vitamin-k-semiquinone-radical and Brain-Ischemia

Observational studies have investigated the effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) used in nonvalvular atrial fibrillation. We performed a systematic review and meta-analysis assessing the risk of ischaemic stroke, thromboembolism (TE) and intracranial haemorrhage (ICH) associated with the use of DOACs and VKAs.. Medline and Embase were systematically searched until April 2021. Observational studies were gathered and hazard ratios (HRs) with 95% confidence intervals (CI) were extracted. Subgroup analyses based on DOAC doses, history of chronic kidney disease, stroke, exposure to VKA, age and sex were performed. A random-effects model was used.. We included 92 studies and performed 107 comparisons. Apixaban was associated with lower risk of stroke (HR: 0.82, 95% CI: 0.68-0.99) compared to dabigatran. Rivaroxaban was associated with lower risk of stroke (HR: 0.90, 95% CI: 0.83-0.98) compared to VKA. Dabigatran (HR: 0.85, 95% CI: 0.80-0.91), rivaroxaban (HR: 0.83, 95% CI: 0.77-0.89) and apixaban (HR: 0.75, 95% CI: 0.65-0.86) were associated with lower risk for TE/stroke compared to VKA. Apixaban (HR: 1.32, 95% CI: 1.03-1.68) and rivaroxaban (HR: 1.58, 95% CI: 1.31-1.89) were associated with higher risk of ICH compared to dabigatran. Dabigatran (HR: 0.48, 95% CI: 0.44-0.52), apixaban (HR: 0.60, 95% CI: 0.49-0.73) and rivaroxaban (HR: 0.73, 95% CI: 0.65-0.81) were associated with lower risk of ICH compared to VKA.. Our study demonstrated significant differences in the risk of ischaemic stroke, TE/stroke and ICH associated with individual DOACs compared to both other DOACs and VKA.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Dabigatran; Humans; Intracranial Hemorrhages; Ischemic Stroke; Pyridones; Rivaroxaban; Stroke; Thromboembolism; Vitamin K

Hypertension is common in patients with atrial fibrillation (AF) and carries an additional risk for complications, most notably stroke and bleeding. We assessed the history of hypertension, level of blood pressure control, and an interaction with the choice of oral anticoagulants on clinical outcomes.. We performed a systematic review and meta-analysis of studies that randomised patients to novel oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) and reported outcomes stratified by presence of hypertension. Collected outcomes were: ischaemic stroke or systemic embolism (SE), haemorrhagic stroke, intracranial haemorrhage and major bleeding. Log adjusted hazard ratios (HR) and corresponding standard error were calculated, and HRs were compared using Mantel-Haenszel random effects. Quality of the evidence was assessed with Cochrane risk of bias tool.. Five high-quality studies were eligible, including 71.527 participants who received NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) or VKAs, with median follow-up of 1.8-2.8 years. Compared with patients without hypertension, those with hypertension had higher adjusted risk for ischaemic stroke/SE (HR: 1.25, 95%-CI:1.09, 1.43) and haemorrhagic stroke (HR:1.98, 1.24-3.16). On a continuous scale, the risk of ischaemic stroke/SE increased 6-7% per 10 mmHg increase in systolic blood pressure. No interactions were found between the efficacy or safety of NOACs versus VKAs in the presence or absence of hypertension. In both groups, the use of NOACs led to a lower risk of ischaemic stroke/SE, haemorrhagic stroke and intracranial haemorrhage compared with patients that used VKAs.. Adequate blood pressure management is vital to optimally reduce the risk of stroke in patients with atrial fibrillation. The benefits of NOACs over VKAs, also apply to patients with elevated blood pressure.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Embolism; Hemorrhage; Hemorrhagic Stroke; Humans; Hypertension; Intracranial Hemorrhages; Ischemic Stroke; Stroke; Vitamin K

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Brain Ischemia; COVID-19; Drug Monitoring; Drug Substitution; Factor Xa Inhibitors; Humans; Inpatients; Prognosis; SARS-CoV-2; Thrombophilia; Venous Thromboembolism; Vitamin K

In this pooled analysis of seven multicentre cohorts potential differences were investigated in the incidence, characteristics and outcomes between intracranial haemorrhages (ICHs) associated with the use of non-vitamin K antagonist oral anticoagulants (NOAC-ICH) or with vitamin K antagonists (VKA-ICH) in ischaemic stroke patients after oral anticoagulant treatment initiation for atrial fibrillation (AF).. Data from 4912 eligible AF patients who were admitted in a stroke unit with ischaemic stroke or transient ischaemic attack and who were treated with either VKAs or NOACs within 3 months post-stroke were included. Fatal ICH was defined as death occurring during the first 30 days after ICH onset. A meta-analysis of available observational studies reporting 30-day mortality rates from NOAC-ICH or VKA-ICH onset was additionally performed.. During 5970 patient-years of follow-up 71 participants had an ICH, of whom 20 were NOAC-ICH and 51 VKA-ICH. Patients in the two groups had comparable baseline characteristics, except for the higher prevalence of kidney disease in VKA-ICH patients. There was a non-significant higher number of fatal ICH in patients with VKAs (11 events per 3385 patient-years) than in those with NOACs (three events per 2623 patient-years; hazard ratio 0.32, 95% confidence interval 0.09-1.14). Three-month functional outcomes were similar (P > 0.2) in the two groups. The meta-analysis showed a lower 30-day mortality risk for patients with NOAC-ICH compared to VKA-ICH (relative risk 0.70, 95% confidence interval 0.51-0.95).. Non-vitamin K oral anticoagulants for intracranial haemorrhages and VKA-ICH occurring during secondary stroke prevention of AF patients have comparable baseline characteristics and outcomes except for the risk of fatal ICH within 30 days, which might be greater in VKA-ICH.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Humans; Intracranial Hemorrhages; Stroke; Vitamin K

To assess the effectiveness of direct oral anticoagulants vs vitamin K antagonists in real-life patients with atrial fibrillation.. A systematic review was performed according to Cochrane methodological standards. The results were reported according to the PRISMA statement. The ROBINS-I tool was used to assess risk of bias.. A total of 27 different studies publishing data in 30 publications were included. In the studies with a follow-up up to 1 year, apixaban (HR, 0.93; 95%CI, 0.71-1.20) and dabigatran (HR, 0.95; 95%CI, 0.80-1.13) did not significantly reduce the risk of ischemic stroke vs warfarin, whereas rivaroxaban significantly reduced this risk (HR, 0.83; 95%CI, 0.73-0.94). Apixaban (HR, 0.66; 95%CI, 0.55-0.80) and dabigatran (HR, 0.83; 95%CI, 0.70-0.97) significantly reduced the major bleeding risk vs warfarin, but not rivaroxaban (HR, 1.02; 95%CI, 0.95-1.10), although with a high statistical heterogeneity among studies. Apixaban (HR, 0.56; 95%CI, 0.42-0.73), dabigatran (HR, 0.45; 95%CI, 0.39-0.51), and rivaroxaban (HR, 0.66; 95%CI, 0.49-0.88) significantly reduced the risk of intracranial bleeding vs warfarin. Reduced doses of direct oral anticoagulants were associated with a slightly better safety profile, but with a marked reduction in stroke prevention effectiveness.. Data from this meta-analysis suggest that, vs warfarin, the stroke prevention effectiveness and bleeding risk of direct oral anticoagulants may differ in real-life patients with atrial fibrillation.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Case-Control Studies; Dabigatran; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hemorrhage; Humans; Male; Middle Aged; Observational Studies as Topic; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Treatment Outcome; Vitamin K; Warfarin

Non-vitamin K antagonist oral anticoagulants (NOAC) are equally or potentially superior in terms of effectiveness in the prevention of ischemic stroke and carry a lower associated risk of intracranial hemorrhage compared to Vitamin K antagonists. Nevertheless, ischemic strokes also occur in patients who are being treated with NOAC. In those particular patients, knowledge about the underlying stroke etiology, clinical presentation, acute management, and complication rates is scarce.. Systematic literature review to provide a comprehensive clinical overview in terms of presentation, laboratory, imaging parameters and outcomes of patients suffering from acute cerebral ischemic events (i.e. TIA and acute ischemic stroke) while on treatment with a NOAC. Only if available, comparison to VKA is presented which was not the primary focus of this analysis.. PubMed/MEDLINE, Scopus and EMBASE from January 1, 2006, to November 20, 2018.. 52 studies providing detailed information on a total of 12247 patients were included. We excluded case reports and case series with less than five patients.. We systematically assessed study quality using a bias tool and pooled consistent data.. Existing data indicates milder stroke severity and smaller infarct size of acute ischemic stroke on treatment with NOAC compared to stroke occurrence on Vitamin K antagonists (VKA). Established risk factors for ischemic events also play a role in stroke while on NOACs, albeit the underlying etiology remains poorly understood. Intravenous thrombolysis and endovascular therapy seem to be safe and effective, but patient selection for recanalization therapies is challenging.. Limited quality of published data, duplicate cases, statistical issues of data pooling, possible incomplete retrieval of identified research and reporting bias might have limited our findings.. Acute ischemic events despite treatment with NOAC therapy are insufficiently investigated.. PROSPERO: CRD42018074853.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Endovascular Procedures; Female; Humans; Ischemic Attack, Transient; Male; Reperfusion; Risk Factors; Stroke; Thrombolytic Therapy; Vitamin K

Hemostasis is a dynamic process that starts in utero. The coagulation system evolves with age, as evidenced by marked physiological differences in the concentration of the majority of hemostatic proteins in early life compared with adulthood. This concept, known as "developmental hemostasis," has important biological and clinical implications. Overall, impaired platelet function, along with physiologically reduced levels of vitamin K-dependent and contact coagulation factors, may cause poorer clot firmness even in healthy neonates. However, increased activity of von Willebrand factor and low levels of coagulation inhibitors that promote hemostasis counterbalance the delicate and immature hemostatic system. Since this hemostatic system has little reserve capacity, preterm neonates or sick infants are extremely vulnerable and predisposed to either hemorrhagic or thrombotic complications. This review will address the concept and manifestations of developmental hemostasis with respect to clinical disease phenotypes. It will discuss bleeding diagnosis in neonates, dealing especially with the devastating complications of intracerebral and pulmonary hemorrhage in preterm infants. Neonates, especially the sickest preterm ones, are also extremely susceptible to thrombotic complications; thus, thrombosis in neonates will be reviewed, with special focus on arterial ischemic perinatal stroke. Based on the concept of developmental hemostasis, the phenotypes of clinically relevant bleeding or thrombotic disorders among neonates may differ from those of older infants and children. Treatment options for these conditions will be suggested and reviewed.

Topics: Brain Ischemia; Female; Hemorrhage; Hemostasis; Humans; Infant, Newborn; Infant, Premature; Male; Stroke; Thrombosis; Vitamin K; von Willebrand Factor

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Hemorrhage; Humans; Stroke; Thromboembolism; Vitamin K; Warfarin

To perform a systematic review and meta-analysis of studies reporting recurrent intracranial hemorrhage (ICH) and ischemic stroke (IS) in ICH survivors with atrial fibrillation (AF) during long-term follow-up.. A comprehensive literature search including MEDLINE, EMBASE, Cochrane library, clinical trials registry was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We considered studies capturing outcome events (ICH recurrence and IS) for ≥3 months and treatment exposure to vitamin K antagonists (VKAs), antiplatelet agents (APAs), or no antithrombotic medication (no-ATM). Corresponding authors provided aggregate data for IS and ICH recurrence rate between 6 weeks after the event and 1 year of follow-up for each treatment exposure. Meta-analyses of pooled rate ratios (RRs) were conducted with the inverse variance method.. Seventeen articles met inclusion criteria. Seven observational studies enrolling 2,452 patients were included in the meta-analysis. Pooled RR estimates for IS were lower for VKAs compared to APAs (RR = 0.45, 95% confidence interval [CI] 0.27-0.74,. In observational studies, anticoagulation with VKA is associated with a lower rate of IS than APA or no-ATM without increasing ICH recurrence significantly. A randomized controlled trial is needed to determine the net clinical benefit of anticoagulation in ICH survivors with AF.

Topics: Atrial Fibrillation; Brain Ischemia; Fibrinolytic Agents; Humans; Intracranial Hemorrhages; Platelet Aggregation Inhibitors; Stroke; Vitamin K

As non-valvular atrial fibrillation (AF) brings a risk of stroke, oral anticoagulants (OAC) are recommended. In 'real world' clinical practice, many patients (who may be, or perceived to be, intolerant of OACs) are either untreated or are treated with anti-platelet agents. We hypothesised that edoxaban has a better net clinical benefit (NCB, balancing the reduction in stroke risk vs increased risk of haemorrhage) than no treatment or anti-platelet agents. We performed a network meta-analysis of published data from 24 studies of 203,394 AF patients to indirectly compare edoxaban with aspirin alone, aspirin plus clopidogrel, and placebo. Edoxaban 30 mg once daily significantly reduced the risk of all stroke, ischaemic stroke and mortality compared to placebo and aspirin. Compared to aspirin plus clopidogrel, there was a lower risk of intra-cranial haemorrhage (ICH). Edoxaban 60 mg once-daily had a reduced risk of any stroke and systemic embolism compared to placebo, aspirin, and aspirin plus clopidogrel. Mortality rates for both edoxaban doses were estimated to be lower compared to any anti-platelet, and significantly lower compared to placebo. With overall reduced risk of ischemic stroke and ICH, both edoxaban doses bring a NCB of mean (SD) 1.68 (0.15) saved events per 100 patients per year compared to anti-platelet drugs in a clinical trial population. The NCB was demonstrated to be lower, at 0.77 (0.12) events saved (p< 0.01) when modeled to data from a 'real world' cohort of AF patients. In conclusion, edoxaban is likely to provide even better protection from stroke and ICH than placebo, aspirin alone, or aspirin plus clopidogrel in both clinical trial populations and unselected community populations. Both edoxaban doses would also bring a positive NCB compared to anti-platelet drugs or placebo/non-treatment based on 'real world' data.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Clopidogrel; Drug Synergism; Drug Therapy, Combination; Embolism; Factor Xa Inhibitors; Humans; Mortality; Numbers Needed To Treat; Observational Studies as Topic; Platelet Aggregation Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Risk; Risk Assessment; Stroke; Thiazoles; Thrombophilia; Ticlopidine; Vitamin K

Non-valvular AF is the most common cardiac arrhytmia. Its incidence increases with age. AF is an independent risk factor for ischaemic stroke, representing a five times higher risk for it, associated with a high mortality rate. Beside AF, there are several other risk factors which influence the risk of stroke. Stroke risk calculator can be used to assess the risk of patient having a stroke. The most endangered group of patients with AF are those who have already suffered from cerebrovascular event. The only effective medication for prevention of stroke due to AF had been the application of vitamin K antagonists (VKA) which considerably decrease the rate of ischaemic event in a patient with AF providing that the INR is in the therapeutic range. VKA have several limitations of use in clinical practice and the fear of bleeding complications results an underusing of these drugs. Only 50% of all patients treated with VKA reaches the therapeutic range of INR. The breakthrough of prevention of stroke in recent years is undisputedly the coming out of novel oral anticoagulants (NOACs, thrombin and Xa-factor inhibitors). Recent studies suggest that these novel drugs prove the same efficacy as VKA drugs, furthermore dabigatran in a dose of 2 x 150 mg or apixaban in 2 x 5 mg was statistically superior to warfarin in the prevention of stroke. NOACs have shown a large reduction in intracranial hemorrhage compared with warfarin. They are given as a fixed dose and do not require persistent monitoring making them much more convenient. NOACs at guidelines of European Society of Cardiology act as a preferable drugs in case of ischaemic stroke with AF Probably the extended use of NOACs in clinical practice will be the mainstream of stroke prevention in the future.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Brain Ischemia; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; International Normalized Ratio; Intracranial Hemorrhages; Pyridines; Risk Assessment; Risk Factors; Stroke; Vitamin K

Stroke is a common disease, which is associated with high morbidity and high mortality. Up to 25% of cerebral ischaemic infarcts are caused by cardio-embolic events, most commonly associated with atrial fibrillation. It has previously been shown that antithrombotic therapy is insufficiently used in patients at increased risk of stroke. This article reviews evidence and practical management of anticoagulant therapy in stroke patients and provides an update on risk stratification for thromboembolism and bleeding complications in patients with atrial fibrillation.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Brain Ischemia; Cerebral Hemorrhage; Dabigatran; Female; Humans; Male; Morpholines; Pyrazoles; Pyridones; Radiography; Risk Assessment; Risk Factors; Secondary Prevention; Stroke; Thiophenes; Thromboembolism; Vitamin K

Stroke and atrial fibrillation (AF) constitute a true vascular epidemic with catastrophic consequences. The most common and devastating complication of AF is cardioembolic stroke but this catastrophic event can be predicted and prevented. Accurate etiologic diagnosis of stroke is essential for effective prevention. The percentage of cryptogenic ischemic strokes is too high and detection of AF and other causes of cardioembolic events should be improved. Cardioembolic cerebral ischemia can be prevented. However, because of physician inertia, lack of patient adherence and the problems of vitamin K antagonists, many patients are at risk of cerebral ischemia. Recently, major advances with drugs such as dronedarone, dabigatran and FXa inhibitors have opened the way to improving stroke prevention, as reflected in therapeutic guidelines, and neurologists should be familiar with these drugs. There is reason to hope that much suffering can be avoided.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Brain Ischemia; Dabigatran; Double-Blind Method; Factor Xa Inhibitors; Fibrinolytic Agents; Heart Diseases; Hemorrhage; Humans; International Normalized Ratio; Intracranial Embolism; Multicenter Studies as Topic; Prevalence; Randomized Controlled Trials as Topic; Risk Factors; Single-Blind Method; Thrombophilia; Vitamin K

Vitamin K antagonists are the only oral anticoagulants available and are considered as well-established treatment to prevent a first stroke or a recurrent stroke in patients with atrial fibrillation. The difficulties in the routine management of these patients cause an underuse of vitamin K antagonists. For long-term use, there is a need for safer and more effective oral anticoagulants that do not require routine monitoring of coagulation. Recently, new drugs have been developed and there are a number of clinical trials for the primary and secondary prevention of stroke in atrial fibrillation. The new anticoagulants that are being investigated target factor Xa or thrombin. The factor Xa inhibitors include indirect inhibitors such as idraparinux and biotinylated idraparinux that inhibit factor Xa by potentiating antithrombin. Also being investigated are apixaban and rivaroxaban, orally active agents that inhibit factor Xa directly. Direct thrombin inhibitors include ximelagatran and dabigatran etexilate. Although ximelagatran was withdrawn early because of liver toxicity, it provided convincing evidence that new oral anticoagulants have the potential to replace warfarin. However, even if these new drugs prove superior to dose-adjusted warfarin, their benefits must be substantial (retaining high efficacy with added safety and convenience) to offset their increased cost.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Brain Ischemia; Factor Xa Inhibitors; Humans; Primary Prevention; Risk Assessment; Secondary Prevention; Stroke; Thrombin; Treatment Outcome; Vitamin K

Stroke outcomes in patients with atrial fibrillation (AF) tend to be worse than those in patients without AF. The objective of this study was to evaluate whether the cost benefits of anticoagulation for stroke prevention in AF may currently be underestimated by existing economic models that do not distinguish between different stroke outcomes.. A literature review was conducted in 3 areas: (1) studies comparing stroke outcomes in AF and non-AF patients; (2) studies providing long-term cost of stroke estimates; and (3) studies modeling the cost-effectiveness of anticoagulation with a vitamin K antagonist (eg, warfarin) in AF patients.. There is considerable evidence that stroke in AF patients has a worse outcome than in patients without AF, including higher mortality, severity, and recurrence rates, and greater functional impairment and dependency. Estimates of the long-term cost of stroke of different severities were between US 24,991 dollars for a mild stroke over 5 years and US 142,251 dollars for a major ischemic stroke over a lifetime (2004 prices). The cost of a severe ischemic stroke may typically be 3-times that of mild stroke. However, cost-effectiveness models for anticoagulation in patients with AF have used average (not AF-specific) cost-of-stroke data, and most have used stroke severity distributions derived from clinical trials, which may differ from those in clinical practice.. Existing economic models underestimate the cost benefits of anticoagulation for stroke prevention because they do not adjust for poorer outcomes associated with cardioembolic strokes.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cerebrovascular Disorders; Clinical Trials as Topic; Cost-Benefit Analysis; Humans; Ischemia; MEDLINE; Middle Aged; Models, Theoretical; Multivariate Analysis; Quality-Adjusted Life Years; Risk Factors; Stroke; Time Factors; Treatment Outcome; Vitamin K; Warfarin

Anticoagulant therapy is used for stroke prevention and proved to be effective and safe in the long term. The study aims to analyse the cost-effectiveness relationship of using of direct-acting oral anticoagulants vs vitamin K antagonists to prevent ischaemic stroke in patients with nonvalvular atrial fibrillation, including all the active ingredients marketed in Spain, prescribed for 2 years in the Primary Care service of the Institut Català de la Salut.. Population-based cohort study, in which the cost of the 2 treatment groups will be evaluated. Direct costs (pharmacy, primary care, emergency and hospitalization) and indirect costs (lost productivity) will be included from a social perspective. Effectiveness (assessed as the occurrence of a health event, the 1 of primary interest being stroke) will be determined, with a 2-year time horizon and a 3% discount rate. The average cost of the 2 groups of drugs will be compared using a regression model to determine the factors with the greatest influence on determining costs. We will carry out a univariate ('one-way') deterministic sensitivity analysis.. We hope to provide relevant information about direct and indirect costs of oral anticoagulants, which, together with aspects of effectiveness and safety, could help shape the consensual decision-making of evaluating bodies.

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cost-Benefit Analysis; Factor Xa Inhibitors; Humans; Pragmatic Clinical Trials as Topic; Primary Health Care; Safety; Spain; Stroke; Treatment Outcome; Vitamin K; Warfarin

Patients with atrial fibrillation (AF) are at an approximately 0.5% to 3% increased risk of thromboembolism during and immediately after catheter ablation. Treatment guidelines recommend periprocedural oral anticoagulation plus unfractionated heparin during ablation. Rivaroxaban and dabigatran are the only non-vitamin K oral anticoagulants for which there are randomized controlled trials assessing uninterrupted anticoagulation in patients undergoing catheter ablation of AF. Edoxaban, a direct factor Xa inhibitor, is noninferior vs warfarin for the prevention of stroke or systemic embolism with less major bleeding in patients with nonvalvular AF. The ELIMINATE-AF (Evaluation of Edoxaban Compared With VKA in Subjects Undergoing Catheter Ablation of Nonvalvular Atrial Fibrillation) trial is a multinational, multicenter, prospective, randomized, open-label, parallel-group, blinded-endpoint evaluation (PROBE) study to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for a dose reduction) vs vitamin K antagonists (VKA) in patients with nonvalvular AF undergoing catheter ablation (http://www.ClinicalTrials.gov: NCT02942576). A total of 560 patients are planned for randomization to edoxaban or VKA (2:1 ratio) to obtain 450 patients fully compliant with the protocol. Patients will complete 21 to 28 days of anticoagulation prior to the ablation and a 90-day post-ablation period. The primary efficacy endpoint is the composite of all-cause death, stroke, and major bleeding. The primary safety endpoint is major bleeding. A magnetic resonance imaging substudy will assess the incidence of silent cerebral lesions post-ablation. ELIMINATE-AF will define the efficacy and safety of edoxaban for uninterrupted oral anticoagulation during catheter ablation of AF.

Topics: Anticoagulants; Atrial Fibrillation; Brain Ischemia; Catheter Ablation; Clinical Protocols; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Magnetic Resonance Imaging; Male; Prospective Studies; Pyridines; Research Design; Risk Factors; Stroke; Thiazoles; Time Factors; Treatment Outcome; Vitamin K; Warfarin

There are limited real-world data comparing the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in Asians with nonvalvular atrial fibrillation. We aimed to compare the effectiveness and safety between NOACs and warfarin users in the Korean atrial fibrillation population, with particular focus on high-risk patients.. Using the Korean National Health Insurance Service database, we analyzed the risk of ischemic stroke, intracranial hemorrhage (ICH) events, and all-cause death in NOAC users (n=11 611 total, n=5681 taking rivaroxaban, n=3741 taking dabigatran, and n=2189 taking apixaban) compared with propensity score-matched warfarin users (n=23 222) among patients with high-risk atrial fibrillation (CHA. NOAC treatment was associated with similar risk of ischemic stroke and lower risk of ICH and all-cause mortality compared with warfarin. All 3 NOACs were associated with a similar risk of ischemic stroke and a lower risk of ICH compared with warfarin. Dabigatran and apixaban were associated with a lower risk of total mortality and the composite net clinical outcome (ischemic stroke, ICH, and all-cause death) compared with warfarin, whereas this was nonsignificant for rivaroxaban. Among previously oral anticoagulant-naive patients (n=23 262), dabigatran and apixaban were superior to warfarin for ICH prevention, whereas rivaroxaban and warfarin were associated with similar risk of ICH.. In real-world practice among a high-risk Asian atrial fibrillation population, all 3 NOACs demonstrated similar risk of ischemic stroke and lower risk of ICH compared with warfarin. All-cause mortality was significantly lower only with dabigatran and apixaban.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Asian People; Atrial Fibrillation; Brain Ischemia; Databases, Factual; Female; Humans; Insurance, Health; Male; Republic of Korea; Risk Factors; Stroke; Vitamin K

In patients who present with acute ischemic stroke while on treatment with non-vitamin K antagonist oral anticoagulants (NOACs), coagulation testing is necessary to confirm the eligibility for thrombolytic therapy. We evaluated the current use of coagulation testing in routine clinical practice in patients who were on NOAC treatment at the time of acute ischemic stroke.. Prospective multicenter observational RASUNOA registry (Registry of Acute Stroke Under New Oral Anticoagulants; February 2012-2015). Results of locally performed nonspecific (international normalized ratio, activated partial thromboplastin time, and thrombin time) and specific (antifactor Xa tests, hemoclot assay) coagulation tests were documented. The implications of test results for thrombolysis decision-making were explored.. In the 290 patients enrolled, nonspecific coagulation tests were performed in ≥95% and specific coagulation tests in 26.9% of patients. Normal values of activated partial thromboplastin time and international normalized ratio did not reliably rule out peak drug levels at the time of the diagnostic tests (false-negative rates 11%-44% [95% confidence interval 1%-69%]). Twelve percent of patients apparently failed to take the prescribed NOAC prior to the acute event. Only 5.7% (9/159) of patients in the 4.5-hour time window received thrombolysis, and NOAC treatment was documented as main reason for not administering thrombolysis in 52.7% (79/150) of patients.. NOAC treatment currently poses a significant barrier to thrombolysis in ischemic stroke. Because nonspecific coagulation test results within normal range have a high false-negative rate for detection of relevant drug concentrations, rapid drug-specific tests for thrombolysis decision-making should be established.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01850797.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Brain Ischemia; Female; Germany; Humans; Male; Prospective Studies; Registries; Stroke; Vitamin K

The safety and efficacy of non-vitamin K oral anticoagulant (NOAC) compared with warfarin in treating patients with non-valvular atrial fibrillation (NVAF) who developed acute ischemic stroke or transient ischemic attack (AIS/TIA), particularly those receiving tissue-plasminogen activator (tPA) therapy, remains unclear. Between April 2012 and December 2014, we conducted a multicenter prospective cohort study to assess the current clinical practice for treating such patients. We divided the patients into two groups according to the administration of oral anticoagulants (warfarin or NOACs) and tPA therapy. The risk of any hemorrhagic or ischemic event was compared within 1 month after the onset of stroke. We analyzed 235 patients with AIS/TIA including 73 who received tPA therapy. Oral anticoagulants were initiated within 2-4 inpatient days. NOACs were administered to 49.8 % of patients, who were predominantly male, younger, had small infarcts, lower NIHSS scores, and had a lower all-cause mortality rate (0 vs. 4.2 %, P = 0.06) and a lower risk of any ischemic events (6.0 vs. 7.6 %, P = 0.797) compared with warfarin users. The prevalence of all hemorrhagic events was equivalent between the two groups. Early initiation of NOACs after tPA therapy appeared to lower the risk of hemorrhagic events, although there was no significant difference (0 vs. 5.6 %, P = 0.240). Although more clinicians are apt to prescribe NOACs in minor ischemic stroke, NOAC treatment may provide a potential benefit in such cases. Early initiation of NOACs after tPA therapy may reduce the risk of hemorrhagic events compared with warfarin.

Topics: Acute Disease; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Female; Humans; Male; Prospective Studies; Stroke; Vitamin K; Warfarin

Apixaban reduces stroke with comparable bleeding risks when compared with aspirin in patients with atrial fibrillation who are unsuitable for vitamin k antagonist therapy. This analysis explores patterns of bleeding and defines bleeding risks based on stroke risk with apixaban and aspirin.. The Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin k Antagonist Treatment (AVERROES) trial randomized 5599 patients with atrial fibrillation and risk factors to receive either apixaban or aspirin. Bleeding events were defined as the first occurrence of either major bleeding or clinically relevant nonmajor bleeding.. The rate of a bleeding event was 3.8%/year with aspirin and 4.5%/year with apixaban (hazard ratio with apixaban, 1.18; 95% CI, 0.92-1.51; P=0.19). The anatomic site of bleeding did not differ between therapies. Risk factors for bleeding common to apixaban and aspirin were use of nonstudy aspirin>50% of the time and a history of daily/occasional nosebleeds. The rates of both stroke and bleeding increased with higher CHADS2 scores but apixaban compared with aspirin was associated with a similar relative risk of bleeding (P interaction 0.21) and a reduced relative risk of stroke (P interaction 0.37) irrespective of CHADS2 category.. Anatomic sites and predictors of bleeding are similar for apixaban and aspirin in these patients. Higher CHADS2 scores are associated with increasing rates of bleeding and stroke, but the balance between risks and benefits of apixaban compared with aspirin is favorable irrespective of baseline stroke risk. Clinical Trial Registration Information- www.clinicaltrials.gov. Unique identifier: NCT 00496769.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Contraindications; Female; Fibrinolytic Agents; Follow-Up Studies; Humans; Male; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Risk Factors; Stroke; Vitamin K; Warfarin

Atrial fibrillation (AF) is a risk factor for brain infarction, which can lead to epilepsy. We aimed to investigate whether treatment of AF with direct oral anticoagulants (DOACs) affects the risk of epilepsy in comparison to treatment with the vitamin K antagonist phenprocoumon (PPC).. We performed an active comparator, nested case-control study based on the German Pharmacoepidemiological Research Database that includes claims data from statutory health insurance providers of about 25 million persons since 2004. In 2011-17, 227 707 AF patients initiated treatment with a DOAC or PPC, of which 1828 cases developed epilepsy on current treatment with an oral anticoagulant. They were matched to 19 084 controls without epilepsy. Patients with DOAC treatment for AF had an overall higher risk of epilepsy with an odds ratio of 1.39, 95% CI (1.24; 1.55) compared to current PPC treatment. Cases had higher baseline CHA2DS2-VASc scores and more frequently a history of stroke than controls. After excluding patients with ischaemic stroke prior to the diagnosis of epilepsy, the risk of epilepsy was still higher on DOACs than on PPC. In contrast, within a cohort of patients with venous thromboembolism, the risk of epilepsy on treatment with DOACs was less elevated [adjusted odds ratio 1.15, 95% CI (0.98; 1.34)].. In patients with AF initiating oral anticoagulation, treatment with a DOAC was associated with an increased risk of epilepsy compared to the vitamin K antagonist PPC. Covert brain infarction may explain the observed elevated risk of epilepsy.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Case-Control Studies; Humans; Phenprocoumon; Risk Factors; Stroke; Vitamin K

Use of oral vitamin K antagonists (VKAs) may place patients undergoing endovascular thrombectomy (EVT) for acute ischemic stroke caused by large vessel occlusion at increased risk of complications.. To determine the association between recent use of a VKA and outcomes among patients selected to undergo EVT in clinical practice.. Retrospective, observational cohort study based on the American Heart Association's Get With the Guidelines-Stroke Program between October 2015 and March 2020. From 594 participating hospitals in the US, 32 715 patients with acute ischemic stroke selected to undergo EVT within 6 hours of time last known to be well were included.. VKA use within the 7 days prior to hospital arrival.. The primary end point was symptomatic intracranial hemorrhage (sICH). Secondary end points included life-threatening systemic hemorrhage, another serious complication, any complications of reperfusion therapy, in-hospital mortality, and in-hospital mortality or discharge to hospice.. Of 32 715 patients (median age, 72 years; 50.7% female), 3087 (9.4%) had used a VKA (median international normalized ratio [INR], 1.5 [IQR, 1.2-1.9]) and 29 628 had not used a VKA prior to hospital presentation. Overall, prior VKA use was not significantly associated with an increased risk of sICH (211/3087 patients [6.8%] taking a VKA compared with 1904/29 628 patients [6.4%] not taking a VKA; adjusted odds ratio [OR], 1.12 [95% CI, 0.94-1.35]; adjusted risk difference, 0.69% [95% CI, -0.39% to 1.77%]). Among 830 patients taking a VKA with an INR greater than 1.7, sICH risk was significantly higher than in those not taking a VKA (8.3% vs 6.4%; adjusted OR, 1.88 [95% CI, 1.33-2.65]; adjusted risk difference, 4.03% [95% CI, 1.53%-6.53%]), while those with an INR of 1.7 or lower (n = 1585) had no significant difference in the risk of sICH (6.7% vs 6.4%; adjusted OR, 1.24 [95% CI, 0.87-1.76]; adjusted risk difference, 1.13% [95% CI, -0.79% to 3.04%]). Of 5 prespecified secondary end points, none showed a significant difference across VKA-exposed vs VKA-unexposed groups.. Among patients with acute ischemic stroke selected to receive EVT, VKA use within the preceding 7 days was not associated with a significantly increased risk of sICH overall. However, recent VKA use with a presenting INR greater than 1.7 was associated with a significantly increased risk of sICH compared with no use of anticoagulants.

Topics: Administration, Oral; Aged; Anticoagulants; Brain Ischemia; Endovascular Procedures; Female; Fibrinolytic Agents; Hemorrhage; Hospital Mortality; Humans; International Normalized Ratio; Intracranial Hemorrhages; Ischemic Stroke; Male; Retrospective Studies; Thrombectomy; Treatment Outcome; Vitamin K

Topics: Brain Ischemia; Endovascular Procedures; Humans; Intracranial Hemorrhages; Retrospective Studies; Stroke; Thrombectomy; Treatment Outcome; Vitamin K

Topics: Brain Ischemia; Endovascular Procedures; Humans; Intracranial Hemorrhages; Retrospective Studies; Stroke; Thrombectomy; Treatment Outcome; Vitamin K

Balancing the risk of thromboembolism and bleeding in patients with liver disease and atrial fibrillation/flutter is particularly challenging.. To examine the risks of thromboembolism and bleeding with use/non-use of oral anticoagulation (including vitamin K-antagonists and direct oral anticoagulants) in patients with liver disease and AF.. Four hundred and nine of 1,238 patients with liver disease and new atrial fibrillation/flutter initiated anticoagulants. Amongst patients with a CHA2DS2-VASc-score of 1-2 (2-3 for women), five-year thromboembolism incidence rates were low and similar in the anticoagulant (6.5%) versus no anticoagulant (5.5%) groups (average risk ratio 1.19 [95%CI, 0.22-2.16]). In patients with a CHA2DS2-VASc-score>2 (>3 for women), incidence rates were 16% versus 24% (average risk ratio 0.66 [95%CI, 0.45-0.87]). Bleeding risks appeared higher amongst patients with cirrhotic versus non-cirrhotic disease but were not significantly affected by anticoagulant status.. Oral anticoagulant initiation in patients with liver disease, incident new atrial fibrillation/flutter, and a high CHA2DS2-VASc-score was associated with a reduced thromboembolism risk. Bleeding risk was not increased with anticoagulation, irrespective of the type of liver disease.

Topics: Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cohort Studies; Female; Hemorrhage; Humans; Liver Diseases; Male; Risk Assessment; Risk Factors; Stroke; Thromboembolism; Vitamin K

This study aimed to evaluate the cerebroprotective potential of a novel synthetic coumarin, (E)-4-amino-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene) benzohydrazide noted (HC) against a pharmaceutically induced ischemic stroke in experimental male

Topics: Animals; Brain Ischemia; Ischemic Stroke; Isoproterenol; Male; Myocardium; Oxidative Stress; Rats; Rats, Wistar; Stroke; Vitamin K; Vitamins

The aim was to evaluate, in patients with atrial fibrillation (AF) and acute ischemic stroke, the association of prior anticoagulation with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) with stroke severity, utilization of intravenous thrombolysis (IVT), safety of IVT, and 3-month outcomes.. This was a cohort study of consecutive patients (2014-2019) on anticoagulation versus those without (controls) with regard to stroke severity, rates of IVT/mechanical thrombectomy, symptomatic intracranial hemorrhage (sICH), and favorable outcome (modified Rankin Scale score 0-2) at 3 months.. Of 8,179 patients (mean [SD] age, 79.8 [9.6] years; 49% women), 1,486 (18%) were on VKA treatment, 1,634 (20%) on DOAC treatment at stroke onset, and 5,059 controls. Stroke severity was lower in patients on DOACs (median National Institutes of Health Stroke Scale 4, [interquartile range 2-11]) compared with VKA (6, [2-14]) and controls (7, [3-15], p < 0.001; quantile regression: β -2.1, 95% confidence interval [CI] -2.6 to -1.7). The IVT rate in potentially eligible patients was significantly lower in patients on VKA (156 of 247 [63%]; adjusted odds ratio [aOR] 0.67; 95% CI 0.50-0.90) and particularly in patients on DOACs (69 of 464 [15%]; aOR 0.06; 95% CI 0.05-0.08) compared with controls (1,544 of 2,504 [74%]). sICH after IVT occurred in 3.6% (2.6-4.7%) of controls, 9 of 195 (4.6%; 1.9-9.2%; aOR 0.93; 95% CI 0.46-1.90) patients on VKA and 2 of 65 (3.1%; 0.4-10.8%, aOR 0.56; 95% CI 0.28-1.12) of those on DOACs. After adjustments for prognostic confounders, DOAC pretreatment was associated with a favorable 3-month outcome (aOR 1.24; 1.01-1.51).. Prior DOAC therapy in patients with AF was associated with decreased admission stroke severity at onset and a remarkably low rate of IVT. Overall, patients on DOAC might have better functional outcome at 3 months. Further research is needed to overcome potential restrictions for IVT in patients taking DOACs. ANN NEUROL 2021;89:42-53.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cohort Studies; Female; Fibrinolytic Agents; Humans; Ischemic Stroke; Male; Middle Aged; Vitamin K

Our objectives were to evaluate the risk of adverse events in a 'real-world' vs 'clinical trial' cohort of atrial fibrillation (AF) patients with chronic kidney disease (CKD).. We studied patient-level data for vitamin K antagonist-treated AF patients with a creatinine clearance <60 mL/min from the Murcia AF Project and AMADEUS trial. The study end-points were ischaemic stroke, major bleeding, all-cause mortality, myocardial infarction and intracranial haemorrhage.. This study included 1,108 AF patients with CKD. The annual rate of the composite study outcome of ischaemic stroke, major bleeding and all-cause mortality was higher in the real-world (13.4%) vs AMADEUS (6.6%) cohort with an IRR of 2.04 (95% CI,1.34-3.09), P < .001. Individual annual rates of major bleeding, all-cause mortality and non-cardiovascular mortality were significantly greater in the real-world cohort. Similar findings were demonstrated even after multivariable adjustment, with the composite outcome HR of 2.85 (95% CI,1.74-4.66), P < .001. In a propensity score matched cohort, this risk remained significantly higher in the real-world cohort (IRR 2.95 [95% CI,1.03-10.28], P = .027), as did the risk of major bleeding and all-cause mortality.. Vitamin K antagonist-treated AF patients with CKD are exposed to significant annual rates of major adverse events including all-cause mortality. This risk may be under-appreciated in the idealised environment of randomised controlled trials.

Topics: Anticoagulants; Atrial Fibrillation; Brain Ischemia; Humans; Renal Insufficiency, Chronic; Stroke; Vitamin K

Acute ischemic stroke (AIS) severity and clinical course are less known in direct oral anticoagulants (DOAC) users. We aimed to explore the outcome of AIS in patients pretreated with vitamin-K-antagonists (VKA) and DOAC.. A retrospective study was performed. Patients pretreated with oral anticoagulants (OAC) for nonvalvular atrial fibrillation admitted for AIS in a stroke unit between 2016-01-01 and 2018-08-31 were included. The primary endpoint was mortality during the hospital stay, and secondary endpoints were neurologic improvement at stroke unit discharge and good functional outcome 90 days after AIS.. A total of 156 patients were included (83 on VKA and 73 on DOAC). Stroke severity (defined by NIHSS on admission) was comparable in both groups (AVK 13.0 [4.0-20.0] versus DOAC 11.0 [4.0-17.0], P = .435). Infratherapeutic levels and/or inappropriate low dose of OAC was also similar between groups (P = .152) and was not associated with stroke severity (P = .631) or mortality (P = .788). VKA (OR 12.616, P = .035, 95%CI 1.19-133.64) and PH2 hemorrhagic transformation (OR 7.516, P = .024, 95%CI 1.31-43.20) were associated with higher mortality in multivariate analysis. Higher stroke severity (OR .101, P < .001, 95%CI .037-.279) and VKA usage (OR .212, P = .003, 95%CI .08-.58) were associated with worse functional outcome at 3 months. Reperfusion therapy was significantly associated with neurologic improvement during stroke unit stay (OR 3.969, P = .009, 95%CI 1.42-11.11) but not with the functional outcome (P = .063).. Nonvalvular atrial fibrillation patients pretreated with DOAC admitted for AIS had a better outcome when compared to VKA, although stroke severity was similar between groups.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Brain Ischemia; Disability Evaluation; Female; Hospital Mortality; Humans; Male; Recovery of Function; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Stroke; Time Factors; Treatment Outcome; Vitamin K

Despite the utility of neuroimaging in the diagnostic and therapeutic management of patients with acute ischemic stroke (AIS), imaging characteristics in patients with preceding direct oral anticoagulants (DOAC) compared to vitamin K antagonists (VKA) have hardly been described. We aimed to determine presence of large vessel occlusion (LVO), thrombus length, infarction diameter, and occurrence of hemorrhagic transformation in AIS patients with preceding DOAC as compared to VKA therapy.. Using a prospectively collected cohort of AIS patients, we performed univariate and multivariable regression analyses regarding imaging outcomes. Additionally, we provide a sensitivity analysis for the subgroup of patients with confirmed therapeutic anticoagulation.. We included AIS in patients with preceding DOAC (N = 75) and VKA (N = 61) therapy, median age 79 (IQR 70-83), 39% female. Presence of any LVO between DOAC and VKA patients (29.3% versus 37.7%, P = 0.361), and target LVO for endovascular therapy (26.7% versus 27.9%, P = 1.0) was equal with a similar occlusion pattern. DOAC as compared to VKA were associated with a similar rate of target LVO for EVT (aOR 0.835, 95% CI 0.368-1.898). The presence of multiple lesions and characteristics of the thrombus were similar in DOAC and VKA patients. Acute ischemic lesion diameter in real world patients was equal in patients taking DOAC as compared to VKA. Lesion diameter in VKA patients (median 13 mm, IQR 6-26 versus median 20 mm, IQR 7-36, P = 0.001), but not DOAC patients was smaller in the setting of confirmed therapeutic VKA. The frequency of radiological hemorrhagic transformation and symptomatic intracranial hemorrhage in OAC patients was low. Sensitivity analysis considering only patients with confirmed therapeutic anticoagulation did not change any of the results.. Preceding DOAC treatment showed equal rates of LVO and infarct size as compared to VKA in AIS patients. This study adds to the knowledge of imaging findings in AIS patients with preceding anticoagulation.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Brain Ischemia; Cohort Studies; Female; Fibrinolytic Agents; Humans; Intracranial Hemorrhages; Magnetic Resonance Imaging; Male; Prospective Studies; Stroke; Vitamin K

Evidence for the efficacy of direct oral anticoagulants (DOACs) to prevent cardiovascular (CV) events and mortality in older individuals with a low estimated glomerular filtration rate (eGFR) is lacking. We sought to characterize the association of oral anticoagulant use with CV morbidity in elderly patients with or without reductions in eGFRs, comparing DOACs with vitamin K antagonists (VKAs).. Population-based retrospective cohort study.. All individuals 66 years or older with an initial prescription for oral anticoagulants dispensed in Ontario, Canada, from 2009 to 2016.. DOACs (apixaban, dabigatran, and rivaroxaban) compared with VKAs by eGFR group (≥60, 30-59, and<30mL/min/1.73m. The primary outcome was a composite of a CV event (myocardial infarction, revascularization, or ischemic stroke) or mortality. Secondary outcomes were CV events alone, mortality, and hemorrhage requiring hospitalization.. High-dimensional propensity score matching of DOAC to VKA users and Cox proportional hazards regression.. 27,552 new DOAC users were matched to 27,552 new VKA users (median age, 78 years; 49% women). There was significantly lower risk for CV events or mortality among DOAC users compared with VKA users (event rates of 79.78 vs 99.77 per 1,000 person-years, respectively; HR, 0.82 [95% CI, 0.75-0.90]) and lower risk for hemorrhage (event rates of 10.35 vs 16.77 per 1,000 person-years, respectively; HR, 0.73 [95% CI, 0.58-0.91]). There was an interaction between eGFR and the association of anticoagulant class with the primary composite outcome (P<0.02): HRs of 1.01 [95% CI, 0.92-1.12], 0.83 [95% CI, 0.75-0.93], and 0.75 [95% CI, 0.51-1.10] for eGFRs of≥60, 30 to 59, and<30mL/min/1.73m. Retrospective observational study design limits causal inference; dosages of DOACs and international normalized ratio values were not available; low event rates in some subgroups limited statistical power.. DOACs compared with VKAs were associated with lower risk for the composite of CV events or mortality, an association for which the strength was most apparent among those with reduced eGFRs. The therapeutic implications of these findings await further study.

Topics: Aged; Aged, 80 and over; Antithrombins; Brain Ischemia; Cause of Death; Comorbidity; Dabigatran; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Male; Mortality; Myocardial Infarction; Myocardial Revascularization; Ontario; Procedures and Techniques Utilization; Propensity Score; Proportional Hazards Models; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Retrospective Studies; Rivaroxaban; Thrombophilia; Vitamin K

Nurses play a central role in the management of atrial fibrillation (AF) patients. An unresolved question is whether a nurse-led clinic would improve clinical outcomes. Herein, we investigated the impact of a nurse-led clinic on anticoagulation therapy and clinical outcomes in a cohort of naïve AF patients.. Prospective study including AF patients starting vitamin K antagonists (VKAs) into a nurse-led AF clinic. These patients were followed in this specific AF clinic. Additionally, AF patients already taking VKAs for 6 months followed according to the routine clinical practice were included as comparison group. The quality of anticoagulation was assessed at 6 months. Efficacy and safety endpoints were recorded during follow-up.. We included 223 patients (Nurse-led clinic: 107; Usual care: 116). The mean time in therapeutic range and the proportion of INRs within the therapeutic range were similar in both groups. During 2.06 (IQR 1.01-2.94) years of follow-up, 64 (28.7%) patients changed to direct-acting oral anticoagulants. The proportion of switchers was higher in the nurse-led clinic (37.4%) than in the usual care group (20.7%) (P = .006) and these patients spent less time to switch (2.0 [IQR 0.7-2.9] vs 6.0 [IQR 3.7-11.2] years; P < .001). Importantly, the annual rate of ischaemic stroke/TIA was significantly lower in the nurse-led clinic (0.47%/year vs 3.88%/year, P = .016), without differences in safety endpoints.. A nurse-led AF clinic may offer a "patient-centered" review and holistic follow-up, and it would be associated with a reduction of ischaemic stroke/TIA, without increasing bleeding complications. Further studies should confirm these results.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Humans; Prospective Studies; Stroke; Vitamin K

The evidence of effectiveness and safety of the non-vitamin K antagonist oral anticoagulants (NOACs) among elderly East Asians is limited.. We aimed to describe the effectiveness and safety outcomes associated with NOACs and warfarin among elderly Koreans aged ≥80 years.. Using the Korean Health Insurance Review and Assessment service database, patients with atrial fibrillation (AF) who were naïve to index oral anticoagulant between 2015 and 2017 were included in this study (20,573 for NOACs and 4086 for warfarin). Two treatment groups were balanced using the inverse probability of treatment weighting (IPTW) method. The clinical outcomes including ischemic stroke, major bleeding including intracranial hemorrhage (ICH) and gastrointestinal bleeding (GIB), and a composite of these outcomes were evaluated.. Compared to warfarin, NOACs were associated with lower risks of ischemic stroke (hazard ratio 0.74 [95% confidence interval 0.62-0.89]), and composite outcome (0.78 [0.69-0.90]). NOACs showed nonsignificant trends towards to lower risks of GIB and major bleeding than warfarin. The risk of ICH of NOAC group was comparable with the warfarin group. Among NOACs, apixaban and edoxaban showed better composite outcomes than warfarin. Among the clinical outcomes, only ischemic stroke and the composite outcome had a significant interaction with age subgroups (80-89 years and ≥90 years, P-for-interaction = .097 and .040, respectively).. NOACs were associated with lower risks of ischemic stroke and the composite outcome (ischemic stroke and major bleeding) compared to warfarin in elderly East Asians. Physicians should be more confident in prescribing NOACs to elderly East Asians with AF.

Topics: Aged, 80 and over; Atrial Fibrillation; Brain Ischemia; Databases, Factual; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Humans; Intracranial Hemorrhages; Male; Pyrazoles; Pyridines; Pyridones; Republic of Korea; Stroke; Thiazoles; Vitamin K; Warfarin

We compared outcomes after treatment with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and a recent cerebral ischemia.. We conducted an individual patient data analysis of seven prospective cohort studies. We included patients with AF and a recent cerebral ischemia (<3 months before starting oral anticoagulation) and a minimum follow-up of 3 months. We analyzed the association between type of anticoagulation (DOAC versus VKA) with the composite primary endpoint (recurrent ischemic stroke [AIS], intracerebral hemorrhage [ICH], or mortality) using mixed-effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs).. We included 4,912 patients (median age, 78 years [interquartile range {IQR}, 71-84]; 2,331 [47.5%] women; median National Institute of Health Stroke Severity Scale at onset, 5 [IQR, 2-12]); 2,256 (45.9%) patients received VKAs and 2,656 (54.1%) DOACs. Median time from index event to starting oral anticoagulation was 5 days (IQR, 2-14) for VKAs and 5 days (IQR, 2-11) for DOACs (p = 0.53). There were 262 acute ischemic strokes (AISs; 4.4%/year), 71 intracranial hemorrrhages (ICHs; 1.2%/year), and 439 deaths (7.4%/year) during the total follow-up of 5,970 patient-years. Compared to VKAs, DOAC treatment was associated with reduced risks of the composite endpoint (HR, 0.82; 95% CI, 0.67-1.00; p = 0.05) and ICH (HR, 0.42; 95% CI, 0.24-0.71; p < 0.01); we found no differences for the risk of recurrent AIS (HR, 0.91; 95% CI, 0.70-1.19; p = 0.5) and mortality (HR, 0.83; 95% CI, 0.68-1.03; p = 0.09).. DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly attributed to lower risks of ICH. ANN NEUROL 2019;85:823-834.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cohort Studies; Female; Follow-Up Studies; Humans; Male; Prospective Studies; Stroke; Vitamin K

Nonvitamin K antagonist oral anticoagulants (NOACs) are considered superior, or at least noninferior, to warfarin in preventing stroke or systemic embolism in patients with nonvalvular atrial fibrillation. Here, we recruited acute ischemic stroke patients with nonvalvular atrial fibrillation and at least one cerebral microbleed (CMB), and evaluated the proportion of patients who had an increased number of CMBs (%) after receiving anticoagulant therapy with NOACs or with warfarin for 12 months.. This was a multicenter, prospective, observational cohort study at 20 centers, conducted between 2015 and 2017, in which we recruited 85 patients with at least one CMB detected by 1.5T magnetic resonance imaging (T2*WI) at baseline, who received NOACs or warfarin for at least 12 months. We compared the proportions of patients with increased numbers of CMBs in the NOACs and warfarin treatment groups.. The proportions of patients with increased numbers of CMBs at month 12 of treatment were 28.6% and 66.7% in the NOACs and warfarin groups, respectively. The new CMBs showed no specific regional localization in either group. In the NOACs and warfarin groups, physicians prescribed lower-than-standard dosing in 13.3% and 50% of the cases, respectively. The administration of reduced doses at physicians' discretion did not appear to alter the incidence of new CMBs.. This is the first evidence to suggest efficacy of NOACs for preventing further CMBs in patients with at least one CMB, although no statistical evaluation was carried out.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Female; Humans; Incidence; Intracranial Hemorrhages; Japan; Magnetic Resonance Imaging; Male; Middle Aged; Pilot Projects; Prospective Studies; Recurrence; Risk Factors; Stroke; Time Factors; Treatment Outcome; Vitamin K; Warfarin

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Asian People; Atrial Fibrillation; Brain Ischemia; Female; Gastrointestinal Hemorrhage; Humans; Intracranial Hemorrhages; Kidney Function Tests; Male; Republic of Korea; Retrospective Studies; Risk Factors; Stroke; Vitamin K

Oral anticoagulant treatments, such as vitamin K antagonists (VKAs), are the main treatments administered to atrial fibrillation (AF) patients in order to prevent ischemic stroke (IS). However, the genes involved in the VKA metabolism can undergo variations in a single nucleotide (SNP). These SNPs may then affect the VKA target enzyme (VKORC1), VKA degradation enzyme (CYP2C9), and vitamin K bioavailability enzyme (CYP4F2). We genotyped these SNPs in a cohort of patients with non-valvular AF who were under VKA treatment after suffering an IS. Clinical variables, CHADS2-VASC score and data about the international normalized ratio (INR) within the therapeutic range were all recorded. DNA was extracted from blood and genotyping was carried out by DNA sequencing. The main endpoint was the time from VKA onset to IS. Of a total of 356 consecutive IS patients monitored, 33 were included in the study. The median time to the event was 2248.0 days (interquartile range [IQR] 896.3-3545.3). The median CHADS2-VASC score was 4.0 (IQR 3.0-6.0). When we considered the risk of IS within 2 years under VKA treatment, we found that only the rs2108622 AA genotype was significantly associated with this endpoint (early IS) (hazard ratio 6.81, 95% CI 1.37-33.92, p = 0.019). Kaplan-Meier curve analysis also showed a significant relationship between early IS and rs2108622 AA genotype (Log rank p = 0.022). The CYP4F2 gene rs2108622 polymorphism was associated with a risk of early IS in NV-AF patients under VKA treatment.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Brain Ischemia; Cytochrome P-450 CYP2C9; Cytochrome P450 Family 4; Female; Genotype; Humans; International Normalized Ratio; Male; Polymorphism, Single Nucleotide; Prospective Studies; Risk Assessment; Stroke; Vitamin K; Vitamin K Epoxide Reductases

The pivotal trials for stroke prevention in non-valvular atrial fibrillation (NVAF) compared rivaroxaban, dabigatran, and apixaban with warfarin, as did most claims-based studies. Comparisons with phenprocoumon, the most frequently used vitamin K antagonist (VKA) in Germany, are scarce.. Risk of bleeding, ischemic stroke, and all-cause mortality in patients with NVAF were analyzed using data for 2010 to 2014 from a large German claims database. New users of oral anticoagulants from January 2012 to December 2013 were included and observed over 1 year. Baseline characteristics were adjusted using propensity score matching and logistic regression. Several sensitivity analyses were carried out.. Fifty-nine thousand four hundred forty-nine rivaroxaban, 23,654 dabigatran, 4894 apixaban, and 87,997 matched phenprocoumon users were included. Adjusted hazard ratios (95% confidence intervals) compared with phenprocoumon were as follows: hospitalized bleedings: rivaroxaban 1.04 (0.97; 1.11), dabigatran 0.87 (0.77; 0.98), and apixaban 0.65 (0.50; 0.86); ischemic stroke: rivaroxaban 1.05 (0.94; 1.17), dabigatran 1.14 (0.96; 1.35), and apixaban 1.84 (1.20; 2.84); all-cause mortality: rivaroxaban 1.17 (1.11; 1.22), dabigatran 1.04 (0.95; 1.13), and apixaban 1.14 (0.97; 1.34).. With rivaroxaban, no significant differences were observed compared to phenprocoumon with regard to hospitalized bleedings or ischemic strokes. Dabigatran was associated with fewer bleedings and a similar risk of ischemic strokes compared to phenprocoumon. Apixaban was also associated with fewer bleedings but was unexpectedly associated with more ischemic strokes, possibly reflecting selective prescribing. The association of rivaroxaban with higher all-cause mortality unrelated to bleedings or strokes has been described previously but remains to be explained.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Databases, Factual; Female; Follow-Up Studies; Germany; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Stroke; Vitamin K; Young Adult

Background and Purpose- Acute ischemic strokes under vitamin K antagonist (VKA) treatment are not uncommon, but intravenous thrombolysis (IVT) is not recommended for international normalized ratio (INR) >1.7 because of the excess bleeding risk. However, VKA-induced anticoagulation can be easily reversed by IV infusions of 4-factor prothrombin complex concentrate bolus and vitamin K. Our pilot study aimed to determine whether IVT immediately after anticoagulation reversal could be feasible and safe in acute ischemic stroke patients under VKA with INR >1.7. Methods- Consecutive acute ischemic stroke patients, otherwise eligible for IVT except for VKA intake and INR >1.7, were given IVT after infusing 4-factor prothrombin complex concentrate and vitamin K. Safety and efficacy were assessed clinically and by cerebral imaging at 24 hours. Results- Twenty-six patients (age, 77.8±12.8 years; atrial fibrillation, 84.6%; initial National Institutes of Health Stroke Scale, 11.6±5.6) were prospectively included. INR values were 2.3±0.6 initially and 1.3±0.2, 5 minutes postreversal. No symptomatic intracranial hemorrhage or thrombotic events occurred during the first 3 days. One patient developed major systemic hemorrhoidal bleeding that required blood transfusion; 61.5% of the patients were independent (modified Rankin Scale score of ≤2) at 3 months. Conclusions- A reversal strategy of 4-factor prothrombin complex concentrate bolus and vitamin K before IVT could be feasible and safe in acute ischemic stroke patients under VKA with INR >1.7. Well-designed, randomized controlled trials are warranted to confirm these preliminary findings.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Female; Hemorrhage; Humans; International Normalized Ratio; Intracranial Hemorrhages; Male; Middle Aged; Pilot Projects; Stroke; Thrombolytic Therapy; Vitamin K

This study aimed to describe patterns of long-term antithrombotic use in acute ischemic stroke (AIS) patients with non-valvular atrial fibrillation (NVAF) in Korea and their impacts on clinical events before introduction of non-vitamin K antagonist oral anticoagulants (NOAC) into practice in 2015.. Patients with NVAF who were admitted due to the AIS and discharged no later than 2008 were enrolled retrospectively. Data were collected at 11 time points during the first 3 years of follow-up. The primary outcome event was a composite of stroke recurrence, major bleeding, and death. Vitamin K antagonist (VKA) users were categorized into a well-controlled INR group and a poorly-controlled INR group (modified TTR ≥47.0% vs <47.0%).. Of 1,350 patients enrolled in this study, 95% were on antithrombotic medications at discharge. The rate of VKA usage decreased over time (77% and 40% at discharge and 3 years, respectively). The cumulative event rates of the primary outcome differed by treatment patterns. Among the 10 most frequent treatment types, the highest outcome rate was observed in patients who started with VKA-only therapy but discontinued VKAs during follow-up without restarting (70.2%); this was followed by those starting with antiplatelet-only therapy and stopping it without restart (66.7%). Among VKA users, the 3-year cumulative primary outcome rates were higher in the poorly-controlled INR group than the well-controlled INR group (24.5% vs 15.7%; p = 0.015).. Our study revealed that, in pre-NOAC era, there was a wide spectrum of long-term antithrombotic use. The incidence of the composite outcome also varied by patterns of antithrombotic use.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Republic of Korea; Retrospective Studies; Stroke; Thrombosis; Treatment Outcome; Vitamin K

Patients with in-hospital strokes (IHS) may be eligible for recanalization therapies. The objective of this study is to compare outcomes in patients with IHS and community-onset strokes (COS) treated by recanalization therapy. We analysed data prospectively collected in consecutive patients treated by thrombolysis, thrombectomy, or both for cerebral ischemia at the Lille University Hospital. We compared four outcomes measures at 3 months in patients with IHS and COS: (1) modified Rankin scale (mRS) 0-1, (2) mRS 0-2, (3) death, and (4) symptomatic intracranial haemorrhage (ECASS 2 definition). Of 1209 patients, 64 (5.3%) had IHS, with an increasing proportion over time (p = 0.001). Their median onset-to-needle time was 128 min vs. 145 in COS (p < 0.001). They were more likely to have had a recent TIA [odds ratio (OR) 30.1; 95% confidence interval (CI) 11.5-78.7], to have been treated by vitamin K antagonist before (OR 4.2; 95% CI 1.4-12.0) and to undergo mechanical thrombectomy (45 vs. 10%, p < 0.001). They were less likely to have a pre-stroke mRS 0-1 (OR 0.22; 95% CI 0.09-0.50). After adjustment, IHS was not associated with any of the four outcome measures. Patients with IHS are treated 17 min earlier than patients with COS, but, taking into account that they were already in the hospital, delays are still too long. Their outcome does not differ from that of patients with COS, suggesting room for improvement if delays can be reduced. IHS being frequent, pre-specified pathways should be organised.

Topics: Administration, Intravenous; Aged; Aged, 80 and over; Brain Ischemia; Female; Fibrinolytic Agents; Follow-Up Studies; Hospitalization; Humans; Intracranial Hemorrhages; Male; Mechanical Thrombolysis; Middle Aged; Prospective Studies; Stroke; Thrombolytic Therapy; Time-to-Treatment; Treatment Outcome; Vitamin K

The optimal timing to administer non-vitamin K oral anticoagulants (NOACs) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and their timing in patients with acute ischemic stroke and atrial fibrillation who received NOACs for secondary prevention.. Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding. For the analysis, 1127 patients were eligible: 381 (33.8%) were treated with dabigatran, 366 (32.5%) with rivaroxaban, and 380 (33.7%) with apixaban. Patients who received dabigatran were younger and had lower admission National Institutes of Health Stroke Scale score and less commonly had a CHA. In patients with acute ischemic stroke and atrial fibrillation, treatment with NOACs was associated with a combined 5% rate of ischemic embolic recurrence and severe bleeding within 90 days.

Topics: Acute Disease; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Dabigatran; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyridones; Recurrence; Rivaroxaban; Survival Rate; Time Factors; Treatment Outcome; Vitamin K

Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) are widely used as stroke prophylaxis in non-valvular atrial fibrillation (AF), but comparative data are sparse.. To compare dabigatran, rivaroxaban, and apixaban vs. VKA and the risk of stroke/thromboembolism (TE) and intracranial bleeding in AF.. Using Danish nationwide registries (2011-15), anticoagulant-naïve AF patients were identified when initiating VKA or an NOAC. Outcomes were stroke/TE and intracranial bleeding. Multiple outcome-specific Cox regression was performed to calculate average treatment effects as standardized differences in 1-year absolute risks.. Overall, 43 299 AF patients initiated VKA (42%), dabigatran (29%), rivaroxaban (13%), and apixaban (16%). Mean CHA2DS2-VASc (SD) score was: VKA 2.9 (1.6), dabigatran 2.7 (1.6), rivaroxaban 3.0 (1.6), and apixaban 3.1 (1.6). Within patient-specific follow-up limited to the first 2 years, 1054 stroke/TE occurred and 261 intracranial bleedings. Standardized absolute risk (95% CI) of stroke/TE at 1 year after initiation of VKA was 2.01% (1.80% to 2.21%). In relation to VKA, the absolute risk differences were for dabigatran 0.11% (-0.16% to 0.42%), rivaroxaban 0.05% (-0.33% to 0.48%), and apixaban 0.45% (-0.001% to 0.93%). For the intracranial bleeding outcome, the standardized absolute risk at 1 year was for VKA 0.60% (0.49% to 0.72%); the corresponding absolute risk differences were for dabigatran -0.34% (-0.47% to - 0.21%), rivaroxaban -0.13% (-0.33% to 0.08%), and apixaban -0.20% (-0.38% to - 0.01%).. Among anticoagulant-naïve AF patients, treatment with NOACs was not associated with significantly lower risk of stroke/TE compared with VKA, but intracranial bleeding risk was significantly lower with dabigatran and apixaban.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cohort Studies; Dabigatran; Denmark; Female; Hospitalization; Humans; Intracranial Hemorrhages; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Vitamin K; Warfarin

It is unclear whether vitamin K antagonists affect stroke severity and outcome in patients with atrial fibrillation (AF). We aimed to evaluate this association. We prospectively studied 539 consecutive patients admitted with acute ischemic stroke (41.2 % males, age 78.9 ± 6.6 years). The severity of stroke was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). The outcome was assessed with dependency rates at discharge (modified Rankin scale 2-5) and with in-hospital mortality. 177 patients had a history of AF. The median NIHSS at admission did not differ between patients on acenocoumarol with INR 2.0-3.0, on acenocoumarol with INR < 2.0, on single antiplatelet treatment, on dual antiplatelet treatment, or on no treatment [4 (range 0-26), 13 (0-39), 8 (0-33), 3 (2-23) and 7 (0-33), respectively; p = 0.433]. Dependency rates were lower in patients on acenocoumarol with INR 2.0-3.0 or on dual antiplatelet treatment than in those on acenocoumarol with INR < 2.0, single antiplatelet treatment, or no treatment (20.0, 22.2, 61.5, 58.7 and 68.0 %, respectively; p = 0.024). Independent predictors of dependency were age, NIHSS at admission and history of ischemic stroke. In-hospital mortality did not differ between patients on acenocoumarol with INR 2.0-3.0, on acenocoumarol with INR < 2.0, on single antiplatelet treatment, on dual antiplatelet treatment, or on no treatment (7.7, 18.2, 16.1, 16.7 and 22.2 %, respectively; p = 0.822). In conclusion, optimally anticoagulated patients with AF have more favorable functional outcome after stroke and a trend for less severe stroke whereas patients with subtherapeutic anticoagulation have similar stroke severity and outcome with those on no treatment.

Topics: Acenocoumarol; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Brain Ischemia; Female; Hospital Mortality; Humans; International Normalized Ratio; Male; Platelet Aggregation Inhibitors; Severity of Illness Index; Stroke; Vitamin K

Patients with atrial fibrillation requiring maintenance haemodialysis are at increased risk of ischaemic stroke and bleeds. Currently, vitamin K antagonists such as warfarin are predominantly used in these patients as limited data are available on the use of non-vitamin K oral anticoagulants, including dabigatran etexilate (dabigatran). Dabigatran is approximately 85 % renally eliminated, thus, its half-life is prolonged in renal impairment. This study simulated the doseexposure relationship of dabigatran in patients undergoing haemodialysis. Dabigatran exposure was modelled at once- and twice-daily doses of 75 mg, 110 mg and 150 mg and at variations in non-renal clearance and dialysis settings. Resultant dose exposure (area under the curve [AUC]) was compared with values simulated from typical patients in the RE-LY® trial (based on a previously characterised pharmacometric model). In this simulation, all twice-daily dosages resulted in exposures above those simulated from typical RE-LY patients (1.5- to 3.3-fold increase in AUC) and thus may not be optimal for use in haemodialysis patients. However, dabigatran doses of 75 mg or 110 mg once daily produced exposures comparable to those simulated in typical RE-LY patients (-13.3 and +4.4 %, respectively). Of patient and dialysis variables, non-renal clearance had the highest impact on exposure (≤ 30.8 % change). These data could potentially inform dose selection in patients undergoing maintenance haemodialysis and the findings warrant investigation in future clinical trials.

Topics: Administration, Oral; Aged; Anticoagulants; Area Under Curve; Atrial Fibrillation; Brain Ischemia; Computer Simulation; Dabigatran; Humans; Kidney Failure, Chronic; Male; Renal Dialysis; Stroke; Vitamin K

The study sought to examine the risk of ischemic events and bleeding episodes associated with differing antithrombotic strategies in patients undergoing transcatheter aortic valve replacement (TAVR) with concomitant atrial fibrillation (AF).. Guidelines recommend antiplatelet therapy (APT) post-TAVR to reduce the risk of stroke. However, data on the efficacy and safety of this recommendation in the setting of a concomitant indication for oral anticoagulation (due to atrial fibrillation [AF]) with a vitamin K antagonist (VKA) are scarce.. A multicenter evaluation comprising 621 patients with AF undergoing TAVR was undertaken. Post-TAVR prescriptions were used to determine the antithrombotic regimen used according to the following 2 groups: monotherapy (MT) with VKA (n = 101) or multiple antithrombotic therapy (MAT) with VKA plus 1 or 2 antiplatelet agents (aspirin or clopidogrel; n = 520). Endpoint definitions were in accordance with Valve Academic Research Consortium-2 criteria. The rate of stroke, major adverse cardiovascular events (stroke, myocardial infarction, or cardiovascular death), major or life-threatening bleeding events, and death were assessed by a Cox multivariate model regression survival analysis according to the antithrombotic regime used.. During a median follow-up of 13 months (interquartile range: 3 to 31 months) there were no differences between groups in the rate of stroke (MT: 5%, MAT: 5.2%; adjusted hazard ratio [HR]: 1.25; 95% confidence interval [CI]: 0.45 to 3.48; p = 0.67), major adverse cardiovascular events (MT: 13.9%, MAT: 16.3%; adjusted HR: 1.33; 95% CI: 0.75 to 2.36; p = 0.33), and death (MT 22.8%, MAT: 19.2%; adjusted HR: 0.93; 95% CI: 0.58 to 1.50; p = 0.76). A higher risk of major or life-threatening bleeding was found in the MAT group (MT: 14.9%, MAT: 24.4%; adjusted HR: 1.85; 95% CI: 1.05 to 3.28; p = 0.04). These results remained similar when patients receiving VKA plus only 1 antiplatelet agent (n = 463) were evaluated.. In TAVR recipients prescribed VKA therapy for AF, concomitant antiplatelet therapy use appears not to reduce the incidence of stroke, major adverse cardiovascular events, or death, while increasing the risk of major or life-threatening bleeding.

Topics: Aged; Aged, 80 and over; Anticoagulants; Aortic Valve; Atrial Fibrillation; Brain Ischemia; Canada; Chi-Square Distribution; Europe; Female; Heart Valve Diseases; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Multivariate Analysis; Platelet Aggregation Inhibitors; Proportional Hazards Models; Risk Factors; Stroke; Time Factors; Transcatheter Aortic Valve Replacement; Treatment Outcome; Vitamin K; Warfarin

Bleeding is a major concern in treatment of atrial fibrillation (AF) with vitamin K antagonist (VKA). This concern is more emphasized in patients with high bleeding risk such as liver cirrhosis (LC).. We retrospectively analyzed incidence of stroke and major bleeding in 321 AF patients with LC, including early [Child-Pugh (CP)-A, n=215] and advanced [CP-B or C, n=106] LC according to VKA prescription. The CHA2DS2-VASc, HAS-BLED and MELD scores were higher in patients with VKA. CP score was positively correlated with HAS-BLED score (rho: 0.602). The incidence of major bleeding was higher in advanced LC than in early LC (14.5%/year vs. 4.9%/year, p<0.001). VKA reduced the risk of ischemic stroke in AF patients with LC, whereas it significantly increased the major bleeding risk. There was no difference in survival free from significant clinical events (SCEs) between the patients with or without VKA (p=0.91). On subgroup analysis, VKA was beneficial in early LC patients, as it decreased stroke without increasing major bleeding risk. However, in advanced LC patients, VKA significantly increased the risk of major bleeding, especially variceal origin, that overwhelms stroke reduction. As a result, VKA treatment reduced the risk of SCEs in early LC patients, whereas it increased the risk of SCEs in advanced LC.. VKA treatment might be beneficial to reduce significant clinical events in the early LC but not in the advanced LC group. However to confirm this hypothesis, a prospective randomized study is needed.

Topics: Anticoagulants; Atrial Fibrillation; Brain Ischemia; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Liver Cirrhosis; Male; Middle Aged; Prospective Studies; Republic of Korea; Risk Assessment; Vitamin K

This study evaluated the rates of new lesions on diffusion-weighted images (DWIs) of magnetic resonance imaging (MRI) and hemorrhagic transformation (HT) during 2 weeks after acute ischemic stroke (AIS) in patients with atrial fibrillation (Af) who were given one of the non-vitamin K antagonist oral anticoagulants (NOACs); this was then compared with those who were given warfarin.. Consecutive AIS patients with Af were enrolled between January 2008 and June 2013, and those selected were patients who had a MRI that included DWIs both on admission and after 2 weeks, and those given only wafrarin (warfarin group) or only one of the NOACs (NOAC group) within 2 weeks of admission. Of all 257 enrolled patients, 50 patients were selected for the NOAC group (median age of 80.0 years) and 125 patients for the warfarin group (median age of 80.0 years). Both NOAC and warfarin were started at a median of the second day after admission. There was no significant difference in the rates of new lesions on DWIs (26.0% vs. 28.0%, P=0.7888) and HT (30.0% vs. 39.2%, P=0.2536) between the NOAC and warfarin groups. The NOAC group had a lower rate of concomitant use of heparin (44.0% vs. 92.8%, P<0.0001) than the warfarin group.. This study suggests that NOACs are suitable for AIS patients with Af, perhaps even better than warfarin, given their simplicity.

Topics: Acute Disease; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Heparin; Humans; Magnetic Resonance Imaging; Male; Radiography; Stroke; Time Factors; Vitamin K; Warfarin

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

Topics: Acute Disease; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Cohort Studies; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Humans; Incidence; Male; Middle Aged; Pilot Projects; Thrombolytic Therapy; Treatment Outcome; Vitamin K

Topics: Adolescent; Adult; Age Factors; Brain Ischemia; Female; Humans; Male; Platelet Aggregation Inhibitors; Protein S Deficiency; Retrospective Studies; Risk Factors; Sjogren's Syndrome; Sneddon Syndrome; Stroke; Vitamin K

Atrial fibrillation is the most common cause of embolic stroke associated to heart disease. Oral anticoagulation with vitamin K antagonists substantially reduces this risk.. We assessed a group of patients with prior diagnosis of atrial fibrillation who sustained an ischemic stroke while receiving an adequate regime of oral anticoagulation.. We evaluated consecutive patients with ischemic stroke and prior diagnosis of atrial fibrillation. We determined demographics, clinical characteristics, TOAST stroke subtypes, CHADS2 scores, and prior or concomitant use of oral anticoagulants.. We studied 112 patients. Thirty nine of them (35%) had received an adequate dose of a vitamin K antagonist during the 24-hour period preceding the stroke. There were no differences in demographics, vascular risk factors, CHADS2 scores, nor medications use between patients who were or were not receiving anticoagulation. Other potential etiologies for stroke occurrence were found in 8 (21%) anticoagulated patients, and in 3 (4%) non-anticoagulated subjects (p<0.01). Anticoagulated patients had a mean international normalized ratio (INR) of 2.3 ± 1.3 (median 2.05), and INR was within therapeutic ranges (i.e., ≥ 2) in 54% of these subjects.. A substantial proportion of patients with atrial fibrillation who have an ischemic stroke are already receiving oral anticoagulation. Sub-optimal levels of anticoagulation and additional etiologies explain, only in part, this failure. Further research is needed to help find adequate therapeutic strategies in atrial fibrillation patients who sustain an ischemic stroke while receiving oral anticoagulation.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Female; Humans; International Normalized Ratio; Male; Risk Factors; Stroke; Treatment Outcome; Vitamin K

The prevalence of AF is higher in men and increases with age. However, the number of elderly women is higher than that of elderly men, and AF should be considered to affect men and women equally. Little information exists on elderly AF patients, and in particular, whether stroke and bleeding risk differs between elderly women and elderly men remains unknown.. We have performed the EPICA Study, a large, multicentre observational study including 4093 elderly patients who started VKA treatment after the age of 80years. In this study, we will focus our analysis on 3015 AF patients followed for 7620 patient-years (pt-yrs) to evaluate if bleeding and stroke risks were different between genders.. During follow-up, we recorded 112 ischemic cerebral events (rate 1.5 ×100pt-years) with no difference between genders. History of previous stroke/TIA, hypertension and artery vascular disease are independently associated with stroke/TIA during treatment. We recorded 132 major bleeds (rate 1.7 ×100pt-years); males showed a higher risk of bleeding (OR 1.5), even if not statistically significant. At multivariate analysis, history of major bleeds, history of falls and active cancer are risk factors independently associated to bleeding.. Elderly patients with AF do not show clear gender related differences in the risk of major adverse events. However, elderly males showed a higher rate of bleeding complications, and females showed a slightly higher rate of stroke, thus suggesting the possibility of a higher net clinical benefit of anticoagulant treatment in females.

Topics: Age Factors; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Female; Hemorrhage; Humans; Italy; Male; Multivariate Analysis; Odds Ratio; Proportional Hazards Models; Risk Assessment; Risk Factors; Sex Factors; Stroke; Time Factors; Treatment Outcome; Vitamin K

Topics: Anticoagulants; Brain Ischemia; Humans; International Normalized Ratio; Prospective Studies; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator; Vitamin K

Patients with prosthetic heart valves have a higher risk of developing valve thrombosis and arterial thromboembolism. Antithrombotic therapy during the early postoperative period after biologic mitral valve replacement (MVR) is controversial. Hence, a retrospective study was conducted to investigate the efficacy of different antithrombotic therapies in patients after MVR with bioprostheses.. Between January 2000 and January 2006, a total of 99 patients presenting with preoperative sinus rhythm underwent isolated bioprosthetic MVR. Of these patients, 59 (58%) received a bovine pericardial xenograft, and 40 (42%) a porcine bioprosthesis. The postoperative antithrombotic therapy was prescribed according to the surgeon's preference.. Fifty-one (51%) patients received acetylsalicylic acid (ASA group, 100 mg/day), 12 (13%) did not receive any specific antithrombotic therapy (NT group), and 36 (36%) received a vitamin K antagonist (VKA group, INR 2-3). The primary endpoints were the rate of cerebral ischemic events, bleeding events, and survival. The mean follow up was 23 months (range: 3-68 months). There were five early deaths (5%), and eight late deaths (8%). There were five episodes of cerebral ischemic events; these included three patients (8.3%) in the VKA group, one patient (2.0%) in ASA group, and one patient (8.3%) in the NT group (p = 0.351). Of these episodes, two occurred between 24 h and three months after surgery. Only one (2.8%) episode of major bleeding occurred (in the VKA group), due to poor anticoagulation management.. Each of the antithrombotic therapies evaluated appeared to be safe. There was no evidence to suggest that any specific antithrombotic therapy would be superior in preventing valve thrombosis in patients undergoing bioprosthetic MVR.

Topics: Aged; Aged, 80 and over; Animals; Anticoagulants; Aspirin; Bioprosthesis; Brain Ischemia; Cattle; Chi-Square Distribution; Drug Administration Schedule; Female; Fibrinolytic Agents; Heart Valve Diseases; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Hemorrhage; Humans; Logistic Models; Male; Middle Aged; Mitral Valve; Practice Guidelines as Topic; Prosthesis Design; Retrospective Studies; Risk Assessment; Risk Factors; Swine; Thrombosis; Time Factors; Treatment Outcome; Vitamin K

Stroke and atrial fibrillation (AF) are a real vascular epidemic, and the consequences are disastrous. The most common complication of AF is stroke.. The correct aetiological diagnosis of stroke is essential for adequate prevention. The percentage of cryptogenic ischaemic strokes is far too high and the detection of AF needs to be improved. Cardio-embolic cerebral ischaemia due to AF is preventable, however due to medical inertia, the lack of compliance by the patient, and the problems with oral vitamin K antagonist anticoagulants, means that many patients with AF are at risk of suffering from a stroke.. The significant recent advances with drugs such as dronedarone and dabigatran, provide real hope for an improvement in its prevention, and for this reason neurologists must know about them.

Topics: Amiodarone; Anticoagulants; Antifibrinolytic Agents; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Brain Ischemia; Dabigatran; Diagnosis, Differential; Dronedarone; Humans; Vitamin K

Use of vitamin K antagonists (VKAs) for stroke prophylaxis in patients with non-valvular atrial fibrillation (NVAF) necessitates frequent monitoring of the international normalized ratio (INR) to avoid the increased risk of hemorrhage associated with excess anticoagulation, or ischemic stroke due to insufficient anticoagulation. We therefore developed a model to estimate the excess morbidity attributable to inadequate INR control in NVAF populations.. Equations expressing the risk of cerebrovascular events as a function of INR were generated using published data. Additional functions were developed to estimate the excess risk attributable to inferior INR control, using the clinical trial setting as the reference.. The derived risk functions were applied to French NVAF patients receiving anticoagulation in routine medical practice. This population achieved a time in therapeutic range (INR 2.0-3.0) of 59%, compared with 68% time in therapeutic range (TTR) in the SPORTIF III and V clinical trials. However, there was considerable variation in the TTR among patients in routine care, of whom 36% were in range for less than 50% of the time. Among this latter group, the relative risk, compared with the clinical trial setting, was 1.47 for ischemic stroke and 2.68 for intracranial hemorrhage. Conversely, for patients achieving a TTR greater than 50%, the relative risks for ischemic stroke and intracranial hemorrhage were 0.99 and 1.16, respectively.. This model permits estimation of the excess risk attributable to inferior INR control in NVAF populations receiving VKA anticoagulation, and has implications for public health planning and management.

Topics: Anticoagulants; Atrial Fibrillation; Blood Coagulation; Brain Ischemia; Cerebral Hemorrhage; France; Humans; International Normalized Ratio; Models, Statistical; Morbidity; Public Health; Quality of Health Care; Risk Factors; Stroke; Vitamin K

This article about hemorrhagic complications of anticoagulant and thrombolytic treatment is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Bleeding is the major complication of anticoagulant and fibrinolytic therapy. The criteria for defining the severity of bleeding vary considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist (VKA)-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that VKA therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0-3.0), is associated with a lower risk of bleeding than therapy targeted at an INR > 3.0. The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism is < 3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (> 70 years). Low-molecular-weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute venous thromboembolism. Higher doses of UFH and LMWH are associated with important increases in major bleeding in ischemic stroke. In ST-segment elevation myocardial infarction, addition of LMWH, hirudin, or its derivatives to thrombolytic therapy is associated with a small increase in the risk of major bleeding, whereas treatment with fondaparinux or UFH is associated with a lower risk of bleeding. Thrombolytic therapy increases the risk of major bleeding 1.5-fold to threefold in patients with acute venous thromboembolism, ischemic stroke, or ST-elevation myocardial infarction.

Topics: Anticoagulants; Brain Ischemia; Evidence-Based Medicine; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Hirudins; Humans; International Normalized Ratio; Myocardial Infarction; Polysaccharides; Risk Factors; Severity of Illness Index; Thrombolytic Therapy; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Apolipoproteins E; Biomarkers; Brain; Brain Ischemia; Case-Control Studies; Cerebral Hemorrhage; Genotype; Humans; International Normalized Ratio; Risk Factors; Tomography, X-Ray Computed; Vitamin K; Warfarin

Menadione bisulphite increased endogenous oxygen-radical production by rat brain synaptosomes, as indicated by H2O2 generation. Increased oxygen-radical production was also demonstrated in synaptosomes prepared from menadione-treated rats and synaptosomes reoxygenated after an anoxic insult. Acetylcholine synthesis de novo was inhibited in synaptosomes incubated with menadione in vitro, in synaptosomes prepared from menadione-treated animals in vivo, and in depolarized post-anoxic synaptosomes. Intrasynaptosomal free Ca2+ was increased by menadione in vitro (50 microM), but this increase was not due to stimulation of Ca2+ entry into the nerve terminals. Acetylcholine release was stimulated by menadione in vitro, possibly as a consequence of the elevated intrasynaptosomal Ca2+ content. The Ca2+ contents of synaptosomes prepared from menadione (10 mg/kg)-treated animals in vivo and synaptosomes reoxygenated after anoxia were unchanged. In synaptosomes prepared from menadione-treated animals, acetylcholine release was no longer significantly stimulated by K+, whereas it was unchanged from control (normoxic) values in synaptosomes reoxygenated after anoxia. None of these treatments caused any measurable damage to the synaptic plasma membrane (as judged by the release of lactate dehydrogenase), or to synaptosomal phospholipases (as judged by choline release from membrane phospholipids). Synaptosomes prepared from menadione-treated rats were found to be a good model for the study of post-anoxic damage to nerve-terminal function.

Topics: Acetylcholine; Animals; Brain Ischemia; Calcium; Choline; Disease Models, Animal; Free Radicals; Hydrogen Peroxide; In Vitro Techniques; Male; Neurons; Oxygen; Rats; Rats, Inbred Strains; Synaptosomes; Vitamin K