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European Journal of Heart Failure 2008 10(6):566-572; doi:10.1016/j.ejheart.2008.04.002
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© 2008 European Society of Cardiology

Effect of atrial fibrillation on long-term survival in patients hospitalised for heart failure with preserved ejection fraction

Dan Rusinaru, Laurent Leborgne, Marcel Peltier and Christophe Tribouilloy*

INSERM, ERI 12, Amiens, France and University Hospital Amiens France Department of Cardiology Avenue René Laënnec, 80054 Amiens Cedex 1, France

* Corresponding author. Tel.: +33 3 22 45 58 83; fax: +33 3 22 45 56 58. E-mail address: tribouilloy.christophe{at}chu-amiens.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The prognostic importance of atrial fibrillation (AF) in heart failure (HF) is not clearly established. Studies conducted in systolic HF have led to discordant results.

Aims: To evaluate the relation between AF and long-term survival in patients with heart failure and preserved ejection fraction (HFPEF).

Methods and results: We prospectively included 368 consecutive patients hospitalised for a first episode of HFPEF during 2000 and compared the 5-year outcome of patients according to the presence or absence of AF on the baseline electrocardiogram. Propensity scores were used to reduce imbalance in baseline characteristics. Baseline AF was observed in 36% (n=132) of the study population. Patients with AF were older and more often had hypertensive heart disease. On univariate analysis, baseline AF was associated with an increased risk of 5-year overall mortality (HR=1.36; 95%CI 1.03–1.79; p=0.03). After adjustment for covariates, baseline AF was no longer a predictor of reduced survival. The risk of adjusted cardiovascular death in patients with and without AF was comparable. In the propensity-matched patients, AF was not related to a poorer outcome (HR=1.08; 95%CI 0.78–1.51; p=0.63).

Conclusion: In patients hospitalised for HFPEF, AF is frequent and associated with an excess mortality mainly related to the advanced age of these patients. After adjustment for covariates, baseline AF is not an independent predictor of long-term mortality.

Key Words: Heart failure • Atrial fibrillation • Ejection fraction • Prognosis

Received December 7, 2007; Revised March 10, 2008; Accepted April 7, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure with preserved ejection fraction (HFPEF) is an increasingly prevalent form of heart failure (HF) associated with increased mortality, frequent hospitalisations and high medical expenditure. It is estimated that more than 50% of patients with HF have preserved (≥50%) left ventricular (LV) ejection fraction (EF) [1-3]. Atrial fibrillation (AF) is a common arrhythmia in patients with HFPEF [2-6]. It may cause haemodynamic deterioration by multiple mechanisms: impaired diastolic filling, reduction in stroke volume, loss of atrioventricular synchrony, increase in mean atrial diastolic pressure and irregularity in ventricular response [7,8].

Studies that have investigated the prognostic impact of AF in patients with systolic HF have produced discordant results. Some studies report that AF is associated with reduced survival in patients with systolic HF [9,10] while in others, AF was not an independent predictor of mortality [11-13]. Results of studies that have included patients with HFPEF are also conflicting as regards the prognostic importance of AF [2,6,14,15]. Moreover, few studies have been designed to specifically assess the impact of AF on prognosis in patients with HFPEF [15].

In this prospective observational study, we followed a cohort of consecutive patients hospitalised for a first episode of HF in 2000. This study was designed to assess the relation between AF and long-term survival in patients with HFPEF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population and inclusion criteria
The Somme is a department of France with a population of 555,551 inhabitants according to the 1999 census. This department has 11 healthcare establishments managing patients with HF: 1 university hospital, 7 general hospitals, 2 private clinics and 1 medium and long-stay unit. The general practitioners, cardiologists and internal physicians from these 11 centres agreed to participate in this study. Eight hundred and eleven consecutive patients aged over 20 years, hospitalised for a first episode of HF in all these establishments during 2000 were prospectively enrolled. Patients living outside the Somme department, patients hospitalised for subsequent episodes of HF and patients with severe valvular heart disease requiring surgery were excluded. The diagnosis of HF was made by the attending physician based on history, symptoms, physical signs and chest X-ray on admission. Two cardiologists specifically recruited for this purpose reviewed all medical records during the index hospitalisation in order to validate the diagnosis of HF according to the Framingham criteria amended by the European Society of Cardiology [16]. The diagnosis was not validated in 12 patients.

Of the 799 eligible patients, EF was available for 662 patients (83%). As usually recommended, a cut-off value of 50% was used to distinguish HFPEF from HF with reduced EF [2,17]. There were 368 patients with an EF≥50%, these represent the actual study population.

2.2. Data collection
Clinical data and results of complementary investigations [laboratory tests, electrocardiogram (ECG), chest X-ray on admission, echocardiography, and in some patients, coronary angiography] were recorded on individual case report forms. The diagnosis of AF was based on a 12-lead standard ECG performed at the time of inclusion in the study. EF was determined during hospitalisation by echocardiography in all patients (n=368). Echocardiograms were recorded according to the guidelines of the American Society of Echocardiography [18]. In 34 patients EF was assessed both by echocardiography and left ventriculography, and an average EF was calculated. An estimate of the glomerular filtration rate on admission was calculated using the simplified Modification of Diet in Renal Disease (sMDRD) formula including age, race, sex, and serum creatinine [19].

Ischaemic aetiology was assumed in patients with a history of coronary artery disease, recent documented history of myocardial infarction or angina pectoris, or significant coronary atherosclerosis confirmed by coronary angiography before the index hospitalisation for HF [20]. A patient was considered to have hypertension in the presence of one of the following criteria: high blood pressure during hospitalisation (>160/95 mmHg), previous diagnosis of hypertension or normal blood pressure with ongoing antihypertensive therapy [21]. Valvular heart diseases were identified on the basis of clinical history, physical examination and echocardiography. Other aetiologies (restrictive cardiomyopathy, hypertrophic cardiomyopathy, and constrictive pericarditis) were diagnosed in a minority of cases.

Medical treatment records were completed at discharge. Prescription of the main HF therapies was recorded.

2.3. Prognosis
One-year, 3-year and 5-year overall mortality and cardiovascular mortality were determined. Sudden death was classified as cardiovascular death. Vital status at 1 year, and at 3 and 5 years was obtained either by a consultation with the general practitioner or the referring cardiologist or by consulting the civil registry. Cause of death was ascertained from hospital records, death certificates, and autopsy records or by contacting the patients' physician or the referring cardiologist. No patients were lost to follow-up at 3 years. Three patients (0.8%) were lost to follow-up at 5 years.

2.4. Statistical analysis
Baseline characteristics of the 368 patients according to the presence or absence of AF were compared using Student t tests for continuous variables or {chi}2 tests for categorical variables. Overall survival curves were generated using Kaplan-Meier survival estimates. Differences in time-to-death between groups were analyzed using two-sided log-rank tests. Univariate and multivariable analyses of mortality were performed using Cox proportional hazards models. Variables considered of potential prognostic impact (age, sex, history of hypertension, ischaemic aetiology, diabetes mellitus, history of myocardial infarction, cancer, stroke, estimated glomerular filtration rate and natraemia) were entered in the multivariable models for overall and cardiovascular mortality. The assumption of proportional hazards was checked using log-minus-log survival plots and by examining time-dependent covariates. For continuous variables, the assumption of linearity was assessed by plotting residuals against independent variables. A separate multivariable analysis was conducted in patients surviving the index hospitalisation (n=358), with adjustment to the treatment at discharge. Cardiovascular mortality was analyzed in a Cox proportional hazards multivariable model while patients who died of non-cardiovascular causes were censored (as non-events) at the time of death. Hazard ratios (HR) and 95% confidence intervals (CI) for the two groups (AF and no-AF) were estimated for cardiovascular death.

The significant imbalance in baseline variables between patients with and without AF was reduced using propensity scores. We estimated the propensity scores for AF for each of the 368 patients using a multivariable logistic model, as previously described [22,23]. Characteristics associated with the presence of AF on univariate analysis (p<0.5) were included in the multivariable logistic model in a forward stepwise regression analysis. Using the resulting selected variables, a propensity score for AF for each patient was estimated by maximum likelihood regression analysis. Goodness-of-fit, assessed by the Hosmer-Lemeshow test ({chi}2=8.4, p=0.39) and discriminatory power of the model (area under the receiver operating characteristic curve; C=0.71) were acceptable. The propensity scores were used to match each patient with AF to a unique control with a propensity score within 1%. First we matched each patient with AF with another patient in the no-AF group that had the same 5-digit propensity score and removed the matched patients from the database. The procedure was repeated on the remaining patients with successive matching by 4-, 3-, and 2-digit scores. One hundred and nine patients (82.5%) of the 132 patients with AF were successfully matched. The mean propensity score in patients with AF before matching was 0.43219 compared to 0.32446 in patients without AF (p<0.001). In the group that resulted after matching, the mean propensity score was 0.40784 in AF patients, comparable to that of the no-AF group (0.40767; p=0.99). Baseline characteristics of the groups resulting after matching were compared using Student t tests and {chi}2 tests, as appropriate. For all tests, a p-value<0.05 was considered statistically significant. Statistical analysis was performed with SPSS 13.0 statistical software (SPSS Inc., Chicago, IL, USA).

2.5. Ethics
The study conforms to the principles outlined in the Declaration of Helsinki and was approved by local institutional review boards. Written informed consent was obtained from all patients. The database was approved by the French computers and privacy commission.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The study population included 368 patients with HFPEF (mean age 76±10 years, female/male sex ratio=1.13). Ninety-five percent of our patients were in NYHA (New York Heart Association) functional class III or IV on admission. The baseline characteristics of the study population grouped according to the presence (n=132, 36%) or absence (n=236, 64%) of AF at baseline are presented in Table 1. Patients with AF were significantly older and more often had hypertensive aetiology of HF. Ischaemic aetiology was more frequent in patients in sinus rhythm at baseline. Patients with AF were more likely to have left ventricular hypertrophy on baseline ECG and cardiomegaly on the chest X-ray on admission (Table 1). Thirty-nine patients (29.5% of patients with AF) had non-sustained AF during the index hospitalisation. In patients surviving the index hospitalisation (n=358), baseline AF was associated with significantly lower discharge prescription rates of ACE-inhibitors, beta-blockers, aspirin, and nitrates (Table 2). On the other hand, digoxin, amiodarone and oral anticoagulants were administered more often at discharge in patients with AF (Table 2). On univariate analysis, prescription of oral anticoagulants at discharge was marginally associated with improved outcome (HR 0.73; 95%CI 0.53-1.02; p=0.07). This relation was no longer observed on multivariable analysis, after adjustment for covariates of prognostic importance (HR 0.85; 95%CI 0.78-1.15; p=0.15).


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  		Table 1 Patient characteristics according to the presence or absence of atrial fibrillation at baseline before and after matching

 


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  		Table 2 Medical treatment in patients alive at discharge in the atrial fibrillation and no-atrial fibrillation groups

 
During the 5-year follow-up, 208 patients died (56.5%). Three- and 5-year overall survival rates were 50% and 36%, respectively, for patients in the AF group compared to 62% (p=0.026), and 47% (p=0.03), respectively, in patients without AF.

On univariate Cox analysis, the presence of AF at baseline was associated with a significant 36% increase in the relative risk of 5-year overall mortality (HR=1.36; 95%CI 1.03 to 1.79; p=0.03). However, after adjustment for age, the relationship was no longer significant (HR=1.16; 95%CI 0.88 to 1.54; p=0.28—Table 3). On multivariable analysis, after adjustment for covariates of potential prognostic impact, AF at baseline was not an independent predictor of increased 5-year overall mortality (Table 3). A similar result was obtained on multivariable analysis in patients surviving the index hospitalisation (n=358—Table 3).


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  		Table 3 Relative risk of all-cause death associated with the presence of atrial fibrillation at baseline in patients with heart failure and preserved ejection fraction—results of Cox univariate and multivariable analyses

 
Cardiovascular causes were responsible for 59% of deaths in the overall study population. On multivariable Cox analysis, the risk of cardiovascular death in patients with AF was not significantly different from that of patients without AF (HR=1.14; 95%CI 0.78 to 1.67; p=0.49).

By multivariable logistic regression analysis, propensity scores were estimated for each of the 132 patients with AF at baseline. One hundred and nine patients in the AF group were successfully matched. After this matching procedure, no difference in baseline variables was observed between the 2 groups (Table 1). Prescription rates of beta-blockers and ACE-inhibitors in matched patients alive at discharge in the AF and no-AF groups were comparable (Table 2). However, digoxin, amiodarone and oral anticoagulants were prescribed more frequently in matched AF patients alive at discharge (Table 2).

In these propensity-matched patients, the presence of AF at baseline was not associated with a significant increase in the relative risk of 5-year overall mortality (HR=1.08; 95%CI 0.78 to 1.51; p=0.63—Fig. 1). After adjustment for age and after adjustment for covariates of potential prognostic impact, baseline AF was not related to lower 5-year overall survival (Table 3). The risk of cardiovascular mortality in matched patients with and without AF at baseline was similar (HR=1.12; 95%CI 0.65 to 1.77; p=0.70).


Figure 01
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  		Fig. 1 Kaplan-Meier 5-year survival curves of matched patients with HFPEF (n=218) according to the presence or absence of atrial fibrillation at baseline.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In the present study we prospectively analyzed a cohort of consecutive patients hospitalised for a first episode of HFPEF. Our patients were old, mostly women and had numerous co-morbidities. Most patients (>90%) were in functional NYHA class III or IV on admission. Baseline AF was present in 132 (36%) of the study population. Our study does not support the association of baseline AF with an adverse long-term prognosis in patients with severe HFPEF requiring hospitalisation. Crude 5-year overall mortality was higher in patients with AF at baseline. However, after adjustment for age and for covariates of potential prognostic impact, this association was no longer detectable. The risk of adjusted cardiovascular mortality was comparable between patients in the AF and no-AF groups. Propensity scores were used to reduce the imbalances in baseline covariates between patients with and without AF at baseline. In the propensity-matched patients, baseline AF was not associated with a significant increase in the risk of 5-year overall mortality.

The interactions between AF and HF are complex. HF induces haemodynamic changes that increase the atrial volume and pressure and leads to alterations of atrial electrical properties: slowed atrial conduction, triggered activity and increased dispersion of atrial refractory period [7]. Neurohormonal changes in HF exacerbate arrhythmogenesis and promote cellular and extracellular remodelling of the atria rendering them more susceptible to the development of AF [24]. On the other hand, a rapid ventricular rate in AF may cause acute HF or exacerbate previously existing chronic HF [7] and may even induce severe HF in individuals with normal LV function [25].

The effect of AF on the mortality of patients with HF is a controversial subject. Most available data come from epidemiologic studies [26] and selected populations with systolic HF in clinical trial settings [9,11-13,15,27]. In the Framingham study the development of new AF but not pre-existing AF was associated with a significant increased risk of death in patients with congestive HF [26]. A report from the SOLVD trial showed that in patients with mild HF, AF was an independent predictor of mortality after adjustment for covariates [9]. In the VALIANT study, in patients with acute myocardial infarction and systolic HF or asymptomatic LV systolic dysfunction, AF was associated with a significantly poorer outcome [27]. In contrast, reports from the VHeFT trials did not find an independent association between AF and outcome in patients with mild-to moderate HF [12]. In a report from the PRIME-II trial focusing on patients with severe systolic HF (mean EF: 23%), Crijns et al. observed higher unadjusted long-term mortality rates in patients with AF at baseline compared with patients in sinus rhythm [13]. However, on multivariable analysis, neither the presence of AF at baseline, nor the development of AF during follow-up were independently related to a poorer prognosis [13]. In a report from the COMET database including patients with systolic HF, AF on the baseline ECG was not an independent predictor of overall mortality (HR=1.07; 95%CI 0.92 to 1.24; p=0.38), despite a greater mortality in the AF group and new-onset AF during follow-up was associated with an increased risk of subsequent mortality [11].

Data on the prognostic impact of AF in patients with HFPEF are scarce and conflicting [2,14,15,28]. In the recently published retrospective analysis of the CHARM database, including 7599 patients with symptomatic chronic HF, over a median follow-up of 37.7 months, the presence of AF on the baseline ECG was associated with a greater increase in the relative risk of cardiovascular events and overall mortality in the group with preserved EF (EF>40%) compared to the reduced EF group [15].

In our study, patients with AF had a higher 5-year crude mortality rate compared to patients in sinus rhythm (47% vs. 36%, p=0.03). One could speculate that this excess mortality might have been related to the haemodynamic abnormalities, increased risk of thromboembolic episodes and possible adverse effects of antiarrhythmic drugs in patients with AF. However, after adjustment for age, patients without AF at baseline no longer had a survival advantage over AF patients, underscoring that older age plays a major part in explaining the observed excess mortality in patients with baseline AF. Moreover, the presence of AF on the baseline ECG was not associated with an increased 5-year overall mortality and cardiovascular mortality after adjustment for covariates of prognostic importance. To reduce the impact of baseline characteristics we performed a propensity score analysis and matched each patient with AF on admission to a unique control in sinus rhythm. Characteristics that had been significantly different between groups in the study population were balanced in propensity-matched pairs. After this matching procedure, AF was not associated with an increased crude or adjusted 5-year overall mortality. Our findings differ from the results reported by Olsson et al. in the analysis of the CHARM database [15] probably as a consequence of differences in study populations. Our patients were older and had severe HFPEF requiring hospitalisation (>90% in NYHA functional classes III and IV) compared with patients in the CHARM Program (>50% of patients with preserved EF were in NYHA functional class II). Moreover, long-term prognosis of patients with HFPEF in observational studies is poor [2,3] and mortality is significantly higher compared with selected populations in pharmacological trials in HFPEF [29]. Therefore, we can speculate that the prognostic impact of AF is mainly related to the clinical severity of HFPEF; in patients with severe HFPEF the prognostic impact of AF appears to be reduced, while it is significant in populations with stable chronic HFPEF. This has been already suggested in patients with systolic HF [30].

The main limitation of our study is the lack of data on the occurrence of new AF during follow-up. Therefore, the potential prognostic implications of subsequent AF in patients with HFPEF cannot be analyzed in our cohort. Also, we could not investigate the potential effect of AF on rehospitalisations as this information was not available in our database. The number of patients in AF at the end of the follow-up was not available. Patients with preserved EF and severe valve disease requiring surgery were excluded from this study. However, valve disease may affect myocardial function even when surgery is not indicated.

We acknowledge that AF represents not only a pathologic finding but also an age-related marker in elderly HF patients with significant co-morbidity. From this point of view, HF appears as a complex syndrome in which age, aetiology, race, sex differences, LV function, symptoms and associated medical conditions can independently influence outcome. Although our propensity analysis emphasises the fact that AF does not significantly affect long-term survival in elderly patients with HFPEF, the limited size of this study population calls for larger prospective studies to better stratify the different profiles of HFPEF patients with AF and the related outcomes.

This study shows that in hospitalised patients with severe HFPEF, AF at admission is frequent and affects older patients. Baseline AF is associated with an excess long-term mortality mainly related to the older mean age of the AF group. Thus, after adjustment for other covariates, the presence of AF is not independently associated with an adverse long-term prognosis. Further studies are needed to clarify the impact of AF on hospitalisations and quality of life in this growing HF population.


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

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