**5.3. Direct oral anticoagulation drugs**

and death from vascular causes. The study showed that in patients with AF where vitamin-K antagonists were deemed unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, in particular stroke, by 28%; however, the combination increased the

The Stroke Prevention in Atrial Fibrillation (SPAF) II study was the only major study to show a positive outcome for use of aspirin in AF for stroke prevention [31]. The study showed that patients treated with aspirin had a statistically significant reduction of 42% in stroke rate over the placebo group [31]. In the more recent Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin-K Antagonist Treatment (AVERROES) study, 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin-K antagonist therapy was unsuitable were assessed and divided into groups whom received apixaban or aspirin [10]. The primary outcome assessed in the study was the occurrence of stroke or systemic embolism. The study was halted at 18 months as a significant benefit from apixaban over aspirin was observed with a 55% risk reduction in ischemic stroke [10]. Furthermore, it was also found that bleeding was comparable between aspirin and apixaban, 44 major bleeding events (a rate of 1.4% per year) among patients taking apixaban and 39 (1.2% per year) among those taking aspirin (hazard

Olesen et al. examined aspirin's use for stroke prevention in patients with AF and CKD. The retrospective cohort study found that aspirin was associated with an increased risk of stroke or systemic thromboembolism among patients who had any form of renal disease, (hazard ratio, 1.17; 95% CI, 1.01–1.35; P = 0.04) [9]. Furthermore, the risk of stroke or systemic thromboembolism in association with CKD was of the same magnitude when adjusted for all base-

Aspirin, however, is still frequently used to reduce stroke risk in many patients with high

Vitamin-K antagonist, for example, warfarin, was first used as an anticoagulant in the 1960s when it was validated through multiple randomized, controlled clinical trials comparing it versus placebo or no therapy, that it had superior efficacy in reducing strokes in patients with NVAF [31, 32]. Warfarin's effectiveness was confirmed in the pivotal 1992 Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) trial [33]. This trial definitively proved that warfarin reduced stroke rates in patients with NVAF by approximately 70% and mortality by approximately 30% [33]. Furthermore, when investigated with regard to intention to treat, it was found that there was a 68% risk reduction in stroke for patients taking warfarin when compared to the control groups who were not anticoagulated [34, 35]. Although warfarin is extremely effective in reducing stroke and mortality, it is an incredibly difficult drug to use in clinical practice. Warfarin has a slow onset and offset of action and has multiple drug and food interactions. Warfarin requires constant monitoring to ensure the INR remains within the therapeutic range of 2–3. Studies have shown that an INR <2 carries

risk of major hemorrhage from 1.3 to 2.0% per year [10, 11].

ratio with apixaban, 1.13; 95% CI, 0.74–1.75; P = 0.57) [10].

CHA2DS2-VASc scores who would benefit from anticoagulation.

line characteristics [9].

74 Anticoagulant Drugs

**5.2. Vitamin-K antagonist**

Currently available oral direct acting anticoagulants are the direct thrombin inhibitor dabigatran, and the factor Xa inhibitors rivaroxaban and apixaban. Their clinical use in the normal population is favored due to their rapid onset and offset of action. Direct oral anticoagulations (DOACs) achieve full anticoagulation within 2 h of dosing, and are mostly excreted within 24 h of taking the last dose. In addition to their appeal, none of the DOACs require routine monitoring to evaluate their extent of anticoagulation performance. There has been minimal evidence in investigating DOACs for stroke prophylaxis in ESKD patients with AF. All major trials, comparing DOACs to warfarin for AF and stroke prophylaxis, excluded patients with a calculated creatinine clearance rate of <25 or 30 mL/min [45, 46].

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].

renal function were given 5 mg twice daily. Bleeding episodes were higher in patients with moderate/severe renal failure when compared to the normal renal function group, however remained lower with apixaban compared to patients with renal impairment on warfarin. In terms of observing patients on warfarin, the ARISTOTLE trial showed that major hemorrhage was at least twice as likely among patients with an eCrCl of 25–50 mL/min compared with others [52]. The ARISTOTLE trial therefore eludes to apixaban being safe for oral anticoagulation in AF patients with creatinine clearance of >25 mL/min, with dose adjustment as decided

Anticoagulation for Atrial Fibrillation in Patients with End-Stage Kidney Disease

http://dx.doi.org/10.5772/intechopen.78022

77

Again, there are no major trials investigating the effectiveness of apixaban on ESKD patients with stroke risks. Further research in this area is awaited. Apixaban like rivaroxaban is not dialyzable and therefore albeit the small renal excretion of 27 and 36%, respectively, they may build up in patients with ESKD [53]. Therefore, it is always advisable to continue monitoring patients with moderate to severe (CrCl 30–80 mL/min) for worsening renal function and pos-

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

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

, Kamal Sud2,3 and Bhadran Bose2,3\*

1 Department of Vascular Surgery, Nepean Hospital, Kingswood, NSW, Australia 2 Department of Renal Medicine, Nepean Hospital, Kingswood, NSW, Australia

3 Nepean Clinical School, The University of Sydney, Sydney, NSW, Australia

\*Address all correspondence to: bhadran.bose@health.nsw.gov.au

risk of bleeding and augmentation of risk of calciphylaxis.

by the treating physician.

sibility of toxicity.

**6. Conclusions**

the future.

Quoc Tran1

**Author details**

, Bassim Jebeili1

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 renal function.

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 were given 5 mg twice daily. Bleeding episodes were higher in patients with moderate/severe renal failure when compared to the normal renal function group, however remained lower with apixaban compared to patients with renal impairment on warfarin. In terms of observing patients on warfarin, the ARISTOTLE trial showed that major hemorrhage was at least twice as likely among patients with an eCrCl of 25–50 mL/min compared with others [52]. The ARISTOTLE trial therefore eludes to apixaban being safe for oral anticoagulation in AF patients with creatinine clearance of >25 mL/min, with dose adjustment as decided by the treating physician.

Again, there are no major trials investigating the effectiveness of apixaban on ESKD patients with stroke risks. Further research in this area is awaited. Apixaban like rivaroxaban is not dialyzable and therefore albeit the small renal excretion of 27 and 36%, respectively, they may build up in patients with ESKD [53]. Therefore, it is always advisable to continue monitoring patients with moderate to severe (CrCl 30–80 mL/min) for worsening renal function and possibility of toxicity.
