Renal Function in Atrial Fibrillation

Cardiac function and renal function gradually decrease with aging. Therefore, atrial fibrillation, as an expression of myocardial dysfunction, and conditions with reduced renal filtration of endogenous and exogenous substances often coexist. Both cardiac dysfunction and renal dysfunction are associated with increased risk of thromboembolism, which is further amplified by concurrent atrial fibrillation. Oral anticoagulation for stroke prevention is therefore commonly used in patients with atrial fibrillation and poor or worsening renal function. The clinical dilemma of balancing the risk of ischemic stroke and the risk of major bleeding when deciding on treatment with a non–vitamin K antagonist oral anticoagulant (NOAC) or vitamin K antagonist is thus frequently being encountered in elderly patients with atrial fibrillation. These issues are highlighted by 2 articles in this issue of Circulation1,2 and several other recent articles.3–7 Nearly 1 of 5 of the patients enrolled in the atrial fibrillation trials comparing different NOACs with warfarin had a creatinine clearance <50 mL/min.4,6,7 In these trials, the risk of stroke, death, and bleeding was higher among patients with lower renal function at baseline in both the warfarin and NOAC arms. Substudies on outcomes in relation to renal function for the factor Xa inhibitors apixaban and rivaroxaban and the factor IIA inhibitor dabigatran have demonstrated that the superior efficacy and safety of these NOACs seen in the overall trial population extend to patients with renal dysfunction.4,6,7 Apixaban was even associated with a larger benefit in major bleeding compared with warfarin in patients with atrial fibrillation and renal dysfunction.7 The consistent effects of factor Xa inhibitors in patients with renal dysfunction are further supported by the current findings from the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48).1 In the main trial, the factor Xa inhibitor edoxaban at a dose of 60 mg once daily was noninferior to warfarin for the prevention of stroke or systemic embolism and lowered the risk of major bleeding by 20%. The current data demonstrated that these results were sustained in patients with renal dysfunction at entry into the trial (creatinine clearance of 30–50 mL/min).8 The NOACs have different pharmacokinetic profiles with variable proportions of renal elimination for each compound.8–11 Thus, for all NOACs, there are recommendations to use a lower dose in patients with poor renal function according to the individual summary of product characteristics. So far, the focus has been on the consequences of renal impairment in relation to cardiovascular risk and the selection of the most suitable antithrombotic treatment. However, little is known about the optimal dose in patients with good renal function, for example, in those with high creatinine clearance (>95 mL/min). This issue was initially highlighted during the US Food and Drug Administration Advisory Committee review on edoxaban with the unexpected finding of higher rates of stroke with edoxaban compared with warfarin in Renal Function in Atrial Fibrillation