**5.1. Antiplatelets**

however, do not necessarily require anticoagulation, and the decision to anticoagulate for

There are several risk scores that can be used to evaluate stroke and bleeding risk in the

oped based on the analysis of 1773 patients in the National Registry for Atrial Fibrillation and in 2006 and was used in the ACC/AHA/ESC guidelines to tailor therapy for stroke prevention in AF [15]. The scoring system includes points for congestive heart failure, hypertension, age, diabetes and stroke [15, 20]. Previous stroke or TIA is the strongest predictor of stroke and equates for two points, whereas the other risk factors carry one point each. The final score

found to be at low risk and was also noted that other risk factors that had been identified were

the 2012 ESC guidelines and 2014 ACC/AHA/HRS guidelines changed their recommenda-

AF is related to age as a continuous variable, the higher risk of stroke in women, and incorporates risk associated with vascular disease, prior MI, complex aortic plaque, and peripheral

be omitted for a score of 0, either oral anticoagulants, aspirin, or no antithrombotic therapy can be considered for a score of 1, and oral anticoagulation is recommended for patients with a prior stroke, TIA, or a score of 2 or more [3, 9, 15, 16, 18, 20, 22–26]. Although CHADS2

correctly predict strokes in approximately 68% of cases [3, 18, 22]. The HAS-BLED scoring system was developed in 2010 as a result of the Euro Heart Survey and aims to assess the 1-year risk of major bleeding in patients with AF [18, 21]. The scoring system includes points for hypertension (Systolic >160 mmHg), abnormal renal function, liver function, stroke in past, bleeding, labile international normalized ratio (INR), age ≥65, consuming drugs and consuming alcohol [19, 21]. The scoring system is based on a maximum of nine points with each risk factor worth one point each [18, 21]. A score of 3 or more indicating an increased 1-year bleed

risk on anticoagulation is sufficient to justify caution or more regular review [19–21].

While there are other more contemporary risk assessment scoring systems available, such as the ABC (age, biomarkers, clinical history) stroke risk score as devised from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARIS-TOTLE) study, their applicability is somewhat limited, as several key risk factors included are not routinely measured, and have also yet to be widely validated in population studies [27].

Information on how to best predict stroke risk in the ESKD population is limited and precludes the ability to identify patients at high risk for stroke. No stroke risk prediction scores have been specifically developed for patients with ESRD with AF. Existing thromboembolic and bleeding risk prediction scores show good standardization of stroke risk in the general population, but performs poorly in the ESKD population. McAlister et al. conducted a retrospective large cohort study comparing the effectiveness of current thromboembolic and


score as not all patients with a CHADS2

and CHA2



DS2

stroke risk scoring system was devel-

DS2

DS2

DS2

scoring system [18, 20, 22].





and

score of 0 were

stroke prevention depends on their individual risk of stroke [15–17].

NVHD sub-group including the HAS-BLED score, the CHADS2

measures the adjusted stroke rate per 100 patient-years [15, 18, 20]. The CHA2

not encompassed by this tool [18, 20, 22]. With the improvement to the CHA2

DS2

DS2

tions to support the use of CHA2DS2-VASc score over the CHADS2

, the CHA2

patients with NVAF, recent studies have shown that the CHA2

and the ATRIA stroke risk score [18–21]. The CHADS2

is an updated version of the CHADS2

arterial disease [18, 20, 22]. The CHA2

In addition to the CHADS2

72 Anticoagulant Drugs

CHA2 DS2

> There are few studies available that directly compare antiplatelet therapy, either single or dual agent, directly with formal anticoagulation. In a study conducted by Connely et al., it was investigated whether the addition of clopidogrel to aspirin in patients would reduce the risk of vascular events in patients with atrial fibrillation [11]. The primary end points examined included stroke, myocardial infarction, noncentral nervous system systemic embolism

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

an increased risk of stroke, whereas an INR of >3 confers an increased risk of bleeding [31, 32, 36, 37]. From an Australian perspective, the difficulties of warfarin's clinical usage were seen in multicenter trials showing the time in therapeutic range (TTR) is near 70% at best, but more often found to be around 50–60% [38]. Interestingly there seems to be an increased risk of bleeding and intracranial hemorrhage (ICH) with warfarin in Asian populations, even in patients with an INR within the therapeutic range. This has seen some major centers in Asia

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

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

75

Formal anticoagulation using Warfarin has been shown to significantly reduce the incidence of stroke in CKD patients with AF. The Stroke Prevention in Atrial Fibrillation [SPAF-III] Study analyzed 516 AF participants with CKD and showed that warfarin was able to reduce ischemic stroke or systemic embolism by 76% (95% CI 42–90, *P* < 0.001) [39]. In a populationbased retrospective cohort study conducted by Mitesh et al., it was found that CKD patients requiring dialysis with AF, warfarin use, in comparison with no-warfarin use, did not reduce the risk for stroke however it was associated with a 44% higher risk for having a bleeding event, whereas warfarin use in nondialysis patients with AF was associated with a 13% lower risk for stroke with a 19% higher risk for bleeding event [32, 40]. Bleeding in this study was grouped and defined as intracerebral bleeding, gastrointestinal bleeding, intraocular bleeding, hematuria, and unspecified location of bleeding. This data should not be surprising though as it is well known that HD patients have both platelet and coagulation abnormalities and also have associated comorbidities such as uncontrolled hypertension and diabetes mellitus, all of which contribute to an increase in the risk for stroke and bleeding [32, 41]. Furthermore, HD patients usually also receive heparin during dialysis, which also adds to their increased risk for bleeding. Warfarin use in HD patients, through the inhibition of matrix Gla protein and Gas-6, thus causing calciphylaxis, can accelerate vascular calcification, which may also increase the risk for ischemic stroke [32, 42, 43]. This is further supported by a 134,410 patient retrospective study cohort by Chen et al. who compared ESRD patients requiring renal replacement therapy with AF receiving either monotherapy with antiplatelets or Warfarin with a control group who were not using either of the medications [44]. They showed that the incidence of ischemic stroke or TIAs was no different between the intervention group and the control group [44]. Furthermore, the results stayed unchanged after propensity match and also showed no beneficial effect of antiplatelet or warfarin therapy in any subgroups, such as

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

adopt a lower therapeutic range of 1.5–2 [31, 32].

age and gender [44].

**5.3. Direct oral anticoagulation drugs**

calculated creatinine clearance rate of <25 or 30 mL/min [45, 46].

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

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 baseline characteristics [9].

Aspirin, however, is still frequently used to reduce stroke risk in many patients with high CHA2DS2-VASc scores who would benefit from anticoagulation.
