Download Lenient vs. strict rate control in patients with atrial fibrillation and

European Journal of Heart Failure Advance Access published June 12, 2013
European Journal of Heart Failure
doi:10.1093/eurjhf/hft093
Lenient vs. strict rate control in patients with atrial
fibrillation and heart failure: a post-hoc analysis
of the RACE II study
1
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 2Department of Cardiology, Maastricht University Medical
Center, Maastricht, The Netherlands; 3Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands; 4Trial Coordination Center, Department of Epidemiology,
University Medical Center Groningen, Groningen, The Netherlands; 5Department of Cardiology, Amphia Hospital, Breda, The Netherlands; and 6Interuniversity Cardiology Institute
Netherlands, Utrecht, The Netherlands
Received 10 April 2013; revised 13 May 2013; accepted 15 May 2013
Aims
It is unknown whether lenient rate control is an acceptable strategy in patients with AF and heart failure. We evaluated
differences in outcome in patients with AF and heart failure treated with lenient or strict rate control.
.....................................................................................................................................................................................
Methods
This post-hoc analysis of the RACE II trial included patients with an LVEF ≤ 40% at baseline or a previous hospitalization
and results
for heart failure or signs and symptoms of heart failure. Primary outcome was a composite of cardiovascular morbidity and
mortality. Secondary endpoints were AF-related symptoms and quality of life. Two hundred and eighty-seven (46.7%) of
the 614 patients had heart failure. Patients with heart failure had significantly higher NT-proBNP plasma levels, a lower
LVEF, and more often used ACE inhibitors, ARBs, and diuretics. At 3 years follow-up, the primary outcome occurred
more frequently in patients with heart failure (16.7% vs. 11.5%, P ¼ 0.04). In heart failure patients, the estimated cumulative incidence of the primary outcome was 15.0% (n ¼ 20) in the lenient and 18.2% (n ¼ 26) in the strict group
(P ¼ 0.53). No differences were found in any of the primary outcome components, in either heart failure hospitalizations
[8 (6.1%) vs. 9 (6.8%) patients in the lenient vs. strict group, respectively], symptoms, or quality of life.
.....................................................................................................................................................................................
Conclusion
In patients with AF and heart failure with a predominantly preserved EF, the stringency of rate control seems to have no
effect on cardiovascular morbidity and mortality, symptoms, and quality of life.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Atrial fibrillation † Heart failure † Rate control
Introduction
Heart failure and AF have been named the two epidemics in cardiovascular disease of the 21st century and often co-exist.1 – 3 Previously,
every effort was made to maintain sinus rhythm, but long-term
success was poor.4 – 6 Recent studies have shown that rate control
is not inferior to pharmacological rhythm control with regard to cardiovascular morbidity and mortality.7,8 Similar findings have been
observed in patients with chronic heart failure.9,10 Therefore, rate
control may now be adopted as first choice treatment in patients
with and without heart failure without severe symptoms.11 The
optimal level of heart rate control with respect to morbidity, mortality, quality of life, and symptoms was never investigated. The recently
published RAte Control Efficacy in permanent AF II (RACE II) trial
showed that lenient rate control was not inferior to strict rate
control therapy.12 Whether this is also applicable for patients with
AF and heart failure is unknown.
Therefore, we undertook the present post-hoc analysis of RACE II
in patients with an LVEF ≤ 40% or a previous hospitalization for heart
failure or signs and symptoms of heart failure, to test the hypothesis
* Corresponding author. Department of Cardiology, Thoraxcenter, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen,
The Netherlands. Tel: +31 50 3611327, Fax: +31 50 3614391, Email: [email protected]
Participants in the RACE II trial for permanent atrial fibrillation are listed elsewhere.13
†
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected].
Downloaded from http://eurjhf.oxfordjournals.org/ at Shanghai Jiao Tong University on July 7, 2013
Bart A. Mulder 1, Dirk J. Van Veldhuisen 1, Harry J.G.M. Crijns 2, Jan G.P. Tijssen 3,
Hans L. Hillege 4, Marco Alings 5, Michiel Rienstra 1, Hessel F. Groenveld 1,
Maarten P. Van den Berg 1, and Isabelle C. Van Gelder 1,6* for the RACE II investigators†
Page 2 of 8
that lenient rate control is comparable with strict rate control in
patients with AF and heart failure in terms of cardiovascular
outcome, symptoms, and quality of life.
Methods
Study population
N-terminal pro brain natriuretic peptide
After inclusion at the outpatient clinic, 10 mL of blood was collected by
vein puncture into an EDTA tube. Within 1 h, the tube was centrifuged
for 10 min, and the plasma was removed and stored at – 808C at the
local hospital. After completion of the study, all samples were transported (on dry ice) to the core laboratory of the University Medical
Center Groningen, The Netherlands for analysis. Measurements of
NT-proBNP were performed in plasma on a Roche Modular E170 analyser, a commercially available electrochemiluminescent immunoassay
(Roche Diagnostics, Mannheim, Germany). Overall machine day-to-day
variation was 2.2% (at a level of 126 pg/mL) and 2.0% (at a level of 4230
pg/mL), with an analytical range of 5 – 35000 pg/mL. NT-proBNP was
determined at baseline and at the end of the study.
Outcome
The primary outcome was a composite of cardiovascular death, hospitalization for heart failure, stroke, systemic embolism, major bleeding, or
arrhythmic events, including syncope, sustained ventricular tachycardia,
cardiac arrest, life-threatening adverse effects of rate control drugs, and
pacemaker or cardioverter-defibrillator implantation.12
Quality of life
The Dutch version of The Medical Outcome Study Short Form-36
(SF-36) was used to assess quality of life. It contains items to assess physical and mental health. Severity of AF-related symptoms was assessed
with the University of Toronto AF Severity Scale.14 The Minnesota
Living with Heart Failure questionnaire is a patient self-assessment
measure being developed to evaluate the therapeutic response to interventions for heart failure.15
Statistical analysis
Baseline descriptive statistics are presented as mean + standard deviation or median (range) for continuous variables, and counts with
percentages for categorical variables. Differences between patients
treated with lenient or strict rate control were evaluated by the
Student t-test, Mann– Whitney U-test, x2 test, and Fisher’s exact test depending on normality and the type of data. The first occurrence of the
composite primary outcome was assessed by Kaplan – Meier curves. All
tests of significance were two-tailed, with P-values of ,0.05 assumed
to indicate significance. All analyses were generated using STATA 11.0
for Windows.
Results
Baseline characteristics
Of 614 patients randomized into RACE II, 287 (47%) had heart failure.
Heart failure was present in 93 of 287 patients (32.4%) because of an
LVEF ≤40% at baseline, in 149/287 (51.9%) because of LVEF .40%
with symptoms, and in 45/287 (15.7%) because of previous hospitalizations for heart failure. Patients with heart failure differed significantly from those without heart failure (n ¼ 327, 53%): they had
significantly higher levels of NT-proBNP (1189 pg/mL vs. 877 pg/
mL, P , 0.001), a lower LVEF (47% vs. 56%, P , 0.001), and more
often used ACE inhibitors or ARBs (55.1% vs. 45.3% P ¼ 0.015),
and diuretics (47.7% vs. 29.7% P , 0.001) at baseline.
Table 1 shows baseline characteristics of the present population of
287 patients with heart failure randomized to lenient or strict rate
control.
Dose adjustment phase
Table 2 shows data recorded at the end of the dose adjustment phase.
Lenient rate control was easier to achieve. Patients were instituted on
fewer rate control drugs and lower dosages. Fewer hospital visits
were necessary. The mean resting heart rate was 94 + 11 b.p.m. in
the lenient vs. 76 + 12 in the strict group (P , 0.001). After 1 and
2 years and at the end of follow-up, the resting heart rates in the
lenient group were 84 + 13, 83 + 13, and 85 + 14 b.p.m., respectively, as compared with 76 + 12, 75 + 12, and 76 + 15 b.p.m., respectively, in the strict group (P , 0.001 for comparisons between
the two groups).
Lenient vs. strict rate control in patients
with heart failure
Kaplan –Meier curves for the primary outcome are shown in Figure 1.
Among patients with heart failure, the 3-year estimated cumulative
incidence was 15.0% in the lenient and 18.2% in the strict group
[hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.46– 1.49;
Table 3]. There were no differences in the components of the
primary outcome, including heart failure hospitalizations. None and
only one death were due to progression of heart failure in the
lenient and strict group, respectively. All-cause mortality occurred
in 10 in the lenient (7.7%) vs. 10 patients in the strict group (7.5%).
Quality of life
No differences in the SF-36, AF severity scale, and the Minnesota
Living with Heart Failure questionnaires were observed at baseline
or at the end of the study (Figure 2).
Downloaded from http://eurjhf.oxfordjournals.org/ at Shanghai Jiao Tong University on July 7, 2013
This analysis includes patients randomized into the RACE II trial stratified
by the presence of heart failure. For the present study, patients were classified as having heart failure in the presence of an LVEF ≤ 40% at baseline
or LVEF .40% with symptoms associated with heart failure (NYHA
functional class II or III), or previous hospitalization for heart failure.
The study design, patient characteristics, and results of the RACE II
study have been published previously.12,13 In brief, the RACE II study
was a Dutch randomized multicentre study comparing long-term
effects of lenient vs. strict rate control on morbidity and mortality in
614 patients with permanent AF. Patients randomized to lenient rate
control had a resting heart rate target ,110 b.p.m. Patients randomized
to strict rate control had two heart rate targets: a resting heart rate target
,80 b.p.m. and a heart rate target during moderate exercise ,110 b.p.m.
Patients were administered one or more negative dromotropic drugs
until the heart rate target(s) were achieved. After achievement of the
rest and activity heart rate targets in the strict group, 24 h Holter monitoring was performed to check for bradycardia. Follow-up outpatient
visits occurred every 2 weeks until the heart rate target(s) were achieved
(dose adjustment phase), and in all patients after 1, 2, and 3 years. Followup was terminated after a follow-up period of 3 years or on 30 June 2009,
whichever came first.
Lenient rate control in heart failure
Page 3 of 8
B.A. Mulder et al.
Table 1 Baseline characteristics of heart failure patients enrolled in RACE II
Lenient rate control (n 5 138)
Strict rate control (n 5 149)
Age, years
69 + 8
68 + 9
0.68
Male sex, n (%)
Duration of any AF, months
87 (63.0)
91 (61.1)
0.73
0.32
P-value
...............................................................................................................................................................................
Median
18
30
Interquartile range
Duration of permanent AF, months
6 –60
6 –66
Median
3
3
Interquartile range
Previous electrical cardioversion, n (%)
1 –7
98 (71.0)
1 –7
105 (70.5)
Hypertension, n (%)
96 (69.6)
87 (58.4)
,0.05
Coronary artery disease, n (%)
Valvular heart disease, n (%)
31 (22.5)
37 (26.8)
22 (14.8)
34 (22.8)
0.09
0.43
Cardiomyopathy, n (%)
14 (10.1)
13 (8.7)
0.66
Diabetes mellitus, n (%)
Previous hospitalization for heart failure, n (%)
18 (13.0)
28 (20.3)
20 (13.4)
32 (21.5)
0.93
0.81
CHADS2 score, median (interquartile range)a
2 (1 –2)
1(1– 2)
0.11
Body mass index, kg/m2b
Blood pressure, mmHg
29 + 5
29 + 5
0.70
138 + 19
135 + 17
0.22
85 + 11
118 (85.5)
82 + 11
124 (83.2)
0.01
0.63
0.92
,0.05
Palpitations
38 (27.5)
56 (37.6)
Dyspnoea
Fatigue
105 (76.1)
53 (38.4)
110 (73.8)
72 (48.3)
I
II
33 (23.4)
89 (65.0)
39 (26.2)
97 (65.1)
III
16 (11.7)
13 (8.7)
100 + 26
1197 (839– 1933)
94 + 22
1162 (730– 1907)
No rate control drugs
Beta-blocker
8 (5.8)
95 (68.8)
10 (6.7)
98 (65.8)
0.81
0.62
Verapamil or diltiazem
21 (15.2)
32 (21.5)
0.22
41 (29.7)
56 (37.6)
0.17
ACE inhibitors and/or ARB
82 (59.4)
76 (51.0)
0.15
Diuretics
Statin
74 (53.6)
50 (36.2)
76 (51.0)
36 (24.2)
0.72
0.03
Vitamin K antagonists
NYHA functional class, n (%)
Creatinine, mmol/L
NT-proBNP, pg/mL, median (interquartile range)
0.95
0.05
0.69
,0.05
0.49
Rate control medication, n (%)
Digoxin
Other medication in use at baseline, n (%)
137 (99.3)
147 (98.7)
1.00
Aspirin
LVEF, %
1 (0.7)
47 + 13
3 (2.0)
48 + 14
0.62
0.42
LVEF ≤40%, n (%)
45 (32.6)
48 (32.2)
0.94
Values are given as means + SD unless indicated otherwise.
a
The CHADS2 score is a measure of the risk of stroke in patients with AF, with scores ranging from 0 to 6 and higher scores indicating a greater risk. Congestive heart failure,
hypertension, 75 years of age or older, and diabetes are each assigned 1 point, and previous stroke or transient ischaemic attack is assigned 2 points; the score is calculated by summing
all the points for a given patient.
b
The body mass index is the weight in kilograms divided by the square of the height in metres.
Role of rate control strategy in symptoms
At the end of the study, AF-related symptoms were present in a comparable number of patients, 80 of 123 (58%) in the lenient and 80 of
136 patients (54%) in the strict group. Symptoms were predominantly dyspnoea (76.3% vs. 73.8% in the lenient vs. strict group, respectively). Palpitations were present in 26.3% vs. 20.0% and fatigue in
Downloaded from http://eurjhf.oxfordjournals.org/ at Shanghai Jiao Tong University on July 7, 2013
Systolic
Diastolic
Complaints, n (%)
0.89
Page 4 of 8
Lenient rate control in heart failure
Table 2 Rate control target and drug therapy at the end of the dose-adjustment phase, according to treatment group
Lenient rate control (n 5 138)
Strict rate control (n 5 149)
P-value
134 (97.1)
108 (72.5)
,0.001
...............................................................................................................................................................................
Rate control target or targets achieved, n (%)
Resting heart rate, n (%)
,70 b.p.m.
1 (0.7)
33 (22.1)
,0.001
70–80 b.p.m.
3 (2.2)
87 (58.4)
,0.001
80–90 b.p.m.
90–100 b.p.m.
47 (34.1)
51 (37.0)
13 (8.7)
9 (6.0)
,0.001
,0.001
.100 b.p.m.
36 (26.1)
7 (4.7)
,0.001
84 + 13
83 + 13
76 + 12
75 + 12
,0.001
,0.001
Heart rate at 1 year
Heart rate at 2 years
85 + 14
76 + 15
,0.001
134 (97.1)
–
120 (80.5)
117 (78.5)
,0.001
–
97 + 16
Holter monitoringa
Mean heart rate, b.p.m.
–
78 + 12
Visits to achieve rate control target or targets, total n
41
347
Median (interquartile range)
Reasons for failure to achieve rate control target or targets, n/total n (%)
0 (0 –0)
2 (1 –3)
Drug-related adverse events
–/5 (–)
13/41 (31.7)
No symptoms or symptoms tolerated
Target impossible to achieve with drugs
5/5 (100.0)
–/5 (–)
17/41 (41.5)
11/41 (26.8)
No rate control drugs
Beta-blocker alone
7 (5.1)
62 (44.9)
1 (0.7)
30 (20.1)
Verapamil or diltiazem alone
8 (5.8)
8 (5.4)
0.88
Digoxin alone
Beta-blocker and either verapamil or diltiazem
8 (5.8)
8 (5.8)
1 (0.7)
18 (12.1)
0.01
0.06
Beta-blocker and digoxin
25 (18.1)
49 (32.9)
0.004
Digoxin and either verapamil or diltiazem
Beta-blocker, digoxin, and either verapamil or ditiazem
12 (8.7)
1 (0.7)
19 (12.8)
17 (11.4)
0.34
,0.001
82 (59.4)
80 (53.7)
0.34
74 (53.6)
82 (55.0)
0.81
Mean heart rate, b.p.m.
,0.001
,0.001
Medication, n (%)
ACE inhibitor/ARB
Diuretics
Dose, mg. (no. of patients)
0.024
,0.001
Beta-blocker (normalized to metoprolol-equivalent doses)
129 + 82 (98)
167 + 91 (116)
0.001
Verapamil
Diltiazem
171 + 62 (25)
215 + 75 (4)
219 + 106 (63)
200 (1)
0.036
0.87
Digoxin
0.2 + 0.1 (49)
0.2 + 0.1 (90)
0.02
Values are given as means + SD unless indicated otherwise.
a
The strict control group had two heart rate targets (resting and exercise), whereas the lenient control group had only one (resting). According to the protocol, exercise tests and 24 h
Holter monitoring were only performed in the strict group.
58.8% vs. 52.5% of the symptomatic patients. NYHA classes were
also comparable between both groups (data not shown).
(P ¼ 0.01) in the lenient, and from 1162 pg/mL to 976 pg/mL (IQR
684–1696, P ¼ 0.26) in the strict group, respectively.
Natriuretic peptide measurements
Measurement of NT-proBNP was available in 259 (90.2%) heart
failure patients [129 (93.5%) in the lenient vs. 130 (87.2%) in the
strict group]. At baseline, NT-proBNP was high: 1189 pg/mL [interquartile range (IQR) 773–1929]. During follow-up, no significant
changes occurred in either group: from a median of 1197 pg/mL at
baseline to 1029 pg/mL (IQR 633 –1544) at the end of follow-up
Discussion
The present post-hoc analysis of the RACE II study shows that in
patients with permanent AF and heart failure, many of whom had a
preserved EF, the occurrence of cardiovascular morbidity and mortality is comparable between lenient and strict rate control. In
Downloaded from http://eurjhf.oxfordjournals.org/ at Shanghai Jiao Tong University on July 7, 2013
Heart rate at end of study
Resting heart rate target achieved, n (%)
Exercise heart rate target achieved, n (%)
Page 5 of 8
B.A. Mulder et al.
Table 3 Cumulative incidence of the composite primary outcome and its components during a follow-up of 3 years in
patients with heart failurea
Primary outcome
Lenient rate control (n 5 138)
Strict rate control (n 5 149)
No. of patients (%)b
No. of patients (%)b
20 (15.0)
26 (18.2)
0.83 (0.46– 1.49)
6 (4.4)
2 (1.5)
6 (4.1)
2 (1.4)
1.10 (0.35– 3.40)
Hazard ratio (95% CI)
...............................................................................................................................................................................
Composite endpoint
Death from cardiovascular cause
From cardiac arrhythmia
0
1 (0.7)
From non-cardiac vascular cause
Heart failure
From cardiac cause other than arrhythmia
4 (3.0)
8 (6.1)
3 (2.1)
9 (6.8)
0.99 (0.38– 2.56)
Stroke
0
6 (4.1)
–
0
0
4 (2.8)
2 (1.4)
Ischaemic
Haemorrhagic
Systemic embolism
0
0
Bleeding
Intracranial
6 (4.6)
0
7 (4.9)
0
Extracranial
6 (4.6)
7 (4.9)
5 (4.2)
6 (4.1)
Arrhythmic events
0.94 (0.32– 2.80)
0.91 (0.28– 2.98)
CI, confidence interval.
a
The tabulations of the composite primary outcome include the first event for each patient. The tabulations of component events include all such events.
b
The cumulative incidence at 3 years of follow-up was determined with use of the Kaplan –Meier curve. Arrhythmic events consists of syncope, life-threatening adverse effects of rate
control drugs, sustained ventricular tachycardia or ventricular fibrillation, implantable cardioverter implantation, and pacemaker implantation.
Downloaded from http://eurjhf.oxfordjournals.org/ at Shanghai Jiao Tong University on July 7, 2013
Figure 1 Kaplan –Meier estimates of the cumulative incidence of the primary outcome, according to treatment group in patients with heart failure.
The numbers at the end of the Kaplan– Meier curves are the estimated cumulative incidence of the primary outcome at 3 years. CI, confidence interval; HR, hazard ratio.
Page 6 of 8
Lenient rate control in heart failure
severity scale at baseline and at the end of the study. Blue, lenient; red, strict.
addition, no differences in symptoms and quality of life were observed
between the groups.
Lenient rate control in patients with heart
failure
It is generally believed that a low heart rate is beneficial, both in
patients with heart failure16,17 and in those with CAD.18 This assumption, however, is primarily derived from studies in patients in sinus
rhythm. In this analysis of the RACE II trial we observed no beneficial
effect of a lower heart rate during AF. Although this may be unexpected, this observation is in accordance with post-hoc analyses of four
beta-blocker trials that showed that a lower heart rate in patients
with AF and heart failure did not improve prognosis, although the
overall results in the main trials were undoubtedly positive in
favour of beta-blockade therapy. In all these analyses, beta-blockade
reduced heart rates to , 80 b.p.m., comparable with our strict rate
control group. The placebo groups all had heart rates well above
80 b.p.m.,19 – 22 comparable with our lenient group. This reduction
in heart rate was not accompanied by a reduction in mortality or cardiovascular hospitalization even in elderly patients with AF and a preserved LV function [Study of Effects of Nebivolol Intervention on
Outcomes and Rehospitalization in Seniors With Heart Failure
(SENIORS)], being in accordance with the present findings.22 In
Downloaded from http://eurjhf.oxfordjournals.org/ at Shanghai Jiao Tong University on July 7, 2013
Figure 2 Outcome of the SF-36 (Medical Outcome Study Short Form-36), Minnesota Living with Heart Failure (MLWHF) questionnaire, and AF
Page 7 of 8
B.A. Mulder et al.
N-terminal pro brain natriuretic peptide
The measured NT-proBNP levels were high in RACE II, with a median
of almost 1200 pg/mL. This is remarkable as in RACE II patients were
included while in a stable condition at the outpatient clinic, and not
during visits to the emergency department for dyspnoea.28 This
may be a sign of the presence of diastolic dysfunction. Comparably,
elevated median levels of NT-proBNP were observed in post-hoc
analysis of the Randomized Evaluation of Long-Term Anticoagulation
Therapy (RE-LY) and Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)
studies, 800 and 714 pg/mL, respectively.29,30
that underlying heart disease rather than the strictness of rate
control itself predominantly influences quality of life.33,34
Study limitations
The results may be particularly true for patients with AF and heart
failure with preserved LV function since our study did not include
patients with a very low LVEF and severe systolic heart failure. The
present study was a post-hoc analysis, thus it was not in essence
designed to determine differences in outcome with lenient or strict
rate control in patients with permanent AF and heart failure. Additionally, due to small sample size, there is low statistical power. Echocardiographic assessment of diastolic function was not performed.
NT-proBNP levels have been shown to be well correlated with diastolic dysfunction.35 Finally, long-term follow up (beyond 3 years) of a
lenient rate control strategy was not evaluated in RACE II.
Conclusions
In patients with permanent AF and heart failure, many of whom had a
preserved EF, lenient rate control seems to be as effective as strict
rate control and easier to achieve. Therefore, a more lenient rate
control strategy may be considered as an initial treatment approach
in this group of patients.
Funding
RACE II was supported by the Netherlands Heart Foundation
(2003B118) and Interuniversity Cardiology Institute, The Netherlands;
unrestricted educational grants from AstraZeneca, Biotronik,
Boehringer Ingelheim, Boston Scientific, Medtronic, Roche, and Sanofi
Aventis France (paid to the Interuniversity Cardiology Institute of the
Netherlands).
Conflict of interest: D.J.V.V. received board membership fees from
Amgen, Vifor, BG Medicine, Sorbent, Johnson & Johnson, and Biocontrol.
H.J.G.M.C. received consulting fees from Boehringer Ingelheim,
Sanofi-Aventis, and AstraZeneca, grant support from St. Jude Medical,
Boston Scientific, Boehringer Ingelheim, Sanofi-Aventis, Medapharma,
and Merck, and honoraria from Medtronic, Sanofi-Aventis, Medapharma,
Merck, Boehringer Ingelheim, and Biosense Webster; M.A. received consulting fees from Boehringer Ingelheim and Sanofi-Aventis; and I.C.V.G.
reports receiving consulting fees from Sanofi-Aventis, Boehringer Ingelheim, and Cardiome, grant support from Medtronic, Biotronik, and
St. Jude Medical, and lecture fees from Sanofi-Aventis, Boehringer Ingelheim, and Medtronic.
References
Symptomatology
There were no differences in symptoms and quality of life between
the lenient and strict group. Dyspnoea was the main symptom and
was significantly associated with baseline Minnesota Living with
Heart Failure questionnaire score, which is associated with prognosis.31 Thus, the well-being of patients with AF seems to be associated
with more factors other than only heart rate, and the physician should
be aware that intensifying rate control therapy does not necessarily
imply fewer symptoms.32 It may even do the opposite due to increasing adverse effects associated with rate control drugs. It is noteworthy that the quality of life analyses of RACE I and II concluded
1. Crijns HJ, Tjeerdsma G, de Kam PJ, Boomsma F, van Gelder IC, van den Berg MP, van
Veldhuisen DJ. Prognostic value of the presence and development of atrial fibrillation
in patients with advanced chronic heart failure. Eur Heart J 2000;21:1238 –1245.
2. Nieuwlaat R, Eurlings LW, Cleland JG, Cobbe SM, Vardas PE, Capucci A,
Lopez-Sendon JL, Meeder JG, Pinto YM, Crijns HJ. Atrial fibrillation and heart
failure in cardiology practice: reciprocal impact and combined management from
the perspective of atrial fibrillation: results of the Euro Heart Survey on atrial fibrillation. J Am Coll Cardiol 2009;53:1690 –1698.
3. Smit MD, Moes ML, Maass AH, Achekar ID, Van Geel PP, Hillege HL, van
Veldhuisen DJ, Van Gelder IC. The importance of whether atrial fibrillation or
heart failure develops first. Eur J Heart Fail 2012;14:1030 –1040.
4. Roy D, Talajic M, Dorian P, Connolly S, Eisenberg MJ, Green M, Kus T, Lambert J,
Dubuc M, Gagne P, Nattel S, Thibault B. Amiodarone to prevent recurrence of
atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med
2000;342:913 –920.
Downloaded from http://eurjhf.oxfordjournals.org/ at Shanghai Jiao Tong University on July 7, 2013
agreement with the above, a recent subanalysis of the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and
morbidity) programme did show that resting heart rate was an important predictor of outcome in patients in sinus rhythm and heart
failure, regardless of LVEF, but not in patients with AF.23
Despite the absence of a difference in cardiovascular hospitalization in RACE II, one cannot exclude that excessive rate control can
be deleterious. In Permanent Atrial Fibrillation Outcome Study
Using Dronedarone on Top of Standard Therapy (PALLAS), the immediate rise in both co-primary composite endpoints in the dronedarone group compared with placebo may have been related to
excessive rate control. This notion is supported by the fact that the
heart rate at 1 month in survivors in the dronedarone arm had
decreased by 7.6 + 14.5 b.p.m. (from 77 + 16 b.p.m. at baseline),
which may have harmed patients.24
An important advantage of lenient rate control was that it was
easier to accomplish: significantly fewer additional hospital visits,
and a lower number and lower dosages of rate control drugs were
necessary to achieve the heart rate target. Thus, although the difference in heart rate between the groups was not as marked as would
have been expected from the design of the study, the strategies to
achieve those heart rates were completely different.
A major concern of a high heart rate in patients with AF has always
been the development or deterioration of heart failure.25,26 This was
not observed, and it was also not observed in a previous trial in
patients with AF and moderate heart failure treated with a more
lenient rate control approach.9 Also, in advanced heart failure
patients, a higher heart rate was not associated with enhanced morbidity and mortality.27 Apparently, lenient rate control in the present
population led to a heart rate that was low enough to prevent excess
heart failure hospitalizations and other cardiovascular morbidity and
mortality.
Page 8 of 8
20. Joglar JA, Acusta AP, Shusterman NH, Ramaswamy K, Kowal RC, Barbera SJ,
Hamdan MH, Page RL. Effect of carvedilol on survival and hemodynamics in patients
with atrial fibrillation and left ventricular dysfunction: retrospective analysis of the US
Carvedilol Heart Failure Trials Program. Am Heart J 2001;142:498 –501.
21. van Veldhuisen DJ, Aass H, El Allaf D, Dunselman PH, Gullestad L, Halinen M,
Kjekshus J, Ohlsson L, Wedel H, Wikstrand J. Presence and development of atrial fibrillation in chronic heart failure. Experiences from the MERIT-HF Study. Eur J Heart
Fail 2006;8:539 –546.
22. Mulder BA, van Veldhuisen DJ, Crijns HJ, Bohm M, Cohen-Solal A, Babalis D,
Roughton M, Flather MD, Coats AJ, Van Gelder IC. Effect of nebivolol on
outcome in elderly patients with heart failure and atrial fibrillation: insights from
SENIORS. Eur J Heart Fail 2012;14:1171 –1178.
23. Castagno D, Skali H, Takeuchi M, Swedberg K, Yusuf S, Granger CB, Michelson EL,
Pfeffer MA, McMurray JJ, Solomon SD, CHARM Investigators. Association of heart
rate and outcomes in a broad spectrum of patients with chronic heart failure:
results from the CHARM (Candesartan in Heart Failure: Assessment of Reduction
in Mortality and morbidity) program. J Am Coll Cardiol 2012;59:1785 –1795.
24. Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, Avezum A,
Blomstrom P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A,
Davy JM, Delacretaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S,
Gonzalez-Hermosillo A, Granger CB, Heidbuchel H, Kautzner J, Kim JS, Lanas F,
Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E,
Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L,
Tomcsanyi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J,
Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R,
Hohnloser SH, PALLAS Investigators. Dronedarone in high-risk permanent atrial
fibrillation. N Engl J Med 2011;365:2268 –2276.
25. Hagens VE, van Veldhuisen DJ, Kamp O, Rienstra M, Bosker HA, Veeger NJ,
Tijssen JG, Crijns HJ, Van Gelder IC. Effect of rate and rhythm control on left ventricular function and cardiac dimensions in patients with persistent atrial fibrillation:
results from the RAte Control versus Electrical Cardioversion for Persistent Atrial
Fibrillation (RACE) study. Heart Rhythm 2005;2:19 –24.
26. Anter E, Jessup M, Callans DJ. Atrial fibrillation and heart failure: treatment considerations for a dual epidemic. Circulation 2009;119:2516 –2525.
27. Rienstra M, Van Gelder IC, van den Berg MP, Boomsma F, Hillege HL, van
Veldhuisen DJ. A comparison of low versus high heart rate in patients with atrial fibrillation and advanced chronic heart failure: effects on clinical profile, neurohormones and survival. Int J Cardiol 2006;109:95 –100.
28. Knudsen CW, Omland T, Clopton P, Westheim A, Wu AH, Duc P, McCord J,
Nowak RM, Hollander JE, Storrow AB, Abraham WT, McCullough PA, Maisel A.
Impact of atrial fibrillation on the diagnostic performance of B-type natriuretic
peptide concentration in dyspneic patients: an analysis from the breathing not properly multinational study. J Am Coll Cardiol 2005;46:838 –844.
29. Hijazi Z, Oldgren J, Andersson U, Connolly SJ, Ezekowitz MD, Hohnloser SH,
Reilly PA, Vinereanu D, Siegbahn A, Yusuf S, Wallentin L. Cardiac biomarkers are
associated with an increased risk of stroke and death in patients with atrial fibrillation:
a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy.
Circulation 2012;125:1605 –1616.
30. Hijazi Z, Wallentin L, Siegbahn A, Andersson U, Christersson C, Ezekowitz J,
Gersh BJ, Hanna M, Hohnloser S, Horowitz J, Huber K, Hylek EM, Lopes RD,
McMurray JJ, Granger CB. NT-proBNP for risk assessment in patients with atrial fibrillation: insights from the ARISTOTLE trial. J Am Coll Cardiol 2013;in press.
31. Iqbal J, Francis L, Reid J, Murray S, Denvir M. Quality of life in patients with chronic
heart failure and their carers: a 3-year follow-up study assessing hospitalization
and mortality. Eur J Heart Fail 2010;12:1002 –1008.
32. Dorian P, Ha AC. Does better rate control improve quality of life? Be still my beating
heart. J Am Coll Cardiol 2011;58:1804 –1806.
33. Groenveld HF, Crijns HJ, Van den Berg MP, Van Sonderen E, Alings AM, Tijssen JG,
Hillege HL, Tuininga YS, Van Veldhuisen DJ, Ranchor AV, Van Gelder IC, RACE II
Investigators. The effect of rate control on quality of life in patients with permanent
atrial fibrillation data from the RACE II (Rate Control Efficacy in Permanent Atrial
Fibrillation II) Study. J Am Coll Cardiol 2011;58:1795 –1803.
34. Hagens VE, Ranchor AV, Van Sonderen E, Bosker HA, Kamp O, Tijssen JG,
Kingma JH, Crijns HJ, Van Gelder IC, RACE Study Group. Effect of rate or rhythm
control on quality of life in persistent atrial fibrillation. Results from the Rate
Control Versus Electrical Cardioversion (RACE) Study. J Am Coll Cardiol 2004;43:
241 –247.
35. Grewal J, McKelvie R, Lonn E, Tait P, Carlsson J, Gianni M, Jarnert C, Persson H. BNP
and NT-proBNP predict echocardiographic severity of diastolic dysfunction. Eur J
Heart Fail 2008;10:252 –259.
Downloaded from http://eurjhf.oxfordjournals.org/ at Shanghai Jiao Tong University on July 7, 2013
5. Singh BN, Singh SN, Reda DJ, Tang XC, Lopez B, Harris CL, Fletcher RD, Sharma SC,
Atwood JE, Jacobson AK, Lewis HD Jr, Raisch DW, Ezekowitz MD. Amiodarone
versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861 –1872.
6. Ahmed S, Rienstra M, Crijns HJ, Links TP, Wiesfeld AC, Hillege HL, Bosker HA,
Lok DJ, van Veldhuisen DJ, Van Gelder IC. Continuous vs episodic prophylactic
treatment with amiodarone for the prevention of atrial fibrillation: a randomized
trial. JAMA 2008;300:1784 – 1792.
7. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC,
Greene HL, Mickel MC, Dalquist JE, Corley SD. A comparison of rate control and
rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825 –1833.
8. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA,
Darmanata JI, Timmermans AJ, Tijssen JG, Crijns HJ. A comparison of rate control
and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J
Med 2002;347:1834 –1840.
9. Hagens VE, Crijns HJ, van Veldhuisen DJ, van den Berg MP, Rienstra M, Ranchor AV,
Bosker HA, Kamp O, Tijssen JG, Veeger NJ, Van Gelder IC. Rate control versus
rhythm control for patients with persistent atrial fibrillation with mild to moderate
heart failure: results from the RAte Control versus Electrical cardioversion (RACE)
study. Am Heart J 2005;149:1106 –1111.
10. Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JM,
Buxton AE, Camm AJ, Connolly SJ, Dubuc M, Ducharme A, Guerra PG,
Hohnloser SH, Lambert J, Le Heuzey JY, O’Hara G, Pedersen OD, Rouleau JL,
Singh BN, Stevenson LW, Stevenson WG, Thibault B, Waldo AL. Rhythm control
versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:
2667 –2677.
11. European Heart Rhythm Association, European Association for Cardio-Thoracic
Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van
Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O,
Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B,
Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH, ESC Committee for Practice Guidelines, Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V,
Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA,
Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas PE, Widimsky P, Document
Reviewers, Vardas PE, Agladze V, Aliot E, Balabanski T, Blomstrom-Lundqvist C,
Capucci A, Crijns H, Dahlof B, Folliguet T, Glikson M, Goethals M, Gulba DC,
Ho SY, Klautz RJ, Kose S, McMurray J, Perrone Filardi P, Raatikainen P,
Salvador MJ, Schalij MJ, Shpektor A, Sousa J, Stepinska J, Uuetoa H, Zamorano JL,
Zupan I. Guidelines for the management of atrial fibrillation: the Task Force for
the Management of Atrial Fibrillation of the European Society of Cardiology
(ESC). Europace 2010;12:1360 –1420.
12. Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM,
Hillege HL, Bergsma-Kadijk JA, Cornel JH, Kamp O, Tukkie R, Bosker HA, van
Veldhuisen DJ, van den Berg MP. Lenient versus strict rate control in patients with
atrial fibrillation. N Engl J Med 2010;362:1363 –1373.
13. Van Gelder IC, van Veldhuisen DJ, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM,
Bosker HA, Cornel JH, Kamp O, Veeger NJ, Volbeda M, Rienstra M, Ranchor AV,
TenVergert EM, van den Berg MP. RAte Control Efficacy in permanent atrial fibrillation: a comparison between lenient versus strict rate control in patients with and
without heart failure. Background, aims, and design of RACE II. Am Heart J 2006;
152:420–426.
14. Dorian P, Jung W, Newman D, Paquette M, Wood K, Ayers GM, Camm J, Akhtar M,
Luderitz B. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am
Coll Cardiol 2000;36:1303 –1309.
15. Rector TS, Cohn JN. Assessment of patient outcome with the Minnesota Living with
Heart Failure questionnaire: reliability and validity during a randomized, doubleblind, placebo-controlled trial of pimobendan. Pimobendan Multicenter Research
Group. Am Heart J 1992;124:1017 –1025.
16. Neuberger HR, Mewis C, van Veldhuisen DJ, Schotten U, van Gelder IC, Allessie MA,
Bohm M. Management of atrial fibrillation in patients with heart failure. Eur Heart J
2007;28:2568 – 2577.
17. Bohm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, Lerebours G,
Tavazzi L, SHIFT Investigators. Heart rate as a risk factor in chronic heart failure
(SHIFT): the association between heart rate and outcomes in a randomised placebocontrolled trial. Lancet 2010;376:886–894.
18. Jouven X, Empana JP, Schwartz PJ, Desnos M, Courbon D, Ducimetiere P. Heart-rate
profile during exercise as a predictor of sudden death. N Engl J Med 2005;352:
1951 –1958.
19. Lechat P, Hulot JS, Escolano S, Mallet A, Leizorovicz A, Werhlen-Grandjean M,
Pochmalicki G, Dargie H. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation 2001;103:1428 –1433.
Lenient rate control in heart failure