Magnetic Resonance Imaging-Guided Intravenous Thrombolysis in Cardioembolic Stroke Patients With Unknown Time of Onset　- Subanalysis of the THAWS Randomized Control Trial.

BACKGROUND: We investigated the clinical effect of intravenous thrombolysis using a magnetic resonance imaging (MRI)-guided approach in cardioembolic stroke (CE) patients with unknown time of onset.Methods and Results: This subanalysis of the THAWS trial assessed the efficacy and safety of alteplase 0.6 mg/kg in CE patients with unknown time of onset and showing diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch. Patients were classified as CE and non-CE using the SSS-TOAST classification system during the acute period. The efficacy outcome was a modified Rankin Scale score of 0-1 at 90 days. In all, 126 patients from the THAWS trial were included in this study, of whom 45 (35.7%) were diagnosed with CE. In the CE group, a favorable outcome was numerically more frequent in the alteplase than control group (52% vs. 35%; adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 0.50-9.99). However, in the non-CE group, favorable outcomes were comparable between the alteplase and control groups (44% vs. 55%, respectively; aOR 0.39; 95% CI 0.12-1.21). Treatment-by-cohort interaction for a favorable outcome was modestly significant between the CE and non-CE groups (P=0.069). In the CE group, no patients experienced symptomatic intracranial hemorrhage (ICH) or parenchymal hematoma Type II following thrombolysis. CONCLUSIONS: When an MRI-guided approach is used, CE patients with unknown time of onset appear to be suitable candidates for thrombolysis.

Efficacy and Safety of Edoxaban in Anticoagulant Therapy Early After Surgical Bioprosthetic Valve Replacement: Rationale and Design of the ENBALV Trial.

BACKGROUND AND PURPOSE: Anticoagulant therapy with vitamin K antagonists is recommended within 3 to 6 months after bioprosthetic valve replacement to prevent thromboembolic events. However, data regarding whether direct oral anticoagulants can be an alternative to warfarin in such patients are limited. The purpose of this study is to compare the efficacy and safety of edoxaban versus warfarin within 3 months after bioprosthetic valve replacement. METHODS: The ENBALV trial is an investigator-initiated, phase 3, randomized, open-label, multicenter study. It involves patients aged 18 to 85 years undergoing bioprosthetic valve replacement at the aortic and/or mitral position. They are randomized 1:1 to receive either edoxaban or warfarin. Administration of edoxaban or warfarin is to be continued for 12 weeks after surgery. The primary outcome is the occurrence rate of stroke or systemic embolism at 12 weeks after surgery. The net clinical outcome is a composite of stroke, systemic embolism, or major bleeding, which is included in the secondary outcomes. CONCLUSION: The ENBALV trial demonstrates the efficacy and safety of edoxaban compared with warfarin in patients early after bioprosthetic valve replacement, including patients with sinus rhythm, which will bring a significant benefit to patients in clinical practice. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) 2051210209. 30 Mar 2022 https://jrct.niph.go.jp/latest-detail/jRCT2051210209 .

Temporal Trajectory of Systolic Blood Pressure and Outcomes in Acute Intracerebral Hemorrhage: ATACH-2 Trial Cohort.

BACKGROUND: To highlight the heterogeneity of acute temporal blood pressure (BP) changes in the ATACH-2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) and associations with the outcomes of intracerebral hemorrhage. METHODS: One thousand patients with acute intracerebral hemorrhage, who had been randomized to intensive (110-139 mm Hg) or standard (140-179 mm Hg) systolic BP (SBP) lowering with intravenous nicardipine in ATACH-2 from 2011 to 2015, were analyzed about temporal changes in hourly maximum SBP up to 24 hours after randomization using group-based trajectory modeling. Outcomes included death or disability (modified Rankin Scale score 4-6) at 3 months, neurological deterioration within 24 hours (≥2-point decrease in Glasgow Coma Scale score or ≥4-point increase in National Institutes of Health Stroke Scale score), and acute kidney injury (≥0.3 mg/dL within 48 hours or ≥1.5-fold increase in serum creatinine) within 7 days after onset. RESULTS: Group-based trajectory modeling revealed 4 SBP trajectory groups: moderate SBP (from ≈190 mm Hg at hospital arrival to 150-160 mm Hg after randomization; n=298), moderate-to-low SBP (from ≈190 mm Hg to <140 mm Hg; n=395), high-to-low SBP (from >210 mm Hg to <140 mm Hg; n=134), and high SBP (from >210 mm Hg to 160-170 mm Hg; n=173). Patients with intensive treatment accounted for 11.1%, 88.6%, 85.1%, and 1.7% of each group, respectively. Compared with the moderate-to-low SBP group, the high-to-low SBP group showed increased risks of death or disability at 3 months (adjusted odds ratio, 2.29 [95% CI, 1.24-4.26]) and acute kidney injury (adjusted odds ratio, 3.50 [95% CI, 1.83-6.69]), while no increase in neurological deterioration was seen in this group (adjusted odds ratio, 0.48 [95% CI, 0.20-1.13]). The moderate SBP and high SBP groups showed no significant risk differences for such outcomes. CONCLUSIONS: Data-driven observation using a group-based trajectory modeling approach may be useful to clarify the relationship between antihypertensive treatment, temporal SBP changes, and outcomes in acute intracerebral hemorrhage. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01176565.

Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage.

BACKGROUND: We evaluated the effect of persistent hyperglycemia on outcomes in 1000 patients with intracerebral hemorrhage enrolled within 4.5 hours of symptom onset. METHODS: We defined moderate and severe hyperglycemia based on serum glucose levels ≥140 mg/dL-<180 and ≥180 mg/dL, respectively, measured at baseline, 24, 48, and 72 hours. Persistent hyperglycemia was defined by 2 consecutive (24 hours apart) serum glucose levels. We evaluated the relationship between moderate and severe hyperglycemia and death or disability (defined by modified Rankin Scale score of 4-6) at 90 days in the overall cohort and in groups defined by preexisting diabetes. RESULTS: In the multivariate analysis, both moderate (odds ratio, 1.8 [95% CI, 1.1-2.8]) and severe (odds ratio, 1.8 [95% CI, 1.2-2.7]) hyperglycemia were associated with higher 90-day death or disability after adjusting for Glasgow Coma Scale score, hematoma volume, presence or absence of intraventricular hemorrhage, hyperlipidemia, cigarette smoking, and hypertension (no interaction between hyperglycemia and preexisting diabetes, P=0.996). Among the patients without preexisting diabetes, both moderate (odds ratio, 1.8 [95% CI, 1.0-3.2]) and severe (odds ratio, 2.0 [95% CI, 1.1-3.7]) hyperglycemia were associated with 90-day death or disability after adjusting for above mentioned potential confounders. Among the patients with preexisting diabetes, moderate and severe hyperglycemia were not associated with 90-day death or disability. CONCLUSIONS: Persistent hyperglycemia, either moderate or severe, increased the risk of death or disability in nondiabetic patients with intracerebral hemorrhage. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01176565.

Early Hyperchloremia is Independently Associated with Death or Disability in Patients with Intracerebral Hemorrhage.

BACKGROUND: On the basis of increased mortality associated with hyperchloremia among critically ill patients, we investigated the effect of occurrence of early hyperchloremia on death or disability at 90 days in patients with intracerebral hemorrhage (ICH). METHODS: We analyzed the data from Antihypertensive Treatment of Cerebral Hemorrhage 2 trial, which recruited patients with spontaneous ICH within 4.5 h of symptom onset. Patients with increased serum chloride levels (110 mmol/L or greater) at either baseline or 24, 48, or 72 h after randomization were identified. We further graded hyperchloremia into one occurrence or two or more occurrences within the first 72 h. Two logistic regression analyses were performed to determine the effects of hyperchloremia on (1) death within 90 days and (2) death or disability at 90 days after adjustment for potential confounders. RESULTS: Among the total of 1,000 patients analyzed, hyperchloremia within 72 h was seen in 114 patients with one occurrence and in 154 patients with two or more occurrences. Patients with one occurrence of hyperchloremia (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-5.5) and those with two or more occurrences (OR 2.6, 95% CI 1.3-5.0) had significantly higher odds of death within 90 days after adjustment for age, race and ethnicity, National Institutes of Health Stroke Scale score strata, hematoma volume, presence or absence of intraventricular hemorrhage, cigarette smoking, previous stroke, and maximum hourly dose of nicardipine. Patients with two or more occurrences of hyperchloremia (OR 3.4, 95% CI 2.1-5.6) had significantly higher odds of death or disability at 90 days compared with patients without hyperchloremia after adjustment for the abovementioned potential confounders. CONCLUSIONS: The independent association between hyperchloremia and death or disability at 90 days suggests that avoidance of hyperchloremia may reduce the observed death or disability in patients with ICH. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01176565.

Magnetic Resonance Imaging-Guided Thrombolysis (0.6 mg/kg) Was Beneficial for Unknown Onset Stroke Above a Certain Core Size: THAWS RCT Substudy.

BACKGROUND AND PURPOSE: We determined to identify patients with unknown onset stroke who could have favorable 90-day outcomes after low-dose thrombolysis from the THAWS (Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg) database. METHODS: This was a subanalysis of an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients with stroke with a time last-known-well >4.5 hours who showed a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg intravenously or standard medical treatment. The patients were dichotomized by ischemic core size or National Institutes of Health Stroke Scale score, and the effects of assigned treatments were compared in each group. The efficacy outcome was favorable outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. RESULTS: The median DWI-Alberta Stroke Program Early CT Score (ASPECTS) was 9, and the median ischemic core volume was 2.5 mL. Both favorable outcome (47.1% versus 48.3%) and any intracranial hemorrhage (26% versus 14%) at 22 to 36 hours were comparable between the 68 thrombolyzed patients and the 58 control patients. There was a significant treatment-by-cohort interaction for favorable outcome between dichotomized patients by ASPECTS on DWI (P=0.026) and core volume (P=0.035). Favorable outcome was more common in the alteplase group than in the control group in patients with DWI-ASPECTS 5 to 8 (RR, 4.75 [95% CI, 1.33-30.2]), although not in patients with DWI-ASPECTS 9 to 10. Favorable outcome tended to be more common in the alteplase group than in the control group in patients with core volume >6.4 mL (RR, 6.15 [95% CI, 0.87-43.64]), although not in patients with volume ≤6.4 mL. The frequency of any intracranial hemorrhage did not differ significantly between the 2 treatment groups in any dichotomized patients. CONCLUSIONS: Patients developing unknown onset stroke with DWI-ASPECTS 5 to 8 showed favorable outcomes more commonly after low-dose thrombolysis than after standard treatment. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02002325. URL: https://www.umin.ac.jp/ctr; Unique Identifier: UMIN000011630.

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Combined evaluation of plasma B-type natriuretic peptide and urinary liver-type fatty acid-binding protein/creatinine ratio is related to worsening renal function in patients undergoing elective percutaneous coronary intervention.

BACKGROUND: There are few reports on the significance for the combined evaluation of blood humoral factors and urinary biomarkers in terms of worsening renal function (WRF) after coronary angiography (CAG)/percutaneous coronary arterial intervention (PCI). METHOD AND RESULTS: Urinary liver type-fatty acid-binding protein (L-FABP), neutrophil gelatinase associated lipocalin (NGAL), and adrenomedullin (AM) were measured less than 24 h before and 3 h, 6 h, 1 day, and 2 days after CAG/PCI. WRF was defined as a > 20% decrease in the estimated GFR. WRF occurred in seven of 100 patients and the increase in L-FABP/creatinine (Cr) at 1 day after CAG/PCI was significantly higher in the WRF group than in the non-WRF group. Plasma B-type natriuretic peptide (BNP) before CAG/PCI and L-FABP/Cr at 1 day after CAG/PCI were independent predictors for WRF. The areas under the receiver-operating characteristic curves were as follows: 0.760 for BNP before CAG/PCI, 0.731 for L-FABP/Cr at 1 day after CAG/PCI, and 0.892 for BNP and L-FABP/Cr. Urinary AM levels after PCI/CAG were negatively correlated only to serum potassium levels. Gene expressions of AM and AM-receptor were detectable in renal tubule epithelial cells. AM increased intracellular second messenger levels in a dose-dependent manner. CONCLUSIONS: Our results suggest that combined evaluation of plasma BNP and urinary L-FABP/Cr is useful as a predictor of renal dysfunction in CAG/PCI patients.

Study Protocol for a Randomized, Double-Blind, Placebo-Controlled, Phase-II Trial: AdrenoMedullin for Ischemic Stroke Study.

OBJECTIVES: Adrenomedullin (AM), a vasoactive peptide, has strong anti-inflammatory and angiogenic properties, which have been reported to ameliorate the consequences of ischemic stroke in several animal models. After a phase I study in healthy volunteers, two phase II trials of AM for inflammatory bowel diseases have been recently completed. The current AdrenoMedullin For Ischemic Stroke (AMFIS) study aims to assess the safety and efficacy of AM in patients with acute ischemic stroke. MATERIALS AND METHODS: The AMFIS study is an investigator-initiated, randomized, double-blind, phase-II trial. AM or placebo will be administered to patients with non-cardioembolic ischemic stroke within 24 h after stroke onset. In the first cohort of the AMFIS study, patients will be randomly allocated to the investigation treatment A (30 µg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). In the second cohort, patients will be assigned to the investigation treatment B (56 µg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). RESULTS: Serious adverse events related to the protocol treatment will be evaluated as the primary outcome. All adverse events will be analyzed as the secondary outcome. Regarding efficacy endpoints, the change in National Institutes of Health Stroke Scale and modified Rankin Scale scores will be compared between investigation treatment and placebo groups. CONCLUSIONS: AM is expected to be a safe and effective treatment for ischemic stroke.

Systolic Blood Pressure Reduction and Acute Kidney Injury in Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: We determined the rates and predictors of acute kidney injury (AKI) and renal adverse events (AEs), and effects of AKI and renal AEs on death or disability in patients with intracerebral hemorrhage. METHODS: We analyzed data from a multicenter trial which randomized 1000 intracerebral hemorrhage patients with initial systolic blood pressure ≥180 mm Hg to intensive (goal 110-139 mm Hg) over standard (goal 140-179 mm Hg) systolic blood pressure reduction within 4.5 hours of symptom onset. AKI was identified by serial assessment of daily serum creatinine for 3 days post randomization. RESULTS: AKI and renal AEs were observed in 149 patients (14.9%) and 65 patients (6.5%) among 1000 patients, respectively. In multivariate analysis, the higher baseline serum creatinine (≥110 µmol/L) was associated with AKI (odds ratio 2.4 [95% CI, 1.2-4.5]) and renal AEs (odds ratio 3.1 [95% CI, 1.2-8.1]). Higher area under the curve for intravenous nicardipine dose was associated with AKI (odds ratio 1.003 [95% CI, 1.001-1.005]) and renal AEs (odds ratio 1.003 [95% CI, 1.001-1.006]). There was a higher risk to death (relative risk 2.6 [95% CI, 1.6-4.2]) and death or disability (relative risk 1.5 [95% CI, 1.3-1.8]) at 90 days in patients with AKI but not in those with renal AEs. CONCLUSIONS: Intracerebral hemorrhage patients with higher baseline serum creatinine and those receiving higher doses of nicardipine were at higher risk for AKI and renal AEs. Occurrence of AKI was associated higher rates of death or disability at 3 months. Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT01176565.

Sex Differences in Blood Pressure-Lowering Therapy and Outcomes Following Intracerebral Hemorrhage: Results From ATACH-2.

BACKGROUND AND PURPOSE: Evidence regarding sex differences in clinical outcomes and treatment effect following intracerebral hemorrhage is limited. Using the ATACH-2 trial (Antihypertensive Treatment in Intracerebral Hemorrhage-2) data, we explored whether sex disparities exist in outcomes and response to intensive blood pressure (BP)-lowering therapy. METHODS: Eligible intracerebral hemorrhage subjects were randomly assigned to intensive (target systolic BP, 110-139 mm Hg) or standard (140-179 mm Hg) BP-lowering therapy within 4.5 hours after onset. Relative risk of death or disability corresponding to the modified Rankin Scale score of 4 to 6 was calculated, and interaction between sex and treatment was explored. RESULTS: In total, 380 women and 620 men were included. Women were older, more prescribed antihypertensive drugs before onset, and had more lobar intracerebral hemorrhage than men. Hematoma expansion was observed less in women. After multivariable adjustment, the relative risk of death or disability in women was 1.19 (95% CI, 1.02-1.37, P=0.023). The relative risk of death or disability between intensive versus standard BP-lowering therapy was 0.91 (95% CI, 0.74-1.13) in women versus 1.13 (95% CI, 0.92-1.39) in men (P for interaction=0.11), with inconclusive Gail-Simmon test (P=0.16). CONCLUSIONS: Women had a higher risk of death or disability following intracerebral hemorrhage. The benefit of intensive BP-lowering therapy in women is inconclusive, consistent with the overall results of ATACH-2. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01176565.

Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset: A Randomized Controlled Trial.

Background and Purpose- We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods- This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Results- Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68-1.41]; P=0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P>0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06-12.58]; P>0.999), respectively. Conclusions- No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02002325.

Clinical Outcomes Depending on Acute Blood Pressure After Cerebral Hemorrhage.

OBJECTIVE: To determine the association between clinical outcomes and acute systolic blood pressure (SBP) levels achieved after intracerebral hemorrhage (ICH). METHODS: Eligible patients who were randomized to the ATACH-2 (Antihypertensive Treatment in Intracerebral Hemorrhage 2) trial (ClinicalTrials.gov: NCT01176565) were divided into 5 groups by 10-mmHg strata of average hourly minimum SBP (<120, 120-130, 130-140, 140-150, and ≥ 150 mmHg) during 2 to 24 hours after randomization. Outcomes included: 90-day modified Rankin Scale (mRS) 4 to 6; hematoma expansion, defined as an increase ≥6 ml from baseline to 24-hour computed tomography; and cardiorenal adverse events within 7 days. RESULTS: Of the 1,000 subjects in ATACH-2, 995 with available SBP data were included in the analyses. The proportion of mRS 4 to 6 was 37.5, 36.0, 42.8, 38.6, and 38.0%, respectively. For the "140 to 150" group relative to the "120 to 130," the odds ratio (OR), adjusting for sex, race, age, onset-to-randomization time, baseline National Institutes of Health Stroke Scale score, hematoma volume, and hematoma location, was 1.62 (95% confidence interval [CI], 1.02-2.58). Hematoma expansion was identified in 16.9, 13.7, 21.4, 18.5, and 26.4%, respectively. The 140 to 150 (OR, 1.80; 95% CI, 1.05-3.09) and "≥150" (1.98; 1.12-3.51) showed a higher frequency of expansion than the 120 to 130 group. Cardiorenal events occurred in 13.6, 16.6, 11.5, 8.1, and 8.2%, respectively. The 140 to 150 (0.43; 0.19-0.88) and ≥ 150 (0.44; 0.18-0.96) showed a lower frequency of the events than the 120 to 130. INTERPRETATION: Beneficial effects of lowering and maintaining SBP at 120 to 130 mmHg during the first 24 hours on clinical outcomes by suppressing hematoma expansion was somewhat offset by cardiorenal complications. ANN NEUROL 2019;85:105-113.

Late Neurological Deterioration after Acute Intracerebral Hemorrhage: A post hoc Analysis of the ATACH-2 Trial.

BACKGROUND: Neurological deterioration (ND) has a major influence on the prognosis of intracerebral hemorrhage (ICH); however, factors associated with ND occurring after 24 h of ICH onset are unknown. METHODS: We performed exploratory analyses of data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial, which compared intensive and standard blood pressure lowering treatment in ICH. NDs were captured on the adverse event case report form. Logistic regression analysis was performed to examine the independent predictors of late ND. RESULTS: Among 1,000 participants with acute ICH, 82 patients (8.2%) developed early ND (≤24 h), and 64 (6.4%) had late ND. Baseline hematoma volume (adjusted OR [aOR] per 1-cm3 increase 1.04, 95% CI 1.02-1.06, p < 0.0001), hematoma volume increase in 24 h (aOR 2.24, 95% CI 1.23-4.07, p = 0.008), and the presence of intraventricular hemorrhage (IVH; aOR 2.38, 95% CI 1.32-4.29, p = 0.004) were independent predictors of late ND (vs. no late ND). Late ND was a significant risk factor for poor 90-day outcome (OR 3.46, 95% CI 1.82-6.56). No statistically significant difference in the incidence of late ND was noted between the 2 treatment groups. CONCLUSIONS: Initial hematoma volume, early hematoma volume expansion, and IVH are independent predictors of late ND after ICH. Intensive reduction in the systolic blood pressure level does not prevent the development of late ND.

A Novel Extracorporeal Continuous-Flow Ventricular Assist System for Patients With Advanced Heart Failure　- Initial Clinical Experience.

BACKGROUND: Bridge-to-decision (BTD) devices providing temporary mechanical circulatory support should be introduced to patients with advanced heart failure. This study evaluated the effectiveness and safety of a BTD device comprising an innovative extracorporeal continuous-flow temporary ventricular assist device (VAD) driven by a novel hydrodynamically levitated centrifugal flow blood pump.Methods and Results:Nine patients, comprising 3 with dilated cardiomyopathy, 3 with fulminant myocarditis, and 3 with ischemic heart disease, and 6 males, whose mean age was 47.7±8.1 years, were enrolled into the study. Six patients had Interagency Registry for Mechanically Assisted Circulatory Support profile 1, and 3 were profile 2. The primary endpoint was a composite of survival free from device-related serious adverse events and complications during circulatory support. Eight patients received left ventricular support, of whom 3 received concomitant right ventricular support using extracorporeal membrane oxygenation circuits, as a consequence of severe respiratory failure. One patient with fulminant myocarditis received biventricular support using the novel VAD system. After 19.0±13.5 days, 3 patients were weaned from circulatory support, because their native cardiac function recovered, and 6 patients required conversion to a durable device as a bridge-to-transplantation. One patient had non-disabling ischemic stroke episodes, and no patients died. CONCLUSIONS: This novel extracorporeal VAD system with a hydrodynamically levitated centrifugal pump can safely and successfully bridge patients with advanced heart failure to subsequent therapeutic stages.

"BAX602" in Preventing Surgical Adhesion after Extracorporeal Ventricular Assist Device Implantation for Refractory Congestive Heart Failure: Study Protocol for a Multicenter Randomized Clinical Trial.

BACKGROUND: The high surgical risk in redo cardiac surgery is largely attributed to adhesions around the epicardium and the great vessels. BAX602 is an adhesion prevention reagent composed of two synthetic polyethylene glycols. Spraying BAX602 over the epicardium and the great vessels reportedly contributes to adhesion prevention after pediatric cardiac surgery. The present study aims to evaluate the safety and effectiveness of BAX602 spray in patients undergoing extracorporeal ventricular assist device implantation surgery to treat refractory congestive heart failure. METHODS AND DESIGN: This investigator-initiated, multicenter, pivotal, two-arm, open-label, randomized trial will include a total of 30 patients. The primary outcome measure is the severity of adhesions, which will be evaluated during re-sternotomy surgery performed 2-12 weeks after the primary extracorporeal ventricular assist device implantation surgery. The adhesion severity will be evaluated at five predefined sites using a four-grade adhesion evaluation score (0 = no adhesion; 1 = filmy and avascular adhesion; 2 = dense/vascular adhesion; 3 = cohesive adhesion). This measure will be summarized in two ways to evaluate the effect of BAX602: (1) the total score of the severity of adhesions at all five sites (ranging from 0 to 15), and (2) the total number of sites with dense/vascular or cohesive adhesions (ranging from 0 to 5). ETHICS AND DISSEMINATION: The study findings will be disseminated at regional, national, and international conferences and through peer-reviewed scientific journals. TRIAL REGISTRATION: The trial was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000038998) on 6 January 2020.

Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage.

BACKGROUND: Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage. METHODS: We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments. RESULTS: Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, P=0.002). CONCLUSIONS: The treatment of participants with intracerebral hemorrhage to achieve a target systolic blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg. (Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center; ATACH-2 ClinicalTrials.gov number, NCT01176565 .).

Association of CYP2C19 Polymorphisms With Clopidogrel Reactivity and Clinical Outcomes in Chronic Ischemic Stroke.

BACKGROUND: CYP2C19variants are associated with the antiplatelet effects of clopidogrel against recurrent cardiovascular events. However, it remains unknown whether the elapsed time from stroke onset affects the relationship between the genetic variants and such events. To address this, we conducted a prospective cohort study to determine the effect ofCYP2C19variants on clinical outcomes in the chronic phase.Methods and Results:In total, 518 Japanese non-acute stroke patients treated with clopidogrel were registered at 14 institutions. Patients were classified into 3 clopidogrel-metabolizing groups according toCYP2C19genotype: extensive metabolizer (EM:*1/*1), intermediate metabolizer (IM:*1/*2or*1/*3), and poor metabolizer (PM:*2/*2,*2/*3, or*3/*3). Antiplatelet effects of clopidogrel were assessed by adenosine diphosphate (ADP)-induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The endpoint was composite cerebrocardiovascular events (CVEs). In 501 successfully followed-up patients, the median time from index stroke to enrollment was 181 days. There were 28 cardiovascular and 2 major bleeding events. There were no significant differences in the rates of cardiovascular events among the groups. CONCLUSIONS: Despite associations betweenCYP2C19variants and on-clopidogrel platelet reactivity, there was no significant difference in rates of CVEs in the chronic stroke phase among the 3 clopidogrel-metabolizing groups ofCYP2C19variants.

Blood Pressure-Attained Analysis of ATACH 2 Trial.

BACKGROUND AND PURPOSE: We compared the rates of death or disability, defined by modified Rankin Scale score of 4 to 6, at 3 months in patients with intracerebral hemorrhage according to post-treatment systolic blood pressure (SBP)-attained status. METHODS: We divided 1000 subjects with SBP ≥180 mm Hg who were randomized within 4.5 hours of symptom onset as follows: SBP <140 mm Hg achieved or not achieved within 2 hours; subjects in whom SBP <140 mm Hg was achieved within 2 hours were further divided: SBP <140 mm Hg for 21 to 22 hours (reduced and maintained) or SBP was ≥140 mm Hg for at least 2 hours during the period between 2 and 24 hours (reduced but not maintained). RESULTS: Compared with subjects without reduction of SBP <140 mm Hg within 2 hours, subjects with reduction and maintenance of SBP <140 mm Hg within 2 hours had a similar rate of death or disability (relative risk of 0.98; 95% confidence interval, 0.74-1.29). The rates of neurological deterioration within 24 hours were significantly higher in reduced and maintained group (10.4%; relative risk, 1.98; 95% confidence interval, 1.08-3.62) and in reduced but not maintained group (11.5%; relative risk, 2.08; 95% confidence interval, 1.15-3.75) compared with reference group. The rates of cardiac-related adverse events within 7 days were higher among subjects with reduction and maintenance of SBP <140 mmHg compared to subjects without reduction (11.2% versus 6.4%). CONCLUSIONS: No decline in death or disability but higher rates of neurological deterioration and cardiac-related adverse events were observed among intracerebral hemorrhage subjects with reduction with and without maintenance of intensive SBP goals. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01176565.

Assessment of Safety and Effectiveness of the Extracorporeal Continuous-Flow Ventricular Assist Device (BR16010) Use as a Bridge-to-Decision Therapy for Severe Heart Failure or Refractory Cardiogenic Shock: Study Protocol for Single-Arm Non-randomized, Uncontrolled, and Investigator-Initiated Clinical Trial.

BACKGROUND: The management of heart failure patients presenting in a moribund state remains challenging, despite significant advances in the field of ventricular assist systems. Bridge to decision involves using temporary devices to stabilize the hemodynamic state of such patients while further assessment is performed and a decision can be made regarding patient management. The purpose of this study (NCVC-BTD_01, National Cerebral and Cardiovascular Center-Bridge to Dicision_01) is to assess the safety and effectiveness of the newly developed extracorporeal continuous-flow ventricular assist system employing a disposable centrifugal pump with a hydrodynamically levitated bearing (BR16010) use as a bridge-to-decision therapy for patients with severe heart failure or refractory cardiogenic shock. METHOD/DESIGN: NCVC-BTD_01 is a single-center, single-arm, open-label, exploratory, medical device, investigator-initiated clinical study. It is conducted at the National Cerebral and Cardiovascular Center in Japan. A total of nine patients will be enrolled in the study. The study was planned using Simon's minimax two-stage phase design. The primary endpoint is a composite of survival free of device-related serious adverse events and complications during device support. For left ventricular assistance, withdrawal of a trial device due to cardiac function recovery or exchange to other ventricular assist devices (VADs) for the purpose of bridge to transplantation (BTT) during 30 days after implantation will be considered study successes. For right ventricular assistance, withdrawal of tal device due to right ventricular function recovery within 30 days after implantation will be considered a study success. Secondary objectives include changes in brain natriuretic peptide levels (7 days after implantation of a trial device and the day of withdrawal of a trial device), period of mechanical ventricular support, changes in left ventricular ejection fraction (7 days after implantation of a trial device and the day of withdrawal of a trial device), and changes in left ventricular diastolic dimension (7 days after implantation of a trial device and the day of withdrawal of a trial device). ETHICS AND DISSEMINATION: We will disseminate the findings through regional, national, and international conferences and through peer-reviewed journals. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR; R000033243) registered on 8 September 2017.