Update on atrial fibrillation

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Available online at www.sciencedirect.com

www.elsevier.com/locate/tcm

Update on atrial fibrillation Amanulla Khaji, MDa, and Peter R. Kowey, MD, FACC, FAHA, FHRSa,b,n a

Lankenau Medical Center, Lankenau Institute of Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096 Jefferson Medical College, Thomas Jefferson University, Wynnewood, PA

b

abstra ct Atrial fibrillation (AF) is the most common arrhythmia with a substantial effect on individual morbidity and mortality as well as healthcare expenditure. The management of AF is complex and fraught with many uncertain and contentious issues. We have seen substantial progress in AF management in the last two decades including better understanding of the epidemiology, genomics, monitoring, drug and non-pharmacological treatment of the arrhythmia, its complications and stroke risk reduction. In this review, we present a comprehensive discussion on AF with emphasis on most recent updates. Key words: Atrial fibrillation, Antiarrythmic drugs, Ablation, Stroke risk, Anticoagulation. & 2016 Elsevier Inc. All rights reserved.

Current and future incidence and prevalence of atrial fibrillation Atrial fibrillation (AF) is the most common arrhythmia and accounts for one-third of hospitalizations for rhythm disorders in the United States [1]. Atrial fibrillation is of public health importance and profoundly increases morbidity, mortality, and health-related expenditures. Morbidities include outcomes such as heart failure, stroke, and the deleterious effects on quality of life (QOL), functional status, and cognition. In the United States and Western Europe, the aging population and the accompanying rise in the prevalence of AF have magnified its toll on morbidity and healthcare costs. The estimated US prevalence of 2.7–6.1 million is expected to increase to 5.6–12.1 million by the middle of this century [2,3]. Cumulative lifetime risk estimates indicate that AF is largely a disease of aging. In the United States and European community-based cohort studies, the lifetime risk of AF is 22–26% in men and 22–23% in women by 80 years of age [3,4].

AF risk doubles in each decade of age; less than 1% in individuals 50–59 years of age are affected, whereas 10% of those 80–84 years and 11–18% of those more than 85 years of age have AF [5]. A recent analysis of medical costs associated with AF in 38 million individuals in the United States demonstrated that individuals with AF had 73% higher medical costs compared with matched control subjects. The incremental cost was $8075 per individual with AF in the United States, resulting in a total national incremental expenditure of $26.0 billion dollars [6] in 2008. There remains a paucity of epidemiological data on AF from many parts of the world, including Eastern Europe, Africa, and South America. Racial differences in AF remain poorly understood as well. Overall, blacks have a higher prevalence of multiple AF risk factors (obesity, diabetes mellitus, hypertension, and heart failure), yet a lower incidence of AF. In the ARIC study, the cumulative risk of AF at 80 years of age reached 21% in white men and 17% in white women, but was only 11% in black men and women [7].

Dr. Kowey has been an ad hoc consultant for several companies including Medtronic, Boehringer-Ingelheim, Daiichi-Sankyo, Johnson & Johnson, Bristol-Myers Squibb, Pfizer, Sanofi, Gilead, Merck, Astra-Zeneca, Portola, and Novartis. He holds no equity interest in any pharmaceutical company. The authors have indicated that there are no conflicts of interest. n Corresponding author at: Lankenau Medical Center, Lankenau Institute of Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096. Tel.: þ1 484 476 2687; fax: þ1 484 476 9000. E-mail address: [email protected] (P.R. Kowey). http://dx.doi.org/10.1016/j.tcm.2016.06.007 1050-1738/& 2016 Elsevier Inc. All rights reserved.

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The contrasting burden of risk factors with decreased AF incidence has been called a “racial paradox” [8]. AF has a profound clinical and public health burden, which has grown over the last several decades. Epidemiological approaches have delineated the major clinical risk factors, but there are large areas of uncertainty. We hope that a better understanding of AF risk factors and risk stratification will facilitate prevention.

Risk factors for AF The past few decades have seen a concerted effort to reduce the population-wide impact of atherosclerosis and cardiovascular disease, for example, by the use of statin therapy, control of hypertension, and attempts to reduce smoking. Despite reduced risk for arteriosclerosis and coronary artery disease, the incidence of AF continues to increase, indicating that the control of traditional risk factors for cardiovascular disease may not reduce AF to a similar extent. There are well-established risk factors specifically for AF. These are age, arterial hypertension, congestive heart failure, including heart failure with impaired or preserved left ventricular systolic function [9], as well as myocardial infarction, valvular heart disease, and diabetes mellitus [10]. Identification of these risk factors may be followed by early intervention and appropriate treatment to prevent disease progression. There are emerging risk factors for AF, which have received much less attention and may provide additional leverage to decrease the incidence of AF. Subclinical hyperthyroidism, obesity, chronic kidney disease, obstructive sleep apnea, heavy alcohol use, and even high-level endurance training associated with an increased risk of AF, although their evidence is lacking that eliminating one or more of these risk factors is protective against recurrence [11,12].

Biomarkers in atrial fibrillation Despite years of research and advances in catheter-based therapies for AF, we are still striving to understand the reasons for the development of AF and the mechanisms underlying the structural abnormalities observed in patients with AF. Various mechanisms including atrial fibrosis, myocyte damage, electric remodeling, atrial dilatation, prothrombotic state have been proposed. Biological substances, enzymes, hormones, and other markers of stress and malfunction, collectively referred to as biomarkers, appear to have clinical importance. Biomarkers derived from the blood, such as markers of inflammation, coagulation, renal function, myocardial injury, and cardiovascular stress, have been associated with clinical events. Biomarkers are potential novel instruments to enhance AF risk prediction and to provide insights into the pathophysiology of the disease, and may help to identify novel targets for therapy. Some markers appear to reflect the pathophysiologic process for development of AF, while others may simply be suited as markers of risk for future cardiovascular events. Biomarkers

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that reflect different pathophysiological mechanisms are shown in Fig. 1. The importance of troponin and Nt-pro BNP in an AF population was first reported from the randomized evaluation of long-term anticoagulant therapy (RE-LY) biomarker substudy performed in 6189 patients with AF and treated with either warfarin or dabigatran because of an increased risk of stroke [14]. The results from the larger ARISTOTLE [15] biomarker study verified and extended the role of NT-pro BNP. This study demonstrated a strong association between elevated risk of ischemic stroke and rising NT-pro BNP levels. Both of these biomarkers have been linked to myocardial cell stress. Reduced renal function with low GFR has been associated with an increased risk of stroke. Cystatin C, a small protein, is minimally influenced by disease states, and is therefore believed to be a better endogenous marker of GFR than creatinine [16]. The significance of cystatin C as a risk marker in an AF population was also reported from the ARISTOTLE and RE-LY biomarker substudies [17,18]. Rising cystatin C levels were independently associated with increased rates of stroke or systemic embolism, mortality, and major bleeding. In addition to cystatin C, the RE-LY biomarker study described a significant association between baseline D-dimer levels and the risk of stroke, cardiovascular death, and major bleeding outcomes independent of established risk factors including the CHADS2 variables [19]. Also, markers of inflammation including C-reactive protein and IL-6 have been independently associated with AF in the above studies. Recently, higher levels of adiponectin were associated with atrial fibrillation [20]. Schnabel et al. [21] chose a panel of 10 candidate AF biomarkers aiming to represent distinct pathophysiological pathways, including inflammation (C-reactive protein and fibrinogen), neurohormonal activation (BNP and N-terminal natriuretic peptide), oxidative stress and endothelial dysfunction (homocysteine), the renin–angiotensin–aldosterone system (renin and aldosterone), thrombosis and endothelial function (D-dimer and plasminogen activator inhibitor type 1), and microvascular damage (urinary albumin excretion). In stepwise-selection models, log-transformed BNP (HR per SD ¼ 1.62; 95% CI: 1.41–1.85; P o 0.0001) and C-reactive protein (HR ¼ 1.25; 95% CI: 1.07–1.45; P ¼ 0.004) remained associated with AF occurrence after multivariable adjustment. Adding BNP and C-reactive protein, separately and together, to an AF risk score based on clinical covariates revealed that only BNP improved risk stratification.

Emerging role of genetics The familial nature of AF was reported as early as 6 decades ago. There have been infrequent reports of families with an apparent Mendelian inheritance of AF. In 1997, Brugada et al. [22] described the first genetic locus for AF; however, the causative gene at the locus remains elusive. Multiple mutations have been identified in potassium and sodium channels, gap junction proteins, and signaling molecules.

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Fig. 1 – Illustration of the pathophysiological mechanisms in atrial fibrillation and associated biomarkers. (Adapted with permission from Hijazi et al. [13].)

Although familial AF has long been recognized, it has only recently been appreciated that AF occurring in the general population is heritable. Great progress has been made in the past decade in defining the heritability and genetic basis of AF. The application of genome-wide association studies (GWAS) to AF has the potential to transform our understanding of molecular mechanisms underlying the arrhythmia. To date, AF GWAS have been successful in identifying at least 14 genetic loci. Of these, three novel genetic loci have been well described [23] (Fig. 2). The first locus, on chromosome 4q25, is upstream of the gene PITX2. The second is located at the transcription factor ZFHX3 on chromosome 16q22. The third is the calciumactivated potassium channel KCNN3 on chromosome 1q21. PITX has been identified as playing an important role in the formation of the atrial septum, outflow tract, SA node, and the pulmonary vein myocardial sleeves [24]. The last of these is of particular importance given the prevalence of ectopic electrical foci arising from the pulmonary vein in patients with AF, and the common approach of electrically isolating the pulmonary veins to treat recurrent AF. This gene variant may be implicated in pulmonary vein ectopic sources of AF.

Whereas recent advances have identified potential new pathways for AF, the reported genomic loci contribute minimally to the risk of AF. So far, studies of familial AF have discovered rare, highly penetrant genetic variants of AF. In contrast, candidate gene studies and GWAS have revealed more common genetic variants with a smaller effect in AF cohorts and the general population. We are also learning that there is a large overlap among genes involved in diverse arrhythmic diseases such as long QT syndrome (LQTS), Brugada syndrome, short QT syndrome (SQTS), SIDS, cardiomyopathy, and AF. These genomic advances, even though in their infancy, will contribute to a comprehensive approach that will help to unravel the pathogenesis, risk stratification, and novel targets for AF therapies.

Subclinical AF AF is highly prevalent and underdetected. With the development of continuous long-term monitoring, it is now apparent that many patients have AF without recognizable symptoms. This phenomenon has been termed subclinical atrial fibrillation (SCAF). Asymptomatic atrial fibrillation and stroke

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Fig. 2 – Chromosomal positions for each of the three loci associated with atrial fibrillation (AF) in meta-analyses. The x-axis displays the chromosomal position; the y-axis indicates the statistical significance for the association between the singlenucleotide polymorphism (SNP) and the phenotype of interest. The dotted line shows the threshold for statistical significance, adjusted for multiple testing. (Adapted with permission from Magnani et al. [23].) evaluation in pacemaker patients and the atrial fibrillation reduction atrial pacing (ASSERT) demonstrated that over 2.5 years, SCAF of more than or equal to 6-min duration was observed in more than 40% of pacemaker patients without a prior history of AF, but led to clinical, ECG-documented AF in less than 15% of cases [25]. SCAF was associated with a 2.5-fold increase in the risk of embolic events. In the mode selection trial (MOST), any atrial highrate episode lasting longer than 5 min predicted clinical atrial fibrillation (hazard ratio ¼ 5.9) and stroke or death (hazard ratio ¼ 2.8) [26]. Although this study demonstrated that these embolic events are associated with an increased risk, whether anticoagulation mitigates this risk will need to be addressed in future investigations. Although the 12-lead electrocardiogram (ECG) remains the gold standard diagnostic test for AF, a major challenge in the diagnosis of this arrhythmia is its paroxysmal nature, particularly in its early stages. Recent studies have shown that more frequent monitoring can improve AF detection, but contemporary monitoring technologies used for AF detection in clinical practice are costly and sometimes burdensome. A smartphonebased app demonstrated excellent sensitivity (0.970), specificity (0.935), and accuracy (0.951) for real-time identification of an irregular pulse during AF in a study by McManus et al. [27]. The app also showed good accuracy for PAC (0.955) and PVC discrimination (0.960). The vast majority of surveyed app users (83%) reported that it was “useful” and “not complex” to use. The SEARCH-AF study screened for silent AF in pharmacies using an iPhone ECG (iECG), and cost-effectiveness was determined [28]. In SEARCH-AF, pharmacists performed pulse palpation and iECG recordings in 1000 pharmacy customers aged Z65 years (mean ¼ 76 7 7 years; 44% male), with cardiologist iECG overreading. Newly identified AF was reported in 1.5% of the cohort and all patients had a CHA2DS2-VASc score Z 2. Thus, AF prevalence was 6.7% and the automated iECG algorithm showed 98.5% sensitivity for AF detection and 91.4% specificity and was cost-effective.

Patients with a high CHADS-VASC score and in sinus rhythm are at high risk of AF. This was studied prospectively by Berkovitch et al. [29] in 19,233 asymptomatic self-referred patients. Kaplan–Meier survival analysis showed that the cumulative probability of AF at 6 years was significantly higher among subjects with CHA2DS2-VASc Z 1 (6%) compared to those with CHA2DS2-VASc ¼ 0 (1%), (P o 0.001). Consistently, multivariable Cox regression analysis demonstrated that patients with high CHADS-VASC score have a fivefold increased risk of developing AF compared with those with low CHADS-VASC score (HR ¼ 5.12; CI: 4.14– 6.32; P o 0.001). Subgroup analysis showed that those with extremely high CHADS-VASC scores (5 or 6) experience a 10.5-fold increased risk of developing AF compared with those with low CHADS-VASC (HR ¼ 10.56; CI: 2.61–42.75; P o 0.001).

Cryptogenic stroke and atrial fibrillation Currently, one in six strokes is attributed to atrial fibrillation, but one in four of the estimated 12 million ischemic strokes annually has no cause identified after a standard diagnostic workup, and are labeled “cryptogenic” [30]. The EMBRACE [31] trial randomized 572 patients who had a cryptogenic ischemic stroke or TIA within the previous 6 months to undergo additional noninvasive ambulatory ECG monitoring with either a 30-day event-triggered recorder (intervention group) or a conventional 24-h monitor (control group). Atrial fibrillation lasting 30 sec or longer was detected in 45 of 280 (16.1%) patients in the intervention group, as compared with only 9 of 277 (3.2%) in the control group (absolute difference ¼ 12.9%). The number needed to screen to identify AF was eight. CRYSTAL AF trial compared long-term monitoring by means of implantable cardiac monitors (ICM) with conventional follow-up in patients with a recent cryptogenic stroke [32]. ICM resulted in a significantly higher rate of detection of

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atrial fibrillation, with greater subsequent use of oral anticoagulants at the discretion of the investigator. In the ICM arm, the rate of detection of AF at 6, 12, and 36 months was 8.9%, 12.4%, and 30%, respectively. Detection of AF in the ICM arm prompted anticoagulation in 97% of these patients.

Pharmacotherapy for maintaining sinus rhythm Antiarrhythmic medications have been available for nearly a century and remain a mainstay in the management of atrial fibrillation (AF). Most antiarrhythmic medications have been developed with the intent of reducing proarrhythmic toxicity. Because of the potential toxicity associated with antiarrhythmic medications, selection among them requires consideration of individual patient comorbidities (Table 1). For patients without demonstrable heart disease, flecainide, propafenone, and sotalol are recommended as initial agents because they carry a relatively low risk of toxicity aside from proarrhythmia, an effect that occurs more commonly in patients with ischemic or structural heart disease. In patients with heart failure, the use of amiodarone or dofetilide is safest. Sotalol, dofetilide, and dronedarone are preferred for patients with coronary artery disease, whereas patients with left ventricular hypertrophy may be prone to proarrhythmia, making amiodarone the prudent choice. Although not approved by the Food and Drug Administration for AF, amiodarone is the most commonly prescribed antiarrhythmic drug for AF, representing 45% of annual drug prescriptions [33]. It is a complex iodinated compound that, along with its active metabolite N-desethylamiodarone, blocks IKr, INa, IKur, Ito, ICaL, IKAch, and If channels with noncompetitive antagonism of α- and β-receptors. It is distinguished by a half-life of weeks and significant distribution into adipose tissue. It is the most effective antiarrhythmic drug currently available, but it is limited by a myriad of noncardiovascular side effects. Dronedarone introduced in 2009 is the first in the group of drugs that have been designed to resemble amiodarone with fewer noncardiovascular side effects. Dronedarone is better tolerated than amiodarone, having demonstrated a trend toward fewer adverse thyroid, neurologic, dermatologic, and ocular events at 1 year [34]. The ATHENA trial assessed the

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efficacy of dronedarone 400 mg BID for the prevention of cardiovascular hospitalization or death from any cause in 4628 patients with AF [35]. Dronedarone reduced the incidence of the primary outcome of unplanned hospitalization for cardiovascular causes or death. In addition, there was a consistent decrease in rates of hospitalization for heart failure in patients with history of heart failure. Dronedarone has been the only antiarrhythmic drug that has demonstrated a reduction of stroke risk in patients with AF, albeit in a post hoc analysis of ATHENA. Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease (ANDROMEDA) study involving 627 patients with heart failure and severe left ventricular systolic dysfunction [36], dronedarone increased mortality, an effect that was largely attributed to heart failure and that suggested a negative inotropic effect. The PALLAS investigators showed that dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation, who were at risk for major vascular events [37]. Therefore, dronedarone remains an important choice as a front-line antiarrhythmic in many patients with AF. However, it should not be used in patients with advanced heart failure or in permanent AF. Dofetilide is also a pure IKr blocker. It is renally cleared and must be dosed according to creatinine clearance. It was approved for use in the United States in 2000 with a 3-day mandatory in-hospital loading period and currently represents E2% of antiarrhythmic drug prescriptions annually [38]. Dofetilide is effective for the maintenance of sinus rhythm as well as for restoring sinus rhythm [39]. It has been studied and shown to be safe in patients with CAD as well as CHF. There are newer drugs under various testing stages or recently approved with the promise of less proarrythmic risk and better tolerability. Vernakalant is a multichannel-blocking antiarrhythmic drug. It acts predominantly on the atrial potassium currents (Ito, IAch, and IKur) with a use or ratedependent effect on cardiac sodium channels, including the late sodium current INaL. It appears to be far more effective for the conversion of AF than atrial flutter, particularly if administered within 7 days of arrhythmia onset. Vernakalant has been approved in Europe and South America, but it has not been approved in the United States and Canada. FDA continued to

Table 1 – Recommendation for antiarrhythmic drugs. No structural heart disease

Coronary artery disease

Heart failure

Severe ventricular hypertrophy

Sotalol Amiodarone Dronedarone Dofetilide

Amiodarone Dofetilide

Amiodarone

First line Flecainide Propafenone Dronedarone Sotalol Second line Amiodarone Dofetilide

Disopyramide Avoid flecainide, propafenone

Avoid flecainide, propafenone, dronedarone

Avoid flecainide, propafenone

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have questions about the safety of the drug. It was agreed with the FDA that a further study should be conducted (ACT V) designed to bolster efficacy data, but most importantly to further explore safety. Unfortunately, the study was placed on clinical hold when a patient died following the infusion of vernakalant. Budiodarone is another structural analogue of amiodarone with similar multichannel-blocking properties. It is an iodinated compound, but is metabolized by plasma and tissue esterases rather than the CYP3A4 system. This difference allows more rapid metabolism and a lower likelihood of side effects. Though early studies were promising, its clinical development has not been pursued. Ranolazine is an anti-anginal agent, which inhibits abnormal late Naþ channel currents in cardiomyocytes and decreases sodium–calcium overload. It is a potent inhibitor of after-depolarizations, which have been implicated in the initiation and propagation of AF. In 6560 patients surviving an acute coronary syndrome, the MERLIN investigators noted that ranolazine was associated with a significant reduction in asymptomatic atrial arrhythmias on holter monitoring [40]. A combination of ranolazine and dronedarone reduced atrial fibrillation burden better than either alone in patients with paroxysmal atrial fibrillation, according to findings from the HARMONY trial [41]. HARMONY-assessed AF burden with midrange ranolazine (750 mg BID) combined with two reduced dronedarone doses (150 mg BID and 225 mg BID) over 12 weeks in 134 patients with paroxysmal AF and an implanted device. Ranolazine 750 mg BID/dronedarone 225 mg BID reduced AFB burden by 59% vs. placebo (P ¼ 0.008), while ranolazine 750 mg BID/dronedarone 150 mg BID reduced AFB by 43% (P ¼ 0.072). Both combinations were well tolerated.

Rate vs. rhythm control Despite extensive research, whether to restore and maintain sinus rhythm (“rhythm control”) or allow atrial fibrillation to continue while controlling ventricular rate (“rate control”) in an individual patient remains a difficult clinical decision. Given the poor outcomes associated with atrial fibrillation, rhythm control makes intuitive sense but has not shown to have an outcome advantage. At least seven randomized trials have compared rate-control and rhythm-control approaches in the broad population of

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patients with atrial fibrillation (AF) and demonstrated equivalent outcomes (such as the rates of death or embolism). Atrial fibrillation follow-up investigation of rhythm management (AFFIRM) [42] trial was the first and largest study to compare rate-control and rhythm-control strategies for the treatment of AF. Among 4060 patients with nonvalvular AF and a high risk of stroke or death, AFFIRM demonstrated no survival advantage between rate-control (using β-blocker, calcium channel blocker, and/or digoxin) and rhythmcontrol strategies. A meta-analysis [43] of five major studies enrolling 5239 patients with AF compared rate-control vs. rhythm-control strategies. Average follow-up ranged from 1 to 3.5 years. A rate-control strategy compared with a rhythm-control approach was associated with a significantly reduced risk of combined end points of all cause death and thromboembolic stroke [OR ¼ 0.84 (0.73, 0.98), P ¼ 0.02], and with a trend toward a reduced risk of death [OR ¼ 0.87 (0.74, 1.02), P ¼ 0.09] and thromboembolic stroke [OR ¼ 0.80 (0.6, 1.07), P ¼ 0.14]. There was no significant difference in the risk of major bleeds [OR ¼ 1.14 (0.9, 1.45), P ¼ 0.28] or systemic embolism [OR ¼ 0.93 (0.43, 2.02), P ¼ 0.90] (Fig. 3). Catheter ablation has consistently shown greater efficacy in maintaining sinus rhythm and more robust improvements in symptoms and quality of life than antiarrhythmic medications. In a recent international multicenter registry of 1273 patients who underwent ablation, atrial fibrillationfree survival was achieved in 85% of patients with paroxysmal atrial fibrillation and 72% of patients with persistent atrial fibrillation (76% and 60% off antiarrhythmic drugs, respectively) at a mean follow-up of 3.1 years, and freedom from atrial fibrillation was the strongest predictor of stroke-free survival (hazard ratio ¼ 0.30, P o 0.001) [44]. However, whether rhythm control using ablation to restore sinus rhythm will actually lead to reductions in stroke and mortality has not been demonstrated in prospective studies Fig. 4. It is also not known whether ablation of AF reduces mortality, but this is being investigated in catheter ablation versus antiarrhythmic drug therapy for atrial fibrillation (CABANA) trial [45]. This trial is designed to test the hypothesis that the treatment strategy of left atrial catheter ablation for the purpose of eliminating AF will be superior to current state-of-the-art therapy with either rate-control or rhythm-

Fig. 3 – Meta-analysis of five major trials comparing rate vs. rhythm control. Single and pooled odds ratio for the combined end points [43].

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Fig. 4 – The comparative efficacy of high dose of new oral anticoagulants and warfarin. NOAC ¼ new oral anticoagulant and RR ¼ risk ratio. nDabigatran 150 mg twice daily. †Rivaroxaban 20 mg once daily. ‡Apixaban 5 mg twice daily. §Edoxaban 60 mg once daily. control drugs for decreasing the incidence of the composite end point of total mortality, disabling stroke, serious bleeding, or cardiac arrest in patients with untreated or incompletely treated AF. It is now enrolling and will include up to 3000 patients followed for an estimated duration of 5 years.

Ablation In the past decade, radiofrequency catheter ablation (RFA) of AF has evolved from an experimental procedure to an important treatment option for selected patients with AF. Paroxysmal AF, especially of short duration, is frequently a purely trigger-dependent phenomenon, whereas persistent AF and permanent AF are generally mechanistically complex, implicating a more diffuse abnormality of the atrial substrate. The pulmonary veins (PVs) have been shown to play a major role in the initiation of AF [46]. Consequently, percutaneous catheter ablation aims to isolate PVs at their ostia. After PV isolation alone, success rates of 60–85% have been reported in patients with paroxysmal AF, who were free of antiarrhythmic drug use at follow-up [47]. PV isolation alone is insufficient for restoration and maintenance of sinus rhythm in most patients with persistent AF. In these patients, additional linear lesions at the roof and mitral isthmus are intended to eliminate more arrhythmogenic substrate and specifically to prevent large atrial reentrant circuits potentially involved in perpetuation of AF. Circumferential PV ablation and adjunctive roof and mitral isthmus ablation significantly reduce the AF burden at 12-month follow-up as measured by 7-day Holter monitoring [48]. Ablation of complex fragmented atrial electrograms (CFAE) [49] along with PV ablation emerged in 2008 with better reported success results for maintaining sinus rhythm. In 2015, the STAR-AF [50] II compared efficacy of PV isolation, CFEA ablation and PV isolation plus additional linear ablation across the left atrial roof and mitral valve isthmus in a randomized prospective trial involving 589 patients with persistent AF and failed to show reduction in the rate of recurrent atrial fibrillation. In 2012, a novel computational mapping approach to detect localized substrates, tested

whether ablation of patient-specific AF sources, namely, focal impulse and rotor modulation (FIRM), acutely modulates AF (by terminating or consistently slowing AF), and improves the long-term success of conventional ablation. This was tested in conventional ablation with or without FIRM (CONFIRM) trial [51]. Assessment of efficacy of catheter ablation with various techniques can be complex and is dependent on multiple variables including patient characteristics, chronicity of AF, and intensity of follow-up (extended ECG monitoring). In addition, these techniques will require validation in multicenter randomized trials. Catheter ablation is not without risk, with major complications reported in up to 6% of procedures performed worldwide [52]. Cardiac tamponade has been reported in 2.2% of cases from high-volume centers that perform AF ablation. Reduction of the power used for radiofrequency ablation has reduced this to 1% [53,54]. Injury to the phrenic nerve, the right substantially more often than the left, is observed in 0.5% of cases, with complete or partial recovery in the majority. The most significant complication of left atrial catheter ablation is atrioesophageal fistula formation [55] with a reported incidence of between 0.05% and 1% [56] and an associated mortality rate in excess of 50%. Pulmonary vein stenosis remains an important complication, with reports suggesting an incidence of between 1% and 10% in those undergoing ablation for AF [57]. Radiofrequency ablation disrupts the cardiac endothelial surface, activates the extrinsic coagulation cascade, and leads to char and thrombus formation, which in turn may lead to systemic thromboembolism. Intra-cardiac echocardiography has identified a 10% incidence of LA thrombus during catheter ablation of AF [58]. Surgery for AF has been performed for over 2 decades. Though large, prospective multicenter clinical trials are lacking, data that are available are encouraging. The Cox maze procedure reported good long-term results when used as a stand-alone procedure or when performed as a concomitant procedure in patients undergoing other indications for cardiac surgery. The advent of ablation technology has simplified the surgical treatment of AF and expanded the indications, particularly for concomitant AF procedures in patients undergoing other cardiac surgery. The referral of

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patients for surgery with symptomatic, medically refractory AF before catheter ablation remains uncommon, especially since head-to-head comparisons of catheter and surgical ablation of AF have not been carried out.

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regular review of reversible factors and careful clinical follow-up.

Pill in the pocket anticoagulation Stroke risk stratification Clinical trials comparing vitamin K antagonists (VKAs) with non–vitamin K antagonist oral anticoagulants (NOACs) in AF were performed among patients with so-called “nonvalvular” AF. For the purposes of most of these trials, “valvular AF” referred to patients with mitral stenosis or artificial heart valves. Patients with mitral regurgitation, aortic stenosis (AS), and aortic insufficiency were included and the outcomes for those patients were no different compared to the general cohort. In the last decade, there have been substantial changes in the landscape of stroke prevention in AF including new ways to define risk. The CHADS2 score was a simple scheme used in many guidelines to define “high-risk” patients. Despite guidelines and the CHADS2 score, numerous studies have shown that low-risk patients were not completely characterized, and high-risk AF patients were undertreated with vitamin K antagonists [59]. In 2012, the CHA2DS2-VASc [60] score was reported and validated to identify low-risk patients with AF (Table 2). Those patients who fulfill the criteria of age less than 65 years and lone AF (irrespective of gender)—essentially a CHA2DS2-VASc score ¼ 0 (males) or 1 (females), were deemed not to may not need antithrombotic therapy. Intracranial hemorrhage (ICH) is the most feared complication of anticoagulation therapy and confers a high risk of death and disability, but major bleeding is also associated with a high mortality. In order to quantify this risk, various bleeding scores have been proposed. Most of the scores are complex and include parameters such as genetic polymorphisms that were not routinely available in everyday clinical practice. In 2010, the HAS-BLED [61] score was proposed, and has since been well validated in multiple independent cohorts. The HAS-BLED score is the only score that has been shown to be predictive of intracranial bleeding. A high HAS-BLED score (Z3) should not be used as a reason for withholding anticoagulation, but it as being indicative of the need for

Though anticoagulation is highly effective at preventing AF-related strokes, chronic anticoagulation exposes patients to the risk of anticoagulant-induced hemorrhage. A strategy in which anticoagulation is used intermittently was tested in REACT AF trial [62]. This multicenter, single-arm study enrolled 59 patients on NOAC with nonpermanent AF and CHADS2 score 1 or 2. After a 60-day run-in with no AF episodes more than 1 h, NOACs were discontinued but reinitiated for 30 days following any AF episode more than 1 h diagnosed through daily implantable cardiac monitor transmissions. This strategy seemed feasible at the conclusion of the study; however, a large study is being planned to evaluate the safety of this approach. A recent study presented at the Heart Rhythm Society (HRS) scientific meeting in 2016 by Pammer et al. [63] showed that as needed dosing of the NOACs can be safe for selected AF patients who meticulously monitor their rhythm manually, or with a mobile health application or implanted device.

Does paroxysmal AF confer less thromboembolic risk than persistent AF? Most previous studies indicated that stroke rates are similar among patients with paroxysmal and persistent atrial fibrillation, which is reflected by guideline recommendations for oral anticoagulation use [64]. However, data are conflicting. The stroke prevention in atrial fibrillation III trial showed similar rates of ischemic stroke during aspirin treatment in patients with paroxysmal (3.2%) and permanent (3.3%) atrial fibrillation [65]. Additionally, the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events substudy showed a similar annualized risk of stroke in paroxysmal (2.0%) and persistent (2.2%) atrial fibrillation patients and no different in those assigned to oral anticoagulation [66]. A recent analysis from the ACTIVE/AVORESS database that involved 6563 aspirin-treated patients showed ischemic stroke rates were 2.1%, 3.0%, and 4.2% for paroxysmal, persistent, and permanent AF, respectively, with adjusted

Table 2 – Stroke and bleeding risk stratification with the CHA2DS2-VASc and HAS-BLED scores. CHA2DS2-VASc

Score

HAS-BLED

Score

Congestive heart failure/LV dysfunction Hypertension Aged Z 75 years Diabetes mellitus Stroke/TIA/TE Vascular disease (prior MI, PAD, or aortic plaque) Aged 65–74 years Sex category (i.e., female gender) Maximum score

1 1 2 1 2 1 1 1 9

Hypertension, i.e., uncontrolled BP Abnormal renal/liver function Stroke Bleeding tendency or predisposition Labile INR Age (e.g., 465) Drugs (e.g., concomitant aspirin or NSAIDSs) or alcohol

1 1 or 2 1 1 1 1 1 9

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hazard ratio of 1.83 (P o 0.001) for permanent vs. paroxysmal and 1.44 (P ¼ 0.02) for persistent vs. paroxysmal [67].

Anticoagulation Since its approval for therapeutic use in 1954, warfarin has been the only effective oral anticoagulant therapy for AF stroke protection. Despite aggressive attempts to develop agents that would be safer, more predictable and better tolerated, it has only been within the last few years that viable alternatives have been available. Four have been approved. Advantages of these agents over warfarin include fixed-dosing, rapid and predictable onset and offset of anticoagulant effect, a wider therapeutic window, few food or drug interactions, and no routine monitoring. A meta-analysis by Ruff et al. [68] included 71,683 participants from the RE-LY (dabigatran), ROCKET AF (rivaroxaban), ARISTOTLE (apixaban), and ENGAGE AF (edoxaban) trials and showed that the new oral anticoagulants, as a group, significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR ¼ 0  81; 95% CI: 0  73–0  91; P o 0  0001), mainly driven by a reduction in hemorrhagic stroke (0  49; 0  38–0  64; P o 0  0001). Even though NOACs are less likely to cause fatal bleeding than warfarin, one of the perceived limitations has been the nonavailability of a reversal agent. Idarucizumab, a monoclonal antibody fragment that binds dabigatran with an affinity that is 350 times as high as that observed with thrombin, was the first approved antidote [69]. In the reversal effects of idarucizumab on active dabigatran (RE-VERSE AD) 5 g of intravenous idarucizumab was administered to 90 patients who had serious bleeding (N ¼ 51) or required an urgent procedure (N ¼ 39) [70]. Idarucizumab rapidly and completely reversed the anticoagulant effect of dabigatran in 88–98% of the patients who had elevated clotting times at baseline. On October 16, 2015, the U.S. Food and Drug Administration granted approval to idarucizumab for the treatment of patients treated with dabigatran (Pradaxa) when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery or urgent procedures, or in life-threatening or uncontrolled bleeding. Andexanet alfa (recombinant modified human factor Xa decoy protein) is a specific reversal agent that is designed to neutralize the anticoagulant effects of both direct and indirect factor Xa inhibitors. Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects [71]. This agent is yet to receive regulatory approval. Although large clinical trials have compared NOACs with warfarin, no studies inform the decision of which NOAC to select for a given patient. Clinicians are left to draw upon data from pharmacological models and clinical trials with regard to dosing, adjustment for renal impairment, and side effects, and consider other clinical and socio-economic factors as well. Another area of uncertainty is anticoagulation discontinuation after successful ablation. There has not been a properly designed and powered study to answer this question and probably never will. Based on current evidence, long-term

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anticoagulation in patients after a successful ablation depends on the patient's stroke risk profile and not the perceived success of the procedure. The concept of rebound thrombosis following withdrawal of anticoagulation has been debated for nearly as long as warfarin has been in the market. Proponents who previously described an increase in thrombotic events after stopping warfarin are questioning whether a more robust manifestation of this phenomenon could occur following NOAC interruption or while switching to the NOACs from other warfarin. Data suggest that an inherent rebound thrombogenic state following cessation of anticoagulation is less likely than the inherent risk of thromboembolism. Furthermore, the magnitude of rebound after interruption of the NOACs compared to warfarin has not been investigated.

Use of anticoagulants with antiplatelet drugs The use of NOACs in patients with acute coronary syndromes who require additional dual antiplatelet is an important issue with the exception of edoxaban, each of the other three NOACs has been tested for safety in large phase II dose-finding trials that included both STEMI and NSTEMI—dabigatran in RE-DEEM [72] (dose-finding study for dabigatran etexilate in patients with acute coronary syndrome), rivaroxaban in ATLAS-1 ACS (rivaroxaban in combination with aspirin alone or with aspirin and a thienopyridine in patients with acute coronary syndromes—thrombolysis in myocardial infarction 46) [73], and apixaban in APPRAISE [74] (apixaban for prevention of acute ischemic and safety events). The majority of patients in these studies were taking both clopidogrel and aspirin. Regardless of the study or the drug, there was a threefold to fourfold excess of major and intracranial bleeding in patients with acute coronary syndromes treated concurrently with NOACs and dual antiplatelet medication. The WOEST trial of 573 patients with CAD and indications for chronic anticoagulant therapy demonstrated that combined use of vitamin K antagonists and clopidogrel reduced bleeding compared to triple therapy including aspirin (HR ¼ 0.36; 95% CI: 0.26–0.50; P o 0.001), while also reducing mortality [75]. In 2014, the joint European consensus document endorsed by the Heart Rhythm Society and Asia Pacific Heart Rhythm Society was published. It provided recommendations on managing patients needing antiplatelet drugs and anticoagulants [76]. Based on the currently available evidence, patients with AF who require antiplatelet therapy for PCI or NSTEMI should be treated with warfarin with DAPT for the shortest duration possible, particularly if PCI is performed using a bare-metal stent or a new-generation drug-eluting stent. Following that, one of the two antiplatelets can be discontinued, with strong consideration given to remaining on the thienopyridine.

Role of mechanical left atrial appendage closure devices Autopsy and surgical data have suggested that 90% of thrombi in nonvalvular AF patients originate from the left atrial appendage [77]. Approaches aimed at occlusion of left

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atrium have proven difficult but continue to be explored. Devices that can isolate this structure from the systemic circulation to obviate the need for long-term anticoagulation have been developed. In contrast to the multitude of large pharmaceutical trials that have randomized over 50,000 patients to either warfarin or an NOAC, only couple of randomized trials of a left atrial appendage (LAA) occlusion device have been published. The PROTECT AF trial, compared the Watchman (Boston Scientific) left atrial appendage occlusion device to warfarin in 707 patients [78]. PROTECT AF demonstrated that device placement was noninferior to warfarin for the primary efficacy end point of stroke (either ischemic or hemorrhagic), cardiovascular death, or systemic thromboembolism using a noninferiority margin of two. This finding was partially offset by the increase in adverse safety events including device embolization, tamponade, and periprocedural stroke in the device group, the majority of which occurred within the first 7 days. Watchman was further studied in the PREVAIL trial that showed safety while confirming efficacy demonstrated in the PROTECT AF trial [79]. There are other devices and concepts that are in pipeline to isolate the left atrial appendage, but none have been adequately studied or have gained regulatory approval.

Conclusion

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We have seen substantial progress in AF management in the last 2 decades including better understanding of the epidemiology, genomics, monitoring, and drug and nonpharmacological treatment of the arrhythmia and its complications. Most impressive has been the development of strategies to identify and reduce the risk of stroke with the new oral anticoagulants. Nevertheless, AF remains a diagnostic and therapeutic challenge in which individualization of patient care has been and remains paramount.

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Acknowledgment

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The authors would like to thank Rose Marie Wells for her help in the preparation of the article.

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