Predictors of Early versus Delayed Neurological Deterioration after Thrombolysis for Ischemic Stroke.

INTRODUCTION: We aimed to determine predictors of early (END) and delayed neurological deterioration (DND) and their association with the functional outcome in patients with acute ischemic stroke (AIS) who participated in the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: END and DND (without END) were defined as scores of a ≥2-point increase on the National Institutes of Health Stroke Scale (NIHSS) or a ≥1-point decrease on the Glasgow coma scale or death, from baseline to 24 h and 24-72 h, respectively. Multivariable logistic regression models were used to determine independent predictors of END and DND and their association with 90-day outcomes (dichotomous scores on the modified Rankin scale [mRS] of 2-6 vs. 0-1 and 3-6 vs. 0-2 and death). RESULTS: Of 4,496 patients, 871 (19.4%) and 302 (8.4%) patients experienced END and DND, respectively. Higher baseline NIHSS score, older age, large-artery occlusion due to significant atheroma, cardioembolic stroke subtype, hemorrhagic infarction and parenchymatous hematoma within 24 h were all independent predictors for both END (all p ≤ 0.01) and DND (all p ≤ 0.024). Moreover, higher baseline systolic blood pressure (BP) (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.02-1.12), higher diastolic BP variability within 24 h (OR 1.07, 95% CI 1.04-1.09), patients from Asia (OR 1.25, 95% CI 1.03-1.52) were the only independent predictors for END. However, Asian ethnicity was negatively associated with DND (OR 0.64, 95% CI 0.47-0.86). Hemorrhagic infarction and parenchymatous hematoma within 24 h were the key predictors of END across all stroke subtypes. END and DND were all associated with a poor functional outcome at 90 days (all p < 0.001). CONCLUSION: We identified overlapping and unique demographic and clinical predictors of END and DND after thrombolysis for AIS. Both END and DND predict unfavorable outcomes at 90 days.

Angioplasty Guidewire-Assisted vs. Conventional Transseptal Puncture for Left Atrial Appendage Occlusion: a multicentre randomized controlled trial.

AIMS: This study was performed to compare the usability, efficiency, and safety of a modified angioplasty guidewire-assisted transseptal puncture (TSP) technique vs. the conventional approach in facilitating access into the left atrium during left atrial appendage occlusion (LAAO) procedures for the treatment of atrial fibrillation. METHODS AND RESULTS: The ADVANCE-LAAO trial (Angioplasty Guidewire-Assisted vs. Conventional Transseptal Puncture for Left Atrial Appendage Occlusion) was an investigator-initiated, prospective, multicentre, randomized controlled trial (NCT05125159). Patients with atrial fibrillation who underwent LAAO were prospectively enrolled from four centres and randomly assigned to an angioplasty guidewire-assisted TSP group (n = 131) or to a conventional Brockenbrough needle TSP group (n = 132). The primary endpoint was the one-time success rate of TSP. We also analysed the TSP procedure time, failure rate of the assigned TSP type, radiation dose, contrast dose, and procedural complications in both groups. All patients in the guidewire-assisted group underwent successful TSP, whereas five in the standard conventional group switched to the guidewire-assisted approach. The guidewire-assisted puncture improved the one-time success rate (92.4 vs. 77.3%, P = 0.001), shortened the TSP procedure time (109.2 ± 48.2 vs. 120.5 ± 57.6 s, P = 0.023), and tended to have a higher rate of good coaxial orientation of the sheath with the left atrial appendage during the LAAO procedure (66.4 vs. 54.5%, P = 0.059). No TSP-related complications occurred in the guidewire-assisted TSP group, whereas two complications occurred in the conventional TSP group. There was no significant difference in the failure rate of the assigned TSP type, the total procedure time, the total radiation dose, the rate of successful LAAO implantation, or the procedural complication rate between the two groups (all P > 0.05). CONCLUSION: This study confirmed that angioplasty guidewire-assisted puncture can effectively improve the success rate of TSP during LAAO procedures. This novel technique has high potential for application in interventional therapies requiring TSP.

Pulmonary vein perforation into the respiratory tract with systemic air embolism: a rare complication of left atrial appendage closure.

BACKGROUND: Pulmonary vein perforation is an uncommon complication during cardiac intervention. We present a rare case of pulmonary vein perforation into the respiratory tract with systemic air embolism during left atrial appendage closure (LAAC). CASE PRESENTATION: A 77-year-old man with persistent nonvalvular atrial fibrillation was referred for percutaneous LAAC under local anaesthesia (CHA2DS2-VASc score of 4, HAS-BLED score of 3, and prior ischaemic stroke). During the procedure, after delivering a super-stiff guidewire into the left superior pulmonary vein (LSPV), the patient suddenly developed a severe cough with haemoptysis upon advancement of a delivery sheath along the guidewire. Fluoroscopy showed signs of blood entering the left main bronchus, and fast transthoracic echocardiography revealed bubbles in the left heart without pericardial effusion. The procedure was terminated because of a major complication indicated by the repeated haemoptysis and headache, and haemostatic drugs were immediately administered. Subsequent chest computed tomography angiography (CTA) revealed a filling defect in the LSPV branches and bubbles in the aorta. The patient was transferred to the critical care unit for haemostasis and antibacterial treatment. Transthoracic echocardiography later that day showed no bubbles in the heart. The headache and haemoptysis significantly abated the following day. The bubbles in the aorta disappeared on chest CTA 7 days later. CONCLUSIONS: Interventional cardiologists should pay attention to anatomical variations of the pulmonary vein, which are associated with a high risk of complications of pulmonary vein perforation during LAAC. Preoperative CTA examination and intraoperative transoesophageal echocardiography might be helpful to avoid this complication.

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis.

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.

Sodium-glucose co-transporter-2 inhibition and ocular outcomes in patients with type 2 diabetes: A systematic review and meta-analysis.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are effective for the treatment of macrovascular complications and nephropathy in type 2 diabetes, but effects on microvascular eye outcomes are unclear. We conducted a systematic review and meta-analysis of randomized placebo-controlled trials to evaluate the effect of SGLT2 inhibition on total ocular events and retinopathy in patients with type 2 diabetes. We searched MEDLINE and Embase for the period from database inception date to October 11, 2019. Two reviewers working independently extracted relevant data. Random-effects models with inverse variance weighting were selected to estimate summary risk ratios (RRs) and 95% confidence intervals (CIs). We included nine studies, involving 39 982 patients with a mean follow-up of 2.8 years. There were 1414 total ocular events, of which 624 were retinopathy events. SGLT2 inhibition was not associated with a change in the risk of total ocular events (RR 0.97, 95% CI 0.85, 1.11) or retinopathy (RR 0.98, 95% CI 0.84, 1.16), with consistent effects across studies (P for heterogeneity = 0.35 and 0.45, respectively). The effects of SGLT2 inhibition on eye disease in individuals with type 2 diabetes are probably null, although the available data cannot exclude small to moderate benefits or harms.

Intensive versus guideline-recommended blood pressure reduction in acute lacunar stroke with intravenous thrombolysis therapy: The ENCHANTED trial.

BACKGROUND AND PURPOSE: This was an investigation of the differential effects of early intensive versus guideline-recommended blood pressure (BP) lowering between lacunar and non-lacunar acute ischaemic stroke (AIS) in the BP arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: In 1,632 participants classified as having definite or probable lacunar (n = 454 [27.8%]) or non-lacunar AIS according to pre-specified definitions based upon clinical and adjudicated imaging findings, mean BP changes over days 0-7 were plotted, and systolic BP differences by treatment between subgroups were estimated in generalized linear models. Logistic regression models were used to estimate the BP treatment effects on 90-day outcomes (primary, an ordinal shift of modified Rankin scale scores) across lacunar and non-lacunar AIS after adjustment for baseline covariables. RESULTS: Most baseline characteristics, acute BP and other management differed between lacunar and non-lacunar AIS, but mean systolic BP differences by treatment were comparable at each time point (all pinteraction  > 0.12) and over 24 h post-randomization (-5.5, 95% CI -6.5, -4.4 mmHg in lacunar AIS vs. -5.6, 95% CI -6.3, -4.8 mmHg in non-lacunar AIS, pinteraction  = 0.93). The neutral effect of intensive BP lowering on functional outcome and the beneficial effect on intracranial haemorrhage were similar for the two subgroups (all pinteraction  > 0.19). CONCLUSIONS: There were no differences in the treatment effect of early intensive versus guideline-recommended BP lowering across lacunar and non-lacunar AIS.

Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial.

BACKGROUND: Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR). METHODS: CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope. RESULTS: At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2). CONCLUSIONS: Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.

Thrombolysis Outcomes in Acute Ischemic Stroke by Fluid-Attenuated Inversion Recovery Hyperintense Arteries.

BACKGROUND AND PURPOSE: To determine factors associated with fluid-attenuated inversion recovery (FLAIR) hyperintense arteries (FLAIR-HAs) on magnetic resonance imaging and their prognostic significance in thrombolysis-treated patients with acute ischemic stroke from the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) trial alteplase-dose arm. METHODS: Patients with acute ischemic stroke (N=293) with brain magnetic resonance imaging (FLAIR and diffusion-weighted imaging sequences) scanned <4.5 hours of symptom onset were assessed for location and extent (score) of FLAIR-HAs, infarct volume, large vessel occlusion (LVO), and other ischemic signs. Logistic regression models were used to determine predictors of FLAIR-HAs and the association of FLAIR-HAs with 90-day outcomes: favorable functional outcome (primary; modified Rankin Scale scores, 0-1), other modified Rankin Scale scores, and intracerebral hemorrhage. RESULTS: Prior atrial fibrillation, LVO, large infarct volume, and anterior circulation infarction were independently associated with FLAIR-HAs. The rate of modified Rankin Scale scores 0 to 1 was numerically lower in patients with FLAIR-HAs versus without (69/152 [45.4%] versus 75/131 [57.3%]), as was the subset of LVO (37/93 [39.8%] versus 9/16 [56.3%]), but not in those without LVO (25/36 [69.4%] versus 60/106 [56.6%]). After adjustment for covariables, FLAIR-HAs were independently associated with increased primary outcome (adjusted odds ratio [95% CI]: overall 4.14 [1.63-10.50]; with LVO 4.92 [0.87-27.86]; no LVO 6.16 [1.57-24.14]) despite an increased risk of hemorrhagic infarct (4.77 [1.12-20.26]). CONCLUSIONS: FLAIR-HAs are more frequent in acute ischemic stroke with cardioembolic features and indicate potential for a favorable prognosis in thrombolysis-treated patients possibly mediated by LVO. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01422616.

Standards for Detecting, Interpreting, and Reporting Noncontrast Computed Tomographic Markers of Intracerebral Hemorrhage Expansion.

Significant hematoma expansion (HE) affects one-fifth of people within 24 hours after acute intracerebral hemorrhage (ICH), and its prevention is an appealing treatment target. Although the computed tomography (CT)-angiography spot sign predicts HE, only a minority of ICH patients receive contrast injection. Conversely, noncontrast CT (NCCT) is used to diagnose nearly all ICH, so NCCT markers represent a widely available alternative for prediction of HE. However, different NCCT signs describe similar features, with lack of consensus on the optimal image acquisition protocol, assessment, terminology, and diagnostic criteria. In this review, we propose practical guidelines for detecting, interpreting, and reporting NCCT predictors of HE. ANN NEUROL 2019;86:480-492.

Clinical prognosis of FLAIR hyperintense arteries in ischaemic stroke patients: a systematic review and meta-analysis.

OBJECTIVE: We performed a systematic review and meta-analysis to determine the association of fluid-attenuated inversion recovery (FLAIR) hyperintense arteries (FLAIR-HAs) on brain MRI and prognosis after acute ischaemic stroke (AIS). METHODS: We searched Medline, Embase and Cochrane Central Register of Controlled Trials for studies reporting clinical or imaging outcomes with presence of FLAIR-HAs after AIS. Two researchers independently assessed eligibility of retrieved studies and extracted data, including from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Outcomes were unfavourable functional outcome (primary, modified Rankin scale scores 3-6 or 2-6), death, intermediate clinical and imaging outcomes. We performed subgroup analyses by treatment or types of FLAIR-HAs defined by location (at proximal/distal middle cerebral artery (MCA), within/beyond diffusion-weighted imaging (DWI) lesion) or extent. RESULTS: We included 36 cohort studies (33 prospectively collected) involving 3577 patients. FLAIR-HAs were not associated with functional outcome overall (pooled risk ratio 0.87, 95% CI 0.71 to 1.06), but were significantly associated with better outcome in those receiving endovascular therapy (0.56, 95% CI 0.41 to 0.75). Contrary to FLAIR-HAs at proximal MCA or within DWI lesions, FLAIR-HAs beyond DWI lesions were associated with better outcome (0.67, 95% CI 0.57 to 0.79). FLAIR-HAs favoured recanalisation (1.21, 95% CI 1.06 to 1.38) with increased risk of intracerebral haemorrhage (2.07, 95% CI 1.37 to 3.13) and early neurological deterioration (1.93, 95% CI 1.30 to 2.85). CONCLUSIONS: FLAIR-HAs were not associated with functional outcome overall but were associated with outcome after endovascular therapy for AIS. FLAIR-HAs were also associated with early recanalisation or haemorrhagic complications, and early neurologic deterioration. PROSPERO REGISTRATION NUMBER: CRD42019131168.

Brain imaging abnormalities and outcome after acute ischaemic stroke: the ENCHANTED trial.

OBJECTIVE: To test the hypothesis that imaging signs of 'brain frailty' and acute ischaemia predict clinical outcomes and symptomatic intracranial haemorrhage (sICH) after thrombolysis for acute ischaemic stroke (AIS) in the alteplase dose arm of ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED). METHODS: Blinded assessors coded baseline images for acute ischaemic signs (presence, extent, swelling and attenuation of acute lesions; and hyperattenuated arteries) and pre-existing changes (atrophy, leucoaraiosis and old ischaemic lesions). Logistic regression models assessed associations between imaging features and death at 7 and 90 days; good recovery (modified Rankin Scale scores 0-2 at 90 days) and sICH. Data are reported with adjusted ORs and 95% CIs. RESULTS: 2916 patients (67±13 years, National Institutes of Health Stroke Scale 8 (5-14)) were included. Visible ischaemic lesions, severe hypoattenuation, large ischaemic lesion, swelling and hyperattenuated arteries were associated with 7-day death (OR (95% CI): 1.52 (1.06 to 2.18); 1.51 (1.01 to 2.18); 2.67 (1.52 to 4.71); 1.49 (1.03 to 2.14) and 2.17 (1.48 to 3.18)) and inversely with good outcome. Severe atrophy was inversely associated with 7-day death (0.52 (0.29 to 0.96)). Atrophy (1.52 (1.08 to 2.15)) and severe leucoaraiosis (1.74 (1.20 to 2.54)) were associated with 90-day death. Hyperattenuated arteries were associated with sICH (1.71 (1.01 to 2.89)). No imaging features modified the effect of alteplase dose. CONCLUSIONS: Non-expert-defined brain imaging signs of brain frailty and acute ischaemia contribute to the prognosis of thrombolysis-treated AIS patients for sICH and mortality. However, these imaging features showed no interaction with alteplase dose.

Effects of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes in women versus men.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors prevent cardiovascular complications in type 2 diabetes. We aimed to study whether they have similar effects in women and men by summarizing the effects of SGLT2 inhibitors compared to placebo on vascular and safety outcomes stratified by sex. We included patients with type 2 diabetes enrolled in the EMPA-REG OUTCOME, CANVAS Program, DECLARE TIMI-58 and CREDENCE trials. There were no differences in the risk ratios between men and women, SGLT2 versus control (placebo), for vascular efficacy outcomes or death (all P for interaction ≥.12), with clear protection shown against major adverse cardiovascular events, heart failure, vascular death and total mortality. SGLT2 inhibitor treatment was also associated with similar relative risks in women and men for the safety outcomes of amputation, fracture, genital infection and urinary tract infection (all P for interaction ≥.17). SGLT2 inhibition provided similar protection against vascular risks and death, and similar risks of serious adverse events, for women and men.

Brain Imaging Signs and Health-Related Quality of Life after Acute Ischemic Stroke: Analysis of ENCHANTED Alteplase Dose Arm.

BACKGROUND AND PURPOSE: The influence of specific brain lesions on health-related quality of life (HRQoL) after acute ischemic stroke (AIS) is uncertain. We aimed to identify imaging predictors of poor HRQoL in alteplase-treated participants of the alteplase dose arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: ENCHANTED was an international trial of low- versus standard-dose intravenous alteplase in AIS patients, with functional outcome (modified Rankin scale [mRS]) and HRQoL on the 5-dimension European Quality of Life Scale (EQ-5D) assessed at 90 days post-randomization. Brain images were analyzed centrally by trained assessors. Multivariable logistic regression was undertaken in the study population randomly divided (2:1) into training (development) and validation (performance) groups, with age (per 10-year increase), ethnicity, baseline National Institutes of Health Stroke Scale (NIHSS) score, diabetes mellitus, premorbid function (mRS score 0 or 1), and proxy respondent, forced into all models. Data are presented with odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Eight prediction models were developed and validated in 2,526 AIS patients (median age 67.5 years; 38.4% female; 61.7% Asian) with complete brain imaging and 90-day EQ-5D utility score data. The best performance model included acute ischemic changes in the right (OR 1.69, 95% CI: 1.24-2.29) and deep (OR 1.50, 95% CI: 1.03-2.19) middle cerebral artery (MCA) regions. Several background features of brain frailty - atrophy, white matter change, and old infarcts - were significantly associated with adverse physical but not emotional HRQoL domains. CONCLUSIONS: In thrombolysed AIS patients, right-sided and deep ischemia within the MCA territory predict poor overall HRQoL, whilst features of old cerebral ischemia are associated with reduced physical HRQoL.

Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program.

AIMS/HYPOTHESIS: An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R. METHODS: This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time. RESULTS: A total of 496 participants recorded ≥1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls. CONCLUSIONS/INTERPRETATION: There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility. TRIAL REGISTRATION: ClinicalTrials.gov NCT01032629, NCT01989754.

Canagliflozin and Stroke in Type 2 Diabetes Mellitus.

Background and Purpose- This study reports the detailed effects of canagliflozin on stroke, stroke subtypes, and vascular outcomes in participants with and without cerebrovascular disease (stroke or transient ischemic attack) at baseline from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program. Methods- The CANVAS Program, comprising 2 similarly designed and conducted clinical trials, randomly assigned 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk to canagliflozin or placebo. Its primary outcome was a composite of major adverse cardiovascular events. The main outcome of interest for this report was fatal or nonfatal stroke. Additional exploratory outcomes were stroke subtypes and other vascular outcomes defined according to standard criteria. Results- There were 1 958 (19%) participants with prior stroke or transient ischemic attack at baseline. These individuals were older, more frequently women, and had higher rates of heart failure, atrial fibrillation, and microvascular disease (all P<0.001) compared with those without such a history. There were 309 participants with stroke events during follow-up (123 had prior stroke or transient ischemic attack at baseline and 186 did not), at a rate of 7.93/1000 patient-years among those assigned canagliflozin and 9.62/1000 patient-years among placebo (hazard ratio, 0.87; 95% CI, 0.69-1.09). Analysis of stroke subtypes found no effect on ischemic stroke (n=253, hazard ratio, 0.95; 95% CI, 0.74-1.22), a significant reduction for hemorrhagic stroke (n=30, hazard ratio, 0.43; 95% CI, 0.20-0.89) and no effect on undetermined stroke (n=29, hazard ratio, 1.04; 95% CI, 0.48-2.22). Effects on other cardiovascular outcomes were comparable among participants with and without stroke or transient ischemic attack at baseline. Conclusions- There were too few events in the CANVAS Program to separately define the effects of canagliflozin on stroke, but benefit is more likely than harm. The observed possible protective effect for hemorrhagic stroke was based on small numbers but warrants further investigation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629 and NCT01989754.

Prevalence of Driving and Traffic Accidents among People with Seizures: A Systematic Review.

BACKGROUND AND OBJECTIVES: Epilepsy influences the ability to drive. We undertook a systematic review to determine the prevalence of driving or holding a driver's license among people with seizures, the prevalence of traffic accidents among those who drive, and factors that may explain heterogeneity in these point estimates. METHOD: We followed MOOSE and PRISMA guidelines in searching 8 databases from inception to June 27, 2018. All published observational studies were included, with the exception of case-control studies where prevalence could not be determined, case reports, and studies with fewer than 50 participants. We assessed external and internal validity and quality of studies, produced forest plots, and conducted meta-regression in "Stata 13." RESULTS: Data were available from 67 studies published between 1967 and 2018. Across the studies there was a wide range in the prevalence of driving (3-90%) and holding a driver's license (8-98%). Up to 39% of people with epilepsy drove in violation of restrictions. Prevalence of traffic accidents ranged from 0 to 61% following seizure onset, or in the past 1-5 years. The percentage of people with seizures who drove decreased as time since diagnosis increased (p = 0.01, adjusted R2 = 31%). The number of people with seizures who drove or held a driver's license appears to have increased over time (p = 0.02, adjusted R2 = 7%) but without a corresponding increase in the number of traffic accidents. There was considerable heterogeneity between studies related to definitions, design, and population differences. CONCLUSIONS: There is considerable variation in the prevalence of driving after a diagnosis of epilepsy and in reported motor vehicle accidents. Further efforts are required to better understand the impact of epilepsy, and epilepsy surgery, on driving and road safety, especially where driving continues in violation of restrictions. Policy changes are needed to encourage the introduction of available and affordable alternatives for driving, for example, developing public transport networks, and promoting subsidy schemes to encourage use of public transport, taxis, Uber, and Lyft, among people experiencing seizures.

Who is driving and who is prone to have traffic accidents? A systematic review and meta-analysis among people with seizures.

INTRODUCTION: Epilepsy influences the ability to drive. We aimed to systematically summarize factors associated with driving, holding a driver's license, and traffic accidents among people with seizures. MATERIAL AND METHODS: Eight databases were searched (from their inception to 27 June 2018). We included all published observational studies, except for case reports and studies with fewer than 50 participants. Pooled mean differences and pooled risk ratios (pRRs) with corresponding confidence intervals (CIs) were calculated using random effects. RESULTS: Data were available from 18 studies, reporting a wide range of factors. There were frequent biases associated with cross-sectional study designs, selection bias, poor statistical quality, small samples, and lack of validation of models. The following six variables were consistently associated with driving: male gender (pRR: 1.42; 95% CI: 1.23 to 1.64), being in paid work (pRR: 1.72; 95% CI: 1.46 to 2.03), married (pRR: 1.26; 95% CI: 1.01 to 1.57), older age at seizure onset or diagnosis (pooled mean difference: 4.83; 95% CI: 0.48 to 9.18 years), less frequent seizures (fewer than monthly, pRR: 1.32; 95% CI: 1.12 to 1.56), and taking one or no antiepileptic drug (pRR: 1.34; 95% CI: 1.09 to 1.63). Lower seizure frequency was also protective for avoiding traffic accidents (pRR: 0.26; 95% CI: 0.10 to 0.66). DISCUSSION: Stable multivariate models to predict driving or traffic accidents among people with seizures have not yet been developed. Current evidence shows that the likelihood of driving is associated with demographic and epilepsy-related factors, while the risk of traffic accidents is associated with seizure frequency.

Comparison of Treatment Rates of Depression After Stroke Versus Myocardial Infarction: A Systematic Review and Meta-Analysis of Observational Data.

OBJECTIVE: Depression after stroke and myocardial infarction (MI) is common but often assumed to be undertreated without reliable evidence being available. Thus, we aimed to determine treatment rates and investigate the application of guidelines in these conditions. METHODS: Databases MEDLINE, EMBASE, PsycInfo, Web of Science, CINAHL, and Scopus were systematically searched without language restriction from inception to June 30, 2017. Prospective observational studies with consecutive recruitment reporting any antidepressant treatment in adults with depression after stroke or MI were included. Random-effects models were used to calculate pooled estimates of treatment rates. RESULTS: Fifty-five studies reported 32 stroke cohorts (n = 8938; pooled frequency of depression = 34%, 95% confidence interval [CI] = 29%-38%) and 17 MI cohorts (n = 10,767; pooled frequency of depression = 24%, 95% CI = 20%-28%). In 29 stroke cohorts, 24% (95% CI = 20%-27%) of 2280 depressed people used antidepressant medication. In 15 MI cohorts, 14% (95% CI = 8%-19%) of 2381 depressed people used antidepressant medication indicating a lower treatment rate than in stroke. Two studies reported use of psychosocial interventions, indicating that less than 10% of participants were treated. CONCLUSIONS: Despite the high frequency of depression after stroke and MI and the existence of efficacious treatment strategies, people often remain untreated. Innovative strategies are needed to increase the use of effective antidepressive interventions in patients with cardiovascular disease.

Effectiveness and Safety of Antibiotics for Preventing Pneumonia and Improving Outcome after Acute Stroke: Systematic Review and Meta-analysis.

BACKGROUND: Pneumonia is a common complication after stroke which increases morbidity and mortality. This systematic review was conducted to evaluate the efficacy and safety of antibiotics for the prevention of pneumonia after acute stroke. METHODS: Medline, EMBASE, and Cochrane databases were searched for randomized controlled trials comparing preventive antibiotics to placebo or no antibiotics after acute stroke. The primary outcome was poststroke pneumonia. Secondary outcomes were all infections, urinary tract infections, death, dependency, length of hospital stay, and adverse events. Treatment effects were summarized using random effects metaanalysis. RESULTS: Six trials (4111 patients) were eligible for inclusion. The median National Institute of Health Stroke Scale score in included trials ranged from 5 to 16.5. The proportion of dysphagia ranged from 26% to 100%. Preventive antibiotics were commenced within 48hours after acute stroke. Compared to control, preventive antibiotics reduced the risk of poststroke pneumonia (RR .75, 95%CI ·.57-.99), and all infections (RR .58, 95%CI .48-.69). There was no significant difference in the risks of dependency (RR 0.99, 95%CI 0·80-1·11), or mortality (RR .96, 95%CI .78-1.19) between the preventive antibiotics and control groups. Preventive antibiotics did not increase the risk of elevated liver enzymes (RR 1.20, 95% CI .97-1.49). Preventive antibiotics had uncertain effects on the risks of other adverse events. CONCLUSION: Preventive antibiotics reduced the risk of post-stroke pneumonia. However, there is insufficient evidence to currently recommend routine use of preventive antibiotics after acute stroke.

Evaluation of carotid plaque vulnerability in vivo: Correlation between dynamic contrast-enhanced MRI and MRI-modified AHA classification.

PURPOSE: To noninvasively monitor carotid plaque vulnerability by exploring the relationship between pharmacokinetic parameters (PPs) of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and plaque types based on MRI-modified American Heart Association (AHA) classification, as well as to assess the ability of PPs in discrimination between stable and vulnerable plaques suspected on MRI. MATERIALS AND METHODS: Of 70 consecutive patients with carotid plaques who volunteered for 3.0T MRI (3D time-of-flight [TOF], T1 -weighted, T2 -weighted, 3D magnetization-prepared rapid acquisition gradient-echo [MP-RAGE] and DCE-MRI), 66 participants were available for analysis. After plaque classification according to MRI-modified AHA Lesion-Type (LT), PPs (Ktrans , kep , ve , and vp ) of DCE-MRI were measured. The Extended Tofts model was used for calculation of PPs. For participants with multiple carotid plaques, the plaque with the worst MRI-modified AHA LT was chosen for analysis. Correlations between PPs and plaque types and the ability of these parameters to distinguish stable and vulnerable plaques suspected on MRI were assessed. RESULTS: Significant positive correlation between Ktrans and LT III to VI was found (ρ = 0.532, P < 0.001), as was the correlation between kep and LT III to VI (ρ = 0.409, P < 0.001). Stable and vulnerable plaques suspected on MRI could potentially be distinguished by Ktrans (sensitivity 83%, specificity 100%) and kep (sensitivity 77%, specificity 91%). CONCLUSION: Ktrans and kep from DCE-MRI can provide quantitative information to monitor plaque vulnerability in vivo and differentiate vulnerable plaques suspected on MRI from stable ones. These two parameters could be adopted as imaging biomarkers for plaque characterization and risk stratification. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:870-876.