edoxaban and Kidney-Failure--Chronic

The Multimorbid Patient: Use of New Oral Anticoagulants in Patients with Chronic Kidney Disease Abstract. Increasing life expectancy in Western countries is associated with a high prevalence of multiple chronic diseases which is defined by the term "multimorbidity". Many of these patients suffer from chronic kidney disease (CKD) and thrombogenic comorbidities such as atrial fibrillation with the need for oral anticoagulation. For decades vitamin K antagonists have been exclusively prescribed for oral anticoagulation. However, due to altered pharmacokinetics and bioavailability of these drugs in CKD, a significant risk of bleeding exists. The introduction of direct oral anticoagulants as a new and promising alternative to vitamin K antagonists was -especially for CKD patients - highly anticipated. However, data from randomized studies are missing for older patients with advanced CKD. Consequently, a careful evaluation of the risk-benefit ratio is recommended for this sensitive patient population.. Zusammenfassung. Die zunehmende Lebenserwartung in den westlichen Ländern führt zu einer gleichzeitigen Zunahme chronischer Krankheiten, was mit «Multimorbidität» bezeichnet wird. Viele dieser Patienten leiden an chronischer Niereninsuffizienz (CKD) sowie thrombogenen Komorbiditäten wie z.B. Vorhofflimmern, weshalb eine orale Antikoagulation indiziert ist. Für lange Zeit standen lediglich die Vitamin-K-Antagonisten zur Verfügung. Aufgrund der unter anderem veränderten Pharmakokinetik sowie Bioverfügbarkeit dieser Medikamente bei CKD besteht jedoch gleichzeitig ein deutlich erhöhtes Blutungsrisiko. Die Einführung der direkten oralen Antikoagulanzien als neue und vielversprechende Alternative zu Vitamin-K-Antagonisten wurde daher insbesondere für die Population der CKD-Patienten mit grosser Spannung erwartet. Aufgrund der noch nicht ausreichenden Datenlage insbesondere bei älteren Patienten mit fortgeschrittener Niereninsuffizienz sollte das Risiko-Nutzen-Verhältnis vor Therapiebeginn sorgfältig evaluiert werden.

Topics: Anticoagulants; Arterial Occlusive Diseases; Atrial Fibrillation; Comorbidity; Contraindications; Coronary Disease; Dabigatran; Glomerular Filtration Rate; Kidney Failure, Chronic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thromboembolism; Vitamin K

Patients with end-stage kidney disease (ESKD) have an elevated incidence of atrial fibrillation (AF) and are at increased risk for thromboembolic events. However, these patients are also at increased risk for bleeding and it is unclear whether they benefit from an oral anticoagulant. Point prevalent on July 1, 2015, only ~28% of dialysis patients with AF were on oral anticoagulation. Warfarin was the most commonly used oral anticoagulant, followed by apixaban, while dabigatran and rivaroxaban were rarely used. This article reviews the current evidence regarding each oral anticoagulant especially as they relate to patients with ESKD.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; Kidney Failure, Chronic; Pyrazoles; Pyridines; Pyridones; Renal Dialysis; Rivaroxaban; Thiazoles; Thromboembolism; Warfarin

Nonvitamin K-dependent oral anticoagulant agents (NOACs) are currently recommended for patients with atrial fibrillation at risk for stroke. As a group, NOACs significantly reduce stroke, intracranial hemorrhage, and mortality, with lower to similar major bleeding rates compared with warfarin. All NOACs are dependent on the kidney for elimination, such that patients with creatinine clearance <25 ml/min were excluded from all the pivotal phase 3 NOAC trials. It therefore remains unclear how or if NOACs should be prescribed to patients with advanced chronic kidney disease and those on dialysis. The authors review the current pharmacokinetic, observational, and prospective data on NOACs in patients with advanced chronic kidney disease (creatinine clearance <30 ml/min) and those on dialysis. The authors frame the evidence in terms of risk versus benefit to bring greater clarity to NOAC-related major bleeding and efficacy at preventing stroke specifically in patients with creatinine clearance <30 ml/min.

Topics: Anticoagulants; Atrial Fibrillation; Creatinine; Dabigatran; Glomerular Filtration Rate; Hemorrhage; Humans; Kidney; Kidney Failure, Chronic; Pyrazoles; Pyridines; Pyridones; Renal Dialysis; Renal Insufficiency, Chronic; Rivaroxaban; Stroke; Thiazoles; Warfarin

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Electric Countershock; Factor Xa Inhibitors; Humans; Kidney Failure, Chronic; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Warfarin

Edoxaban is an oral, direct, once-daily, factor Xa inhibitor developed for stroke prevention in patients with atrial fibrillation and for the treatment and secondary prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism. Among elderly patients who require anticoagulation therapies, some may have end-stage renal disease (ESRD). This open-label, phase 1, randomised, two-way crossover study was conducted to evaluate the pharmacokinetics of edoxaban in 10 subjects on haemodialysis. Eligible subjects with ESRD on chronic haemodialysis received a single, oral dose of edoxaban 15 mg 2 hours (h) prior to (on-dialysis) or in between (off-dialysis) haemodialysis sessions. Haemodialysis resulted in a minor decrease in mean total exposure (AUC0-∞; 676.2 ng·h/ml) as compared with that observed in subjects off-dialysis (691.7 ng·h/ml). Mean maximum observed plasma concentration (Cmax) values were comparable between on-dialysis and off-dialysis treatments (53.3 vs 56.3 ng/ml, respectively). Mean apparent total body clearance (CL/F) values were 24.1 and 22.5 l/h during the on-dialysis and off-dialysis treatment periods, respectively. Dialyser clearance was 5.7 l/h and haemodialysis clearance was 6.1 l/h. Haemodialysis clearance was only 6.1 l/h, suggesting that it only accounts for one-fourth of the total clearance in these subjects. A single, oral dose of 15 mg of edoxaban was well tolerated by subjects with ESRD. In conclusion, based on these single-dose PK data, a supplementary dose of edoxaban may not be required following a haemodialysis session. Importantly, haemodialysis is not an effective mechanism for removal of edoxaban from the blood.

Topics: Administration, Oral; Adult; Area Under Curve; Cross-Over Studies; Drug Administration Schedule; Drug Monitoring; Factor Xa Inhibitors; Female; Half-Life; Humans; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Pyridines; Renal Dialysis; Thiazoles; Treatment Outcome

Stroke risk may be more than 3-fold higher among patients with chronic kidney disease stage 5D (CKD-5D) compared to the general population, with the highest stroke rates noted among those 85 years and older. Atrial fibrillation (AF), a strong risk factor for stroke, is the most common arrhythmia and affects >7% of the population with CKD-5D. Warfarin use is widely acknowledged as an important intervention for stroke prevention with nonvalvular AF in the general population. However, use of oral anticoagulants for stroke prevention in patients with CKD-5D and nonvalvular AF continues to be debated by the nephrology community. In this National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) controversies report, we discuss the existing observational studies that examine warfarin use and associated stroke and bleeding risks in adults with CKD-5D and AF. Non-vitamin K-dependent oral anticoagulants and their potential use for stroke prevention in patients with CKD-5D and nonvalvular AF are also discussed. Data from randomized clinical trials are urgently needed to determine the benefits and risks of oral anticoagulant use for stroke prevention in the setting of AF among patients with CKD-5D.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Kidney Failure, Chronic; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Renal Dialysis; Rivaroxaban; Stroke; Thiazoles; Warfarin