© 2002 European Society of Cardiology
Impact of atrial fibrillation on mortality in patients with chronic heart failure
Department of Cardiology, Thorax Centre, University Hospital Groningen Hanzeplein 1, 9713 GZ Groningen, The Netherlands
* Corresponding author. Tel.: +31-50-361-2355; fax: +31-50-361-4391. E-mail address: m.p.van.den.berg{at}thorax.azg.nl
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Abstract |
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 Top Abstract 1. Introduction2. Mortality studies3. CommentReferences |
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Chronic heart failure and atrial fibrillation often occur together. The aim of the study is to review the available literature on the impact of atrial fibrillation on mortality in patients with heart failure. Using MEDLINE six full papers were identified. In the studies with severe heart failure atrial fibrillation did not emerge as an independent predictor of mortality beyond standard clinical variables. In contrast, atrial fibrillation was associated with increased mortality in case of mild-to-moderate heart failure.
Key Words: Heart failure • Atrial fibrillation • Prognosis • Mortality
Received September 4, 2001; Revised November 22, 2001; Accepted February 4, 2002
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1. Introduction |
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TopAbstract1. Introduction2. Mortality studies3. CommentReferences |
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Chronic heart failure (HF) is a large, still increasing epidemiological problem, particularly in the elderly. The same is true of atrial fibrillation (AF). Moreover, depending on the severity of HF, the two often occur together [1,2]. While AF is relatively uncommon in mild-to-moderate HF, it is a common concomitant disorder in severe disease. Previous studies have shown that AF may cause or aggravate HF. Loss of atrial systole in the setting of left ventricular dysfunction may thus precipitate HF. Further, the irregularity of the heartbeat in AF exerts a detrimental effect on left ventricular function [3]. Finally, uncontrolled high ventricular rates in the setting of AF may cause so-called tachycardiomyopathy [4,5].
Despite recent pharmacological advances the prognostic significance of HF in terms of survival is still poor, particularly in case of severe disease. Given the above hemodynamic effects of AF it seems of interest to determine whether AF further adds to the mortality in the setting of HF. In other words, what is the independent impact of concomitant AF per se on survival in patients with HF? In the present paper the available studies which have addressed this issue are reviewed. The significance of AF in the setting of acute myocardial infarction is beyond the scope of this review. In addition, this report does not deal with ‘diastolic’ HF (preserved systolic left ventricular but diastolic dysfunction) due to the lack of data.
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2. Mortality studies |
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TopAbstract1. Introduction2. Mortality studies3. CommentReferences |
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We searched for articles in MEDLINE using the following combination of reference terms: heart failure, atrial fibrillation, prognosis and mortality. We thus identified 169 articles, which were then screened for their primary endpoint. Only articles with the impact of AF on mortality in the setting of HF as the primary endpoint were accepted. Six of the 169 articles met this criterion [6–11]. Essential features are listed in Table 1, including total number of patients, percentage of patients with AF, severity and etiology of HF, left ventricular ejection fraction, and medication. AF was based on electrocardiographic evidence in all instances. Three studies used databases from large drug-trials [7,9,11]. The study by Carson et al. is based on both V-HeFT I and V-HeFT II (Vasodilator in Heart Failure Trials). VHeFT-I compared prazosin with hydralazine/isosorbide dinitrate and VHeFT-II compared enalapril with hydralazine/isosorbide dinitrate. The study by Dries et al. used the database of the SOLVD (Studies on Left Ventricular Dysfunction), which investigated the effect of enalapril in asymptomatic patients (prevention-arm) and symptomatic patients (treatment-arm). The study by Crijns et al. used data from the PRIME-study, which investigated the added value of ibopamine. The three drug-trials had the usual exclusion-criteria: unstable coronary disease, significant valvular or obstructive myocardial disease, uncontrolled arrhythmia, chronic pulmonary disease and any other disease likely to limit survival. The three other studies dealt with patients referred for evaluation for heart transplantation [6,8,10]. The study by Stevenson et al. focussed on the potential impact on mortality of advances in the pharmacological treatment of HF and AF (angiotensin converting enzyme-inhibitors and amiodarone instead of vasodilators and class I antiarrhythmics). Two treatment periods were thus compared (1985–1989 vs. 1990–1993). Of note, this study included most of the patients in the study by Middlekauff et al. and these patients are therefore presented twice. Complying with the concept that the prevalence of AF depends on the severity of HF, the prevalence of AF in the study by Dries et al. was relatively low (6%) compared with the other studies (13–27%). The analysis of the impact of AF on mortality was comparable in all six studies. In addition to AF, standard clinical variables (severity and etiology of HF and parameters of left ventricular function (ejection fraction)) were analyzed in a univariate and a multivariate fashion. When available, additional parameters were also incorporated. In the study by Crijns et al. data on neurohormones were added to the analysis, and the studies by Middlekauff et al., Stevenson et al. and Mahoney et al. used invasive hemodynamic parameters (wedge pressure, cardiac output), collected as part of evaluation for heart transplantation.
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Data obtained during follow-up are summarized in Table 2. The findings confirm the poor prognosis of HF in general, mortality rates in the patients with sinus rhythm ranging from 23% to as high as 64%. In the studies by Carson et al. and Mahoney et al. AF did not turn out to be predictive of mortality, mortality rates being comparable in patients with sinus rhythm and patients with AF. In contrast, mortality was higher in patients with AF in the studies by Middlekauff et al., Dries et al. and Crijns et al. AF was also a univariate predictor of mortality in the study by Stevenson et al. pertaining to the first treatment period, but not to the second treatment period. However, after multivariate analysis to correct for other variables, AF did not emerge as an independent predictor of mortality in the study by Crijns et al. In contrast, AF maintained its predictive value in the studies by Stevenson et al. (first treatment period) and Dries et al. Of interest, the multivariate predictive value of AF in the study by Middlekauff et al. depended on pulmonary capillary wedge pressure. In case of a high wedge pressure AF had no predictive value, but the presence of AF was found to be an independent predictor of increased mortality when wedge pressure was low (cut-off value 16 mmHg) (Fig. 1). As to the mode of death, most studies provided data on sudden death as opposed to non-sudden death, the latter group presumably largely consisting of patients who died of progressive pump-failure. In none of these studies was AF predictive of a higher non-sudden death rate, with the exception of the study by Dries et al. In that study, after multivariate analysis AF remained significantly associated with all-cause mortality (relative risk 1.34, P=0.002) and progressive pump-failure death (relative risk 1.42, P=0.01), but not sudden death (relative risk 1.13, P=0.55) (Fig. 2).
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In addition to the above full papers, we are aware of one recent abstract on the impact of AF on mortality in patients with HF. In a large population undergoing echocardiography, Pai et al. investigated the effect of AF on mortality relative to left ventricular systolic dysfunction [12]. The prevalence of AF in this population was 13%. The cumulative hazard of death during 5 years follow-up was 32% in patients with sinus rhythm and 60% in patients with AF (P<0.0001). Interestingly, the predictive value of AF was a function of ejection fraction: the impact of AF on mortality was most pronounced in patients with normal left ventricular function (ejection fraction >55%), followed by those with mild dysfunction (ejection fraction 41–54%), whereas AF had no predictive value in patients with moderate to severe dysfunction (ejection fraction <40%).
Very few data are available on the impact of new-onset AF during follow up on mortality in patients with HF. With the exception of the study by Crijns et al. none of the other studies (Table 1) addressed this issue. Of the 325 patients in the study by Crijns et al. who had sinus rhythm at baseline, 30 patients (9%) developed AF in the course of the study. Fourteen of these patients (47%) died during the course of the study, which was in fact identical to the mortality in patients who remained in sinus rhythm throughout the study (139 out of the 295 patients: 47%). In a study in 344 HF patients who were referred for evaluation for heart transplantation, Pozzoli et al. also investigated the impact of new-onset AF [13]. During a mean follow-up of 19 months, 28 patients developed AF, which became permanent in 18 patients. Nine of these 18 patients (50%) developed a major cardiac event (death, urgent transplantation), compared to 114 of the remaining 326 patients (33%) during the remainder of the study. When the first 300 days from the onset of AF were considered, AF was significantly associated with these major events (P=0.02, odds ratio 4), but new-onset AF had no influence on patients who lived longer than that period. In addition, the investigators admitted that it was unclear whether AF was the consequence of hemodynamic deterioration or vice versa. In other words, the apparent association of AF with major events might well have been due to the fact that AF merely reflected prior hemodynamic deterioration.
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3. Comment |
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TopAbstract1. Introduction2. Mortality studies3. CommentReferences |
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It is difficult to wrap together the different studies. Moreover, the individual studies themselves are also subject to bias. In particular, all studies were retrospective. In addition, three studies were medication trials which inevitably implies that the patients were not fully representative of clinical practice due to exclusion criteria. These factors hamper the interpretation of the data. Nonetheless, we believe that the available data point to the following concept: it would appear that concomitant AF in the setting of severe HF does not have an additional impact on mortality. In contrast, in patients with mild-to-moderate HF the presence of AF per se appears to portend an increased risk of dying, added to the already considerable risk inherent to HF. AF was not an independent predictor of mortality in the studies by Carson et al, Mahony et al. and Crijns et al. which included patients with ‘severe’ HF in terms of clinical status (inclusion of patients in NYHA functional class IV, peak VO2, evaluation for transplantation). In contrast, AF was an independent predictor of increased mortality in the large study by Dries et al. which included on average patients with less severe HF. Supporting this finding, Middlekauff et al. showed that the impact of AF is a function of left ventricular filling pressure, a relatively low value (<16 mmHg) but not a higher value predicting increased mortality. Finally, the concept is also supported by the observation by Lai et al. that AF increases mortality only in patients with a relatively preserved ejection fraction.
Assuming the above concept is correct, one would like to explain the concept in terms of the underlying pathophysiologic mechanism(s). A potentially important hemodynamic factor is loss of atrial systole. Previous studies have shown that severe HF as opposed to mild-to-moderate HF is often characterized by ‘restrictive physiology’, implying that the atrial contribution to left ventricular filling is rather limited due to severe diastolic dysfunction [14]. It may therefore be surmised that loss of atrial systole is probably of limited hemodynamic importance in patients with severe HF but of greater importance in patients with mild-to-moderate HF. Another possibility is irregularity of the heartbeat in AF [3]. Previous studies indicate that the degree of irregularity decreases along with worsening of HF due to progressive neurohormonal activation [15,16]. As such, it is conceivable that AF has more hemodynamic impact in patients with less severe HF. Induction of tachycardiomyopathy is also a possibility [4,5] However, heart rate at baseline in patients with AF and heart rate in patients with sinus rhythm (Table 1) was fairly comparable in all studies, including the studies which showed an independent impact of AF on mortality. This observation argues against an important role for tachycardiomyopathy. Finally, the role of antiarrhythmics should be considered. In addition to proarrhythmia which would lead to increased incidence of sudden death, these agents (particularly class I antiarrhythmics) may cause further deterioration of left ventricular function due to their negative inotropic effects.
Putting the concept differently, AF would by itself actively cause progression of disease in patients with mild-to-moderate HF. As such, the concept may have practical implications since treatment of AF, that is, restoration of sinus rhythm would seem desirable in these patients. However, there are as yet no solid data showing that restoration of AF improves prognosis. Two prospective randomized studies are now underway, namely AFFIRM [17] and the Dutch RACE study [18], which are sufficiently powered to address this issue. Both studies compare a strategy of ‘rhythm control’ using serial electrical cardioversion and antiarrhythmics and a ‘rate control’ strategy. The results of these two important studies have to be awaited.
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Acknowledgements |
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Dr. van Veldhuisen is a Clinical Established Investigator of The Netherlands Heart Foundation, grant 079.017.
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References |
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