in acute stroke/TIA (clinicatrials.gov NCT02295826). Non-cardio-embolic stroke/TIA patients (NIHSS score ≤9, infarct volume < 25 ml) who did not receive thrombolytic therapy or thrombectomy were randomised 1:1 to dabigatran 150 mg BID (110 mg BID in patients ≥80 or if CrCl <50 ml/min) or aspirin (81 mg OD). Magnetic resonance imaging was performed prior to randomisation and was repeated at day 30, with clinical assessments at 30 and 90 days. Imaging endpoints were ascertained centrally by readers blinded to treatment. The primary endpoint was symptomatic HT within 37 days of randomisation. Secondary endpoints included asymptomatic HT and recurrent cerebral infarcts. Findings: A total of 305 patients, mean age 66±13.21 years, were randomised to dabigatran or aspirin a mean of 40.10±19.44 hours after symptom onset. The qualifying event was a TIA in 21%, and ischaemic stroke in79% of patients. Median NIHSS (IQR) was 1 (0-2), and mean infarct volume 3.2±6.5 ml. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (RR=2.32, 95% CI 0.78, 6.85). Baseline infarct volume predicted incident HT (OR 1.07; 95% CI 1.03-1.12, p=0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran and 14/142 (9.8%) of aspirin patients (RR=0.62, 95% CI 0.26, 1.48). There were no major bleeding events with either treatment. Interpretation: Dabigatran given to patients with acute minor non-cardioembolic ischaemic stroke/TIA was safe and was associated with a risk of HT similar to aspirin. Trial Registration Number: clinicatrials.gov NCT02295826 Funding Statement: DATAS II was funded by the Canadian Institutes for Health Research (G327075). Declaration of Interests: Dr. Butcher has served as an advisory board consultant and received speaker’s fees and investigatorinitiated grant support from Boehringer-Ingelheim, Bayer, BMS-Pfizer and Servier. Dr. Sharma has served as an advisory board consultant and or received speaker’s fees and investigator-initiated grant support from Boehringer-Ingelheim, Bayer, BMS-Pfizer, Daiichi Sankyo and Servier. Dr. Benavente has served as an advisory board consultant and or received speaker’s fees from Boehringer-Ingelheim, Bayer, BMS-Pfizer and Servier. Dr. Field has served as an advisory board consultant and received speaker’s fees from BoehringerIngelheim, Bayer, BMS-Pfizer and Servier and investigator-initiated grant support from BoehringerIngelheim and Bayer (study medication). Dr. Hill has served as a consultant for Boehringer-Ingelheim. He has received grants to the University of Calgary from Medtronic, Stryker, Boehringer-Ingelheim Canada, Bayer Canada. Dr. Gioia has received speaker honoraria from Bayer, and BMS Pfizer and has served as an advisory board consultant for Bayer, and Servier Inc. Dr. Coutts has served as an advisory board consultant for BMS-Pfizer. Boehringer-Ingelheim is providing study drug for an investigator-initiated study led by Dr. Coutts. Ethics Approval Statement: The trial was approved by research ethics review boards at each institution.

Increased circulating endothelial progenitor cells and improved short-term outcomes in acute non-cardioembolic stroke after hyperbaric oxygen therapy

BackgroundAcute ischemic stroke is a leading cause of mortality and long-term disability, and profiles of endothelial progenitor cells (EPCs) reflect the degree of endothelial impairment. This study tested the hypothesis that hyperbaric oxygen therapy (HBOT) both improves the clinical short-term outcomes and increases the number of circulating EPCs and antioxidant capacity.MethodsThe numbers of circulating EPCs [CD133+/CD34+ (%), KDR+/CD34+ (%)], biomarkers for oxidative stress (thiols and thiobarbituric acid-reactive substances), and clinical scores (National Institutes of Health Stroke Scale [NIHSS], Barthel index [BI], and modified Rankin Scale [MRS]) were prospectively evaluated in 25 patients with acute non-cardioembolic stroke under HBOT at two time points (pre- and post-HBOT). The biomarkers and clinical scores were compared with those of 25 age- and sex-matched disease controls.ResultsThe numbers of KDR+/CD34+ (%) in the HBOT group following HBOT increased significantly, whereas the numbers of CD133+/CD34+ (%) also showed a tendency to increase without statistical significance. The mean high-sensitivity C-reactive protein levels showed significant decrease post-HBOT follow-up in the HBOT group. The changes in KDR+/CD34+EPC (%) numbers were positively correlated with changes in clinical outcomes scores (BI, NIHSS, and MRS) in the HBOT group.ConclusionsBased on the results of our study, HBOT can both improve short-term clinical outcomes and increase the number of circulating EPCs in patients with acute non-cardioembolic stroke.

Triple versus guideline antiplatelet therapy to prevent recurrence after acute ischaemic stroke or transient ischaemic attack: the TARDIS RCT.

Two antiplatelet agents are better than one for preventing recurrent stroke after acute ischaemic stroke or transient ischaemic attack (TIA). Therefore, intensive treatment with three agents might be better still, providing it does not cause undue bleeding. To compare the safety and efficacy of intensive therapy with guideline antiplatelet therapy for acute ischaemic stroke and TIA. International prospective randomised open-label blinded end-point parallel-group superiority clinical trial. Acute hospitals at 106 sites in four countries. Patients > 50 years of age with acute non-cardioembolic ischaemic stroke or TIA within 48 hours of ictus (stroke). Participants were allocated at random by computer to 1 month of intensive (combined aspirin, clopidogrel and dipyridamole) or guideline (combined aspirin and dipyridamole, or clopidogrel alone) antiplatelet agents, and followed for 90 days. The primary outcome was the incidence and severity of any recurrent stroke (ischaemic, haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days by blinded telephone follow-up. Analysis using ordinal logistic regression was by intention to treat. Other outcomes included bleeding and its severity, death, myocardial infarction (MI), disability, mood, cognition and quality of life. The trial was stopped early on the recommendation of the Data Monitoring Committee after recruitment of 3096 participants (intensive, n = 1556; guideline, n = 1540) from 106 hospitals in four countries between April 2009 and March 2016. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy in 3070 (99.2%) participants with data [93 vs. 105 stroke/TIA events; adjusted common odds ratio 0.90, 95% confidence interval (CI) 0.67 to 1.20; p = 0.47]. Major (encompassing fatal) bleeding was increased with intensive as compared with guideline therapy [39 vs. 17 participants; adjusted hazard ratio (aHR) 2.23, 95% CI 1.25 to 3.96; p = 0.006]. There were no differences between the treatment groups in all-cause mortality, or the composite of death, stroke, MI and major bleeding (aHR 1.02, 95% CI 0.77 to 1.35; p = 0.88). Patients and investigators were not blinded to treatment. The comparator group comprised two guideline strategies because of changes in national guidelines during the trial. The trial was stopped early, thereby reducing its statistical power. The use of three antiplatelet agents is associated with increased bleeding without any significant reduction in recurrence of stroke or TIA. The safety and efficacy of dual antiplatelet therapy (combined aspirin and clopidogrel) versus aspirin remains to be defined. Further research is required on identifying individual patient response to antiplatelets, and the relationship between response and the subsequent risks of vascular recurrent events and bleeding complications. Current Controlled Trials ISRCTN47823388. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 48. See the NIHR Journal Library website for further project information. The Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) vanguard phase was funded by the British Heart Foundation (grant PG/08/083/25779, from 1 April 2009 to 30 September 2012) and indirect funding was provided by the Stroke Association through its funding of the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK. There was no commercial support for the trial and antiplatelet drugs were sourced locally at each site. The trial was sponsored by the University of Nottingham.

Therapeutic-Induced Hypertension in Patients with Non-Cardioembolic Acute Stroke: A Multicentre, Randomised Controlled Trial

Background: In this multicentre, randomised controlled trial, we evaluated the safety and efficacy of induced hypertension in patients with acute ischaemic stroke. Methods: Patients with acute non-cardioembolic ischaemic stroke within 24 hours of onset who were ineligible for revascularisation therapy and those with progressive stroke during hospitalization were randomly assigned (1:1) to the control and intervention groups. In the intervention group, phenylephrine was intravenously administered to increase systolic blood pressure (SBP) up to 200 mmHg. The primary efficacy endpoint was early neurological improvement (reduction in NIHSS score ≥ 2 points during the first 7 days). The secondary efficacy endpoint was a modified Rankin scale score of 0-2 at 90 days. Safety outcomes included symptomatic intracranial haemorrhage/oedema, myocardial infarction, and death. Findings: Totals of 76 and 77 patients were included in the intervention and control groups, respectively. Relative to the control group, patients in the intervention group were younger, exhibited higher baseline NIHSS values, and were more likely to experience progressive stroke and large vessel occlusion. Sixty-seven (88·2%) patients of the intervention group exhibited improvements in NIHSS scores ≥2 during induced hypertension (mean SBP: 179·7±19·1 mmHg). After adjusting for age and initial stroke severity, induced hypertension increased the occurrence of the primary (odds ratio: 2·49; 95% CI: 1·25-4·96; P=0·010) and secondary efficacy endpoints (odds ratio: 2·97; 95% CI: 1·32-6·68; P=0·009). The numbers needed to treat were 3·7 and 8·4 for the primary and secondary endpoints, respectively. Safety outcomes did not significantly differ between groups. Interpretation: Among patients with non-cardioembolic stroke who were ineligible for revascularisation therapy and those with progressive stroke, phenylephrine-induced hypertension was safe and resulted in early neurological improvement and long-term functional independence (class IB evidence). Clinical Trial Number: This trial is registered with ClinicalTrials.gov (NCT01600235). Funding: Samsung Medical Center and IlDong Pharma, Inc. Seoul, South Korea. Declaration of Interests: All authors declare no competing interests. Ethic Approval Statement: Patients from eight sites in South Korea were enrolled between June 2012 and December 2017. The trial was approved by the appropriate national regulatory authorities and relevant ethnics committee at each participating site. All participants provided written informed consent.

Retrospective Analysis of Argatroban in 353 Patients with Acute Noncardioembolic Stroke

Argatroban is a thrombin inhibitor agent for acute noncardioembolic ischemic stroke in Japan. We studied the prognosis in patients with acute stroke treated by argatroban in comparison with the control group with ozagrel in our hospital. A total of 513 patients with acute noncardioembolic ischemic stroke were enrolled retrospectively from our hospital database. Of all patients with stroke, 353 were administered with argatroban. The other 160 control patients were administered with ozagrel. The patients were examined as to their stroke types, the neurological severity according to the National Institutes of Health Stroke Scale (NIHSS), and clinical outcomes on discharge were determined according to the modified Rankin Scale (mRS). A total of 353 patients with acute noncardioembolic stroke, including 138 with lacunar infarction (LIs) and 215 with atherothrombotic infarction (ATI) showed functional recovery by argatroban, but the effectiveness of argatroban was not superior to ozagrel therapy defined by the control group. A total of 255 patients with ATI who were treated with both argatroban and ozagrel showed improvement by 1 point. We could not find any significant difference between argatroban and ozagrel in the 2 stroke subtypes, LI and ATI. We also found that combination therapy of argatroban and edaravone was not superior to argatroban monotherapy in clinical outcome. Argatroban therapy was not superior to control with ozagrel therapy in acute noncardioembolic ischemic stroke, including LI and ATI, regardless of the use of edaravone.

Abstract 91: Moyamoya Disease Susceptibility Gene, RNF213 p.R4810K Variant, is a Common Risk Factor for Atherothrombotic Brain Infarction in a Japanese Population

Background and Purpose: RNF213 has been identified as a susceptibility gene for moyamoya disease. The p.R4810K variant is found in about 80% of East Asian patients with moyamoya disease, and 20 - 25% of those with proximal intracranial arterial stenosis. In this study, we examined the association of RNF213 p.R4810K variant with non-cardioembolic stroke in a Japanese population. Methods: We analyzed 383 consecutive patients with acute non-cardioembolic stroke, who were admitted to the National Cerebral and Cardiovascular Center from June 2012 to May 2017 and participated in NCVC Biobank, and 1011 healthy local Japanese controls. Patients diagnosed with moyamoya disease were excluded. Written informed consent was obtained from all study participants. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age, sex, and conventional risk factors for stroke. Results: The RNF213 p.R4810K variant was found in 5.2% of acute non-cardioembolic stroke patients and in 2.1% of healthy controls (adjusted OR 3.9, 95% CI 1.6 - 9.3, p=0.003). The mean age of stroke onset was lower in patients with the RNF213 p.R4810K variant than those without the variant (58.1±15.5 years vs. 69.1±13.2 years, p&lt;0.001). Among stroke subtypes, only atherothrombotic brain infarction (ATBI) was significantly associated with this variant (adjusted OR 11.5, 95% CI 3.4 - 36.2, p&lt;0.001, see also Table 1). When stratified by sex, these associations were more evident in women (Men: adjusted OR for ATBI 1.9, 95% CI 0.3 - 10.2, p=0.47; Women: adjusted OR for ATBI 58.0, 95% CI 10.3 - 327.3, p&lt;0.001, see also Table 1). Conclusion: The RNF213 p.R4810K variant is a genetic risk factor for non-cardioembolic stroke in Japan, especially for atherothrombotic brain infarction in women.