betrixaban and Stroke

Non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban and rivaroxaban, which inhibit factor Xa. In large clinical trials comparing the NOACs with the vitamin K antagonist (VKA) warfarin, dabigatran, apixaban, rivaroxaban and edoxaban were at least as effective for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, but were associated with less intracranial bleeding. In addition, the NOACs are more convenient to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. Consequently, the NOACs are now replacing VKAs for these indications, and their use is increasing. Although, as a class, the NOACs have a favourable benefit-risk profile compared with VKAs, choosing among them is complicated because they have not been compared in head-to-head trials. Therefore, selection depends on the results of the individual trials, renal function, the potential for drug-drug interactions and preference for once- or twice-daily dosing. In addition, several 'special situations' were not adequately studied in the dedicated clinical trials. For these situations, knowledge of the unique pharmacological features of the various NOACs and judicious cross-trial comparison can help inform prescription choices. The purpose of this position article is therefore to help clinicians choose the right anticoagulant for the right patient at the right dose by reviewing a variety of special situations not widely studied in clinical trials.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Atrial Fibrillation; Benzamides; Biomarkers; Blood Coagulation; Clinical Trials as Topic; Dabigatran; Drug Administration Schedule; Factor Xa; Heart Diseases; Humans; Piperazines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Risk; Rivaroxaban; Stroke; Thiazoles; Thrombin; Venous Thromboembolism; Vitamin K; Warfarin

Acutely ill hospitalized medical patients remain at high thromboembolic risk for several weeks after discharge. Previous trials with extended-duration thromboprophylaxis using enoxaparin, apixaban, and rivaroxaban failed to achieve acceptable net clinical benefit, largely due to excess of major bleeding. Betrixaban is a novel factor Xa inhibitor with unique pharmacokinetic properties, including low renal clearance, long half-life, and low peak-to-trough ratio. The phase III APEX trial (N = 7513) compared a betrixaban 160 mg loading dose followed by 80 mg once daily for 35-42 days, with enoxaparin 40 mg once daily for 6-14 days; the betrixaban dose was reduced for renal impairment or a concomitant strong P-glycoprotein (P-gp) inhibitor. The primary efficacy endpoint of composite thrombotic events was not different between treatment arms in cohort 1 (D-dimer ≥ 2 × upper limit of normal). Subsequent exploratory analyses showed a statistically significant difference favoring betrixaban for symptomatic venous thromboembolism and net clinical benefit in the overall population. For the primary safety outcome, betrixaban did not significantly increase major bleeding compared with enoxaparin. Based on available data from the APEX trial and subanalyses, the use of betrixaban in patients similar to those enrolled in the APEX trial can reduce the risk of thromboembolic events without increasing the risk of major bleeding. Patients who may benefit more from betrixaban therapy include those with elevated D-dimer, history of venous thromboembolism, hospitalized for ischemic stroke, hospitalized for heart failure with N-terminal pro-B-type natriuretic peptide ≥ 1975 ng/L, or two or more VTE risk factors. Reduced-dose betrixaban does not appear to provide the same clinical utility as full-dose betrixaban.

Topics: Anticoagulants; Benzamides; Drug Therapy, Combination; Enoxaparin; Factor Xa Inhibitors; Hemorrhage; Hospitalization; Humans; Pyridines; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Stroke; Treatment Outcome; Venous Thromboembolism

Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Benzamides; Blood Coagulation; Embolism; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Morpholines; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombophilia; Thrombosis

Prevention of stroke and systemic emboli is paramount in the management of atrial fibrillation. Although warfarin is the predominant anticoagulant used in patients with atrial fibrillation, it has significant limitations that have impeded appropriate use of stroke prophylaxis in eligible patients with atrial fibrillation. Consequently, much research has been focused on finding an alternative to warfarin. We review the potential alternatives in development and evaluate the current evidence concerning their safety and efficacy.. Oral direct factor Xa inhibitors are potentially well tolerated and effective replacements for warfarin. These agents do not require cofactors and offer selective inhibition at a critical step of amplification in the coagulation cascade. Multiple direct anti-factor Xa agents are currently undergoing evaluation in phase I, II, and III trials. Early results suggest that these novel anticoagulants have favorable pharmacokinetic and pharmacodynamic profiles with minimal-to-no requirements for therapeutic monitoring. Two direct factor Xa inhibitors are emerging from phase II trials (betrixaban and YM150) and three are being evaluated in phase III trials (apixaban, edoxaban, and rivaroxaban) for the prevention of stroke and systemic emboli in patients with atrial fibrillation. The phase III trials of apixaban and rivaroxaban have completed enrollment and are in the follow-up phase.. Given the growing population of patients with atrial fibrillation, there is a great interest in finding new therapies for oral anticoagulation. The direct factor Xa inhibitors may offer several promising alternatives to warfarin therapy.

Topics: Anticoagulants; Atrial Fibrillation; Benzamides; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thromboembolism; Warfarin

Among patients hospitalized with acute heart failure (HF), the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in short-term stroke prediction remains unclear.. In the APEX trial, 7513 patients hospitalized for an acute medical illness were randomized to receive either extended-duration betrixaban (80 mg once daily for 35-42 days) or standard-of-care enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. Baseline NT-proBNP concentrations were obtained in 3261 patients admitted for HF. Stroke events were adjudicated by an independent clinical events committee blinded to thromboprophylaxis allocation. The association of NT-proBNP level and other risk factors and biomarkers with stroke was assessed at 77 days after randomization.. Baseline NT-proBNP concentration was associated with short-term stroke among patients hospitalized with acute HF. Stroke risk assessment models should consider incorporation of NT-proBNP measurement.

Topics: Acute Disease; Aged; Aged, 80 and over; Benzamides; Enoxaparin; Female; Heart Failure; Hospitalization; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Pyridines; Risk Assessment; Stroke; Venous Thrombosis

Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion.. Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin.. Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Benzamides; Dose-Response Relationship, Drug; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Humans; Male; Pyridines; Stroke; Treatment Outcome; Warfarin

Topics: Benzamides; Enoxaparin; Female; Humans; Male; Myocardial Infarction; Pyridines; Risk Factors; Stroke

Data from recent randomized controlled trials indicate that the incidence of stroke among acutely ill medical patients is unexpectedly high and approximates 1% at 90 days. Preliminary data suggest that betrixaban may reduce ischemic stroke in patients without atrial fibrillation. There is an unmet demand for stroke risk stratification schemes targeting hospitalized medical patients. The prognostic value of biomarkers such as natriuretic peptides and D-dimer in predicting short-term stroke remains uncertain. Future research should focus on identifying the high-risk subsets in which the benefit of anticoagulation significantly outweighs the associated hemorrhagic risk. Clinical trials: NCT00457002, NCT00571649, NCT01583218.

Topics: Aged; Aged, 80 and over; Anticoagulants; Benzamides; Female; Humans; Incidence; Inpatients; Male; Middle Aged; Myocardial Infarction; Pyridines; Randomized Controlled Trials as Topic; Risk; Stroke; Thrombosis

Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban).. Hospitalized acutely medically ill subjects (n=7513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35-42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10±4 days) for venous thromboprophylaxis. Stroke events were adjudicated by an independent, blinded event adjudication committee.. The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk [RR]=0.56; 95% confidence interval, 0.32-0.96;. Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01583218.

Topics: Aged; Anticoagulants; Benzamides; Enoxaparin; Female; Humans; Male; Pyridines; Stroke; Venous Thromboembolism

Topics: Anticoagulants; Benzamides; Humans; Pyridines; Stroke

The recently introduced oral anticoagulants, dabigatran, rivaroxaban and apixaban, were shown, in randomized controlled trials, to be at least as effective and safe as monitored warfarin therapy for the treatment of venous thromboembolism and stroke prevention in atrial fibrillation. These new oral anticoagulants have predictable pharmacology, less variability in anticoagulant effect and fewer drug and food interactions than warfarin, allowing unmonitored and fixed dosing, which renders their use appealing. The remaining limitations of currently available new oral anticoagulants include their dependence on renal and hepatic clearance, and the lack of an antidote, which is problematic in bleeding patients and those requiring urgent surgery. Betrixaban is a new direct factor Xa inhibitor with distinct pharmacological characteristics, including a long half-life, minimal renal clearance and minimal hepatic metabolism. Betrixaban was tested in Phase II studies in orthopedic thromboprophylaxis (EXPERT) and atrial fibrillation (EXPLORE-Xa), and is being evaluated in a Phase III trial of extended thromboprophylaxis in medical patients (APEX). This article details the pharmacology, preclinical and clinical development of betrixaban.

Topics: Atrial Fibrillation; Benzamides; Blood Coagulation; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Pyridines; Stroke; Venous Thromboembolism

Topics: Acenocoumarol; Anticoagulants; Benzamides; Benzimidazoles; beta-Alanine; Dabigatran; Heparin; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thromboembolism; Thrombosis; Warfarin

Interpatient variability in the safety and efficacy of oral anticoagulation with warfarin presents several challenges to clinicians, thus underscoring the emergent need for new orally available anticoagulants with predictable pharmacokinetic and pharmacodynamic profiles and ability to target circulating clotting factors. Seven compounds including rivaroxaban, apixaban, betrixaban, and eribaxaban are orally available direct inhibitors of activated factor X currently in development for the prevention and treatment of venous thromboembolism and for thromboprophylaxis in patients with atrial fibrillation or following an acute coronary syndrome. At doses used in phase 2 and 3 clinical trials, rivaroxaban and apixaban demonstrated a predictable onset of effect, maximal plasma concentration, and half-life that was unaffected by age, renal, or hepatic disease. In clinical trials for the treatment and prevention of venous thromboembolism, rivaroxaban and apixaban produced equivalent or superior reductions in the development or progression of venous thromboembolism compared with either low molecular weight heparin or warfarin. Trials comparing the efficacy of rivaroxaban or apixaban to standard therapy for stroke prophylaxis in patients with atrial fibrillation are in process. Rivaroxaban, the sentinel compound in this class, is already approved in the European Union and Canada. It is likely to be approved for use in the United States in 2010.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzamides; Blood Coagulation Disorders; Clinical Trials as Topic; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Thromboembolism; Warfarin