Ole Dyg Pedersen a, T, Henning Bagger b, Lars Kbber c, Christian Torp-Pedersen a FACC, on behalf of the TRACE Study Group

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1 International Journal of Cardiology 100 (2005) Impact of congestive heart failure and left ventricular systolic function on the prognostic significance of atrial fibrillation and atrial flutter following acute myocardial infarction Ole Dyg Pedersen a, T, Henning Bagger b, Lars Kbber c, Christian Torp-Pedersen a FACC, on behalf of the TRACE Study Group a Department of Cardiology Y, Bispebjerg University Hospital, Bispebjerg Bakke 23, 2400 Kbbenhavn NV, Denmark b Department of Internal Medicine, Viborg Sygehus, Denmark c Department of Cardiology B, Rigshospitalet, Copenhagen, Denmark Received 25 March 2004; accepted 17 June 2004 Abstract Background: Reports on the prognostic importance of atrial fibrillation following myocardial infarction have provided considerable variation in results. Thus, this study examined the impact of left ventricular systolic function and congestive heart failure on the prognostic importance of atrial fibrillation in acute myocardial infarction patients that might explain previous discrepancies. Methods: The study population was 6676 patients consecutively admitted to hospital with acute myocardial infarction. Information on the presence of atrial fibrillation/flutter, left ventricular systolic function and congestive heart failure were prospectively collected. was followed for 5 years. Results: In patients with left ventricular ejection fraction b5, atrial fibrillation/atrial flutter was associated with an increased in-hospital mortality (OR=1.8 ( ); pb5) but not an increased 30-day mortality. In patients with 5Vleft ventricular ejection fractionv5, atrial fibrillation/atrial flutter was associated with an increased in-hospital mortality (OR=1.7 ( ); pb01) and an increased 30-day mortality (OR=1.7 ( ); pb01). In-hospital and 30-day mortality was not increased in patients with left ventricular ejection fraction N5. In patients with congestive heart failure, atrial fibrillation/atrial flutter was associated with an increased in-hospital mortality (OR=1.5 ( ); pb01) and increased 30-day mortality (OR=1.4 ( ); pb01) but not in patients without congestive heart failure. In hospital survivors, atrial fibrillation/atrial flutter was associated with an increased long-term mortality in all subgroups except those with left ventricular ejection fraction b5. Conclusions: Atrial fibrillation/atrial flutter is primarily associated with increased in-hospital mortality in heart failure patients. Long-term mortality is increased in all subgroups except those with left ventricular ejection fraction b25%. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Acute myocardial infarction; Atrial fibrillation/flutter; Left ventricular systolic function; Congestive heart failure 1. Introduction In patients with an acute myocardial infarction atrial fibrillation is found in up to 20% of cases, and increasing evidence supports that atrial fibrillation is associated with T Corresponding author. Tel.: ; fax: address: odplc@mail.dk (O.D. Pedersen). an increased risk of death [1 7]. The reported risk has varied substantially and possible the heterogeneous patient populations studied may explain the differences. Patients in available studies have different selection bias being either participants in clinical trials, elderly patients or more unselected consecutive patients. Congestive heart failure is a frequent complication in atrial fibrillation patients compared to those in sinus rhythm. Most studies have reported a twofold higher occurrence of congestive /$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:1016/j.ijcard

2 66 O.D. Pedersen et al. / International Journal of Cardiology 100 (2005) heart failure in atrial fibrillation patients compared to patients in sinus rhythm and an incidence as high as 65% [1 7] and variation from 45% to 65%. The opposite is also true and congestive heart failure is an important predictor of atrial fibrillation during hospitalization [6]. It is well known, that congestive heart failure and/or left ventricular systolic function are major determinants of the prognosis following acute myocardial infarction. Consequently, the variable risk of death associated with atrial fibrillation could possible be explained by the variable incidence of congestive heart failure. No previous study has in detail examined the risk of atrial fibrillation according to the presence or absence of congestive heart failure, or according to the degree of left ventricular dysfunction. In one study of consecutive patients, atrial fibrillation was associated with an increased mortality only in congestive heart failure patients [2], whereas other studies have found increased risk in patient materials with few congestive heart failure patients [4,7]. The TRAndolapril Cardiac Evaluation (TRACE) study register contains information from nearly 7000 consecutive acute myocardial infarction patients [8] screened for entry into the TRACE study. Data on left ventricular function, heart failure and atrial fibrillation were carefully registered and this material therefore allows further exploration of the risk associated with atrial fibrillation in relevant subgroups. 2. Material and methods The study population consisted of 6676 consecutive patients with acute myocardial infarction admitted to 27 coronary care units in Denmark between May 1990 and July These patients were screened for inclusion into the TRAndolapril Cardiac Evaluation (TRACE) study [9]. A detailed description of the entire screened population has been reported previously [8]. In brief, consecutive patients above 18 years old were screened between day 2 and day 6 after the onset of symptoms in relation to the acute myocardial infarction. The presence of a myocardial infarction required that chest pain and/or electrocardiographic changes suggestive of infarction or ischemia were accompanied by an increase of one or more cardiac enzymes to at least twice the upper limit of the normal value at the laboratory of the participating hospital. Data on medical history and clinical events during the entire hospitalization were recorded. Based on all available 12-leads electrocardiographic recordings and reports of continuous electrocardiographic monitoring, the investigators had to report whether atrial fibrillation/atrial flutter was present in the following periods during hospitalization: days 1 2, days 3 4 and from day 5 until discharge from hospital. The diagnosis of atrial fibrillation and atrial flutter was left to the discretion of the investigators as previously described [8]. Left ventricular systolic function was determined by echocardiography. The echocardiographic method used for the screening procedure has previously been described in detail [10]. Briefly, by the use of a nine segment model of the left ventricle, wall motion index was estimated using a reverse scoring system as described by Berning et al. [11]. With this method, wall motion index multiplied by provides an estimate of left ventricular ejection fraction (LVEF), which we report in this study. In order to investigate the risk of atrial fibrillation/atrial flutter in patients with different degrees of reduced left ventricular function, the patients were stratified into four groups: LVEFb5, 5VLVEFV5, 5bLVEFV0 and LVEFN0. It was possible to obtain an echocardiogram in 6232 of the 6676 consecutive patients. In the remaining 444 an echocardiogram was not obtained either due to technical reasons or early death after admission to hospital. Of the 5958 patients who survived the initial Table 1 Baseline characteristics in 6232 acute myocardial infarction patients with and without atrial fibrillation/flutter () stratified according to left ventricular ejection fraction (LVEF) LVEFb5 5VLVEFV5 5bLVEFV0 LVEFN0 (N=112) (N=224) (N=579) (N=1561) (N=293) (N=1293) (N=309) (N=1875) Age (years) Male gender (%) T 57 69TTT Thrombolytic treatment (%) TT 32 48TTT 31 44TTT Prior myocardial infarction Angina pectoris (%) T Hypertension (%) TT Congestive heart failure (%) TT 19 9TTT 22 7TTT Diabetes (%) atrial fibrillation/flutter; LVEF left ventricular ejection fraction. T Pb5. TT Pb1. TTT Pb01.

3 O.D. Pedersen et al. / International Journal of Cardiology 100 (2005) Table 2 Baseline characteristics in 6676 consecutive acute myocardial infarction patients with and without atrial fibrillation/flutter stratified according to the presence/ absence of congestive heart failure Without CHF With CHF (N=364) (N=2732) (N=1031) (N=2549) Age (years) 71 63TTT 75 71TTT Male gender (%) Left ventricular ejection fraction 5 1TTT 3 6TTT Thrombolysis (%) 38 48TTT 29 38TTT Prior myocardial infarction (%) T Angina pectoris (%) TT Hypertension (%) Diabetes (%) atrial fibrillation/flutter, CHF congestive heart failure. T Pb5. TT Pb1. TTT Pb01. hospitalization, an echocardiogram was available in In addition, the patients were separated into groups with and without congestive heart failure. Congestive heart failure was defined as either a known history of congestive heart failure and/or killip class N1 at any time during hospitalization and need for diuretic treatment [12]. Informed consent was obtained before screening. The Ethics committees of the participating hospitals approved the study Statistical methods Continuous variables were compared with rank sum tests and categorical variables with Chi-square tests. In-hospital and 30-day mortalities were analyzed using linear logistic regression models and long-term mortality 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 Variable In-hospital mortality LVEF < 5 Hazard ratio (95% CI) rate 24% 39% LVEF 6-5 LVEF 6-0 LVEF > 0 10% 4% 3% 20% 10% 6% 30-day mortality LVEF < 5 LVEF 6-5 LVEF 6-0 LVEF > 0 Long-term mortality LVEF < 5 LVEF 6-5 LVEF 6-0 LVEF > 0 30% 13% 6% 3% 40% 24% 10% 8% 0 1,0 2,0 3,0 Fig. 1. Estimated hazard ratios for in-hospital mortality, 30-day mortality and long-term mortality in 6232 acute myocardial infarction patients with and without atrial fibrillation/flutter stratified in groups according to left ventricular ejection fraction. Abbreviations: LVEF left ventricular ejection fraction; atrial fibrillation/flutter; CI confidence interval.

4 68 O.D. Pedersen et al. / International Journal of Cardiology 100 (2005) valid unless otherwise indicated. A p-value b5 was considered significant. All analyses were performed with the SAS system (SAS, Cary, North Carolina). 3. Results 3.1. Baseline characteristics The distribution of the baseline characteristics in subgroups of left ventricular systolic function and in subgroups with and without congestive heart failure is shown in Tables 1 and 2, respectively according to left ventricular systolic function The unadjusted in-hospital mortality and 30-day mortality according to left ventricular systolic function is shown in Fig. 1, left column. Long-term mortality rates of patients discharged from hospital alive and stratified according to left ventricular systolic function are shown in Fig. 2. Fig. 1 shows that the unadjusted in-hospital mortality and 30-day mortality were increased in patients with atrial fibrillation/atrial flutter in all subgroups of LVEF. Similarly, in patients discharged from hospital alive, the unadjusted long-term mortality was increased in all subgroups of LVEF, except those with LVEFb5, Fig. 2. After adjustment for age, gender, diabetes, hypertension, prior myocardial infarction, ventricular arrhythmias, thrombolytic treatment and congestive heart failure (Fig. 1), the presence of during hospitalization was associated with a nearly twofold increase of the in-hospital mortality risk in patients with LVEF V5, whereas the risk was not increased in patients with LVEFN5. In patients with LVEF between 5 and 5, the risk with respect to 30- day mortality remained increased at this level, but not in the other LVEF groups. In patients surviving hospitalization, atrial fibrillation/ atrial flutter was associated with a moderate increased long- LVEF < 5 + LVEF LVEF LVEF > Fig. 2. Kaplan Meier plots of the unadjusted long-term mortality in 5622 patients with and without atrial fibrillation/flutter discharged from hospital after acute myocardial infarction stratified in groups according to left ventricular ejection fraction. Abbreviations: LVEF left ventricular ejection fraction; atrial fibrillation/flutter.

5 O.D. Pedersen et al. / International Journal of Cardiology 100 (2005) term mortality risk in patients with LVEFz5, whereas the risk was not increased in patients with LVEF below 5, Fig. 1. Analysis of interaction between different LVEF groups and the presence of atrial fibrillation/atrial flutter confirmed that the presence of atrial fibrillation/atrial flutter in patients with LVEFb5 was associated with a worse short-term outcome, compared to atrial fibrillation/atrial flutter in patients with LVEFN5 ( P=2). For long-term prognosis, the interaction parameter between LVEF and the presence of atrial fibrillation/atrial flutter was also statistically significant with P= according to presence/absence of congestive heart failure The unadjusted in-hospital mortality of atrial fibrillation/ atrial flutter patients without congestive heart failure was low, but otherwise the presence of atrial fibrillation/atrial flutter was associated with an increased short-term mortality risk in all subgroups Fig. 3. After adjustment for age, gender, diabetes, hypertension, prior myocardial infarction, ventricular arrhythmias, thrombolytic treatment and LVEF, the presence of atrial fibrillation/atrial flutter during hospitalization was associated with a moderate increased in-hospital mortality and 30-day mortality in patients with congestive heart failure, but not in patients without congestive heart failure, Fig. 3. In hospital survivors, the presence of atrial fibrillation/atrial flutter was associated with an increased long-term mortality in both patients with and without congestive heart failure, Figs. 3 and 4. For neither in-hospital mortality or long-term mortality the + ; + CHF + ; no CHF ; no CHF ; + CHF Fig. 4. Kaplan Meier plot of the unadjusted long-term mortality in patients with and without atrial fibrillation/flutter stratified according to the presence/absence of congestive heart failure in 5958 patients discharged from hospital after acute myocardial infarction. Abbreviations: CHF congestive heart failure; atrial fibrillation/flutter. Without CHF Hazard ratio (95% CI) rate In-hospital mortality 2% 4% 30-day mortality 3% 6% Long-term mortality With CHF In hospital mortality 15% 23% 30-day mortality 18% 25% Long-term mortality 0 1,0 2,0 3,0 Fig. 3. Estimated hazard ratios for in-hospital mortality and 30-day mortality in 6676 acute myocardial infarction patients with and without atrial fibrillation/ flutter separated in groups according to the presence or absence of congestive heart failure. Abbreviations: CHF congestive heart failure; atrial fibrillation/flutter; CI confidence intervals.

6 70 O.D. Pedersen et al. / International Journal of Cardiology 100 (2005) interaction between the presence of atrial fibrillation/atrial flutter and congestive heart failure was statistically significant ( pn5). 4. Discussion The most interesting finding of this study is that inhospital mortality is increased nearly twofold in patients with atrial fibrillation/atrial flutter and reduced left ventricular function. This observation may have important clinical implications because treatment of atrial fibrillation in this particular group could result in a mortality reduction. To our knowledge, this study is the first study to examine the risk of atrial fibrillation/atrial flutter in patients with acute myocardial infarction according to the degree of left ventricular dysfunction. Importantly, in patients with moderate (LVEF between 5 and 5) to severely (LVEF below 5) reduced left ventricular systolic function the presence of atrial fibrillation/atrial flutter was associated with a nearly twofold increase of inhospital mortality, whereas in patients with normal or slightly reduced LVEF (above 5) the in-hospital risk was not significantly increased. Atrial fibrillation/atrial flutter retained the increased risk of death in patients with moderate reduced left ventricular systolic function with respect to 30-day mortality. In patients surviving hospitalization, atrial fibrillation/atrial flutter was associated with an increased risk of death in all subgroups of LVEF with respect to long-term mortality, except those with LVEFb5. But, few patients survived until discharge in this group, which reduces the statistical power of the analysis. Interaction analysis confirmed that the importance of atrial fibrillation is dependent on left ventricular systolic function. Our study is the first to demonstrate that in the acute phase and the first 30 days after acute myocardial infarction, atrial fibrillation/atrial flutter is associated with a markedly increased mortality in patients with reduced left ventricular function and/or congestive heart failure. However, our analysis of interaction indicate that measurement of LVEF is the best tool to identify a high risk group of atrial fibrillation/atrial flutter patients, whereas stratification according to presence/absence of congestive heart failure is less efficient in this aspect. Our study also demonstrates that the long-term risk of atrial fibrillation/ atrial flutter appears to be increased in nearly all patients, independent of left ventricular systolic function, although we were unable to show this in the group with marked LVEF reduction. Only one study has examined the risk of atrial fibrillation/atrial flutter in consecutive acute myocardial infarction patients stratified according to the presence/ absence congestive heart failure in the thrombolytic era [2]. Although Eldar et al. did not report a detailed analysis of patients with and without congestive heart failure, it appears that the increased long-term risk (1 year) of atrial fibrillation was mainly found in patients with congestive heart failure. They did not examine the in-hospital risk and they had a much shorter follow-up than in the present study. Our study shows that inhospital mortality and 30-day mortality were increased in atrial fibrillation/atrial flutter patients with congestive heart failure. Although we did not find a statistical increased risk in patients without congestive heart failure with respect to in-hospital mortality and 30-day mortality, our analysis of interaction indicates that there is no major difference between the groups with and without congestive heart failure. In patients surviving hospitalization, atrial fibrillation/atrial flutter was associated with increased long-term (5 years) risk of death in both patients with and without congestive heart failure. In accordance with our result, others have observed an increased long-term risk in studies with few patients having congestive heart failure and at low risk of death [1,7]. The fact that we observed an increased long-term risk in both patients with and without congestive heart failure and Eldar et al. did not, may be a result of differences in the size of the study populations and the length of follow-up. However, despite differences in outcome in these studies, together they indicate that atrial fibrillation is associated with increased long-term mortality both in patients with and without congestive heart failure. The mechanism by which atrial fibrillation/atrial flutter may increase mortality is not completely understood and the mechanisms by which atrial fibrillation/atrial flutter affects short-term mortality may be different from the effect on long-term mortality. The increased risk associated with atrial fibrillation/atrial flutter during hospitalization in patients with moderate to severe reduced left ventricular function may be caused by an immediate deterioration of left ventricular function due to the decreased cardiac output caused by atrial fibrillation/atrial flutter [13] Clinical implications Recently, a subgroup analysis of patients with atrial fibrillation complicating acute myocardial infarction from the GUSTO-III trial showed a strong trend towards a lower mortality in patients treated with class I antiarrhythmic agents and sotalol [14]. Other studies indicate that intervention such as restoration and maintenance of sinus rhythm in patients with congestive heart failure and reduced left ventricular function may improve survival in patients with atrial fibrillation [15,16]. In contrast, two important studies testing the hypothesis of whether a strategy of rhythm control (i.e., restoration and maintenance of sinus rhythm) is better than rate control (i.e., regulation of the ventricular response) [17,18], showed no difference with respect to mortality. However, these studies investigated patients that

7 O.D. Pedersen et al. / International Journal of Cardiology 100 (2005) were highly different from the patients in this study. Approximately 20% had congestive heart failure in the AFFIRM trial and the prevalence of ischemic heart disease was approximately 30% in each study. This study suggest, that if aggressive intervention against atrial fibrillation/atrial flutter such as restoration and maintenance of sinus rhythm should be tested in patients with acute myocardial infarction, the group most likely to benefit is patients with moderate to severely reduced left ventricular systolic function. It has never been studied whether early restoration of sinus rhythm in patients with atrial fibrillation after myocardial infarction improves outcome in comparison to rate regulation. Such an intervention should probably be initiated shortly after acute myocardial infarction Limitations Our study has several limitations. We were not able to distinguish between patients with atrial fibrillation and atrial flutter, because they were recorded as a single category. But, atrial fibrillation is much more prevalent in the setting of acute myocardial infarction and atrial fibrillation and atrial flutter frequently coexist. We did not adjust for medical treatment in our multivariate regression model, because data on prescription of medical treatment were not available after admission to hospital or during follow-up. However, medical treatment changes occur frequently during followup, which limits the value of such adjustments. We did not distinguish between paroxysmal and permanent or persistent atrial fibrillation, and we were unable to evaluate the permanence of atrial fibrillation after hospitalization. Acknowledgments The TRACE Study was supported by a grant from the Danish Heart Association. References [1] Crenshaw BS, Ward SR, Granger CB, Stebbins AL, Topol EJ, Califf RM. Atrial fibrillation in the setting of acute myocardial infarction: the GUSTO-I experience. Global utilization of streptokinase and TPA for occluded coronary arteries. J Am Coll Cardiol 1997;30: [2] Eldar M, Canetti M, Rotstein Z, Boyko V, Gottlieb S, Kaplinsky E, et al. Significance of paroxysmal atrial fibrillation complicating acute myocardial infarction in the thrombolytic era. SPRINT and Thrombolytic Survey Groups. Circulation 1998;97: [3] Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. The occurrence and prognostic significance of atrial fibrillation/-flutter following acute myocardial infarction. TRACE Study group. TRAndolapril cardiac evaluation. Eur Heart J 1999;20: [4] Wong CK, White HD, Wilcox RG, Criger DA, Califf RM, Topol EJ, et al. New atrial fibrillation after acute myocardial infarction independently predicts death: the GUSTO-III experience. Am Heart J 2000;140: [5] Sakata K, Kurihara H, Iwamori K, Maki A, Yoshino H, Yanagisawa A, et al. Clinical and prognostic significance of atrial fibrillation in acute myocardial infarction. Am J Cardiol 1997;80: [6] Rathore SS, Berger AK, Weinfurt KP, Schulman KA, Oetgen WJ, Gersh BJ, et al. Acute myocardial infarction complicated by atrial fibrillation in the elderly: prevalence and outcomes. Circulation 2000;101: [7] Pizzetti F, Turazza FM, Franzosi MG, Barlera S, Ledda A, Maggioni AP, et al. Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: the GISSI-3 data. Heart 2001;86: [8] The TRACE study group. The TRAndolapril Cardiac Evaluation (TRACE) study: rationale, design, and baseline characteristics of the screened population. Am J Cardiol 1994;73:44C 55C. [9] Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lynborg K, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor TRAndolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. 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Management and outcome of patients with atrial fibrillation during acute myocardial infarction: the GUSTO-III experience. Global use of strategies to open occluded coronary arteries. Heart 2002;88: [15] Deedwania PC, Singh BN, Ellenbogen K, Fisher S, Fletcher R, Singh SN. Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: observations from the veterans affairs congestive heart failure survival trial of antiarrhythmic therapy (CHF-STAT). The Department of Veterans Affairs CHF-STAT Investigators. Circulation 1998;98: [16] Pedersen OD, Bagger H, Keller N, Marchant B, Kober L, Torp- Pedersen C. Efficacy of dofetilide in the treatment of atrial fibrillationflutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy. Circulation 2001;104: [17] Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. 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