Carotid Sources of Stroke.

The ancient Greeks used the term karotides for the great arteries in the neck, compression of which could plunge the victim into karoun: deep sleep or stupor. The artery name aside, studies of the patterns of brain infarction and their clinical severity have been an unbroken chain of growing sophistication in the past 150 years. Two main patterns emerged: perfusion failure with high-convexity infarction from hemodynamically important ipsilateral carotid stenosis or embolism from nonstenosing carotid plaque.

Heart Failure Severity and Quality of Warfarin Anticoagulation Control (From the WARCEF Trial).

Previous studies in patients with atrial fibrillation showed that a history of heart failure (HF) could negatively impact anticoagulation quality, as measured by the average time in therapeutic range (TTR). Whether additional markers of HF severity are associated with TTR has not been investigated thoroughly. We aimed to examine the potential role of HF severity in the quality of warfarin control in patients with HF with reduced ejection fraction. Data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial were used to investigate the association between TTR and HF severity. Multivariable logistic regression models were used to examine the association of markers of HF severity, including New York Heart Association (NYHA) class, Minnesota Living with HF (MLWHF) score, and frequency of HF hospitalization, with TTR ≥70% (high TTR). We included 1,067 participants (high TTR, N = 413; low TTR, N = 654) in the analysis. In unadjusted analysis, patients with a high TTR were older and less likely to have had strokes or receive other antiplatelet agents. Those patients also had lower NYHA class, better MLWHF scores, greater 6-minute walk distance, and lower frequency of HF hospitalizations. Multivariable analysis showed that NYHA class III and/or IV (Odds ratio [OR] 0.68 [95% confidence intervals [CIs] 0.49 to 0.94]), each 10-point increase in MLWHF score (i.e., worse health-related quality of life) (OR 0.92 [0.86 to 0.99]), and higher number of HF hospitalization per year (OR0.45 [0.30 to 0.67]) were associated with decreased likelihood of having high TTR. In HF patients with systolic dysfunction, NYHA class III and/or IV, poor health-related quality of life, and a higher rate of HF hospitalization were independently associated with suboptimal quality of warfarin anticoagulation control. These results affirm the need to assess the new approaches, such as direct oral anticoagulants, to prevent thromboembolism in this patient population.

Functional impairments for outcomes in a randomized trial of unruptured brain AVMs.

OBJECTIVE: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA). METHODS: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013. RESULTS: After a median of 33.3 months of follow-up (interquartile range 16.3-49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score ≥2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11-0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04-0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001). CONCLUSION: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades. CLINICALTRIALSGOV IDENTIFIER: NCT00389181. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over ≈3 years.

Aspirin Does Not Increase Heart Failure Events in Heart Failure Patients: From the WARCEF Trial.

OBJECTIVES: The aim of this study was to determine whether aspirin increases heart failure (HF) hospitalization or death in patients with HF with reduced ejection fraction receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). BACKGROUND: Because of its cyclooxygenase inhibiting properties, aspirin has been postulated to increase HF events in patients treated with ACE inhibitors or ARBs. However, no large randomized trial has addressed the clinical relevance of this issue. METHODS: We compared aspirin and warfarin for HF events (hospitalization, death, or both) in the 2,305 patients enrolled in the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial (98.6% on ACE inhibitor or ARB treatment), using conventional Cox models for time to first event (489 events). In addition, to examine multiple HF hospitalizations, we used 2 extended Cox models, a conditional model and a total time marginal model, in time to recurrent event analyses (1,078 events). RESULTS: After adjustment for baseline covariates, aspirin- and warfarin-treated patients did not differ in time to first HF event (adjusted hazard ratio: 0.87; 95% confidence interval: 0.72 to 1.04; p = 0.117) or first hospitalization alone (adjusted hazard ratio: 0.88; 95% confidence interval: 0.73 to 1.06; p = 0.168). The extended Cox models also found no significant differences in all HF events or in HF hospitalizations alone after adjustment for covariates. CONCLUSIONS: Among patients with HF with reduced ejection fraction in the WARCEF trial, there was no significant difference in risk of HF events between the aspirin and warfarin-treated patients. (Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial [WARCEF]; NCT00041938).

Protein interaction networks at the host-microbe interface in Diaphorina citri, the insect vector of the citrus greening pathogen.

The Asian citrus psyllid (Diaphorina citri) is the insect vector responsible for the worldwide spread of 'Candidatus Liberibacter asiaticus' (CLas), the bacterial pathogen associated with citrus greening disease. Developmental changes in the insect vector impact pathogen transmission, such that D. citri transmission of CLas is more efficient when bacteria are acquired by nymphs when compared with adults. We hypothesize that expression changes in the D. citri immune system and commensal microbiota occur during development and regulate vector competency. In support of this hypothesis, more proteins, with greater fold changes, were differentially expressed in response to CLas in adults when compared with nymphs, including insect proteins involved in bacterial adhesion and immunity. Compared with nymphs, adult insects had a higher titre of CLas and the bacterial endosymbionts Wolbachia, Profftella and Carsonella. All Wolbachia and Profftella proteins differentially expressed between nymphs and adults are upregulated in adults, while most differentially expressed Carsonella proteins are upregulated in nymphs. Discovery of protein interaction networks has broad applicability to the study of host-microbe relationships. Using protein interaction reporter technology, a D. citri haemocyanin protein highly upregulated in response to CLas was found to physically interact with the CLas coenzyme A (CoA) biosynthesis enzyme phosphopantothenoylcysteine synthetase/decarboxylase. CLas pantothenate kinase, which catalyses the rate-limiting step of CoA biosynthesis, was found to interact with a D. citri myosin protein. Two Carsonella enzymes involved in histidine and tryptophan biosynthesis were found to physically interact with D. citri proteins. These co-evolved protein interaction networks at the host-microbe interface are highly specific targets for controlling the insect vector responsible for the spread of citrus greening.

CHA2 DS2 -VASc score and adverse outcomes in patients with heart failure with reduced ejection fraction and sinus rhythm.

AIMS: The aim of this study was to determine whether the CHA2 DS2 -VASc score can predict adverse outcomes such as death, ischaemic stroke, and major haemorrhage, in patients with systolic heart failure in sinus rhythm. METHODS AND RESULTS: CHA2 DS2 -VASc scores were calculated for 1101 patients randomized to warfarin and 1123 patients randomized to aspirin. Adverse outcomes were defined as death or ischaemic stroke, death alone, ischaemic stroke alone, and major haemorrhage. Using proportional hazards models, we found that each 1-point increase in the CHA2 DS2 -VASc score was associated with increased hazard of death or ischaemic stroke events [hazard ratio (HR) for the warfarin arm = 1.21, 95% confidence interval (CI) 1.13-1.30, P < 0.001; for aspirin, HR = 1.20, 95% CI 1.11-1.29, P < 0.001]. Similar increased hazards for higher CHA2 DS2 -VASc scores were observed for death alone, ischaemic stroke alone, and major haemorrhage. Overall performance of the CHA2 DS2 -VASc score was assessed using c-statistics for full models containing the risk score, treatment assignment, and score-treatment interaction, with the c-statistics for the full models ranging from 0.57 for death to 0.68 for major haemorrhage. CONCLUSIONS: The CHA2 DS2 -VASc score predicted adverse outcomes in patients with systolic heart failure in sinus rhythm, with modest prediction accuracy.

Left Ventricular Ejection Fraction and Risk of Stroke and Cardiac Events in Heart Failure: Data From the Warfarin Versus Aspirin in Reduced Ejection Fraction Trial.

BACKGROUND AND PURPOSE: In heart failure (HF), left ventricular ejection fraction (LVEF) is inversely associated with mortality and cardiovascular outcomes. Its relationship with stroke is controversial, as is the effect of antithrombotic treatment. We studied the relationship of LVEF with stroke and cardiovascular events in patients with HF and the effect of different antithrombotic treatments. METHODS: In the Warfarin Versus Aspirin in Reduced Ejection Fraction (WARCEF) trial, 2305 patients with systolic HF (LVEF≤35%) and sinus rhythm were randomized to warfarin or aspirin and followed for 3.5±1.8 years. Although no differences between treatments were observed on primary outcome (death, stroke, or intracerebral hemorrhage), warfarin decreased the stroke risk. The present report compares the incidence of stroke and cardiovascular events across different LVEF and treatment subgroups. RESULTS: Baseline LVEF was inversely and linearly associated with primary outcome, mortality and its components (sudden and cardiovascular death), and HF hospitalization, but not myocardial infarction. A relationship with stroke was only observed for LVEF of <15% (incidence rates: 2.04 versus 0.95/100 patient-years; P=0.009), which more than doubled the adjusted stroke risk (adjusted hazard ratio, 2.125; 95% CI, 1.182-3.818; P=0.012). In warfarin-treated patients, each 5% LVEF decrement significantly increased the stroke risk (adjusted hazard ratio, 1.346; 95% CI, 1.044-1.737; P=0.022; P value for interaction=0.04). CONCLUSIONS: In patients with systolic HF and sinus rhythm, LVEF is inversely associated with death and its components, whereas an association with stroke exists for very low LVEF values. An interaction with warfarin treatment on stroke risk may exist. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938.

The first prognostic model for stroke and death in patients with systolic heart failure.

BACKGROUND: Patients with systolic heart failure (HF) are at increased risk of both ischemic stroke and death. Currently, no risk scores are available to identify HF patients at high risk of stroke or death. The Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial studied 2305 HF patients, in sinus rhythm, followed for up to 6 years (3.5±1.5 years). This trial showed no overall difference in those treated with warfarin vs aspirin with regard to death or stroke. The present study develops the first prognostic model to identify patients at higher risk of stroke or death based on their overall risk profile. METHODS AND RESULTS: A scoring algorithm using 8 readily obtainable clinical characteristics as predictors, age, gender, hemoglobin, blood urea nitrogen, ejection fraction, diastolic blood pressure, diabetes status, and prior stroke or transient ischemic attack (C-index=0.65, 95% CI: 0.613-0.681), was developed. It was validated internally using a bootstrap method. In predicting 1-year survival for death alone, our 8-predictor model had an AUC of 0.63 (95% CI: 0.579-0.678) while the 14-predictor Seattle model had an AUC of 0.72. The Seattle model did not report stroke. CONCLUSIONS: This novel prognostic model predicts the overall risk of ischemic stroke or death for HF patients. This model compares favorably for death with the Seattle model and has the added utility of including stroke as an endpoint. Use of this model will help identify those patients in need of more intensive monitoring and therapy and may help identify appropriate populations for trials of new therapies. CLINICAL TRIAL REGISTRATION: http://www.Clinicatrials.govNCT00041938.

Bleeding Risk and Antithrombotic Strategy in Patients With Sinus Rhythm and Heart Failure With Reduced Ejection Fraction Treated With Warfarin or Aspirin.

We sought to assess the performance of existing bleeding risk scores, such as the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly (HAS-BLED) score or the Outpatient Bleeding Risk Index (OBRI), in patients with heart failure with reduced ejection fraction (HFrEF) in sinus rhythm (SR) treated with warfarin or aspirin. We calculated HAS-BLED and OBRI risk scores for 2,305 patients with HFrEF in SR enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial. Proportional hazards models were used to test whether each score predicted major bleeding, and comparison of different risk scores was performed using Harell C-statistic and net reclassification improvement index. For the warfarin arm, both scores predicted bleeding risk, with OBRI having significantly greater C-statistic (0.72 vs 0.61; p = 0.03) compared to HAS-BLED, although the net reclassification improvement for comparing OBRI to HAS-BLED was not significant (0.32, 95% confidence interval [CI] -0.18 to 0.37). Performance of the OBRI and HAS-BLED risk scores was similar for the aspirin arm. For participants with OBRI scores of 0 to 1, warfarin compared with aspirin reduced ischemic stroke (hazard ratio [HR] 0.51, 95% CI 0.26 to 0.98, p = 0.042) without significantly increasing major bleeding (HR 1.24, 95% CI 0.66 to 2.30, p = 0.51). For those with OBRI score of ≥2, there was a trend for reduced ischemic stroke with warfarin compared to aspirin (HR 0.56, 95% CI 0.27 to 1.15, p = 0.12), but major bleeding was increased (HR 4.04, 95% CI 1.99 to 8.22, p <0.001). In conclusion, existing bleeding risk scores can identify bleeding risk in patients with HFrEF in SR and could be tested for potentially identifying patients with a favorable risk/benefit profile for antithrombotic therapy with warfarin.

Management of unbled brain arteriovenous malformation study.

In a recent trial limited to arteriovenous malformations discovered not to have bled, medical management was superior to medical management plus intervention. The trial was halted after 226 randomizations and a mean follow-up of 3.3 years owing to a disparity favoring the medical arm. Eligible patients were selected as suitable for lesion eradication. The initial sample size of 800 and follow-up plans for a mean of 7 years were lowered and shortened, respectively, by the outcome data. An application for extended follow-up was given poor priority scores owing to estimations that the disparities in outcomes would not change significantly.

Acute management of brain arteriovenous malformations.

OPINION STATEMENT: Major reasons to treat brain arteriovenous malformations (AVMs) are to reduce the risk of brain hemorrhage, control intractable seizure, and in some cases alleviate neurologic deficits. Once an AVM has hemorrhaged, the risk of further hemorrhage is increased and it should be treated. The treatment plan ideally is based on interdisciplinary discussion between neurosurgery, endovascular neuroradiology, and radiotherapy, moderated by neurology in an experienced center. Complete removal or obliteration of the malformation should be the goal, as partial treatment only exposes the patient to treatment risks with a residual hemorrhage risk. If an AVM is surgically accessible with acceptable treatment risk, neurosurgical removal leads to the fastest and most complete reduction of hemorrhage risk. Radiotherapy is best used in small AVMs with contraindications to surgery. Endovascular embolization can be used as an adjunct for both to facilitate removal or obliteration or to reduce risks from associated aneurysms or high-flow fistulae, and may in some cases lead to complete occlusion. Unbled AVMs require a thorough assessment of projected hemorrhage risk versus treatment risks, as the natural course is influenced by clinical and morphological factors. Given recent scientific evidence, those with low projected hemorrhage risks should be managed conservatively, receiving the best medical treatment of accompanying symptoms, and careful clinical and follow-up imaging monitoring. Thorough and objective counselling of the patients about pros and contras of therapy, detailed explanation of recommendations, and possible reevaluation of treatment decisions at later timepoints are recommended.

Quality of anticoagulation control in preventing adverse events in patients with heart failure in sinus rhythm: Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial substudy.

BACKGROUND: The aim of this study is to examine the relationship between time in the therapeutic range (TTR) and clinical outcomes in heart failure patients in sinus rhythm treated with warfarin. METHODS AND RESULTS: We used data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial to assess the relationship of TTR with the WARCEF primary outcome (ischemic stroke, intracerebral hemorrhage, or death), with death alone, ischemic stroke alone, major hemorrhage alone, and net clinical benefit (primary outcome and major hemorrhage combined). Multivariable Cox models were used to examine how the event risk changed with TTR and to compare the high TTR, low TTR, and aspirin-treated patients, with TTR being treated as a time-dependent covariate. A total of 2217 patients were included in the analyses; among whom 1067 were randomized to warfarin and 1150 were randomized to aspirin. The median (interquartile range) follow-up duration was 3.6 (2.0-5.0) years. Mean (±SD) age was 61±11.3 years, with 80% being men. The mean (±SD) TTR was 57% (±28.5%). Increasing TTR was significantly associated with reduction in primary outcome (adjusted P<0.001), death alone (adjusted P=0.001), and improved net clinical benefit (adjusted P<0.001). A similar trend was observed for the other 2 outcomes, but significance was not reached (adjusted P=0.082 for ischemic stroke and adjusted P=0.109 for major hemorrhage). CONCLUSIONS: In patients with heart failure in sinus rhythm, increasing TTR is associated with better outcome and improved net clinical benefit. Patients in whom good quality anticoagulation can be achieved may benefit from the use of anticoagulants. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938.

Cognitive function in ambulatory patients with systolic heart failure: insights from the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.

We sought to determine whether cognitive function in stable outpatients with heart failure (HF) is affected by HF severity. A retrospective, cross-sectional analysis was performed using data from 2, 043 outpatients with systolic HF and without prior stroke enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial. Multivariable regression analysis was used to assess the relationship between cognitive function measured using the Mini-Mental Status Exam (MMSE) and markers of HF severity (left ventricular ejection fraction [LVEF], New York Heart Association [NYHA] functional class, and 6-minute walk distance). The mean (SD) for the MMSE was 28.6 (2.0), with 64 (3.1%) of the 2,043 patients meeting the cut-off of MMSE <24 that indicates need for further evaluation of cognitive impairment. After adjustment for demographic and clinical covariates, 6-minute walk distance (ß-coefficient 0.002, p<0.0001), but not LVEF or NYHA functional class, was independently associated with the MMSE as a continuous measure. Age, education, smoking status, body mass index, and hemoglobin level were also independently associated with the MMSE. In conclusion, six-minute walk distance, but not LVEF or NYHA functional class, was an important predictor of cognitive function in ambulatory patients with systolic heart failure.

Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial.

BACKGROUND: The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy. METHODS: Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181. FINDINGS: Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months [SD 19·7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14-0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management. INTERPRETATION: The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Stroke in heart failure in sinus rhythm: the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial.

BACKGROUND: The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses. METHODS: We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions. RESULTS: Twenty-nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3-5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic, possible cardioembolic and noncardioembolic stroke including both warfarin and aspirin groups. CONCLUSIONS: The observed benefits in the reduction of IIS for warfarin compared to aspirin are most significant for cardioembolic IIS among patients with low ejection fraction in sinus rhythm. This is supported by trends to lower frequencies of severe IIS and possible cardioembolic IIS in patients on warfarin compared to aspirin.