Cardiovascular Risk and Renal Disease

Edited byNicolas Roberto Robles

www.esciencecentral.org/ebooks

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Atrial Fibrillation and Chronic Kidney Disease

IntroductionAtrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Epidemiologic studies have

reported an increased prevalence of AF with increasing age [1]. The increased prevalence of AF over the previous years was initially attributed to the expanding population of elders in the population. Subsequent epidemiologic studies reported that even on adjustment for age and other comorbidities the prevalence of AF was increasing suggesting possible influence of other underlying conditions [2-6].

Renal failure and cardiovascular diseases share many common risk factors like age, hypertension, diabetes and many more. Recently, the association of these two conditions has gained special relevance not only because of common risk factors but because of important prognostic implications associated with these conditions occurring together, especially in an elderly population [7,8]. Over the last couple of decades, an increase in prevalence of AF has been reported in hemodialysis (HD) patients [9]. The issues associated with AF in patients with chronic kidney disease (CKD) have been discussed in this section.

Prevalence and IncidenceAtrial fibrillation is the most common arrhythmia in clinical practice. Epidemiologic studies report a prevalence of

0.5% to 1% in the community. Most of the cases are seen during the later years of life. Before 50 years, the prevalence of AF is less than 0.5% while during the 8th decade, the prevalence increases to more than 8% [3].

Studies on HD patients have reported prevalence of AF ranging from 10% to 27% [9]. Similar prevalence has also been reported in patients with moderate CKD, not on dialysis [9-11]. Compared to data from epidemiologic studies, the prevalence of AF in patients with moderate CKD and HD patients is 10 to 15 times higher as compared to age matched general population [9].

Independent risk factors associated with prevalent AF in HD patients are advanced age, duration of hemodialysis, left atrial enlargement, male gender, coronary artery disease, right atrial enlargement, low Karnofsky index, higher BMI, diabetes mellitus, congestive heart failure, history of prior stroke [6]. In patients with moderate CKD, deteriorating e GFR is an independent predictor of prevalent AF. Increased prevalence of AF with deterioration in parameters of renal functions has been reported in a community based study of healthy individuals and stable cardiac patients [9,12-15].

Longitudinal studies in HD patients conducted over a period of 1 to 7 years reported incidence of AF from 1.0 to 5.9 cases/100 patient years [9,16–20]. On comparison with data from epidemiologic studies, the incidence of new onset AF was 6 to 12 times higher in HD patients as compared to age matched general population [9]. Advanced age, left ventricular hypertrophy (LVH), non use of angiotensin converting enzyme inhibitors (ACEI), higher pulse pressure, a history of cerebrovascular accident (CVA) or transient ischemic attacks (TIA) bundle branch block, valvular calcifications, low ejection fraction and anemia were independent predictors for new AF in this patient population [9].

Apparently healthy participants of community based longitudinal studies, when segregated on the basis of parameters of renal function revealed an incidence of AF between 0.2 to 2.6 new cases/100 patient years in participants with worst renal parameters, which was 2 to 5 times higher as compared to that in participants with normal renal parameters [9,21–23]. The incidence of AF in patients with mild to moderate CKD, not on dialysis, has not been reported separately. A recent study has reported that incident AF in patients with moderate CKD accelerates progression to end stage renal disease [24].

PathophysiologyAtrial fibrillation is characterized by chaotic atrial depolarization resulting in loss of organized atrial contraction. It is

easily diagnosed on electrocardiogram (ECG) but the underlying pathophysiological mechanism is complex and not yet clearly understood. Its association with a variety of underlying conditions suggests that it may occur through multiple pathways, some of which have been studied extensively in animal models [25].

Amar M Salam*, Imtiaz Salim, Wissam Ghadban, and Jassim Al SuwaidiHamad Medical Corporation, Doha, Qatar

*Corresponding author: Amar M Salam, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar, Tel: (+974)-447-45408; Fax: (+974)-447-45616; E-mail: amaramin@yahoo.com

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Historically, it was demonstrated that AF was triggered by spontaneous depolarization in the myocardial sleeve of the pulmonary veins (PVs) [26]. Further, it was demonstrated that electrical isolation of PVs by radio frequency ablation (RFA) resulted in termination of the arrhythmia and prevented further recurrence [26]. Subsequent studies demonstrated the presence of regions on the atrial surface which facilitated persistence of the triggered AF thus giving rise to the concept of trigger and substrate in the pathogenesis of AF [27]. It was observed that when these substrates were also ablated during RFA of PVs, recurrence of AF was significantly lower as compared to RFA of PVs alone [27]. Markers of systemic inflammation have been associated with the presence of AF. It also predicts the occurrence of a new episode of AF as well as recurrence after cardioversion [28-30]. Studies have reported efficacy of corticosteroid therapy in preventing occurrence of AF after cardiac surgery and preventing recurrence after catheter ablation [31,32].

Proper functioning of the intracellular ion channels, integrity of intercellular gap junction formed by trans membrane protein called ‘Connexins’ and electrical homogeneity of the extracellular matrix is essential for electrical stability and proper conduct of atrial electrical impulse [33]. Experimental studies have shown that cytokines and reactive oxygen species (ROS) released from the leucocytes, under the influence of proinflammatory cytokines and hormones, result in dysfunction of intracellular ion channel and intercellular connexin. It also promotes extracellular fibrosis. Overall, it leads to electrical and structural remodeling in the atrial tissue which increases susceptibility for AF [33].

Increased levels of ROS and markers of inflammation have been reported in patients with CKD [34,35]. In a recent animal model of CKD and AF, it was demonstrated that the experimental rats exhibited increased expression of ROS, angiotensin II (AT II) and interstitial fibrosis in the left atrial tissue. Moreover, AF was easily induced in the isolated heart. Further, it was observed that infusion of a potent antioxidant agent inhibited the expression of ROS and AT II as well as induction of AF in the atrial tissue [36].

The exact mechanism of initiation and perpetuation of AF in patients with CKD is still not clearly known. However, on the basis of clinical and experimental studies available till date, it is reasonable to believe that ROS and inflammatory cytokines play key role in the pathogenesis of AF in patients with CKD.

ThromboembolismAtrial fibrillation and CKD are hypercoagulable states and are individually characterized by an increased risk for

incident CVA. Occurring individually, presence of AF is associated with 3–5 times increased risk of CVA while ESRD alone is associated with 4–10 times increased risk for incident CVA [37-39]. Studies done in HD dialysis patients reported that incidence of CVA was 4.9 to 17 times higher in patients with AF as compared to HD patients without AF [9,10,40,41].

Study based on Danish national registry of patients with AF reported incident CVA as 3.61, 6.44 and 5.61 cases/100 patient years in patients with AF and normal kidneys, AF with moderate CKD and AF with ESRD respectively [9,42].

Traditionally, CHADS2 and CHA2 DS2 VASc scores have been used to assess the risk of CVA associated with non valvular AF [43,44]. Recently, it has been demonstrated that adding Creatinine Clearance <60 ml/min to CHADS2 or CHA2 DS2 VASc scheme resulted in a significant improvement in risk assessment [45].

MortalityThe presence of AF increases mortality by 1.5 to 1.9 times in general population [46]. Studies in HD patients have

reported mortality rates of around 25% per year in patients with AF [9,47]. Moreover, the mortality is 1.9 to 3 times higher in HD patients with coexistent AF as compared to HD patients without AF [9]. Atrial fibrillation, ischemic heart disease, diabetes mellitus and valvular heart disease are associated with 2-3 times increase in cardiovascular mortality, while old age, and duration of HD are independent predictors of non cardiovascular mortality in HD patients [9,17].

Study based on 12 years data from Danish national registry of patients with AF reported mortality as 11.21, 38.65 and 29.35 per 100 patient years in patients with AF and normal kidneys, AF with moderate CKD and AF with ESRD respectively [9,42].

ManagementThe clinical management of patients with AF and coexistent CKD is not significantly different as compared to that of

patients with AF alone. All patients with AF and hemodynamic instability or ongoing myocardial ischemia or infarction should undergo prompt electrical cardioversion regardless of the status of renal function. However, recurrence of AF after electrical cardioversion is higher in patients with moderate to severe renal impairment as compared to patients with normal renal functions [48].

Either rate control or a strategy of rhythm control can be followed in stable patients with AF as both strategies are associated with similar outcome in terms of morbidity, mortality and health related quality of life parameters [49-54]. However, it should be noted that the use of antiarrhythmic drugs (AAD) is associated with higher adverse events [54-56]. In HD patients, the adverse events associated with use of AAD or rate reducing drugs may be higher because of accumulation in the blood as a result of impaired elimination or interaction with electrolyte imbalance during HD or both. Complete heart block has been reported with use of verapamil in HD patients with mild hyperkalemia [57]. Digoxin may accumulate rapidly in HD patients and may produce toxicity in the presence of fluctuating serum potassium levels

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during HD sessions [58]. Prolongation of QTc interval on electrocardiogram (ECG) is reported in dialysis patients and has been related with sudden death [59]. Although the use of amiodarone in HD patients is not associated with increased mortality [60], HD patients on amiodarone should be closely monitored for QTc prolongation on ECG in view of possible risk for developing polymorphic ventricular tachycardia specially in the presence of hypokalemia [61].

Catheter ablation of AF is more effective than AAD in achieving sinus rhythm and preventing recurrence [62–64]. It is reported to be more effective in preventing stroke and mortality as compared to patients with AF treated medically [65]. However, recurrence of AF is more after catheter ablation in patients with CKD [66].

AnticoagulationAs discussed earlier, AF occurring alone or in association with CKD is associated with high risk for stroke and

peripheral thromboembolism. Chronic anticoagulation therapy is the corner stone of therapy in such patients to reduce the risk of stroke and peripheral thromboembolism. Long term dose adjusted therapy with warfarin has been reported to reduce the risk of stroke by 60% in patients with AF [67]. The safety and efficacy of warfarin regarding stroke prevention in patients with AF has not been properly evaluated in patients with CKD [37]. The use of warfarin in patients with the dual disease is controversial. Earlier studies in HD patients reported that use of warfarin in patients with AF was associated with increase in ischemic as well as hemorrhagic stroke [20,37,47,68] but the more recent studies reported a significant reduction in incidence of stroke associated with use of warfarin in HD patients although at a higher bleeding rates [37,42,69-70]. The risk of bleeding associated with the use of warfarin is higher in patients with CKD even when the INR (international normalized ratio) is maintained in the therapeutic range [71]. Patients with the dual disease on warfarin should be closely monitored for occult or manifest bleeding.

The direct thrombin inhibitor, dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban has potentials to make chronic anticoagulation therapy more convenient and predictable however these agents have not been evaluated in patients with ESRD [37,72-74]. Recently, pharmacokinetic and pharmacodynamic characteristics of dabigatran was studied in HD patients but the results were not published [75,76]. These new agents have been studied in patients with e GFR between 50–30 ml/min/1.73 m2. These studies reported that incidence of bleeding with dabigatran increased with progressive deterioration in e GFR but with apixaban, bleeding was lower in patients with CKD, probably because of lower dose of apixaban used in patients with renal dysfunction in the study [37,73].

The United States Food and Drug Administration (FDA) has approved dabigatran for thromboprophylaxis in AF in dose of 150 mg twice daily in patients with Creatinine Clearance (Cr Cl) >30ml/min. However, in view of higher bleeding noted in patients with Cr Cl between 50–30 ml/min, the lower dose of 110 mg twice daily may be prudent in these patients as this dose has been shown to be as effective as warfarin in the RE–LY trial. Apixaban has been recently approved by FDA for thromboprophylaxis in paients with AF in a dose of 5 mg twice daily [77]. In patients with two or more of the following, age 80 years or more, body weight 60 kg or less and serum creatinine 1.5 mg per deciliter, 2.5 mg twice daily dose is recommended [78].

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