Recent Advances for Stroke Prevention in Patients With Atrial Fibrillation and Advanced Kidney Disease

Novel Oral Anticoagulants and Chronic Kidney Disease

Novel oral anticoagulant agents (NOACs), have been adopted in the last few years as alternative therapy to warfarin for thromboembolism risk reduction in patients with AF. These drugs have been shown to be equal or more effective than vitamin K–dependent oral anticoagulant agents (VKA), have an improved safety profile, and do not require continuous level monitoring. An important limitation of NOACs, besides their increased cost and our limited experience with their antidotes, is the fact that they all depend on renal elimination to a varying degree. There is a risk of drug accumulation in the presence of renal disease, particularly in patients with advanced CKD. The presence of an estimated glomerular filtration rate (eGFR) of less than 30 mL/min was an exclusion criterion for patient enrollment in all four randomized trials comparing NOACs with warfarin, contributing to the lack of evidence regarding their use in patients with advanced and end-stage renal disease (ESRD). In fact, current cardiology guidelines for the management of patients with AF suggest not using NOACs in the setting of severe CKD. Despite this, data from the Fresenius Medical Care records show there is a considerable proportion of patients with AF and eGFR below 30 mL or on hemodialysis taking NOACs (23.5% and 11.6%, respectively). The kidney, primarily through renal filtration, eliminates these drugs, so in patients with CKD the pharmacokinetics are altered and their half-life is increased. Dosage and frequency of administration must be corrected to avoid problems with accumulation and toxicity.

Renal function is estimated by a variety of equations. Traditionally, these calculations are based on the value of plasma creatinine. Currently, however, the most validated equations to estimate GFR are the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology (CKD-EPI). Patients enrolled in the trials that compared NOACs with warfarin were included or excluded from the studies based on eGFR values calculated by the older Cockroft-Gault formula instead of the more current equations. Furthermore, these formulas can be used only in patients with stable creatinine values. They lose reliability in patients with a fluctuating creatinine as in the case acute renal failure. In contrast to warfarin, which is exclusively hepatically metabolized, all NOACs have some level of renal elimination. For example, renal elimination accounts for 80% of the drug elimination for dabigatran, 36% for rivaroxaban, 27% for apixaban, and 50% for edoxaban. Furthermore, the binding of different NOACs with plasma proteins varies greatly. High protein binding makes some of these drugs virtually nondialyzable. Levels of protein binding range from 35% for dabigatran, 55% for edoxaban, 87% for apixaban, and up to 95% for rivaroxaban. In the absence of reversal agents (the only one currently available is the idarucizumab, a reversal agent of dabigatran) or the ability to dialyze, accumulation of these drugs can cause severe bleeding. Currently four NOACs have been approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA): dabigatran, rivaroxaban, apixaban, and edoxaban. The only direct thrombin inhibitor is dabigatran, whereas the other three act by inhibiting factor Xa activation. Randomized trials have been performed using these four agents, comparing their safety and efficacy to warfarin. Posthoc analyses also were performed, analyzing the subgroup of patients with eGFR of less than 50 mL/min. The RE-LY study, which excluded patients with an eGFR less than 30 mL/min, demonstrated the superiority of dabigatran (150 mg twice daily) compared with warfarin in terms of protection from thromboembolism, with an equal risk of hemorrhage. Using a lower dose of dabigatran (110 mg twice a day) provided the same level of protection from thromboembolism when compared with warfarin with a decreased risk of bleeding. A subgroup analysis comparing warfarin with dabigatran in relation to baseline renal function showed that the efficacy of dabigatran was maintained irrespective of eGFR, but both dabigatran dosages displayed significantly lower rates of major bleeding in patients with eGFR of at least 80 mL/min. However, in this study, although the eGFR decreased gradually over time in patients treated with warfarin or dabigatran, the decline in eGFR was significantly lower in the high- and low-dose dabigatran group, suggesting a possible nephroprotective effect of this NOAC.

The ROCKET-AF study demonstrated a noninferiority of rivaroxaban against warfarin in the prevention of thromboembolic events, with no difference in bleeding. This study excluded patients with an eGFR less than 30 mL/min and adjusted doses based on eGFR. Patients with eGFR exceeding 50 mL/min took 20 mg/day of rivaroxaban, whereas those with eGFR between 30 to 50 mL/min took 15 mg/day. There was no significant difference in rivaroxaban's efficacy and risk of hemorrhage in both groups.

The ARISTOTLE study compared the use of apixaban with warfarin and included patients with a plasma creatinine up to 2.5 mg/dL. Patients were randomized to a low-dose (2.5 mg twice daily) and high-dose (5 mg twice daily) apixaban group. Patients who had at least two risk factors: creatinine between 1.25 and 2.5 mg/dL, age over 80 years old or body weight below 60 kg were placed in the low-dose group, whereas the rest of the patients were placed in the higher-dose group. The study demonstrated a superiority of apixaban in the protection of thromboembolism, compared with warfarin, with a lower incidence of bleeding events. A subgroup analysis, performed in patients with an eGFR below 50 mL/min, showed a similar trend with a nonsignificant reduction of thromboembolic events and a significant decrease in bleeding risk. When the efficacy and safety as a function of the deterioration of renal function over time were investigated, apixaban maintained its advantage compared with warfarin, in terms of protection from thromboembolic events and of reduction of bleeding.

The ENGAGE-AF study included patients with eGFR above 30 mL/min and included a different dosing regimen of the drug edoxaban for patients with a eGFR between 30 and 50 mL/min versus eGFR exceeding 50 mL/min. Subjects with eGFR between 30 and 50 mL/min took 30 mg of edoxaban twice a day versus 60 mg twice a day for patients with an eGFR exceeding 50 mL/min. The study showed no evidence of inferiority of edoxaban compared with warfarin in the prevention of stroke and systemic thromboembolism, with a simultaneous reduction of bleeding events. Similar results were obtained in the subgroup analysis of patients with an eGFR between 30 and 50 mL/min.

The information about the use of NOACs in ESRD patients is very scarce. Chan et al. recently published data from Fresenius Medical Care records regarding the use of dabigatran and rivaroxaban in hemodialysis patients. They identified an increased risk of hospitalization or death from bleeding in patients receiving NOACs compared with those taking warfarin. Another study showed similar drug levels in 18 hemodialysis patients taking 10 mg/day of rivaroxaban compared with healthy volunteers taking 20 mg/day. There was, however, accumulation of the drug after a few days despite receiving hemodialysis, which had no effect on plasma concentrations of the drug. Given its high rate of renal elimination, dabigatran accumulates when administered to patients with end-stage renal disease ; however, it is the only of the four NOACs that is eliminated quickly by hemodialysis because of its low rate of binding to plasma proteins.

Although EMA has not approved the use of any of the four NOACs in ESRD patients, the FDA approved only apixaban. This controversial decision was made on the results of two small studies suggesting that a dose adjustment of apixaban is not required on the basis of renal function alone. In 2014 the FDA approved a labeling change for apixaban, indicating that the full dosage of 10 mg/day can be prescribed to ESRD/dialysis patients. A reduced dose of 5 mg/day is indicated only with the presence of one of the following clinical characteristics: age ≥ 80 years or weight ≤ 60 kg.

In conclusion, there are limited data to suggest the safe and effective use of NOACs in patients with moderate renal impairment (i.e., eGFR between 30 and 50 mL/ min). The question still remains whether NOACs can be used in patients with an eGFR below 30 mL/min because there are no published studies addressing this subject. Patients on hemodialysis with a high thromboembolic risk and demonstrated intolerance to vitamin K inhibitors conceivably could use apixaban (2.5 mg or 5 mg twice daily). Other options include using rivaroxaban or edoxaban at a reduced dose. There is a paucity of data to support the use of these agents in this patient population, so alternative, non–drug-related therapies, such as LAA closure, should be taken into consideration.