Clinical research
European Heart Journal (2006) 27, 2866–2870
doi:10.1093/eurheartj/ehl359
Arrhythmia/electrophysiology
Atrial fibrillation, ischaemic heart disease, and the risk
of death in patients with heart failure
Ole Dyg Pedersen1*, Peter Søndergaard2, Tonny Nielsen3, Søren Junge Nielsen4,
Eric Steen Nielsen5, Niels Falstie-Jensen6, Ingolf Nielsen7, Lars Køber8, Hans Burchardt7,
Marie Seibæk9, and Christian Torp-Pedersen1 on behalf of the DIAMOND study group investigators
1
Received 7 March 2006; revised 19 September 2006; accepted 19 October 2006; online publish-ahead-of-print 13 November 2006
See page 2740 for the editorial comment on this article (doi:10.1093/eurheartj/ehl321)
KEYWORDS
Atrial fibrillation;
Congestive heart failure;
Mortality;
Ischaemic heart disease
Aims Atrial fibrillation (AF) is a risk factor for death in patients with a myocardial infarction, but highly
variable results are reported in patients with heart failure. We studied the prognostic impact of AF in
heart failure patients with and without ischaemic heart disease.
Methods and results During a period of 2 years, 3587 patients admitted to hospital because of heart
failure were included in this study. All patients were examined by echocardiography and the presence
of AF was recorded. Follow-up was available for 8 years. Twenty four percent of those discharged
alive from hospital had AF. After 4 and 8 years of follow-up, mortality was higher in patients with AF
than in patients without, 56 vs. 52% and 77 vs. 73%, respectively. Cox multivariable regression analysis
showed a small but significant importance of AF for long-term mortality [hazard ratio (HR) 1.12, 95% confidence limits (CI), 1.02–1.23, P ¼ 0.018]. There was a significant interaction between the importance of
AF and the presence of ischaemic heart disease (P ¼ 0.034). In patients with AF at the time of discharge
and ischaemic heart disease, HR was 1.25 (95% CI: 1.09–1.42) and P , 0.001; in patients with AF at
discharge and without ischaemic heart disease, HR was 1.01 (95% CI: 0.88–1.16) and P ¼ 0.88.
Conclusion AF is associated with increased risk of death only in patients with ischaemic heart disease.
This finding may explain the variable results of studies of the prognosis associated with AF in heart failure.
Introduction
Atrial fibrillation (AF) is the most common arrhythmia among
patients with congestive heart failure and occurs in up to
50% of those with advanced disease.1 In majority of the
studies, AF has been shown to be an independent risk
factor of mortality in patients with ischaemic heart
disease and in the general population,2,3 whereas conflicting
results have been found in congestive heart failure
patients.4 Whether AF is related to an increased risk of
death in patients with congestive heart failure remains
unresolved and the inconsistency of the results in this particular group is strikingly different from what has been
found in patients with ischaemic heart disease and in the
general population. Some studies have found an increase
in the risk of death in patients with AF and congestive
heart failure,5–11 whereas others have found no increased
risk12–19 and one study even a decreased risk.20 A recent
* Corresponding author. Tel: þ45 353 13333; fax: þ45 353 13226.
E-mail address: odplc@mail.dk
study in a large group of congestive heart failure patients
revealed no independent importance of chronic AF for mortality and some importance of new onset AF.21 Because of
the continued inconsistency between studies of ischaemic
heart disease and studies of populations with heart failure,
we speculated that this difference might be a consequence
of a complicated interaction between AF resulting from
heart failure on ischaemic basis and AF causing heart
failure. We therefore performed this retrospective study
of 3587 consecutive patients admitted to hospital because
of a worsening of congestive heart failure and followed
these patients for 8 years. The aim of this study was to
investigate the prognostic importance of AF in the total
cohort of patients as well as to study whether the prognostic
importance of AF differed in patients with and without
ischaemic heart disease.
Materials and methods
During a 2-year period, from November 1993 to November 1995,
5548 patients were admitted to hospital because of a clinical
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on September 30, 2016
Department of Cardiology, Bispebjerg University Hospital, Bispebjerg Bakke 23, 2400 Copenhagen, Denmark; 2 Department
of Cardiology, Herlev University Hospital, Herlev, Denmark; 3 Department of Cardiology, Esbjerg Hospital, Esbjerg, Denmark;
4
Department of Cardiology, Frederiksberg Hospital, Frederiksberg, Denmark; 5 Department of Cardiology, Viborg Hospital,
Viborg, Denmark; 6 Department of Cardiology, Hjørring Hospital, Hjørring, Denmark; 7 Department of Cardiology, Roskilde
Hospital, Roskilde, Denmark; and 8 Department of Cardiology, The Heart Centre, University Hospital, Rigshospitalet,
Copenhagen, Denmark and 9 Department of Cardiology, Glostrup Hospital, Glostrup, Denmark
AF, ischaemic heart disease, and the risk of death in patients with heart failure
Statistical methods
Differences between groups with respect to medical history and
clinical data were examined by the use of x 2 and Mann–Whitney
tests for categorical and continuous variables, respectively.
Categorical variables are presented as counts and percentages.
Continuous variables are presented as median values and 5 and 95
percentiles. Differences in mortality between groups were examined by use of log-rank tests and presented as Kaplan–Meier
curves. Mortality of AF was studied with Cox proportional hazard
models. The model assumptions (proportional hazard assumption,
lack of interaction, and linearity of continuous variables) were
tested and found valid unless otherwise indicated. In multivariable
analyses we adjusted for age, gender, WMI, history of ischaemic
heart disease, and diabetes. The prognostic impact of AF was
studied in the whole population and in two subgroups of patients
with and without ischaemic heart disease (history of angina pectoris
and/or previous myocardial infarction). Interaction analyses were
performed by a likelihood ratio test. A P-value , 0.05 was considered significant. All analyses were performed with the SAS
system (SAS version 9, Cary, NC, USA).
Results
Study size and baseline variables
The study population consisted of 3587 patients. The prevalence of different categories of AF is shown in Table 1. Up to
29% of the patients had AF once during hospitalization. Five
percent developed AF during hospitalization and 24% of
those discharged from hospital had AF. Ten percent were
classified as having paroxysmal AF during hospitalization.
Of those patients discharged from hospital with AF, 78%
had a history of persistent/permanent AF, 95% had AF on
the baseline ECG, 91% had continuous AF during hospitalization, and 6% had new onset AF. Baseline characteristics of
patients without AF in comparison with those having AF at
the time of discharge from hospital are shown in Table 2.
Patients with AF at the time of discharge were slightly
older than patients without AF, whereas patients without
AF had a decreased LV function and more patients suffered
from angina pectoris or had a previous myocardial infarction. Otherwise, the groups were fairly similar regarding a
number of other baseline variables.
Mortality
In-hospital mortality was not increased in patients with AF
at the baseline ECG, 32 deaths of 1040 patients with baseline AF, 76 deaths in 2547 patients without baseline AF
[HR ¼ 0.90 (95% CI: 0.61–1.35), P ¼ 0.62]. During long-term
follow-up, 634 deaths occurred in 818 patients with AF at
the time of discharge vs. 1951 deaths occurred in 2661
without AF (Figure 1). Mortality analyses by Cox proportional hazard regression analyses of the different categories of AF are shown in Table 3, adjusted for age,
gender, WMI, diabetes, and history of ischaemic heart
disease. Baseline AF or presence of continuous AF during
hospitalization were not associated with an increased risk
of death during long-term follow-up, whereas development
of AF during hospitalization and AF present at the time of
Table 1 Prevalence of AF in 3587 patients
History of AF
Persistent/permanent AF
Paroxysmal AF
In-hospital AF
AF at baseline ECG
Continuous AF in hospital
New-onset AF
Paroxysmal AF
AF at discharge
ECG, electrocardiogram.
16% (n ¼ 584)
7% (n ¼ 266)
29%
22%
5%
10%
24%
(n ¼ 1040)
(n ¼ 774)
(n ¼ 193)
(n ¼ 351)
(n ¼ 818)
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worsening of heart failure and screened at 34 centres for possible
participation in the Danish Investigations of Arrhythmia and
Mortality ON Dofetilide (DIAMOND) Congestive Heart Failure (CHF)
trial.22 Twenty-two centers (n ¼ 3892 patients) agreed on participating in the present retrospective analysis and they identified all
patients with AF at the initial hospitalization. Data on AF were availably in a high number of patients, n ¼ 3587 (92%) and the remaining
305 were excluded from the present analysis. Only three patients
were lost to follow-up. Patients qualified for inclusion in the
DIAMOND register (and to be screened for inclusion into the
DIAMOND study) were consecutive patients hospitalized with new
or worsening congestive heart failure and who within the preceding
month had had at least one episode of shortness of breath on
minimal exertion or at rest [New York Heart Association (NYHA)
functional class III or IV) or paroxysmal nocturnal dyspnoea. NYHA
classes used in the study are those recorded at the time of inclusion
in the study. For all screened patients demographic data, prior diseases, medication, and hospital complications were noted and a
two-dimensional echocardiography was recorded on videotape.
Left ventricular (LV) systolic function was determined by echocardiography, a method previously described in detail.22 It was assessed
by calculation of wall motion index (WMI), using a 16-segment
model of the LV and a reverse scoring system. WMI multiplied by
0.3 gives an estimate of ejection fraction. The following intervals
gives an estimate on the relation between WMI and left ventricular
ejection fraction (LVEF): WMI 0.8 (LVEF , 0.25), WMI ¼ 0.9–1.2
(LVEF ¼ 0.25–0.35), WMI ¼ 1.3–1.6 (LVEF ¼ 0.36–0.50), and
WMI . 1.6 (LVEF . 0.50).
Patients with a WMI 1.2 were considered for inclusion in
DIAMOND CHF trial and those eventually included were randomized
to dofetilide treatment or placebo.
The diagnosis of AF was documented by electrocardiograms
obtained during hospitalization and had to fulfil the following criteria: AF—absence of P waves, coarse or fine fibrillatory waves,
and completely irregular RR-intervals. In particular, the investigators had to distinguish AF from atrial flutter (AFL) defined as: presence of regular P waves with a rate between 250 and 350/min and
regular or irregular RR-intervals. The investigators were asked to
classify the duration of AF during hospitalization and whether the
patients had AF at the baseline electrocardiogram (ECG), new
onset AF during hospitalization, continuous AF, AF at the time of discharge, and whether they had a history of paroxysmal or persistent/
permanent AF. Baseline AF required that AF was present at the ECG
obtained at baseline. New onset AF required that the patients did
not have AF at the baseline electrocardiogram and developed AF
during hospitalization. Continuous AF during hospitalization
required that AF was present at the baseline ECG, any time during
hospital stay and at the time of discharge. Paroxysmal AF was
defined as AF being present at baseline or any time during hospitalization but not at the time of discharge.
The presence or absence of ischaemic heart disease relied on the
clinical judgment of the investigator who specifically reported
whether ischaemic heart disease was diagnosed. Formal criteria
were not specified. In our analysis, history of ischaemic heart
disease included patients with either angina or previous myocardial
infarction or both.
The study was approved by the Ethics Committee and all patients
gave informed consent to participate in the study.
2867
2868
O.D. Pedersen et al.
Table 2 Baseline characteristics of patients in relation to AF at
discharge from hospital
Without AF
(n ¼ 2661)
72
1590
938
1099
1229
1617
(52–86)
(60%)
(35%)
(41%)
(46%)
(61%)
455
665
135
851
1117
500
1.30
1184
(17%)
(25%)
(5%)
(32%)
(42%)
(19%)
(0.6–2.0)
(44%)
75
490
227
193
252
357
114
205
39
257
359
146
1.50
692
P-value
(56–86)
(60%)
(28%)
(24%)
(31%)
(44%)
,0.001
0.93
,0.001
,0.001
,0.001
,0.001
(14%)
(25%)
(5%)
(31%)
(44%)
(18%)
(0.6–2.0)
(85%)
,0.05
0.97
0.79
,0.001
,0.001
1407 (53%)
408 (50%)
0.13
2276 (86%)
704 (86%)
0.70
ACE, angiotensin converting enzyme; AMI, acute myocardial infarction;
NYHA, New York Heart Association class; WMI, Wall Motion Index.
History of AF
Baseline AF
Continuous AF
New onset AF
AF at discharge
AF þ non-IHD
AF þ IHD
Hazard ratio (95% CI)
P-value
1.05 (0.96–1.15)
1.03 (0.94–1.12)
1.06 (0.97–1.17)
1.28 (1.09–1.50)
1.12 (1.02–1.16)
1.01 (0.88–1.23)
1.25 (1.09–1.42)
0.08
0.49
0.22
0.003
0.018
0.88
,0.001
Variables included in the multivariable model: age, gender, WMI, diabetes, history of ischaemic heart disease. IHD, ischaemic heart disease.
hazard regression analyses showed that presence of AF at
the time of discharge from hospital was associated with an
increased risk of death in patients with ischaemic heart
disease [HR ¼ 1.25 (95% CI: 1.09–1.42), P , 0.001], while
adjusting for age, gender, WMI, history of ischaemic heart
disease, and diabetes. Separation of this group completely
eliminated the risk in those with AF but without ischaemic
heart disease [HR ¼ 1.01 (95% CI: 0.88–1.16), P ¼ 0.88]
with similar adjustments (Table 3 at the bottom).
Interaction analysis showed that there was significant interaction between AF and ischaemic heart disease. Interaction
was found to be significant for baseline AF (P ¼ 0.003),
continuous AF (P ¼ 0.007), and AF at discharge (P ¼ 0.034).
Other analyses
Significantly more patients with AF than without were
treated with digoxin on discharge from hospital (Table 2).
Adding digoxin therapy to the multivariable models resulted
in AF not predicting mortality overall [HR ¼ 1.08 (95% CI:
0.97–1.19), P ¼ 0.14]. Because digoxin therapy was to a
large extent a routine treatment of AF it becomes an intermediary variable and it was therefore not included in the
main models.
Discussion
Figure 1 Shows the long-term mortality in patients with and without AF
discharged from hospital.
discharge were associated with an increased risk of death
during the follow-up of 8 years. Paroxysmal AF during hospitalization [HR ¼ 1.01 (95% CI: 0.89–1.15), P ¼ 0.86] and a
history of AF were not associated with an increased risk
during hospitalization or during long-term follow-up. In
order to examine the influence of ischaemic heart disease,
we separated those with AF at discharge from hospital and
with ischaemic heart disease from those with AF at discharge but without ischaemic heart disease (Table 4).
Long-term mortality of these subgroups is shown in
Figure 2. Patients with the combination of AF and ischaemic
heart disease had a significantly worse outcome than those
without ischaemic heart disease and AF. Cox proportional
It has been a mystery why AF has a clear prognostic impact
in cohorts of patients with ischaemic heart disease and in
the general population, whereas this is not the case in
patients with congestive heart failure.4 In this study, we
find that AF is associated with an increased long-term mortality in patients admitted to hospital with clinical worsening of heart failure and discharged with AF, and for the
first time we are able to demonstrate that the risk of
death is specifically associated to patients with AF and
ischaemic heart disease in heart failure patients (Figure 2
and Table 3). By separation of patients who suffered from
both conditions, i.e. AF and ischaemic heart disease, from
the cohort of patients with AF but without ischaemic heart
disease, we find that those with AF and ischaemic heart
disease are those who carry an increased risk of death.
In the present study, 29% of those admitted to hospital with
worsening heart failure had AF at the baseline electrocardiogram and 24% of those discharged from hospital had AF. This is
slightly more than that observed in previous studies.4 It is
most likely explained by the fact that the median age of our
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Age
Male gender
Smoker
Previous AMI
Angina
History of
ischaemic
heart disease
Diabetes
Hypertension
NYHA I
NYHA II
NYHA III
NYHA IV
WMI
Digoxin at
discharge
ACE-inhibitor at
discharge
Diuretic at
discharge
AF at discharge
(n ¼ 818)
Table 3 Cox proportional Hazards regression analyses showing
the risk of death associated with different categories of AF
AF, ischaemic heart disease, and the risk of death in patients with heart failure
2869
Table 4 Baseline characteristics of patients separated into subgroups with and without AF at discharge from hospital and ischaemic heart
disease or no ischaemic heart disease
No AF
No IHD (n ¼ 1044)
IHD (n ¼ 1617)
No IHD (n ¼ 461)
IHD (n ¼ 357)
73 (50–87)
575 (55)
401 (38)
260 (25)
155 (15)
73 (7)
311 (30)
436 (42)
195 (18)
1.5 (0.6–2.0)
465 (45)
870 (83)
460 (44)
774
72 (53–85)
1015 (63)
537 (33)
405 (25)
300 (19)
62 (4)
540 (33)
681 (42)
305 (19)
1.2 (0.5–2.0)
942 (58)
1406 (87)
724 (45)
1207
74 (54–86)
264 (57)
135 (29)
108 (23)
55 (12)
26 (6)
145 (31)
196 (43)
84 (18)
1.6 (0.6–2.0)
256 (44)
395 (86)
399 (87)
327
75 (60–86)
226 (63)
92 (26)
96 (27)
59 (17)
13 (4)
112 (31)
163 (46)
62 (17)
1.3 (0.5–2.0)
203 (57)
309 (87)
293 (82)
307
The actual number of deaths rates are shown at the bottom. NYHA, New York Heart Association class; ACE, angiotensin converting enzyme; IHD, ischaemic
heart disease.
Figure 2 Shows influence of ischaemic heart disease (IHD) on the long-term
mortality in patients with and without AF discharged from hospital.
cohort patients was approximately 10 years older than these
studies, bearing in mind the well known association between
increasing age and the prevalence of AF. Our analysis also
revealed that most patients discharged with AF (95%) also
had AF at baseline. Furthermore, of the patients discharged
with AF, 78% had a history of persistent/permanent AF. On
the other hand, of the patients having AF at baseline, 76%
had AF at discharge from hospital.
In this study, we focused our analysis on patients discharged with AF, because baseline AF was not associated
with an increased in-hospital mortality and paroxysmal AF
was not associated with an increased long-term mortality.
Patients with AF at discharge differed with respect to a
number of baseline characteristics from those without AF.
Although the groups had a similar distribution of NYHA
class, the group of patients with AF had better LV systolic
function. This finding is different from what one would
expect, when considering that mortality was higher in
patients with AF. LV systolic function is a major determinant
of the prognosis in patients and although we adjusted for
this variable in the multivariable analyses, AF retained its
prognostic impact. These facts led us to speculate whether
another major determinant of outcome, namely presence
or absence of ischaemic heart disease, might have significant impact in this particular group. Fewer patients suffered
from ischaemic heart disease in the group with AF, which is
in accordance with findings in previous studies.
The prognostic impact associated with AF reported in
previous heart failure studies has been highly variable.
In an analysis from a major heart failure study, the
Studies of LV Dysfunction (SOLVD) study,5 AF was associated
with an independent increase in the risk of death, whereas
in a similar analysis from another heart failure study, the
Vasodilator-Heart Failure Trial (V-HEFT),19 AF was not
associated with an increase in risk of death. More recently,
data from the Carvedilol or Metoprolol European Trial
(COMET) study adds further to the discussion.21 In this
study, AF was associated with an increased risk of death in
univariable analysis, but following adjustment for baseline
variables in multivariable analysis the risk disappeared.
Other studies have reported similar differences and made
it unclear whether AF has a prognostic impact in heart
failure patients or not.5–21
In the present study, we find that in patients admitted to
hospital with a worsening of heart failure and who have AF
at discharge and ischaemic heart disease have a significant
and clear association with an increased risk of death,
whereas the risk was not increased in patients with AF and
without ischaemic heart disease. This could be an explanation of the differences found in previous studies and fits
perfectly with the results found in patients with ischaemic
heart disease.2 We suggest two possible explanations. In
patients without ischaemic heart disease, there may be
many cases where AF was the cause of heart failure and
given that the mechanism of heart failure is different it is
not surprising that the prognosis should be different.
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Age (range)
Male gender (%)
Smoker (%)
Hypertension (%)
Diabetes (%)
NYHA I (%)
NYHA II (%)
NYHA III (%)
NYHA IV (%)
WMI (range)
ACE-inhibitor at discharge (%)
Diuretic at discharge (%)
Digoxin at discharge (%)
Deaths
AF
2870
Another explanation is that patients with ischaemia tolerate
the tachycardia less well leading to a worse outcome. LV systolic function was slightly lower in patients with AF and
ischaemic heart disease, but we adjusted for this variable
in the multivariable analysis.
O.D. Pedersen et al.
3.
4.
Limitations
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Conclusion
AF is a common condition in patients admitted to hospital
with a worsening of heart failure and once present it is
indeed very likely that it persists. In this study, AF at the
time of discharge was associated with a slight increase in
the risk of death during long-term follow-up. Subgroup
analysis demonstrate that patients with AF at the time of
discharge, but without a history of ischaemic heart disease
have a favourable prognosis, whereas those with ischaemic
heart disease have an increased risk of death.
15.
16.
17.
18.
Acknowledgements
19.
Danish Investigations of Arrhythmia and Mortality ON Dofetilide
(DIAMOND) study was sponsored by Pfizer.
Conflict of interest: Dr Torp-Pedersen has received payment for
speaker’s bureau appointments and received honoraria payment.
No other conflicts of interest.
20.
21.
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