rivaroxaban and Cerebral-Hemorrhage

Atrial fibrillation (AF) and venous thromboembolism (VTE) are highly prevalent conditions with a significant healthcare burden, and represent the main indications for anticoagulation. Direct oral anticoagulants (DOACs) are the first choice treatment of AF/VTE, and have become the most prescribed class of anticoagulants globally, overtaking vitamin K antagonists (VKAs). Compared to VKAs, DOACs have a similar or better efficacy/safety profile, with reduced risk of intracerebral hemorrhage (ICH), while the risk of major bleeding and other bleeding harms may vary depending on the type of DOAC. We have critically reviewed available evidence from randomized controlled trials and observational studies regarding the risk of bleeding complications of DOACs compared to VKAs in patients with AF and VTE. Special patient populations (e.g., elderly, extreme body weights, chronic kidney disease) have specifically been addressed. Management of bleeding complications and possible resumption of anticoagulation, in particular after ICH and gastrointestinal bleeding, are also discussed. Finally, some suggestions are provided to choose the optimal DOAC to minimize adverse events according to individual patient characteristics and bleeding risk.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Dabigatran; Gastrointestinal Hemorrhage; Humans; Rivaroxaban; Stroke; Venous Thromboembolism

We present a case of a fatal cerebral haemorrhage in an 82-year-old male patient with coronavirus disease 2019 (COVID-19), who was taking prophylactic oral anticoagulation because of atrial fibrillation (rivaroxaban 20 mg q.d. for two years). On admission, the patient was deeply comatose, mechanically ventilated, with tachycardia up to 150 bpm, high blood pressure >210/120 mmHg and a body temperature >39°C. A computed tomography scan of the head showed a large intracerebral haemorrhage located in the deep structures of the right hemisphere, with a mass effect and bleeding to the ventricles. Rivaroxaban was discontinued at admission. The patient tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but he did not have typical symptoms of pneumonia. In the following days, the patient's neurological condition did not improve, and a fever of up to 40°C and abnormal coagulation parameters remained resistant to pharmacotherapy. The patient developed multi-system organ failure and died on day 8. Here, we review the recent literature and discuss the possible association of SARS-CoV-2-mediated endothelial injury and cardiovascular disorders with cerebrovascular complications. We postulate that anti-inflammatory treatment in COVID-19 and the stabilisation of endothelium functions can be particularly important in patients with pre-existing cardiovascular conditions.

Topics: Aged, 80 and over; Atrial Fibrillation; Cerebral Hemorrhage; COVID-19; Factor Xa Inhibitors; Fatal Outcome; Humans; Hypertension; Hypotension; Male; Multiple Organ Failure; Respiratory Insufficiency; Rivaroxaban; SARS-CoV-2; Stroke; Tachycardia

Occult atrial fibrillation (AF) is a leading cause of stroke of unclear cause. The optimal approach to secondary stroke prevention for these patients remains elusive. The term embolic stroke of undetermined source (ESUS) was coined to describe ischemic strokes in which the radiographic features demonstrate territorial infarcts resembling those seen in patients with confirmed sources of embolism but without a clear source of embolism detected. It was assumed that patients with ESUS had a high rate of occult AF and would benefit from treatment with direct oral anticoagulants, which are at least as effective as vitamin K antagonists for secondary stroke prevention in patients with AF, but with a much lower risk of intracerebral hemorrhage. Two recent large randomized trials failed to show superiority of direct oral anticoagulants over aspirin in ESUS patients. These findings prompt a reexamination of the ESUS concept, with the goal of improving specificity for detecting patients with a cardioembolic cause. Based on the negative trial results, there is renewed interest in the role of long-term cardiac monitoring for AF in patients who fit the current ESUS definition, as well as the clinical implication of detecting AF. Ongoing trials are exploring these questions. Current ESUS definitions do not accurately detect the patients who should be prescribed direct oral anticoagulants, potentially because occult AF is less common than expected in these patients and/or anticoagulants may be less beneficial in patients with ESUS but no AF than they are for patients with stroke with established AF. More specific criteria to identify patients who may be at higher risk for occult AF and reduce their risk of subsequent stroke have been developed and are being tested in ongoing clinical trials.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Cerebral Hemorrhage; Clinical Trials as Topic; Dual Anti-Platelet Therapy; Embolic Stroke; Factor Xa Inhibitors; Humans; Intracranial Embolism; Rivaroxaban; Secondary Prevention

The characteristics and natural history of acute non-vitamin K antagonists oral anticoagulants (NOAC)-associated intracerebral haemorrhage (ICH) are largely unknown. We performed a comprehensive systematic review and meta-analysis to compare baseline ICH volume, haematoma expansion and clinical outcomes between NOAC-ICH versus vitamin K antagonists-ICH (VKA-ICH).. We searched PubMed and conference abstracts for observational studies comparing baseline characteristics and outcomes in patients with NOAC-ICH versus VKA-ICH using an appropriate keyword/MeSH term search strategy. Data were extracted following PRISMA and MOOSE guidelines. The main outcome measures were mortality and unfavourable functional outcome (modified Rankin Score: 4-6) at discharge and at 3 months, as well as ICH volumes and haematoma expansion rates in the two groups. Random-effects models with DerSimonian-Laird weights were used for pooled estimates calculation.. Twelve studies including 393 NOAC-ICH and 3482 VKA-ICH were pooled in meta-analysis. There was no difference in mean ICH-volume between the two groups (standard mean difference: -0.24; 95% CI -0.52 to 0.04, p=0.093). The rates of haematoma expansion were comparable in NOAC-ICH versus VKA-ICH (OR: 0.76; 95% CI 0.49 to 1.19, p=0.236). We did not find any difference between patients with NOAC-ICH versus VKA-ICH in all-cause mortality at discharge (OR: 0.66; 95% CI 0.42 to 1.05, p=0.077) and unfavourable functional outcome at discharge (OR: 0.77; 95% CI 0.41 to 1.44, p=0.413). The 3-month outcome was also comparable between the two ICH groups. Moderate-to-substantial statistical heterogeneity was noted.. Our results confirm that ICH volume, haematoma expansion, mortality and functional outcome appear to be similar for NOAC-ICH versus VKA-ICH. Large prospective cohorts and updated meta-analyses are needed to provide more precise estimates.

Topics: Anticoagulants; Antithrombins; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Hematoma; Humans; Mortality; Odds Ratio; Phenprocoumon; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Severity of Illness Index; Thiazoles; Vitamin K; Warfarin

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cerebral Hemorrhage; Contraindications; Dabigatran; Drug Administration Schedule; Drug Interactions; Endovascular Procedures; Factor Xa Inhibitors; Female; Humans; Infusions, Intravenous; Kidney Function Tests; Male; Middle Aged; Practice Guidelines as Topic; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thrombectomy; Thrombolytic Therapy; Tissue Plasminogen Activator

Rivaroxaban is a factor-Xa-inhibitor which has been shown to be non-inferior to the vitamin-K-antagonist (VKA) warfarin in atrial fibrillation patients. In the manufacturer-sponsored trial, the rate of intracranial hemorrhage in rivaroxaban-treated patients was lower than in VKA-treated. It is unknown if this advantage of rivaroxaban is also present outside clinical trials. We report a patient with fatal cerebral bleeding 4months after initiation of rivaroxaban. Bleeding might be favored by hypertension, hypoalbuminemia, renal impairment, hepatopathy and drug-drug interactions of rivaroxaban with amiodarone and bisoprolol. Patients have to be monitored closely after initiation of rivaroxaban, especially if they are treated with possibly interacting drugs. Additionally, hepatic function, albumin level, and renal function have to be closely monitored. Therapy with VKA seems more convenient, safer and more favorable for the patient than rivaroxaban with its associated uncertainties concerning metabolization and drug-drug interactions and no possibility to reverse its activity in emergency situations.

Topics: Aged; Cerebral Hemorrhage; Factor Xa Inhibitors; Fatal Outcome; Humans; Male; Rivaroxaban

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Gastrointestinal Hemorrhage; Humans; Intracranial Embolism; Morpholines; Postoperative Complications; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thiophenes; Thrombosis; Vitamin K; Warfarin

AF might be a life threatening disease. Patients have been under oral antithrombotic treatment in order to avoid thrombotic events. Although this treatment proved to be effective in the last decades there was always the inconvenience of a regular blood control. In the last months NOACs have been flooding the market promising to be as effective as their older concurrents in certain circumstances and highlighting the fact that the control of INR has become obsolete. However, as there is no specific antidote up to date, NOACs might present a life threatening event in case of an intracerebral haemorrhage. The brain surgeons might find themselves in a difficult situation when they have to decide whether to operate on a patient with a compromised haemostasis or not. We present four patients who were treated with NOACs for AF. Three of them were admitted with intracerebral haemorrhage in our neurosurgical unit from January to October 2013. The fourth patient bled one week after stopping his treatment with NOAC. Furthermore we take a closer look to the existing literature and try to portray the issue from a neurosurgical point of view.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Female; Humans; Hypertension; Male; Morpholines; Rivaroxaban; Thiophenes

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation Factors; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Humans; Monitoring, Physiologic; Morpholines; Prodrugs; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Thrombin; Thromboembolism; Vitamin K; Warfarin

Atrial fibrillation treatment relies on anticoagulation therapy that reduces the risk of stroke. Vitamin K antagonists (VKA) were the only oral anticoagulant drugs for more than 50 years, but they are difficult to manage especially in the elderly. In France, VKA are the main cause of iatrogenic hospitalizations with about 17,000 hospitalizations per year and around 4,000 to 5,000 deaths per year. Pharmacologic properties of VKA, especially the narrow therapeutic margin explain the complexity of their management. Several studies have shown that patients treated with VKA were on average only 50% of the time with an INR in the therapeutic range. In other words, patients are, half of the time, either-under treated or over-treated. Within this framework, development of new oral anticoagulant drugs appeared necessary, in order to obtain drugs with larger therapeutic margin and a better risk/benefit profile than VKA. Three large randomized clinical trials including almost 50,000 patients with 20,000 subjects over 75 years old and 8,000 over 80 years old, show a better risk/benefit profile of the new oral anticoagulants (NOAC) than VKA, characterized by a 50% reduction of cerebral hemorrhages, 22% reduction of stroke and 12% reduction of total mortality. Meanwhile, their renal elimination and the lack of control of the biological efficacy need to be taken into account for their prescription. Renal failure (estimated glomerular filtration rate according to Cockcroft formula < 30 mL/min) contraindicates their use. Their half-life is shorter than that of VKA and the biological monitoring is not available, thus a good adherence to the treatment is important. Studies specifically conducted among geriatric older population with poly-pathologies and frail are therefore needed to evaluate tolerance of NOAC in real life conditions.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Drugs, Investigational; Half-Life; Humans; Intracranial Embolism; Metabolic Clearance Rate; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Vitamin K

A network meta-analysis of the three new oral anticoagulants was performed from the three trials comparing dabigatran, rivaroxaban and apixaban with warfarin in patients with atrial fibrillation.. Data were extracted of the RE-LY study of dabigatran 110 mg bid and dabigatran 150 mg bid, the ROCKET AF trial of rivaroxaban and the ARISTOTLE trial of apixaban for the composite outcome of ischemic stroke and systemic embolism, for major bleeding, intracerebral bleeding, mortality and myocardial infarction.. Dabigatran (150 mg bid) showed superior efficacy in preventing ischemic stroke plus systemic embolism to dabigatran (110 mg bid, P=0.0364) and rivaroxaban (P=0.0388). Apixaban had equivalent efficacy with rivaroxaban and dabigatran (either dose). Apixaban was safer (less major bleeding) than dabigatran (150 mg bid, P=0.036) or rivaroxaban (P=0.0002). Intracerebral hemorrhage occurred with equal frequency for all agents except for rivaroxaban (higher risk than dabigatran 110 mg bid, P=0.0070). Myocardial infarction occurred less frequently with rivaroxaban and apixaban compared to either dose of dabigatran (all P<0.05).. All-cause mortality was not different for any agent or regimen. In the absence of head-to-head comparisons, this network meta-analysis suggests that apixaban and dabigatran 110 mg bid may offer the best benefit-risk balance for stroke prevention in non-valvular atrial fibrillation. Dabigatran 150 mg bid may be preferred for patients with a high risk for embolism.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Chi-Square Distribution; Dabigatran; Embolism; Female; Humans; Male; Middle Aged; Morpholines; Myocardial Infarction; Odds Ratio; Pyrazoles; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome

Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown.. To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies.. At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression.. Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52-1.7).

Topics: Aged; Aspirin; Brain Infarction; Cerebral Hemorrhage; Double-Blind Method; Embolic Stroke; Factor Xa Inhibitors; Female; Humans; Intracranial Embolism; Magnetic Resonance Imaging; Male; Prospective Studies; Rivaroxaban; Stroke

The reported associations of cerebral microbleeds with recurrent stroke and intracerebral hemorrhage have raised concerns regarding antithrombotic treatment in patients with a history of stroke and microbleeds on magnetic resonance imaging.. To characterize microbleeds in embolic strokes of undetermined source (ESUS) and report interactions between microbleeds and the effects of random assignment to anticoagulant vs antiplatelet therapy.. Subgroup analyses of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) international, double-blind, randomized, event-driven phase 3 clinical trial. Participants were enrolled between December 2014 and September 2017 and followed up for a median of 11 months. The study setting included 459 stroke recruitment centers in 31 countries. Patients aged 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of these 7213 NAVIGATE ESUS participants, 3699 (51%) had information on cerebral microbleeds reported on their baseline clinical magnetic resonance imaging and were eligible for these analyses. Patients with a prior history of symptomatic intracerebral hemorrhage were excluded from the NAVIGATE ESUS trial.. Rivaroxaban, 15 mg, compared with aspirin, 100 mg, daily.. The primary outcome was recurrent stroke. Secondary outcomes were ischemic stroke, intracerebral hemorrhage, and all-cause mortality.. Microbleeds were present in 395 of 3699 participants (11%). Of patients with cerebral microbleeds, mean (SD) age was 69.5 (9.4) years, 241 were men (61%), and 201 were White (51%). Advancing age (odds ratio [OR] per year, 1.03; 95% CI, 1.01-1.04), East Asian race/ethnicity (OR, 1.57; 95% CI, 1.04-2.37), hypertension (OR, 2.20; 95% CI, 1.54-3.15), multiterritorial infarcts (OR, 1.95; 95% CI, 1.42-2.67), chronic infarcts (OR, 1.78; 95% CI, 1.42-2.23), and occult intracerebral hemorrhage (OR, 5.23; 95% CI, 2.76-9.90) were independently associated with microbleeds. The presence of microbleeds was associated with a 1.5-fold increased risk of recurrent stroke (hazard ratio [HR], 1.5; 95% CI, 1.0-2.3), a 4-fold risk of intracerebral hemorrhage (HR, 4.2; 95% CI, 1.3-13.9), a 2-fold risk of all-cause mortality (HR, 2.1; 95% CI, 1.1-4.3), and strictly lobar microbleeds with an approximately 2.5-fold risk of ischemic stroke (HR, 2.3; 95% CI, 1.3-4.3). There were no interactions between microbleeds and treatment assignments for recurrent stroke, ischemic stroke, or all-cause mortality. The HR of intracerebral hemorrhage on rivaroxaban was similar between persons with microbleeds (HR, 3.1; 95% CI, 0.3-30.0) and persons without microbleeds (HR, 3.0; 95% CI, 0.6-14.7; interaction P = .97).. Microbleeds mark an increased risk of recurrent stroke, ischemic stroke, intracerebral hemorrhage, and mortality in ESUS but do not appear to influence effects of rivaroxaban on clinical outcomes.. ClinicalTrials.gov Identifier: NCT02313909.

Topics: Aged; Anticoagulants; Aspirin; Cerebral Hemorrhage; Double-Blind Method; Embolic Stroke; Female; Humans; Male; Middle Aged; Prevalence; Recurrence; Rivaroxaban

Risks, sites, and predictors of major bleeding during antithrombotic therapies have not been well defined for patients with recent embolic stroke of undetermined source.. Exploratory analysis of major bleeds defined by International Society of Thrombosis and Hemostasis criteria occurring among 7213 participants in international NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial) embolic stroke of undetermined source randomized trial comparing rivaroxaban 15 mg daily with aspirin 100 mg daily.. During a median follow-up of 11 months, 85 major bleeds occurred. The most frequent site was gastrointestinal (38%), followed by intracranial (29%). Assignment to rivaroxaban (hazard ratio [HR], 2.7 [95% CI, 1.7-4.3]), East Asia region (HR, 2.5 [95% CI, 1.6-3.9]), systolic blood pressure ≥160 mm Hg (HR, 2.2 [95% CI, 1.2-3.8]), and reduced estimated glomerular filtration rate (HR, 1.2 per 10 mL/min per 1.73 m. Among embolic stroke of undetermined source patients participating in an international randomized trial, independent predictors of major bleeding were assignment to rivaroxaban, East Asia region, increased systolic blood pressure, and impaired renal function. East Asia as a region was strongly associated with risk of intracerebral hemorrhage. Estimated glomerular filtration rate should be a consideration for stratifying bleeding risk. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Topics: Adult; Aged; Asia, Eastern; Asian People; Cerebral Hemorrhage; Double-Blind Method; Factor Xa Inhibitors; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Intracranial Embolism; Male; Middle Aged; Risk Factors; Rivaroxaban; Stroke

Information about rivaroxaban plasma level (RivLev) may guide treatment decisions in patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) taking rivaroxaban.. In a multicenter registry-based study (Novel Oral Anticoagulants in Stroke Patients collaboration; ClinicalTrials.gov: NCT02353585) of patients with stroke while taking rivaroxaban, we compared RivLev in patients with AIS and ICH. We determined how many AIS patients had RivLev ≤ 100ng/ml, indicating possible eligibility for thrombolysis, and how many ICH patients had RivLev ≥ 75ng/ml, making them possibly eligible for the use of specific reversal agents. We explored factors associated with RivLev (Spearman correlation, regression models) and studied the sensitivity and specificity of international normalized ratio (INR) thresholds to substitute RivLev using cross tables and receiver operating characteristic curves.. RivLev did not differ between patients with AIS and ICH. Half of the patients with AIS under rivaroxaban had a RivLev low enough to consider thrombolysis. In ICH patients, two-thirds had a RivLev high enough to meet the eligibility for the use of a specific reversal agent. INR thresholds perform poorly to inform treatment decisions in individual patients. Ann Neurol 2018;83:451-459.

Topics: Aged; Aged, 80 and over; Brain Ischemia; Cerebral Hemorrhage; Cohort Studies; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Male; Registries; Rivaroxaban; Stroke

Early anticoagulation after cardioembolic stroke remains controversial because of the potential for hemorrhagic transformation (HT). We tested the safety and feasibility of initiating rivaroxaban ≤14 days after cardioembolic stroke/transient ischemic attack.. A prospective, open-label study of patients with atrial fibrillation treated with rivaroxaban ≤14 days of transient ischemic attack or ischemic stroke (National Institute of Health Stroke Scale <9). All patients underwent magnetic resonance imaging <24 hours of rivaroxaban initiation and day 7. The primary end point was symptomatic HT at day 7.. Sixty patients (mean±SD age 71±19 years, 82% stroke/18% transient ischemic attack) were enrolled. Median (interquartile range) time from onset to rivaroxaban was 3 (5) days. At treatment initiation, median National Institute of Health Stroke Scale was 2 (4), and median diffusion-weighted imaging volume was 7.9 (13.7) mL. At baseline, HT was present in 25 (42%) patients (hemorrhagic infarct [HI]1=19, HI2=6). On follow-up magnetic resonance imaging, no patients developed symptomatic HT. New asymptomatic HI1 developed in 3 patients, and asymptomatic progression from HI1 to HI2 occurred in 5 patients; otherwise, HT remained unchanged at day 7.. These data support the safety of rivaroxaban initiation ≤14 days of mild-moderate cardioembolic stroke/transient ischemic attack. Magnetic resonance imaging evidence of petechial HT, which is common, does not appear to increase the risk of symptomatic HT.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Cerebral Hemorrhage; Drug Administration Schedule; Factor Xa Inhibitors; Female; Glomerular Filtration Rate; Humans; Intracranial Embolism; Ischemic Attack, Transient; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Prospective Studies; Recurrence; Rivaroxaban; Time Factors; Treatment Outcome

Apixaban and rivaroxaban are replacing vitamin K antagonists for the treatment of venous thromboembolism (VTE) in adults; however, head-to-head comparisons remain limited.. To assess the effectiveness and safety of apixaban compared with rivaroxaban in patients with VTE.. Retrospective new-user cohort study.. U.S.-based commercial health care insurance database from 1 January 2015 to 30 June 2020.. Adults with VTE who were newly prescribed apixaban or rivaroxaban.. The primary effectiveness outcome was recurrent VTE, a composite of deep venous thrombosis and pulmonary embolism. The primary safety outcome was a composite of gastrointestinal and intracranial bleeding.. Of 49 900 eligible patients with VTE, 18 618 were new users of apixaban and 18 618 were new users of rivaroxaban. Median follow-up was 102 days (25th, 75th percentiles: 30, 128 days) among apixaban and 105 days (25th, 75th percentiles: 30, 140 days) among rivaroxaban users. After propensity score matching, apixaban (vs. rivaroxaban) was associated with a lower rate for recurrent VTE (hazard ratio, 0.77 [95% CI, 0.69 to 0.87]) and bleeding (hazard ratio, 0.60 [CI, 0.53 to 0.69]). The absolute reduction in the probability of recurrent VTE with apixaban versus rivaroxaban was 0.006 (CI, 0.005 to 0.011) within 2 months and 0.011 (CI, 0.011 to 0.013) within 6 months of initiation. The absolute reduction in the probability of gastrointestinal and intracranial bleeding with apixaban versus rivaroxaban was 0.011 (CI, 0.010 to 0.011) within 2 months and 0.015 (CI, 0.013 to 0.015) within 6 months of initiation.. Short follow-up.. In this population-based cohort study, patients with VTE who were new users of apixaban had lower rates for recurrent VTE and bleeding than new users of rivaroxaban.. None.

Topics: Aged; Cerebral Hemorrhage; Databases, Factual; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Recurrence; Retrospective Studies; Risk Factors; Rivaroxaban; United States; Venous Thromboembolism

 Intracranial hemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinase (MMP) inhibition has been proposed as a novel pharmacological approach for ICH treatment..  We evaluated the effects of CM-352 (MMP-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin complex concentrate (PCC)..  ICH was induced by collagenase injection into the striatum of wild type (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and.  Only PCC reduced hemorrhage volume and improved functional outcome in warfarin-ICH, but both PCC and CM-352 treatments diminished hemorrhage volume (46%,.  CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihemorrhagic strategy for rivaroxaban-associated ICH.

Topics: Animals; Anticoagulants; Benzamides; Blood Coagulation Factors; Cerebral Hemorrhage; Disease Models, Animal; Hydroxamic Acids; Interleukin-6; Intracranial Hemorrhages; Matrix Metalloproteinase 10; Mice; Mice, Inbred C57BL; Plasminogen Activator Inhibitor 1; Rivaroxaban; Warfarin

Existing research recommends either andexanet alfa (AA) or four-factor prothrombin complex concentrate (4F-PCC) as an antidote for major bleeding events due to apixaban or rivaroxaban. Currently, there is limited published research that directly compares the risks and benefits of the two agents in patients with oral factor Xa inhibitor related traumatic and spontaneous intracerebral hemorrhages. Additional head-to-head data is needed to support favoring either AA or 4F-PCC when it comes to efficacy, safety, and cost.. A retrospective chart review was conducted to assess patients admitted to a multi-center healthcare system and a stand-alone teaching hospital in central Florida from June 2016 to December 2020. Patients included in the study were at least 18 years of age, taking apixaban or rivaroxaban prior to admission, had radiographical evidence of an intracranial hemorrhage, and received either AA or 4F-PCC as a reversal agent. The primary outcome analyzed was the level of excellent hemostasis achieved, based on a standardized rating system for effective hemostasis defined by the International Society of Thrombosis and Hemostasis (ISTH), after administration of AA or 4F-PCC. Secondary outcomes analyzed included changes in the initial hemorrhage volume as reported on computed tomography (CT) scan and at 12 to 24 h post treatment, rate of thromboembolic events, rate of inpatient mortality, and total cost of treatment after AA or 4F-PCC administration.. A total of 109 patients were included in the study with 47 in the AA group (43.1%) and 62 in the 4F-PCC group (56.9%). There were no statistically significant differences between AA and 4F-PCC in terms of the primary and secondary outcomes with the exception of total cost of treatment. The level of excellent hemostasis achieved after reversal administration of AA was seen in 27 patients (71.1%) and 41 patients (70.7%) after 4F-PCC administration (p = 1, p adjusted = 0.654 after controlling for age, ICH score, regional mass effect, and midline shift). There was no statistically significant difference in the median percentage change in hemorrhagic volume from baseline to 12-24 h after reversal treatment (0 [-0.17--0.24] vs. 0 [-0.021-0.29], p = 0.439, adjusted p = 0.601) in the AA and 4F-PCC groups, respectively. The total incidence of thromboembolic events (4 [8.5%] vs. 6 [9.7%], p = 1, adjusted p = 0.973) and rate of inpatient mortality was similar between the two groups (16 [34.0%] vs. 13 [21.0%], p = 0.134, adjusted p = 0.283). A statistically significant difference was observed with the total cost of reversal treatment: $23,602 for treatment with AA and $6692 for treatment with 4F-PCC.. No statistically significant differences were identified in primary or secondary outcomes between the two agents with the exception of total treatment cost. There is insufficient evidence based on this study to recommend AA over 4F-PCC for patients with intracranial hemorrhages associated with the use of apixaban or rivaroxaban.

Topics: Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Factor Xa; Factor Xa Inhibitors; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridones; Recombinant Proteins; Retrospective Studies; Rivaroxaban; Thromboembolism

Topics: Cerebral Hemorrhage; Factor Xa; Factor Xa Inhibitors; Humans; Recombinant Proteins; Rivaroxaban

Andexanet alfa was recently approved as a reversal agent for the factor Xa inhibitors (FXais) apixaban and rivaroxaban, but its impact on long-term outcomes in FXai-associated intracerebral hemorrhage (ICH) is unknown. We aimed to explore potential clinical implications of andexanet alfa in FXai-associated ICH in this simulation study.. We simulated potential downstream implications of andexanet alfa across a range of possible hemostatic effects using data from a single center that treats FXai-associated ICH with prothrombin complex concentrate (PCC). We determined baseline probabilities of inadequate hemostasis across patients taking FXai and those not taking FXai via multivariable regression models and then determined the probabilities of unfavorable 3-month outcome (modified Rankin Scale score 4-6) using models comprising established predictors and each patient's calculated probability of inadequate hemostasis. We applied bootstrapping with model parameters from this derivation cohort to simulate a range of hemostatic improvements and corresponding outcomes and then calculated absolute risk reduction (relative to PCC) and projected number needed to treat (NNT) to prevent 1 unfavorable outcome.. Training models using real-world patients (n = 603 total, 55 on FXai) had good accuracy in predicting inadequate hemostasis (area under the curve [AUC] 0.78) and unfavorable outcome (AUC 0.78). Inadequate hemostasis was strongly associated with unfavorable outcome (odds ratio 4.5, 95% confidence interval [CI] 2.0-9.9) and occurred in 11.4% of patients taking FXai. Across simulated patients taking FXai comparable to those in A Study in Participants With Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study, predicted absolute risk reduction of unfavorable outcome was 4.9% (95% CI 1.3%-7.8%) when the probability of inadequate hemostasis was reduced by 33% and 7.4% (95% CI 2.0%-11.9%) at 50% reduction, translating to projected NNT of 21 (cumulative cost $519,750) and 14 ($346,500), respectively.. Even optimistic simulated hemostatic effects suggest that the costs and potential benefits of andexanet alfa should be carefully considered. Placebo-controlled randomized trials are needed before its use can definitively be recommended.

Topics: Cerebral Hemorrhage; Factor Xa; Factor Xa Inhibitors; Humans; Recombinant Proteins; Rivaroxaban

Direct oral anticoagulants have been evaluated in the general population, but proper evidence for their safe use in the geriatric population is still missing. We compared the bleeding risk of a direct oral anticoagulant (rivaroxaban) and vitamin K antagonists (VKAs) among French geriatric patients with non-valvular atrial fibrillation (AF) aged ≥80 years.. We performed a sequential observational prospective cohort study, using data from 33 geriatric centres. The sample comprised 908 patients newly initiated on VKAs between September 2011 and September 2014 and 995 patients newly initiated on rivaroxaban between September 2014 and September 2017. Patients were followed up for up to 12 months. One-year risks of major, intracerebral, gastrointestinal bleedings, ischaemic stroke and all-cause mortality were compared between rivaroxaban-treated and VKA-treated patients with propensity score matching and Cox models.. Major bleeding risk was significantly lower in rivaroxaban-treated patients (7.4/100 patient-years) compared with VKA-treated patients (14.6/100 patient-years) after multivariate adjustment (HR 0.66; 95% CI 0.43 to 0.99) and in the propensity score-matched sample (HR 0.53; 95% CI 0.33 to 0.85). Intracerebral bleeding occurred less frequently in rivaroxaban-treated patients (1.3/100 patient-years) than in VKA-treated patients (4.0/100 patient-years), adjusted HR 0.59 (95% CI 0.24 to 1.44) and in the propensity score-matched sample HR 0.26 (95% CI 0.09 to 0.80). Major lower bleeding risk was largely driven by lower risk of intracerebral bleeding.. Our study findings indicate that bleeding risk, largely driven by lower risk of intracerebral bleeding, is lower with rivaroxaban than with VKA in stroke prevention in patients ≥80 years old with non-valvular AF.

Topics: Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Factor Xa Inhibitors; Female; France; Hemorrhage; Humans; Ischemic Stroke; Male; Mortality; Outcome and Process Assessment, Health Care; Risk Assessment; Rivaroxaban; Warfarin

Direct oral anticoagulants (DOACs) are increasingly used in place of warfarin, but evidence about their effectiveness and safety in patients with valvular atrial fibrillation (AF) remains limited.. To assess the effectiveness and safety of DOACs compared with warfarin in patients with valvular AF.. New-user retrospective propensity score-matched cohort study.. U.S.-based commercial health care database from 1 January 2010 to 30 June 2019.. Adults with valvular AF who were newly prescribed DOACs or warfarin.. The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial or gastrointestinal bleeding.. Among a total of 56 336 patients with valvular AF matched on propensity score, use of DOACs (vs. warfarin) was associated with lower risk for ischemic stroke or systemic embolism (hazard ratio [HR], 0.64 [95% CI, 0.59 to 0.70]) and major bleeding events (HR, 0.67 [CI, 0.63 to 0.72]). The results for the effectiveness and safety outcomes remained consistent for apixaban (HRs, 0.54 [CI, 0.47 to 0.61] and 0.52 [CI, 0.47 to 0.57], respectively) and rivaroxaban (HRs, 0.74 [CI, 0.64 to 0.86] and 0.87 [CI, 0.79 to 0.96], respectively); with dabigatran, results were consistent for the major bleeding outcome (HR, 0.81 [CI, 0.68 to 0.97]) but not for effectiveness (HR, 1.03 [CI, 0.81 to 1.31]).. Relatively short follow-up; inability to ascertain disease severity.. In this comparative effectiveness study using practice-based claims data, patients with valvular AF who were new users of DOACs had lower risks for ischemic stroke or systemic embolism and major bleeding than new users of warfarin. These data may be used to guide risk-benefit discussions regarding anticoagulant choices for patients with valvular AF.. None.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Comparative Effectiveness Research; Dabigatran; Embolism; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Ischemic Stroke; Male; Propensity Score; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Treatment Outcome; Warfarin

Non-valvular atrial fibrillation patients receiving non-vitamin K antagonist oral anticoagulants (NOACs) have half the incidence of intracerebral hemorrhage (ICH) compared to those receiving warfarin. However, the differences in outcomes of NOAC-associated ICH (NICH) and warfarin-associated ICH (WICH) remain controversial. In this study, we investigated the clinical outcome and radiologic findings of ICH in Asian patients receiving NOACs or warfarin. We retrospectively reviewed the medical records of 544 ICH patients admitted to our hospital from January 2013 through December 2017, and compared the baseline demographics, clinical characteristics, ICH-related radiologic findings, and clinical outcome between the WICH and NICH groups. WICH and NICH were diagnosed in 46 and 13 patients, respectively. Lesions were located more frequently in the supratentorial deep area (45.7% and 46.2%) than the lobar area (30.4% and 30.8%) or brainstem and cerebellum (23.9% and 23.1%) in the WICH and NICH groups, respectively. The hematoma expansion and concomitant intraventricular hemorrhage (IVH) rate was significantly higher in the WICH group than in the NICH group (58.7% versus 7.7%, P = 0.001 and 50.0% versus 15.4%, P = 0.030, respectively). Hematoma expansion (odds ratio [OR]: 50.546; 95% confidence interval [CI]: 2.763-924.748; P = 0.008) and concomitant IVH (OR: 9.240; 95% CI: 1.450-58.892; P = 0.019) were independently associated with mortality at three months, after adjustment for confounding variables. Our results indicate that the radiological findings and clinical outcome at three months in patients with ICH are more favorable in those receiving NOAC therapy than in those receiving warfarin treatment.

Topics: Administration, Oral; Aged; Anticoagulants; Asian People; Atrial Fibrillation; Cerebral Hemorrhage; Dabigatran; Female; Humans; Male; Middle Aged; Odds Ratio; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Warfarin; Young Adult

Anticoagulant therapy presents iatrogenic effects such as intracerebral hemorrhage (ICH). The latest anticoagulants on the market, direct oral anticoagulants (DOACs) such as apixaban, dabigatran and rivaroxaban, are reported to cause less ICH than other anticoagulants. Next to the ICH area, the thrombin is accumulated and the blood-brain barrier (BBB) is opened. The effects of thrombin on the BBB are largely mediated by the protease activated receptor (PAR) family, especially the PAR-1 isoform. Our hypothesis is that DOACs may limit the effects of thrombin on endothelial cells (of the BBB) alteration by a mechanism probably involving PAR-1 activation. To test this hypothesis in vitro, we used HBEC-5i human brain endothelial cells as a human BBB model. The effects of thrombin under warfarin, heparin, rivaroxaban, apixaban, and dabigatran treatment on endothelial cells were then investigated by measuring of permeability and junction proteins: ZO-1 and VE-cadherin expressions and PAR-1 cleavage. Depending on the anticoagulant used, we observed three profiles of response of the endothelial cells after thrombin exposure: i) dabigatran treatment allowed maintaining the tightness of the endothelial monolayer; ii) other DOACs limited thrombin-induced alteration of the endothelial monolayer; and iii) pretreatment with warfarin and heparin did not protect from thrombin-induced BBB breakdown. Pretreatment with DOACs clearly limited the impact of thrombin on PAR-1 cleavage in our model, contrary to other anticoagulants, associated with ZO-1 and VE-cadherin expressions. In conclusion, DOACs seem to limit the alteration of the monolayer of endothelial cells of the BBB mediated by the thrombin/PAR-1 pathway.

Topics: Administration, Oral; Anticoagulants; Antigens, CD; Blood-Brain Barrier; Cadherins; Cell Line; Cerebral Hemorrhage; Endothelial Cells; Heparin; Humans; Protein Serine-Threonine Kinases; Pyrazoles; Pyridones; Receptor, PAR-1; Rivaroxaban; Thrombin; Warfarin; Zonula Occludens-1 Protein

Topics: Antidotes; Blood Coagulation Factors; Blood Component Transfusion; Blood Loss, Surgical; Cerebral Hemorrhage; Drug Administration Schedule; Emergencies; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Intraoperative Care; Premedication; Preoperative Care; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Wounds and Injuries

Topics: Brain; Brain Ischemia; Cerebral Hemorrhage; Humans; Rivaroxaban; Stroke

Direct oral coagulants (DOAC) have been shown to decrease the frequency of intracerebral hemorrhage (ICH) compared with warfarin. However, the precise characteristics, such as the size and locations of the hemorrhage, and outcome and onset time of ICH in patient taking DOAC are not fully elucidated.. We retrospectively analyzed the characteristics of symptomatic patients with ICH taking either DOAC or warfarin between January 2012 and December 2015.. Out of 400 consecutive patients with ICH, 15 patients were DOAC-ICH and 24 patients were warfarin-ICH. DOAC-ICH was observed in 6 patients with 10 mg of rivaroxaban, 5 patients with 15 mg of rivaroxaban, and 1 patient with 10 mg of apixaban, 5 mg of apixaban, 30 mg of edoxaban, and 60 mg of edoxaban. Prothrombin time was well controlled in most of the warfarin-ICH patients (83.3%). The locations of ICH were similar in both groups; however, median ICH volume was significantly smaller in DOAC-ICH patients than in warfarin-ICH patients (P < .01) and ICH around basal ganglia seemed to show great difference between the groups. DOAC-ICH patients showed better neurological outcome at the time of discharge than warfarin patients (P < .01), and the ratio of good prognosis was significantly higher in the DOAC-ICH patients than in the warfarin-ICH patients (P < .01). The onset of warfarin-ICH was frequently observed in the morning and evening, whereas DOAC-ICH did not show any specific onset time.. Patients with DOAC-ICH showed smaller ICH volume and better clinical outcomes than patients with warfarin-ICH, and DOAC-ICH did not show any specific onset peak.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Circadian Rhythm; Female; Humans; Male; Middle Aged; Prothrombin Time; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Thiazoles; Time Factors; Treatment Outcome; Warfarin

To identify differences in clinical characteristics and severity of cerebral small vessel disease (CSVD) including cerebral microbleeds (CMBs), between patients suffering ischemic stroke (IS) or intracerebral hemorrhage (ICH) while taking novel (non-vitamin K antagonists) oral anticoagulants (NOACs).. Multicenter, prospective, observational cohort study performed at 38 centers between 2012 and 2015. We compared demographics, comorbidity, and functional status (before and after stroke) between NOAC-IS and NOAC-ICH patients. Extent of white matter lesions (WML), and location and counts of CMBs were analyzed in a subgroup of patients for whom MRI including hemorrhage-sensitive sequences was available.. A total of 351 patients were included (290 NOAC-IS, 61 NOAC-ICH). Functional status was worse in NOAC-ICH patients before and after stroke. No significant differences were found for demographic variables and cardiovascular comorbidity. In the subgroup with available MRI (n = 116), the proportion of patients with at least one CMB was higher in NOAC-ICH than in NOAC-IS (15/19 [79%] vs 36/97 [37%], P < .001), as was the absolute number of CMBs (median 5 [IQR 1-24] vs 0 [0-1], P < .001). WML were more extensive in NOAC-ICH than in NOAC-IS patients. Adjusted for WML, logistic regression analysis showed higher odds of NOAC-ICH in patients with CMB than without (OR 5.60 [1.64-19.14], P = .006).. Patients with NOAC-ICH have similar clinical characteristics but a higher prevalent burden of CSVD compared to NOAC-IS. The role of neuroimaging in selection of patients for anticoagulation with NOAC requires further investigation in longitudinal studies.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cerebral Small Vessel Diseases; Comorbidity; Dabigatran; Female; Humans; Magnetic Resonance Imaging; Male; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thrombolytic Therapy

The aim of this study was to obtain a better insight into the adverse effects profiles of the new direct-acting oral anticoagulants (DOACs).. A review was undertaken of all reports of adverse effects for warfarin, dabigatran, rivaroxaban and apixaban reported to the regional medicines information and pharmacovigilance centres (RELIS) in the period June 2013-May 2015.. Approximately 65 000 persons used direct-acting oral anticoagulants and 80 000 used warfarin in the period of the study. A total of 409 reports of adverse effects were included. Altogether 55 % of the reports applied to men. In 76 % of the reports for direct-acting oral anticoagulants and 85 % for warfarin, the patients were more than 70 years of age. The most common adverse effects were haemorrhages (48 % for direct-acting oral anticoagulants and 75 % for warfarin), most of which were cerebral haemorrhages (91 for direct-acting oral anticoagulants and 92 for warfarin). Blood clots (therapeutic failure), cognitive effects, headache and hair loss were some of the other adverse effects. The highest comorbidity was among the patients who died. The number of reported deaths was highest for rivaroxaban (1.1 deaths/1000 users) with a declining incidence for apixaban (0.9 ‰), dabigatran (0.7 ‰) and warfarin (0.6 ‰). There were different degrees of reporting for these medications, and the spontaneous reporting system cannot therefore be used to compare the incidence of adverse effects for the drugs.. Adverse effects, including serious effects, may occur when using all anticoagulants. Factors that may increase the risk of adverse effects are advanced age, high comorbidity, reduced renal function, and polypharmacy.

Topics: Age Distribution; Anticoagulants; Cerebral Hemorrhage; Comorbidity; Dabigatran; Databases, Factual; Drug Utilization; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Registries; Risk Factors; Rivaroxaban; Sex Distribution; Time Factors; Warfarin

Patients undergoing anticoagulation therapy often experience intracerebral hemorrhages (ICHs), and warfarin in particular is known to increase hematoma expansion in ICHs, which results in a poor outcome. Recent studies reported that, in comparison with warfarin, direct oral anticoagulants (DOACs) cause fewer ICHs with better functional outcome. However, since it is still unknown whether DOACs are associated with a smaller hematoma volume of ICHs, we aimed to compare the volume, hematoma expansion, and outcomes associated with ICHs treated with DOACs and warfarin.. We performed a prospective multicenter cross-sectional study. The subjects included patients with acute ICHs who received either DOACs or warfarin. We evaluated the clinical characteristics, and measured initial and follow-up ICH volumes. The volume of ICHs and hematoma expansion were compared between the DOAC and warfarin groups. Mortality and modified Rankin score at discharge were evaluated as outcomes.. There were 18 patients in the DOAC group and 71 in the warfarin group. The baseline characteristics were similar between the 2 groups. Initial median hematoma volume of ICHs in the DOAC group was significantly lower than that in the warfarin group (6.2 vs. 24.2 mL, respectively; p = 0.04). In cases involving follow-up computed tomography scanning, the median hematoma volume of ICHs at follow-up was lower in the DOAC group than in the warfarin group (initial: DOACs 4.4 vs. warfarin 13.5 mL; follow-up: 5.0 vs. 18.4 mL, respectively; p = 0.05). Further, the hematoma in ICHs associated with DOACs did not expand. Although the mortality of ICHs associated with DOACs (11%) was lower than that associated with warfarin (24%), this difference was not statistically significant. The univariate analysis showed that the anticoagulant type (DOACs vs. warfarin) and sex (male vs. female) were associated with ICH volume. The multivariable linear regression showed that the use of DOACs (compared to warfarin; β: -0.23, p = 0.03) and female sex (compared to male; β: -0.25, p = 0.02) were associated with a small hematoma volume.. Based on the results of the present study, in terms of the risks associated with ICHs, the use of DOACs appears to be safer than warfarin for anticoagulation therapy. Further studies are required to validate these findings.
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Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Blood Coagulation; Cerebral Hemorrhage; Chi-Square Distribution; Cross-Sectional Studies; Dabigatran; Disability Evaluation; Factor Xa Inhibitors; Female; Hematoma; Humans; Japan; Linear Models; Male; Middle Aged; Multivariate Analysis; Patient Discharge; Prospective Studies; Pyrazoles; Pyridones; Registries; Risk Factors; Rivaroxaban; Tomography, X-Ray Computed; Treatment Outcome; Warfarin

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

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Dabigatran; Female; Humans; Male; Peptide Fragments; Prothrombin; Rivaroxaban; Warfarin

Limited real-world data exist comparing each non-vitamin K antagonist oral anticoagulant (NOAC) to warfarin in patients with nonvalvular atrial fibrillation who have had a previous ischemic stroke or transient ischemic attack.. Using MarketScan claims from January 2012 to June 2015, we identified adults newly initiated on oral anticoagulation, with ≥2 diagnosis codes for nonvalvular atrial fibrillation, a history of previous ischemic stroke/transient ischemic attack, and ≥180 days of continuous medical and prescription benefits before anticoagulation initiation. Three analyses were performed comparing 1:1 propensity score-matched cohorts of apixaban versus warfarin (n=2514), dabigatran versus warfarin (n=1962), and rivaroxaban versus warfarin (n=5208). Patients were followed until occurrence of a combined end point of ischemic stroke and intracranial hemorrhage (ICH) or major bleed, switch/discontinuation of index oral anticoagulation, insurance disenrollment, or end of follow-up. Mean follow-up was 0.5 to 0.6 years for all matched cohorts.. Using Cox regression, neither apixaban nor dabigatran reduced the combined primary end point of ischemic stroke or ICH (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.33-1.48 and HR, 0.53; 95% CI, 0.26-1.07) and had nonsignificant effect on hazards of major bleeding (HR, 0.79; 95% CI, 0.38-1.64 and HR, 0.58; 95% CI, 0.26-1.27) versus warfarin. Rivaroxaban reduced the combined end point of ischemic stroke or ICH (HR, 0.45; 95% CI, 0.29-0.72) without an effect on major bleeding (HR, 1.07; 95% CI, 0.71-1.61). ICH occurred at rates of 0.16 to 0.61 events per 100 person-years in the 3 NOAC analyses, with no significant difference for any NOAC versus warfarin.. Results from our study of the 3 NOACs versus warfarin in nonvalvular atrial fibrillation patients with a previous history of stroke/transient ischemic attack are relatively consistent with their respective phase III trials and previous stroke/transient ischemic attack subgroup analyses. All NOACs seemed no worse than warfarin in respect to ischemic stroke, ICH, or major bleeding risk.

Topics: Adolescent; Adult; Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Cerebral Hemorrhage; Cohort Studies; Dabigatran; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Ischemic Attack, Transient; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Treatment Outcome; Warfarin; Young Adult

Intracerebral hemorrhage (ICH) during oral anticoagulation therapy with an oral vitamin K epoxidase reductase such as warfarin is a life-threatening complication. However, whether direct oral anticoagulants (DOACs) are associated with larger hematoma volume and higher mortality rates remains controversial. We evaluated the hematoma volume and pathophysiology of ICH during anticoagulation with warfarin or rivaroxaban, an orally active direct factor Xa inhibitor.. Mice were orally pretreated with rivaroxaban (10 or 30 mg/kg), warfarin (4 mg/kg), or vehicle. ICH was induced by intrastriatal collagenase-injection. Hematoma volume and neurological deficits 24 h after ICH induction were significantly decreased in the rivaroxaban-pretreated group in comparison with the warfarin-pretreated group. Rivaroxaban did not increase the hematoma volume relative to that observed for vehicle, and improved survival rate 7 days after ICH induction compared with warfarin.. We evaluated blood-brain barrier (BBB) permeability 6 h after ICH induction using Evans blue spectrophotometry. Evans blue extravasation was significantly reduced in the rivaroxaban group compared with the warfarin group. To investigate the mechanism underlying hematoma expansion and BBB permeability, we focused on thrombin, a clot-derived factor and one of the major contributors to ICH-induced brain injury. To investigate the effects of anticoagulant agents on thrombin-induced injuries, human brain endothelial cells were used in membrane permeability assays. Rivaroxaban, but not warfarin, significantly mitigated the thrombin-induced increase in membrane permeability.. These findings indicate that rivaroxaban decreases BBB disruption after ICH, and limits early hematoma expansion in these experimental models compared with warfarin. Our study suggests that rivaroxaban has advantages over warfarin with respect to ICH, an important complication during long-term anticoagulation therapy.

Topics: Animals; Anticoagulants; Blood-Brain Barrier; Cells, Cultured; Cerebral Hemorrhage; Disease Models, Animal; Electric Impedance; Endothelial Cells; Factor Xa Inhibitors; Hematoma; Isothiocyanates; Mice; Neurologic Examination; Permeability; Rivaroxaban; Treatment Outcome; Warfarin

This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin (0.2 mg/kg/day), low-dose rivaroxaban (60 mg/kg/day), high-dose rivaroxaban (120 mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90 min, followed by reperfusion with tPA (10 mg/kg/10 ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials. © 2016 Wiley Periodicals, Inc.

Topics: Animals; Anticoagulants; Cerebral Hemorrhage; Down-Regulation; Factor Xa Inhibitors; Fibrinolytic Agents; Male; Rats; Rats, Wistar; Receptor, PAR-1; Receptor, PAR-2; Rivaroxaban; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator; Warfarin

Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase.. Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P ≤ 0.05 were statistically significant.. We retrieved 32 972 reports. We identified 204 ADRs with a ROR >1 (P ≤ 0.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47-1.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28-0.34)]. We identified other potential signals that have not been associated with DOACs previously.. As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred.

Topics: Administration, Oral; Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Child; Child, Preschool; Dabigatran; Databases, Factual; Female; Gastrointestinal Hemorrhage; Humans; Infant; Infant, Newborn; Male; Middle Aged; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Warfarin; World Health Organization; Young Adult

Early or delayed onset of oral anticoagulant therapy in patients with acute ischemic stroke with atrial fibrillation is an unsolved issue. Retrospectively, 294 patient records at two hospitals were scrutinized according to a protocol consisting of 20 items regarding choice of therapy (warfarin or NOAC), time for onset of therapy, CT findings of bleeding, capacity to swallow, and occurrence of clinical deterioration during the acute phase. Out of 249 patients who survived the acute phase, 116 (47%) patients were given a new prescription of warfarin or NOAC at discharge, while 43 (17 %) continued with anticoagulant therapy already prescribed before the onset of stroke. The median value for new prescriptions in relation to stroke admission was 5 days. The pattern was similar for warfarin and NOAC. Patients in whom anticoagulant therapy was started early were characterized by good capacity to swallow and no signs of bleeding on initial CT. The question »early or delayed onset of oral anticoagulant therapy after acute ischemic stroke with atrial fibrillation« needs to be tested in a randomized clinical trial.

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Dabigatran; Deglutition Disorders; Humans; Medical Records; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Rivaroxaban; Stroke; Time Factors; Time-to-Treatment; Treatment Outcome; Warfarin

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Antithrombins; Blood Loss, Surgical; Cerebral Hemorrhage; Clinical Trials as Topic; Dabigatran; Drug Approval; Emergencies; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; United States; United States Food and Drug Administration

We report a case of repeated cerebral hemorrhage associated with administration of rivaroxaban and apixaban. A 74-year-old man had undergone catheter ablation for non-valvular paroxysmal atrial fibrillation in 2 years prior. Warfarin treatment was continued after successful catheter ablation, and was then changed to rivaroxaban in 1 year prior. Three months later, he developed subcortical cerebral hemorrhage in the right occipital lobe and pharmacotherapy was changed to apixaban. At the current presentation, he complained of headache and left visual field defect, and was admitted to our hospital. Computed tomography of the head revealed recurrent hematoma at the same site as the previous hemorrhagic lesion. Administration of apixaban was subsequently stopped. Magnetic resonance imaging of the head revealed no vascular anomalies around the hemorrhagic lesion, except for two microbleeds in the left cerebral cortex, suggesting amyloid angiopathy. We report the current case from the perspective of whether anticoagulation should be continued after successful catheter ablation, and whether anticoagulation is appropriate in patients with microbleed signals in the cerebral cortex.

Topics: Aged; Cerebral Angiography; Cerebral Hemorrhage; Factor Xa Inhibitors; Humans; Magnetic Resonance Imaging; Male; Multimodal Imaging; Pyrazoles; Pyridones; Rivaroxaban; Tomography, X-Ray Computed

The neuroradiological findings and its outcomes of intracerebral hemorrhage (ICH) were compared between the non-vitamin K antagonist oral anticoagulant (NOAC) therapy and warfarin therapy. In the latest 3 years, 13 cases of nonvalvular atrial fibrillation on NOAC therapy were admitted for ICH. For comparison, 65 age- and gender-comparable patients with ICH on warfarin therapy were recruited. Three NOACs had been prescribed: dabigatran (n = 4), rivaroxaban (n = 2), and apixaban (n = 7). The average ages were 76 ± 9 and 78 ± 8 years in the warfarin (n = 65) and NOAC groups (n = 13), respectively. There was no difference in the clinical features, including the CHADS2 score or HAS-BLED score: 2.62 ± 1.31 versus 2.62 ± 1.33, or 1.09 ± 0.43 versus 1.00 ± 0.41, for the warfarin and NOAC groups, respectively. The volume of ICH <30 ml was found in 84.6% of the patients on NOACs, but it was found in 53.8% of the patients on warfarin (p = 0.0106). The expansion of hematoma was limited to 7 patients (10.8%) of the warfarin group. A lower hospital mortality and better modified Rankin Scale were observed in the NOAC group than in the warfarin group: 1 (7.7%) versus 27 (41.5%; p = 0.0105) and 3.2 ± 1.4 versus 4.5 ± 1.6 (p = 0.0057), respectively. In conclusion, ICH on NOAC therapy had smaller volume of hematoma with reduced rate of expansion and decreased mortality compared with its occurrence on warfarin.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Brain; Case-Control Studies; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Female; Hematoma; Hospital Mortality; Humans; Male; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Tomography, X-Ray Computed; Warfarin

Patients with intracerebral hemorrhage during rivaroxaban treatment have small hematoma and favorable outcomes compared with those with warfarin. We investigated its possible mechanism, focusing on prothrombin fragment 1+2 (F1+2), a marker of thrombin generation.. In 65 patients with acute cardioembolic stroke (median 77years), rivaroxaban was initiated at 5days after the onset. Plasma F1+2 level (normal range, 69-229pmol/L), prothrombin time (PT), and rivaroxaban concentration evaluated by anti-Xa activity were serially measured.. Rivaroxaban retains a normal thrombin generation even at its peak level with prolonged PT, whereas warfarin at therapeutic levels inhibits thrombin generation. This may partly explain different outcomes in patients complicated with bleeding events.

Topics: Acute Disease; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Factor Xa Inhibitors; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Humans; Male; Peptide Fragments; Prothrombin; Prothrombin Time; Rivaroxaban; Stroke; Warfarin

The introduction of non-vitamin K antagonist oral anticoagulants (NOACs) has been a major advance for stroke prevention in atrial fibrillation (AF). Patients and clinicians now have a choice between different NOACs, but there is no direct comparative effectiveness evidence to guide decision-making. We aimed to compare the effectiveness and safety of dabigatran, rivaroxaban, and apixaban in clinical practice.. Using a large US administrative claims database, we created three one-to-one propensity-score-matched cohorts of patients with nonvalvular AF who were users of dabigatran, rivaroxaban, or apixaban between October 1, 2010 and February 28, 2015 (rivaroxaban vs dabigatran, n = 31,574; apixaban vs dabigatran, n = 13,084; and apixaban vs rivaroxaban, n = 13,130). The primary outcomes were stroke and systemic embolism (effectiveness) and major bleeding (safety) that occurred during treatment. Cox proportional hazards models were used to compare outcomes in propensity-score-matched cohorts.. We found no differences between the three NOACs in the risk of stroke or systemic embolism (hazard ratio [HR], 1.00; 95% CI, 0.75-1.32 for rivaroxaban vs dabigatran; HR, 0.82; 95% CI, 0.51-1.31 for apixaban vs dabigatran; and HR, 1.05; 95% CI, 0.64-1.72 for apixaban vs rivaroxaban). Apixaban was associated with a lower risk of major bleeding (HR, 0.50; 95% CI, 0.36-0.70; P < .001 vs dabigatran and HR, 0.39; 95% CI, 0.28-0.54; P < .001 vs rivaroxaban). Rivaroxaban was associated with an increased risk of major bleeding (HR, 1.30; 95% CI, 1.10-1.53; P < .01) and intracranial bleeding (HR, 1.79; 95% CI, 1.12-2.86; P < .05) compared with dabigatran.. Dabigatran, rivaroxaban, and apixaban appear to have similar effectiveness, although apixaban may be associated with a lower bleeding risk and rivaroxaban may be associated with an elevated bleeding risk.

Topics: Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Propensity Score; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; United States

Bleeding, the most frightening adverse effect of anticoagulants,may occur in different parts of the body.When intracerebral hemorrhage in individuals used anticoagulant drugs is compared with normal coagulation function, the volume of bleeding is increased and the prognosis is worse. There are few studies in the literature regarding the presence of intracerebral hemorrhage and the volume and prognosis of bleeding associated with rivaroxaban, a new oral anticoagulant.Therefore, the clinical and radiologic findings and follow-up of an 80-year-old male patient with intracerebral hemorrhage who uses rivaroxaban for anticoagulation are presented in this article.

Topics: Aged, 80 and over; Cerebral Hemorrhage; Factor Xa Inhibitors; Humans; Male; Morpholines; Rivaroxaban; Thiophenes

The management of life-threatening bleeding associated with rivaroxaban remains a challenge for physicians due to the lack of evidence about clinically effective options for anticoagulation reversal. We report a favorable outcome in a patient receiving rivaroxaban prophylaxis, who developed a spontaneous subdural hematoma treated by a surgical evacuation and administration of 4-factor prothrombin complex concentrate. Classical coagulation variables were associated with impaired thrombin generation. Reversal with prothrombin complex concentrates improved all thrombin generation measures. Thrombin generation tests may be suitable for assessing the clinical utility of reversal drugs on rivaroxaban-induced coagulopathy.

Topics: Aged; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Cerebral Hemorrhage; Factor Xa Inhibitors; Hematoma, Subdural; Humans; Male; Rivaroxaban; Thrombin

The management of acute ischemic stroke during anticoagulation with a novel oral anticoagulant (NOAC) is challenging because intravenous thrombolysis is contraindicated because of a putative increased risk of intracerebral hemorrhagic complications. We examined the risk of secondary postischemic hemorrhage after thrombolysis in rodents pretreated with rivaroxaban or warfarin. Mice were pretreated with either rivaroxaban (30 mg/kg), warfarin (target international normalized ratio 2 to 3) or vehicle. After 2 or 3 hours, middle cerebral artery occlusion (MCAO), mice received 9 mg/kg recombinant tissue plasminogen activator. Twenty-four hours after MCAO, secondary hemorrhage was quantified using a macroscopic hemorrhage score and hemoglobin spectrophotometry. Blood-brain barrier (BBB) permeability was measured by Evans Blue spectrofluorometry. To increase the validity of our findings, experiments were also performed using a thromboembolic model in anticoagulated rats. Infarct size did not differ among groups. Pretreatment with warfarin led to significantly more secondary hemorrhage compared with rivaroxaban and nonanticoagulated controls after 2- and 3-hour ischemia in mice as well as in rats. Blood-brain barrier permeability was significantly higher in the warfarin group compared with rivaroxaban and control. Thus, rivaroxaban in contrast to warfarin does not increase secondary hemorrhage after thrombolysis in experimental cerebral ischemia. Less effects of rivaroxaban on postischemic BBB permeability may account for this difference.

Topics: Animals; Anticoagulants; Blood-Brain Barrier; Brain Ischemia; Cerebral Hemorrhage; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Morpholines; Rats; Rats, Wistar; Rivaroxaban; Stroke; Thiophenes; Thrombolytic Therapy; Time Factors

Topics: Aged; Anticoagulants; Brain; Cerebral Hemorrhage; Fatal Outcome; Female; Hematoma, Subdural, Intracranial; Humans; Morpholines; Neuroimaging; Rivaroxaban; Stroke; Thiophenes; Tomography, X-Ray Computed

Neuroradiological characteristics and functional outcomes of patients with intracerebral hemorrhage (ICH) during novel oral anticoagulant treatment were not well defined. We examined these in comparison with those during warfarin treatment.. The consecutive 585 patients with ICH admitted from April 2011 through October 2013 were retrospectively studied. Of all, 5 patients (1%) had ICH during rivaroxaban treatment, 56 (10%) during warfarin, and the other 524 (89%) during no anticoagulants. We focused on ICH during rivaroxaban and warfarin treatments and compared the clinical characteristics, neuroradiological findings, and functional outcomes.. Patients in the rivaroxaban group were all at high risk for major bleeding with hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly (HAS-BLED) score of 3 and higher rate of past history of ICH. Moreover, multiple cerebral microbleeds (≥4) were detected more frequently in rivaroxaban group than in warfarin (80% versus 29%; P=0.04). Hematoma volume in rivaroxaban group was markedly smaller than that in warfarin (median: 4 versus 11 mL; P=0.03). No patient in the rivaroxaban group had expansion of hematoma and surgical treatment. Rivaroxaban group showed lower modified Rankin Scale at discharge relative to warfarin, and the difference between modified Rankin Scale before admission and at discharge was smaller in rivaroxaban than in warfarin (median: 1 versus 3; P=0.047). No patient in the rivaroxaban group died during hospitalization, whereas 10 (18%) warfarin patients died.. Rivaroxaban-associated ICH occurs in patients at high risk for major bleeding. However, they had a relatively small hematoma, no expansion of hematoma, and favorable functional and vital outcomes compared with warfarin-associated ICH.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Female; Hemorrhage; Humans; Male; Middle Aged; Morpholines; Retrospective Studies; Risk; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Warfarin

Topics: Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Humans; Morpholines; Rivaroxaban; Thiophenes

Warfarin has unmet medical needs such as blood coagulation monitoring, limitation of vitamin K intake, and interaction with other drugs, while novel oral anticoagulants (NOACs) do not have such kind of unmet medical needs. Therefore, NOACs are recommended to busy patients or patients far from hospitals, or who do not want to limit vitamin K or use many other drugs concomitantly. NOACs are also recommended to patients with low time in therapeutic range (TTR). NOACs are also recommended to warfarin-naïve patients. Warfarin is recommended to patients with economical difficulty because it is much cheaper than NOACs. If needed, warfarin should be selected in patients with renal insufficiency or under hemodialysis because NOACs are contraindicated. New guidelines by the European Society of Cardiology recommend NOACs to low risk patients with CHA2DS2-VASc score 1, and also as the first line to those with CHA2DS2-VASc 2 or more. Finally, drug should be determined by patients' preference. Doctors should give adequate information helpful for patients' selection.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Humans; International Normalized Ratio; Morpholines; Practice Guidelines as Topic; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Warfarin

Rivaroxaban has recently been approved for stroke prevention in atrial fibrillation. However, lack of an effective antidote represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with rivaroxaban, and to examine the effectiveness of different hemostatic factors in preventing excess hematoma expansion.. In C57BL/6 mice receiving 10 or 30 mg/kg rivaroxaban by gastric gavage, plasma concentration, prothrombin time, and coagulation factor activities were measured repeatedly. Thirty minutes after inducing ICH by intrastriatal collagenase-injection, mice received an intravenous injection of either saline, prothrombin complex concentrate (100 U/kg), murine fresh frozen plasma (200 μL), or recombinant human Factor VIIa (1 mg/kg). ICH volume was quantified on brain cryosections and using hemoglobin spectrophotometry 24 hours later.. Rivaroxaban in 30 mg/kg dose substantially increased the hematoma volume in ICH induced by 0.060 U collagenase. Prothrombin complex concentrate, fresh frozen plasma, or Factor VIIa prevented excess hematoma expansion caused by anticoagulation. Prevention of hematoma expansion by prothrombin complex concentrate was dose-dependent. None of the 3 agents completely corrected the prolonged prothrombin time, although they restored the activities of deficient FII and X.. Prothrombin complex concentrate, Factor VIIa, and fresh frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with rivaroxaban. The efficacy and safety of this reversal strategy must be further evaluated in clinical studies.

Topics: Animals; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Dose-Response Relationship, Drug; Factor VIIa; Hematoma; Hemostatic Techniques; Male; Mice; Mice, Inbred C57BL; Models, Animal; Morpholines; Plasma; Rivaroxaban; Thiophenes; Treatment Outcome

The oral anticoagulant rivaroxaban is recommended for venous thromboembolic prophylaxis following lower limb arthroplasty. Concerns regarding high rates of wound complications following its use have prompted this multicenter comparison with low-molecular-weight heparins.. English hospital trusts that replaced a low-molecular-weight heparin with rivaroxaban for thromboprophylaxis in lower limb arthroplasty during 2009 were identified. Prospectively collected national data for these units were analyzed to determine the thirty-day rates of wound complications and major bleeding (cerebrovascular event or gastrointestinal hemorrhage) and the ninety-day rates of symptomatic deep venous thrombosis (proximal or distal), symptomatic pulmonary embolism, and all-cause inpatient mortality before and after the change to rivaroxaban. A total of 2762 patients prescribed rivaroxaban following knee or hip arthroplasty were compared with 10,361 patients prescribed a low- molecular weight heparin. Data were analyzed with use of odds ratios (ORs).. There were significantly fewer wound complications in the low-molecular-weight heparin group (2.81% compared with 3.85%; OR = 0.72, 95% confidence interval [CI] = 0.58 to 0.90; p = 0.005). There were no significant differences between the low-molecular-weight heparin and rivaroxaban groups in the rates of pulmonary embolism (0.55% compared with 0.36%; OR = 1.52, 95% CI = 0.78 to 2.98), major bleeding (OR = 0.73, 95% CI = 0.48 to 1.12), or all-cause mortality (OR = 0.93, 95% CI = 0.46 to 1.89). There were significantly more symptomatic deep venous thromboses in the low-molecular-weight heparin group (0.91% compared with 0.36%; OR = 2.51, 95% CI = 1.31 to 4.84; p = 0.004).. The rivaroxaban group had a higher wound complication rate and a lower deep venous thrombosis rate; there were no differences in symptomatic pulmonary embolism or all-cause mortality. Longer follow-up is needed to assess any potential relationship between wound complications and joint stiffness, latent infection, and limb consequences of deep venous thrombosis.

Topics: Age Distribution; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Cerebral Hemorrhage; Cohort Studies; Confidence Intervals; Databases, Factual; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Middle Aged; Morpholines; Odds Ratio; Postoperative Complications; Retrospective Studies; Risk Assessment; Rivaroxaban; Sex Distribution; Surgical Wound Infection; Survival Analysis; Thiophenes; Treatment Outcome; Venous Thrombosis; Wound Healing

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

Topics: Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Humans; Intracranial Embolism; Morpholines; Rivaroxaban; Thiophenes; Warfarin