**6. Conclusions**

The RE-LY study was the first open label study to compare dabigatran, a direct thrombin inhibitor, to warfarin in patients with one or more risk factors for stroke [45]. The study concluded that a higher dose (110 and 150 twice daily) of dabigatran was superior to warfarin in reducing stroke and systemic embolism. The study also revealed the effect of creatinine clearance and renal function on dabigatran's action and pharmacokinetics. Dabigatran is highly dependent on renal excretion with 80% being excreted unchanged in the urine. A 20% of patients in the RE-LY study had a CrCl of 30–50 mL/min (Patients with CrCl<30 were excluded). These patients had a higher risk of major bleeding compared to patients with a CrCl of >80 mL/min [46]. The RE-LY study also saw that warfarin-assigned patients with an eCrCl of 30–49 mL/min had a significant rate of major hemorrhage at 5.4% per year compared to other participants at 3.2% per year [45]. Largescale trials for dabigatran use in CKD patients are not available, and although dabigatran is partially removed by dialysis, it remains not recommended for anticoagulation during HD [47]. The Rivaroxaban—once daily, oral, direct factor Xa inhibition compared with vitamin-K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial examined rivaroxaban versus warfarin in patients with two or more risk factors for a stroke. The study showed that rivaroxaban had similar efficacy to warfarin in reducing stroke and embolism but a significant reduction in ICH. The study was also able to show a statistically significant trend toward a decrease in all-cause mortality, as with other DOACs [48]. Patients with CrCl <30 mL/min were excluded from the trial, whereas patients with moderate renal insufficiency (CrCl of 30–50 mL/min) were included but given an adjusted dose of 15 mg daily based on data showing 25–30% higher residual serum concentration of rivaroxaban in these patients compared to patients with normal renal clearance [49, 50]. The ROCKET AF study was unable to demonstrate noninferiority or superiority of rivaroxaban in patients with moderate renal insufficiency in comparison with warfarin therapy. The rates of stroke and systemic embolism were higher in patients with moderate renal impairment compared to patients with better renal function [47]. The ROCKET AF trial also examined the primary outcome of major hemorrhage in comparison with warfarin and was shown to occur in 3.2% of patients per year for those with an eCrCl of >50 mL/min as compared to 4.7% per year in those with an eCrCl of 30–49 mL/min [48]. There are no major trials for rivaroxaban therapy in patients with a creatinine clearance of <30 mL/min or on dialysis. Rivaroxaban has been shown to be able to be completely and immediately reversed with 50 U/kg prothrombin complex concentrate on patients with normal renal function [51].

Apixaban's effectiveness was examined in the ARISTOTLE trial, which was similar to the other DOAC trials, included patients with one or more risk factors for stroke. The trial revealed that apixaban was superior to warfarin in stroke reduction and systemic embolism [52]. Major and clinically relevant nonmajor bleeding was also found to be significantly less with apixaban when compared to warfarin with ICH being also significantly reduced [3, 52]. Of the three DOACs available, only apixaban has proven to be statistically significant for reduction in total mortality when compared with warfarin, regardless of

The ARISTOTLE trial involved examining the efficacy of a apixaban in patients with creatinine of 133–221 μmol/L (1.5–2.5 mg/dL) and lower or creatinine clearance of >25 mL/min [45], and noted that the incidence of major bleeding events with apixaban was inversely related to renal functions [8]. Patients with moderate to severe renal insufficiency (creatinine 133–221 μmol/L or CrCl of <25 mL/min) were given 2.5 mg doses twice daily while patients with normal

renal function.

76 Anticoagulant Drugs

In conclusion, patients with ESKD have higher prevalence of AF. In the absence of DOACs that can be used in patients with ESRD, vitamin-K antagonists still remain the gold standard for systemic anticoagulation in this group of patients. Anticoagulation with vitamin-K antagonist in patients with ESKD is challenging due to the adverse events such as increased risk of bleeding and augmentation of risk of calciphylaxis.

The risks of administering vitamin-K antagonists in patients with ESRD should be carefully weighed against benefits of these agents in preventing embolic episodes. Since newer DOACs may have a better benefit-risk profile in dialysis patients than vitamin-K antagonists, provided appropriate dose reductions are made, this strategy may yield more on-target anticoagulation, reduce the risk of intracerebral bleeding, and not interfere with vascular calcification biology. Clinical trials with direct oral anticoagulant in dialysis patients are eagerly awaited. In addition, development of a DOAC that has nonrenal mode of excretion and can be safely given in patients on dialysis may also result in lower rates of bleeding complications, thereby shifting the risk-benefit balance toward systemic anticoagulation with this group of agents in the future.
