Download Rate control versus rhythm control for patients with persistent atrial

Electrophysiology
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
Vincent E. Hagens, MD,a Harry J.G.M. Crijns, MD,b Dirk J. Van Veldhuisen, MD,a Maarten P. Van Den Berg, MD,a
Michiel Rienstra, MD,a Adelita V. Ranchor, PhD,c Hans A. Bosker, MD,d Otto Kamp, MD,e Jan G.P. Tijssen, PhD,f
Nic J.G.M. Veeger, MSc,g and Isabelle C. Van Gelder, MD,a for the RAte Control versus Electrical cardioversion for
persistent atrial fibrillation study group Groningen, Maastricht, Arnhem, and Amsterdam, The Netherlands
Background This study was conducted to compare rate- and rhythm-control therapy in patients with persistent atrial
fibrillation (AF) and mild to moderate chronic heart failure (CHF). Rate control is not inferior to rhythm control in preventing
mortality and morbidity in patients with AF. In CHF, this issue is still unsettled.
Methods
In this predefined analysis of the RACE study, a total of 261 patients were in New York Heart Association
(NYHA) classes II and III at baseline. These patients were analyzed. The primary end point was a composite of cardiovascular
mortality, hospitalization for CHF, thromboembolic complications, bleeding, pacemaker implantation, and life-threatening
drug side effects. Furthermore, quality of life was compared.
Results
After 2.3 F 0.6 years, the primary end point occurred in 29 (22.3%) of the 130 rate-control patients and in
32 (24.4%) of the 131 rhythm-control patients. More cardiovascular deaths, hospitalization for CHF, and bleeding occurred
under rate control. Thromboembolic complications, drug side effects, and pacemaker implantation were more frequent under
rhythm control. Quality of life did not differ between strategies. In patients successfully treated with rhythm control, the
prevalence of end points was not different from those who were in AF at study end. However, the type of end point was
different: mortality, bleeding, hospitalization for heart failure, and pacemaker implantation occurred less frequently.
Conclusions In patients with mild to moderate CHF, rate control is not inferior to rhythm control. However, if sinus
rhythm can be maintained, outcome may be improved. A prospective randomized trial is necessary to confirm these results.
(Am Heart J 2005;149:1106 -11.)
See related Editorial on page 957.
Atrial fibrillation (AF) is the most common sustained
cardiac arrhythmia, and rhythm control using cardio-
From the aDepartment of Cardiology, University Medical Center Groningen, Groningen,
The Netherlands, bDepartment of Cardiology, University Hospital, Maastricht, The
Netherlands, cDepartment of Cardiology, Northern Center for Healthcare research,
Groningen, The Netherlands, dDepartment of Cardiology, Rijnstate Hospital, Arnhem,
The Netherlands, eDepartment of Cardiology, VU University Medical Center, Amsterdam, The Netherlands, fDepartment of Cardiology, Academical Medical Center,
Amsterdam, The Netherlands, and gDepartment of Cardiology, Trial Coordination
Center, Groningen, The Netherlands.
Submitted April 29, 2004; accepted November 13, 2004.
Reprint requests: Isabelle C. Van Gelder, MD, Department of Cardiology, Thoraxcenter,
University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen,
The Netherlands.
E-mail: [email protected]
0002-8703/$ - see front matter
n 2005, Elsevier Inc. All rights reserved.
doi:10.1016/j.ahj.2004.11.030
version and prophylactic antiarrhythmic drugs is often
applied.1,2 Drawbacks of cardioversion are the low
success rate and the risks of life-threatening proarrhythmia. The alternative, that is, rate control, is aimed
at controlling the ventricular rate at rest and during
exercise. Recent clinical trials showed that rate control
was not inferior to rhythm control in the prevention of
morbidity and mortality in patients with persistent AF.3 - 6
Similar to AF, chronic heart failure (CHF) is an ever
increasing condition with a significant impact on
morbidity and mortality.7 In CHF, there is an increased
risk of AF development.8 With the restoration and
maintenance of sinus rhythm, left ventricular function,
exercise capacity, and maximal oxygen consumption
may improve because of the restoration of atrial
contribution to ventricular filling, the restoration of a
regular heart beat, and the reversal of tachycardiainduced cardiomyopathy.9 - 11 However, antiarrhythmic
drug treatment to maintain sinus rhythm is less effective
American Heart Journal
Volume 149, Number 6
in CHF and may even worsen the prognosis.12,13 A
recent retrospective analysis showed that there was no
difference in mortality after 2 years of rate-control or
rhythm-control treatments in patients with congestive
heart failure in predominantly New York Heart Association (NYHA) functional classes III and IV.14
Despite this analysis, it is still unsettled whether
adequate rate control suffices with AF in CHF or rhythm
control should rather be encouraged in these patients.15
In this predefined substudy, we compared rate and
rhythm control in patients with persistent AF and mild
to moderate CHF included in the RACE study for
persistent AF.3 Furthermore, the quality of life (QoL)
was investigated.
Hagens et al 1107
Quality of life assessment
The Medical Outcomes Study Short-Form Health Survey
(SF-36) questionnaire was used to assess QoL.16,17 It contains
items to assess physical health (general health perception,
physical functioning, role limitations due to adverbial physical
problems, and bodily pain) and mental health (social functioning, role limitations due to emotional problems and mental
health, and vitality). For each of the 8 subscales, scores are
transformed to a scale ranging from 0 to 100, with lower scores
representing lower QoL. For the QoL analysis, only patients
who completed the self-administered QoL questionnaire at
baseline and at the end of follow-up were considered. Patients
who died during the follow-up of the RACE study were not
analyzed. At baseline and at the end of the study, QoL was
compared between the rate- and rhythm-control groups.
Statistical analysis
Methods
Study design
In the RACE study, 522 patients with persistent AF were
included from June 1, 1998, until July 1, 2001. In the
present study, only patients with CHF in NYHA functional
classes II and III at inclusion were selected from the original
population. A total of 261 patients were analyzed with 130
and 131 patients randomized to rate- and rhythm-control
groups, respectively.
A detailed description of the RACE design was recently
published.3,16 In short, rate control was achieved using
negative chronotropic drugs including digitalis, h-blocker, and
nondihydropyridine calcium channel blocker. Rhythm control
consisted of serial electrical cardioversion with institution of
antiarrhythmic drugs (sotalol, class IC drugs, or amiodarone).
Class IC drugs were only prescribed in case of mild CHF in the
absence of coronary artery disease or (previous) overt CHF. For
CHF, NYHA class was ensured at baseline in all patients.
Around electrical cardioversion, oral acenocoumarol or fenprocoumon (target International Normalized Ratio [INR]
2.5-3.5) was given. If sinus rhythm was present at 1 month,
anticoagulation drugs could be stopped or changed to 80 to
100 mg of aspirin daily. In patients younger than 65 years,
aspirin was allowed. All other patients received oral anticoagulation drugs. The study was approved by the institutional
review boards at each participating hospital, and all patients
gave written informed consent.
Primary end point
The primary end point of the RACE study was the
composite of cardiovascular death, hospitalization for CHF,
thromboembolic complication, bleeding, pacemaker implantation, or severe adverse effects of antiarrhythmic drugs. The
definition for the primary end point was published previously.3 All components of the primary end point that occurred
between randomization and July 1, 2001, were recorded, with
a maximum of 3 years of follow-up. A committee of experts
who were unaware of the treatment assignments adjudicated
all possible end points. Afterwards, all electrocardiograms
were reviewed by an experienced electrophysiologist. Additional analysis of the occurrence of cardiovascular mortality
was performed in patients who did not use class IC drugs
in follow-up.
The primary objective of the RACE study was to show the
noninferiority of rate control as compared with rhythm control
with respect to the occurrence of the primary end point.3 For
this substudy in patients with CHF, no power calculation was
performed, and all comparisons between rate control and
rhythm control were considered as descriptive rather than
conclusive. In these analyses, all patients were taken into
account in accordance with the assigned strategy (intention-totreat principle). Furthermore, the occurrence of primary end
points (per patient first occurrence) was estimated by using the
Kaplan-Meier method.
Baseline descriptive quantitative variables were compared
between groups using a 2-tailed t test for normally distributed
variables and a Wilcoxon 2-sampled test for skewed distributed variables. For the qualitative variables (categorical or
ordered), group differences were evaluated using a Fisher
exact test or a m2 test. Accordingly, baseline characteristics are
given in mean F SD, median and range (min-max), or
percentages. For these baseline comparisons, P b .05 was
considered statistically significant.
Results
Patient characteristics
A total of 261 patients with AF in NYHA functional
classes II and III for CHF were included in this study
(Table I). Except for slightly more patients with
hypertension in the rhythm-control strategy, no other
significant differences in clinical characteristics between
the groups were present.
Treatment
After a mean follow-up of 2.3 F 0.6 years, 47 (36%)
patients in the rhythm-control group were in sinus
rhythm. Use of antiarrhythmic drugs and cardioversions
were comparable to the main study. In the rate-control
group, 18 (14%) patients were in sinus rhythm at the
end of the study. The mean resting heart rate was
significantly lower in the rhythm-control group (77 F
20 beat/min) than in the rate-control group (84 F 17
beat/min). The number of patients who received oral
anticoagulant therapy during follow-up ranged from 91%
American Heart Journal
June 2005
1108 Hagens et al
Table I. Patient characteristics
Rate control
(n = 130)
Age (y)
69 F 9
Male
85 (65)
Total AF duration (d)
499 (14-12473)
34 (1-399)
Duration present
episode of AF (d)
Complaints of AF
111 (85)
Fatigue
61 (55)
Dyspnea
73 (66)
Palpitations
42 (38)
Heart rate at inclusion
91 F 20
(beats/min)
Blood pressure (mm Hg)
Systolic
142 F 21
Diastolic
84 F 12
Underlying diseases
Coronary artery
38
disease
Previous myocardial
22
infarction
Valvular disease
21
Cardiomyopathy
18
NYHA class for heart
95/5
failure (II/III)
History of
42
hypertension
History of chronic
28
obstructive lung disease
Diabetes mellitus
13
History of
13
cerebrovascular accident
No cardiovascular
13
disease demonstrable
Treatment at inclusionT
Digitalis
69
h-Blockery
21
Verapamil or
27
diltiazem
Class IC
5
antiarrhythmic drugs
Sotalol
24
Amiodarone
0
Angiotensin-converting
43
enzyme inhibitor
Diuretics
49
Echocardiographic parameters
Left ventricular
57 F 7
end-diastolic diameter (mm)
Left ventricular end41 F 9
systolic diameter (mm)
Fractional shortening (%)
29 F 10
Left atrial diameter,
46 F 7
parasternal long axis (mm)
Left atrial diameter,
65 F 9
apical view (mm)
Rhythm control
(n = 131)
69 F 8
85 (65)
562 (40-8513)
31 (2-376)
113 (86)
64 (57)
73 (65)
35 (31)
90 F 20
145 F 21
86 F 12
34
Table II. Incidence of the primary end point and its components
according to the treatment group
Rate control
(n = 130)
Primary end point
Cardiovascular mortality
Sudden death
Progression of heart
failure
Thromboembolic
complications
Bleeding
Hospitalization for heart
failure
Thromboembolic
complications
Bleeding
Adverse effects of
antiarrhythmic drugs
Pacemaker implants
22.3
11.5
4.6
2.3
(29)
(15)
(6)
(3)
Rhythm control
(n = 131)
24.4 (32)
6.1 (8)
3.1 (4)
–
–
1.5 (2)
4.6 (6)
5.4 (7)
1.5 (2)
3.8 (5)
6.2 (8)
8.4 (11)
8.5 (11)
0.8 (1)
3.1 (4)
5.3 (7)
–
4.6 (6)
22
19
9
93/7
56
18
11
5
15
57
15
17
12
44
1
53
47
55 F 8
40 F 8
28 F 9
46 F 7
64 F 9
Data are presented as mean F SD, number (%) of subjects, median value (range), or
percentage of subjects.
TAll patients used combinations of these drugs.
yExcluding sotalol.
No double counts within lines; between lines double counts are possible. Data are
presented as % (n).
to 95% in the rate-control group and from 86% to 99% in
the rhythm-control group. Under rate control, 85% of
the patients were on continuous oral anticoagulation
during the whole study versus 66% of the rhythmcontrol patients.
Outcome—primary end point
The primary end point occurred in 29 (22.3%) of
the 130 patients in the rate-control group and in 32
(24.4%) of the 131 patients in the rhythm-control group
(Table II) Figure 1.
More patients died under rate-control treatment. Six
patients in the rate-control group and 4 patients in the
rhythm-control group died suddenly; 1 was on flecainide, 1 was on sotalol, 1 was on propafenone, and 1 did
not use antiarrhythmic drugs. Under rate control, more
hospitalizations for CHF and bleeding were observed.
Thromboembolic complications, pacemaker implantations, and adverse effects of antiarrhythmic drugs were
more frequent under rhythm control.
A total of 14 of the 19 thromboembolic complications
occurred under inadequate oral anticoagulant therapy
(INR below 2.5). All patients with thromboembolic
complication had one or more stroke risk factors. Major
bleeding occurred nearly solely under an INR well above
3.5: 8 (73%) of the 11 patients under rate control and in
all 4 (100%) patients under rhythm control.
A total of 8 patients suffered from severe adverse
effects of antiarrhythmic drugs. Under rate control,
1 patient had digitalis intoxication with bidirectional
ventricular tachycardia. Under rhythm control, 3 patients
had a third-degree atrioventricular (AV)-nodal block, 2 on
amiodarone (both suffered from a total AV-nodal block
American Heart Journal
Volume 149, Number 6
Hagens et al 1109
Figure 1
Table III. SF-36 QoL scores
SF-36 subscale
100
General health
Event-free survival (%)
90
Physical functioning
Rate control
80
Physical role limitations
Rhythm control
70
Bodily pain
60
Mental health
50
Social functioning
0
0.0
No. at risk
Rate control
130
Rhythm control 131
Emotional role limitations
0.5
1.0
1.5
2.0
2.5
3.0
Time (y)
120
117
114
108
111
105
Vitality
90
79
39
31
5
7
Kaplan-Meier survival curves for event-free survival in the ratecontrol and rhythm-control groups.
in sinus rhythm necessitating pacemaker implantation;
1 patient was known to be with a right bundle branch
block), and 1 on flecainide (transient AV-nodal block
directly after electrical cardioversion from AF; flecainide was discontinued). The patient on flecainide also
used digoxin; the 2 patients on amiodarone did not use
other AV-nodal–blocking agents. One patient had a
rapid hemodynamically significant AV conduction
during atrial flutter on flecainide; 1 had suffered from
exercise-induced ventricular tachycardia during inhospital loading, thereafter, flecainide was discontinued;
1 had drug-induced heart failure on flecainide; and
1 had sick sinus syndrome on amiodarone.
The occurrence of cardiovascular mortality was evaluated for the subgroup of patients who did not use class
IC drugs in follow-up. For the rate control group,
14 (11.9%) of the 118 patients suffered from cardiovascular death. In the rhythm control group, 5 (6.3%) of the
80 patients died of cardiovascular cause. These
percentages do not differ significantly from those of the
total group (Table II).
Impact of chronic sinus rhythm in the rhythm-control
group
Post hoc analysis in the rhythm-control group showed
that the eventual rhythm did not affect the incidence of
end points. However, the distribution of the components of the primary end points was importantly
different according to whether the patient had sinus
rhythm or AF at the end of follow-up. Of the 47 patients
with sinus rhythm at study end, 11 (23.4%) reached an
end point versus 21 (25%) who fell back to AF. The
StrategyT
Rate
Rhythm
Rate
Rhythm
Rate
Rhythm
Rate
Rhythm
Rate
Rhythm
Rate
Rhythm
Rate
Rhythm
Rate
Rhythm
Baseline
49
51
57
58
37
41
76
80
72
72
74
76
67
68
56
57
(17)
(18)
(24)
(23)
(43)
(44)
(23)
(22)
(18)
(18)
(24)
(23)
(43)
(43)
(21)
(20)
Study end
52
52
58
60
50
46
77
79
74
76
80
78
74
67
54
60
(18)
(19)
(22)
(26)
(44)y
(44)
(23)
(22)
(16)y
(18)y
(22)y
(23)
(39)
(41)
(20)
(21)
Data are presented as mean F SD.
TNinety rate-control and 93 rhythm-control patients were analyzed.
yP b .05 compared with baseline score.
components of the primary end point for patients
in sinus rhythm compared with those in AF at the study
end were the following: cardiovascular mortality,
0% versus 9.5%; progression of CHF, 2.1% versus
4.8%; thromboembolic complication, 10.6% versus 7.1%;
bleeding, 0% versus 4.8%; adverse drug effects, 8.5%
versus 3.6%; pacemaker implantation, 2.1% versus
6.0%, respectively.
Quality of life
QoL was evaluated in 90 patients randomized to rate
control and in 93 patients randomized to rhythm
control (Table III). At baseline and also at the end of
the study, there were no differences between the
groups. During follow-up, QoL improved slightly but
significantly in 3 subscales under rate control and in
1 subscale under rhythm control. The change in QoL
from baseline to study end was comparable for the
rate- and rhythm-control strategies. Patients with AFrelated complaints at study inclusion showed improvement of QoL ( P b .05) irrespective of the randomized
strategy. Furthermore, the presence of sinus rhythm at
study end was a determinant of QoL improvement
( P b .05 for the scales of physical functioning, role
physical limitations, and vitality).
Discussion
The present study shows that in patients with AF and
mild CHF the occurrence of cardiovascular morbidity
and mortality is comparable between those treated with
rate control and those treated with rhythm control.
However, we observed an important difference in the
type of end points between both groups. There was a
1110 Hagens et al
trend for a higher mortality and major bleedings under
rate control. In addition, rhythm control was associated
with excellent survival if sinus rhythm could be maintained. Of note, rhythm control did not ameliorate
progression of CHF. For both treatment options, QoL
was comparable.
Mortality
The impact of AF on survival remains controversial.
Several studies in patients with CHF showed that AF did
not increase mortality.18-20 In contrast, others showed
that AF was an independent mortality risk factor.21-23
This discrepancy may relate to the fact that AF seems
associated with an increased mortality only in mild to
moderate CHF but not in severe CHF.24
In the present study, mortality in patients with mild
CHF was higher under rate control. By contrast, the
present results suggest that chronic sinus rhythm under
rhythm control is associated with excellent survival.
Therefore, in patients with AF and CHF, restoring and
maintaining sinus rhythm may reduce cardiovascular
mortality and morbidity. This is currently investigated in
the AF-CHF study.15
Thromboembolic complications and bleeding
Fatal and nonfatal bleedings occurred frequently and
more often under rate control. Thromboembolic complications also importantly contributed to cardiovascular morbidity and mortality. Both end points were
predominantly encountered at the moment that oral
anticoagulation drug was inadequate (INR too high or
too low, respectively). These findings elucidate that
(inadequate) treatment with oral anticoagulation drugs
importantly affects outcome in AF patients. In this
respect, new anticoagulation drugs, such as oral
thrombin inhibitors that possibly are as effective but
safer and easier to dose, may improve prognosis of AF
in CHF.25
Antiarrhythmic drugs in CHF
The use of prophylactic antiarrhythmic drugs significantly contributed to end points in the rhythm-control
arm and obviously not in the rate-control arm. Severe
adverse effects did not occur during sotalol treatment;
although, 1 patient died suddenly while on sotalol. Class
IC drugs were instituted only in the absence of coronary
artery disease and (previous) overt CHF. Life-threatening
adverse events were encountered in 4 patients on class
IC drugs, 1 during inhospital institution of the drug. In
addition, 2 patients died suddenly while being treated
with class IC drugs. Subanalysis of the occurrence of
cardiovascular mortality for patients who did not use
class IC drugs showed percentages comparable for the
whole study population with more events under rate
control. Amiodarone was safe and only caused nonfatal
American Heart Journal
June 2005
bradyarrhythmias. This was expected because amiodarone does not have a negative impact on survival in
patients with CHF.26 In patients with AF and CHF,
Deedwania et al27 described a lower mortality rate in
patients who were in AF at baseline and converted to
sinus rhythm on amiodarone compared with those who
did not. The present and previous observations indicate
that amiodarone is an effective and safe antiarrhythmic
drug in patients with AF and CHF.26-28 As has been
recommended before, class IC drugs should not be used
in any patient with CHF.29
Quality of life
No differences were observed in QoL between
patients randomized to rate or rhythm control at
baseline. During long-term treatment in both groups,
QoL did not change importantly. Thus, no differences in
QoL between the rate control- and rhythm-control
groups were present at the end of follow-up. This
observation is in accordance with data from the AFFIRM
and PIAF investigators who could also not demonstrate
any difference in QoL and AF-related symptoms between
the 2 treatment approaches in patients with moderate
heart failure.4,30 Like in the CTAF, we also found that
sinus rhythm at the end of the study was the most
important determinant of QoL improvement.31 In the
CTAF and in the present study, improvements were
present for both physical and mental health scales
indicating that sinus rhythm may improve exercise
tolerance and sense of vitality. Thus, rhythm control may
be beneficial in improving QoL if effective. Therefore,
better means of maintaining sinus rhythm may have a
major general impact on QoL in patients with persistent
AF and mild CHF.
Limitations
The present study is a prespecified substudy of the
RACE study. Because the study was not powered to find
noninferiority, no firm conclusions can be drawn from
this analysis. Furthermore, the degree of CHF was
determined by assessment of the functional class for
CHF. However, this is the first randomized comparison
between rate and rhythm controls for patients with AF
in the setting of mild and moderate heart failure. Larger
trials are warranted to show whether rate control is
indeed comparable to rhythm control in these patients.
Conclusions
In patients with persistent AF and mild CHF, rate
control was not inferior to rhythm control. However,
more patients died or were hospitalized for CHF under
rate control. Pacemaker implantations and adverse
effects of antiarrhythmic therapy were more frequent
under rhythm control. Effective rhythm control may be
beneficial for the prevention of severe cardiovascular
American Heart Journal
Volume 149, Number 6
events. Whether this relates to the presence of sinus
rhythm itself or the selection of patients (patients
who maintain sinus rhythm are less sick) remains to
be determined.
Hagens et al 1111
17.
18.
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