Which Anticoagulants Should Be Used for Stroke Prevention in Non-Valvular Atrial Fibrillation and Severe Chronic Kidney Disease?

Philip A. Kalra; Alexandru Burlacu; Charles J. Ferro; Adrian Covic

Disclosures

Curr Opin Nephrol Hypertens. 2018;27(6):420-425. 

In This Article

Non-vitamin K Oral Anticoagulants in Patients With Severe Chronic Kidney Disease and Atrial Fibrillation

There have been several landmark RCTs comparing the efficacy and safety of NOAC with VKA in large populations of patients with atrial fibrillation.[15–18] These studies with the factor Xa inhibitors, apixaban, rivaroxaban and edoxaban,[15–17] and the thrombin inhibitor, dabigatran,[18] have all shown that the NOAC are noninferior to warfarin in terms of efficacy but that the risk of serious bleeding, most notably intracranial haemorrhage, is reduced by approximately 50% with their use. In all of the RCTs and phase 2 studies renal function was estimated with the Cockroft and Gault formula using actual body weight (no adjustment for ideal weight) and this was then reported as creatinine clearance (CrCl); dosing recommendations have been based upon this methodology. This important point has been emphasized in a recent review by Shroff et al.;[19] as most clinicians routinely use the modification of diet in renal disease-derived eGFR for patient management the potential for inappropriate dosing exists for some NOACs if the summary of product characteristics guidance is applied to eGFR instead of creatinine clearance.

In the RCTs the majority of patients had well preserved renal function but large proportions of patients with early stage CKD were included. However, patients with severe CKD were excluded – with apixaban (ARISTOTLE) patients with CrCl less than 25 ml/min were excluded,[15] and the exclusion CrCl cut-off in the three other major RCTs, ROCKET-AF (rivaroxaban),[16] ENGAGE-AF TIMI (edoxaban)[17] and RE-LY (dabigatran)[18] was 30 ml/min. There are therefore no data that demonstrate efficacy of NOAC in severe CKD. The pharmacokinetics of 3 of the NOAC have been tested in small studies (7–18 subjects) of haemodialysis patients; De Vriese et al.[20] have shown that use of 10 mg of rivaroxaban results in plasma levels similar to the 20 mg dose in patients with normal renal function, and Mavrakanas et al.[21] found that apixaban given in a dose of 2.5 mg twice daily to haemodialysis patients had similar accumulation to the 5 mg twice daily dose in those with preserved kidney function. The pharmacokinetics of dabigatran in stage 4 CKD patients, but not those with stage 5D, have also been published. On the basis of these limited pharmacokinetic studies the Federal Drugs Agency (FDA) have approved the use of apixaban and rivaroxaban in patients with stage 5 and 5D CKD with the dose modifications described above, and dabigatran has similarly been approved for stage 4 CKD. However, it should be emphasized that this approval has occurred in the absence of any clinical safety data with use of these agents in severe CKD, and to date similar approvals are not in place in Europe.

There have been several helpful review articles published in 2018. Potpara et al.[22] have emphasized the advantages of NOACs over VKA, with fixed dose regimens, no requirement for anticoagulant monitoring and low likelihood of food and drug interactions; the review also included a detailed mechanistic description of the pathophysiology of thrombotic risk in CKD. Heine et al.[23] concluded that for patients with CrCl more than 25–30 ml/min and nonvalvular atrial fibrillation NOAC should be used in preference to VKA if risk scores showed intermediate embolic risk; however, they emphasized that for patients with more severe CKD than this cut-off, the relative merits of NOAC versus VKA were undecided. A recent Kidney Disease: Improving Global Outcomes 'controversies' conference considered the topic of CKD and arrhythmias and offered less cautious advice. Expert consensus was that apixaban 2.5 mg BD could be considered for use in CKD 5/5D when anticoagulation was indicated for nonvalvular atrial fibrillation, while awaiting more efficacy and safety data.[24] RCT data comparing these important outcomes will test whether NOACs (here apixaban) have advantages over VKA in two currently recruiting trials in Germany (AXADIA: NCT02933697) and the United States (RENAL-AF: NCT02942407).

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