Endovascular Therapy for Acute Stroke with a Large Ischemic Region.

BACKGROUND: Endovascular therapy for acute ischemic stroke is generally avoided when the infarction is large, but the effect of endovascular therapy with medical care as compared with medical care alone for large strokes has not been well studied. METHODS: We conducted a multicenter, open-label, randomized clinical trial in Japan involving patients with occlusion of large cerebral vessels and sizable strokes on imaging, as indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) value of 3 to 5 (on a scale from 0 to 10, with lower values indicating larger infarction). Patients were randomly assigned in a 1:1 ratio to receive endovascular therapy with medical care or medical care alone within 6 hours after they were last known to be well or within 24 hours if there was no early change on fluid-attenuated inversion recovery images. Alteplase (0.6 mg per kilogram of body weight) was used when appropriate in both groups. The primary outcome was a modified Rankin scale score of 0 to 3 (on a scale from 0 to 6, with higher scores indicating greater disability) at 90 days. Secondary outcomes included a shift across the range of modified Rankin scale scores toward a better outcome at 90 days and an improvement of at least 8 points in the National Institutes of Health Stroke Scale (NIHSS) score (range, 0 to 42, with higher scores indicating greater deficit) at 48 hours. RESULTS: A total of 203 patients underwent randomization; 101 patients were assigned to the endovascular-therapy group and 102 to the medical-care group. Approximately 27% of patients in each group received alteplase. The percentage of patients with a modified Rankin scale score of 0 to 3 at 90 days was 31.0% in the endovascular-therapy group and 12.7% in the medical-care group (relative risk, 2.43; 95% confidence interval [CI], 1.35 to 4.37; P = 0.002). The ordinal shift across the range of modified Rankin scale scores generally favored endovascular therapy. An improvement of at least 8 points on the NIHSS score at 48 hours was observed in 31.0% of the patients in the endovascular-therapy group and 8.8% of those in the medical-care group (relative risk, 3.51; 95% CI, 1.76 to 7.00), and any intracranial hemorrhage occurred in 58.0% and 31.4%, respectively (P<0.001). CONCLUSIONS: In a trial conducted in Japan, patients with large cerebral infarctions had better functional outcomes with endovascular therapy than with medical care alone but had more intracranial hemorrhages. (Funded by Mihara Cerebrovascular Disorder Research Promotion Fund and the Japanese Society for Neuroendovascular Therapy; RESCUE-Japan LIMIT ClinicalTrials.gov number, NCT03702413.).

Association between body mass index and long-term clinical outcomes in patients with non-valvular atrial fibrillation taking oral anticoagulants.

BACKGROUND AND AIMS: The association between body mass index (BMI) and clinical outcomes of patients with non-valvular atrial fibrillation (NVAF) taking oral anticoagulants (OACs) are controversial, and we thus analyzed the large registry data to elucidate them. METHODS AND RESULTS: We conducted a historical cohort study at 71 centers in Japan and included outpatients with NVAF taking vitamin K antagonists (VKAs). Physicians in charge could change VKAs to direct OACs based on their judgement during follow-up period. We categorized patients into four BMI groups (kg/m2): underweight (BMI < 18.5), normal weight (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30), and obese (30 ≤ BMI). The effects of each BMI group relative to the normal weight group on clinical outcomes consisting of all-cause death, ischemic events, and bleeding events were estimated using Cox proportional hazard models adjusting for potential confounders. We also constructed restricted cubic spline regression model adjusted by multivariable Cox proportional hazard models. We included 6927 patients consisting of an underweight (n = 386), normal weight (n = 3785), overweight (n = 2174), and obese (n = 582) groups. The median follow-up period was 3.9 years. In the underweight group, the adjusted hazard ratios (HRs) for all-cause death and ischemic events were 1.75 (1.30-2.34) and 1.61 (1.04-2.50). The HR for all-cause death was 0.63 (0.49-0.82) in the overweight group. Restricted cubic spline regression models confirmed that lower BMI showed significantly higher risks for all-cause death and ischemic events. CONCLUSION: Among NVAF patients taking OACs, underweight patients had higher risks of all-cause death and ischemic events than other patients. Overweight patients had lower risk of all-cause death.

Effect of concomitant antiplatelet therapy on ischemic and hemorrhagic events in patients taking oral anticoagulants for nonvalvular atrial fibrillation in daily clinical practice.

PURPOSE: Antiplatelet therapy (APT) is challenging in patients taking oral anticoagulants (OACs) for nonvalvular atrial fibrillation (NVAF) with concomitant atherosclerotic diseases. We scrutinized the generalizability of recent randomized clinical trials showing OAC use alone was superior to OAC plus antiplatelet use in patients with NVAF and coronary artery diseases (CAD). METHODS: We conducted a historical multicenter registry at 71 centers in Japan. The inclusion criterion was taking OACs for NVAF. The exclusion criteria were mechanical heart valves or history of pulmonary thrombosis or deep vein thrombosis. Consecutive patients (N = 7826) were registered in February 2013 and were followed until February 2017. The co-primary endpoints were ischemic events and major bleedings. Secondary endpoints were ischemic stroke, hemorrhagic stroke, and all-cause mortality. RESULTS: The mean patient age was 73 years; 67% were men. Antiplatelets were administered in 25% of patients and 27% had history of CAD. Cumulative incidences of ischemic events and major bleedings at 4 years were 5.9% and 9.6% in the APT group and 5.3% and 7.0% in the No-APT group, respectively. The adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of the APT group for ischemic events and major bleedings were 1.12 (0.84-1.49) and 1.26 (1.01-1.57), respectively. The adjusted HRs (95% CIs) for ischemic stroke, hemorrhagic stroke, and all-cause mortality were 1.16 (0.86-1.57), and 1.31 (0.70-2.48), and 1.02 (0.82-1.26), respectively. CONCLUSIONS: APT in patients taking OACs for NVAF did not prevent ischemic events but significantly increased major bleedings in the real-world setting.

Simplified Prehospital Prediction Rule to Estimate the Likelihood of 4 Types of Stroke: The 7-Item Japan Urgent Stroke Triage (JUST-7) Score.

OBJECTIVE: Prehospital prediction models to estimate the likelihood of several types of stroke (large vessel occlusion [LVO], intracranial hemorrhage [ICH], and subarachnoid hemorrhage [SAH], and other types of stroke) should be useful to transfer those with suspected stroke to appropriate facilities. We recently reported Japan Urgent Stroke Triage (JUST) score with 21 items had excellent predictive abilities, and we further tried to simplify the score with parsimonious items and comparable predictive abilities. METHODS: We conducted historical and prospective multicenter cohort studies at 8 centers from June 2015 to March 2018. We developed the prediction rules with select variables from JUST score for LVO, ICH, SAH and other types of stroke in 2236 patients with suspected stroke in historical derivation cohort. We validated the developed prediction rules in 964 patients in prospective validation cohort. RESULTS: There were 1150 stroke, including 235 LVO, 352 ICH, 107 SAH and 456 other types of stroke in the derivation cohort. We developed the scores with 7 items (high blood pressure, arrhythmia, conjugate deviation, headache, dysarthria, disturbance of consciousness, paralysis of upper limbs) and the developed scores had area under the receiver-operating curve (AUC) of 0.84 for any type of stroke, 0.89 for LVO, 0.79 for ICH, and 0.90 for SAH in the derivation cohort. There were 490 stroke, including 102 LVO, 138 ICH, 28 SAH and 222 other types of stroke in the validation cohort. The scores well discriminated these strokes in the validation cohort (AUC of 0.76 for any type of stroke; 0.81 for LVO, 0.73 for ICH, and 0.85 for SAH). CONCLUSIONS: The simplified 7-item JUST (JUST-7) score had good predictive ability and can help healthcare providers to estimate the likelihood of different types of stroke and decide the referral hospital.

[What Are the Important Aspects of Catheter Selection and Navigation?]

The goal of coil embolization for cerebral aneurysms is to occlude the cerebral aneurysm to prevent rupture while maintaining the patency of the parent artery. The integrity of cerebral aneurysm occlusion is affected by many factors, including cerebral aneurysm morphology, dome-neck size, dome-neck ratio, and the location of the aneurysm and its parent artery. These factors are then considered pre-operatively and the position of each catheter that allows for the most efficient embolization is assumed. To navigate each catheter to the ideal position, it is necessary to know the characteristics(shape, flexibility, size, etc.)of each catheter. In addition, it is necessary to know the procedure and positioning of balloon catheters or stenting catheters if you use adjunctive techniques. This article will provide guidance for beginners who start coil embolization and provide basic knowledge of how to use catheters, their combinations, and basic methods to help the physician performing optimal coil embolization.

Incidence and Prognostic Impact of Intracranial Hemorrhage after Endovascular Treatment for Acute Large Vessel Occlusion.

INTRODUCTION: Endovascular treatment (EVT) is effective against acute cerebral large vessel occlusion (LVO). However, it has been associated with a high incidence of intracranial hemorrhage (ICH). Because the incidence of ICH and prognostic impact of ICH were not scrutinized in general patients, we investigated the impact of ICH after EVT on functional outcome at 90 days in patients with acute LVO. METHODS: RESCUE-Japan Registry 2 was a multicenter registry that enrolled 2,420 consecutive patients with acute LVO within 24 h of onset. We analyzed 1,281 patients who received EVT and compared the functional outcomes between those with and without ICH (ICH and no-ICH groups, respectively) within 24 h after EVT. We explored the factors associated with ICH and prognostic impact of symptomatic ICH (SICH) among patients with ICH. We estimated the adjusted odds ratios (ORs) for good functional outcome as modified Rankin Scale scores 0-2 and mortality. We also explored the prognostic impact of symptomatic ICH (SICH) among patients with ICH. RESULTS: ICH occurred in 333 patients (26.0%). Several factors such as perioperative edaravone, stent retriever, and baseline glucose were associated with development of ICH within 24 h. A good outcome was observed in 80 (24.0%) and 454 (47.9%) patients in the ICH and no-ICH groups, respectively, and the adjusted OR was 0.3 (95% confidence interval [CI] = 0.2-0.5, p < 0.0001). Incidence of mortality within 90 days was not significantly different between the groups (adjusted OR 1.2; 95% CI: 0.7-1.9, p = 0.5). SICH was observed in 36 (10.8%) of 333 patients with ICH, and the good outcomes were 8.3 and 25.9% in patients with SICH and asymptomatic ICH (AICH), respectively (p = 0.02). Mortality at 90 days was 30.6 and 7.1% in patients with SICH and AICH, respectively (p < 0.0001). CONCLUSIONS: The functional outcomes at 90 days were significantly worse in patients who developed ICH after receiving EVT for acute LVO, but the mortality was generally similar.

Diffusion-Weighted Imaging-Fluid-Attenuated Inversion Recovery Mismatch Is Associated with 90-Day Functional Outcomes in Patients Undergoing Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR) mismatch is an early sign of acute ischemic stroke. DWI-FLAIR mismatch was reported to be valuable to select patients with unknown onset stroke who are eligible to receive intravenous thrombolysis (IVT), but its utility is less studied in patients undergoing mechanical thrombectomy (MT) for acute large vessel occlusion (LVO). We thus investigated the functional outcomes at 90 days between patients with DWI-FLAIR mismatch and those with match who underwent MT for LVO. METHODS: We conducted a historical cohort study in consecutive patients who were evaluated by magnetic resonance imaging for suspected stroke at a single center. We enrolled patients with occlusion of internal carotid artery or horizontal or vertical segment of middle cerebral artery who underwent MT within 24 h after they were last known to be well. DWI-FLAIR mismatch was defined when a visible acute ischemic lesion was present on DWI without traceable parenchymal hyperintensity on FLAIR. Image analysis was done by 2 stroke neurologists independently. We estimated the adjusted odds ratio (OR) of DWI-FLAIR mismatch relative to DWI-FLAIR match for moderate outcome defined as modified Rankin Scale (mRS) 0-3, favorable outcome defined as mRS 0-2 and mortality at 90 days after the onset, and symptomatic intracranial hemorrhage (sICH) within 72 h after the onset. RESULTS: Of the 380 patients who received MT, 202 were included. Patients with DWI-FLAIR mismatch (146 [72%]) had significantly higher baseline National Institutes of Health Stroke Scale (median 16 vs. 13, p = 0.01), more transferred-in (78 vs. 63%, p = 0.02), more IVT (45 vs. 18%, p = 0.0003), more cardioembolism (69 vs. 54%, p = 0.03), and shorter onset-to-hospital door times (median 175 vs. 371 min, p < 0.0001) than patients with DWI-FLAIR match. Patients with DWI-FLAIR mismatch had more moderate outcome than those with DWI-FLAIR match (61 vs. 52%, p = 0.24), and the adjusted OR was 3.12 (95% confidence interval [CI]: 1.35-7.19, p = 0.008). sICH within 72 h was less frequent in the DWI-FLAIR mismatch group (10 vs. 20%, p = 0.06), with an adjusted OR of 0.36 (95% CI: 0.13-0.97, p = 0.044). The adjusted ORs for favorable outcome and mortality were 0.87 (95% CI: 0.39-1.94, p = 0.73) and 0.63 (95% CI: 0.20-2.05, p = 0.44), respectively. CONCLUSIONS: DWI-FLAIR mismatch was associated with more moderate outcome and less sICH in the adjusted analysis in patients receiving MT for acute LVO. DWI-FLAIR mismatch could be useful to select patients with unknown onset stroke who are eligible to receive MT for acute LVO.

Impact of anemia on major bleeding in patients taking oral anticoagulants for nonvalvular atrial fibrillation.

Background: Anemia is encountered in patients with nonvalvular atrial fibrillation (NVAF) on oral anticoagulants (OACs) but the prognostic impact was not well scrutinized in real-world settings. Methods: We conducted a historical multicenter registry of patients with NVAF taking OACs at 71 centers in Japan. Those with mechanical heart valves or a history of pulmonary thrombosis or deep venous thrombosis were excluded. Anemic patients were divided into three groups of hemoglobin (Hb) level: moderate/severe (Hb < 11.0 g/dL), mild (men: Hb of 11.0-12.9 g/dL; women: Hb of 11.0-11.9 g/dL), and no anemia. The endpoints included major bleeding, hemorrhagic stroke, ischemic events, ischemic stroke, and all-cause mortality. Results: Among 7558 consecutive patients (mean age, 73 years; men 67%) registered in February 2013 and followed until February 2017, 2100 (28%) patients had anemia. The anemic patients were older (moderate/severe: 79 years; mild: 77 years; no anemia: 71 years, p < .001), and HAS-BLED score was significantly higher in the anemic patients (p < .001). The cumulative incidences at 4 years of major bleeding in moderate/severe, mild, and no anemia group, were 14.9%, 10.7%, and 6.4%, respectively. The adjusted hazard ratios (HRs) (95% confidential intervals (CIs)) of major bleeding of moderate/severe and mild anemia group were 1.96 (1.49-2.58) and 1.48 (1.17-1.87) compared to no anemia group. The adjusted HRs (95% CIs) for ischemic events were 0.63 (0.39-0.99) and 1.03 (0.76-1.39). Conclusions: The severity of anemia in the patients with NVAF on OACs was associated with major bleeding.

Statins Reduce Bleeding Risk in Patients Taking Oral Anticoagulants for Nonvalvular Atrial Fibrillation: A Retrospective Registry Study.

BACKGROUND: The effects of statins in patients with non-valvular atrial fibrillation (NVAF) taking oral anticoagulants (OACs) are not well-studied. This study was a historical multicenter registry of patients with NVAF taking OACs in Japan. METHODS: We excluded those patients with mechanical heart valves or a history of pulmonary or deep vein thrombosis. Overall, 7826 patients were registered on 26 February 2013 and followed until 25 February 2017. We compared those with versus without statin treatment (statin vs. no-statin groups) for the primary outcome of major bleeding and secondary outcomes of all-cause mortality, ischemic events, hemorrhagic stroke, and ischemic stroke. RESULTS: Statins were administered in 2599 (33%) patients. The statin group was more likely to have paroxysmal AF (37% vs. 33%; p = 0.0003), hypertension (84% vs. 76%; p < 0.0001), diabetes mellitus (41% vs. 27%; p < 0.0001), and dyslipidemia (91% vs. 30%; p < 0.0001) than the no-statin group. The cumulative incidence of major bleeding was 6.9% and 8.1% (p = 0.06). The adjusted hazard ratio [HR] (95% confidence interval [CI]) of the statin group for major bleeding was 0.77 (0.63-0.94) compared with the no-statin group. The adjusted HR (95% CI) for all-cause mortality, ischemic events, hemorrhagic stroke, and ischemic stroke were 0.58 (0.47-0.71), 0.77 (0.59-0.999), 0.85 (0.48-1.50), and 0.79 (0.60-1.05), respectively. CONCLUSIONS: Statins significantly reduced the risk of major bleeding, all-cause mortality, and ischemic events in patients with NVAF taking OACs. Their additive benefits should be considered in routine practice and thus be further researched.

Prognostic Factors in Patients with Unruptured Vertebral and Basilar Fusiform Aneurysms Treated with Endovascular Procedures : A Single Center Retrospective Analysis.

PURPOSE: Large vertebral and basilar fusiform aneurysms (VFA) are sometimes difficult to cure by endovascular treatment (EVT). We aimed to elucidate indicators of poor outcomes of EVT in patients with VFAs. METHODS: Clinical data from 48 patients with 48 unruptured VFAs in the Hyogo Medical University were retrospectively analyzed. The primary outcome was defined as satisfactory aneurysm occlusion (SAO) according to Raymond-Roy grading scale. The secondary and safety outcomes were a modified Rankin scale (mRS) score of 0-2 at 90 days, retreatment, major stroke, and aneurysm-related death after EVT. RESULTS: The EVT included stent-assisted coiling (n = 24; 50%), flow diverter (n = 19; 40%), and parent artery occlusion (n = 5; 10%). The SAO was less frequently observed in large or thrombosed VFAs at 12 months (64%, p = 0.021 and 62%, p = 0.014, respectively), especially when the aneurysms were both large and thrombosed (50%, p = 0.0030). Retreatment was more common in large aneurysms (29%, p = 0.034), thrombosed (32%, p = 0.011), and large thrombosed aneurysms (38%, p = 0.0036). Although the proportion of mRS 0-2 at 90 days and major stroke showed no significant differences, that of post-treatment rupture was significantly larger in large thrombosed VFAs (19%, p = 0.032). Aneurysm-related death occurred by aneurysm rupture and was more frequent in large thrombosed VFA (19%, p = 0.032). Multivariate analysis showed SAO at 12 months was less common (adjusted odds ratio, OR: 0.036, 95% confidence interval, CI 0.00091-0.57; p = 0.018), and retreatment was more common (adjusted OR 43, 95% CI 4.0-1381; p = 0.0012) in large thrombosed VFA. CONCLUSION: The large thrombosed VFAs were associated with poor outcomes after EVT including flow diverter.

Association between dihydropyridine calcium channel blockers and ischemic strokes in patients with nonvalvular atrial fibrillation.

Outside of clinical trials, the prophylactic effect of dihydropyridine calcium channel blockers (CCBs) on ischemic events in patients with nonvalvular atrial fibrillation (NVAF) has not been confirmed. We compared the effect of dihydropyridine CCBs on ischemic events in anticoagulated NVAF patients. We conducted a multicenter historical cohort study at 71 centers in Japan. The inclusion criterion was taking vitamin K antagonists for NVAF. The exclusion criteria were mechanical heart valves and a history of pulmonary thrombosis or deep vein thrombosis. Consecutive patients (N = 7826) were registered in February 2013 and were followed until February 2017. The primary outcomes were ischemic events and ischemic strokes; the secondary outcomes were all-cause mortality, major bleeding, and hemorrhagic strokes. The mean patient age was 73 years old, and 67% of the patients were male. Seventy-eight percent of the patients had hypertension, and dihydropyridine CCBs were used by 2693 (34%) patients (CCB group). The cumulative incidences of ischemic events and ischemic strokes at 4 years in the CCB and No-CCB groups were 5.9% vs. 5.2% and 5.6% vs. 4.8%, respectively. The adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of the CCB group for ischemic events and ischemic strokes were 1.22 (0.95-1.57) and 1.32 (1.02-1.71), respectively; the adjusted HRs (95% CIs) of the CCB group for all-cause mortality, major bleeding, and hemorrhagic strokes were 0.85 (0.69-1.04), 1.12 (0.92-1.35), and 1.08 (0.62-1.88), respectively. Dihydropyridine CCB use by anticoagulated NVAF patients significantly increased ischemic strokes in a real-world setting.

Development of Machine Learning Models to Predict Probabilities and Types of Stroke at Prehospital Stage: the Japan Urgent Stroke Triage Score Using Machine Learning (JUST-ML).

In conjunction with recent advancements in machine learning (ML), such technologies have been applied in various fields owing to their high predictive performance. We tried to develop prehospital stroke scale with ML. We conducted multi-center retrospective and prospective cohort study. The training cohort had eight centers in Japan from June 2015 to March 2018, and the test cohort had 13 centers from April 2019 to March 2020. We use the three different ML algorithms (logistic regression, random forests, XGBoost) to develop models. Main outcomes were large vessel occlusion (LVO), intracranial hemorrhage (ICH), subarachnoid hemorrhage (SAH), and cerebral infarction (CI) other than LVO. The predictive abilities were validated in the test cohort with accuracy, positive predictive value, sensitivity, specificity, area under the receiver operating characteristic curve (AUC), and F score. The training cohort included 3178 patients with 337 LVO, 487 ICH, 131 SAH, and 676 CI cases, and the test cohort included 3127 patients with 183 LVO, 372 ICH, 90 SAH, and 577 CI cases. The overall accuracies were 0.65, and the positive predictive values, sensitivities, specificities, AUCs, and F scores were stable in the test cohort. The classification abilities were also fair for all ML models. The AUCs for LVO of logistic regression, random forests, and XGBoost were 0.89, 0.89, and 0.88, respectively, in the test cohort, and these values were higher than the previously reported prediction models for LVO. The ML models developed to predict the probability and types of stroke at the prehospital stage had superior predictive abilities.

Association between Acid-Suppressive Drugs and Clinical Outcomes in Patients with Nonvalvular Atrial Fibrillation.

PURPOSE: Acid-suppressive drugs (ASDs) are often prescribed for patients with nonvalvular atrial fibrillation (NVAF) taking oral anticoagulants (OACs). However, the risk-benefit balance of ASDs prescription for patients with NVAF taking OACs is still unclear. This study aimed to assess the association between ASDs and clinical outcomes in patients taking OACs for NVAF. METHODS: This study is a subanalysis of an historical registry study from 71 centers in Japan. We included patients taking vitamin K antagonists for NVAF and excluded those with mechanical heart valves or a history of pulmonary thrombosis or deep vein thrombosis. We registered consecutive patients in February 2013 and followed them up until February 2017. The primary outcomes were ischemic events, major bleedings, and all-cause mortality. Ischemic stroke, acute myocardial infarction, and hemorrhagic stroke comprised the secondary outcomes. RESULTS: We included 7826 patients with a mean age of 73 years, 5274 (67%) of whom were males. The adjusted hazard ratios (95% confidence intervals) for ischemic events, major bleedings, and all-cause mortality in the ASD group compared with the no-ASD group were 0.998 (0.78-1.27), 0.98 (0.81-1.18), and 1.22 (1.02-1.47), respectively, while those for ischemic stroke, acute myocardial infarction, and hemorrhagic stroke were 0.96 (0.74-1.24), 0.82 (0.36-1.88), and 1.17 (0.69-1.99), respectively. CONCLUSIONS: ASDs were significantly associated with all-cause mortality in patients with NVAF taking OACs.

Effect of current smoking on ischemic events in patients with atrial fibrillation taking vitamin K antagonist.

Purpose: We investigated the association between current smoking and clinical outcomes in patients with atrial fibrillation (AF) prescribed vitamin K antagonist (VKA). Methods: We conducted a retrospective study at 71 centers in Japan. The inclusion criterion was taking a VKA for AF. Exclusion criteria were mechanical heart valves or history of pulmonary thrombosis or deep vein thrombosis. Consecutive patients were registered in February 2013 and followed until February 2017. The primary outcomes included ischemic events and major bleedings. The secondary outcomes were ischemic stroke, hemorrhagic stroke, and all-cause mortality. Results: A total of 7826 patients were included, with a mean age of 73 years; 5274 (67%) were men. The adjusted hazard ratios (HRs; 95% confidence intervals [CIs]) of current smokers relative to non-current smokers for ischemic events and major bleedings were 1.64 (1.05-2.57) and 1.09 (0.72-1.65), respectively. The adjusted HRs (95% CIs) of current smokers relative to non-current smokers for ischemic stroke, hemorrhagic stroke, and all-cause mortality were 1.65 (1.03-2.64), 0.52 (0.12-2.15), and 1.26 (0.83-1.92), respectively. Conclusions: There were significant associations between current smoking and ischemic events or ischemic stroke in patients with AF on VKA.

Experience and awareness of research integrity among Japanese physicians: a nationwide cross-sectional study.

OBJECTIVES: To explore the awareness and practice of clinical research integrity among Japanese physicians. DESIGN: A nationwide cross-sectional study conducted in March 2020. SETTING: All hospitals in Japan. PARTICIPANTS: Physicians aged <65 years who work at hospitals participated in clinical research over the past 5 years. The sample was stratified according to geographical location and subspecialty, and 1100 physicians were proportionally selected. PRIMARY AND SECONDARY OUTCOME MEASURES: Knowledge and awareness of research integrity. RESULTS: Among the 1100 participants, 587 (53%) had the experience of being the first author, 299 (27%) had been co-authors only and 214 (19%) had no authorship. A total of 1021 (93%) had experienced learning research integrity, and 555 (54%) became aware of research integrity. The experience of learning about research integrity was highest among those with first authorship (95%) and lowest among those without authorship (89%) (p=0.003). The majority of participants learnt about research integrity for passive reasons such as it being 'required by the institution' (57%) or it being 'required to obtain approval of institutional review board (IRB)' (30%). Potentially inappropriate research behaviours were observed in participants, with 11% indulging in copying and pasting for writing the paper, 11% for gifted authorship and 5.8% for the omission of IRB approval. Factors significantly associated with copying and pasting were being below 40 years old (OR: 1.84; 95% CI: 1.05 to 3.26), being the first presenter (OR: 1.64; 95% CI: 1.05 to 2.57) or having passive reasons for learning research integrity (OR: 2.96; 95% CI: 1.57 to 5.59). Furthermore, gifted authorship was significantly associated with being a co-author only (OR: 1.84; 95% CI: 1.18 to 2.87) and having passive reasons for learning about research integrity (OR: 1.79; 95% CI: 1.03 to 3.12). CONCLUSIONS: Most physicians conducting clinical research have learnt about research integrity, but potentially inappropriate research behaviours are associated with passive reasons for learning.