Direct oral anticoagulants and chronic kidney disease: it is time to be brave

Abstract

We read with great interest the consensus paper on the use of direct oral anticoagulants (DOACs) in patients with chronic kidney disease (CKD) by Grandone et al. [1], underlining the risks associated with the use of DOACs as compared to vitamin K antagonists in this of patients. Ageing, with reduction in glomerular filtration rate, baseline impaired renal function and polypharmacy all increase the risk of DOAC-related bleeding. Moreover, heterogeneity of studies and lack of prospective and randomized data represent important drawbacks for the use of DOACs in CKD patients, especially with glomerular filtration rate < 30 ml/min. As a result, patients with CKD and atrial fibrillation needing anticoagulation represent a clinical conundrum, whereby balancing thromboembolic and bleeding risk is challenging. Current guidelines recommend DOAC use as the preferred anticoagulant strategy in patients with moderately to severely reduced renal function following dose reduction criteria specified in landmark trials. Indeed, in this category of CKD patients, several studies have demonstrated the superiority of DOACs, as compared to warfarin, in reducing atrial fibrillation-related thromboembolic complications and with lower risk of bleeding events [2]. A meta-analysis of randomized controlled trials comparing outcomes of DOACs vs warfarin in 72,608 patients with atrial fibrillation and glomerular filtration rate ≥ 30 ml/min showed statistically significant lower rates of stroke and major bleeding when using DOACs, both in patients with mild and moderate renal dysfunction. Due to the lack of randomized data, current guidelines recommend cautious use of DOACs in patients with severely decreased kidney function. Concerns about increased bleeding risk often lead to prefer vitamin K antagonists in patients with atrial fibrillation and CKD, especially for patients with glomerular filtration rate 15–30 ml/min. Nevertheless, increasing evidence suggests that DOACs may represent a suitable alternative to warfarin in patients with reduced kidney function [3]. Using a U.S. administrative claims database including 34,569 new users of oral anticoagulants with glomerular filtration rate ≥ 15 ml/min, Yao et al. found that, relative to warfarin, DOACs were less frequently prescribed in patients with lower glomerular filtration rate: 73.5% of patients with glomerular filtration rate ≥ 90 ml/min received DOACs, but only 45% of patients with severely decreased renal function were prescribed DOACs. However, propensity score weighted population analyses, stratified by baseline kidney function, showed that apixaban, rivaroxaban and dabigatran were not inferior to warfarin in terms of rates of stroke and major bleeding in patients with glomerular filtration rate 15–29 ml/min. In particular, even dabigatran, that has about 80% of renal elimination, was associated with a similar risk of stroke but a lower risk of major bleeding as compared to warfarin. DOAC use has been consistently associated with a reduction of all-cause mortality in patients with normal renal function [3]. Survival benefit related to DOAC use as compared to warfarin seems to be maintained also in patients with impaired renal function. Indeed, in a population of 21,733 patients, Makani et al. found lower mortality rates in DOAC users in comparison to warfarin users. Interestingly, this benefit was consistent across all CKD stages, with hazard ratios favouring DOAC use of 0.76 (p value < 0.001), 0.74 (p value < 0.001) and 0.76 (p value < 0.001), in patients with glomerular filtration rate > 60 ml/min, 30–60 ml/ min and < 30 ml/min or in dialysis, respectively. These results have been recently confirmed in a high-dimensional * Marco Valerio Mariani [email protected]