Takehiko Nagao

Dual Antithrombotic Therapy Increases Severe Bleeding Events in Patients With Stroke and Cardiovascular Disease A Prospective, Multicenter, Observational Study

Background and Purpose— We sought to determine the incidence and severity of bleeding events in patients with stroke and cardiovascular diseases who were taking oral antithrombotic agents in Japan, where the incidence of hemorrhagic stroke is higher than in Western countries. Methods— A prospective, multicenter, observational study was conducted; 4009 patients who were taking oral antithrombotic agents for stroke and cardiovascular diseases were enrolled. The patients were classified into 4 groups according to their antithrombotic treatment: the single antiplatelet agent group (47.2%); the dual antiplatelet agent group (8.7%); the warfarin group (32.4%); and the warfarin plus antiplatelet agent group (11.7%). The primary end point was life-threatening or major bleeding according to the MATCH trial definition. Results— During a median follow-up of 19 months, there were 57 life-threatening and 51 major bleeding events, including 31 intracranial hemorrhages. The annual incidence of the primary end point was 1.21% in the single antiplatelet agent group, 2.00% in the dual antiplatelet agent group, 2.06% in the warfarin group, and 3.56% in the warfarin plus antiplatelet agent group (P<0.001). After adjustment for baseline characteristics, adding an antiplatelet agent to warfarin increased the risk of the primary end point (relative risk=1.76; 95% CI, 1.05 to 2.95), and adding another antiplatelet agent to single antiplatelet agent therapy increased the secondary end point of any bleeding, including minor events (relative risk=1.37; 95% CI, 1.07 to 1.76). Conclusions— The incidence of bleeding events during antithrombotic therapy in Japan was similar to that reported for Western countries, although the trials used different study designs. Dual antithrombotic therapy was independently related to an increased risk of bleeding events.

Antithrombotic Therapy Influences Location, Enlargement, and Mortality from Intracerebral Hemorrhage

Background: To determine whether the use of oral antithrombotic agents before the onset of intracerebral hemorrhage (ICH) affects hematoma features and early patient outcome. Methods: A retrospective, multicenter study involving 1,006 consecutive Japanese patients (607 men, 67 ± 12 years of age) hospitalized within 24 h after the onset of nontraumatic ICH was conducted. Results: One hundred and eighty patients were taking oral antiplatelet agents (17.9%, AP group), 67 were taking warfarin (6.7%, W group), and 21 were taking both (2.1%, W + AP group). After adjustment for age, sex, and known confounders, the taking of each kind of antithrombotic therapy was independently related to cerebellar hemorrhage; the odds ratios (OR) and 95% CI, with patients taking no antithrombotic agents as the reference group, were 2.31 (1.23–4.32) for the AP group, 2.90 (1.26–6.63) for the W group, and 3.43 (1.02–11.59) for the W + AP group. Similarly, the taking of each kind of antithrombotic therapy was independently related to hematoma enlargement within the initial 24 h (OR and 95% CI: AP group, 1.92, 1.10–3.34; W group, 4.80, 2.12–10.87; W + AP group, 4.94, 1.31–18.61) and mortality at 3 weeks post-ICH (OR and 95% CI: AP group, 2.70, 1.56–4.68; W group, 2.50, 1.05–5.96; W + AP group, 9.41, 2.78–31.88). Conclusions: Prior medication with antiplatelet agents, warfarin, or both was predictive of cerebellar hemorrhage, hematoma enlargement, and early death in Japanese ICH patients.

Blood Pressure Levels and Bleeding Events During Antithrombotic Therapy: The Bleeding With Antithrombotic Therapy (BAT) Study

Background and Purpose— A prospective, multicenter, observational cohort study was conducted to clarify the association between major bleeding events and blood pressure (BP) levels during follow-up before development of bleeding events in antithrombotic users. Methods— A total of 4009 patients taking oral antithrombotic agents for cardiovascular or cerebrovascular diseases (2728 men, 69±10 years old) were followed. Changes in systolic and diastolic BPs between entry and the last clinic visit before intracranial hemorrhage (ICH) or extracranial hemorrhage were assessed. Results— Over a median follow-up of 19 months, ICH developed in 31 patients and extracranial hemorrhage developed in 77. Entry BP levels were similar among patients with ICH, those with extracranial hemorrhage, and those without hemorrhagic events. Both systolic BP and diastolic BP were relatively high during follow-up as compared with the levels at entry in patients with ICH, whereas they showed plateaus in patients with extracranial hemorrhage and patients without hemorrhagic events. Average systolic BP levels between 1 and 6 months (hazard ratio, 1.45; 95% CI, 1.08 to 1.92 per 10-mm Hg increase) and between 7 and 12 months (hazard ratio, 1.47; 95% CI, 1.05 to 2.01) as well as average diastolic BP levels between 7 and 12 months (hazard ratio, 2.05; 95% CI, 1.15 to 3.62) were independently associated with development of ICH after adjustment for established ICH predictors. The optimal cutoff BP level to predict impending risk of ICH was ≥130/81 mm Hg using receiver operating characteristic curve analysis. Conclusions— An increase in BP levels during antithrombotic medication was positively associated with development of ICH, suggesting the importance of adequate BP control for avoiding ICH. BP levels did not appear to be associated with extracranial hemorrhage.

Recanalization therapies in acute ischemic stroke patients: impact of prior treatment with novel oral anticoagulants on bleeding complications and outcome

Background— We explored the safety of intravenous thrombolysis (IVT) or intra-arterial treatment (IAT) in patients with ischemic stroke on non-vitamin K antagonist oral anticoagulants (NOACs, last intake <48 hours) in comparison with patients (1) taking vitamin K antagonists (VKAs) or (2) without previous anticoagulation (no-OAC). Methods and Results— This is a multicenter cohort pilot study. Primary outcome measures were (1) occurrence of intracranial hemorrhage (ICH) in 3 categories: any ICH (ICHany), symptomatic ICH according to the criteria of the European Cooperative Acute Stroke Study II (ECASS-II) (sICHECASS-II) and the National Institute of Neurological Disorders and Stroke (NINDS) thrombolysis trial (sICHNINDS); and (2) death (at 3 months). Cohorts were compared by using propensity score matching. Our NOAC cohort comprised 78 patients treated with IVT/IAT and the comparison groups of 441 VKA patients and 8938 no-OAC patients. The median time from last NOAC intake to IVT/IAT was 13 hours (interquartile range, 8–22 hours). In VKA patients, median pre-IVT/IAT international normalized ratio was 1.3 (interquartile range, 1.1–1.6). ICHany was observed in 18.4% NOAC patients versus 26.8% in VKA patients and 17.4% in no-OAC patients. sICHECASS-II and sICHNINDS occurred in 2.6%/3.9% NOAC patients, in comparison with 6.5%/9.3% of VKA patients and 5.0%/7.2% of no-OAC patients, respectively. At 3 months, 23.0% of NOAC patients in comparison with 26.9% of VKA patients and 13.9% of no-OAC patients had died. Propensity score matching revealed no statistically significant differences. Conclusions— IVT/IAT in selected patients with ischemic stroke under NOAC treatment has a safety profile similar to both IVT/IAT in patients on subtherapeutic VKA treatment or in those without previous anticoagulation. However, further prospective studies are needed, including the impact of specific coagulation tests.

Recanalization Therapies in Acute Ischemic Stroke Patients: Impact of Prior Treatment with Novel Oral Anticoagulants on Bleeding Complications and Outcome - A Pilot Study

Background— We explored the safety of intravenous thrombolysis (IVT) or intra-arterial treatment (IAT) in patients with ischemic stroke on non-vitamin K antagonist oral anticoagulants (NOACs, last intake <48 hours) in comparison with patients (1) taking vitamin K antagonists (VKAs) or (2) without previous anticoagulation (no-OAC). Methods and Results— This is a multicenter cohort pilot study. Primary outcome measures were (1) occurrence of intracranial hemorrhage (ICH) in 3 categories: any ICH (ICHany), symptomatic ICH according to the criteria of the European Cooperative Acute Stroke Study II (ECASS-II) (sICHECASS-II) and the National Institute of Neurological Disorders and Stroke (NINDS) thrombolysis trial (sICHNINDS); and (2) death (at 3 months). Cohorts were compared by using propensity score matching. Our NOAC cohort comprised 78 patients treated with IVT/IAT and the comparison groups of 441 VKA patients and 8938 no-OAC patients. The median time from last NOAC intake to IVT/IAT was 13 hours (interquartile range, 8–22 hours). In VKA patients, median pre-IVT/IAT international normalized ratio was 1.3 (interquartile range, 1.1–1.6). ICHany was observed in 18.4% NOAC patients versus 26.8% in VKA patients and 17.4% in no-OAC patients. sICHECASS-II and sICHNINDS occurred in 2.6%/3.9% NOAC patients, in comparison with 6.5%/9.3% of VKA patients and 5.0%/7.2% of no-OAC patients, respectively. At 3 months, 23.0% of NOAC patients in comparison with 26.9% of VKA patients and 13.9% of no-OAC patients had died. Propensity score matching revealed no statistically significant differences. Conclusions— IVT/IAT in selected patients with ischemic stroke under NOAC treatment has a safety profile similar to both IVT/IAT in patients on subtherapeutic VKA treatment or in those without previous anticoagulation. However, further prospective studies are needed, including the impact of specific coagulation tests.

Persistence of non-vitamin K antagonist oral anticoagulant use in Japanese patients with atrial fibrillation: A single-center observational study

Non‐vitamin K antagonist oral anticoagulants (NOACs) show a favorable balance between efficacy and safety compared with warfarin for patients with non‐valvular atrial fibrillation (NVAF). In “real‐world” practice, however, NOAC adherence and persistence among patients are not clear. The aim of this study is to evaluate NOAC and warfarin persistence in Japanese patients with NVAF who newly started these drugs.

Transient neurological attack before vertebrobasilar stroke

BACKGROUND Patients with vertebrobasilar (VB) circulation ischemia can present with nonspecific symptoms, which complicate the distinction of transient ischemic attack (TIA) from other benign disorders. According to previously accepted classifications, typical TIA does not occur with VB symptom such as vertigo, diplopia, or dysarthria in isolation. However, there is a lack of evidence to support this hypothesis. METHODS This hospital-based study included 214 consecutive patients with acute ischemic VB stroke. We defined transient neurological attacks (TNAs) as temporary (<24h) episodes with neurological symptoms, and further divided them into TIA, nonspecific TNA, or other specific disorder groups. We investigated the incidence and clinical symptoms of TNAs within 3months prior to the stroke episode, and comparisons were made between patients with and without previous TNA history with respect to their background and stroke profiles. RESULTS Among 214 patients with VB stroke, 56 (26.2%) had previous TNAs. Six of them were diagnosed with other specific disorders and excluded from the analysis. The remaining 33 and 17 were diagnosed with TIA and nonspecific TNA, respectively. Twenty-one (42.0%) had attacks with a nonfocal symptom in isolation, and acute infarction in neuroimaging was confirmed in 4 of these patients. Vertigo was the most frequent nonspecific TNA symptom. Patients with prior TNA had a significantly higher rate of atherothrombotic stroke than those without TNA (40.0% vs. 21.5%, P=0.009). CONCLUSIONS A considerable fraction of TIAs due to VB circulation ischemia may be overlooked among clinically nonfocal TNAs.

Prolonged QTc Interval Predicts Poststroke Paroxysmal Atrial Fibrillation

Background and Purpose— Paroxysmal atrial fibrillation (PAF) is often difficult to detect in patients with acute ischemic stroke. We aimed to assess the predictive value of a prolonged QT interval corrected for heart rate (QTc) in PAF detection after acute ischemic stroke. Methods— We enrolled 972 patients with acute ischemic stroke consecutively extracted from our observational stroke registry system. Exclusion criteria were as follows: (1) AF on the initial 12-lead ECG (n=171); (2) previously diagnosed PAF (n=47); and (3) the use of a cardiac pacemaker (n=10). Of the 972 patients, 744 (mean age, 67.6 years; men, 62.6%) were eligible for analysis. The clinical characteristics and 12-lead ECG findings of the patients with and without PAF were compared, and multiple logistic regression analysis was performed to identify predictors of poststroke PAF. Results— The poststroke cardiac work-up yielded 69 (9.3%) de novo PAF cases among the 744 patients. The QTc interval was significantly longer in patients with PAF than in those without PAF (436 versus 417 ms; P<0.001). Each 10-ms increase in the QTc interval was associated with an increased risk of PAF after multivariate adjustments (odds ratio, 1.41; 95% confidence interval, 1.24–1.61; P<0.001). The optimal threshold value of QTc interval calculated by a receiver-operating characteristic curve was 438 ms, and the area under the curve was 0.73 in this data set. Conclusions— The QTc interval prolongation is potentially a strong and useful predictor for poststroke PAF.

Examination timing and lesion patterns in diffusion-weighted magnetic resonance imaging of patients with classically defined transient ischemic attack.

BACKGROUND This study investigated factors associated with the presence of acute ischemic lesions after transient ischemic attack (TIA), using diffusion-weighted imaging (DWI) data from a multicenter retrospective, observational study. METHODS Of the 464 patients admitted to 13 stroke centers in Japan within 7 days after TIA onset, 458 patients underwent a DWI examination in this registry. Patients were divided into those with acute ischemic lesions and those without. We analyzed associations between DWI lesions and baseline characteristics, including age, sex, comorbidities, large artery atherosclerosis (LAA), type and duration of symptoms, the presence of multiple occurrences of TIA within 90 days before hospital visits (multiple TIAs) and the time from symptom onset to DWI examination (time-to-DWI). RESULTS Among the 458 patients (291 men, 68.4±13.2 years old), 374 (81.7%) underwent a DWI examination within the initial 24 hours after the symptom onset. DWI lesions were found in 96 patients (21.0%), and divided into a single lesion (56 patients, 12.2%) or multiple lesions (40 patients, 8.7%). The presence of DWI lesions had an association with male sex (odds ratio [OR] 1.84; 95% confidence interval [CI] 1.07-3.29), time-to-DWI longer than 24 hours (OR 2.96; CI 1.57-5.52), and intracranial LAA (OR 1.99; CI 1.02-3.79). The presence of a single DWI lesion had an association with atrial fibrillation (OR 2.70; CI 1.41-5.03), and multiple DWI lesions did with time-to-DWI longer than 24 hours (OR 6.20; CI 2.60-15.20), multiple TIAs (OR 3.04; CI 1.35-6.76), intracranial LAA (OR 3.63; CI 1.44-8.89), and extracranial LAA (OR 3.53; CI 1.08-10.78). CONCLUSIONS Acute ischemic lesions on DWI were associated with time-to-DWI and LAA in patients with classically defined TIA. Additionally, we identified some differences in relating factors between patients with single and multiple DWI lesions. These results indicate that time-to-DWI and DWI lesion pattern may be important for the diagnosis and management of TIA.

Cerebral arteriopathy with extracranial artery involvement in a patient with ulcerative colitis

Arteriopathy of the central nervous system (CNS) complicated with ulcerative colitis is a rare condition, moreover the involvement of extracranial arteries has not been documented. An 18-year-old female complained of a severe pulsatile headache and nausea. She had been diagnosed and treated for ulcerative colitis for four years. Magnetic resonance imaging of the brain showed normal results; however, magnetic resonance angiography (MRA) revealed severe irregularity of the intracerebral arteries. After treatment with prednisolone, the patient fully recovered and the irregularity of the intracerebral arteries was dramatically improved. Vasculitis was strongly suggested as the cause of arteriopathy of the CNS in the present case. Involvement of extracranial arteries such as the carotid artery was also incidentally discovered by duplex ultrasonography and the HLA typing suggested genetic susceptibility to Takayasus arteritis. Findings from our patient suggest that extracranial arterial involvement should be considered in the case of arteriopathy of the CNS associated with ulcerative colitis.