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European Journal of Heart Failure 2007 9(3):258-265; doi:10.1016/j.ejheart.2006.08.004
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© 2007 European Society of Cardiology

Prevalence and prognostic significance of atrial fibrillation in outpatients with heart failure due to left ventricular systolic dysfunction

Pernille Corella,*, Finn Gustafssonb, Morten Schoua, John Markenvardc, Tonny Nielsend and Per Hildebrandta

a Department of Cardiology and Endocrinology E, Frederiksberg University Hospital Ndr. Fasanvej 57 2000 Frederiksberg, Denmark
b Department of Cardiology B, Copenhagen University Hospital Rigshospitalet, Denmark
c Department of Internal Medicin Fredericia Hospital, Denmark
d Department of Internal Medicine Ribe County Hospital, Esbjerg, Denmark

* Corresponding author. Tel.: +45 38 16 43 81; fax: +45 38 16 43 59. E-mail address: pernillecorell{at}dadlnet.dk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Introduction: Atrial fibrillation (AF) is common in patients with heart failure (HF) due to left ventricular systolic dysfunction (LVSD), with conflicting prognostic data. The aim of our study was to assess the prevalence and incidence of AF in patients with HF and to determine the prognostic impact of baseline AF and the development of new onset AF.

Methods and results: We included 1019 outpatients with HF due to LVSD; follow-up time ranged from 3 to 64months. At baseline 26.4% of patients had AF. Of the 284 patients with a follow-up ECG and baseline SR, 18.7% developed new onset AF.

Patients with AF were older (p<0.001), more often male (p=0.04), and more likely to have a history of stroke (p=0.03), but were less likely to have IHD (p<0.001). Baseline rhythm was independent of LVEF and NYHA-class. Baseline AF was associated with increased all-cause mortality (HR 1.38; CI 1.07–1.78, p=0.01) and all-cause mortality/hospitalisation (HR 1.43; CI 1.22–1.68, p<0.001). When adjusted for baseline covariates, baseline AF was independently associated with an increased risk of experiencing the combined endpoint (HR 1.29; CI 1.05–1.58; p=0.02), but did not predict all-cause mortality. By multivariable analyses, new-onset AF was associated with increased risk of all-cause mortality/hospitalisation (HR 1.45; CI 1.05–2.00; p=0.02).

Conclusion: In outpatients with HF due to LVSD, AF is a common co-morbidity, which adversely affects morbidity and mortality outcomes.

Key Words: Atrial fibrillation • Heart failure • Systolic function • Prognosis

Received March 3, 2006; Revised June 18, 2006; Accepted August 16, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Atrial fibrillation (AF) is a common condition in patients with heart failure (HF) due to left ventricular systolic dysfunction. The prevalence of AF increases with age and severity of the disease, with a prevalence reported to range from 10% to 50% [1-9]. It is currently not clear which factors predispose to the development of AF in patients with HF.

The haemodynamic consequences of AF which compromise cardiac function include irregular and often rapid ventricular rate, loss of atrial contraction, loss of atrioventricular synchrony, and elevated filling pressures causing atrial dilatation and reduction in stroke volumes [10,11]. Despite the negative haemodynamic consequences of AF, the prognostic influence of AF in patients with HF remains controversial. The results of previous studies analysing the independent effect of AF on survival in HF have been conflicting [2,4,6,12-16]. Previous studies were retrospective and most [2,4,14,16] were based on data collected from randomised drug trials, raising the possibility that the patients may not have been representative of patients seen in daily clinical practice. Two of the studies included only patients referred for heart transplantation [6,15].

Therefore, the aims of our study were to assess the prevalence of AF in a population of patients with HF due to left ventricular systolic dysfunction and to determine the prognostic impact of baseline AF and new onset of AF on mortality and admission to hospital compared to patients with sinus rhythm (SR).


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Study population
Patients were recruited between September 1999 and September 2004, from three HF clinics participating in the Danish Network of Heart Failure Clinics [17]. Essentially, the design of these nurse-based HF outpatient clinics is the same and has been described previously [18]. Briefly, patients with documented HF due to systolic dysfunction are referred to the clinics, either directly from general practitioners or from the departments of internal medicine or cardiology in the hospital. There are no specific exclusion criteria for referral to these clinics, and generally, all patients with HF due to systolic dysfunction are eligible. However, as this is a clinical database, rather than an epidemiological study, there is no documentation that all eligible patients in the community are referred. Clinical data on all patients followed in the three participating clinics are registered prospectively in a HF database, HJERTER+(Microsoft, Access) [17]. The database serves as a combined medical record and research tool in the clinics. For the current study, we retrospectively collected data from the HJERTER+database.

2.2. Study design
During the initial visit to the HF clinic (baseline visit), all patients were examined by a senior physician with training in cardiology at a specialist level and a HF nurse. The following information was recorded: medical history, medication, physical examination, NYHA classification, ECG, echocardiography, resting blood pressure, heart rate and blood sample for the measurement of electrolytes and creatinine.

Echocardiography was performed in all patients. Left ventricular ejection fraction (LVEF) was estimated by 9-segment wall motion score index (WMI). WMI multiplied by 0.3 gives an estimate of LVEF [19]. If echocardiography was technically insufficient, radionuclide ventriculography was performed. Patients were classified as having HF due to systolic dysfunction if LVEF was ≤45%.

2.3. Diagnosis of atrial fibrillation
The diagnosis of baseline AF (a distinction from atrial flutter was not made) was based on a 12-lead standard electrocardiogram (ECG) performed at the time of referral (baseline). The diagnosis of new onset AF was based on the follow-up ECG at the time of (1) the last recording prior to the collection of endpoint data for this study or (2) the last recording before the patient was discharged from the clinic to the primary care physician; (3) the last recording before the patient died or (4) from hospital admission. This assessment was only completed in one of the three participating hospitals, and thus, only a subgroup of 415 patients were used for this analysis. Patients with SR at baseline and ECG documented AF during follow-up were classified as new onset AF.

2.4. Endpoint data
Endpoint data were recorded 3 months after the baseline visit of the last included patient resulting in a follow-up time of 3-64 months. Mortality data were obtained in December 2004 from the Danish Central Person Registry in which all deaths are recorded within 2 weeks of occurrence. Hospital admissions were recorded by the discharge registry of the Danish National Board of Health which records all primary hospital discharge diagnoses in Denmark. The registry has been described and validated previously [20]. Hospital admission data were obtained in December 2004.

2.5. Ethics
The investigation conforms to the principles outlined in the Declaration of Helsinki. The ethics committee of Copenhagen and Frederiksberg approved implementation of the clinical database. Patients were not asked to provide written consent for entering of clinical data into the electronic medical record/database, since this was part of the routine clinical practice in the HF clinics. The database was approved by the Danish Data Protection Agency.

2.6. Statistical analysis
Comparison between the SR and the AF group was performed using Student's t-tests for continuous variables and Fisher's exact test for categorical data. Independent predictors of new-onset AF were examined using multivariable logistic regression analyses. Variables included in the regression analyses were age, sex, LVEF, NYHA class and previous acute myocardial infarction (AMI). The unadjusted cumulative survival and incidence of the combined endpoint (all cause death and all cause hospital admission) for patients with AF and SR were compared using Kaplan-Meier survival analyses and statistical significance was tested using a log rank test. Hazard ratios were generated by a Cox regression analysis. To estimate adjusted hazard ratios (HR), we used a Cox proportional hazard model with backward elimination. Covariates included in the model were age, sex, LVEF, NYHA functional class, diabetes, previous AMI, p-creatinine, heart rhythm (AF/SR). Formal interaction testing between AF and relevant covariates was performed using a likelihood ratio test in a univariable Cox model.

The statistical software package SPSS version 11.5 was used for all analyses. A p-value <0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
During the inclusion period, a total of 1313 patients were recorded in the databases at the three hospitals. Of these, 251 patients were excluded from this study due to either LVEF>45%, no documented LVEF or no baseline ECG. In addition, patients with a permanent pacemaker with an ECG showing paced rhythm (n=43) were also excluded, because paced rhythm might lead to an incorrect diagnosis of underlying atrial rhythm. Therefore, a total of 1019 patients with LVEF≤45% were included in this study.

3.1. Baseline characteristics
Baseline characteristics of the study population grouped according to the presence (n=269) or absence (n=750) of AF at baseline are presented in Table 1. Patients with AF at baseline were older and were more often male than patients with SR. There was no difference in mean LVEF, NYHA class distribution, heart rate, or body mass index (BMI) between the groups. Patients with AF had higher p-creatinine and higher diastolic blood pressure, while there was no difference in systolic blood pressure. Patients with SR were more likely to have bundle branch block and to have a history of ischaemic heart disease (IHD), AMI and coronary artery bypass graft (CABG). Patients with AF were more likely to have a history of stroke.


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  		Table 1 Baseline characteristics

 
Significantly more patients in SR than in AF were receiving angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blocker (ARB) and beta-blockers (Table 1). The number of patients treated with beta-blockers was low at the initial visit to the HF clinic, but increased during follow-up, since initiation and uptitration of ACE-inhibitors and beta-blockers were major goals in the clinics (data not shown). As expected, more patients with AF were treated with digoxin and oral anticoagulants. In total 64 patients (6.3%) were treated with anti-arrhythmic drugs, of these 53 (5.2%) received amiodarone. There was no difference in the use of anti-arrhythmic agents between the AF and SR groups.

3.2. Mortality and hospitalisation
Endpoint data were recorded 3 months after the baseline visit of the last included patient resulting in a follow-up time of 3-64 months. For mortality, follow-up time to an endpoint or censoring was 644 days (350-984 days) median; (25-75 percentiles). Seven hundred and sixteen patients (70%) reached the combined end-point (all cause death or all cause admission to hospital).

The unadjusted mortality rate (all-cause death) was significantly higher in patients with baseline AF (33%) compared to patients with SR (24%), resulting in an HR for death in AF patients of 1.38 (CI, 1.07-1.78, p=0.01) (Fig. 1). Patients with baseline AF also experienced a significantly higher rate of all-cause death or all-cause hospitalisation 79% vs. 67%, (HR 1.43, CI, 1.22-1.68; p<0.001) (Fig. 2). After adjustment for baseline covariates in the Cox regression analysis, presence of AF at baseline (HR 1.29; CI 1.05-1.58; p=0.02), presence of NYHA class III and IV (HR 1.25; CI 1.03-1.52; p=0.02) and increasing p-creatinine (HR 1.01; CI 1.00-1.01; p=<0.001) were associated with a significantly increased risk of experiencing the combined endpoint. In contrast, baseline AF did not significantly predict death in the multivariate model (HR 1.06; CI 0.75-1.56; p=0.73). In this model increasing age (HR 1.05; CI 1.03-1.07; p<0.001), presence of diabetes (HR 1.45; CI 1.04-2.03; p=0.03) increasing p-creatinine (HR 1.01; CI 1.00-1.01; p<0.001) and presence of NYHA III/IV (HR 1.65; CI 1.21-2.26; p=0.002) significantly predicted mortality.


Figure 01
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  		Fig. 1 Cumulative all-cause mortality for patients with baseline atrial fibrillation (AF) and sinus rhythm (SR).

 


Figure 02
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  		Fig. 2 Cumulative all-cause mortality or all-cause hospitalisation (combined endpoint) for patients with baseline atrial fibrillation (AF) and sinus rhythm (SR).

 
However, with regard to mortality, a significant interaction between AF and sex and between AF and LVEF was present (p=0.02 and p=0.007, respectively). Sixty-six females had AF at baseline, and among those 25 (38%) died during follow-up. Females with baseline AF had a significantly increased mortality (HR 1.65; CI 1.03-2.65; p=0.04) compared to females with SR (Fig. 3A). In contrast, there was no significant difference in mortality between males with baseline AF and SR (HR 1.3; CI 0.96-1.77, p=0.09) Fig. 3B.


Figure 03
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  		Fig. 3 (A) Cumulative all-cause mortality in females with baseline atrial fibrillation (AF) and sinus rhythm (SR). (B) Cumulative all-cause mortality in males with baseline atrial fibrillation (AF) and sinus rhythm (SR).

 
In patients with LVEF above the median (LVEF≥30%) the presence of AF at baseline was associated with a significant increase in mortality (HR 1.46; CI 1.04-2.07; p=0.03) compared to patients with SR (Fig. 4A). In patients with LVEF below the median (LVEF<30%), there was no significant difference (HR 1.24; CI 0.85-1.80; p=0.27) between patients with baseline AF and SR (Fig. 4B). There was no significant interaction between AF and sex, LVEF or age for the combined end-point.


Figure 04
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  		Fig. 4 (A) Cumulative all-cause mortality in patients with left ventricular ejection fraction (LVEF)>30% with baseline atrial fibrillation (AF) and sinus rhythm (SR). (B) Cumulative all-cause mortality in patients with left ventricular ejection fraction (LVEF)<30% with baseline atrial fibrillation (AF) and sinus rhythm (SR).

 
3.3. New-onset AF
Evaluation of new onset AF was only performed in the subgroup of 415 patients in whom a follow-up ECG was available. Of these patients, 178 (42.9%) had AF. Two hundred and eighty four patients were in SR at baseline; of these 53 (18.7%) developed new onset AF during the follow-up. Six patients converted from AF to SR during follow-up. Time elapsing from the first ECG to the last ECG taken on the patients was 803 (396-1345) days median; (25-75 percentile), corresponding to an average risk of 6.2% per year. Patients who developed AF during follow-up were significantly older than patients who remained in SR (73.9 (±10.0) vs. 70.6 (±10.5) years (p=0.001)). In a multivariate logistic regression analysis including age, sex, LVEF, NYHA class and previous AMI, no single factor was found to be a significant predictor for development of new-onset AF.

3.4. Risk after new onset AF during follow-up
Of the 284 patients with SR at baseline, 229 patients (81%) reached the combined end-point (all cause death or all cause admission to hospital). The unadjusted rate of the combined endpoint was significantly higher in patients with new-onset AF (94%) compared to patients who remained in SR (67%) the hazard ratio (HR) in patients with new-onset AF being 1.48 (CI, 1.08-2.03, p=0.02).

After adjustment for covariates (age, sex, LVEF, NYHA class) new-onset AF (HR 1.45; CI 1.05-2.00; p=0.02) was still associated with a significantly higher risk of all-cause death or all-cause hospitalisation compared to SR. Ninety patients (32%) with SR at baseline and a follow-up ECG died during follow-up. Among patients with new-onset AF a higher proportion died (40%) compared to patients with SR (30%). This difference did not reach statistical significance (p=0.46).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The main result of the present study is that the presence of AF in outpatients with HF due to left ventricular systolic dysfunction is associated with increased mortality and morbidity. The increase in mortality appeared to be larger in females and in patients with less severe left ventricular systolic dysfunction.

4.1. Occurrence of AF
We found that 26% of our study population had AF at baseline. In other studies, the reported prevalence has ranged from 10% to 50%, with the highest prevalence in patients with more advanced disease [1-9]. The prevalence is high in our study given the fact that the population was relatively asymptomatic, 67% of patients being in NYHA class I/II. The high prevalence of AF is probably due to the high mean age of the population, which was higher than in most previous studies [2,4,14-16].

We did not find a relationship between the presence of AF and LVEF; this may be because only patients with systolic HF were included. The finding is, however, consistent with previous studies [14,16].

In our study, 6.2% of patients per year had new-onset AF during follow-up. The incidence of AF during follow-up in randomised clinical trials conducted in patients with HF is not generally reported; however, the reported incidence in the few available studies ranges from 3% to 5% per year [14,16,21-23]. There may be several explanations for this variability in the occurrence of AF, such as differences between study populations with regard to severity of HF, age and drug treatment. Furthermore, studies differ in their manner of reporting data on new-onset AF. In some studies, AF was only reported as an adverse event whereas in others systematic assessment of ECGs was performed. The incidence of AF is probably greatly underestimated in view of the insensitive methods used for identification of new-onset AF. There are data suggesting a very high incidence of silent AF [24].

4.2. Prognostic impact of baseline AF
In our study, we found that baseline AF was significantly associated with an increased risk of death and of the combined endpoint of death or hospitalisation. However, when adjusted for baseline covariates, the prognostic impact was lost for mortality, but retained for the composite endpoint.

Previous studies on the impact of AF on survival in HF has shown inconsistent results. Some studies found that the presence of AF was not independently associated with poor outcomes [2,14-16], while others reported that AF was associated with higher mortality [4,6,12,13]. Middlekauff et al [6] evaluated the relationship of AF to overall survival and sudden death in 390 consecutive patients with advanced HF. They showed that the 1-year survival rate was significantly higher for patients with AF than for patients with SR, and that AF was independently associated with an increased risk of sudden death. Aronow et al. and Ahmed et al. reported that in older persons with HF an independent, significantly higher mortality rate among patients with AF compared to patients with SR [12,13]. In a retrospective analysis of the SOLVD study with 6500 patients with LVEF<35%, baseline AF was an independent predictor of all-cause mortality, progressive pump-failure death, and of the combined endpoint of death, or hospitalisation for HF but not for arrhythmic death [4]. Several studies [2,14,15,25] have found no significant, independent association between AF and mortality rate. These results are supported by recent data from a retrospective analysis of the COMET study including 3029 patients with LVEF<35%. In this study, Swedberg et al. found that baseline AF significantly increased the risk for death and HF hospitalisation, but AF was not an independent risk factor for mortality after adjusting for other predictors of prognosis [16].

In our study, we found that in the sub-group of patients with LVEF≥30%, patients with AF had a clearly increased mortality compared to patients with SR. In the group of patients with more depressed LVEF (<30%) we found no difference. This result is in keeping with the fact that studies exclusively including patients with low ejection fraction or severe symptomatic HF generally did not find an independent effect of AF on mortality [2,14,15]. In the TRACE study, Pedersen et al. found that long-term mortality was increased in all sub-groups of patients with AF except those with LVEF<25% [26]. Indeed, based on data from the available studies, it appears that the effect of AF on mortality is inversely related the severity of HF. Theoretically, such a relationship could be explained as follows: in patients with severe HF or very low ejection fraction, prognosis is primarily determined by the advanced pump failure; whereas in patients with relatively preserved left ventricular function and longer expected survival, the negative cardiac and non-cardiac consequences of AF have time to develop [6,15,26-28].

In our study, we found a significant interaction between sex and AF implying that women with AF had a significantly higher mortality rate compared to women with SR, whereas no difference between SR and AF in men could be demonstrated. Indeed, the difference in mortality between the group of women with AF and SR was statistically significant, despite the fact that the study included a limited number of females. This interaction has not been previously studied in HF patients, but studies in general populations have shown that females with AF have a worse prognosis compared to men with AF primarily due to an increased risk of stroke [29-31].

4.3. Impact of new-onset AF
The development of new-onset AF was an independent predictor of the combined end-point of death or hospitalisation. In contrast, new-onset AF did not have a significant impact on all-cause mortality but the power of this analysis was limited. Other studies have reported that new-onset AF is independently associated with increased mortality rates [14,16,21,22] and in the DIG trial, this event was associated with a significantly greater risk of stroke [22]. As expected, development of new-onset AF resulted in an increased rate of hospitalisation. A possible explanation might be that patients with HF with a limited cardiac reserve who develop new-onset AF are likely to experience aggravation of symptoms resulting in hospitalisation. Another reason might be that HF progression often results in hospitalisation, which in turn is associated with an increased risk of developing AF.

4.4. Study limitations
The present study encompasses some limitations. The size of the population was limited and so are the number of deaths and the number of patients developing AF during follow-up. The results of the analysis of patients with new onset AF must be regarded as hypothesis generating, as the number of patients is too low to draw firm conclusions. Presumably, the study included some patients with tachycardia-induced cardiomyopathy. If treated, this condition may be reversible, and thus, these patients may have a better prognosis compared to patients with left ventricular dysfunction due to other causes. However, from a clinical point of view, we decided that all possible heart failure patients referred to the clinic should be included, since they fulfilled the definition for heart failure due to left ventricular systolic dysfunction at baseline. Furthermore, if some patients with tachycardia-induced cardiomyopathy were included, they would be likely to have blunted the results of the present analyses, and as such, they would not have biased the conclusions.

One further limitation is that estimation of LVEF may be imprecise in patients with AF due to differences in stroke volume given the irregular heart rate and to the possible occurrence of tachycardia. However, average heart rate in the AF group of the current study was low, indicating that the arrhythmia in most patients was well controlled, which minimizes the problems of LVEF estimation in AF.

The presence of AF on the baseline ECG was used as the definition of baseline AF. Consequently, we cannot evaluate the importance of paroxysmal compared to sustained AF. The impact of AF is therefore probably underestimated in this analysis. In the current study all forms of atrial fibrillation, i.e. paroxysmal, persistent or permanent, were considered as one entity, and this is of course a simplification. Further, we do not have specific information about previous or future treatment strategies for the AF patients (rhythm- or rate control, cardioversion or radio frequency ablation), which could potentially be important. However, previous studies, AFFIRM and RACE [32,33] did not demonstrate a mortality difference between patients with AF treated with rate control versus rhythm control, so from a prognostic point of view this may be of less importance.

In the current study, only patients with left ventricular ejection fraction <45% documented by echocardiography were included. Therefore, the results of this study cannot be extrapolated to patients with non-systolic HF.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In outpatients with HF due to left ventricular systolic dysfunction, AF is a common co-morbidity, which adversely affects morbidity and mortality. The specific prognostic impact of AF in women with HF deserves further investigation.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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