Effect of omega-3 fatty acids on cardiovascular events in high-risk patients with hypertriglyceridemia in Japan: a 3-year post-marketing surveillance study (OCEAN3 survey).

BACKGROUND: Studies on the efficacy of prescription omega-3 polyunsaturated fatty acids to reduce cardiovascular events have produced conflicting results. RESEARCH DESIGN AND METHODS: This 3-year prospective post-marketing surveillance study evaluated the effect of omega-3-acid ethyl esters (O3AEE; usual dosage 2 g/day) on cardiovascular events in high-risk statin-treated Japanese patients with hypertriglyceridemia. Statin-treated patients not receiving O3AEE were included as a reference cohort. The composite primary endpoint was cardiovascular death, myocardial infarction, stroke, angina requiring coronary revascularization, or peripheral arterial disease requiring surgery or peripheral arterial intervention. RESULTS: At 3 years, Kaplan-Meier estimated cumulative incidence of the primary endpoint was 2.5% (95% confidence interval, 2.1%-2.9%) in O3AEE-treated patients (N = 6,580) and 2.7% (2.4%-3.1%) in non-O3AEE-treated patients (N = 7,784; hazard ratio, 0.99; 95% confidence interval, 0.79-1.23). Incidence of heart failure requiring hospitalization was 0.4% with O3AEE versus 0.8% in non-O3AEE-treated patients (hazard ratio, 0.47; 95% confidence interval, 0.28-0.78; P < 0.05). CONCLUSIONS: Among patients receiving statins, cardiovascular event incidence did not differ significantly between O3AEE-treated patients and non-O3AEE-treated patients. Further studies are required before definitive conclusions can be drawn on the effect of O3AEE on cardiovascular event incidence in high-risk patients with hypertriglyceridemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02285166.

Branch atheromatous disease diagnosed as embolic stroke of undetermined source: A sub-analysis of NAVIGATE ESUS.

BACKGROUND: Branch atheromatous disease (BAD) is distinctive from large and small arterial diseases, which is single subcortical infarction larger than lacunar stroke in the territories of deep perforators without relevant arterial stenosis. BAD meets the current criteria of embolic stroke of undetermined source. We performed an exploratory analysis of BAD in patients recruited to NAVIGATE embolic stroke of undetermined source, a randomized controlled trial to compare rivaroxaban and aspirin in embolic stroke of undetermined source patients. METHODS AND RESULTS: Among 3972 stroke patients in cerebral hemispheres with intracranial arterial imaging, 502 (12.6%) patients met the criteria for BAD. BAD was associated with younger age (years; OR: 0.97, 95% CI: 0.96-0.98), race (Asian; OR: 1.78, 95% CI: 1.44-2.21), region (Eastern Europe; OR: 2.49, 95% CI: 1.87-3.32), and higher National Institute of Health Stroke Scale (OR: 1.17, 95% CI: 1.12-1.22) at randomization. During follow-up, stroke or systemic embolism (2.5%/year vs. 6.2%/year, p = 0.0022), stroke (2.1%/year vs. 6.2%/year, p = 0.0008), and ischemic stroke (2.1%/year vs. 5.9%/year, p = 0.0013) occurred less frequently in BAD than non-BAD patients. There were no differences in annual rates of stroke or systemic embolism (2.5%/year vs. 2.5%/year, HR: 1.01, 95% CI: 0.33-3.14) or major bleeding (1.3%/year vs. 0.8%/year, HR: 1.51, 95% CI: 0.25-9.05) between rivaroxaban and aspirin groups among BAD patients. CONCLUSIONS: BAD was relatively common, especially in Asian and from Eastern Europe among embolic stroke of undetermined source patients. Stroke severity was higher at randomization but recurrence of stroke was fewer in BAD than non-BAD patients. The efficacy and safety of rivaroxaban and aspirin did not differ among BAD patients.

[Measurement of Prothrombin Fragment 1+2 for the Assessment of Anticoagulant Activity in Patients Treated with Warfarin or Non-vitamin K Antagonist Oral Anticoagulant].

[Background and purpose] Prothrombin fragment 1+2 (PF1+2) is a sensitive marker for blood coagulation system. In order to evaluate anticoagulant activity in patients treated with warfarin or non-vitamin K antagonist oral anticoagulant (NOAC), we measured plasma levels of PF1+2 and evaluated anticoagulant activity by each anticoagulant agent. [Methods] Subjects were 28 patients, 17 men and 11 women, 77±6 year old, with oral anticoagulant therapy for secondary prevention of stroke. We measured plasma levels of PF1+2 in 70 times in 7 patients treated with warfarin, and 154 times in 27 patients treated with NOAC. PT-INR was simultaneously measured in patients treated with warfarin. [Results] In warfarin treatment groups, PT-INR values were median 1.96 (IQR 1.8-2.1) and PF1+2 levels were median 111 pmol/l (IQR 95-141). All PF1+2 levels were below the upper limit of normal range, but 12 values (17%) of them in 5 patients were below the lower limit of normal range. 8 of the 12 values were at PT-INR below 2.5, and 1 of whom developed intracerebral hemorrhage. Plasma levels of PF1+2 in patients treated with dabigatran 150mg BID, dabigatran 110mg BID, rivaroxaban 15mg QD, rivaroxaban 10mg QD, apixaban 5mg BID, apixaban 2.5mg BID, and edxaban 30mg QD were median 116 pmol/l (IQR 99-136), 132 pmol/l (IQR 99-162), 109 pmol/l (IQR 100-125), 133 pmol/l (IQR 100-177), 88 pmol/l (IQR 76-102), 148 pmol/l (IQR 93-167), 221 pmol/l (IQR 208-234). They were all above the lower limit of the normal range, 3 of which were above the upper limit of the normal range. Excessive suppression of thrombin production was more frequently seen in warfarin treatment than in NOAC treatment (p<0.05). [Conclusion] In warfarin treatment, thrombin production was suppressed excessively in 17%, although it was not in NOAC treatment. (Received September 21, 2016; Accepted December 26, 2016; Published May 1, 2017).

Multinational, double-blind, randomised, placebo-controlled, prospective study of esomeprazole in the prevention of recurrent peptic ulcer in low-dose acetylsalicylic acid users: the LAVENDER study.

OBJECTIVES: To evaluate if esomeprazole prevents recurrent peptic ulcer in adult patients with a history of peptic ulcer receiving low-dose acetylsalicylic acid (ASA, aspirin) for cardiovascular protection in East Asia. METHODS: In this prospective, randomised, double-blind, placebo-controlled trial conducted in Japan, Korea and Taiwan, eligible patients receiving low-dose ASA for cardiovascular protection (81-324 mg/day) were randomised to esomeprazole 20 mg/day or placebo for ≤72 weeks. All patients received concomitant mucosal protection (gefarnate 100 mg/day). The primary endpoint was time to ulcer recurrence (Kaplan-Meier analysis). Efficacy findings are presented up to week 48, as per a planned interim analysis within the study protocol. RESULTS: A total of 364 patients (79.9% men; mean age, 67.1 years) comprised the full analysis set (esomeprazole, n=182; placebo, n=182). There was a statistically significant difference in the time to ulcer recurrence between esomeprazole and placebo (HR 0.09; 96.65% CI 0.02 to 0.41; p<0.001). The estimated ulcer-free rate at week 12 was 99.3% (esomeprazole) and 89.0% (placebo). The high estimated ulcer-free rate for esomeprazole was maintained through to week 48 (98.3% vs. 81.2% of placebo-treated patients). No factors, other than female gender, reduced time to ulcer recurrence in addition to the effect of esomeprazole (p<0.001). Treatment with esomeprazole was generally well tolerated. CONCLUSIONS: Daily esomeprazole 20 mg is efficacious and well tolerated in reducing the recurrence of peptic ulcer in East-Asian patients with a history of ulcers who are taking low-dose ASA for cardiovascular protection. CLINICALTRIALGOV IDENTIFIER: NCT01069939.

[Management of intracranial hemorrhage during anticoagulant therapy with warfarin or novel anticoagulants].

Novel anticoagulants including dabigatran and rivaroxaban have lower incidence of intracranial hemorrhage compared to warfarin. Therefore, in patients with high risks for intracranial hemorrhage, such as past history of brain infarction, brain hemorrhage, microbleeds on MRI, or concomitant use of antiplatelet, novel anticoagulant may be appropriate. Irrespective of any anticoagulants, it is essential to manage controllable risk factors, such as hypertension, diabetes mellitus, smoking habit, and excessive alcohol drinking. Combination therapy of other antithrombotic agents had better be avoided as long as possible. In emergency of hemorrhage complications, discontinuation of anticoagulants, procedure to stop bleeding, and appropriate intravenous infusion is quite important and lowering blood pressure is also important when intracranial hemorrhage happens. There is no antidote to novel anticoagulants. However, oral activated charcoal may be effective if early after taking medicine. The dabigatran can be dialysed. Some experimental evidences support the role of prothrombin complex concentrate to stop bleeding. However, their usefulness in clinical setting has not been established. Collecting and analyzing data regarding immediate reversal of novel anticoagulants is required in near future.

Factors influencing cooperation among healthcare providers in a community-based stroke care system in Japan.

Community-based stroke care in Japan is currently provided in acute hospitals, convalescent rehabilitation units, general practices, sanatorium-type wards, nursing care facilities, and in-home/commuting care services. We conducted a nationwide survey to identify factors influencing cooperation among the various providers of community-based stroke care. We sent questionnaires to 11,178 facilities and assessed the independent variables of excellent and fair cooperation among the care providers. Of the providers that responded, 66% were engaged in medical practice or long-term care for stroke patients. The following independent variables were inversely associated with excellent or fair cooperation in the community: area with the higher population density among 3 groups divided by tertile threshold (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.41-0.69), facilities covered by long-term care insurance (OR, 0.27; 95% CI, 0.22-0.34), and insufficient communication with local government (OR, 0.19; 95% CI, 0.14-0.24). Positive independent variables of excellent or fair cooperation were the sharing of patient information in the community (OR, 2.53; 95% CI, 1.78-3.66), use of a scale for assessing activities of daily living (OR, 1.93; 95% CI, 1.42-2.63), appropriate utilization of care support managers (OR, 1.91; 95% CI, 1.43-2.55), and adequate comprehension of the long-term care insurance system (OR, 1.54; 95% CI, 1.24-1.92). Our findings suggest that improved communication between healthcare providers and local government, along with appropriate attention to the problems facing providers covered by long-term care insurance, may improve community-based stroke care in Japan.

[Cerebellar infarction in a young adult due to traumatic vertebral artery dissection after lateral mass fracture at the sixth cervical vertebrae].

A 23-years-old man fell off stairs and got a blow on the left head and right shoulder. He felt dysesthesia at the right thumb on the following day, and received chiropractic therapy from the forth day after injury. On the sixth day after injury, he developed dizziness and nausea, and was urgently hospitalized in our cerebrovascular center. On admission, he had horizontal nystagmus and truncal ataxia. Diffusion-weighted magnetic resonance imaging showed high intensity lesions in right cerebellum hemisphere of posterior inferior cerebellar artery territory, indicating fresh infarcts. On angiogram, right vertebral artery showed tapering occlusion at C6 level, indicating dissection. Computed tomogram showed fracture of the right lateral mass at C6 which extended into the transverse foramen. Under diagnosis of the traumatic vertebral artery dissection due to cervical fracture, we started anticoagulation therapy, which was followed by oral antiplatelet therapy in the chronic stage. Extracranial vertebral artery dissection due to cervical fracture is an important cause of brain infarction in a young adult. Radiological examinations are necessary to rule out traumatic vertebral artery dissection for patients with prolonged dizziness after head injury.

Recurrent embolic stroke originating from an internal carotid aneurysm in a young adult.

An unruptured intracranial aneurysm is an uncommon but possible embolic source to the brain. We report a young patient who developed recurrent ischemic strokes occurring mainly in the left internal carotid arterial territory within a short interval; the first stroke occurred midway through a long-distance race, and the second stroke occurred immediately following a bowel movement. The angiographical contrast deficit indicated a thrombus in the left anterior cerebral artery as a result of the embolism. A saccular aneurysm of the left distal internal carotid artery was the only detectable potential embolic source. Initially anticoagulant therapy was given, and then surgical clipping of the aneurysm was performed. The patient has been free from stroke recurrence. As a cause of ischemic stroke in young adults, a carotid saccular aneurysm should be considered. Hard exercise and a Valsalva maneuver may be important triggers of thrombus detachment from the aneurysm.

Recurrent small-artery disease in hyperhomocysteinemia: widowers' stroke syndrome?

Hyperhomocysteinemia is thought to cause ischemic strokes. We report two middle-aged widowers with frequent recurrences of small-artery strokes, two capsular infarcts and a thalamic hemorrhage in one patient, and two thalamic and pontine infarcts in the other. Blood tests following the final stroke showed hyperhomocysteinemia and methylenetetrahydrofolate reductase C677T gene mutation, with low concentration of vitamin B6. Multivitamin supplementation normalized plasma homocysteine levels in both patients. Hyperhomocysteinemia is treatable; therefore, serum homocysteine should be measured as a potential risk factor for stroke recurrence in relatively young patients with recurrent small-artery infarctions or hemorrhage, especially those with insufficient lifestyle factors.

[Brain hemorrhage with medical treatment: prediction of early outcome and production of critical paths].

The first purpose of this study was to detect clinical and radiological factors on admission which predict early outcome of patients in brain hemorrhage with medical treatment. For 50 consecutive patients in our Cerebrovascular Center, NIH Stroke Scale score was a useful indicator for prediction of independent daily life, discharge to home, and death in the acute stage; the score < or = 4, < or = 7, and > or = 23 were the most appropriate cut-off values for the above events, respectively. The second purpose of this study was to produce critical paths of medical management for brain hemorrhage based on the above results. We prepared three courses of paths according to clinical severity. As inclusion criteria for each course, we used the above three cut-off values and hematoma volume. Duration of hospitalization of the three courses was 16, 20, and 28 days. When we applied the paths to 200 patients with brain hemorrhage who were enrolled in the research grant supported by the Japanese ministry of health, labor and welfare (12C-10), duration of hospitalization for the majority of the patients were 5 days or more than the planned duration in the paths. It is indispensable to manage acute stroke patients according to critical paths, because standard and efficient strategies of clinical medicine have been stressed these years. We will immediately apply the new paths in this study to patients in our center, and renew them at short intervals. We think that we can contribute to new evidences for standard medical management of brain hemorrhage by our approach to the critical paths.

Analysis of hospital charges for ischemic stroke in Fukuoka, Japan.

OBJECTIVES: Stroke is a heavy economic burden on individuals, society, and health services in Japan, where health expenditures are rising rapidly. The objective of the present study was to examine medical services and demographic factors associated with increased inpatient charges for ischemic stroke in Japan. SUBJECTS AND METHODS: The study subjects were 316 patients with a principal diagnosis of acute ischemic stroke who were discharged from the National Kyushu Medical Center Hospital from 1 July 1995 through 31 June 1999. Demographic, clinical, and administrative data were retrospectively collected from medical records and the hospital Clinical Financial Information System (CFIS). The influence of social and medical factors on total charges was analyzed using the stepwise multiple regression model. RESULTS: Among the total subjects, the mean (median) length of hospital stay (LOHS) was 33 (30) days (range, 2-155 days). The mean (median) hospital charge per patient was US dollars 9020 (dollars 7974) with a range of dollars 336-54,509. The distribution of charges was 42% for fundamental, 17% for injection therapies, 13% for radiological test, 11% for other laboratory examinations, 3% for drugs, and 3% for operations. Stepwise multiple regression analysis revealed that LOHS was the key determinant of the hospital charge (partial R2=0.5993, P=0.0001). Operations (P=0.0001) and angiography (P=0.03) were also independent but less contributory determinants of the hospital charge. CONCLUSIONS: LOHS was strongly, positively associated with inpatient charges for ischemic stroke in Japan. This implies that significant charge reductions are more likely to rely on shortening LOHS, which probably can be achieved by altering reimbursement policies.

Processivity of the single-headed kinesin KIF1A through biased binding to tubulin.

Conventional isoforms of the motor protein kinesin behave functionally not as 'single molecules' but as 'two molecules' paired. This dimeric structure poses a barrier to solving its mechanism. To overcome this problem, we used an unconventional kinesin KIF1A (refs 5, 6) as a model molecule. KIF1A moves processively as an independent monomer, and can also work synergistically as a functional dimer. Here we show, by measuring its movement with an optical trapping system, that a single ATP hydrolysis triggers a single stepping movement of a single KIF1A monomer. The step size is distributed stochastically around multiples of 8 nm with a gaussian-like envelope and a standard deviation of 15 nm. On average, the step is directional to the microtubule's plus-end against a load force of up to 0.15 pN. As the source for this directional movement, we show that KIF1A moves to the microtubule's plus-end by approximately 3 nm on average on binding to the microtubule, presumably by preferential binding to tubulin on the plus-end side. We propose a simple physical formulation to explain the movement of KIF1A.