Download Is Heart Rate Important for Patients With Heart Failure in Atrial

JACC: Heart Failure
2014 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 2, No. 3, 2014
ISSN 2213-1779/$36.00
http://dx.doi.org/10.1016/j.jchf.2014.01.005
Is Heart Rate Important for Patients With
Heart Failure in Atrial Fibrillation?
Damien Cullington, MD, Kevin M. Goode, BENG, PHD, Jufen Zhang, PHD,
John G. F. Cleland, MD, Andrew L. Clark, MA, MD
Kingston upon Hull, United Kingdom
Objectives
This study sought to investigate the relationship between resting ventricular rate and mortality in patients with
chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) who were in sinus rhythm (SR) or
atrial fibrillation (AF).
Background
Slower heart rates are associated with better survival in patients with CHF in SR, but it is not clear whether this
is true for those in AF.
Methods
We assessed 2,039 outpatients with CHF and LVEF 50% undergoing baseline assessment, of whom 24%
(n ¼ 488) were in AF; and 841 outpatients reassessed after attempted treatment optimization at 1 year, of whom
22% (n ¼ 184) were in AF. Cox proportional hazards models were used to assess the relationships between heart
rate and survival in patients with CHF and AF or sinus rhythm. We analyzed heart rate and rhythm data recorded at
the baseline review and after 1-year follow-up. Proportional hazards assumptions were checked by Schoenfeld and
Martingale residuals.
Results
The median survival for those in AF was 6.1 years (interquartile range [IQR]: 5.3 to 6.9 years) and 7.3 years (IQR: 6.5
to 8.1 years) for those in SR. In univariable analysis, patients with AF had a worse survival (hazard ratio [HR]: 1.26,
95% confidence interval [CI]: 1.08 to 1.47; p ¼ 0.003) but after covariate adjustment, survival rates were similar.
After adjusting Cox regression models, there was no association between heart rate (per 10 beats/min increments)
and survival in patients with AF before (HR: 0.94, 95% CI: 0.88 to 1.00, p ¼ 0.07) or after (HR: 1.00, 95% CI: 0.99 to
1.00, p ¼ 0.84) therapy optimization. For patients in SR, higher heart rates were associated with worse survival,
both before (HR: 1.10, 95% CI: 1.05 to 1.15, p <0.0001) and after (HR: 1.13, 95% CI: 1.03 to 1.24, p ¼ 0.008)
therapy optimization.
Conclusions
In patients with CHF and a reduced LVEF, slower resting ventricular rate is associated with better survival for patients
in SR but not for those with AF. (J Am Coll Cardiol HF 2014;2:213–20) ª 2014 by the American College of
Cardiology Foundation
Resting heart rate is a powerful prognostic marker in a
broad range of subjects in sinus rhythm (SR), with or
without cardiovascular disease (1–3). In patients with
chronic heart failure (CHF) in SR due to left ventricular
systolic dysfunction (LVSD), a lower resting heart rate is
associated with better survival and fewer hospital readmissions due to heart failure (4,5). In contrast, a lower
resting ventricular rate (<80 beats/min) is not associated
with better survival in patients with permanent atrial
fibrillation (AF), although studies have included few
From the Department of Cardiology, Postgraduate Medical Institute, Hull York
Medical School, University of Hull, Kingston upon Hull, United Kingdom.
Dr. Cullington has received honoraria from Servier. Dr. Cleland has received
research funding from Servier. Drs. Goode and Clark have received honoraria from
Servier. Dr. Zhang has reported that he has no relationships relevant to the contents
of this paper to disclose.
Manuscript received December 17, 2012; revised manuscript received January 15,
2014, accepted January 17, 2014.
patients with CHF (6–8). Furthermore, there is little evidence that lower resting ventricular rate in patients with
CHF and AF is important physiologically or improves
quality of life (9–11). Accordingly, we investigated the
relationship between ventricular rate and survival in patients with CHF due to LVSD who were in AF or SR.
Methods
Study population and data collection. We included outpatients with CHF who attended a community-based
heart failure program in Kingston-Upon-Hull, United
Kingdom, serving a population of 600,000 people, between
September 1999 and October 2010. Patients were referred
for diagnosis and/or management of CHF. Patients gave
written consent for their data to be stored electronically
and used for research purposes. A large proportion of surviving patients were reassessed at 1 year after attempts had
214
Cullington et al.
Importance of Heart Rate in Patients With CHF and AF
been made to optimize therapy
in accordance with UK guidelines for the management of
ACE-I = angiotensinchronic heart failure (12).
converting enzyme inhibitor
All patients underwent a
AF = atrial fibrillation
standardized clinical examinaARB = angiotensin receptor
tion, 12-lead electrocardiography,
blocker
echocardiography, spirometry, and
CHF = chronic heart failure
routine blood tests. Cardiac rhythm
DBP = diastolic blood
and resting heart rate were deterpressure
mined from a 12-lead electroHR = heart rate
cardiogram, which was obtained
IHD = ischemic heart
after at least 5 min rest in the
disease
supine position, using a MAC
IQR = interquartile range
5000 machine (GE Healthcare,
LBBB = left bundle branch
Milwaukee, Wisconsin). We used
block
the arbitrary definitions of the
LVSD = left ventricular
RACE II (Rate Control Efficacy
systolic dysfunction
in Permanent Atrial Fibrillation:
NYHA = New York Heart
a Comparison between Lenient
Association
versus Strict Rate Control II)
SBP = systolic blood
study to categorize patients in
pressure
AF into those with “lenient” (80
SR = sinus rhythm
and <110 per min) or “strict”
(<80 per min) ventricular rate control (7). Patients who
were permanently paced were excluded from the analysis.
All echocardiograms were performed by experienced
echocardiographers in accordance with recommendations
of the British Society of Echocardiography. For echocardiogram acquisition, a Vivid 5 or Vivid 7 system (GE
Healthcare) using a 3.4-MHz probe was used. When
possible, the Simpson’s biplane method was used to measure
the left ventricular ejection fraction (LVEF), and, in all
cases, a visual approximation was made. Only patients with
at least mild left ventricular systolic dysfunction (LVSD)
were included.
The primary endpoint of the study was all-cause mortality. Mortality data were captured electronically by National Health Service information systems and reported to
the hospital and were complete to the censor date of August
31, 2011.
Ethics. The investigation conformed to the principles
outlined in the Declaration of Helsinki. It was approved by
the Hull and East Yorkshire Research Ethics Committee
(Heart Care Study ELSY 2642). All subjects gave written
informed consent.
Statistical methods. Data were tested for normality using
the Kolmogorov-Smirnov test. Normally distributed data are
presented as mean SD; other data are presented as medians and interquartile ranges (IQR). Categorical data are
given as percents. Differences in categorical variables between groups were compared with the chi-square test.
Differences between groups with normally distributed data
were analyzed using Student’s t test, and non-normally
distributed data were analyzed using the Mann-Whitney
U test.
Abbreviations
and Acronyms
JACC: Heart Failure Vol. 2, No. 3, 2014
June 2014:213–20
Kaplan-Meier curves used for analysis of survival and
significance tests between groups were tested using the logrank test. Univariate and multivariate Cox regression models
were constructed to investigate the relationship between
potential covariates and outcome. To avoid overfitting, we
included only variables significantly associated with outcome
in the univariate analysis (p < 0.05) in the forward conditional stepwise Cox analysis. Proportional hazards assumptions were checked by Schoenfeld residuals, and Martingale
residuals plots were used to evaluate linearity (13,14).
Results are presented as hazard ratios (HRs) with 95%
confidence intervals (CIs). Analyses were performed using
SPSS version 19 (IBM Corp., Armonk, New York) and
Stata 13 software (StataCorp., College Station, Texas).
Results
Baseline patient characteristics. A total of 2,039 patients
was included in the baseline analysis, of whom 24%
(n ¼ 488) had AF (Table 1). Compared to patients in
SR, patients in AF were older and less likely to be diabetic or to have ischemic heart disease. Although there
were no differences in severity of LVSD, patients with
AF were more symptomatic than patients in SR. Patients
with AF were less likely to be prescribed a beta-blocker,
aldosterone antagonist, statin, or aspirin but more likely
to be prescribed warfarin, digoxin, or a loop diuretic
agent. The median resting heart rate was higher for
patients with AF than for patients with SR (81 per min
[IQR: 69 to 98 per min] versus 70 per min (IQR: 60 to
83 per min), respectively, p ¼ 0.0001).
Relationship between heart rhythm and survival. During
the follow-up period, 229 patients (47%) with AF died
compared to 639 patients (41%) with SR. The 1-year
mortality rate for patients with AF was 15% (n ¼ 74)
versus 11% for patients with SR (n ¼ 170). Overall median
follow-up was 3.6 years (IQR: 1.7 to 6.9 years). The overall
median survival for patients with AF was 6.1 years
(IQR: 5.3 to 6.9 years) compared to 7.3 years (IQR: 6.5 to
8.1 years) for patients with SR.
In a multivariable model using baseline data that was corrected for age, sex, weight, QRS duration, heart rate, systolic
blood pressure, New York Heart Association (NYHA)
functional class III/IV versus I/II, ischemic heart disease
(IHD) status (yes/no), diabetic status (yes/no), angiotensinconverting enzyme/angiotensin receptor blocker (ACE/
ARB) use (yes/no), LVSD severity (moderate vs.
<moderate), loop diuretic agent use (yes/no), aldosterone
antagonist use (yes/no), beta-blocker use (yes/no), digoxin use
(yes/no), and amiodarone use (yes/no), survival rates among
patients with AF or SR were no different (HR: 0.94; 95% CI:
0.77 to 1.14, p ¼ 0.53).
Relationship between heart rate at baseline and survival.
In the univariable analysis restricted to patients in AF, each
increase in resting heart rate of 10 beats/min was associated
with a 7% decrease in mortality per year (HR: 0.93; 95%
JACC: Heart Failure Vol. 2, No. 3, 2014
June 2014:213–20
CI: 0.88 to 0.99, p ¼ 0.02) (Table 2). After multivariable
adjustment, heart rate as a continuous variable was not significantly associated with survival (HR: 0.94; 95% CI: 0.88
to 1.00, p ¼ 0.07), nor was it when split by quartiles (Fig. 1).
For patients in SR, in the multivariable model, an increase
in resting heart rate by 10 beats/min was associated with a
10% increase in mortality per year (HR: 1.10; 95% CI: 1.04
to 1.15, p <0.0001]. The group was divided into quartiles
according to heart rate: <60 beats/min (referent); 60 to 70
beats/min; 71 to 83 beats/min, and >83 beats/min. Compared to the referent group, only patients with a resting heart
rate >83/min had significantly worse survival (HR: 1.69;
95% CI: 1.30 to 2.21, p ¼ 0.0001).
Patient characteristics at 1 year. A total of 841 patients
was seen after the first year of active treatment in the clinic,
of whom 22% (n ¼ 184) were in AF (Table 1). Patients
who had AF were older and weighed more but otherwise
had similar characteristics to patients in SR. Patients with
AF had higher resting heart rate than patients in SR (72
beats/min [IQR: 63 to 82 beats/min]) vs. 63 beats/min
[IQR: 57 to 71 beats/min], respectively; p ¼ 0.0001).
Prescription of beta-blockers, ACE inhibitors/ARBs, or
aldosterone antagonists was similar in the 2 groups. Patients in AF were more likely to be prescribed loop diuretic
agents, digoxin, and warfarin but less likely to be prescribed
statins, aspirin, or clopidogrel.
Relationship between heart rate at 1 year and survival. In
univariable analysis restricted to the patients in AF, ventricular rate was not a significant predictor of survival (HR:
per 10 beats/min increase in heart rate, 1.01; 95% CI: 0.90
to 1.13, p ¼ 0.84) (Fig. 2, Table 3).
In contrast, for patients in SR, heart rate was significantly
associated with survival. In the multivariable model, each
increase in resting heart rate by 10 beats/min was associated
with an 13% increase in annual mortality (HR: 1.13, 95%
CI: 1.03 to 1.24, p ¼ 0.008). The group was subdivided into
quartiles according to heart rate: <57 beats/min; 57 to 62
beats/min; 63 to 70 beats/min; and >70 beats/min. Only
patients with a resting heart rate >70 beats/min had worse
survival than referent group (<57 beats/min; HR: 1.47; 95%
CI: 1.03 to 2.13, p ¼ 0.04).
Discussion
This analysis suggests that after adjusting for age and
other differences, patients with CHF and LVSD who are
in AF or SR have a similar prognosis, despite patients in AF
having a substantially higher ventricular rate. After 1 year of
follow-up and optimization of medical therapy, resting ventricular rate was <80 beats/min in 70% of patients with AF
and the median ventricular rate was only 72 beats/min
(IQR: 63 to 83 beats/min), although this remained somewhat
higher than the median rate for patients in SR (63 beats/min;
IQR: 57 to 71 beats/min). Thus, adequate rate control
might have contributed to the similar survival of patients
in AF and SR. In contrast to patients in SR, higher
Cullington et al.
Importance of Heart Rate in Patients With CHF and AF
215
ventricular rates were not associated with increased mortality in patients with CHF, LVSD, and AF. Similar
conclusions have been found from post-hoc analysis of the
CHARM (Candesartan in Heart Failure: Assessment of
Reduction in Mortality and morbidity) studies (15).
There is a strong association between ventricular rate
and mortality for patients with CHF in SR (4). If this
is solely a rate-mediated effect, then a similar relationship would be expected for patients in AF. However, a
growing body of evidence suggests that ventricular rate
may be less important among patients with AF (8,9,11).
Pooled data from the AFFIRM (Atrial Fibrillation
Follow-up Investigation of Rhythm Management) and
RACE studies suggest that chronic resting heart rates
>100 beats/min might be detrimental (16). Current
recommendations suggest that resting ventricular rate
should be lowered to <100 beats/min for the asymptomatic
patient and, more aggressively (i.e., <80 beats/min at rest
and <110 beats/min with moderate exercise) if symptoms persist or if LVEF deteriorates (17,18). Some patients
with AF and CHF have better symptom control and higher
LVEF when a lower ventricular rate is achieved by using a
combination of carvedilol and digoxin (10).
The RACE II study (n ¼ 614), is the only prospectively
designed randomized controlled trial to investigate whether
“strict” or “lenient” ventricular rate control should be
preferred in patients with AF (7). Neither strategy was
associated with any significant difference in mortality, hospitalizations, or symptoms during 3-year follow-up. Only
10% of the patients enrolled had a history of heart failure,
and the mean LVEF was 51%, thus, extrapolation of the
data to steer the management of patients with CHF would
seem inappropriate.
Clearly, there must be a ventricular rate below which
harm occurs. The notion that sudden cardiac death in
patients with CHF is largely due to tachyarrhythmia may
be exaggerated. The CARISMA (Cardiac Arrhythmias
and Risk Stratification After Acute Myocardial Infarction) trial analyzed data over 2 years from implantable
loop recorders in 297 patients with IHD and a reduced
LVEF (19). After multivariate adjustment, high degree
atrioventricular block was the strongest predictor of cardiac
death (HR: 6.75, 95% CI: 2.55 to 17.84, p < 0.001), followed by sinus bradycardia (HR: 4.15, 95% CI: 1.37 to
12.62, p ¼ 0.012). The number of patients enrolled with AF
was small (n ¼ 8 permanent and n ¼ 17 paroxysmal), but
half of the patients with permanent, and 12% with paroxysmal AF went on to develop high-degree atrioventricular
block compared to only 8% of patients in SR (20). Similarly,
patients in strict heart rate control groups in the AFFIRM
and RACE trials (most of whom did not have LVSD) had a
higher incidence of pacemaker implantation (16). In a
substudy of PRIME II (Second Prospective Randomised
Study of Ibopamine on Mortality and Efficacy), patients
with AF and advanced heart failure with a baseline resting
heart rate <80 beats/min had worse survival (HR: 2.9, 95%
Cullington et al.
Importance of Heart Rate in Patients With CHF and AF
216
Table 1
JACC: Heart Failure Vol. 2, No. 3, 2014
June 2014:213–20
Characteristics of Patients in AF and SR at Baseline and at 1-Year Follow-Up
Baseline Review
% of Patients in AF (n ¼ 488)
Age, yrs
Male
Weight, kg
% of Total Patient Cohort
“Strict” HR
(n ¼ 219)
“Lenient” HR
(n ¼ 200)
HR 110 beats/min
(n ¼ 69)
76 (70–81)
74 (68–80)
72 (63–78)
75
76
80 (67–92)
83 (69–97)
Patients in AF
(n ¼ 488)
Patients In SR
(n ¼ 1,551)
p Value
0.01
74 (68–80)
70 (63–77)
0.0001
64
0.11
74
72
0.45
84 (69–97)
0.25
81.6 (68–95)
78.9 (67–91)
0.01
0.04
15
19
0.03
0.0001
53
69
0.0001
9
9
17
Diabetic patient
15
19
6
IHD
61
52
32
11
7
NYHA functional class
I
p Value
0.0001
0.09
II
53
45
45
49
51
III
35
43
41
40
29
IV
1
3
6
2
2
SBP, mm Hg
130 (112–147)
127 (116–146)
122 (110–136)
128 (112–145)
130 (115–147)
DBP, mm Hg
74 (65–87)
80 (70–90)
84 (76–96)
79 (68–90)
75 (66–83)
23
17
16
19
17
0.0001
0.003
LVSD
Mild
0.12
0.18
Mild-to-moderate
14
18
13
15
12
Moderate
25
18
7
20
23
Moderate-to-severe
21
22
26
22
23
Severe
17
26
38
24
25
67 (59–73)
90 (85–98)
121 (113–132)
0.0001
81 (69–98)
70 (60–83)
112 (98–138)
104 (92–120)
102 (90–116)
0.0001
106 (96–128)
110 (96–136)
HR, beats/min
QRS duration, ms
0.002
Beta-blocker*
0.09
0.0001
0.0001
0.10
0.02
None
39
51
67
48
40
Low dose
29
27
22
32
34
Moderate dose
24
18
12
15
19
7
5
0
5
7
ACE-I/ARB
82
68
77
0.003
76
79
0.07
Aldosterone antagonist
25
20
7
0.005
20
25
0.03
High dose
Loop diuretic agent
83
77
81
0.29
80
71
0.0001
Digoxin
51
51
48
0.88
51
8
0.0001
Amiodarone
10
8
7
0.69
8
8
0.70
1
5
7
0.03
3
3
0.72
Verapamil/diltiazem
Statin
41
35
23
0.03
36
57
0.0001
Warfarin
38
49
13
0.06
58
12
0.0001
Aspirin
50
38
13
0.06
29
59
0.0001
5
5
3
0.75
13
5
0.0001
Clopidogrel
Continued on the next page
CI: 1.4 to 5.8, p ¼ 0.002) than patients with heart rates >80
beats/min (21). Atrial fibrillation causes loss of “atrial kick,”
reduced LV diastolic filling, and a fall in stroke volume. An
increase in ventricular rate may compensate for these
changes to maintain adequate cardiac output; therefore,
aggressive rate lowering in patients with CHF and AF may
be hemodynamically detrimental (22). Tight daytime control of ventricular rate may, for selected patients, be associated with an exacerbation of nocturnal pauses which may
increase the likelihood of pause-dependent ventricular
tachycardia (10,23).
The prevalence of AF in patients with CHF is estimated
to be 30% to 40%, which increases with worsening LVSD (24). The baseline prevalence of AF in
randomized trials of beta-blockers to treat CHF ranges from
13% to 35%. Bisoprolol, metoprolol, and nebivolol have
not been shown to improve outcomes in patients with
AF and CHF, although carvedilol may (25,26). If betablockers are less effective or ineffective in patients with heart
failure and AF, this may reflect the lack of importance of
ventricular rate control or that exacerbation of nocturnal
pauses detracts from the benefits of rate control. Settling this
issue is important for future clinical practice.
Study limitations. This was a post-hoc analysis of prospectively collected data with all the limitations that imposes. Resting heart rate is a simple but poor indicator
of heart rate control during activity, and we appreciate that a
better assessment of risk might be obtained from 24-h
JACC: Heart Failure Vol. 2, No. 3, 2014
June 2014:213–20
Table 1
217
Cullington et al.
Importance of Heart Rate in Patients With CHF and AF
Continued
1-Year Review
% of Patients in AF (n ¼ 184)
% of Total Patient Cohort
“Strict” HR
(n ¼ 129)
“Lenient” HR
(n ¼ 48)
HR 110 beats/min
(n ¼ 7)
73 (67–79)
75 (64–80)
77 (66–79)
82
79
85 (74–97)
Patients in AF
(n ¼ 184)
Patients in SR
(n ¼ 657)
p Value
0.85
73 (66–79)
69 (62–75)
0.0001
57
0.26
80
75
0.14
83 (69–96)
73 (69–100)
0.43
84.6 (73–97)
81.1 (70–92)
0.03
19
28
17
0.45
20
18
0.38
66
60
57
0.74
69
64
p Value
0.01
0.25
0.06
12
13
43
13
22
71
52
14
64
60
16
33
43
22
17
2
2
0
2
1
124 (110–141)
127 (112–151)
116 (103–134)
0.37
125 (110–141)
126 (115–143)
0.16
72 (65–83)
80 (68–92)
65 (62–86)
0.06
73 (65–84)
72 (64–80)
0.08
24
29
14
25
22
15
6
43
14
14
19
23
14
20
23
27
17
14
24
24
15
25
14
17
17
65 (59–73)
85 (83–91)
120 (114–126)
0.0001
72 (63–82)
63 (57–71)
114 (102–144)
110 (94–134)
90 (84–96)
0.0001
114 (98–142)
110 (96–138)
0.17
0.91
0.005
0.0001
0.44
0.75
11
27
29
16
14
41
19
57
36
34
33
25
14
30
34
16
29
0
18
18
94
94
100
0.79
94
92
0.31
35
23
29
0.31
32
28
0.35
88
85
100
0.58
88
74
0.0001
55
52
43
0.79
54
10
0.0001
12
10
0
0.58
11
10
0.47
1
4
0
0.27
2
2
0.86
43
31
57
0.25
40
66
0.0001
20
23
29
0.82
78
18
0.0001
83
67
71
0.06
21
55
0.0001
4
0
14
0.11
3
12
0.0001
Values are median (interquartile range) or n. *Doses of beta-blocker: None, 0%; Low dose, 1% to 33%; Moderate dose, 34% to 66%; High dose, 67% to 100%. Values of p 0.05 are in bold.
ACE-I/ARB ¼ angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; AF ¼ atrial fibrillation; DBP ¼ diastolic blood pressure; HR ¼ heart rate; IHD ¼ ischemic heart disease;
IQR ¼ interquartile range; LBBB ¼ left bundle branch block; LVSD ¼ left ventricular systolic dysfunction; NYHA ¼ New York Heart Association; SBP ¼ systolic blood pressure; SR ¼ sinus rhythm.
monitoring. The analysis does not control for any medical
treatment changes or pacemaker implantation after 1 year
of follow-up. We sampled patients at 2 time points and did
not control for patients who switched rhythms, although
such patients were few. Atrial fibrillation may be an independent predictor of an adverse outcome in patients with
CHF and preserved ejection fraction, but we did not
explore this because follow-up data collection was restricted
to patients with LVSD. We could not define whether betablockers were associated with a lower mortality in our
observational study, but the analysis may have lacked power
and could not adjust for unmeasured confounders.
Conclusions
For patients with chronic heart failure in SR, lower
heart rates are associated with lower mortality, but this
is not the case for similar patients in AF. Whether it is
advantageous to lower heart rate in CHF patients with
AF to a range similar to that recommended for patients in sinus rhythm (<70 beats/min) is uncertain and
requires further investigation. The benefits of daytime
ventricular rate reduction may be balanced by an increased risk, possibly due to exacerbation of nocturnal
pauses.
218
Univariable and Multivariable Analyses of Patients in AF and SR at Baseline*
Patients in AF
HR Represents
Age
Per decade increase
Univariate Model
HR (95% CI)
1.65 (1.41–1.93)
Patients in SR
p Value
Multivariate Model
HR (95% CI)y
<0.0001
1.53 (1.29–1.82)
p Value
Univariate Model
HR (95% CI)
p Value
Multivariate Model
HR (95% CI)y
p Value
<0.0001
1.76 (1.61–1.92)
<0.0001
1.73 (1.58–1.90)
<0.0001
Sex
Men vs. women
1.09 (0.81–1.45)
0.59
–
–
1.26 (1.06–1.49)
0.008
–
–
Weight
Per 5-kg increase
0.95 (0.92–0.98)
0.004
–
–
0.92 (0.90–0.94)
<0.0001
–
–
1.05 (1.005–1.10)
QRS duration
Per 10-ms increase
1.07 (1.02–1.12)
0.004
LVI severity
Moderate vs. <moderate
1.30 (0.97–1.73)
0.08
–
0.03
–
1.03 (1.00–1.05)
0.04
–
–
1.30 (1.08–1.56)
0.005
–
–
Heart rate
Per 10-beats/min increase
0.93 (0.88–0.99)
0.02
–
–
1.15 (1.10–1.20)
<0.0001
1.10 (1.05–1.15)
<0.0001
Systolic BP
Per 5-U increase
0.97 (0.94–1.00)
0.03
–
–
0.97 (0.96–0.99)
0.001
0.97 (0.96–0.99)
0.002
NYHA functional class
III/IV vs. I/II
1.82 (1.40–2.38)
<0.0001
1.51 (1.14–1.99)
0.004
1.80 (1.53–2.12)
<0.0001
1.32 (1.11–1.57)
0.002
IHD
Yes vs. no
1.63 (1.25–2.13)
<0.0001
1.53 (1.14–2.04)
0.005
1.09 (0.92–1.30)
0.32
Diabetic patient
Yes vs. no
1.15 (0.80–1.64)
–
–
1.31 (1.09–1.59)
0.005
ACE/ARB
Yes vs. no
0.86 (0.65–1.15)
0.32
–
–
0.78 (0.65–0.93)
0.006
0.80 (0.66–0.97)
0.021
Loop diuretic agent use
Yes vs. no
1.34 (0.94–1.89)
0.10
–
–
2.21 (1.81–2.70)
<0.0001
1.69 (1.35–2.11)
<0.0001
–
1.29 (1.08–1.53)
0.005
–
–
0.71 (0.60–0.82)
<0.0001
–
–
0.45
0.22
–
–
–
1.36 (1.11–1.66)
0.003
Aldosterone Antagonist
Yes vs. no
1.22 (0.89–1.69)
Beta-blocker
Yes vs. no
0.67 (0.516–0.874)
Digoxin
Yes vs. no
0.92 (0.71–1.19)
0.50
–
–
1.48 (1.14–1.93)
0.003
1.50 (1.14–1.98)
0.004
Amiodarone
Yes vs. no
1.27 (0.83–1.93)
0.28
–
–
1.31 (1.01–1.70)
0.046
1.37 (1.04–1.80)
0.026
0.003
0.71 (0.53–0.94)
0.02
Cullington et al.
Importance of Heart Rate in Patients With CHF and AF
Table 2
*Hazard ratios for primary endpoint mortality. yVariables retained in the multivariate Cox model are shown. Values in bold indicate hazard ratios with a value of p 0.05.
ACE/ARB ¼ angiotensin-converting enzyme/angiotensin receptor blocker; AF ¼ atrial fibrillation; BP ¼ blood pressure; CI ¼ confidence interval; HR ¼ hazard ratio; IHD ¼ ischemic heart disease; LVSD ¼ left ventricular systolic dysfunction; NYHA ¼ New York Heart Association;
SR ¼ sinus rhythm.
JACC: Heart Failure Vol. 2, No. 3, 2014
June 2014:213–20
Figure 2
Multivariable Adjusted Survival Curves for
Patients in Atrial Fibrillation after 1-Year Follow-Up
Divided by Heart Rate Quartiles
Abbreviations as in Figure 1.
1.05 (0.99–1.13)
1.65 (1.09–2.49)
Per 5-kg increase
Per 10-ms increase
Moderate vs. <moderate
Per 10-beats/min increase
Per 5-U increase
III/IV vs. I/II
Yes vs. no
Yes vs. no
Yes vs. no
Yes vs. no
Yes vs. no
Yes vs. no
Yes vs. no
Yes vs. no
Weight
QRS duration
LVSD severity
Heart rate
Systolic BP
NYHA functional class
IHD
Diabetic patient
ACE/ARB use
Loop diuretic use
Aldosterone antagonist use
Beta-blocker use
Digoxin use
Amiodarone use
0.48
0.65
0.48
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
0.021
–
–
2.48 (1.15–5.36)
–
–
–
0.024
–
–
–
–
–
1.61 (1.07–2.45)
0.001
p Value
1.55 (1.21–1.99)
Multivariate Model
HR (95% CI)y
1.13 (0.77–1.66)
1.74 (1.17–2.57)
0.53 (0.40–0.71)
1.20 (0.93–1.55)
2.10 (1.53–2.87)
0.67 (0.46–0.98)
1.30 (0.97–1.74)
0.96 (0.75–1.24)
2.26 (1.73–2.95)
1.00 (0.97–1.02)
1.13 (1.03–1.23)
1.56 (1.21–2.02)
1.05 (1.03–1.08)
0.91 (0.88–0.95)
1.25 (0.96–1.63)
2.16 (1.88–2.50)
Univariate Model
HR (95% CI)
0.54
0.006
<0.0001
–
–
–
–
1.42 (1.02–1.99)
<0.0001
0.17
–
–
–
1.68 (1.26–2.25)
–
1.13 (1.03–1.24)
1.36 (1.04–0.78)
1.03 (1.00–1.06)
–
0.04
0.08
0.76
<0.0001
0.77
0.008
0.001
<0.0001
<0.0001
–
2.01 (1.75–2.33)
<0.0001
0.09
Multivariate Model
HR (95% CI)y
p Value
Patients in SR
p Value
–
–
–
–
0.039
–
–
–
<0.0001
–
0.008
0.025
0.035
–
–
<0.0001
Cullington et al.
Importance of Heart Rate in Patients With CHF and AF
*Hazard ratios for the primary endpoint mortality. yVariables retained in the multivariate Cox model are shown. Values in bold indicate hazard ratios with a value of p 0.05.
Abbreviations as in Table 2.
1.24 (0.69–2.22)
0.91 (0.62–1.35)
0.83 (0.49–1.40)
0.61
0.02
2.47 (1.15–5.33)
0.90 (0.58–1.38)
0.93
0.15
0,96 (0.42–2.20)
1.41 (0.89–2.23)
0.66
0.05
1.53 (0.99–2.35)
1.10 (0.73–1.65)
0.95
0.84
0.02
0.11
0.15
0.99
1.00 (0.96–1.04)
1.01 (0.90–1.13)
0.96 (0.91–1.01)
1.004 (0.62–1.62)
Men vs. women
Sex
0.001
1.51 (1.19–1.91)
Per decade increase
Age
p Value
CI ¼ confidence interval; HR ¼ hazard ratio.
Univariate Model
HR (95% CI)
Multivariable Adjusted Survival Curves for
Patients in Atrial Fibrillation at Baseline Divided
by Heart Rate Quartiles
HR Represents
Patients in AF
Univariable and Multivariable Analyses of Patients in AF and SR at 1 Year*
Figure 1
Table 3
JACC: Heart Failure Vol. 2, No. 3, 2014
June 2014:213–20
219
220
Cullington et al.
Importance of Heart Rate in Patients With CHF and AF
Reprint requests and correspondence: Dr. Damien Cullington,
Yorkshire Heart Centre, Department of Adult Congenital Heart
Disease, Jubilee Building, Leeds General Infirmary, Leeds,
West Yorkshire LS1 3EX, United Kingdom. E-mail:
[email protected].
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Key Words: atrial fibrillation
sinus rhythm.
-
heart failure
-
heart rate
-
prognosis
-