It is well established that patients with atrial fibrillation (AF) and chronic kidney disease (CKD) are at a higher risk of ischemic stroke, although the presence of CKD (renal impairment) is not implemented in the currently recommended risk stratification^1,2 for the prevention of thromboembolism using the CHA₂DS₂-VASc score (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, and sex category). Several overlapping pathophysiological factors related to alterations in the 3 components of the Virchow triad (changes in blood constituents, blood flow, and vessel wall and / or atrial tissue) contribute to the prothrombotic state in AF coexisting with CKD.³

In parallel, patients with CKD also exhibit an increased bleeding risk due to several mechanisms (eg, dysregulated platelet and vascular function) that contribute to the prohemorrhagic state.³ Hence, abnormal renal function is considered a risk factor for bleeding in the HAS‑BLED score.⁴ The anticipated higher bleeding risk in patients with concomitant AF and CKD represented a potential reason for withholding oral anticoagulation (OAC) despite an indication for prophylaxis of ischemic stroke and systemic embolism in this population.⁵ In addition, the phase III randomized controlled trials (RCTs) that compared direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) for the prevention of thromboembolism in AF excluded patients with an estimated creatinine clearance below 25 to 30 ml/min (representing CKD stages 4 and 5).

However, based on their favorable pharmacokinetic profile with a renal elimination rate of up to 50%,⁶ in many countries worldwide, the factor Xa inhibitors among the DOACs were approved for use in clinical practice in AF patients with advanced CKD stage 4, that is, those with an estimated glomerular filtration rate (eGFR) between 15 and 29 ml/min/1.73 m², despite a lack of RCT‑based outcome data. Consequently, real‑world evidence data could be obtained to assess their effectiveness and safety. Hence, unlike the 2020 European guidelines,¹ the 2023 guidelines of the American Heart Association / American College of Cardiology / Heart Rhythm Society considered such real‑world evidence data. According to these guidelines, treatment with warfarin or labeled doses of DOACs is reasonable to reduce the risk of stroke (class of recommendation 2a; level of evidence B‑NR) in patients with CKD stage 4.²

Several observational studies indeed support the recommendation of using OAC in patients with advanced CKD and AF.^7-9 Additional comparative studies suggest that the benefits of DOAC over VKA treatment observed in AF patients without CKD or CKD stages equal to or above 3 may also extend to patients with eGFR values below 30 ml/min/1.73 m².^10-13 Of interest, beyond the classic efficacy and safety outcomes, that is, stroke / systemic embolism and bleeds, other outcomes,¹⁴ including kidney‑related ones,^15,16 emerged as clinically important factors that could be differentially affected by the treatment with VKA or DOACs. With respect to kidney outcomes, an early real‑world study that analyzed 9769 AF patients from an administrative database in the United States indicated that the use of either dabigatran or rivaroxaban, but not apixaban, was associated with lower rates of adverse kidney outcomes, including lower rates of acute kidney injury and kidney function worsening.¹⁷ Increased vascular injury, including calcification processes, has been identified as a possible mechanism contributing to the decline of renal function in patients with CKD.¹⁸ Moreover, a disturbance in the calcium–phosphate balance, accumulation of uremic toxins, and severe vitamin K deficiency have been additionally implicated in patients with more advanced CKD. In this respect, the use of VKAs or DOACs can exhibit a differential impact on vascular injury and calcification. These processes are mediated by the matrix γ-carboxyglutamic acid protein (MGP), which is a vitamin K–dependent protein.^19,20 In the vascular wall, MGP is mainly produced in vascular smooth muscle cells, and represents the most potent endogenous protector against vascular calcification. Its diminished function has been linked to vascular calcification during VKA treatment.²⁰ In contrast, DOACs, such as rivaroxaban, lack this negative impact on MGP and may even exert protective effects against vascular injury and renal functional decline by decreasing vascular inflammation, remodelling, and calcifications through reduced protease‑activated receptor (PAR) signalling via PAR‑1 and PAR‑2.^21,22 Thus, the use of VKAs in patients with AF and CKD may aggravate the inherent predisposition for vascular calcification and injury,²³ also in the vascular bed of the kidney, and thereby contribute to worsening of renal function in these patients.^24,25

Subsequently, several additional studies indicated a potential kidney benefit of rivaroxaban, as compared with VKA.^26-29 However, even though some of these real‑world studies included an impressively large number of patients, all of them were limited by their retrospective design and analysis of observational data that were often obtained from health care records. In contrast, the more recently published XARENO (Factor Xa‑inhibition in Renal Patients with Non‑Valvular Atrial Fibrillation Observational Registry; NCT02663076) study,³⁰ despite being observational, had a prospective design,³¹ and compared adverse kidney outcomes in patients with AF and advanced CKD receiving rivaroxaban or VKA. The study included patients with AF and an eGFR between 15 and 49 ml/min/1.73 m². In a blinded, adjudicated outcome analysis using propensity score overlap weighting Cox regression analysis, adverse kidney outcomes (a composite of eGFR decline to <⁠15 ml/min/1.73 m², need for chronic kidney replacement therapy, or development of acute kidney injury) were significantly less frequent in the patients treated with rivaroxaban (hazard ratio [HR], 0.62; 95% CI, 0.43–0.88), including a 61% reduction in the need for chronic kidney replacement therapy (HR, 0.39; 95% CI, 0.17–0.89). The composite net‑clinical benefit outcome (stroke or systemic embolism, major bleeding, myocardial infarction, acute coronary syndrome, or cardiovascular death) was similar in both groups.

The XARENO data again document a turning point regarding the use of DOACs in patients with AF and advanced CKD, from a rather negative to positive attitude toward their application. Thus, these drugs can now be proactively used in these patients to protect the kidneys in addition to their established primary aim of preventing stroke and systemic embolism.