**3. Goals of therapy for AF**

Patients with AF are managed with antiarrhythmic agents to control their heart rate and with anticoagulant agents to prevent thromboembolic events. The benefits of anticoagulation in patients with AF (without kidney disease) are well established; however, the benefits and

In this chapter, we discuss the prevalence of AF in ESKD and management of AF in these patients focusing on anticoagulation including the direct oral anticoagulants (DOACs).

The 2010 Global Burden of Disease (GBD) study estimated that the prevalence of AF approximated at 33.5 million individuals worldwide [1]. In particular, AF is believed to affect between 2.2 and 5.0 million Americans, 4.5 million Europeans and is estimated to affect 1.4% of Australians [1, 2]. The prevalence of AF is expected to increase globally over the next decade [3]. The prevalence of AF increases with age, occurring in approximately 1% of the population under 60 years of age and 15% of the population over 80 years of age. Furthermore, the age-adjusted prevalence of AF is higher for men than women [1, 4]. In terms of complications of AF, ischemic stroke is the most common cause of cerebrovascular incident with 75% of these strokes directly linked to AF [3]. In addition, proportion of strokes from embolic sources increases with age, and greater than 35% of strokes in patients over 80 years of age are cardiac in origin, predominantly due to AF [3], making AF the commonest cause of stroke in this patients older than 80 years [1, 3, 4]. The health burden of renal disease is high for patients as well as for health services globally. The 2010 GBD study found that chronic kidney disease (CKD), which previously ranked 27th in the list of causes of total number of global deaths in 1990, ranked 18th in 2010 [1, 5]. The incidence and prevalence of ESKD vary significantly across different countries. The incidence of ESKD is increasing, with reports indicating doubling in the number of patients being treated for ESKD in Europe, the Americas, and Australia, with diabetes and hypertension being the most common causes in developed and many developing countries; however, glomerulonephritis and "undetermined causes" were more common in Asia and sub-Saharan Africa [5]. Cardiovascular disease and its sequelae occur more frequently in patients with CKD, compared to the general population, and it is often more severe [6]. Patients with impaired renal function (estimated glomerular filtration rate (eGFR) ≤80 mL/min) are deemed to be at higher risk for all cardiovascular events. Current literature examining the prevalence of AF in hemodialysis (HD) patients varies widely, describing a range from 7 to 27% [4]. Furthermore, paroxysmal AF was present in 3.5%, persistent AF in 9.6% of patients and permanent AF in 13.9% of patients [4]. In a large cohort study conducted by Cheng-Huang et al., the prevalence of AF in patients receiving peritoneal dialysis and HD was examined [7]. The incidence rate ratios for AF were 2.07 and 1.78 in HD and PD groups, respectively. Additionally, after adjusting for age, gender and comorbidities, the hazard ratios for the AF risk were 1.46 and 1.32 in HD

In particular, in a study reported by Hohnloser et al., the risk of stroke in patients with CKD increased with decreasing eGFRs, the annual stroke rate was 1.05% in patients with an eGFR of >80 mL/min, 1.46% in patients with an eGFR of 50–80 mL/min and 2.39% in patients with

safety of anticoagulation in patients with AF and ESKD are still not clear.

**2. Epidemiology**

70 Anticoagulant Drugs

and PD groups, respectively.

an eGFR of ≤50 mL/min [8].

The mechanisms initiating and maintaining AF may be multifactorial in individual patients, including electrophysiological and structural abnormalities. The primary goals of therapy for AF are to control symptomatic effects of the disease and to prevent any disease-related complications such as thromboembolism and tachycardia-induced cardiomyopathy [9]. The management of AF therefore revolves around strategies for rate control, rhythm control and prevention of thromboembolic strokes. In relation to the former two strategies, multiple international guidelines, including the American College of Cardiology (ACC), the American Heart Association (AHA), European Society of Cardiology (ESC) and the Heart Rhythm Society (HRS) recommend that patients with no structural heart disease should be initiated with dofetilide, dronedarone, flecainide, propafenone, or sotalol, as these agents are found to have the lowest level of cardiac toxicity [9]. If first line therapy is contraindicated or shown to be ineffective, second-line therapy is considered and includes either amiodarone or catheterdirected ablation [9]. Interestingly, amiodarone is considered as first line therapy in patients with substantial left ventricular (LV) hypertrophy as these patients are seen to be at increased proarrhythmic risk with most other first line antiarrhythmic drugs.

The prevention of thromboembolism including stroke prevention has been widely proven with the use of anticoagulants such as warfarin and DOACs. Stroke is seen to be the most common clinical thromboembolic event in patients with AF, with AF attributing to 36% of all strokes in individuals aged 80–89 years [10]. Furthermore, stroke occurring in patients who have AF tend to have a higher degree of severity as compared to those without AF [11]. Clinical markers predicting increased risk of stroke in patients with AF include previous history of transient ischemic attacks (TIA) or prior strokes, coronary artery disease, mitral stenosis, left ventricular dysfunction, heart failure (HF), hypertension, diabetes mellitus, female gender and age more than 75 years [9].

Thrombus formation within the left atrial appendage occurs secondary to reduced blood flow velocities due to the loss of organized mechanical contraction in this anatomical area [12, 13]. Along with reduced flow velocity, other factors have also been attributed to the enhanced thrombogenicity in patients with AF. This includes reduced nitric oxide (NO) production in the left atrial endocardium, increased levels of the prothrombotic protein plasminogen activator inhibitor 1 (PAI-1), as well as elevated levels of β-thromboglobulin and platelet factor 4, von Willebrand factor (vWF), soluble thrombomodulin and fibrinogen [14].
