Oral Anticoagulants in Atrial Fibrillation with Severe or End Stage Chronic Kidney Disease. The Lack of Strong Evidence and the Current Trends Toward a Better Practice. A Mini Review

Rami Riziq Yousef Abumuaileq. Oral Anticoagulants in Atrial Fibrillation with Severe or End Stage Chronic Kidney Disease. The Lack of Strong Evidence and the Current Trends Toward a Better Practice. A Mini Review. Biomed J Sci & Tech Res 23(2)-2019. BJSTR.

highest incidence of AF is seen in end stage renal disease (ESRD) patients (15.1%) compared with non-end-stage CKD (9.6%) and with normal renal function (2.6%). Several studies concluded that AF may contribute to an accelerated progression of CKD to ESRD independent of other known risk factors. Patients with AF and renal dysfunction are more likely to develop thromboembolic (TE) events compared to those with AF and normal renal function [1][2][3]. Moreover, renal dysfunction is an independent predictor of major bleeding and is one of the variables which constitute the known HASBLED and ORBIT bleeding risk scores. Moreover, the prevalence of both comorbidities is common in the elderly/very elderly and with ageing of the world population, their prevalence is expected to increase.

Accurate Estimation of Renal Function is Essential Before Starting Oral Anticoagulation in AF
Patients with AF are often elderly with multiple comorbidities which need pharmacotherapy of growing complexity, and this makes the reliable estimation of renal function to be undeniably a critical issue. Moreover, the availability of the new non vitamin K antagonists' oral anticoagulants (NOACs) has renewed the great interest toward the accurate evaluation of renal function in patients with AF. Serum creatinine might not be the best estimate of renal function status particularly in elderly and in over or under weight patients. Glomerular filtration rate (GFR) is poorly inferred from serum creatinine alone. GFR is related inversely and nonlinearly to serum creatinine, age, gender, and race which all affect muscle mass and, in turn, serum creatinine level. The commonly used formulas to estimate GFR include variables to account for serum creatinine variation with age, gender, and race. Several equations were devel-

Vitamin K Antagonists in AF Patients with Severe CKD (Potential Adverse Effects)
Poor anticoagulation control with warfarin could induce acute kidney injury by causing profuse glomerular haemorrhage and renal tubular obstruction by red blood cell casts in some patients, especially in those with CKD. This condition is known as warfarin-related nephropathy which could be more pronounced if high quality anticoagulation control with Vitamin K antagonists (VKAs) could not be achieved and maintained [6]. VKAs are known to aggravate vascular calciphylaxis which is seen in severe CKD and this in turn might adversely affect the patient renal status and might have additional adverse systemic effects. Calciphylaxis with VKAs could be a result of their inhibition of the vitamin K cycle and γ-carboxylation of matrix Gl a protein [7]. Really, poor quality anticoagulation control with VKAs is common in patients with severe CKD. The proportion of time in therapeutic range (TTR) ≥ 60% decreased in severe CKD and only 21% of patients on dialysis achieving TTR ≥ 60%.
After multivariate adjustment, the magnitude of TTR reduction increased with increasing CKD severity. These findings have implications for more intensive warfarin management strategies in severe CKD or alternative therapies such as NOACs [8,9].
Really, the support to use VKAs in severe CKD came mainly from the findings of large retrospective studies (i.e., not from randomized trials), which have shown VKAs to offer protection from cardiovascular events without increasing bleeding in severe CKD [10].
However, in a recent meta-analysis, VKAs did not offer reduction in deaths, ischemic events, or strokes but increased the incidence of major bleeding in dialysis patients [11]. In addition due to the lack of convincing efficacy and more concern about potential harm in patients with ESRD or dialysis, warfarin has been implicated in the accelerated decline of renal function either through parenchymal micro-bleeds particularly in the setting of poor quality anticoagulation control with VKAs and/or due to aggravation of vascular calcifications with VKAs. A recently published retrospective study on a large cohort of Medicare beneficiaries in the United States of America has demonstrated that apixaban use in AF patients with ESRD on dialysis could be associated with a lower risk of major bleeding compared with VKAs, and the standard 5 mg twice a day dose of apixaban was associated with reductions in thromboembolic and mortality risk [12].

Severe CKD and ESRD in the Landmark Randomized Trials of NOACs
Patients with GFR< 30 mL/min in the dabigatran-RELY trial, rivaroxaban-ROCKET AF trial and edoxaban-ENGAGE AF trial and patients with GFR< 25 mL/min in apixaban-ARISTOTLE trial were excluded from the pivotal clinical trials of NOACs. This could explain the gap of evidence regarding oral anticoagulation in severe CKD and ESRD. In subgroup analysis of the ARISTOTLE trial, Apixaban was more effective than warfarin to prevent stroke and systemic embolism in the three distinct subgroups of renal function (i.e., GFR > 80, GFR > 50-80 and GFR 25 -50 mL/min). Patients with the moderate CKD (i.e., GFR <50 ml/min) benefitted from the greatest reduction of major bleeding on apixaban compared to warfarin [13].

Oral Anticoagulants in AF Patients with Severe CKD and ESRD (The Current Practice Guidelines)
The The recent 2019 American Heart Association/ American College of Cardiology AHA/ACC focused updates have stated that for AF patients with high TE risk and ESRD, it might be reasonable to prescribe VKAs or apixaban for oral anticoagulation (class II b) [15].

Optimal Follow Up Intervals for Renal Function Assessment in CKD
The current ESC practice guidelines and experts opinion proposed a reasonable follow up intervals for renal function assessment which depends on obtaining the baseline GFR and divide it by 10 (e.g., in a patient with baseline GFR of 40 ml/min, divide 40 by 10, so his renal function should be assessed every 4 months-this could be more frequent in case of acute worsening conditions) [14,16].

Lack of Strong Evidence and A Need for Controlled Randomized Trials
Our current practice regarding the use of oral anticoagulants in AF patients with ESRD is supported mainly by the findings of retrospective studies and not by sizable controlled randomized trials.  h) Optimal follow up intervals for renal function assessmentdepending on baseline GFR, complete blood count and liver function test.