atrial fibrillation: state of the art; vorhofflimmern – state of the art;

13
review article Atrial fibrillation: state of the art 1 3 Summary Atrial fibrillation (AF) is by far the most fre- quent heart rhythm disorder and is associated with a significantly increased risk of stroke, heart failure and death. Despite improvements in prevention and treat- ment, the prognosis has not changed significantly. To use new and promising pharmacological and interventional concepts for thromboembolic prophylaxis and treatment of AF, as well as prevention of recurrence, patient compli- ance has to be improved, physicians have to be trained and experience hast to be gained. A consistently carried ‘anticoagulation pass’ might be a promising piece of the puzzle. Keywords Atrial fibrillation · Atrial flutter · Oral anti- coagulation · Stroke risk · Bleeding risk · CHA 2 DS 2 -VASc score · HAS-BLED score · DOACs · Atrial appendage occlusion · Cardioversion · Pill in the pocket · Catheter ablation · MAZE intervention · Triple therapy · Preop- erative management Vorhofflimmern – State of the Art Zusammenfassung Vorhofflimmern ist die mit Abstand häufigste Herzrhythmusstörung und mit einem signifi- kant höheren Mortalität und Risiko einen Schlaganfall oder eine Herzinsuffizienz zu erleiden, assoziiert. Trotz Verbesserung der Prävention und Behandlung, hat sich die Prognose nicht signifikant verändert. Um vielversprechende neue pharmakologische, als auch interventionelle Behandlungskonzepte zur (Rezidiv-) Prophylaxe und erapie von Vorhofflim- mern einsetzen zu können, muss die Patienten-Com- pliance verbessert, Ärzte in ihrem Umgang geschult und Erfahrung gewonnen werden. Ein sorgfältig geführter „Antikoagulations-Ausweis“ könnte dahingehend ein erfolgversprechender Puzzlestein sein. Schlüsselwörter Vorhofflimmern · Vorhofflattern · Orale Antikoagulation · Schlaganfallrisiko · Blutung- srisiko CHA 2 DS 2 -VASc score · HAS-BLED score · DOACs · Vorhofsohrverschluss · Kardioversion · Pill in the pocket · Katheterablation · MAZE Intervention · Triple erapie · Präoperatives Management Introduction Atrial fibrillation (AF) is the most frequent heart rhythm disorder with a rapidly growing prevalence of 1.5–2 % in developed countries. e average age is between 75 and 85 years [1]. Lifetime risk accounts for approximately 25 % after the age of 40 years [2]. AF is associated with a fivefold increase in stroke incidence, a threefold risk of developing heart failure and a twofold risk of death when compared with people with sinus rhythm (SR) [1]. Approximately 15 % of all cerebrovascular strokes are related to AF [3]. is is partially due to an increase in life expectancy and age-related diseases. e most relevant risk factors are arterial hypertension, diabetes mellitus, overweight, coronary heart disease, heart fail- ure, valve disease, nicotine abuse and age (prevalence: approximately 0.3 % for age 55–64 years, 3.5 % for age >  85 years). Structural alterations of the heart (e.g. left atrial enlargement, decrease of fractional shortening, left ven- tricular hypertrophy) also enhance the incidence of AF. e co-occurrence with heart failure is common, and the question arises which is the chicken and which the egg Univ. Prof. Dr. F. Weidinger, MD () · M. Hasun, MD · E. Gatterer, MD 2. Medizinische Abteilung, Krankenanstalt Rudolfstiftung, Juchgasse 25, 1030 Vienna, Austria e-mail: [email protected] Received: 25 August 2014 / Accepted: 22 October 2014 © Springer-Verlag Wien 2014 Wien Klin Wochenschr DOI 10.1007/s00508-014-0667-5 Atrial fibrillation: state of the art Matthias Hasun · Eduard Gatterer · Franz Weidinger

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review article

Atrial fibrillation: state of the art 11 3

Summary Atrial fibrillation (AF) is by far the most fre-quent heart rhythm disorder and is associated with a significantly increased risk of stroke, heart failure and death. Despite improvements in prevention and treat-ment, the prognosis has not changed significantly. To use new and promising pharmacological and interventional concepts for thromboembolic prophylaxis and treatment of AF, as well as prevention of recurrence, patient compli-ance has to be improved, physicians have to be trained and experience hast to be gained. A consistently carried ‘anticoagulation pass’ might be a promising piece of the puzzle.

Keywords Atrial fibrillation  · Atrial flutter  · Oral anti-coagulation · Stroke risk · Bleeding risk · CHA2

DS2-VASc

score  · HAS-BLED score  · DOACs  · Atrial appendage occlusion  · Cardioversion  · Pill in the pocket  · Catheter ablation  · MAZE intervention  · Triple therapy  · Preop-erative management

Vorhofflimmern – State of the Art

Zusammenfassung Vorhofflimmern ist die mit Abstand häufigste Herzrhythmusstörung und mit einem signifi-kant höheren Mortalität und Risiko einen Schlaganfall oder eine Herzinsuffizienz zu erleiden, assoziiert. Trotz Verbesserung der Prävention und Behandlung, hat sich die Prognose nicht signifikant verändert.

Um vielversprechende neue pharmakologische, als auch interventionelle Behandlungskonzepte zur

(Rezidiv-) Prophylaxe und Therapie von Vorhofflim-mern einsetzen zu können, muss die Patienten-Com-pliance verbessert, Ärzte in ihrem Umgang geschult und Erfahrung gewonnen werden. Ein sorgfältig geführter „Antikoagulations-Ausweis“ könnte dahingehend ein erfolgversprechender Puzzlestein sein.

Schlüsselwörter Vorhofflimmern  · Vorhofflattern  · Orale Antikoagulation  · Schlaganfallrisiko  · Blutung-srisiko CHA2

DS2-VASc score · HAS-BLED score · DOACs ·

Vorhofsohrverschluss · Kardioversion · Pill in the pocket · Katheterablation · MAZE Intervention · Triple Therapie · Präoperatives Management

Introduction

Atrial fibrillation (AF) is the most frequent heart rhythm disorder with a rapidly growing prevalence of 1.5–2 % in developed countries. The average age is between 75 and 85 years [1]. Lifetime risk accounts for approximately 25 % after the age of 40 years [2]. AF is associated with a fivefold increase in stroke incidence, a threefold risk of developing heart failure and a twofold risk of death when compared with people with sinus rhythm (SR) [1]. Approximately 15 % of all cerebrovascular strokes are related to AF [3]. This is partially due to an increase in life expectancy and age-related diseases. The most relevant risk factors are arterial hypertension, diabetes mellitus, overweight, coronary heart disease, heart fail-ure, valve disease, nicotine abuse and age (prevalence: approximately 0.3 % for age 55–64 years, 3.5 % for age > 85 years). Structural alterations of the heart (e.g. left atrial enlargement, decrease of fractional shortening, left ven-tricular hypertrophy) also enhance the incidence of AF. The co-occurrence with heart failure is common, and the question arises which is the chicken and which the egg

Univ. Prof. Dr. F. Weidinger, MD () · M. Hasun, MD · E. Gatterer, MD2. Medizinische Abteilung, Krankenanstalt Rudolfstiftung,Juchgasse 25,1030 Vienna, Austriae-mail: [email protected]

Received: 25 August 2014 / Accepted: 22 October 2014© Springer-Verlag Wien 2014

Wien Klin WochenschrDOI 10.1007/s00508-014-0667-5

Atrial fibrillation: state of the art

Matthias Hasun · Eduard Gatterer · Franz Weidinger

review article

2 Atrial fibrillation: state of the art 1 3

[4]. Although men suffer more frequently from AF than women (1.5 fold), the overall mortality is higher in female patients. However, this was not detected in ‘lone atrial fibrillation’ (without underlying disease) [2, 4, 5].

Based on crucial results of large trials and grow-ing clinical experience with ‘direct oral anticoagulants’ (DOACs), antiarrhythmic drugs and catheter ablation, the recent guidelines of the European Society of Car-diology (ESC) of 2010 were updated in 2012. Currently, the detection of ‘silent’ (asymptomatic) AF has become a new focus of interest. Large clinical trials have shown a linear correlation between ‘AF burden’ (cumulative duration of AF) and the risk of stroke. In the ASSERT trial, 35 % of the study population with AF > 65 years of age and recently implanted pacemaker (PM) or implantable cardioverter defibrillator (ICD) showed silent episodes of AF within the first 3 months of follow-up, leading to a 2.5-fold increase in incidence of stroke regardless of other risk factors or symptomatic periods. Silent AF was detected eight times more often than symptomatic AF and was associated with a higher risk of developing symptomatic episodes (Fig.  1) [2, 6]. The updated ESC guidelines recommend an electrocardiogram (ECG) and

frequent pulse palpation of heart rhythm in individuals aged > 65 (class I, level B) [1].

Disease pattern

Electrocardiographic criteria of AF are supra-ventricu-lar, arrhythmic tachycardia with a very high frequency (350–550/min) and low amplitude atrial excitation (oscil-lation), and irregular atrio-ventricular (AV) transition (Fig.  2). An incomplete AV block, as well as ventricular or AV-junctional tachycardia, may complicate diagnosis due to regular-appearing QRS complexes [7].

AF can be classified according to its ventricular rate (bradycardic, normofrequent, tachycardic), duration (paroxysmal, persistent, permanent), pathogenesis (val-vular, non-valvular) and clinical pattern (symptomatic, asymptomatic).

Paroxysmal AF is characterized by recurrent, sponta-neously terminating episodes lasting for not longer than 7 days. If these periods become more frequent and longer, persistent AF can develop because of electrical changes of cell properties (electrical and cellular remodelling).

Fig. 1 The risk of clinical atrial tachyarrhythmias and of ischaemic stroke or systemic embolism, according to the presence or absence of subclinical atrial tachyarrhyth-mias. a The risk of electrocar-diographically documented clinical atrial tachyarrhythmias after the 3-month visit, ac-cording to whether subclinical atrial tachyarrhythmias were or were not detected between enrolment and the 3-month visit. b The risk of ischaemic stroke or systemic embolism after the 3-month visit, ac-cording to whether subclinical atrial tachyarrhythmias were or were not detected between enrolment and the 3-month visit. The insets show the same data on an enlarged y-axis [3]

review article

Atrial fibrillation: state of the art 31 3

tence of AF for more than 1 year is called long-standing AF. Even if treated with catheter ablation, the probability

Per definition, persistent AF lasts more than 7 days and requires medical or electrical termination. The persis-

Fig. 2 Tachycardic atrial fibrillation

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4 Atrial fibrillation: state of the art 1 3

because of shorter diastole, further decreasing coro-nary blood flow. Moreover, non-specific symptoms like exhaustion, nervousness, anxiety, fatigue and weakness can be an expression of cardiac arrhythmia. Nonetheless, it should be mentioned once again that silent AF is very frequent and that thromboembolic complications often lead to the final diagnosis of AF [7].

Diagnosis

Early detection of silent episodes and avoidance of serious complications are crucial, and therefore, frequent palpa-tion of the heart rhythm is the first important step. If AF is suspected, a 12-channel ECG should be performed. AF is defined as every arrhythmia that meets ECG criteria and persists long enough to be detected by 12-channel ECG, or lasts for more than 30 s in rhythm strip [18]. Long-time ECG monitoring (Holter ECG, loop recorder) is especially indicated in highly symptomatic patients, cryptogenic stroke or syncope, detecting underlying arrhythmia in 5–10 % of cases. Unfortunately, AF is detected subsequent to complications in many cases [19, 20].

In the future, serum analysis (atrial natriuretic pep-tide (ANP)/brain natriuretic peptide (BNP) interleukin 6), echocardiographic parameters like atrial size and myocardial function, magnetic resonance imaging for pre-interventional planning and detection of fibrosis as pro-arrhythmic marker and genetic analysis (increased AF incidence in Brugada-, short-/long-QT syndrome) may be helpful to quantify the individual risk of develop-ing AF [18−23].

Large cohort trials have to show whether these factors will be important in risk stratification. Investigators of the ‘Euro Heart Survey’ defined the so called ‘HATCH-score’, based on risk factors leading to AF progress (heart fail-ure, transient ischemic attack/stroke, chronic obstruc-tive pulmonary disease (COPD), arterial hypertension), to evaluate the probability of developing persistent out of paroxysmal AF. However, further large prospective trials are necessary [24].

Differential diagnosis

Various supra-ventricular arrhythmias, like atrial flut-ter, and atrial tachycardia have to be differentiated. The underlying electrophysiological mechanisms, concern-ing impulse generation and conduction, are complex and differ from one another. They are based on abnor-mal automatisms, ectopic impulse generation (e.g. atrial myocardium, pulmonary vein myocytes, vena cava supe-rior) and re-entry cycles, which are the most common source [10].

Unlike AF, atrial flutter is characterized by a lower atrial rate (240–320/min) and usually regular conduc-tion block (e.g. 2:1, 3:1) [25]. A 2:1 block, meaning every second atrial impulse is conducted to the ventricles, results in a heart rate of approximately 150/min, thereby

to eliminate the arrhythmia is low. This AF subtype fre-quently makes more invasive procedures for termination (e.g. extended catheter ablation) necessary. If there is no treatment possibility and AF is accepted as the underly-ing rhythm, AF is called ‘permanent’ [7, 8].

What determines the occurrence and maintenance of AF is the interaction between trigger (supra-ventricular extra beat, salvo, focal tachycardia) and substrate (e.g. mitral stenosis, dilated atrium). Due to shorter refractory periods and sudden changes in the orientation of myo-cyte fibres, pulmonary veins have the greatest potential of generating tachycardic arrhythmia [9]. Once AF is origi-nated, molecular, cellular and extracellular changes, also known as ‘structural remodelling’, may occur. Thereby, proliferation and differentiation of fibroblasts into myofi-broblasts, fibrosis and increased formation of connective tissue lead to electrical dissociation, further supporting development and maintenance of AF (circulus vitio-sus) [10]. Subsequently, small re-entry cycles keep the arrhythmia ongoing, further leading to electrophysio-logical, functional and ultra-structural alterations within the atrium. Moreover, tachycardia-induced cellular Ca2+ overload shortens refractory period, thereby making the cells more vulnerable to new excitation [11]. The more often and longer these stimuli persist, the longer AF peri-ods will last and the less stimulus is necessary to trigger persistent AF (‘electrical remodelling’) [12].

Even extrinsic factors and their influence on the auto-nomic nervous system play an important role in the pathogenesis of AF (e.g. nicotine, alcohol, cocaine, can-nabis, heart surgery, competitive/endurance sport). Fur-thermore, sleep apnoea is associated with an increased risk of AF [13−17].

Clinical signs

Clinical presentation of AF is typically diverse. Often, patients with ‘lone atrial fibrillation’ are more symptom-atic than patients with concomitant disease such as heart failure, which limits physical activity. Similar to heart failure classification, the European Heart Rhythm Asso-ciation (EHRA) proposed an AF classification, dependent on everyday impairment (Table 1) [10].

Among the most frequent AF-related symptoms are palpitation, sweating, vertigo, headache and dyspnoea, which might be an expression of underlying cardiac decompensation. In patients suffering from coronary artery disease, tachycardia can lead to angina pectoris

Table 1 Classification of AF-related symptoms (European Heart Rhythm Association (EHRA) score) [10]

EHRA class Explanation

EHRA I ‘No symptoms’

EHRA II ‘Mild symptoms’; normal daily activity not affected

EHRA III ‘Severe symptoms’; normal daily activity affected

EHRA IV ‘Disabling symptoms’; normal daily activity discontinued

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Atrial fibrillation: state of the art 51 3

as ‘low risk’ based on a CHADS2 score of 0 have stroke

rates > 1.5 %/year, which may qualify them for oral anti-coagulant (OAC) therapy [1]. Therefore, in the presence of a CHA

2DS

2-VASc score of 1, oral anticoagulation has

received a class IIa recommendation [1].A European register recently showed that the inci-

dence of AF directly correlates with the risk profile (Fig. 4).

In decision finding whether to start anticoagula-tion, the individual bleeding risk has to be weighed up towards the thromboembolic risk. According to that, the ‘HAS-BLED score’ is recommended [30]. A value of 3 or more implies an increased bleeding risk, and potentially reversible risk factors have to be adjusted (Table 4) [10].

impressing as regular tachycardia in ECG. Atrial flut-ter can even be conducted 1 by 1, leading to a heart rate of more than 200/min. Typical atrial flutter is caused by re-entry mechanisms (counter clockwise) next to the tri-cuspid annulus and is characterized by saw-tooth like, negative flutter waves in II, III, aVF and positive waves in V1, or vice versa if excitation goes clockwise (Fig.  3) [26]. Both subtypes are even known as ‘typical isthmus-dependent atrial flutter’. Other subtypes have their origin in the left atrium, do not meet the aforementioned crite-ria and are therefore called ‘atypical’ [26, 27].

Therapy of non-valvular AF

Embolism prophylaxis

AF is associated with an increased thromboembolic risk. Thrombus formation and subsequent cerebrovascu-lar embolization especially occur within the left atrium and left atrial appendage (LAA), whereas peripheral embolism is less frequent. The most important strategy to improve prognosis is oral anticoagulation based on the patient risk [28]. For that purpose, the ‘CHA

2DS

2-

VASc score’ is recommended exclusively since 2012, which more accurately identifies patients with a very low risk profile (lone AF) when compared with the former ‘CHADS

2 score’ (Tables 2 and 3) [10]. In patients with a

score of 0, the risk of bleeding is higher than the risk of thromboembolism, and oral anticoagulation should be avoided. On the contrary, individuals with a CHA

2DS

2-

VASc score of ≥ 2 are classified as ‘high risk’ and should therefore be anticoagulated, as the yearly stroke risk is 3.7 %. On the other hand, many patients classified

Fig. 3 Typical isthmus- dependent atrial flutter

Table 2 The risk factor approach expressed as a point-based scoring system, with the acronym CHA2DS2-VASc [10]

Risk factor Score

Congestive heart failure/left ventricular dysfunction

1

Hypertension 1

Age: ≥ 75 years 2

Diabetes mellitus 1

Stroke/transient ischemic attack/thromboembolism (TE)

2

Vascular diseasea 1

Age: 65–74 years 1

Sex category (i.e. female gender) 1

Maximum score 9

Maximum score is 9 since age may contribute 0, 1 or 2 points

aPrior myocardial infarction, peripheral artery disease, aortic plaque

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6 Atrial fibrillation: state of the art 1 3

debate [33]. Results of a recently published retrospective study, including 29,457 patients, suggest that this could be reached with INR self-measurement. The mean TTR for the entire study population was 69.7 % [34].

Limitations of VKA therapy include a narrow thera-peutic range, need for adjustment of therapy, drug inter-actions as well as interaction with nutritional elements, leading to low TTR values [35].

Direct oral anticoagulants

All the aforementioned limitations of VKA therapy led to the development of DOACs, which selectively act on spe-cific coagulation factors [35].

DabigatranDabigatran, a direct thrombin inhibitor, was introduced for thromboembolic prophylaxis after release of the RELY data in 2009. During a median follow-up period of 4.3 years, compared with VKA, a 35 % risk reduction of stroke and a 60 % risk reduction of intracranial bleeding were detected with the recommended dose of 2 × 150  mg/day [36]. Whereas its ability to lower ischaemic stroke turned out to be superior, incidence of severe bleeding complications is equal when compared with warfarin. Patients aged > 80 years and with high bleeding risk may be treated with 2 × 110  mg/day. With this lower dose of dabigatran, stroke protection is similar, while bleeding risk is reduced compared with warfarin [36, 37].

Within the past years, decisive pharmacological inno-vations took place. Due to equal efficacy and improved safety and comfort, DOACs are gaining more and more importance when compared with vitamin K antagonists. Platelet inhibitors are no longer recommended. If oral anticoagulation is contraindicated or the patient refuses OACs, the combination of ASA and clopidogrel can be given (risk reduction of approximately 20 %) [1, 31].

Vitamin K antagonists

Vitamin K antagonists (VKA) like phenprocoumon and acetocoumarol are used for thromboembolic prophy-laxis since many decades. Through the inhibition of vita-min K-dependent coagulation factors (II, VII, IX, X), as well as protein S and C, thromboembolic risk is reduced by 65 % per year, whereas the bleeding risk is increased two- to fivefold [32]. When compared with acetylsalicylic acid, VKA show a relative risk reduction of 40 %, but no difference concerning bleeding complications [28, 32]. The therapeutic target is defined as an international normalized ratio (INR) of 2–3 and a ‘time in therapeu-tic range’ (TTR) of nearly 70 % in recent guidelines, but whether this goal is realistic in daily practice is a matter of

Table 4 Clinical characteristics comprising the HAS-BLED bleeding risk score [10]

Letter Clinical characteristics Points awarded

H Hypertension 1

A Abnormal renal and liver function (1 point each)

1 or 2

S Stroke 1

B Bleeding tendency or predisposition 1

L Labile international normalized ratios (INRs) (if taking vitamin K antagonists)

1

E Elderly (e.g. age > 65 years, frail condition) 1

D Drugs (concomitant aspirin, non-steroidal anti-inflammatory drugs) or alcohol (1 point each)

1 or 2

Maximum 9 points

Fig. 4 Correlation between risk profile and incidence of AF. Proportion of patients with a given AF pattern (paroxysmal, persistent, long-standing persistent or permanent, plotted as percentage, y axis) in the study population plotted by the num-ber of concomitant cardiovascular diseases and age as sum-marized in the CHA2DS2VASc score (x-axis). The proportion of patients with permanent AF increases in each CHA2DS2VASc stratum, while the proportion of patients with paroxysmal AF decreases [29]

Table 3 Adjusted stroke rate according to CHA2DS2-VASc score [10]

CHA2DS2-VASc

score

Patients

(n = 73,538)

Stroke and thromboembolism event

rate at 1-year follow-up (%)

0 6369 0.78

1 8203 2.01

2 12,771 3.71

3 17,371 5.92

4 13,887 9.27

5 8942 15.26

6 4244 19.74

7 1420 21.50

8 285 22.38

9 46 23.64

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Atrial fibrillation: state of the art 71 3

comparison of the single DOACs, none of them can be favoured.

Atrial appendage occlusion

Due to the fact that the LAA is the most frequent site where thrombus formation occurs, it is possible to occlude it for thromboembolic prophylaxis if oral antico-agulation is contraindicated. Compared with VKA, it was similarly effective in reducing the combined endpoint of stroke, cardiovascular death and systemic embolism in one RCT (PROTECT AF) [42]. An increased event rate might be related to the learning curve and peri-interven-tional complications at the beginning [43].

Rate and rhythm control

The AFFIRM trial first showed that rate control in case of AF is non-inferior to rhythm control regarding mortal-ity. Which kind of treatment strategy should be favoured depends on the patient’s complaints, type and onset of AF. Age and co-morbidities are also important for the choice of treatment strategy. The AFFIRM trial suggested that with increasing age and concomitant heart failure, patients significantly benefit from heart rate control [44].

Heart rate control

Beta-blockers and Ca2+ antagonist (non-dihydropyridine type) are drugs of first choice. A recent work showed an advantage of diltiazem over beta-blockers and verapamil, but further large prospective trials are necessary. In case of underlying heart failure, digoxin and amiodarone are preferred. Patients suffering from bradycardia–tachycar-dia syndrome often require PM backup before lowering heart rate properly [10].

Heart rhythm control

In up to two out of three patients, acute AF terminates spontaneously. In case of severely affected patients, who still are symptomatic after lowering heart rate, pharma-cological or electrical cardioversion (CV) is indicated (Fig. 5).

Pharmacological cardioversionFlecainide and propafenone (Vaughn–Williams clas-sification IC, Na-channel blocker) can be administered orally or intravenously. These drugs are effective for CV in 50–90 % of cases if AF onset recently occurred [10].

Ibutilide, which can only be administered intrave-nously, is often used for CV because of its instant effect. The main disadvantage of ibutilide is the increased risk of torsades de pointes. In any case, patients should be monitored during the first administration, and potas-sium should be within the normal range [10].

Vernakalant, a new antiarrhythmic drug, is only avail-able for intravenous use and indicated within the first 7

RivaroxabanRivaroxaban, a direct factor Xa inhibitor, approved for thromboembolic prophylaxis since 2011, is associated with similar risk reduction of stroke and bleeding com-pared with warfarin, thereby especially lowering the risk of intracerebral and fatal bleeding (ROCKET-AF). In contrast, the risk of gastrointestinal bleeding and bleed-ing requiring transfusion is increased. The approved standard dosage is 1 × 20 mg/day, whereas patients with impaired renal function should be treated with 1 × 15 mg/day (glomerular filtration rate (GFR): 30–49 mg/dl) [38].

ApixabanAnother factor Xa inhibitor, apixaban, has been investi-gated in the ARISTOTLE trial, which documented a sig-nificant decrease in the overall mortality, risk of bleeding and risk of the combined endpoint stroke and systemic embolism. Among all available DOACs, apixaban was the only drug that has shown to be associated with a decrease in the overall mortality. The risk of gastrointestinal bleed-ing was comparable to that with warfarin. Common dos-ages are 2 × 5  mg/day and 2 × 2.5  mg/day (≥ 80 years, ≤ 60 kg, creatinine: ≥ 1.5 mg/dl) [39, 40].

EdoxabanEdoxaban was evaluated in the ENGAGE AF-TIMI 48 trial and is not yet approved. Nevertheless, edoxaban showed not to be inferior concerning prevention of stroke and embolism, while bleeding and incidence of cardiovascu-lar death were significantly lowered [41].

To use DOACs safely and effectively, the EHRA pub-lished practical instructions, pointing out the importance to implement an ‘anticoagulation pass’ [31]. Importantly, renal function has to be evaluated carefully, as all DOACs are partially excreted through the renal system. Accord-ing to the EHRA recommendation, creatinine clearance (CrCl) should be evaluated once per year if renal function is not compromised, every 6 months if CrCl is 30–60 ml/min and in patients older than 75 years or every 3 months if CrCl is lower than 30  ml/min [31]. Due to increased bleeding risk, dose adjustment in case of impaired renal function is necessary. To guarantee adequate thrombo-embolic prophylaxis, drug adherence and patient com-pliance are crucial due to the short half-life of DOACs. This also relates to qualitative and quantitative deter-mination of clotting effect (e.g. maximal plasma level after 3  h, trough level). Non-specific tests for qualita-tive quantification of clotting effect are activated partial thromboplastin time (aPTT) (dabigatran) and throm-bin time (factor Xa inhibitors). Currently, a quantitative coagulation test, called ‘diluted thrombin time’ (dTT), is only available for dabigatran (Haemoclot®) [31]. Finally, specific antidotes in case of bleeding complications are under development [1].

In summary, DOACs offer an improved or at least similar efficacy and comfort compared with VKA and are associated with enhanced safety concerning severe or even lethal intracerebral bleeding. Due to different demographic patient characteristics and lack of direct

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8 Atrial fibrillation: state of the art 1 3

cient, trans-oesophageal echocardiography (TEE) has to be performed to rule out atrial thrombi. After successful CV, oral anticoagulation has to be maintained for at least 4 weeks, as the thromboembolic risk is increased due to CV-associated left atrial dysfunction within this time period. In haemodynamically unstable patients, electri-cal CV should be performed after the administration of unfractionated heparin or low-molecular-weight hepa-rin. Usually overlapping OAC is started additionally after CV. To avoid a delay of 3 weeks’ adjustment of OAC, TEE has to be performed prior to immediate CV and preced-ing heparin application. After successful CV, establish-ment of OAC is necessary for at least 4 weeks (class Ib recommendation) [1, 10].

Pill in the pocketIn case of highly symptomatic patients, suffering from paroxysmal AF and prolonged asymptomatic inter-vals, flecainide and propafenone can be taken orally on demand. The first administration should be performed during ECG monitoring [47].

Pharmacological relapse prophylaxisIn patients without underlying structural heart disease, propafenone, flecainide, sotalol and dronedarone may

days of AF onset and within 3 days after aortocoronary bypass grafting (CABG). The most important benefit is a rapid effect after 8–14 min and selective action in the atria [45]. Vernakalant is contraindicated in case of arte-rial hypotension, acute coronary syndrome within the past 30 days, heart failure NYHA III–IV, QT prolongation and aortic valve stenosis [1, 45, 46].

In patients without structural heart disease, there is a class Ia indication for all the previously mentioned sub-stances. Amiodarone is not recommended as the first-line strategy because of its delayed onset of action. In case of advanced heart failure and haemodynamic insta-bility, however, it is the preferred drug [1, 10].

Electrical cardioversionThe electrical CV is a synchronized, R-wave-triggered application of direct current via two thoracic electrodes under short anaesthesia. It is especially indicated in hae-modynamically unstable patients, acute cardiac failure and in case of contraindication for antiarrhythmic ther-apy [10]. Whether a concomitant pharmacological ther-apy is helpful is poorly documented by study data.

Before CV, adequate oral anticoagulation (OAC) is necessary for at least 3 weeks. If AF onset lies in between 48 h and 7 days, but oral anticoagulation was not suffi-

Fig. 5 Indications for electrical and pharmacological cardioversion and choice of antiarrhythmic drugs for pharmacological car-dioversion in patients with recent-onset AF [1]

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Atrial fibrillation: state of the art 91 3

can be achieved without PVI. The longer the AF persists, the more rotors can be detected. If AF persists for not more than 6 months, the success rate is correspondingly higher. In general, 40–60 % of the patients are AF free after the first ablation, independent of the concomitant phar-macological therapy [51].

The most frequent reason for recurrence of paroxys-mal AF after PVI is the reconnection of one or more pul-monary veins. After a second intervention, more than 80 % of patients are free of AF after 1 year. Whether con-tact force measured at catheter tip influences outcome after ablation is the subject of current research [56−58].

A recent evaluation of > 93,000 investigations in USA between 2000 and 2010 revealed an in-hospital compli-cation rate of 6.29 %, showing cardiac reasons to be the most important (2.54 %). Furthermore, vascular (1.53 %), respiratory (1.3 %) and neurologic complications were found. Intrahospital mortality was 0.46 %.

In a selected patient group without underlying struc-tural cardiac disease, ablation can be chosen as the first-line strategy (class IIa, level B). There is growing evidence that these interventions should be performed without interruption of oral anticoagulation [1, 59].

Surgical therapy

Through a procedure called MAZE intervention, iso-lation lines are cut into the left atrium, separating the atrium into segments not large enough to maintain AF.

be considered for relapse prophylaxis. If patients suffer from coronary artery disease, sotalol is indicated, or ami-odarone in case of heart failure [1, 10]. However, despite treatment with antiarrhythmic drugs, recurrence rate after successful CV still accounts for 65 % per year. On the one hand, special care has to be taken in patients treated with sotalol, as it may cause QT prolongation (especially in female and those with impaired renal function) [48]. On the other hand, amiodarone is associated with sev-eral side effects affecting the thyroid gland, lung, liver, skin, and peripheral nerves [1, 10]. After the promising data of the registration trial ATHENA, the results of the PALLAS study restricted the broad application of drone-darone to prevent AF recurrence. Initiation of therapy is only recommended in patients with SR and contraindi-cated at NYHA classification II or higher [49, 50].

Catheter ablation

High radio-frequency catheter ablation is still a young, but rapidly increasing, treatment modality to obtain SR in a selective patient population. In patients suffering from paroxysmal AF, pulmonary vein isolation (PVI; high frequency, cryo or laser) is the method of choice [51]. Conversely, persistent AF is recently treated with specific mapping methods (‘focal impulse and rotor modulation’, FIRM) to detect and ablate the so-called rotors (focal impulse formations, Fig. 6) [52−55]. Recent data showed that in these cases, long-lasting recurrence-free intervals

Fig. 6 Focal rotor formation  [53]

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10 Atrial fibrillation: state of the art 1 3

ing risk (2.6–4.6 %). In contrast, bleeding risk rises up to 7.4–10.3 % after 12 months. The WOEST trial showed that dual therapy with clopidogrel and VKA, when compared with the triple therapy, is associated with a significant decrease in bleeding risk, without increasing thrombo-embolic risk [63]. A European registry study including 12,165 patients documented a significant reduction of overall mortality using this dual regimen (Fig.  7). More prospective trials are necessary to justify a dual therapy from the beginning. Comparable data for DOACs are still lacking.

In patients at high bleeding risk, bare metal stent may be preferred to a drug-eluting stent to avoid the need for prolonged triple therapy. Furthermore, triple therapy should be switched to a clopidogrel-based dual regime after 4 weeks [65]. Patients with stable coronary artery

Although long-term success rates as high as 96 % have been reported, the procedure requires open heart sur-gery and is therefore only justified in selected cases, mostly as concomitant procedure to bypass surgery [60]. A modified MAZE procedure within mitral valve surgery (intraoperative high-frequency ablation) is performed more often [61, 62].

Frequently asked questions

Triple therapy

In patients with AF and previous stent implantation, triple therapy with ASS, clopidogrel and VKA is recom-mended, if short as possible, due to acceptable bleed-

Fig. 7 Overall mortality: triple therapy vs. dual regimen. Significant reduction of the overall mortality using dual regimen (OAC + clopidogrel) [64]

Fig. 8 Preoperative DOAC management  [31]

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Atrial fibrillation: state of the art 111 3

3. Healey JS, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012;366:120–9.

4. Benjamin EJ, et al. Independent risk factors for atrial fibril-lation in a population-based cohort. The Framingham Heart Study. JAMA. 1994;271:840–4.

5. Stewart S, Hart CL, Hole DJ, McMurray JJV. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med. 2002;113:359–64.

6. Hohnloser SH, et al. ASymptomatic atrial fibrillation and Stroke Evaluation in pacemaker patients and the atrial fibrillation Reduction atrial pacing Trial (ASSERT). Am Heart J. 2006;152:442–7.

7. Fuster V, et al. ACC/AHA/ESC 2006 guidelines for the man-agement of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Associa-tion Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 guidelines for the management of patients with atrial fibrillation) devel-oped in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace. 2006;8:651–745.

8. Cappato R, et al. Updated worldwide survey on the meth-ods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol. 2010;3;32–8.

9. Haïssaguerre M, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659–66.

10. European Heart Rhythm Association, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace. 2010;12:1360–420.

11. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysi-ological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev. 2011;91:265–325.

12. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chron-ically instrumented goats. Circulation. 1995;92:1954–68.

13. Chamberlain AM, et al. Smoking and incidence of atrial fibrillation: results from the Atherosclerosis Risk in Com-munities (ARIC) study. Heart Rhythm. 2011;8:1160–6.

14. Kodama S, et al. Alcohol consumption and risk of atrial fibrillation: a meta-analysis. J Am Coll Cardiol. 2011;57:427–36.

15. Kaireviciute D, et al. Intracardiac expression of mark-ers of endothelial damage/dysfunction, inflammation, thrombosis, and tissue remodeling, and the development of postoperative atrial fibrillation. J Thromb Haemost. 2011;9:2345–52.

16. Stevenson IH, et al. Atrial electrophysiology is altered by acute hypercapnia but not hypoxemia: implications for promotion of atrial fibrillation in pulmonary disease and sleep apnea. Heart Rhythm. 2010;7:1263–70.

17. Guasch E, et al. Atrial fibrillation promotion by endurance exercise: demonstration and mechanistic exploration in an animal model. J Am Coll Cardiol. 2013;62:68–77.

18. Hobbs FDR, et al. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study. Health Technol Assess. 2005;9:iii–iv, ix–x, 1–74.

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disease and without intervention should receive VKA only, as it is non-inferior compared with ASA concerning secondary prevention of cardiovascular disease [1]. Due to missing data for triple therapy with DOACs, conver-sion from DOACS to VKA is recommended.

Electrical cardioversion and DOACs

Data from the RE-LY study showed that electrical CV is safe after 3 weeks of oral anticoagulation with dabiga-tran and subsequent continuation of therapy for 4 weeks, compared with previous TEE [66]. The prerequisite is an adequate patient compliance. Data for rivaroxaban und apixaban are currently lacking [1]. A post hoc analysis of the ROCKET-AF trial showed that rivaroxaban is com-parable with warfarin concerning long-time stroke risk and mortality after CV. However, hospitalization rate was increased with rivaroxaban [67].

Preoperative management

Although preoperative bridging with low molecular weight heparin (LMWH) is not necessary in most cases, the thromboembolic risk has to be weighed against the bleeding risk. As soon as definite haemostasis has been reached, OAC can be started [1]. Effective anticoagu-lation is achieved soon afterwards. Weltermann et al. recently published Austrian guidelines for the preopera-tive management with dabigatran treatment. According to these guidelines, cessation of OAC is not necessary prior to dental extraction, whereas treatment should be withheld on the day before elective coronary angi-ography and not started before 4  h afterwards. Prior to surgery with increased bleeding risk, oral anticoagula-tion with dabigatran should be stopped 1–3 days before, dependent on renal function, and started 3 days after-wards. If the preoperative pause takes longer than 1 day and CHA2

DS2-VASc score accounts for ≥ 2, bridging with

LMWH is necessary [68].A comparable guide for the preoperative DOAC man-

agement has been defined by the EHRA (Fig. 8).

Conflict of interestWe declare that there is no financial relationship between us and any organization, no conflict of interest.

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