Atrial fibrillation, ischaemic heart disease, and the risk of death in patients with heart failure

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1 European Heart Journal (2006) 27, doi: /eurheartj/ehl359 Clinical research Arrhythmia/electrophysiology Atrial fibrillation, ischaemic heart disease, and the risk of death in patients with heart failure Ole Dyg Pedersen 1 *, Peter Søndergaard 2, Tonny Nielsen 3, Søren Junge Nielsen 4, Eric Steen Nielsen 5, Niels Falstie-Jensen 6, Ingolf Nielsen 7, Lars Køber 8, Hans Burchardt 7, Marie Seibæk 9, and Christian Torp-Pedersen 1 on behalf of the DIAMOND study group investigators 1 Department of Cardiology, Bispebjerg University Hospital, Bispebjerg Bakke 23, 2400 Copenhagen, Denmark; 2 Department of Cardiology, Herlev University Hospital, Herlev, Denmark; 3 Department of Cardiology, Esbjerg Hospital, Esbjerg, Denmark; 4 Department of Cardiology, Frederiksberg Hospital, Frederiksberg, Denmark; 5 Department of Cardiology, Viborg Hospital, Viborg, Denmark; 6 Department of Cardiology, Hjørring Hospital, Hjørring, Denmark; 7 Department of Cardiology, Roskilde Hospital, Roskilde, Denmark; and 8 Department of Cardiology, The Heart Centre, University Hospital, Rigshospitalet, Copenhagen, Denmark and 9 Department of Cardiology, Glostrup Hospital, Glostrup, Denmark Received 7 March 2006; revised 19 September 2006; accepted 19 October 2006; online publish-ahead-of-print 13 November 2006 See page 2740 for the editorial comment on this article (doi: /eurheartj/ehl321) KEYWORDS Atrial fibrillation; Congestive heart failure; Mortality; Ischaemic heart disease Introduction Atrial fibrillation (AF) is the most common arrhythmia among patients with congestive heart failure and occurs in up to 50% of those with advanced disease. 1 In majority of the studies, AF has been shown to be an independent risk factor of mortality in patients with ischaemic heart disease and in the general population, 2,3 whereas conflicting results have been found in congestive heart failure patients. 4 Whether AF is related to an increased risk of death in patients with congestive heart failure remains unresolved and the inconsistency of the results in this particular group is strikingly different from what has been found in patients with ischaemic heart disease and in the general population. Some studies have found an increase in the risk of death in patients with AF and congestive heart failure, 5 11 whereas others have found no increased risk and one study even a decreased risk. 20 A recent * Corresponding author. Tel: þ ; fax: þ address: odplc@mail.dk Aims Atrial fibrillation (AF) is a risk factor for death in patients with a myocardial infarction, but highly variable results are reported in patients with heart failure. We studied the prognostic impact of AF in heart failure patients with and without ischaemic heart disease. Methods and results During a period of 2 years, 3587 patients admitted to hospital because of heart failure were included in this study. All patients were examined by echocardiography and the presence of AF was recorded. Follow-up was available for 8 years. Twenty four percent of those d alive from hospital had AF. After 4 and 8 years of follow-up, mortality was higher in patients with AF than in patients without, 56 vs. 52% and 77 vs. 73%, respectively. Cox multivariable regression analysis showed a small but significant importance of AF for long-term mortality [hazard ratio (HR) 1.12, 95% confidence limits (CI), , P ¼ 0.018]. There was a significant interaction between the importance of AF and the presence of ischaemic heart disease (P ¼ 0.034). In patients with AF at the time of and ischaemic heart disease, HR was 1.25 (95% CI: ) and P, 0.001; in patients with AF at and without ischaemic heart disease, HR was 1.01 (95% CI: ) and P ¼ Conclusion AF is associated with increased risk of death only in patients with ischaemic heart disease. This finding may explain the variable results of studies of the prognosis associated with AF in heart failure. study in a large group of congestive heart failure patients revealed no independent importance of chronic AF for mortality and some importance of new onset AF. 21 Because of the continued inconsistency between studies of ischaemic heart disease and studies of populations with heart failure, we speculated that this difference might be a consequence of a complicated interaction between AF resulting from heart failure on ischaemic basis and AF causing heart failure. We therefore performed this retrospective study of 3587 consecutive patients admitted to hospital because of a worsening of congestive heart failure and followed these patients for 8 years. The aim of this study was to investigate the prognostic importance of AF in the total cohort of patients as well as to study whether the prognostic importance of AF differed in patients with and without ischaemic heart disease. Materials and methods During a 2-year period, from November 1993 to November 1995, 5548 patients were admitted to hospital because of a clinical & The European Society of Cardiology All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 AF, ischaemic heart disease, and the risk of death in patients with heart failure 2867 worsening of heart failure and screened at 34 centres for possible participation in the Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) Congestive Heart Failure (CHF) trial. 22 Twenty-two centers (n ¼ 3892 patients) agreed on participating in the present retrospective analysis and they identified all patients with AF at the initial hospitalization. Data on AF were availably in a high number of patients, n ¼ 3587 (92%) and the remaining 305 were excluded from the present analysis. Only three patients were lost to follow-up. Patients qualified for inclusion in the DIAMOND register (and to be screened for inclusion into the DIAMOND study) were consecutive patients hospitalized with new or worsening congestive heart failure and who within the preceding month had had at least one episode of shortness of breath on minimal exertion or at rest [New York Heart Association (NYHA) functional class III or IV) or paroxysmal nocturnal dyspnoea. NYHA classes used in the study are those recorded at the time of inclusion in the study. For all screened patients demographic data, prior diseases, medication, and hospital complications were noted and a two-dimensional echocardiography was recorded on videotape. Left ventricular (LV) systolic function was determined by echocardiography, a method previously described in detail. 22 It was assessed by calculation of wall motion index (WMI), using a 16-segment model of the LV and a reverse scoring system. WMI multiplied by 0.3 gives an estimate of ejection fraction. The following intervals gives an estimate on the relation between WMI and left ventricular ejection fraction (LVEF): WMI 0.8 (LVEF, 0.25), WMI ¼ (LVEF ¼ ), WMI ¼ (LVEF ¼ ), and WMI. 1.6 (LVEF. 0.50). Patients with a WMI 1.2 were considered for inclusion in DIAMOND CHF trial and those eventually included were randomized to dofetilide treatment or placebo. The diagnosis of AF was documented by electrocardiograms obtained during hospitalization and had to fulfil the following criteria: AF absence of P waves, coarse or fine fibrillatory waves, and completely irregular RR-intervals. In particular, the investigators had to distinguish AF from atrial flutter (AFL) defined as: presence of regular P waves with a rate between 250 and 350/min and regular or irregular RR-intervals. The investigators were asked to classify the duration of AF during hospitalization and whether the patients had AF at the baseline electrocardiogram (ECG), new onset AF during hospitalization, continuous AF, AF at the time of, and whether they had a history of paroxysmal or persistent/ permanent AF. Baseline AF required that AF was present at the ECG obtained at baseline. New onset AF required that the patients did not have AF at the baseline electrocardiogram and developed AF during hospitalization. Continuous AF during hospitalization required that AF was present at the baseline ECG, any time during hospital stay and at the time of. Paroxysmal AF was defined as AF being present at baseline or any time during hospitalization but not at the time of. The presence or absence of ischaemic heart disease relied on the clinical judgment of the investigator who specifically reported whether ischaemic heart disease was diagnosed. Formal criteria were not specified. In our analysis, history of ischaemic heart disease included patients with either angina or previous myocardial infarction or both. The study was approved by the Ethics Committee and all patients gave informed consent to participate in the study. Statistical methods Differences between groups with respect to medical history and clinical data were examined by the use of x 2 and Mann Whitney tests for categorical and continuous variables, respectively. Categorical variables are presented as counts and percentages. Continuous variables are presented as median values and 5 and 95 percentiles. Differences in mortality between groups were examined by use of log-rank tests and presented as Kaplan Meier curves. Mortality of AF was studied with Cox proportional hazard models. The model assumptions (proportional hazard assumption, lack of interaction, and linearity of continuous variables) were tested and found valid unless otherwise indicated. In multivariable analyses we adjusted for age, gender, WMI, history of ischaemic heart disease, and diabetes. The prognostic impact of AF was studied in the whole population and in two subgroups of patients with and without ischaemic heart disease (history of angina pectoris and/or previous myocardial infarction). Interaction analyses were performed by a likelihood ratio test. A P-value, 0.05 was considered significant. All analyses were performed with the SAS system (SAS version 9, Cary, NC, USA). Results Study size and baseline variables The study population consisted of 3587 patients. The prevalence of different categories of AF is shown in Table 1. Upto 29% of the patients had AF once during hospitalization. Five percent developed AF during hospitalization and 24% of those d from hospital had AF. Ten percent were classified as having paroxysmal AF during hospitalization. Of those patients d from hospital with AF, 78% had a history of persistent/permanent AF, 95% had AF on the baseline ECG, 91% had continuous AF during hospitalization, and 6% had new onset AF. Baseline characteristics of patients without AF in comparison with those having AF at the time of from hospital are shown in Table 2. Patients with AF at the time of were slightly older than patients without AF, whereas patients without AF had a decreased LV function and more patients suffered from angina pectoris or had a previous myocardial infarction. Otherwise, the groups were fairly similar regarding a number of other baseline variables. Mortality In-hospital mortality was not increased in patients with AF at the baseline ECG, 32 deaths of 1040 patients with baseline AF, 76 deaths in 2547 patients without baseline AF [HR ¼ 0.90 (95% CI: ), P ¼ 0.62]. During long-term follow-up, 634 deaths occurred in 818 patients with AF at the time of vs deaths occurred in 2661 without AF (Figure 1). Mortality analyses by Cox proportional hazard regression analyses of the different categories of AF are shown in Table 3, adjusted for age, gender, WMI, diabetes, and history of ischaemic heart disease. Baseline AF or presence of continuous AF during hospitalization were not associated with an increased risk of death during long-term follow-up, whereas development of AF during hospitalization and AF present at the time of Table 1 Prevalence of AF in 3587 patients History of AF Persistent/permanent AF 16% (n ¼ 584) Paroxysmal AF 7% (n ¼ 266) In-hospital AF AF at baseline ECG 29% (n ¼ 1040) Continuous AF in hospital 22% (n ¼ 774) New-onset AF 5% (n ¼ 193) Paroxysmal AF 10% (n ¼ 351) AF at 24% (n ¼ 818) ECG, electrocardiogram.

3 2868 O.D. Pedersen et al. Table 2 Baseline characteristics of patients in relation to AF at from hospital Without AF (n ¼ 2661) AF at (n ¼ 818) P-value Age 72 (52 86) 75 (56 86),0.001 Male gender 1590 (60%) 490 (60%) 0.93 Smoker 938 (35%) 227 (28%),0.001 Previous AMI 1099 (41%) 193 (24%),0.001 Angina 1229 (46%) 252 (31%),0.001 History of 1617 (61%) 357 (44%),0.001 ischaemic heart disease Diabetes 455 (17%) 114 (14%),0.05 Hypertension 665 (25%) 205 (25%) 0.97 NYHA I 135 (5%) 39 (5%) 0.79 NYHA II 851 (32%) 257 (31%) NYHA III 1117 (42%) 359 (44%) NYHA IV 500 (19%) 146 (18%) WMI 1.30 ( ) 1.50 ( ),0.001 Digoxin at 1184 (44%) 692 (85%),0.001 ACE-inhibitor at 1407 (53%) 408 (50%) 0.13 Diuretic at 2276 (86%) 704 (86%) 0.70 ACE, angiotensin converting enzyme; AMI, acute myocardial infarction; NYHA, New York Heart Association class; WMI, Wall Motion Index. Figure 1 Shows the long-term mortality in patients with and without AF d from hospital. were associated with an increased risk of death during the follow-up of 8 years. Paroxysmal AF during hospitalization [HR ¼ 1.01 (95% CI: ), P ¼ 0.86] and a history of AF were not associated with an increased risk during hospitalization or during long-term follow-up. In order to examine the influence of ischaemic heart disease, we separated those with AF at from hospital and with ischaemic heart disease from those with AF at but without ischaemic heart disease (Table 4). Long-term mortality of these subgroups is shown in Figure 2. Patients with the combination of AF and ischaemic heart disease had a significantly worse outcome than those without ischaemic heart disease and AF. Cox proportional Table 3 Cox proportional Hazards regression analyses showing the risk of death associated with different categories of AF hazard regression analyses showed that presence of AF at the time of from hospital was associated with an increased risk of death in patients with ischaemic heart disease [HR ¼ 1.25 (95% CI: ), P, 0.001], while adjusting for age, gender, WMI, history of ischaemic heart disease, and diabetes. Separation of this group completely eliminated the risk in those with AF but without ischaemic heart disease [HR ¼ 1.01 (95% CI: ), P ¼ 0.88] with similar adjustments (Table 3 at the bottom). Interaction analysis showed that there was significant interaction between AF and ischaemic heart disease. Interaction was found to be significant for baseline AF (P ¼ 0.003), continuous AF (P ¼ 0.007), and AF at (P ¼ 0.034). Other analyses Significantly more patients with AF than without were treated with digoxin on from hospital (Table 2). Adding digoxin therapy to the multivariable models resulted in AF not predicting mortality overall [HR ¼ 1.08 (95% CI: ), P ¼ 0.14]. Because digoxin therapy was to a large extent a routine treatment of AF it becomes an intermediary variable and it was therefore not included in the main models. Discussion Hazard ratio (95% CI) P-value History of AF 1.05 ( ) 0.08 Baseline AF 1.03 ( ) 0.49 Continuous AF 1.06 ( ) 0.22 New onset AF 1.28 ( ) AF at 1.12 ( ) AF þ non-ihd 1.01 ( ) 0.88 AF þ IHD 1.25 ( ),0.001 Variables included in the multivariable model: age, gender, WMI, diabetes, history of ischaemic heart disease. IHD, ischaemic heart disease. It has been a mystery why AF has a clear prognostic impact in cohorts of patients with ischaemic heart disease and in the general population, whereas this is not the case in patients with congestive heart failure. 4 In this study, we find that AF is associated with an increased long-term mortality in patients admitted to hospital with clinical worsening of heart failure and d with AF, and for the first time we are able to demonstrate that the risk of death is specifically associated to patients with AF and ischaemic heart disease in heart failure patients (Figure 2 and Table 3). By separation of patients who suffered from both conditions, i.e. AF and ischaemic heart disease, from the cohort of patients with AF but without ischaemic heart disease, we find that those with AF and ischaemic heart disease are those who carry an increased risk of death. In the present study, 29% of those admitted to hospital with worsening heart failure had AF at the baseline electrocardiogram and 24% of those d from hospital had AF. This is slightly more than that observed in previous studies. 4 It is most likely explained by the fact that the median age of our

4 AF, ischaemic heart disease, and the risk of death in patients with heart failure 2869 Table 4 Baseline characteristics of patients separated into subgroups with and without AF at from hospital and ischaemic heart disease or no ischaemic heart disease No AF AF No IHD (n ¼ 1044) IHD (n ¼ 1617) No IHD (n ¼ 461) IHD (n ¼ 357) Age (range) 73 (50 87) 72 (53 85) 74 (54 86) 75 (60 86) Male gender (%) 575 (55) 1015 (63) 264 (57) 226 (63) Smoker (%) 401 (38) 537 (33) 135 (29) 92 (26) Hypertension (%) 260 (25) 405 (25) 108 (23) 96 (27) Diabetes (%) 155 (15) 300 (19) 55 (12) 59 (17) NYHA I (%) 73 (7) 62 (4) 26 (6) 13 (4) NYHA II (%) 311 (30) 540 (33) 145 (31) 112 (31) NYHA III (%) 436 (42) 681 (42) 196 (43) 163 (46) NYHA IV (%) 195 (18) 305 (19) 84 (18) 62 (17) WMI (range) 1.5 ( ) 1.2 ( ) 1.6 ( ) 1.3 ( ) ACE-inhibitor at (%) 465 (45) 942 (58) 256 (44) 203 (57) Diuretic at (%) 870 (83) 1406 (87) 395 (86) 309 (87) Digoxin at (%) 460 (44) 724 (45) 399 (87) 293 (82) Deaths The actual number of deaths rates are shown at the bottom. NYHA, New York Heart Association class; ACE, angiotensin converting enzyme; IHD, ischaemic heart disease. Figure 2 Shows influence of ischaemic heart disease (IHD) on the long-term mortality in patients with and without AF d from hospital. cohort patients was approximately 10 years older than these studies, bearing in mind the well known association between increasing age and the prevalence of AF. Our analysis also revealed that most patients d with AF (95%) also had AF at baseline. Furthermore, of the patients d with AF, 78% had a history of persistent/permanent AF. On the other hand, of the patients having AF at baseline, 76% had AF at from hospital. In this study, we focused our analysis on patients d with AF, because baseline AF was not associated with an increased in-hospital mortality and paroxysmal AF was not associated with an increased long-term mortality. Patients with AF at differed with respect to a number of baseline characteristics from those without AF. Although the groups had a similar distribution of NYHA class, the group of patients with AF had better LV systolic function. This finding is different from what one would expect, when considering that mortality was higher in patients with AF. LV systolic function is a major determinant of the prognosis in patients and although we adjusted for this variable in the multivariable analyses, AF retained its prognostic impact. These facts led us to speculate whether another major determinant of outcome, namely presence or absence of ischaemic heart disease, might have significant impact in this particular group. Fewer patients suffered from ischaemic heart disease in the group with AF, which is in accordance with findings in previous studies. The prognostic impact associated with AF reported in previous heart failure studies has been highly variable. In an analysis from a major heart failure study, the Studies of LV Dysfunction (SOLVD) study, 5 AF was associated with an independent increase in the risk of death, whereas in a similar analysis from another heart failure study, the Vasodilator-Heart Failure Trial (V-HEFT), 19 AF was not associated with an increase in risk of death. More recently, data from the Carvedilol or Metoprolol European Trial (COMET) study adds further to the discussion. 21 In this study, AF was associated with an increased risk of death in univariable analysis, but following adjustment for baseline variables in multivariable analysis the risk disappeared. Other studies have reported similar differences and made it unclear whether AF has a prognostic impact in heart failure patients or not In the present study, we find that in patients admitted to hospital with a worsening of heart failure and who have AF at and ischaemic heart disease have a significant and clear association with an increased risk of death, whereas the risk was not increased in patients with AF and without ischaemic heart disease. This could be an explanation of the differences found in previous studies and fits perfectly with the results found in patients with ischaemic heart disease. 2 We suggest two possible explanations. In patients without ischaemic heart disease, there may be many cases where AF was the cause of heart failure and given that the mechanism of heart failure is different it is not surprising that the prognosis should be different.

5 2870 O.D. Pedersen et al. Another explanation is that patients with ischaemia tolerate the tachycardia less well leading to a worse outcome. LV systolic function was slightly lower in patients with AF and ischaemic heart disease, but we adjusted for this variable in the multivariable analysis. Limitations During follow-up of this study, standard care of heart failure has changed in a number of aspects. Medical therapy of heart failure changes rapidly and improves the prognosis. Altered prescription patterns of beta-blockers, aldosterone antagonists, anti-ischaemic, anti-coagulation drugs, and introduction of invasive treatment such as percutaneous coronary interventions (PCIs) since our study may have changed the risks associated with the clinical characteristics discussed in our study. Studies with long-term follow-up as this one (inclusion ended late in 1995 and the follow-up was up to 8 years) are often at risk of changes in treatment during the follow-up, which is impossible to make adjustments for in the multivariable analysis. Digitalis therapy was not included in the multivariable analysis since it may be regarded as an intermediate variable. The diagnosis of ischaemic heart disease relied on the investigators judgment at the local hospital, which may have lead to some misclassifications. However, our registration of ischaemic heart disease is close to what has been observed in previous studies and we also find a lower frequency of ischaemic heart disease in patients with AF in accordance with previous studies. 5,19,21 Statistical analyses have limitations and we cannot exclude that our finding of AF being associated with a worse prognosis primarily in patients with an ischaemic aetiology of heart failure may be a result of play of chance. Conclusion AF is a common condition in patients admitted to hospital with a worsening of heart failure and once present it is indeed very likely that it persists. In this study, AF at the time of was associated with a slight increase in the risk of death during long-term follow-up. Subgroup analysis demonstrate that patients with AF at the time of, but without a history of ischaemic heart disease have a favourable prognosis, whereas those with ischaemic heart disease have an increased risk of death. Acknowledgements Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) study was sponsored by Pfizer. Conflict of interest: Dr Torp-Pedersen has received payment for speaker s bureau appointments and received honoraria payment. No other conflicts of interest. References 1. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316: Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. The occurrence and prognostic significance of atrial fibrillation/flutter following acute myocardial infarction. TRACE (TRAndolapril Cardiac Evaluation) Study group. Eur Heart J 1999;20: 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: Pedersen OD, Brendorp B, Kober L, Torp-Pedersen C. Prevalence, prognostic significance, and treatment of atrial fibrillation in congestive heart failure with particular reference to the DIAMOND-CHF study. Congest Heart Fail 2003;9: Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waclawiw MA, Stevenson LW. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trials. J Am Coll Cardiol 1998;32: Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure. A study of 390 patients. Circulation 1991;84: Mathew J, Hunsberger S, Fleg J, Mc Sherry F, Williford W, Yusuf S. Incidence, predictive factors, and prognostic significance of supraventricular tachyarrhythmias in congestive heart failure. Chest 2000;118: Maggioni A, Gorini M, Midi P, Lussi D, Tavazzi L; on behalf of the IN-CHF investigators. Predictors of 1-year mortality in 2086 outpatients with congestive heart failure: data from the Italian network on congestive heart failure. J Am Coll Cardiol 1998;34(Suppl. A):218A. 9. Lengyel M, Kokeny M. Follow-up study in congestive (dilated) cardiomyopathy. Acta Cardiol 1981;36: Hofmann T, Meinertz T, Kasper W, Geibel A, Zehender M, Hohnloser S, Stienen U, Treese N, Just H. Mode of death in idiopathic dilated cardiomyopathy: a multivariate analysis of prognostic determinants. Am Heart J 1988;116: Maggioni AP, Latini R, Carson PE, Singh SN, Barlera S, Glazer R, Masson S, Cere E, Tognoni G, Cohn JN. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J 2005;149: Diaz RA, Obasohan A, Oakley CM. Prediction of outcome in dilated cardiomyopathy. Br Heart J 1987;58: Fuster V, Gersh BJ, Giuliani ER, Tajik AJ, Brandenburg RO, Frye RL. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981;47: Juilliere Y, Danchin N, Briancon S, Khalife K, Ethevenot G, Balaud A, Gilgenkrantz JM, Pernot C, Cherrier F. Dilated cardiomyopathy: long-term follow-up and predictors of survival. Int J Cardiol 1988;21: Keogh AM, Baron DW, Hickie JB. Prognostic guides in patients with idiopathic or ischaemic dilated cardiomyopathy assessed for cardiac transplantation. Am J Cardiol 1990;65: Koide T, Kato A, Takabatake Y, Iizuka M, Uchida Y, Ozeki K, Morooka S, Makihana M, Serizawa T, Tanaka S, Ohya T, Momomura S, Murao S. Variable prognosis in congestive cardiomyopathy. Role of left ventricular function, alcoholism, and pulmonary thrombosis. Jpn Heart J 1980;21: Romeo F, Pelliccia F, Cianfrocca C, Cristofani R, Reale A. Predictors of sudden death in idiopathic dilated cardiomyopathy. Am J Cardiol 1989;63: Crijns HJ, Tjeerdsma G, de Kam PJ, Boomsma F, van Gelder IC, van den Berg MP, van Veldhuisen DJ. Prognostic value of the presence and development of atrial fibrillation in patients with advanced chronic heart failure. Eur Heart J 2000;21: Carson PE, Johnson GR, Dunkman WB, Fletcher RD, Farrell L, Cohn JN. The influence of atrial fibrillation on prognosis in mild to moderate heart failure. The V-HeFT Studies. The V-HeFT VA Cooperative Studies Group. Circulation 1993;87(Suppl. 6):VI102 VI Convert G, Delaye J, Beaune J, Biron A, Gonin A. Prognosis of primary non-obstructive cardiomyopathies. Arch Mal Coeur Vaiss 1980;73: Swedberg K, Olsson LG, Charlesworth A, Cleland J, Hanrath P, Komajda M, Metra M, Torp-Pedersen C, Poole-Wilson P. Prognostic relevance of atrial ibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET. Eur Heart J 2005; 26: Torp-Pedersen C, Moller M, Bloch-Thomsen PE, Kober L, Sandoe E, Egstrup K, Agner E, Carlsen J, Videbaek J, Marchant B, Camm AJ. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. NEnglJMed1999;341: