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Europace. Jan 2012; 14(1): 8–27.
Published online Jul 26, 2011. doi:  10.1093/europace/eur241
PMCID: PMC3236658

Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options—a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference

Abstract

While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF.

Keywords: atrial fibrillation, management, outcomes, antithrombotic therapy, rate control, rhythm control, risk factors, early therapy

Introduction

Atrial fibrillation (AF) is one of the major common and chronic disorders in modern cardiology. Due to its loss of heart rate control, diminished atrial contraction, and especially its propensity to thrombogenesis, AF can cause ischaemic stroke and systemic thromboembolism, heart failure, impaired quality of life, and frequent prolonged hospitalizations. Furthermore, mortality rates are doubled in patients with AF, with acute coronary syndromes and other vascular complications being frequent. Despite recent advances in AF therapy, including the broader use of anticoagulant therapy, adequate rate control, and newer, safer techniques to maintain sinus rhythm, which may prospectively help to prevent adverse outcomes in AF patients, mortality and morbidity in AF patients remains unacceptably high.

To discuss and propose the next steps and the perspectives to improve AF management, the German Atrial Fibrillation Competence NETwork (AFNET, www.kompetenznetz-vorhofflimmern.de) and the European Heart Rhythm Association (EHRA, www.escardio.org/ehra) convened over 60 experts from university and industry settings for the 3rd AFNET/EHRA consensus conference on AF (for reference to the 1st and 2nd conference, see Kirchhof et al.1,2). The conference was held in the European Heart House, the headquarters of the European Society of Cardiology (ESC) in Sophia Antipolis from 7 to 9 November 2010, shortly after the release of the new ESC guidelines on AF.3

The participants of this conference discussed several aspects of AF management. For this report, these were grouped into four main sections:

  1. risk factors and risk markers for AF,
  2. pathophysiological classification of AF,
  3. relevance of monitored AF duration for AF-related outcomes,
  4. perspectives and needs for implementing better antithrombotic therapy.

Risk factors and markers for atrial fibrillation

The past few decades have seen an immense effort to reduce the population-wide impact of atherosclerosis and cardiovascular disease, e.g. 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.

Many risk factors contribute to AF—presumably with some additive or cumulative effects that increase the individual risk of developing AF, although many interrelated interactions are likely.4 Arterial hypertension and congestive heart failure, including heart failure with impaired or preserved left ventricular systolic function,58 as well as myocardial infarction, valvular heart disease and diabetes mellitus, all contribute to development of AF.9 These risk factors are well established and validated for AF, and as such, identification of these risk factors requires early intervention and appropriate treatment to prevent disease progression. Preventing these risk factors may also reduce the risk of developing AF.2,10 On the other hand, there are emerging risk factors for AF that have received much less attention and may provide additional leverage to decrease the incidence of AF, which is emerging as the new epidemic.

What increases the risk for incident atrial fibrillation?

Table 1 gives a list of risk factors for incident AF. These are split into ‘established’ and ‘emerging’ risk factors. Among the established risk factors, the best validated risk factors that lead to the development of AF include age, hypertension, diabetes mellitus, and heart failure.

Table 1
Factors for incident atrial fibrillation, progression atrial fibrillationa, and associated events

Age is one of the key risk factors for AF.9,12,59,70,71 Depending on the type of study, duration of follow-up and age at start of follow-up, hazard ratios range between 1.1 and 5.9 per decade of age. Age-related fibrosis,72 intracellular age-related changes, or accumulation of accompanying disorders that occur with increasing frequency with older age may explain this association. On the contrary, if AF occurs at young age, genetic factors play a major role (heritable AF, see below).

Another important and well-established factor is hypertension. Indeed, the higher the blood pressure, the greater the risk of incident AF.19,23,24 Interestingly, a systolic blood pressure as low as 130 mmHg and a high pulse pressure amplitude may also increase the risk of AF.23 This may imply that pre-clinical hypertension may commonly underlie AF, and suggests that tighter blood pressure control may be prudent in our efforts to prevent AF. On the other hand, the association between blood pressure and AF may be J-shaped, as has been proposed for other cardiovascular events.24 Lower blood pressures were associated with an increased risk for AF, possibly, in part, due to severe illness like sepsis or end-stage heart failure.

Other factors such as heart failure are less well defined or used in a broad sense.9,12,59,70,73 Also included are patients with heart failure and preserved left ventricular function6,8 and patients with coronary artery disease, the latter mainly when they present with left ventricular dysfunction.8,15,16,18,19 The underlying pathophysiological link and the common pathway for hypertension or heart failure to lead to AF is atrial pressure and/or volume overload as well as diastolic ventricular dysfunction8,9,11,12,33,37,70 which may lead to atrial dilatation, fibrosis, and electrical remodelling that finally provides the stimulus and the substrate for the development of AF.

In a similar way, valvular heart disease leads to pressure and/or volume overload of the atria, especially the left atrium in left-sided disease, and has been associated with the development of AF.9,12,70

Male gender has often been associated with incident AF.9,11,1518,20,59 Notably, few females have been included in trials but some data suggest that females are older and suffer from more concomitant cardiovascular disease when included.74 This contrasts with the consistent observation that female gender is a risk factor for stroke in patients with established AF.75,76 These contrasting associations are difficult to explain: Whether male gender pre-disposes to AF, whether AF is more often symptomatic and hence earlier diagnosed in males, or whether males accrue more (possibly less well validated) risk factors for AF, or whether females are less likely to seek medical attention when suffering from AF can only be answered by additional epidemiological data. Despite a higher burden of risk factors, blacks appear to be at less risk of developing AF.

Metabolic factors such as diabetes mellitus and hyperthyroidism have been recognized as independent risk factors for AF.8,9,11,1820,37,70,77 More recently, the metabolic syndrome has been recognized as a less well-established risk factor, although this term may also describe the summation of several risk factors.35 However, even in this setting, whether some modifying genetic factors account for the genesis of AF in individual cases, is unknown.

Less well-established risk factors for incident atrial fibrillation

There is a range of less well-established risk factors that are associated with incident AF or with AF-related complications such as stroke, heart failure, or death. Deciphering the functional consequences of genetic changes associated with AF in the population78,79 and epigenetic analyses can teach us more about risk factors for AF.80 Identifying genetic ‘biomarkers’ that promote the development of subclinical disease might open new pathways for risk stratification and prevention of AF (see below).

Traditionally, subclinical hyperthyroidism [normal peripheral thyroid hormone levels but suppressed thyroid stimulating hormone (TSH)] has been considered as a modifying factor for the development of AF, but recent data suggest that even in a pre-subclinical setting (a newly defined term in this context), the incidence of AF is increased, i.e. when TSH remains in the lower level of normal or T4 increases within the normal range.20,4042

Obesity has recently been revisited as a less well-validated risk factor for the development of AF in population-based studies15,16,18,19,21,3034 (Table 1). High body mass index also associates with increased left atrial volume.81 One study suggests that high birth weight already associates with AF in women >45 years of age.67 Increased epicardial fat also has been associated with increased AF persistence independent of other risk factors.82,83 Tall stature also increases the risk of developing AF.22,37

Newer markers of increased risk for AF include the sleep apnea syndrome which appears to be associated with obesity.16 In addition, chronic obstructive pulmonary disease14 has been associated with progression of AF to more permanent forms. Chronic kidney disease also appears to be a valid marker of increased risk for AF.45,48

Environmental factors such as excessive alcohol consumption,22,43,44 possibly also moderate alcohol consumption84 and smoking9,11,21 are well-established risk markers for AF. Recent data confirm the deleterious effects of smoking on incident AF in contemporary cohorts.15,19,22,85 Many of these factors are components of the so-called metabolic syndrome, and may share biological causes and AF-related effects.

While moderate exercise may protect against AF and can clearly help to reduce metabolic risk factors for AF, high-level endurance training is associated with an increased risk of AF in athletes,52,8688 possibly associated with training-related hypertrophy, diastolic dysfunction, atrial dilatation, and fibrosis as has been demonstrated in trained rats.89

Biomarkers for atrial fibrillation

Analysis of patient serum, assessment of cardiac size and function by imaging including electrocardiogaphy, and genetic analyses all provide biomarkers that may be helpful to refine assessment of AF risk. Although validation in large patient sets is pending, it is conceivable that serum biomarkers may help to assess AF risk.

Natriuretic peptides are emerging as new serum risk factors. In a population-based sample of middle-aged people, these biomarkers had incremental value for the prediction of incident AF.58,64,9093 Notably, atrial natriuretic peptide (ANP) might be a better predictor for AF than brain natriuretic peptide (BNP),59 although other studies have shown the opposite.61 Preliminary data suggest that higher levels of natriuretic peptides (and of C-reactive protein, see below) may also increase the risk for stroke in AF patients.

C-reactive protein and interleukin-6

Analysis of myocardial biopsies demonstrates infiltration by inflammatory cells in patients with AF.47,62,94 Likewise, (high-sensitivity) C-reactive protein or interleukin-617,47,59,95,96 is associated with AF. Overall, the association of serum biomarkers with AF is not uniformly found.17,65,90

Echocardiographic estimators of left atrial size may provide an ‘integral’ of the degree of left atrial structural changes over time, and thereby relate to incident AF or to AF-related complications, including death.97,98 Left atrial size or volume and left ventricular mass may predict AF, and left atrial volume even relates to death.13,99,100 In addition, abnormal ventricular relaxation and diastolic dysfunction were predictors of first diagnosed non-valvular AF among elderly men and women,8 and large size and anatomy of the atrial appendages may also relate to AF and its complications.101,102

Detailed imaging of atrial function

Left atrial size and volumes can be assessed routinely with M-mode echocardiography. 2D echocardiography is more precise, but also more operator-dependent.103 Three-dimensional imaging techniques (echocardiography, computed tomography, and cardiac magnetic resonance imaging) provide the most accurate information on the exact atrial size, shape, and volume.104,105 From 3D echocardiography and cardiac magnetic resonance imaging,106 the total atrial emptying fraction, active atrial emptying fraction (active contraction), passive atrial emptying fraction (conduit function), and atrial expansion index (reservoir function) can be assessed.107,108 Moreover, the left atrial velocities and active deformation (strain) can also be assessed with sophisticated echocardiography,109 and left atrial synchronicity can also be derived.110,111 Despite the availability of these modalities, there is still a lack of data showing correlations between such parameters and incident AF as well as of complications of AF. In addition, whether improvements of these parameters are associated with better outcome needs to be assessed. Transoesophageal echocardiography may furthermore provide information on stroke risk beyond traditional stroke risk factors.112

Visualizing atrial scars and fibrosis

Another important measurement is the detection of left atrial fibrosis and scar tissue as assessed by delayed-enhanced magnetic resonance imaging. The technique is relatively sensitive and specific for transmural radio frequency-induced lesions.113,114 The extent of scar tissue and fibrosis on 3D delayed-enhanced magnetic resonance imaging is inversely related to left atrial performance measured by echocardiographic left atrial strain and strain rate,115 and large areas of delayed enhancement in the left atrium may predict recurrent AF after catheter ablation.113 Hyper-enhancement of the left atrial wall was observed after ablation, representing scar tissue, and the extent of scar tissue 3 months after the ablation was related to freedom of AF after ablation.116118 Technicalities of magnetic resonance-based imaging of atrial fibrosis and scar render reproducibility of these findings challenging, and visualization of scars is likely limited to transmural lesions.

ECG-based parameters

ECG-based parameters such as long (within the normal range) or prolonged PR interval clearly relate to AF in the population,15,119 possibly related to atrial structural remodelling and delayed intra-atrial conduction.15,19,57 Similarly, longer P wave duration also associates with the risk for developing AF.120122

Depressed heart rate variability may pre-dispose survivors of a myocardial infarction to AF.123 Furthermore, the observation of an episode of AF after cardiac surgery may identify patients at high subsequent risk of developing AF. Similar to the serum biomarkers discussed above, electrocardiogram (ECG) changes may be proxies or ‘integrators’ of other risk factors, e.g. prolongation of PR interval may be a sign of sodium channelopathies (see ‘genetic factors’), but may also reflect damage to atrial conduction.

Genetic factors

Genetic factors are associated with AF, especially of pre-mature onset of AF. In a small number of patients (~5% of AF patients, more in patients with early onset-AF), mutations associated with genetically conferred cardiomyopathies can be identified such as long QT syndrome,124129 Brugada syndrome,130 short QT syndrome,128,131 atrial septal defects,132 or hypertophic cardiomyopathy.133135 Some of these patients carry a familial predisposition to AF (25,26,131,136; see overview in Kirchhof et al.2). On the population level, several single nucleotide polymorphisms (SNPs) close to the PITX2 gene located on chromosome 4q25 strongly associate with AF,28,137 especially with early-onset AF.138 Other, weaker associations are found on chromosome 1q2527 and on chromosome 16.29 Association of other polymorphisms with AF, found in smaller cohorts, could often not be replicated, indicating the risk of overreporting of ‘false positive’ results.139 The molecular mechanisms conferring AF in such a setting have recently been investigated in genetically modified models for long QT syndrome140 and in models with reduced PITX2 expression.78,79

Open questions

Distinction between risk factors and risk markers

AF risk factors are clinically measurable indicators of a biological process that relates to AF, while risk markers are proxies to an AF-causing process, but do not contribute by themselves to the biology of AF. A clear separation between risk markers and risk factors is not always possible since not all biological causes of AF are well understood (Table 1). Moreover, it is not well understood how these risk factors and risk markers interact, i.e. aggravate or mask each other, and whether there are special subgroups where risk factors have a different meaning. Future research will hopefully give us more insight into risk factors and markers that predispose to AF and its associated complications.

Role of biomarkers

With the notable exception of the Framingham cohort study and population-wide genomic analyses, most reports on serum, imaging-based, or genetic biomarkers have been done in small patient cohorts and require validation in other patient series that allow sufficient control of confounding factors.18,25,26,141 Some of the large antithrombotic trials may provide opportunities to relate AF recurrences and other outcomes to biomarkers.

Are there specific factors for progression of AF?

The vast majority of patients experience AF as a chronically progressive disease that will eventually end up in permanent AF.1,142 The available data suggest that these factors overlap largely with factors that lead to the development of AF (see above). In the German Atrial Fibrillation Network (AFNET) registry, the more of these factors were present, the greater the likelihood that patients had persistent or even permanent AF.143 Likewise, the EuroHeartSurvey investigators recently proposed the ‘HATCH’ score (based on risk factors for AF progression—Heart failure, age, previous transient ischaemic attack or stroke, chronic obstructive pulmonary disease, and hypertension) which identifies patients who will progress from paroxysmal to persistent AF.14 There is a clear and unmet need to identify and characterize factors associated with progression of AF, and the relative contribution of established risk factors for progression, first occurrence, or first recurrence of AF.

In summary, many of the classical clinical parameters used to assess stroke risk are also risk factors for the development of AF. The impact of each risk factor may vary by age: genetic factors, obesity, and endurance sports may be more likely to predict AF in younger patients, while other factors may be more prevalent and relevant in older AF patients. Disease severity (e.g. blood pressure value in hypertension, actual left ventricular function, among others) will be relevant for risk assessment. Many factors are interrelated and their interaction may enhance or even annihilate the impact of the new marker with respect to established markers. The available data on ‘new’ risk factors are often derived from observational studies with technical limitations. Furthermore, there is a complex interaction between risk factors and ‘disease severity’. Several of the newly proposed markers may reflect disease severity, while others such as left atrial size may integrate the total atrial damage. Almost all currently available data sets are based on detection of AF by a simple, short ECG. This does not take into account that risk factors may contribute to perpetuation of AF, also neglects ‘silent’ AF which may be diagnosed by intensified ECG monitoring (see below) and may impact the relevance of several risk factors.1,144,145 There is a clear need to investigate and quantitate the impact of the known risk factors on ‘early AF’ and silent AF and to better characterize their interrelation.

A pathophysiologically oriented classification of atrial fibrillation to guide therapy

Currently, AF is classified by duration (paroxysmal, persistent, long-standing persistent, permanent)3,146 and by the extent of AF-causing symptoms (EHRA score I–IV, or CCS-SAF score 0–IV).3,147 The symptom classification reflects the need for therapeutic interventions, especially rhythm control therapy. In part, the duration of AF gives a simple reflection of the extent of ‘atrial structural damage’, but this is a very indirect assessment at best. A classification of AF types based on the underlying pathophysiology, in contrast, could help to better select therapies for specific AF patients based on the type of underlying cause and/or the degree of atrial damage. Thereby, the guideline-supported recommendation to treat underlying conditions would be substantiated.3,146 Therefore, to better guide therapy, the group proposes a classification of AF types based on the presumed AF-causing mechanisms, the validity of which requires further clinical studies (Table 2).

Table 2
Atrial Fibrillation Competence NETwork/European Heart Rhythm Association classification of atrial fibrillation by aetiology and suggested ‘type-specific’ therapy

Inherited atrial fibrillation

This type of AF is best characterized by AF with familial clustering, often of early onset. Early onset has been defined by a diagnosis of AF before the age of 65 years.138

Monogenic forms

Atrial fibrillation is a common finding in patients with inherited, monogenic cardiomyopathies, and other, infrequent familial forms of AF occur without other signs of heart disease.131,136 Monogenic forms of AF appear to underlie the arrhythmia in ~5% of AF patients.2,3,148 It is conceivable that specific therapy of the underlying cardiomyopathy, including specific antiarrhythmic drugs in patients with ‘electrical cardiomyopathies’, may help to prevent AF in these patients. In families with early-onset AF in the absence of known cardiomyopathies, it may be worth studying the subtle ECG abnormalities such as a slightly prolonged or shortened QT interval, QRS amplitudes within the upper range of normal, or slight changes of the right pre-cordial ST segments.

Polygenic forms

A family history of AF is one of the risk factors for incident AF, outside of clear familial clustering (Table 1). In the past years, several population- and genome-wide association studies have identified small genetic changes [single nucleotide polymorphisms (SNPs)] that are associated with AF. The strongest association with AF and stroke is found on chromosome 4q25,28,138 close to the PITX2 gene (see above). Deletion of pitx2 has recently been implicated in AF genesis in transgenic models.78,79 In addition to these genetic factors, epigenetic modifiers and other modifiers of concomitant conditions may also contribute to ‘polygenic’ AF. There is an overlap between polygenic forms of AF and complex AF. At present, there is no specific therapy for polygenic AF forms, but understanding the pathophysiology associated with these genetic abnormalities may help to develop such therapies in the future.

Focal atrial fibrillation

In the absence of severe cardiac disease, the initial event that conveys AF is often atrial ectopy from the pulmonary veins.149 Many short episodes of AF are a good clinical indicator for this pathophysiology. There is a continuum from atrial ectopy, atrial ‘runs', and short lasting atrial tachycardias to self-terminating AF. It is worth emphasizing that this type of AF should be differentiated from other (longer-lasting) forms of AF. Atrial fibrillation due to one or a few re-entrant drivers will also present with very similar electrical and clinical characteristics.150152 Long-lasting focal AF may lead to multiple wavelet complex AF.

Complex atrial fibrillation

This form of AF identifies the ‘typical’ AF patient, often at advanced age, who is suffering from concomitant cardiovascular diseases (e.g. those listed in Table 1), and who usually has pre-existing left atrial damage and/or enlargement. ‘Complex AF’ is a consequence of several pathophysiological processes, including (but not limited to) AF-induced electrical remodelling, structural changes in the atria, pressure and volume overload secondary to external conditions such as ventricular cardiac dysfunction or arterial hypertension, subtle genetic pre-disposition, and age.148 Within this group of patients, the degree of ‘complexity’ is highly variable between patients. The most direct description of the complexity of AF stems from assessment of the number of fibrillation waves by direct contact mapping.153156 Patients with persistent AF harbour a several fold higher number of fibrillation waves than patients with acute AF. Also, non-invasive assessment of the AF substrate using ECG-based imaging has recently shown large variability in complexity of AF.157 It is worthwhile to study whether non-invasive assessment of the AF substrate is capable to resolve the AF substrate complexity in clinically meaningful ranges.158160

In animal studies, the number of fibrillation waves increased with both shortening of refractoriness as well as accumulation of collagen in the extracellular matrix161,162 resulting in increasing electrical dissociation within the epicardial layer163 and between the epicardial layer and the endocardial bundle network.164 In these studies, the number of fibrillation waves inversely correlated with the ability of antiarrhythmic drugs to cardiovert AF, suggesting that complexity might serve as a relevant predictor for successful rhythm control. It appears reasonable to assume that less complex forms of AF respond better to rhythm control therapy, but this has not been tested yet. In cases with a higher degree of complexity, more extended ablation procedures might be required and antiarrhythmic drugs might be less effective. Such a graded therapy2 might help to identify the best treatment option for an individual patient, to enhance the success rate of pharmacological cardioversion or catheter ablation therapy, to avoid unnecessary complications due to inadequate rhythm control therapy, and finally to reduce AF-related health care costs. In cases of very high substrate complexity, one may refrain from any attempt of rhythm control therapy. This concept requires testing in controlled clinical trials, e.g. by assessing AF complexity at baseline.

Post-operative atrial fibrillation

Post-operative AF is an intriguing subform of AF. One in five to one in three patients undergoing cardiac surgery suffer from post-operative AF. Many transient factors contribute to the occurrence of post-operative AF. Such patients undergo severe changes in fluid, electrolyte, and haemodynamic status, suffer from a systemic inflammatory reaction, enhanced sympathetic tone,93,165168 and surgical trauma to the atria.169 Manifestation of AF post-surgery may also indicate the existence of a pre-disposing substrate possibly due to the underlying structural heart disease,155 and hence AF often recurs months to years after an episode of post-operative AF. As enhanced sympathetic tone and inflammation are the most relevant factors pre-disposing to post-operative AF, beta-blockers and anti-inflammatory compounds can be effective in its prevention. In any case, the transient nature of AF has to be considered in the decision making process (e.g. transient use of antiarrhythmic drugs or anticoagulation therapy).

‘Silent’ atrial fibrillation and the significance of atrial fibrillation detected by long-term monitoring devices

Atrial fibrillation is a chronically progressive disease1,170 that will eventually be picked up by palpating the pulse, followed by an ECG to establish diagnosis.3 Indeed, prolonged monitoring, usually by prolonged Holter ECG recordings for 7 days, may detect AF in 1 in 20 or even 1 in 10 patients admitted with acute stroke and being in sinus rhythm at the time of admission.171173 Unfortunately, many patients with AF are only diagnosed after the first complication of the arrhythmia, often an ischaemic stroke, substantiating the need for early detection and therapy of AF.2,3,10,174 Recent advances in long-term ECG monitoring such as prolonged use of Holter ECG devices for up to 30 days or telemetric ECG surveillance in hospitals have already extended the possibilities of detecting ‘silent’ AF. The need for more accurate and extended diagnostic periods may also be met by implanted devices which could theoretically provide continuous information on atrial rhythm, or by long-term external recording devices.170,175,176

Whether short atrial high-rate episodes (AHRE) recorded by an implanted device from an intracardiac lead have the same clinical implications and prognostic impact in patients without ECG-documented AF as AF documented by ECG is not clear. This open questions has two aspects: (i) the need for more data on the validity and reliability of implanted subcutaneous monitors to detect ‘true’ AF and (ii) the clinical need to demonstrate that such ‘silent’ AF episodes have the same prognostic impact as AF detected by conventional methods. These open questions notwithstanding, the available data suggest that these patients are at increased risk for stroke and also put forward the concept that patients who spend more time in AF are at higher risk for complications than patients who spend less time in AF.144,145,175,177179

The conundrum of atrial fibrillation burden

The term ‘AF burden’ has been proposed as the total amount of time spent in AF per monitored time period. It should be considered that AF burden represents a heterogeneous entity; for example, many short episodes of AHRE could result in the same AF burden as a single long-standing episode, and may have different biological effect on atrial electrical and contractile function, and on remodelling and coagulation processes.

Mainly driven by the technical accuracy of AF detection, a duration of >5–6 min has been associated with stroke and death.145,175,177 Other analyses also suggest that longer times spent in AF are associated with slightly higher stroke risk, and that this increased risk is independent of classical stroke risk factors.175,177,178,180 There is a clear need to unify the definitions of AHRE across device manufacturers, and to investigate the impact of short AHRE episodes (<5 min duration) on outcomes and stroke risk estimation. It may be speculated that prevention of AF could help to reduce residual strokes in patients with AF on anticoagulant therapy.174,181 This will be tested in the EAST (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) trial (ISRCTN04708680).

Implantable subcutaneous devices can provide continuous cardiac rhythm monitoring in patients that do not require pacemakers or defibrillators.182 The diagnostic accuracy of subcutaneous ECG monitors is good, but implanted monitors may not detect all episodes of AF picked up by conventional, manually analysed Holter ECG.183 For a balanced approach to patients with AHRE detected by implanted devices, the group proposes a stepwise procedure to document AHRE (Figure 1). To establish the diagnosis from intracardiac recordings or implanted devices, criteria may differ from established criteria to diagnose AF in the surface ECG.3 A uniform (company-independent) standard for the definition of AHRE by subcutaneous and intracardiac devices is clearly needed for the clinical evaluation and implementation of detecting silent AF by such devices.

Figure 1
Approach to patients with atrial high-rate episodes  detected by implanted devices. AHRE, atrial high rate episode.

Improving stroke prevention by antithrombotic therapy

Oral anticoagulation clearly prevents ischaemic strokes in AF patients3 and most patients with AF are likely to benefit from anticoagulant therapy.3,184186 In general, AF patients at risk of stroke can be identified by validated stroke risk factors, and recent guidelines reflect a paradigm shift in recommending an approach in which anticoagulation is a default antithrombotic therapy in AF patients.3,146,184,187 But this effective and potentially life-saving therapy comes at the price of inducing relatively infrequent but potentially severe bleeding events. Numerically, events that are counted as major bleeds in large trials occur in similar frequency compared to ischaemic strokes. In some of the recent trials, bleeding events even outnumber strokes. The majority of these bleeding events, however, have less clinical impact than ischaemic strokes: major bleeding events include clinically relevant and less significant events ranging from the rare but severe intracranial haemorrhage to less relevant smaller gastrointestinal bleeds.184,186189 However, it is important to remember that ischaemic strokes that can be prevented by anticoagulant therapy outnumber intracerebral haemorrhages in most AF patients.189191

Furthermore, the likely introduction of newer, potentially safer antithrombotic agents into clinical practice may influence decisions for anticoagulant therapy, at least according to decision models.192

Detecting an increased risk for intracranial bleeds

The available data suggest that patients—in contrast to their treating physicians—are often willing to accept excess bleeds if this helps to prevent ischaemic strokes.193 Nonetheless, challenges remain in stroke risk assessment, especially in patients at increased risk for bleeding. Unfortunately for the decision models, most bleeding risk factors overlap with stroke risk factors.194196 Nonetheless, variable international normalized ratio (INR) values, excess consumption of alcohol or drugs, enzymatically detected liver damage and renal dysfunction,194,195 incontinence and gait apraxia, as well as certain genetic factors197 and potentially subclinical lesions (detectable as amyloid angiopathy) on cerebral magnetic resonance imaging198202 may identify patients at high bleeding risk. Furthermore, bleeding events accumulate in the first year after initiation of vitamin K antagonist therapy.203

Whether consideration of such clinical or imaging signals can help to avoid anticoagulant-induced severe bleeds remains to be assessed.

Careful classification of intracranial bleeds

Intracranial bleeds are usually investigated by cerebral imaging (computed tomography and/or magnetic resonance imaging). For the acute management of such events as well as for the interpretation in light of anticoagulant therapy, a careful classification of intracranial bleeds is important. This requires differentiation between parenchymal brain haemorrhage, epidural or subdural haematoma, and subarachnoidal haemorrhage (Figure 2). Haemorrhagic transformation of cerebral ischaemia is not considered as a primary bleeding complication. Combination therapy with acetylsalicylic acid is a major risk factor for intracranial haemorrhage in anticoagulated patients.204,205 Intracranial haemorrhages appear to be less prevalent with dabigatran and also to some extent with rivaroxaban as compared to warfarin.187,190 The reasons for this outcome remain speculative, and potential explanations may include that dabigatran and rivaroxaban do not cross the blood–brain barrier, at least not in pre-clinical studies,206 or the fact that dabigatran or rivaroxaban do not interfere with the formation of TF-VIIa complexes, thereby preserving local haemostatic mechanims.

Figure 2
Cerebral computed tomograms of four types of intracranial bleeding (true intracerebral haemorrhage, subdural haematoma, subarachnoidal haematoma, epidural haematoma).

Information needed for the clinical use of newer anticoagulants

Strokes in AF patients not receiving anticoagulant therapy confer a 30-day mortality of 24%.207 Vitamin K antagonists are widely used throughout Europe and the USA, but their effectiveness is limited by their narrow therapeutic range, drug–food, and drug–drug interactions, and the difficulty to maintain patients in the therapeutic range. This limits utilization of vitamin K antagonists.143,208,209 There is extensive knowledge about vitamin K antagonists in the medical community and anticoagulated patients are familiar with the oral anticoagulation regimen. This knowledge and experience is lacking at present for the newer anticoagulants. Therefore, there is a need to educate physicians, including general physicians,209 and patients about these new compounds, ideally before they are used (Table 3).

Table 3
Patient groups likely to benefit (upper part) or not to benefit (lower part) from therapy with new anticoagulants, including a switch from existing therapy with vitamin K antagonists to one of the newer substances

Physicians will need thorough and balanced information on the therapeutic principles, drug effects, and side effects, management of (bleeding) complications, and appropriate action in the case of overdose. Such information can be communicated with credibility by independent bodies, e.g. professional and patient organizations. Furthermore, physicians will need timely and comprehensive information on drug–drug interactions for each of the new compounds, including interactions with over the counter-medications and drugs that given transiently for other indications (e.g. antibiotics).

Important information on new anticoagulants in comparison to vitamin K antagonists for physicians. This information should be provided by the drug manufacturer

Information on AF and concomitant comorbidities.

Characteristics of the novel anticoagulant (trial data, pharmacokinetics, drug interactions, special precautions):

  • shorter half-life requires attention to adherence;
  • shorter half-life may make periprocedural issues easier, but this has not been formally tested. Attention to haemostasis may help to decide on the time point of operations. For vitamin K antagonists, there are good data for many procedures that continuation of vitamin K antagonist (with keeping the INR in the lower therapeutic range) is better than bridging. When to restart?;
  • drug–drug interactions including cytochrome p450 isoenzymes;210
  • antagonising the drug in emergencies;
  • metabolism and interaction with renal and/or hepatic dysfunction.

Patient preference threshold for stroke and excess bleeding.

Awareness of patient's knowledge and understanding of antithrombotic therapy.

Importance of maintaining drug use.

Monitor renal function in selected patients (recent illness/renal dysfunction).

What to do in special situations (surgery, acute coronary syndromes/stents, accidents).

In patients requiring antiplatelet therapy (specifically dual antiplatelet therapy, e.g. after stenting or acute coronary syndrome), there is no published trial experience available, and guidance is dependent upon case series and cohort data.211,212 The data on combining acetylsalicylic acid with dabigatran (40% of patients in RELY received aspirin at baseline187) also show that a combination of antiplatelet therapy and anticoagulation is associated with more bleeding, with no appreciable impact on efficacy outcomes.213 Recent data suggest that ‘triple therapy'214 may be relatively safe with dabigatran, but the experience even in the large RELY trial is limited.215 Therefore, we suggest to follow the recommendation for combination of antiplatelets and vitamin K antagonists in current guidelines.3,212

Monitoring of anticoagulation with the newer anticoagulants will only be needed in special situations (e.g. a patient suffering a stroke on one of the newer substances or emergency). Direct thrombin inhibitors and factor Xa inhibitors will have an effect on activated partial thromboplastin time (aPTT), while conventional assessment of factor Xa activation will not suffice to detect the anticoagulant effect of these substances. Factor Xa antagonists have a dose-dependent effect on prothrombin time (PT), with a close correlation to plasma concentrations if neoplastin is used for the assay. The readout needs to be in seconds as the INR normalization is only validated for vitamin K antagonists. Dabigatran will increase ecarin clotting time which may be used to monitor the anticoagulant effect.216 Although the new antithrombotics affect aPTT, and a marked elevation of aPTT may relate to bleeding risk, such measures should probably not affect drug dose. Specific calibrators and controls are currently under development for commercialization, or have recently been made available for clinical use. Although repeated blood testing to measure anticoagulant effect has disadvantages, the requirement for repeated blood testing may increase therapy adherence, and adherence may decrease when newer drugs that do not require frequent monitoring are used. Providing anticoagulant therapy without the need for INR monitoring may, on the other hand, free health care resources for a more comprehensive management approach to AF patients.

Renal dysfunction—a risk marker for stroke in a complicated situation

A small but challenging group of patients that is increasing are those with severe renal dysfunction [glomerular filtration rate (GFR)<30 mL/min]. These patients are at high risk for stroke and bleeds,48 and it is likely that renal function will deteriorate over time in most patients with renal dysfunction. It is unlikely that renal dysfunction—unlike other risk factors—would favour bleeds in excess of ischaemic events, but it is difficult to validate as this would require large cohorts with repetitive assessment of renal dysfunction over time, to assess time trends. Hence, it appears reasonable to consider severe renal dysfunction as an additional risk factor for stroke. These patients have been excluded from antithrombotic trials in AF, and they are also at high risk of death, myocardial infarction, cardiovascular events, and bleeding. Based on pharmacokinetic data, the Food and Drug Administration (FDA) approved the use of a lower dose of one of the newer anticoagulants (dabigatran, 75 mg bid) in patients with severe renal dysfunction (GFR 15–30 mL/min), rather than any prospective data from randomised controlled trials per se. Of note, patients who entered the trial had a creatinine clearance of 30 mL/min or more.187 In the typical elderly AF patient with renal dysfunction, renal function can deteriorate over time, and may be associated with increase in bleeding events. This is reminiscent of the high bleeding rate in stroke patients receiving intravenous thrombolysis.217 Even experience with vitamin K antagonists in those with renal dysfunction is limited at present,218 and therefore the choice of oral antithrombotic agents cannot be based on controlled data. The newer anticoagulants have so far only very rarely been evaluated in dialysis patients, and some can be removed by dialysis.216,219

Patient values and preferences in atrial fibrillation management

Patients need information on AF, but the degree and type of information demanded differs between patients. Improvement in AF patient education appears necessary given the comparatively higher willingness of valve patients to receive oral anticoagulants compared to AF patients.193 Public campaigns to palpate your pulse, followed by ECG screening, may be suitable ways to communicate to the general public about AF and its associated risk to relevant populations, e.g. the elderly, or diabetics. Integration of such activities into information programmes is helpful.

The home pages of the Atrial Fibrillation Association (UK www.afa.co.uk), the Stop AF campaign (www.StopAF.org), Anticoagulation Europe (www.anticoagulationeurope.org), the Stroke Association (www.stroke.org.uk), and AFNET (Germany, www.kompetenznetz-vorhofflimmern.de) may provide examples for providing information to AF patients, with links to country-specific information. The advent and commercialization of new anticoagulants generates a need to inform and educate patients better. This is an opportunity for health-care professionals and health-care providers alike to better inform patients about AF and the risk for stroke. Seizing this opportunity could help to achieve earlier and comprehensive management of AF patients.2 In addition to this general need for information on AF and its complications, there is also a specific need for information on the new anticoagulants, which will differ for patients naive to or experienced with vitamin K antagonists. Dedicated AF clinics may be an opportunity to close information gaps for patients.

Questions and answers for patient education on the use of anticoagulants

How do clots form?

What are the different options to prevent clots?

What are the benefits of anticoagulation (in general)?

What are the benefits of the drug that I shall receive?

What are the side effects, in particular, how high is my risk for bleeding during anticoagulant therapy?

Are there other therapeutic options, e.g. other drugs?

Does the drug interact with food or other drugs (e.g. over the counter NSAIDs)?

What happens when I do not take the drug for a day, for a week, for a month (compliance, adherence)?

How do I take the medication?

  • When?
  • Before/during/after food (intake of intact capsule in case of dabigatran)?
  • Can I take the drug with other medication?
  • What to do in case of a missed dose?
  • Explain why the novel anticoagulants do not need monitoring (particularly for vitamin K antagonist-experienced patients).

Keep a list of all drugs that you take with you.

Information on lifestyle changes (contact sports, use of an electric razor, pilot’s licence).

What to do in case of overdose and in case of bleeding (stop medication, local haemostasis, haemodialysis).

The group recommends collaboration between pharmaceutical and medical device companies, ideally co-ordinated by professional and scientific organizations, to establish and produce generic patient education materials. Such a collaboration could end up in a toolkit for physicians that will help to educate patients, but also (e.g. internet-based) industry-independent information to patients. Patient groups will be helpful in the dissemination of this information, especially when they are independent of industry.

Information for payers

In addition to the medical and general need for information, institutions and decision makers will need information on the cost of new anticoagulants. Such information will need to account for the local practice of anticoagulant therapy and the local potential for delivery of the new therapies. Cost estimates should include cost of the drug, direct and indirect cost of oral anticoagulant therapy, safety profile, and ideally result in a cost–benefit analysis over vitamin K antagonists in different European countries. There is also a clear need to generate data on the external validity of trial results during clinical use. The use of the new drugs will require careful analyses of the benefits of the drugs with respect to ‘global’ cost reduction.220 The group recognizes that the pricing of new drugs and the reimbursement frames set up by payers will markedly influence the use of the new drugs, and that all currently available cost-effectiveness estimates are based on assumptions as well as on data.

Interventional stroke prevention in atrial fibrillation patients?

In patients deemed unsuitable for vitamin K antagonist therapy, often on the basis of bleeding risk, transcatheter closure of the left atrial appendage has been evaluated as an alternative for stroke prevention in AF.221 Another possibility is offered by an epicardial suture device that can occlude the left atrial appendage during concomitant open heart surgery. While technically feasible and approved in some countries, this intervention will need to be re-evaluated compared to newer, potentially safer anticoagulants in patients who are considered unsuitable for vitamin K antagonist therapy221: Some of those patients will be eligible for newer anticoagulants, but patients who have suffered from an unexplained intracranial haemorrhage on oral anticoagulation, those who are unlikely to comply with anticoagulation, patients with clear and absolute contraindications for anticoagulant therapy, or patients who have suffered an ischaemic stroke on anticoagulant therapy, may still remain candidates for a left atrial appendage occluder. The group suggests a trial of such a device in patients with established contraindications to oral anticoagulation, possibly involving one of the newer anticoagulants as comparator therapy.

Stroke prevention beyond anticoagulant therapy

Continuous oral anticoagulation is the cornerstone of stroke preventing in AF patients, and relies on adequate delivery of anticoagulant therapy as evidenced by e.g. achieving therapeutic INR values.207,222 But even on optimal anticoagulant therapy in controlled trials, the residual stroke rate in AF patients remains unacceptably high at ~1.5% per year.184,186,187,223,224

Almost all available studies so far have investigated the effect of anticoagulant therapy in patients with established AF, often long-lasting AF. The long-term impact of ‘transient’ AF (e.g. post-operative AF) and of ‘silent’ AF2,3 is much less well studied, although even short episodes of AF detected by devices relate to a stroke risk (see above). Based on this information, it appears unlikely that rhythm control therapy alone can be sufficient to prevent AF-related strokes. Nonetheless, there is a signal of reduced stroke rates by dronedarone in the ATHENA trial.185 Whether this effect was related to preventing AF is not clear. There are two surveys after ablation of AF (n= 750 and 3300 patients) that detected low stroke event rates in patients who discontinued anticoagulation.225 The authors of those studies propose that stopping anticoagulation may be acceptable, but the stroke risk in these populations and follow-up times was not sufficient to accrue adequate stroke numbers, especially when considering the reports on very late recurrences of AF after ablation.226,227

Hence, rhythm control does not appear to suffice to prevent strokes in AF in the absence of oral anticoagulation. On the other hand, rhythm control therapy could well contribute to reduce residual stroke rates in patients on anticoagulation. It is likely that a comprehensive approach to AF management (‘early and comprehensive therapy of AF'2) can help to improve outcomes in patients with AF on top of optimal anticoagulation. This concept of ‘comprehensive rhythm control therapy’ for reducing relevant outcomes in AF patients will be tested in controlled trials in the near future, including the EAST trial (ISRCTN04708680, NCT01288352).

Conflict of interest: P.K. received consulting fees/honoraria from 3M Medica, ASTRAZENECA, Bayer Healthcare, Boehringer, MEDA Pharma, Medtronic, Merck, MSD, Pfizer/BMS, Sanofi, Servier, Siemens, St Jude Medical, TAKEDA, and received travel support from the European Heart Rhythm Association and the European Society of Cardiology. C.B.L. received consulting fees/honoraria from Medtronic, Sanofi, St Jude, Octopus, Biotronic. G.Bo. received travel support from the European Heart Rhythm Association. A.B. received consulting fees/honoraria from Biotronik, Boehringer-Ingelheim, Bristol-Myers Squibb, Medtronic, MSD, Sanofi-Aventis, St Jude Medical. G.Br. received honoraria from Sanofi-Aventis, Boehringer Ingelheim, Boston Scientific, Bayer Health Care, and for advisory boards from Sanofi-Aventis, Boehringer Ingelheim, Boston Scientific, Bayer Health Care, Otsuka Pharma. J.C. received honoraria for speakers’ bureaus from Cardiome, Sanofi Aventis, Menarini, Daiichi, Pfizer, and honoraria for advisory boards from Merck, BMS, Sanofi Aventis, ARYx, Xention, Daiichi, Cardiome, CVT, Menarini (coronary disease), Servier, Novartis, Actelion; expert witness on behalf of Johnson and Johnson at London Arbitration courts against various insurers in the matter of cisapride: Sanofi Aventis at FDA and EMEA/CHMP re Dronedarone and at EMEA re Clopidogrel and Servier at EMEA/CHMP re ivabradine; and for DSMB member from Servier, Novartis, BMS. H.D. received honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from Abbott, AstraZeneca, Bayer Vital, BMS, Boehringer Ingelheim, CoAxia, D-Pharm, Fresenius, GlaxoSmithKline, Janssen Cilag, Knoll, MSD, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Sankyo, Schering-Plough, Servier, Solvay, Thrombogenics, Wyeth, Yamaguchi. D.D. received consulting fees/honoraria from Biotronik, MSD, Sanofi, Boehringer, and travel support from the European Heart Rhythm Association and the European Society of Cardiology. P.D. received consulting fees/honoraria from Bayer Healthcare, Boehringer Ingleheim, Pfizer / BMS, Sanofi, Servier, St Jude Medical, and travel support from the European Heart Rhythm Association and the European Society of Cardiology. S.D. received consulting fees/honoraria from Boehringer. N.E. received consulting fees/honoraria from AstraZeneca, Medtronic. M.E. received consulting fees from Boehringer Ingelheim, ARYx Therapeutics, Pfizer, Sanofi, Bristol Myers Squibb, PORTOLA, Astra Zeneca, Diachi Sanko, Medtronic, Eisai. L.F. received consulting fees/honoraria from Boehringer-Ingelheim, Sanofi-Aventis, Bayer. A.G. received consulting fees/honoraria from Bayer Healthcare, Boehringer, Daiichi-Sankyo, MSD, Sanofi-Aventis. R.H. received consulting fees/honoraria from Lecturing honoraria: Bayer Healthcare, Boehringer Ingelheim, Medtronic, Sanofi-Zentiva Slovakia, Servier. H.H. received consulting fees/honoraria from Bayer, Biotronik, Boehringer, Medtronic, MSD, Sanofi, Siemens. E.H. received consulting fees/honoraria from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, General Electric, Merck, Ortho-McNeil, Portola, Pfizer. S.K. received consulting fees/honoraria from Bayer, Boehringer Ingelheim, Biotronik, Boston Scientific, Medtronic, MSD, Sanofi, Servier, and travel support from the European Heart Rhythm Association and the European Society of Cardiology. L.K. received consulting fees/honoraria from Medtronic Europe, Schiller SS. J.K. received consulting fees/honoraria from Abbott, Astra Zeneca, Biosense Webster, Biotronik, Boehringer Ingelheim, Boston Scientific, GE Healthcare, Hansen Medical, Medtronic, Pfizer, St Jude Medical, SanofiAventis, Siemens Healthcare and travel support from the European Heart Rhythm Association and the European Society of Cardiology. D.L. received consulting fees/honoraria from Bayer Healthcare, BMS Pfizer, Boehringer Ingelheim, Otsuka, Thrombosis Research Institute, and travel support from AstraZeneca and sanofi-aventis. G.L. received consulting fees/honoraria from Bayer, Astellas, Merck, Daiichi, Cardiome, Biotronik, AstraZeneca, Sanofi, BMS/Pfizer, and Boehringer. L.M. received consulting fees/honoraria from Bard; Biosense Webster; Medtronic; Boston Scientific, St Jude Medical; Sanofi Aventis; Biotronik; Sorin Group. M.N. received consulting fees/honoraria from Bayer Healthcare, Boehringer, MSD, and travel support has been provided by the European Heart Rhythm Association and the European Society of Cardiology. M.O. received consulting fees/honoraria from MSD, Lilly, Sanofi Aventis, Biosense Webster, Medtronic, Landesärztekammer Brandenburg, and travel support from the European Heart Rhythm Association and the European Society of Cardiology. U.R. received consulting fees/honoraria from Astra-Zeneca, MEDA Pharma, MSD, Sanofi. U.S. received consulting fees/honoraria from MSD, Astra Zeneca. G.S. received consulting fees/honoraria from Bayer HealthCare, Boehringer, Medtronic, Sanofi, Biotronic, St Jude Medical. L.S. received consulting fees/honoraria from Medtronic, Biotronik, Biosence-Webster, St Jude Medical, Sanofi-Aventis, and travel support from the European Heart Rhythm Association and the European Society of Cardiology. I.C.V.G. received consulting fees/honoraria from Boehringer Ingelheim, Sanofi-Aventis, Medtronic, MSD, and travel support from the European Heart Rhythm Association and the European Society of Cardiology. P.V. received consulting fees/honoraria from Astra Zeneca, Bayer Healthcare, Boehringer Ingelheim, Medtronic Inc., Sanofi Aventis, Servier, Menarini, and travel support from the European Heart Rhythm Association and the European Society of Cardiology. K.W. received consulting fees/honoraria from Biotronik, Medtronik, Merck, Takeda. S.W. received consulting fees/honoraria from Boehringer, St Jude Medical, MSD, Sanofi.

Funding

P.K. received research grants from 3M Medica, Cardiovascular Therapeutics, German Federal  Ministry for Education and Research (BMBF), Fondation LeDucq, German Research Foundation (DFG), European Union (EU), MEDA Pharma, Medtronic, OMRON, Sanofi, St Jude Medical. J.B. received research grants from Biotronik, Medtronic, GE, Lantheus, St Jude, Servier, Boston Scientific, Edwards Lifescience. C.B.L. received research grants from Medtronic, Octopus, Atricure. A.B. received research grants from Biotronik, Boehringer-Ingelheim, Medtronic, MSD, Sanofi-Aventis, St Jude Medical. G.Br. received research grants from 3M, Sanofi-Aventis, St Jude. J.C. received research grants from Daiichi, BMS, and Sanofi for thrombolytic trials, and from Servier for an antiarrhythmic trial. H.D. received research grants from Astra/Zeneca, GSK, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syngis, Talecris. The Department of Neurology at the University Duisburg-Essen received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, NIH, Bertelsmann Foundation and Heinz-Nixdorf Foundation. D.D. received research grants from German Federal Ministry for Education and Research (BMBF), Fondation Leducq, German Research Foundation (DFG), European Union (EU). P.D. received research grants from Boehringer Ingleheim, Medtronic, Sanofi, St Jude Medical. S.D. received research grants from Biotronik andMedtronic. M.E. received grant support from Boehringer Ingelheim, ARYx Therapeutics, PORTOLA, Diachi Sanko. L.F. received research grants from Astra-Zeneca, Boehringer-Ingelheim, Sanofi-Aventis, Bristol-Myers-Squibb. A.G. received research grants from Bayer Healthcare, Daiichi-Sankyo, 3M Medica, German Federal Ministry for Education and Research (BMBF), European Union (EU), Sanofi-Aventis. R.H. received research grants from Biotronik, Medtronic. H.H. received unconditional research grants (through the University of Leuven) from Medtronic, Boston Scientific, Biotronik, St Jude Medical, and Astra Zeneca, research grants for developmental cooperation (through the University of Leuven) from Siemens, and for National Coordinator (through the University of Leuven) from Daiichi-Sankyo, Sanofi, Bayer, Biotronik, Boehringer-Ingelheim. E.H. received research grants from Bristol-Myers Squibb, National Institutes of Health (NIH), Ortho-McNeil. S.K. received research grants from German Federal Ministry for Education and Research (BMBF), Fondation LeDucq, German Resarch Foundation (DFG), National Institutes of Health (NIH). L.K. received research grants from Swiss CTI, Medtronic, Schiller. J.K. received research grants from Biosense Webster, Biotronik, Boston Scientific, CardioFocus, Medtronic, Rhythmia. D.L. received research grants from Bayer Healthcare, National Institute for Health Research (UK). G.L. received research grants from Bayer, Sanofi. L.M. received research grants from Biosense Webster; Medtronic; Boston Scientific; St Jude Medical. M.N. received research grants from German Federal Ministry for Education and Research (BMBF), German Resarch Foundation (DFG), OMRON, Novartis. M.O. received research grants from European Union (EU), German Federal Ministry for Education and Reserarch (BMBF), Zukunftsagentur Brandenburg (ZAB). U.R. received research grants from Cardiome, MSD, Neurosearch, Pfizer, Xention. U.S. received research grants from CTMM (Centre for Molecular and Translational Medicine, The Netherlands), NWO (Dutch Research Organisation), Dutch Heart Foundation, German Federal  Ministry for Education and Research (BMBF), Fondation LeDucq, European Union (EU). G.S. received research grants from Medtronic, St Jude Medical, Biotronic, Boehringer Ingelheim, Bayer Health Care. L.S. received research grants from Polish Ministry of Science and Higher Education, European Union (EU), Biotronik. I.C.V.G. received research grants from Medtronic, Biotronik, Netherlands Heart Foundation (NHS), Interuniversity Cardiology Institute the Netherlands (ICIN), Center for Translational Molecular Medicine (CTMM). P.V. received research grants from Servier, Astra Zeneca, Sanofi Aventis, Medronic Inc., St Jude Medical. K.W. received research grants from Bayer Healthcare, German Federal Ministry for Education and Research (BMBF), ResMed, Sanofi.

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