Skip Navigation


European Heart Journal Advance Access originally published online on September 25, 2007
European Heart Journal 2007 28(22):2803-2817; doi:10.1093/eurheartj/ehm358
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
28/22/2803    most recent
ehm358v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (13)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Kirchhof, P.
Right arrow Articles by Breithardt, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kirchhof, P.
Right arrow Articles by Breithardt, G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Outcome parameters for trials in atrial fibrillation: executive summary

Recommendations from a consensus conference organized by the German Atrial Fibrillation Competence NETwork (AFNET) and the European Heart Rhythm Association (EHRA)

Paulus Kirchhof1,2,*, Angelo Auricchio3, Jeroen Bax4, Harry Crijns5, John Camm6, Hans-Christoph Diener7, Andreas Goette2,8, Gerd Hindricks9, Stefan Hohnloser10, Lukas Kappenberger11, Karl-Heinz Kuck2,12, Gregory Y.H. Lip13, Bertil Olsson14, Thomas Meinertz2,15, Silvia Priori16, Ursula Ravens2,17, Gerhard Steinbeck2,18, Elisabeth Svernhage19, Jan Tijssen20, Alphons Vincent21 and Günter Breithardt1,2

1 Department of Cardiology and Angiology, University Hospital Münster, Albert-Schweitzer-Straße 33, D-48149 Münster, Germany
2 German Atrial Fibrillation competence NETwork (AFNET), Germany
3 Fondazione Cardiocentro Ticino, Lugano, Switzerland
4 University Hospital Leiden, The Netherlands
5 Department of Cardiology, University of Maastricht, The Netherlands
6 British Heart Foundation Professor, St George's University of London, London, UK
7 Department of Neurology, University of Duisburg-Essen, Germany
8 Department of Cardiology, University of Magdeburg, Germany
9 Department of Cardiology, University of Leipzig, Germany
10 Department of Cardiology, University of Frankfurt/Main, Germany
11 Cardio-Met, Geneva, Switzerland
12 Department of Cardiology, General Hospital St Georg, Hamburg, Germany
13 Haemostasis Thrombosis & Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK
14 Department of Cardiology/Clinical Sciences, University Hospital, Lund, Sweden
15 Department of Cardiology, University of Hamburg, Germany
16 University of Pavia, Italy
17 Department of Pharmacology, Technical University Dresden, Germany
18 Department of Cardiology, Ludwigs-Maximilian University of Munich, Germany
19 Astra Zeneca R&D, Mölndal, Sweden
20 Academic Medical Center, Amsterdam, The Netherlands
21 Medtronic, Arnhem, The Netherlands

Received 25 April 2007; revised 16 July 2007; accepted 26 July 2007; online publish-ahead-of-print 25 September 2007.

* Corresponding author. Tel: +49 0251 83 45341; fax: +49 0251 83 45343. E-mail address: kirchhp{at}uni-muenster.de


   Abstract
Top
 Abstract
Introduction
 General considerations
 Assessment of specific outcome...
 Specific design issues in...
 Conclusion
 Funding
 Appendix
 Acknowledgements
 References
 
Atrial fibrillation (AF), the most common atrial arrhythmia, has a complex aetiology and causes relevant morbidity and mortality due to different mechanisms, including but not limited to stroke, heart failure, and tachy- or bradyarrhythmia. Current therapeutic options (rate control, rhythm control, antithrombotic therapy, ‘upstream therapy’) only prevent a part of this burden of disease. Several new treatment modalities are therefore under evaluation in controlled trials. Given the multifold clinical consequences of AF, trials in AF patients should assess the effect of therapy in each of the main outcome domains. This paper describes an expert consensus of required outcome parameters in seven relevant outcome domains, namely death, stroke, symptoms and quality of life, rhythm, left ventricular function, cost, and emerging outcome parameters. In addition to these ‘requirements’ for outcome assessment in AF trials, further, more detailed outcome parameters are described. In addition to a careful selection of a relevant primary outcome parameter, coverage of outcomes in all major domains of AF-related morbidity and mortality is desirable for any clinical trial in AF.

Key Words: Atrial fibrillation • Controlled trial • Outcome parameter • Therapy, treatment • Randomized trial • End-point • Stroke death • Quality of life • Left ventricular function • Catheter ablation • Antiarrhythmic drugs • Cardioversion • Rate control • Rhythm control • Anticoagulation


   Introduction
Top
 Abstract
 Introduction
General considerations
 Assessment of specific outcome...
 Specific design issues in...
 Conclusion
 Funding
 Appendix
 Acknowledgements
 References
 
Atrial fibrillation (AF) affects a relevant, increasing part of the population of the European Union:1 25% of the currently 40-year-olds will develop AF.2,3 AF causes relevant mortality and morbidity.4–7 The clinical syndrome ‘AF’ includes a broad spectrum of pathophysiological processes, ranging from ‘electrical accidents’8,9 to long-term systemic processes.10 Likewise, the clinical consequences of AF are difficult to predict in an individual patient. Death, stroke, or severe limitations of exercise capacity in some patients contrast with frequent asymptomatic AF episodes in others.11–13 Treatment includes antithrombotic medicines,14 control of ventricular rate by drugs or pacemakers,15 rhythm-control interventions,16–18 and the so-called ‘upstream therapy’.19

The limited effectiveness and at times unfavourable side-effect profile of available therapeutic options has resulted in a massive surge of randomized trials in AF in the past two decades (Figure 1). Due to the diverse therapeutic options and desired outcomes, trials that assess different treatment options for AF often use completely different outcome parameters. This makes AF a difficult topic in the context of controlled trials and clinical day-to-day management.


Figure 1
View larger version (8K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Number of randomized trials in atrial fibrillation published in Medline from 1967 to 2006. Dots indicate the mean number of trials per year over a given decade and error bars indicate the standard deviation.

 
To tackle this problem, the German Atrial Fibrillation competence NETwork (AFNET, www.kompetenznetz-vorhofflimmern.de) and the European Heart Rhythm Association (EHRA www.escardio.org/ehra) convened 60 scientists and industry representatives at the European Heart House in Sophia Antipolis, France, for a consensus conference on 22–23 January 2007 to define minimal and reasonable outcome parameters for the assessment of AF in controlled clinical trials. This paper reports the summarized consensus reached during this conference. Seven relevant outcome domains are covered in a hierarchical structure: Death, stroke, symptoms and quality of life, changes in rhythm, left ventricular (LV) function and development of heart failure, health economics, and emerging outcome parameters.

Natural time course of AF, frequency, and timing of complications
AF is often a chronic, progressive arrhythmia. The first detected episode of AF is usually self-terminating or amenable to rhythm control interventions, mostly followed by intervals of sinus rhythm, interrupted by episodes of the arrhythmia (‘paroxysmal AF’). The distribution and duration of AF episodes slowly increases over time, but is rather clustered20,21 than random.22 This biological pattern renders AF burden a cumbersome outcome parameter in terms of statistical power (Figure 2).21,23 The recurrence of persistent AF, in contrast, is a single event and ‘time to recurrence’ is a reasonable outcome since this event often triggers a modification of therapy. After restoration of sinus rhythm, e.g. by cardioversion, persistent AF recurs in 25–50% of all patients in the first month after cardioversion.12,24 Thereafter, AF recurs in ~10% of patients per year (Table 1).


Figure 2
View larger version (11K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2 Time course of atrial fibrillation (AF). Shown is a typical chaotic pattern of time in AF (black) and time in sinus rhythm (grey) over time (X-axis). AF progresses from undiagnosed to first diagnosed, paroxysmal, persistent, and finally to permanent AF. Flashes indicate cardioversions as examples for therapeutic interventions that influence the ‘natural’ time course of the arrhythmia.

 

View this table:
[in this window]
[in a new window]

  		Table 1 Points to consider on the natural time course of atrial fibrillation

 
AF causes a variety of complications, most notably thromboembolic complications and reduced cardiac performance. The frequency of AF-related complications depends on the baseline patient characteristics.25,26 Furthermore, complications vary over time: The risk of severe bleeding appears highest in the first months after initiation of antithrombotic treatment. Death is highest in the first year after the initial manifestation of AF,5,27 and occurs steadily thereafter at 1.6–4.2% per annum in more recent controlled trials.16,22,28 Moreover, complication rates have decreased over the years in AF trials.14


   General considerations
Top
 Abstract
 Introduction
 General considerations
Assessment of specific outcome...
 Specific design issues in...
 Conclusion
 Funding
 Appendix
 Acknowledgements
 References
 
Patient characterization
The inherent risk for recurrent AF and AF-related complications is heavily influenced by patient characteristics. There are published lists of such baseline data by ACC/AHA29 and the society of Thoracic Surgeons.30 The panel suggests to refer to them, especially to the more general ACC/AHA recommendations.29 Table 2 lists a set of required, minimal baseline characteristics for publication of an AF trial.


View this table:
[in this window]
[in a new window]

  		Table 2 Minimal clinical parameters that should be given for baseline characterization of patients in an atrial fibrillation trial

 
Choice of outcome parameters in AF trials
Different AF trials will require different primary outcome parameters, but the complex consequences of AF will require assessment of a variety of outcome domains in every trial (Table 3). Ideally, the primary outcome reflects the efficacy of treatment. Safety concerns about the study treatments should be reflected in the primary safety outcome parameter. Outcome parameters reflecting net benefit should usually be presented as secondary outcome parameters. Generally, objectively measured parameters are preferred (but see section on Symptoms). If outcome measures do not cover all main outcome domains, at times pivotal information may be disguised.


View this table:
[in this window]
[in a new window]

  		Table 3 Examples for primary outcome parameters in prior and ongoing clinical trials in AF

 

   Assessment of specific outcome parameters
Top
 Abstract
 Introduction
 General considerations
 Assessment of specific outcome...
Specific design issues in...
 Conclusion
 Funding
 Appendix
 Acknowledgements
 References
 
Death
AF is associated with increased and premature mortality.4,5 Furthermore, many available treatment modalities, e.g. but not limited to antithrombotic medicines, antiarrhythmic drugs, catheter interventions, or operations, will at times cause death as a serious adverse event (SAE). All deaths therefore need to be measured and reported in any trial of AF on an ‘intention-to-treat’ basis from the time of randomization. There are several causes of death (Table 4). Deaths should be classified according to the mode of death using all available methods, including autopsy, doctors' reports, read-out of ICDs/monitoring devices, or Holter ECG recordings. Death unrelated to AF (e.g. death due to cancer) will dilute the effect of any treatment aimed at reducing AF-related mortality in a controlled trial. This effect will be more prominent in elderly study participants who are prone to die. Mortality should only be part of the primary outcome parameter when the therapy or intervention tested is aimed at reducing mortality and the trial has sufficient statistical power and sufficient follow-up time to detect an effect on mortality. This will only be possible in large trials that enrol patients at relatively high risk for death who are followed for a sufficient time. In short-term studies, studies in patients at low risk of death, and in studies in which the intervention will not affect mortality to a relevant extent, death is not a reasonable primary outcome parameter. Death should always be assessed as a secondary outcome parameter in such trials. Generally, death from unrelated causes should not be included in the primary outcome parameter unless the study is adequately designed to detect an effect of therapy on total death. However, all deaths should be reported as a safety outcome parameter.


View this table:
[in this window]
[in a new window]

  		Table 4 Classification of deaths in atrial fibrillation trials

 
AF-related death is conceptually an attractive outcome parameter for AF trials, because it implies that the effect of the arrhythmia on mortality is directly measured. AF-related death should not substitute ‘total death’ as an outcome parameter, because AF-related death will be difficult to assess in a clinical trial, rendering AF-related death a potentially unreliable measurement, similar to and even more pronounced than cardiovascular death. Furthermore, there are no validated means to determine AF-related death. The panel acknowledges the potential relevance and the shortcomings of this outcome parameter and suggests a step-wise exclusion process to determine ‘AF-related death’: All deaths without a clearly determined non-cardiovascular cause should be classified as cardiovascular deaths. All cardiovascular deaths that do not have a clearly defined other cause (e.g. rupture of an aneurysm, pulmonary embolism, cardiac tamponade, myocardial infarction, among others) should be classified as AF-related death when AF was present during the 7 days prior to death. All deaths that are a consequence of AF-related treatment (SAE) should be reported in the primary safety outcome and counted as AF-related deaths. This process to determine AF-related death requires validation in prospective trials.

Requirements:

  • Mortality is a valid outcome parameter in AF trials when trials are adequately powered and designed to detect differences in mortality between treatment groups.
  • In the majority of trials, death is not a feasible primary outcome parameter, but may be part of a composite outcome parameter when the study treatment is aimed at reducing deaths.
  • Death is a required secondary outcome parameter. All deaths should be reported on an intention-to-treat basis, and information on vital status needs to be assessed at regular intervals (minimum: at enrolment and at the end of the trial).
  • All deaths must be reported in a safety outcome parameter.

Stroke
AF causes a relevant portion of all strokes (15–25%)31, and AF-associated mortality is in part attributable to stroke and its consequences.32 Strokes in patients with AF are more severe than other forms of stroke.33 ‘Silent stroke’ is associated with AF and can be seen by cerebral imaging. Epidemiological data have associated silent cerebral ischaemic events with dementia.34 Stroke is often caused by cardioembolism in AF patients, most frequently from the left atrial (LA) appendage.35 Even in controlled trials, the residual stroke rate on optimal antithrombotic treatment (vitamin K antagonists, target INR range 2–3) is relatively high (1.3% per year in individuals without prior stroke, 3% per year in individuals with prior stroke)36–39. Therefore, stroke is one of the most important outcome parameters in AF trials. Stroke should be evaluated using the best possible methods (including MRI/CT brain imaging, assessing intensity of anticoagulation, severity of stroke, and neurological end result). All stroke events should be adjudicated by a committee that is usually blind to treatment/study arm.

Intracerebral bleed is the natural counterpart of ischaemic stroke in anticoagulated patients. All bleeding events need to be reported. Bleeds become more prevalent during supratherapeutic anticoagulation (INR>3.540). Risk factors for bleeds include age, typical cardiovascular risk factors, and presence of cerebral small vessel disease. A bleeding event is major when it is fatal; haemoglobin concentration falls by more than 2 g/dL; requires transfusion of whole blood cells or operation; affects areas of concern, e.g. retroperitoneal, intracranial, intraspinal, or intraocular; or results in treatment cessation. Other bleeding events are minor. Intracranial bleeds may be included in a composite stroke outcome because the combination of strokes and intracerebral bleeds can reflect the clinical benefit of antithrombotic treatment. Subdural or epidural haemorrhages are not strokes, but should be reported as SAEs, together with a statement whether they appear attributable to treatment. Data on transient ischaemic attacks (TIAs) with acute lesion matching the symptoms on imaging should be collected and reported, as there is discussion on the classification of such outcome events, and a new definition that might classify such events as ‘stroke’ is under consideration at the World Health Organization. TIAs should always be adjudicated for the presence of stroke, and the clinical adjudication may determine the ultimate classification as stroke or TIA. Cause of stroke should be classified according to TOAST criteria, stroke end results by the Rankin score (Table 5, 41,42). Usually, cerebral vascular events and other major cardiovascular events (e.g. myocardial infarction, pulmonary embolism) should be assessed as separate outcome parameters.


View this table:
[in this window]
[in a new window]

  		Table 5 TOAST criteria for classification of strokes (modified from Adams et al.41), and Rankin score for stroke severity (modified from Rankin42)

 
Cerebral imaging should be used to identify baseline cerebral defects in patients who suffered a cerebrovascular accident prior to trial inclusion. The preferred method of imaging is magnetic resonance imaging (MRI). Computed tomography may substitute MRI in specific situations. To measure cognitive function in trials, we recommend the Mini-Mental State Examination at baseline and during follow-up. Additional psychometric tests may be reasonable when cognitive function is part of the outcome. A minimal requirement is assessment of mini-mental state at enrolment and at the end of trial.

Requirements:

  • All strokes (ischaemic and haemorrhagic) and systemic embolic events should be recorded and reported separately.
  • All clinical events fulfilling the criteria of stroke should be verified by brain imaging, ideally by MRI.
  • TIAs are not counted as a stroke and should not be used as part of the stroke outcome.
  • Major bleeding should be reported separately, usually as a safety outcome parameter.
  • To assess cognitive function in trials, the Mini-Mental State examination should be recorded at baseline and at least also at the end of follow-up. If cognitive function is an outcome parameter, additional psychometric tests are recommended.

Symptoms and AF-related quality of life
AF is associated with poor quality of life.43 Rate- or rhythm control interventions can improve quality of life in AF patients.13,44,45 Symptoms and perceived suffering from the arrhythmia are the most common reason for AF patients to seek medical attention, and the main indication for rate- or rhythm-control therapy at present.35,46 Quality of life, and suffering or ‘illness intrusiveness’47,48 are difficult to measure objectively. The elusive relation between symptoms and arrhythmia recurrences, and specifically the high incidence of asymptomatic AF recurrences in patients with symptomatic AF, suggest that symptoms may at times not be related to AF, but rather an expression of other disease-causing processes. This renders symptoms and disease-related quality of life a potentially unreliable outcome parameter in AF trials. Therefore, symptoms and quality of life are only recommended as secondary outcome parameters.

Several instruments have been used to measure AF-related quality of life, usually as self-administered questionnaires [e.g. SF 36, symptoms check list, atrial fibrillation symptoms scale (AFSS), and the living with heart failure questionnaire (LWHF)]. These instruments are validated for global illness intrusiveness, but are—with the exception of the AFSS—not specific for AF-related symptoms. Furthermore, they are not available in many languages. Such standard instruments are recommended in AF trials, but the authors acknowledge their shortcomings in assessing AF-related symptoms. The panel recommends to design, validate, and use further, AF-specific instruments to assess AF-related quality of life, especially when improvement of symptoms and quality of life are the intended primary outcome of a trial. In selected studies in low-risk patients, robust, validated measures of quality of life may in the future become a primary outcome parameter, especially in small, hypothesis-generating trials.

Proposal of a symptom classification for AF
Having noticed the apparent discrepancy between the clinical relevance of AF-related symptoms for treatment decisions in AF and the lack of a practicable instrument to assess AF-related symptoms, the panel agreed to suggest a score to assess symptoms related to AF (see discussion in49). The panel suggests the so-called EHRA classification to describe AF-related symptoms (Table 6). The EHRA classification relates specifically to the time when the patient feels to be in the arrhythmia. The panel is aware of the fact that this classification requires prospective validation.


View this table:
[in this window]
[in a new window]

  		Table 6 EHRA atrial fibrillation symptoms classification

 
Requirements:
  • Symptoms are the main reason for AF patients to seek medical attention. At present, symptoms and quality of life are recommended as secondary outcome parameters because there are no reliable instruments to quantify AF-related symptoms.
  • Symptoms and quality of life should be assessed at entry and during follow-up in all AF trials.
  • In trials enrolling symptomatic patients, symptoms should be related to the underlying rhythm.
  • When the tested intervention is expected to primarily affect symptoms and quality of life, measures of quality of life and symptoms are potentially the primary outcome parameter. In such studies, the design, validation, and use of ‘specific’ instruments for AF-related symptoms in addition to standard instruments is recommended.
Once validated, the suggested EHRA AF symptoms classification may be helpful to compare AF-related symptoms across trials and in clinical practice.

Assessment of rhythm and other ECG-based outcome parameters
ECG-based outcome measures have been used in almost all trials that assessed interventions for rhythm or rate control (Table 7). In the past, we have learned that AF often recurs without clinical signs or symptoms: ECG recordings triggered by symptoms will miss more than half of all AF episodes, even in symptomatic patients.12,38,50,51 To detect both symptomatic and asymptomatic AF recurrences, systematic (scheduled) ECG recordings are therefore needed. Continuous ECG monitoring, the gold standard for detection of recurrent AF, is not available at present, and will be available only using advanced technology in the foreseeable future.


View this table:
[in this window]
[in a new window]

  		Table 7 ECG-based outcome parameters for atrial fibrillation trials and available methods to assess them

 
In all patients, AF should be documented by ECG at enrolment, persistent, or permanent AF by Holter ECG. Seven day Holter ECG recording and daily plus symptom-activated transtelephonic ECG monitoring are equally powerful to detect recurrent paroxysmal AF51–54 and detect ~70% of AF recurrences. One has to accept that the negative predictive value for ‘freedom from AF’ is 25–40% in paroxysmal AF patients with the aforementioned monitoring intensity, indicating that only one in three patients without any detected AF in all monthly Holter ECGs or daily transtelephonic monitoring during a 1-year follow-up period will really be free of AF.23,53

On the basis of this knowledge, we suggest the following: All ECG recordings should be analysed blind-to-treatment in a core laboratory. Every perceived (symptomatic) episode of AF should trigger an ECG. Single-lead ECGs are sufficient for this monitoring. Additional scheduled regular ECG recordings are mandatory, either by scheduled 24 h/month Holter ECG, or by daily 30–60 s short-term (e.g. transtelephonic) ECG recordings.21,23,51–53 Daily transtelephonic monitoring may be more feasible because it allows recordings of additional ECGs during times of perceived symptoms. Holter ECG recordings, in contrast, have the advantage that the duration of AF episodes can be assessed.

When the outcome parameter is freedom from persistent or permanent AF, daily or twice-weekly short-term (e.g. transtelephonic) ECG recording followed by rapidly scheduled confirmatory Holter recording in case of a documented AF recurrence are sufficient.12,24,55

Any arrhythmia that has the ECG characteristics of AF and lasts longer than 30 s should be reported as recurrent AF. Persistent or permanent AF is assumed to be present when the episode does not terminate spontaneously or is terminated by an intervention. In rhythm control trials, recurrent arrhythmias on drug or after catheter ablation will not always be AF, but at times constitute atrial tachycardias or atrial flutter. These should be included in the arrhythmia recurrence outcome parameter. Often, only a 12-lead ECG will distinguish these arrhythmias from AF.

Recurrent AF after cardioversion is time-dependent.56–62 We suggest the following definitions: Cardioversion is successful when AF has been terminated. When AF recurs in the first 5 min after cardioversion, this event should be described as immediate recurrence of AF. AF recurrences within 6 min and 28 days after cardioversion should be called early recurrence of AF. Recurrent AF more than 4 weeks after cardioversion is ‘late’.63–65

Safety
Safety issues may require additional ECG recordings to detect tachycardia and bradycardia signals. Bradycardia detection may require night-time ECG monitoring. Any arrhythmia that might constitute a proarrhythmic event (e.g. torsades de pointes, atypical or typical atrial flutter, or symptomatic bradycardia) must be reported as an adverse event.

Control of ventricular rate should be assessed by a resting ECG and a standardized submaximal exercise test (e.g. treadmill ECG, two-flights-of-stairs test, or a 6 min walk test). Maximal heart rate and potentially mean heart rate on Holter ECG may be used instead of an exercise test. Studies that compare rate- and rhythm-control strategies require detailed ECG monitoring like rhythm control studies (discussed earlier). In trials that do not target rate or rhythm, regular 12-lead ECGs should be performed, e.g. in 6 months intervals, to document the presence or absence of AF.

Requirements:

  • Every arrhythmia with the ECG characteristics of AF and a duration >30 s should be reported as an AF recurrence.
  • Every symptomatic event should trigger an ECG recording.
  • Regular scheduled additional ECG recordings are needed to detect asymptomatic episodes.
    • For detection of persistent or permanent AF, daily or twice-weekly short-term ECG recordings with rapidly ensuing confirmatory Holter in case of an arrhythmia recurrence are sufficient.
    • For detection of paroxysmal AF, regular Holter ECGs (24 h/month) or regular transtelephonic short-term ECGs (30–60 s once daily) are recommended. Even this intensity of ECG monitoring will not detect all patients with recurrent AF.

  • Ventricular rate should be assessed by resting ECG and a standardized exercise test. Alternatively, heart rate on Holter ECG may be used.
  • Safety measures may require additional ECG recordings, e.g. to detect proarrhythmia.

Left ventricular function and heart failure
AF may impair LV function. On the other hand, AF and its complications may also occur in the presence of LV dysfunction. Rate- or rhythm-control therapy can improve LV function.66–73

LV size and function
LV function should be measured at baseline in every AF study patient.35 Echocardiography is widely available and provides real-time imaging. Long axis M-mode measurements assess LV size (LVEDD, LVESD) and estimate global LV function. M mode echocardiography will be sufficient in many trials in AF patients to give a global estimate of LV systolic function. When regionally or severely abnormal LV function is expected, apical 2-dimensional LV planimetry using a (modified) Simpson's approach is preferred.74 LV function should be measured at a normal heart rate (60–100 b.p.m.). In patients with irregular ventricular rhythm, averaging of LV measurements (five consecutive beats) is recommended. Analysis should be done by a core lab. There is epidemiological evidence of co-existence of diastolic dysfunction and AF.5 When the diagnostic or therapeutic value of diastolic function is evaluated, transmitral pulsed wave Doppler measurements can be used. M-mode imaging from the parasternal long-axis view gives a unidimensional measurement (antero-posterior direction) and first impression of LA size. Better LA size information can be obtained from 2D or volumetric LA measurements. In patients with sinus rhythm, the maximal A-wave amplitude or its velocity–time integral on pulsed Doppler echocardiography provides information on LA function. Flow velocities (pulsed Doppler imaging) in the LA appendage provide adequate information on LA contractile function, even in AF, but this measurement requires transoesophageal echocardiography.

Highly reliable information on LV volumes and function can be obtained using computed tomography,75 MRI, or gated nuclear imaging.76 In contrast to the real-time imaging obtained by echocardiography, these modalities rely on ECG-based signal averaging. This technical requirement has prevented the use of these techniques in trials of AF patients so far. Furthermore, nuclear imaging techniques and computed tomography require exposure to ionizing radiation.

Heart failure should be a secondary outcome parameter because it is difficult to quantify. NYHA class is widely accepted but not very sensitive to change. Hospitalization for heart failure is a reasonable way to measure the consequences of heart failure in a clinical trial. In addition, VO2(max), 6 min walking distance, and nt-proBNP may be helpful as general measures of cardiac strain and performance.

Requirements:

  • All trials of rate- or rhythm-control interventions should report standard transthoracic echocardiographic data at entry and during follow-up. The assessment should include LA size (M Mode), LV size (M Mode), LV function (M Mode, preferably 2-dimensional echocardiography, modified Simpson technique).
  • For trials assessing other (e.g. antithrombotic) interventions, echocardiography assessment is required at entry and strongly recommended during follow-up.
  • When LV function or heart failure are part of the main outcome parameter set, it is reasonable to supplement echocardiography with a test for exercise capacity (6 min walk test, standardized exercise test) and potentially with a serologic marker (e.g. nt-proBNP).
  • Hospitalizations may serve as an intermediary outcome parameter for heart failure that is easily quantified.

Emerging surrogates as outcome parameters
A limitation of current trials is that AF is considered as one entity. Emerging surrogates will allow to better identify pathophysiological mechanisms underlying AF in a given patient. Different diseases induce different ‘substrates’ for AF. Hence, different forms of AF may require different therapies.77–86 In better defined patient populations, it might be easier to demonstrate a therapeutic effect of a given intervention. As an unproven working hypothesis, we propose that the therapy of the cause will be more efficient than the therapy of a symptom. Given the extensive list of potential surrogate markers (Table 8), it is the educated guess of the panel that some of them may develop into novel diagnostic techniques for tiered therapy of AF.10,87–90


View this table:
[in this window]
[in a new window]

  		Table 8 Emerging surrogate outcome parameters in atrial fibrillation trials

 
Health economics
The mere number of AF patients and the frequency of complications of the arrhythmia cause large cost, often not visible within traditional health care budgets. Use of new treatment options may reduce this economic burden, but causes additional cost for treatment. It is important that any large-scale controlled AF trial includes a detailed analysis of cost. The result of such exploration should be extended beyond the actual study, projecting the application of the study results on a more general basis. This recommendation is issued with the notice that comparison of health-care related cost is difficult between different health-care systems. Important information related to cost may include hospitalizations including total duration of time spent in a hospital and number and timing of interventions, but also type and duration of medication, time spent on sick-leave, and cost of ambulatory health-care provision.


   Specific design issues in atrial fibrillation trials
Top
 Abstract
 Introduction
 General considerations
 Assessment of specific outcome...
 Specific design issues in...
Conclusion
 Funding
 Appendix
 Acknowledgements
 References
 
Composite outcome parameters in atrial fibrillation
Composite outcome parameters should usually be spared for secondary analyses. In any case, the relative contribution of each of these parameters for the composite outcome should be reported and accounted for upfront. At times, a larger or longer trial with less frequent follow-up may yield more important clinical information (e.g. on death or stroke) than a smaller trial with more intensive follow-up details (e.g. on the composite of death, hospitalization, myocardial infarction, and stroke).

Cardiovascular hospitalizations
Cardiovascular hospitalizations have been used as primary outcome parameter or as the main component of a composite primary outcome parameter for AF trials (Table 3). Cardiovascular hospitalizations can be easily and reliably measured in multi-centre trials, but integrate information from several outcome domains, depending on the primary reason for admission, including rhythm, further interventions, heart failure, thromboembolic complications, adverse events, and health economics. Local treatment routines will influence whether a given medical condition is treated on an out-patient basis or in hospital (e.g. cardioversion, initiation of antiarrhythmic drug treatment). Last but not least, a potentially relevant portion of cardiovascular hospitalizations may be unrelated to AF (e.g. myocardial infarctions, see section on AF-related deaths). Hence, number of hospitalizations will measure AF-related and unrelated effects. At times, the time spent in hospital may be more relevant than the number of hospitalizations. The panel recommends to use cardiovascular hospitalizations as a secondary outcome parameter, to report the time (e.g. days) spent in hospital, and to report the contribution of the different causes of cardiovascular hospitalization to this composite outcome parameter.

Further interventions
The necessity for repeated treatment has been used as an outcome parameter in AF trials, especially in trials investigating rhythm-control interventions. Ideally, such ‘further interventions’ are pre-specified parts of the study protocol, rendering them part of the tested (e.g. rhythm control) strategy. The underlying arrhythmia, not the repeated intervention per se, should be defined as outcome parameter.

Time-based assessment of outcome parameters
When a rhythm-based primary outcome event is reached, the patient often ends his/her trial participation. This has been a problem in AF trials. After reaching a time-based (e.g rhythm) primary outcome event, all patients should be followed until the end of the trial to assess death, stroke, and potentially other outcome domains.

‘Blanking’ or ‘therapy stabilization’ periods
Such a period is defined as the time interval during which episodes of recurrent AF should be documented but not counted as components of the ECG-based outcome parameter. As the term ‘blanking period’ can cause confusion among investigators and protocols, it is suggested to use the term ‘stabilization period’. While there are aspects of trial design that strongly argue against such periods, there is sometimes a relevant biological rationale for such a ‘stabilization’ period. If used, however, there are several principles that should be observed: (i) All events during the ‘stabilization period’ need to be recorded and reported. (ii) For reasons of design (intention-to-treat, equal treatment in all study arms), such a ‘stabilization period’ must be pre-specified in the protocol, begin at the time of randomization, and comprise an equal period for all study arms. (iii) All events not related to the ECG-based outcome, e.g. performance measures and adverse events, have to be recorded and counted from the time of randomization.

Assessment of radiation exposure
Catheter ablation procedures and radiation-based imaging (e.g. computed tomography of brain and heart) cause considerable exposure to ionizing radiation for patients91,92 and operators.91,93,94 Assessment of radiation dose is therefore a required part of the safety outcome in every trial that includes fluoroscopy-based interventions or radiation-based imaging, e.g. to guide therapy. Fluoroscopy time is not adequate to measure radiation exposure. Dose–area products (expressed in Gyxcm2) are readily available and recommended to measure radiation energy delivered to the patient and to the operator. They can be used to estimate effective patient-doses.95,96 Radiation exposure must include all exposure including those resulting from pre- or post-procedural imaging (e.g. cardiac CT scans for image fusion).


   Conclusion
Top
 Abstract
 Introduction
 General considerations
 Assessment of specific outcome...
 Specific design issues in...
 Conclusion
Funding
 Appendix
 Acknowledgements
 References
 
AF has a complex aetiology and causes morbidity and mortality due to many different mechanisms. A controlled trial in AF patients requires assessment of the effect of therapy in each of the main outcome categories. A careful selection of relevant outcome parameters is mandatory for any AF trial. This paper describes an expert consensus of required outcome parameters in seven relevant outcome domains and gives information on additional, more intensive monitoring of outcome. Although this exceeds current practice in some trials, the panel recommends basal assessment of all major outcome domains in AF trials. Only such a comprehensive set of outcome parameters will allow to compare the effects of different treatments across trials.


   Funding
Top
 Abstract
 Introduction
 General considerations
 Assessment of specific outcome...
 Specific design issues in...
 Conclusion
 Funding
Appendix
 Acknowledgements
 References
 
The Consensus Conference and the preparation of the two consensus documents simultaneously published in the European Heart Journal (Executive Summary) and in Europace (Full Paper) have been funded by the European Heart Rhythm Association (EHRA) and by the German Atrial Fibrillation competence NETwork (AFNET). AFNET receives funds from the Federal German Ministry of Education and Research (BMBF, 01Gi0204). In addition, participation fees were used to cover expenses.


   Appendix
Top
 Abstract
 Introduction
 General considerations
 Assessment of specific outcome...
 Specific design issues in...
 Conclusion
 Funding
 Appendix
Acknowledgements
 References
 
Additional contributors: A.M. Baczynska (EMEA, London, Great Britain); S. Berkowitz (Bayer. Leverkusen, Germany); R. Bilke (Boehringer, Ingelheim, Germany); C. Blomstrom-Lundqvist (Uppsala, Sweden); A. Bollmann (Magdeburg, Germany); M. Brignole (Lavagna, Italy); J. Brugada (Spain); N. Edvardsson (AstraZeneca, Sweden); T. Fetsch (IKKF, München, Germany); K.G. Häusler (Berlin, Germany); W. Haverkamp (Berlin, Germany); H. Heidbüchel (Leuven, Belgium); E. Hoffmann (Munich, Germany); A. Huemmer (St. Jude Medical, Frankfurt, Germany); C. Israel (Frankfurt, Germany); E. Köfüncü (Sanofi-Aventis. Berlin, Germany); K.-H. Ladwig (Munich, Germany); S. Lévy (Marseille, France); F. Lindemans (Medtronic, Maastricht, the Netherlands); J. Merino (Madrid, Spain); F. Misselwitz (Bayer); M. Näbauer (Munich, Germany); M. O' Donnell (Biosense Webster); M. Oeff (Brandenburg, Germany); N. Osypka-Rubenstein (Osypka, Grenzach-Whylen, Germany); R. Peeters (Sorin); P. Ramge (Sanofi-Aventis, Berlin, Germany); S. Schepels (Biosense Webster); M. Schwertfeger (Sanofi-Aventis, Berlin, Germany); C. Stoeppler (St. Jude Medical, Frankfurt, Germany); R. Sutton (London, Great Britain); I. Van Gelder (Groningen, the Netherlands); P. Vardas (Crete, Greece); T. Weiß (AFNET, Münster, Germany); S. Willems (Hamburg, Germany); R. Woker (Boehringer, Ingelheim, Germany).


   Acknowledgements
Top
 Abstract
 Introduction
 General considerations
 Assessment of specific outcome...
 Specific design issues in...
 Conclusion
 Funding
 Appendix
 Acknowledgements
References
 
We would like to thank the staff of the Heart House, Sophia Antipolis, especially Sophie Janiszewski, as well as the AFNET staff, especially Angelika Leute, for excellent support of the conference.

Conflict of interest: Many of the authors of this document have been involved in the design, conduct, and analysis of clinical trials in AF, and have been supported by industry or other research financing bodies.

AFNET and EHRA support a policy of transparency towards such involvements as required by the ESC journals. Therefore, the following table lists potential conflicts of interest of the authors. Furthermore, corporate affiliations of the other contributors to this document, who are listed in the Appendix section are indicated after the respective names.
Name Consulting fees/honoraria Speaker's bureau Ownership/partnership/employee Research grants Principal investigator (PI)/Steering committee (SC) Salary
Paulus Kirchhof 3M Medica
AstraZeneca
Medtronic
Sanofi-Aventis
Servier
Siemens
Takeda		 None None Cardiovascular Therapeutics
3M Medica/MEDAPharma
Medtronic
OMRON
German Federal Ministry
for Education and
Research (BMBF)
Fondation LeDucq
German Resarch
Foundation (DFG)		 APAL
MOBIPAPA
MOBIPAPA II
Flec-SL
AFNET		 None
Angelo Auricchio Medtronic
Boston Scientific
Sorin
Biotronic
Takeda		 None None Medtronic
Boston Scientific		 None None
Jeroen Bax None None None Boston/Guidant
GE Medical
Medtronic
St. Jude Medical		 None None
Harry Crijns Sanofi-Aventis
AstraZeneca
Cardiome
Meda		 Sanofi-Aventis
AstraZeneca
St. Jude
Medical
Meda		 None Medtronic
St. Jude Medical
Sanofi-Aventis		 TIARA
RACE II
ATHENA
ICARIOS
CardioFit
Cardiome
CORYFEE
MAIA		 None
John Camm Sanofi-Aventis
Medtronic
Cryocor
Servier
Xention
Prism
GlaxoSmithKline
Novartis
Lundbeck
Guidant
Sorin		 Sanofi-Aventis
Bristol Myer
Squibb		 None Pfizer
Sanofi-Aventis
Bristol Myer Squibb
Guidant
Hans-Christoph Diener Abbott
AstraZeneca
Bayer Vital
BMS
Boehringer Ingelheim
D-Pharm
Fresenius
GlaxoSmithKline
Janssen Cilag
MSD
Novartis
NovoNordisk
Paion
Parke-Davis
Pfizer
Sanofi-Aventis
Sankyo
Servier
Solvay
Thrombogenics
Wyeth
Yamaguchi		 None None AstraZeneca
GlaxoSmithKline
Boehringer Ingelheim
Novartis
Janssen-Cilag
Sanofi-Aventis
Bertelsmann Foundation
Heinz-Nixdorf Foundation
European Union
German Federal Ministry
for Education and
Research
German Resarch
Foundation (DFG)		 None None
Andreas Goette Daiichi-Sankyo
Sanofi-Aventis
3M Medica
Boehringer
Servier
BMS
AstraZeneca		 None None German Federal Ministry for
Education and Research
(AFNET; NBL3)
Sanofi-Aventis
Daiichi-Sankyo
3M Medica/MEDAPharma
OMRON		 ANTIPAF
CREATIVE AF
AFNET		 None
Gerd Hindricks Bard
St. Jude Medical		 Biosense
Biotronik
Philips
Stereotaxis
St. Jude		 None St. Jude Medical
Biotronik
Biosense
Stereotaxis		 None None
Stefan Hohnloser St. Jude Medical
Sanofi-Aventis
BMS
P&G
Boehringer Ingelheim		 Sanofi-Aventis None St. Jude Medical
Sanofi-Aventis
Boehringer Ingelheim		 Numerous trials in
the past and
present
(sponsors to
the right)		 None
Lukas Kappenberger Medtronic None None Medtronic
Schiller		 None None
Karl-Heinz Kuck Biosense-Webster
St. Jude Medical
Cryocath
Edwards		 None None BMBF
Stereotaxis
St. Jude Medical
Cryocath
Medtronic		 AMICA
GAP-AF
VTACH
SMS
PPT		 None
Gregory Y.H. Lip AstraZeneca
Bayer
Astellas
Daiichi Sankyo
Sanofi-Aventis
Takeda		 AstraZeneca
Bayer		 None AstraZeneca
Pfizer
Sanofi-Aventis
Medical Research Council		 Trials sponsored by AstraZeneca
Astellas
Daiichi		 None
Bertil Olsson AstraZeneca
Boehringer-Ingelheim
Daiishi-Sankyo		 None AstraZeneca
Pfizer		 AstraZeneca
NordForsk
Swedish Heart Lung
Foundation
Lund Univ/Hosp
Local foundations		 Stroke prevention studies with AZ None
Thomas Meinertz 3M Medica
Sanofi-Aventis
Servier		 None None Daiishi-Sankyo
Medtronic
German Federal Ministry
for Education and
Research (BMBF)		 ANITPAF
AFNET		 None
Silvia Priori Pfizer
P&G
Reliant Pharmaceuticals
Medifacts Corp.		 None None Medtronic None None
Ursula Ravens Cardiome Pharma Corporation
Aventis		 None None German Federal Ministry for Education and Research (BMBF)
Fondation Leducq
German Resarch Foundation (DFG)		 None None
Gerhard Steinbeck Medtronic
St. Jude Medical
Astra Zeneca
Sanofi-Aventis		 None None Medtronic
St. Jude Medical
Guidant		 IRIS None
Elisabeth Svernhage None None Employee of AstraZeneca None None Yes
Jan Tijssen None None None None None None
Alphons Vincent None None Employee of Medtronic None None Yes
Günter Breithardt Boston Scientific
Johnson&Johnson
Bayer
Sanofi-Aventis		 None None 3M Medica/MEDAPharma
Medtronic		 Flec-SL
AFNET
E-SIRIUS
RECORD AF
ROCKET
CAD-Ref Registry		 None


   References
Top
 Abstract
 Introduction
 General considerations
 Assessment of specific outcome...
 Specific design issues in...
 Conclusion
 Funding
 Appendix
 Acknowledgements
 References
 

  1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. Jama (2001) 285:2370–2375.[Abstract/Free Full Text]
  2. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH, Stijnen T, Lip GY, Witteman JC. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J (2006) 27:949–953.[Abstract/Free Full Text]
  3. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Lifetime risk for development of atrial fibrillation: The Framingham Heart Study. Circulation (2004) 110:1042–1046.[Abstract/Free Full Text]
  4. Stewart S, Hart CL, Hole DJ, McMurray JJ. 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) 113:359–364.[CrossRef][Web of Science][Medline]
  5. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation (1998) 98:946–952.[Abstract/Free Full Text]
  6. Jouven X, Desnos M, Guerot C, Ducimetiere P. Idiopathic atrial fibrillation as a risk factor for mortality. The Paris Prospective Study I. Eur Heart J (1999) 20:896–899.[Abstract/Free Full Text]
  7. Vidaillet H, Granada JF, Chyou PH, Maassen K, Ortiz M, Pulido JN, Sharma P, Smith PN, Hayes J. A population-based study of mortality among patients with atrial fibrillation or flutter. Am J Med (2002) 113:365–370.[CrossRef][Web of Science][Medline]
  8. Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, Jin HW, Sun H, Su XY, Zhuang QN, Yang YQ, Li YB, Liu Y, Xu HJ, Li XF, Ma N, Mou CP, Chen Z, Barhanin J, Huang W. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science (2003) 299:251–254.[Abstract/Free Full Text]
  9. Kirchhof P, Eckardt L, Franz MR, Mönnig G, Loh P, Wedekind H, Schulze-Bahr E, Breithardt G, Haverkamp W. Prolonged atrial action potential durations and polymorphic atrial tachyarrhythmias in patients with long QT syndrome. J Cardiovasc Electrophysiol (2003) 14:1027–1033.[CrossRef][Web of Science][Medline]
  10. Wachtell K, Lehto M, Gerdts E, Olsen MH, Hornestam B, Dahlof B, Ibsen H, Julius S, Kjeldsen SE, Lindholm LH, Nieminen MS, Devereux RB. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol (2005) 45:712–719.[Abstract/Free Full Text]
  11. Page RL, Wilkinson WE, Clair WK, McCarthy EA, Pritchett EL. Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia. Circulation (1994) 89:224–227.[Abstract/Free Full Text]
  12. Fetsch T, Bauer P, Engberding R, Koch HP, Lukl J, Meinertz T, Oeff M, Seipel L, Trappe HJ, Treese N, Breithardt G. Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial. Eur Heart J (2004) 25:1385–1394.[Abstract/Free Full Text]
  13. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation—Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet (2000) 356:1789–1794.[CrossRef][Web of Science][Medline]
  14. Lip GY, Edwards SJ. Stroke prevention with aspirin, warfarin and ximelagatran in patients with non-valvular atrial fibrillation: a systematic review and meta-analysis. Thromb Res (2006) 118:321–333.[CrossRef][Web of Science][Medline]
  15. Farshi R, Kistner D, Sarma JS, Longmate JA, Singh BN. Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: a crossover open-label study of five drug regimens. J Am Coll Cardiol (1999) 33:304–310.[Abstract/Free Full Text]
  16. AFFIRM I. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med (2002) 347:1825–1833.[Abstract/Free Full Text]
  17. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, LeMouroux A, LeMetayer P, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med (1998) 339:659–666.[Abstract/Free Full Text]
  18. Cox JL. Cardiac surgery for arrhythmias. Pacing Clin Electrophysiol (2004) 27:266–282.[CrossRef][Medline]
  19. Healey JS, Morillo CA, Connolly SJ. Role of the renin-angiotensin-aldosterone system in atrial fibrillation and cardiac remodeling. Curr Opin Cardiol (2005) 20:31–37.[Web of Science][Medline]
  20. Gillis AM, Rose MS. Temporal patterns of paroxysmal atrial fibrillation following DDDR pacemaker implantation. Am J Cardiol (2000) 85:1445–1450.[CrossRef][Web of Science][Medline]
  21. Warman EN, Grammatico A, Padeletti L. Sample size estimates for atrial fibrillation endpoints. Heart Rhythm (2004) 1:B58–B62. discussion B63.[Web of Science][Medline]
  22. Pritchett EL, Anderson JL. Antiarrhythmic strategies for the chronic management of supraventricular tachycardias. Am J Cardiol (1988) 62:1D–2D.[Medline]
  23. Ziegler PD, Koehler JL, Mehra R. Comparison of continuous versus intermittent monitoring of atrial arrhythmias. Heart Rhythm (2006) 3:1445–1452.[CrossRef][Web of Science][Medline]
  24. Singh BN, Singh SN, Reda DJ, Tang XC, Lopez B, Harris CL, Fletcher RD, Sharma SC, Atwood JE, Jacobson AK, Lewis HD Jr, Raisch DW, Ezekowitz MD. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med (2005) 352:1861–1872.[Abstract/Free Full Text]
  25. Berger M, Schweitzer P. Timing of thromboembolic events after electrical cardioversion of atrial fibrillation or flutter: a retrospective analysis. Am J Cardiol (1998) 82:1545–1547. A8.[CrossRef][Web of Science][Medline]
  26. Gallagher MM, Hennessy BJ, Edvardsson N, Hart CM, Shannon MS, Obel OA, Al-Saady NM, Camm AJ. Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion. J Am Coll Cardiol (2002) 40:926–933.[Abstract/Free Full Text]
  27. Godtfredson J. Atrial Fibrillation, Etiology, Course and Prognosis. In: A Follow-up Study of 1212 Cases (1975) Copenhagen: University of Copenhagen.
  28. Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet (2003) 362:1691–1698.[CrossRef][Web of Science][Medline]
  29. McNamara RL, Brass LM, Drozda JP Jr, Go AS, Halperin JL, Kerr CR, Levy S, Malenka DJ, Mittal S, Pelosi F Jr, Rosenberg Y, Stryer D, Wyse DG, Radford MJ, Goff DC Jr, Grover FL, Heidenreich PA, Malenka DJ, Peterson ED, Redberg RF. ACC/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Data Standards on Atrial Fibrillation). Circulation (2004) 109:3223–3243.[Free Full Text]
  30. Shemin RJ, Cox JL, Gillinov AM, Blackstone EH, Bridges CR. Guidelines for reporting data and outcomes for the surgical treatment of atrial fibrillation. Ann Thorac Surg (2007) 83:1225–1230.[Abstract/Free Full Text]
  31. Grau AJ, Weimar C, Buggle F, Heinrich A, Goertler M, Neumaier S, Glahn J, Brandt T, Hacke W, Diener HC. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke (2001) 32:2559–2566.[Abstract/Free Full Text]
  32. Kimura K, Minematsu K, Yamaguchi T. Atrial fibrillation as a predictive factor for severe stroke and early death in 15,831 patients with acute ischaemic stroke. J Neurol Neurosurg Psychiatry (2005) 76:679–683.[Abstract/Free Full Text]
  33. Jorgensen HS, Nakayama H, Reith J, Raaschou HO, Olsen TS. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke (1996) 27:1765–1769.[Abstract/Free Full Text]
  34. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med (2003) 348:1215–1222.[Abstract/Free Full Text]
  35. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: A report of the American College of Cardiology/American Heart Association 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) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace (2006) 8:651–745.[Free Full Text]
  36. Albers GW. Stroke prevention in atrial fibrillation: pooled analysis of SPORTIF III and V trials. Am J Manag Care (2004) 10:S462–S469. discussion S469–S473.[Web of Science][Medline]
  37. Diener HC. Stroke prevention using the oral direct thrombin inhibitor ximelagatran in patients with non-valvular atrial fibrillation. Pooled analysis from the SPORTIF III and V studies. Cerebrovasc Dis (2006) 21:279–293.[CrossRef][Web of Science][Medline]
  38. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet (1993) 342:1255–1262.[Web of Science][Medline]
  39. Akins PT, Feldman HA, Zoble RG, Newman D, Spitzer SG, Diener HC, Albers GW. Secondary stroke prevention with ximelagatran versus warfarin in patients with atrial fibrillation. Pooled analysis of SPORTIF III and V clinical trials. Stroke (2007).
  40. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med (1996) 335:540–546.[Abstract/Free Full Text]
  41. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE III. Classification of subtype of acute ischemic stroke Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke (1993) 24:35–41.[Abstract/Free Full Text]
  42. Rankin J. Cerebral vascular accidents in patients over the age of 60, II: prognosis. Scot Med J (1957) 2:200–215.[Medline]
  43. Thrall G, Lane D, Carroll D, Lip GY. Quality of life in patients with atrial fibrillation: a systematic review. Am J Med (2006) 119:448. e1–e19.
  44. Singh SN, Tang XC, Singh BN, Dorian P, Reda DJ, Harris CL, Fletcher RD, Sharma SC, Atwood JE, Jacobson AK, Lewis HD Jr, Lopez B, Raisch DW, Ezekowitz MD. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program Substudy. J Am Coll Cardiol (2006) 48:721–730.[Abstract/Free Full Text]
  45. Dorian P, Paquette M, Newman D, Green M, Connolly SJ, Talajic M, Roy D. Quality of life improves with treatment in the Canadian Trial of Atrial Fibrillation. Am Heart J (2002) 143:984–990.[CrossRef][Web of Science][Medline]
  46. Testa L, Biondi-Zoccai GG, Dello Russo A, Bellocci F, Andreotti F, Crea F. Rate-control vs. rhythm-control in patients with atrial fibrillation: a meta-analysis. Eur Heart J (2005) 26:2000–2006.[Abstract/Free Full Text]
  47. Bloom JR, Stewart SL, Johnston M, Banks P. Intrusiveness of illness and quality of life in young women with breast cancer. Psychooncology (1998) 7:89–100.[CrossRef][Medline]
  48. Devins GM. Illness intrusiveness and the psychosocial impact of lifestyle disruptions in chronic life-threatening disease. Adv Ren Replace Ther (1994) 1:251–263.[Medline]
  49. Wyse DG. Overview of endpoints in atrial fibrillation studies. Heart Rhythm (2004) 1:B3–B7. discussion B7.[Web of Science][Medline]
  50. Israel CW, Gronefeld G, Ehrlich JR, Li YG, Hohnloser SH. Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device: implications for optimal patient care. J Am Coll Cardiol (2004) 43:47–52.[Abstract/Free Full Text]
  51. Patten M, Maas R, Bauer P, Luderitz B, Sonntag F, Dluzniewski M, Hatala R, Opolski G, Muller HW, Meinertz T. Suppression of paroxysmal atrial tachyarrhythmias—results of the SOPAT trial. Eur Heart J (2004) 25:1395–1404.[Abstract/Free Full Text]
  52. Hindricks G, Piorkowski C, Tanner H, Kobza R, Gerds-Li JH, Carbucicchio C, Kottkamp H. Perception of atrial fibrillation before and after radiofrequency catheter ablation: relevance of asymptomatic arrhythmia recurrence. Circulation (2005) 112:307–313.[Abstract/Free Full Text]
  53. Piorkowski C, Kottkamp H, Tanner H, Kobza R, Nielsen JC, Arya A, Hindricks G. Value of different follow-up strategies to assess the efficacy of circumferential pulmonary vein ablation for the curative treatment of atrial fibrillation. J Cardiovasc Electrophysiol (2005) 16:1286–1292.[Web of Science][Medline]
  54. de Voogt WG, van Hemel NM, van de Bos AA, Koistinen J, Fast JH. Verification of pacemaker automatic mode switching for the detection of atrial fibrillation and atrial tachycardia with Holter recording. Europace (2006) 8:950–961.[Abstract/Free Full Text]
  55. Kirchhof P, Fetsch T, Hanrath P, Meinertz T, Steinbeck G, Lehmacher W, Breithardt G. Targeted pharmacological reversal of electrical remodeling after cardioversion—rationale and design of the Flecainide Short-Long (Flec-SL) trial. Am Heart J (2005) 150:899.[Medline]
  56. Lown B, Amarasinghem R, Neumann J. New method for termination cardiac arrhythmias: use of synchronized capacitor discharge. JAMA (1962) 182:548–555.[Abstract/Free Full Text]
  57. Kirchhof P, Eckardt L, Loh P, Weber K, Fischer RJ, Seidl KH, Böcker D, Breithardt G, Haverkamp W, Borggrefe M. Anterior–posterior versus anterior-lateral electrode positions for external cardioversion of atrial fibrillation: a randomised trial. Lancet (2002) 360:1275–1279.[CrossRef][Web of Science][Medline]
  58. Mittal S, Ayati S, Stein KM, Schwartzman D, Cavlovich D, Tchou PJ, Markowitz SM, Slotwiner DJ, Scheiner MA, Lerman BB. Transthoracic cardioversion of atrial fibrillation: comparison of rectilinear biphasic versus damped sine wave monophasic shocks. Circulation (2000) 101:1282–1287.[Abstract/Free Full Text]
  59. Marinsek M, Larkin GL, Zohar P, Bervar M, Pekolj-Bicanic M, Mocnik FS, Noc M, Podbregar M. Efficacy and impact of monophasic versus biphasic countershocks for transthoracic cardioversion of persistent atrial fibrillation. Am J Cardiol (2003) 92:988–991.[CrossRef][Web of Science][Medline]
  60. Page RL, Kerber RE, Russell JK, Trouton T, Waktare J, Gallik D, Olgin JE, Ricard P, Dalzell GW, Reddy R, Lazzara R, Lee K, Carlson M, Halperin B, Bardy GH. Biphasic versus monophasic shock waveform for conversion of atrial fibrillation: the results of an international randomized, double-blind multicenter trial. J Am Coll Cardiol (2002) 39:1956–1963.[Abstract/Free Full Text]
  61. Ermis C, Zhu AX, Sinha S, Iskos D, Sakaguchi S, Lurie KG, Benditt DG. Efficacy of biphasic waveform cardioversion for atrial fibrillation and atrial flutter compared with conventional monophasic waveforms. Am J Cardiol (2002) 90:891–892.[CrossRef][Web of Science][Medline]
  62. Kirchhof P, Mönnig G, Wasmer K, Heinecke A, Breithardt G, Eckardt L, Böcker D. A trial of self-adhesive patch electrodes and hand-held paddle electrodes for external cardioversion of atrial fibrillation (MOBIPAPA). Eur Heart J (2005) 26:1292–1297.[Abstract/Free Full Text]
  63. Rossi M, Lown B. The use of quinidine in cardioversion. Am J Cardiol (1967) 19:234–238.[CrossRef][Web of Science][Medline]
  64. Van Noord T, Van Gelder IC, Schoonderwoerd BA, Crijns HJ. Immediate reinitiation of atrial fibrillation after electrical cardioversion predicts subsequent pharmacologic and electrical conversion to sinus rhythm and amiodarone. Am J Cardiol (2000) 86:1384–1385. A5.[CrossRef][Web of Science][Medline]
  65. Tieleman RG, Van Gelder IC, Crijns HJ, De Kam PJ, Van Den Berg MP, Haaksma J, Van Der Woude HJ, Allessie MA. Early recurrences of atrial fibrillation after electrical cardioversion: a result of fibrillation-induced electrical remodeling of the atria? J Am Coll Cardiol (1998) 31:167–173.[Abstract/Free Full Text]
  66. Brignole M, Gianfranchi L, Menozzi C, Bottoni N, Bollini R, Lolli G, Oddone D, Gaggioli G. Influence of atrioventricular junction radiofrequency ablation in patients with chronic atrial fibrillation and flutter on quality of life and cardiac performance. Am J Cardiol (1994) 74:242–246.[CrossRef][Web of Science][Medline]
  67. Natale A, Zimerman L, Tomassoni G, Kearney M, Kent V, Brandon MJ, Newby K. Impact on ventricular function and quality of life of transcatheter ablation of the atrioventricular junction in chronic atrial fibrillation with a normal ventricular response. Am J Cardiol (1996) 78:1431–1433.[CrossRef][Web of Science][Medline]
  68. Rodriguez LM, Smeets JL, Xie B, de Chillou C, Cheriex E, Pieters F, Metzger J, den Dulk K, Wellens HJ. Improvement in left ventricular function by ablation of atrioventricular nodal conduction in selected patients with lone atrial fibrillation. Am J Cardiol (1993) 72:1137–1141.[CrossRef][Web of Science][Medline]
  69. Brignole M, Gianfranchi L, Menozzi C, Alboni P, Musso G, Bongiorni MG, Gasparini M, Raviele A, Lolli G, Paparella N, Acquarone S. Assessment of atrioventricular junction ablation and DDDR mode-switching pacemaker versus pharmacological treatment in patients with severely symptomatic paroxysmal atrial fibrillation: a randomized controlled study. Circulation (1997) 96:2617–2624.[Abstract/Free Full Text]
  70. Brignole M, Menozzi C, Gianfranchi L, Musso G, Mureddu R, Bottoni N, Lolli G. Assessment of atrioventricular junction ablation and VVIR pacemaker versus pharmacological treatment in patients with heart failure and chronic atrial fibrillation: a randomized, controlled study. Circulation (1998) 98:953–960.[Abstract/Free Full Text]
  71. Weerasooriya R, Davis M, Powell A, Szili-Torok T, Shah C, Whalley D, Kanagaratnam L, Heddle W, Leitch J, Perks A, Ferguson L, Bulsara M. The Australian intervention randomized control of rate in atrial fibrillation trial (AIRCRAFT). J Am Coll Cardiol (2003) 41:1697–1702.[Abstract/Free Full Text]
  72. Hsu LF, Jais P, Sanders P, Garrigue S, Hocini M, Sacher F, Takahashi Y, Rotter M, Pasquie JL, Scavee C, Bordachar P, Clementy J, Haissaguerre M. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med (2004) 351:2373–2383.[Abstract/Free Full Text]
  73. Hagens VE, Van Veldhuisen DJ, Kamp O, Rienstra M, Bosker HA, Veeger NJ, Tijssen JGP, Crijns HJ, Van Gelder I. Effect of rate and rhythm control on left ventricular function and cardiac dimensions in patients with persistent atrial fibrillation: results from the RAte Control versus Electrical cardioversion for persistent atrial fibrillation (RACE) study. Heart Rhythm (2005) 2:19–24.[CrossRef][Web of Science][Medline]
  74. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr (2005) 18:1440–1463.[CrossRef][Web of Science][Medline]
  75. Yamanaka K, Fujita M, Doi K, Tsuneyoshi H, Yamazato A, Ueno K, Zen E, Komeda M. Multislice computed tomography accurately quantifies left atrial size and function after the MAZE procedure. Circulation (2006) 114:I5–I9.[CrossRef][Web of Science][Medline]
  76. Abidov A, Hachamovitch R, Rozanski A, Hayes SW, Santos MM, Sciammarella MG, Cohen I, Gerlach J, Friedman JD, Germano G, Berman DS. Prognostic implications of atrial fibrillation in patients undergoing myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol (2004) 44:1062–1070.[Abstract/Free Full Text]
  77. Nattel S. New ideas about atrial fibrillation 50 years on. Nature (2002) 415:219–226.[CrossRef][Medline]
  78. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation (1999) 100:87–95.[Abstract/Free Full Text]
  79. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation (1997) 96:1180–1184.[Abstract/Free Full Text]
  80. Rocken C, Peters B, Juenemann G, Saeger W, Klein HU, Huth C, Roessner A, Goette A. Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation. Circulation (2002) 106:2091–2097.[Abstract/Free Full Text]
  81. Ausma J, Wijffels M, Thone F, Wouters L, Allessie M, Borgers M. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation (1997) 96:3157–3163.[Abstract/Free Full Text]
  82. Sohara H, Amitani S, Kurose M, Miyahara K. Atrial fibrillation activates platelets and coagulation in a time-dependent manner: a study in patients with paroxysmal atrial fibrillation. J Am Coll Cardiol (1997) 29:106–112.[Abstract]
  83. Christ T, Boknik P, Wohrl S, Wettwer E, Graf EM, Bosch RF, Knaut M, Schmitz W, Ravens U, Dobrev D. L-type Ca2+ current downregulation in chronic human atrial fibrillation is associated with increased activity of protein phosphatases. Circulation (2004) 110:2651–2657.[Abstract/Free Full Text]
  84. Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, Carnes CA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A, Van Wagoner DR. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation (2001) 104:2886–2891.[Abstract/Free Full Text]
  85. Aime-Sempe C, Folliguet T, Rucker-Martin C, Krajewska M, Krajewska S, Heimburger M, Aubier M, Mercadier JJ, Reed JC, Hatem SN. Myocardial cell death in fibrillating and dilated human right atria. J Am Coll Cardiol (1999) 34:1577–1586.[Abstract/Free Full Text]
  86. Conway DS, Pearce LA, Chin BS, Hart RG, Lip GY. Prognostic value of plasma von Willebrand factor and soluble P-selectin as indices of endothelial damage and platelet activation in 994 patients with nonvalvular atrial fibrillation. Circulation (2003) 107:3141–3145.[Abstract/Free Full Text]
  87. Dudley SC Jr, Hoch NE, McCann LA, Honeycutt C, Diamandopoulos L, Fukai T, Harrison DG, Dikalov SI, Langberg J. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation (2005) 112:1266–1273.[Abstract/Free Full Text]
  88. Dernellis J, Panaretou M. Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. Eur Heart J (2004) 25:1100–1107.[Abstract/Free Full Text]
  89. El-Armouche A, Boknik P, Eschenhagen T, Carrier L, Knaut M, Ravens U, Dobrev D. Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation. Circulation (2006) 114:670–680.[Abstract/Free Full Text]
  90. Shiroshita-Takeshita A, Schram G, Lavoie J, Nattel S. Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs. Circulation (2004) 110:2313–2319.[Abstract/Free Full Text]
  91. Calkins H, Niklason L, Sousa J, el-Atassi R, Langberg J, Morady F. Radiation exposure during radiofrequency catheter ablation of accessory atrioventricular connections. Circulation (1991) 84:2376–2382.[Abstract/Free Full Text]
  92. Kovoor P, Ricciardello M, Collins L, Uther J, Ross D. Risk to patients from radiation associated with radiofrequency ablation for supraventricular tachycardia. Circulation (1998) 98:1534–1540.[Abstract/Free Full Text]
  93. Dragusin O, Weerasooriya R, Jais P, Hocini M, Ector J, Takahashi Y, Haissaguerre M, Bosmans H, Heidbuchel H. Evaluation of a radiation protection cabin for invasive electrophysiological procedures. Eur Heart J (2007) 28:183–189.[Abstract/Free Full Text]
  94. Berrington de Gonzalez A, Darby S. Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries. Lancet (2004) 363:345–351.[CrossRef][Web of Science][Medline]
  95. Hart D, Wall BF. Estimation of effective dose from dose-area product measurements for barium meals and barium enemas. Br J Radiol (1994) 67:485–489.[Abstract/Free Full Text]
  96. Ector J, Dragusin O, Adams J, Adriaenssens B, Pison L, Willems R, Ector H, Heidbuchel H. Obesity is a major determinant of radiation dose in patients undergoing pulmonary vein isolation for atrial fibrillation. J Am Coll Cardiol (2007) 50:234–242.[Abstract/Free Full Text]
  97. Van Gelder I, Hagens VE, Bosker HA, Kingma H, Kamp O, Kingma T, Said SA, Darmanata JI, Timmermanns AJM, Tijssen JGP, Crijns HJ. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med (2002) 347:1834–1840.[Abstract/Free Full Text]
  98. Opolski G, Torbicki A, Kosior DA, Szulc M, Wozakowska-Kaplon B, Kolodziej P, Achremczyk P. Rate control vs. rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest (2004) 126:476–486.[CrossRef][Web of Science][Medline]
  99. Carlsson J, Miketic S, Windeler J, Cuneo A, Haun S, Micus S, Walter S, Tebbe U. Randomzied trial of rate-control versus rhythm-control in persistent atrial fibrillation. J Am Coll Cardiol (2003) 41:1690–1696.[Abstract/Free Full Text]
  100. Roy D, Talajic M, Dorian P, Connolly S, Eisenberg MJ, Green M, Kus T, Lambert J, Dubuc M, Gagne P, Nattel S, Thibault B. Amiodarone to prevent recurrence of atrial fibrillation Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med (2000) 342:913–920.[Abstract/Free Full Text]
  101. Brignole M, Menozzi C, Gasparini M, Bongiorni MG, Botto GL, Ometto R, Alboni P, Bruna C, Vincenti A, Verlato R. An evaluation of the strategy of maintenance of sinus rhythm by antiarrhythmic drug therapy after ablation and pacing therapy in patients with paroxysmal atrial fibrillation. Eur Heart J (2002) 23:892–900.[Abstract/Free Full Text]
  102. Madrid AH, Bueno MG, Rebollo JM, Marin I, Pena G, Bernal E, Rodriguez A, Cano L, Cano JM, Cabeza P, Moro C. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation (2002) 106:331–336.[Abstract/Free Full Text]
  103. Ueng KC, Tsai TP, Yu WC, Tsai CF, Lin MC, Chan KC, Chen CY, Wu DJ, Lin CS, Chen SA. Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation. Results of a prospective and controlled study. Eur Heart J (2003) 24:2090–2098.[Abstract/Free Full Text]
  104. Natale A, Newby KH, Pisano E, Leonelli F, Fanelli R, Potenza D, Beheiry S, Tomassoni G. Prospective randomized comparison of antiarrhythmic therapy versus first-line radiofrequency ablation in patients with atrial flutter. J Am Coll Cardiol (2000) 35:1898–1904.[Abstract/Free Full Text]
  105. Wazni OM, Marrouche NF, Martin DO, Verma A, Bhargava M, Saliba W, Bash D, Schweikert R, Brachmann J, Gunther J, Gutleben K, Pisano E, Potenza D, Fanelli R, Raviele A, Themistoclakis S, Rossillo A, Bonso A, Natale A. Radiofrequency ablation vs. antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA (2005) 293:2634–2640.[Abstract/Free Full Text]
  106. Pappone C, Augello G, Sala S, Gugliotta F, Vicedomini G, Gulletta S, Paglino G, Mazzone P, Sora N, Greiss I, Santagostino A, LiVolsi L, Pappone N, Radinovic A, Manguso F, Santinelli V. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study. J Am Coll Cardiol (2006) 48:2340–2347.[Abstract/Free Full Text]
  107. Oral H, Chugh A, Good E, Igic P, Elmouchi D, Tschopp DR, Reich SS, Bogun F, Pelosi F Jr, Morady F. Randomized comparison of encircling and nonencircling left atrial ablation for chronic atrial fibrillation. Heart Rhythm (2005) 2:1165–1172.[CrossRef][Web of Science][Medline]
  108. Karch MR, Zrenner B, Deisenhofer I, Schreieck J, Ndrepepa G, Dong J, Lamprecht K, Barthel P, Luciani E, Schomig A, Schmitt C. Freedom from atrial tachyarrhythmias after catheter ablation of atrial fibrillation: a randomized comparison between 2 current ablation strategies. Circulation (2005) 111:2875–2880.[Abstract/Free Full Text]
  109. Oral H, Pappone C, Chugh A, Good E, Bogun F, Pelosi F Jr, Bates ER, Lehmann MH, Vicedomini G, Augello G, Agricola E, Sala S, Santinelli V, Morady F. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med (2006) 354:934–941.[Abstract/Free Full Text]
  110. Gaita F, Riccardi R, Caponi D, Shah D, Garberoglio L, Vivalda L, Dulio A, Chiecchio A, Manasse E, Gallotti R. Linear cryoablation of the left atrium versus pulmonary vein cryoisolation in patients with permanent atrial fibrillation and valvular heart disease: correlation of electroanatomic mapping and long-term clinical results. Circulation (2005) 111:136–142.[Abstract/Free Full Text]
  111. Roy D. Rationale for the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial. Card Electrophysiol Rev (2003) 7:208–210.[CrossRef][Medline]
  112. Brignole M, Gammage M, Puggioni E, Alboni P, Raviele A, Sutton R, Vardas P, Bongiorni MG, Bergfeldt L, Menozzi C, Musso G. Comparative assessment of right, left, and biventricular pacing in patients with permanent atrial fibrillation. Eur Heart J (2005) 26:712–722.[Abstract/Free Full Text]
  113. Van Gelder IC, Van Veldhuisen DJ, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM, Bosker HA, Cornel JH, Kamp O, Veeger NJ, Volbeda M, Rienstra M, Ranchor AV, TenVergert EM, Van den Berg MP. RAte Control Efficacy in permanent atrial fibrillation: a comparison between lenient versus strict rate control in patients with and without heart failure. Background, aims, and design of RACE II. Am Heart J (2006) 152:420–426.[CrossRef][Web of Science][Medline]
  114. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet (1989) 1:175–179.[Web of Science][Medline]
  115. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med (1990) 323:1505–1511.[Abstract]
  116. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation (1991) 84:527–539.[Abstract/Free Full Text]
  117. Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Colling CL, Gornick CC, Krause-Steinrauf H, Kurtzke JF, Nazarian SM, Radford MJ, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med (1992) 327:1406–1412.[Abstract]
  118. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol (1991) 18:349–355.[Abstract]
  119. Gullov AL, Koefoed BG, Petersen P, Pedersen TS, Andersen ED, Godtfredsen J, Boysen G. Fixed minidose warfarin and aspirin alone and in combination vs. adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med (1998) 158:1513–1521.[Abstract/Free Full Text]
  120. SPAF II Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet (1994) 343:687–691.[CrossRef][Web of Science][Medline]
  121. SPAF III Investigators. Adjusted-dose warfarin versus low-intensity fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet (1996) 348:633–638.[CrossRef][Web of Science][Medline]
  122. Albers GW, Diener HC, Frison L, Grind M, Nevinson M, Partridge S, Halperin JL, Horrow J, Olsson SB, Petersen P, Vahanian A. Ximelagatran vs. warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA (2005) 293:690–698.[Abstract/Free Full Text]
  123. Perez-Gomez F, Alegria E, Berjon J, Iriarte JA, Zumalde J, Salvador A, Mataix L. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol (2004) 44:1557–1566.[Abstract/Free Full Text]
  124. Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Yusuf S. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet (2006) 367:1903–1912.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 EuropaceHome page
P. Kirchhof, J. Bax, C. Blomstrom-Lundquist, H. Calkins, A. J. Camm, R. Cappato, F. Cosio, H. Crijns, H.-C. Diener, A. Goette, et al.
Early and comprehensive management of atrial fibrillation: Proceedings from the 2nd AFNET/EHRA consensus conference on atrial fibrillation entitled 'research perspectives in atrial fibrillation'
Europace, July 1, 2009; 11(7): 860 - 885.
[Full Text] [PDF]

Home page
 Eur Heart JHome page
P. Kirchhof, J. Bax, C. Blomstrom-Lundquist, H. Calkins, A. John Camm, R. Cappato, F. Cosio, H. Crijns, H.-C. Diener, A. Goette, et al.
Early and comprehensive management of atrial fibrillation: executive summary of the proceedings from the 2nd AFNET-EHRA consensus conference 'research perspectives in AF'
Eur. Heart J., June 17, 2009; (2009) ehp235v1.
[Abstract] [Full Text] [PDF]

Home page
 Circ Arrhythmia ElectrophysiolHome page
P. Dorian, P. G. Guerra, C. R. Kerr, S. S. O'Donnell, E. Crystal, A. M. Gillis, L. B. Mitchell, D. Roy, A. C. Skanes, M. S. Rose, et al.
Validation of a New Simple Scale to Measure Symptoms in Atrial Fibrillation: The Canadian Cardiovascular Society Severity in Atrial Fibrillation Scale
Circ Arrhythmia Electrophysiol, June 1, 2009; 2(3): 218 - 224.
[Abstract] [Full Text] [PDF]

Home page
 HeartHome page
L V Andersen, P Vestergaard, P Deichgraeber, J S Lindholt, L S Mortensen, and L Frost
Warfarin for the prevention of systemic embolism in patients with non-valvular atrial fibrillation: a meta-analysis
Heart, December 1, 2008; 94(12): 1607 - 1613.
[Abstract] [Full Text] [PDF]

Home page
 EuropaceHome page
H. L. Estner, G. Hessling, G. Ndrepepa, J. Wu, T. Reents, S. Fichtner, C. Schmitt, C. V. Bary, C. Kolb, M. Karch, et al.
Electrogram-guided substrate ablation with or without pulmonary vein isolation in patients with persistent atrial fibrillation
Europace, November 1, 2008; 10(11): 1281 - 1287.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
S. Knecht, C. Oelschlager, T. Duning, H. Lohmann, J. Albers, C. Stehling, W. Heindel, G. Breithardt, K. Berger, E. B. Ringelstein, et al.
Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy
Eur. Heart J., September 1, 2008; 29(17): 2125 - 2132.
[Abstract] [Full Text] [PDF]

Home page
 QJMHome page
O. Jolobe
It is important to identify the presence of atrial fibrillation more accurately
QJM, June 1, 2008; 101(6): 506 - 507.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
28/22/2803    most recent
ehm358v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (13)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Kirchhof, P.
Right arrow Articles by Breithardt, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kirchhof, P.
Right arrow Articles by Breithardt, G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?