Safety and Efficacy of DOACs in Patients with Advanced and End-Stage Renal Disease

Safety and Efficacy of DOACs in Patients with Advanced and End-Stage Renal Disease

  • Post category:Review Article
  • Reading time:10 mins read

Introduction

Chronic kidney disease (CKD) is becoming more prevalent as the population ages and increasing risk factors such as hypertension, arteriosclerosis, and obesity multiply. Renal dysfunction raises the risk of both bleeding and thrombosis.

To avoid thromboembolic events in patients with CKD who require anticoagulation, there are two types of orally given drugs: vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). Although VKAs remain the first-line treatment in patients with severe CKD, they are difficult to use due to challenges in maintaining the optimal anticoagulation level, a tendency to accelerate vascular calcification, and a quicker development of CKD in V-treated patients.

On the other hand, preliminary findings suggest that the pleiotropic impact of DOACs, including vascular protection and anti-inflammatory qualities, as well as comparable effectiveness and safety of therapy with DOACs compared to VKAs, stimulates the use of DOACs in patients with CKD.

VKA in Patients with CKD

There are two main indications for VKA in which DOACs should not be used, including (i) vascular AF and (ii) patients with mechanical prosthetic valves. For example, patients with rheumatic mitral valve disease have the highest risk of venous thromboembolism (VTE) among those with any form of vascular heart disease, and the efficacy of DOACs has not been directly evaluated in patients with mitral stenosis. In patients with mechanical heart valves, in turn, DOACs increased the risk of thromboembolic and bleeding complications compared to warfarin. In contrast to valvular AF and mechanical valves, advanced CKD is a relative contraindication to DOACs. Since patients with CKD were underrepresented in clinical trials comparing DOACs and VKAs, VKAs are traditionally used in patients with advanced CKD, based on the expert consensus. However, treatment of patients with CKD with VKAs has at least three disadvantages.

First, it is difficult to determine the VKA dosage to maintain the therapeutic range (R) in patients with CKD. Hence, it seems that the benefits of treatment with VKAs might not outweigh the risk of the progression of vascular calcification and potential complications.

Second, VKAs inhibit the activation of vitamin K-dependent calcification inhibitors. One of these inhibitors is matrix Gla protein (MGP), which is a well-established inhibitor of vascular calcification. Inhibited activation of MGP in the presence of VKAs results in accelerated vascular calcification and induces a vulnerable plaque phenotype.

Third, fibroblast growth factor-23 (FGF-23) concentrations increase markedly in chronic kidney disease. Furthermore, FGF-23 has been associated with endothelial dysfunction and vascular calcification, which, in cooperation with vascular calcification promoted by VKA use, can lead to faster progression of CKD and an increase in AF incidence.

Furthermore, warfarin can cause acute kidney injury in patients with INR > 3.0 due to glomerular bleedings. The disadvantages of VKA treatment in patients with advanced CKD are presented in Fig 2. Altogether, VKAs might not be the optimal treatment strategy in CKD.

Direct Oral Anticoagulants

The alternative to VKAs are DOACs.DOACs have a beer pharmacokinetic prole due to the quick onset of action and therefore do not require bridge therapy with heparin in the first few days of treatment.

Anti-Inflammatory Activity of DOACs

The anti-inflammatory activity of DOACs was demonstrated in multiple studies. For example, dabigatran and rivaroxaban were shown to decrease the plasma concentration of pro-inflammatory markers, including (ICAM-1, VCAM-1), cytokines (interleukin [IL]-8), chemoattractant chemokines (CCL2, CXCL2) and tissue factor. Apixaban, in turn, was reported to exert an anti-inflammatory effect by reducing the production of free radicals in an in vitro ischemic stress model.

In this study, the concentration of IL-6 and pentraxin 3 (PTX3) in the presence of apixaban decreased to the same extent as in the presence of antiplatelet drugs. Of note, in another study, apixaban and dabigatran were shown to inhibit platelet aggregation following agonist stimulation in vitro, indicating that these DOACs may have not only an anti-inflammatory but also an antiplatelet effect.

The anti-inflammatory effects of DOACs were also shown in clinical studies. In 26 patients with acute ischemic stroke, both dabigatran and apixaban had anti-inflammatory effects by decreasing the stroke-induced inflammatory response as resected by reduced concentrations of IL-6 and high sensitivity C-reactive protein are 1 week of treatment.

Vascular Protection by DOACs

Endothelial injury is a part of the Virchow triad of thrombosis. As mentioned before, DOACs dampen inflammation, thereby protecting vascular endothelial cells. In addition, DOACs were shown to induce vasorelaxation due to increased endothelial nitric oxide synthase (eNOS) activity. Since NO release decreases platelet activation and aggregation, the DOAC-mediated increase in NO release from endothelial cells may also contribute to the effectiveness of DOACs in VTE and stroke prophylaxis. Finally, it was shown that apixaban enhances vasodilation. The pleiotropic effects of DOACs are presented in Figure 3.

Efficacy and Safety of DOACs in Stage 3 and 4 CKD

In a recent meta-analysis, which included hallmark randomized controlled trials comparing DOACs against VKA subgroup analysis of patients with CKD was performed. It was observed that DOACs may slightly reduce the rate of all strokes and systemic embolism in comparison to warfarin, both in stage 3 CKD (relative risk (RR) 0.82, 95% confidence interval (CI) 0.66 to 1.02) and in stage 4 CKD (RR 0.68, 95% CI 0.23 to 2.00).

In turn, DOACs reduced the number of major bleeding events in comparison to warfarin in stage 4 CKD (RR 0.30, 95% CI 0.11 to 0.80). Further, DOACs seemed to reduce the rate of intracranial hemorrhage in comparison to warfarin in the total population of CKD patients (RR 0.43, 95% CI 0.27 to 0.69). Based on these results, DOACs seem to be as efficient as warfarin to prevent stroke and systemic embolism, without increasing or even decreasing the risk of major bleeding events among AF patients with CKD.

In a recent study, which enrolled 269 patients with atrial fibrillation and advanced chronic kidney disease (defined as CrCl 25 to 30 mL/min), the safety of apixaban versus warfarin was compared. Apixaban caused less major bleeding (hazard ratio, 0.34 (95% CI, 0.14–0.80)) and major or clinically relevant nonmajor bleeding (hazard ratio, 0.35 (95% CI, 0.17–0.72)) compared with warfarin.

Efficacy and Safety of DOACs in ESRD

One study found an increase in prescribing both dabigatran and rivaroxaban in patients undergoing HD shortly after their approval for use in the US, despite the exclusion of patients with ESRD from landmark studies and lack of evidence regarding DOAC safety in this population. In the case of rivaroxaban, it is recommended to use a reduced dose (15 mg once daily) in patients with a creatinine clearance of <30 mL/min.

A study in 16 patients showed that the deterioration of renal filtration function from stage 3 CKD to ESRD does not have a significant impact on rivaroxaban pharmacokinetics and pharmacodynamics. Rivaroxaban 15 mg once daily results in comparable drug exposure for patients with stage 3, stage 4, or ESRD.

Conclusion

Data about the safety and efficacy of DOACs in CKD are limited, but there are a few studies in progress that may provide evidence of either superiority or inferiority of DOACs over VKAs. At present, DOACs are preferred over warfarin in patients with mild to moderate CKD and might be considered in patients with advanced CKD. European recommendations contraindicate the use of all DOACs in patients with eGFR < 15 mL/min or on hemodialysis, whereas the U.S. Food and Drug Administration allows for apixaban use in those cases. Hence, DOACs are gradually replacing VKAs in the prevention of thromboembolic events in patients with CKD due to beer safety prole and comparable efficacy. However, treating physicians should be aware of the higher risk for bleeding in the CKD population, regardless of the choice of anticoagulant, and individualize the therapy according to patient risk factors, including HAS-BLED score, and history of bleeding events and concomitant antiplatelet therapy.

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