Download Rate Control vs Rhythm Control in Patients With

Rate Control vs Rhythm Control in
Patients With Nonvalvular Persistent
Atrial Fibrillation*
The Results of the Polish How to Treat Chronic
Atrial Fibrillation (HOT CAFE) Study
Grzegorz Opolski, MD, PhD; Adam Torbicki, MD, PhD;
Dariusz A. Kosior, MD, PhD; Marcin Szulc, MD, PhD;
Beata Wożakowska-Kapłon, MD, PhD; Piotr Kołodziej, MD, PhD; and
Piotr Achremczyk, MD, PhD; for the Investigators of the Polish HOT CAFE
Trial
Study objectives: The relative risks and benefits of strategies of rate control vs rhythm control in
patients with atrial fibrillation (AF) remain to be fully explored.
Design: The How to Treat Chronic Atrial Fibrillation (HOT CAFE) Polish trial was designed to
evaluate in a randomized, multicenter, and prospective manner the feasibility and long-term
outcomes of rate control vs rhythm control strategies in patients with persistent AF.
Patients: Our study population comprised 205 patients (134 men and 71 women; mean [ⴞ SD]
age, 60.8 ⴞ 11.2 years) with a mean AF duration of 273.7 ⴞ 112.4 days. The mean observation
period was 1.7 ⴞ 0.4 years. One hundred one patients were randomly assigned to the rate control
group and received rate-slowing therapy guided by repeated 24-h Holter monitoring. Direct
current cardioversion and atrioventricular junctional ablation with pacemaker placement were
alternative nonpharmacologic strategies for patients with tachycardia that was resistant to
medical therapy. One hundred four patients were randomized to sinus rhythm restoration and
maintenance using serial cardioversion supported by a predefined stepwise antiarrhythmic drug
regimen (ie, disopyramide, propafenone, sotalol, and amiodarone). In both groups, thromboembolic prophylaxis followed current guidelines.
Measurements and results: At the end of follow-up, 63.5% of patients in the rhythm control arm
remained in sinus rhythm. No significant differences in the composite end point (ie, all-cause
mortality, number of thromboembolic events, or major bleeding) were found between the rate
control group and the rhythm control group (odds ratio, 1.98; 95% confidence interval, 0.28 to
22.3; p > 0.71). The incidence of hospital admissions was much lower in the rate control arm
(12% vs 74%, respectively; p < 0.001). New York Heart Association functional class improved in
both study groups, while mean exercise tolerance, as measured by the maximal treadmill
workload, improved only in the rhythm control group (5.2 ⴞ 5.1 vs 7.6 ⴞ 3.3 metabolic equivalents, respectively; p < 0.001). The rhythm control strategy led to an increased mean left
ventricular fractional shortening (29 ⴞ 7% vs 31 ⴞ 7%, respectively; p < 0.01). One episode of
pulmonary embolism occurred in the rate control group despite oral anticoagulation therapy,
while three patients in the rhythm control arm of the study experienced ischemic strokes (not
significant).
Conclusions: The Polish HOT CAFE study revealed no significant differences in major end points
between the rate control group and the rhythm control group.
(CHEST 2004; 126:476 – 486)
Key words: antiarrhythmic therapy; atrial fibrillation; electrocardioversion rate control; rhythm control
Abbreviations: AF ⫽ atrial fibrillation; AFFIRM ⫽ Atrial Fibrillation Follow-up Investigation of Rhythm Management; HOT CAFE ⫽ How to Treat Chronic Atrial Fibrillation; INR ⫽ international normalized ratio; NYHA ⫽ New
York Heart Association; PIAF ⫽ Pharmacological Intervention in Atrial Fibrillation; RACE ⫽ Rate Control vs Electrical
Cardioversion for Persistent Atrial Fibrillation
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Clinical Investigations
goal in patients with atrial fibrilT helationtherapeutic
(AF) can be either the restoring and
maintaining of sinus rhythm (mainly with antiarrhythmic therapy) or allowing persistent AF to become permanent, while controlling the ventricular
rate and preventing systemic thromboembolism.1,2
The debate over rate control vs rhythm control in the
treatment of AF still is ongoing. It has been a
standard practice to maintain sinus rhythm, primarily
through the use of antiarrhythmic drugs and cardioversion, which relieves symptoms and may retard or
prevent progression to permanent AF. Rhythm control, however, carries a risk of proarrhythmias and
negative inotropic effects due to the use of antiarrhythmic agents.3–5 The prevention of AF recurrence with antiarrhythmic drug therapy, regardless
of the agent, is achieved in only approximately 50%
of patients at 6 months to 1 year.6,7 Moreover,
optimal thromboembolic prevention in the rhythm
control strategy has not yet been defined. While rate
control is easier to achieve and leads toward improved hemodynamics, it allows AF to persist and
may not eliminate AF symptoms (eg, palpitations,
dyspnea, chest pain, fatigue, and dizziness).8
The How to Treat Chronic Atrial Fibrillation
(HOT CAFE) study was designed to compare the
strategy of sinus rhythm restoration and maintenance
with that of ventricular rate control and chronic
thromboembolic prophylaxis. We report the results
of the initial phase of the study, which involved six
clinical centers and a limited number of patients.
This phase was implemented to confirm the study
protocol and its methods before the planned main
phase of the study, which was ultimately abandoned
due to the results of other trials.9 –11
*From the Departments of Cardiology (Drs. Opolski and Kosior)
and Internal Medicine and Hypertension (Dr. Szulc), Medical
University of Warsaw, Warsaw, Poland; the Department of Chest
Medicine (Dr. Torbicki), National Institute of Tuberculosis and
Pulmonary Disease, Warsaw, Poland; the Department of Cardiology (Dr. Wożakowska-Kapłon), Municipal Hospital, Kielce,
Poland; the Department of Cardiology (Dr. Kolodziej), Municipal Hospital, Siedlce, Poland; and the Department of Cardiology
(Dr. Achremczyk), Municipal Hospital, Radom, Poland.
The study results were presented at the 24th Congress of the
European Society of Cardiology, Berlin, Germany, in October
2002.
The study was supported by Polish Government research grant
No. PO5B06012.
Manuscript received August 8, 2003; revision accepted February
11, 2004.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: Grzegorz Opolski, MD, PhD, Chair, Department of Cardiology, Medical University of Warsaw, Warsaw,
Poland; e-mail: [email protected]
Materials and Methods
The HOT CAFE study12 was a prospective, randomized, open
multicenter clinical trial that was designed to evaluate the effects
of rhythm control vs rate control in patients with persistent AF.
The study involved six cardiology centers in central Poland, five
of which enrolled patients. The study was approved by the
institutional review board or ethics committee at those centers,
and consecutive, eligible patients provided written informed
consent. Recruitment began in March 1997, randomization was
concluded in December 2000, and follow-up was terminated in
December 2002.
Inclusion and Exclusion Criteria
Eligible patients had to meet the following inclusion criteria:
50 to 75 years of age; and AF had to be known to be present for
at least 7 days, but not for ⬎ 2 years. Only patients with a first
clinically overt persistent episode of AF were enrolled. Persistent
AF was defined as a non-self-terminating arrhythmia requiring
electrical cardioversion to restore sinus rhythm.
The following were exclusion criteria: documented inefficiency; intolerance to or contraindications for treatment with
antiarrhythmic drugs; presence of arrhythmia associated with an
acute reversible condition; thyroid dysfunction; pregnancy or
lactation; history of myocardial infarction within 3 months preceding enrollment into the study; acute myocarditis; cardiac
surgery during the previous 30 days; severe cardiac disability (ie,
New York Heart Association [NYHA] functional class IV); severe
systemic hypertension not responding to treatment (diastolic
pressure, ⬎ 115 mm Hg); hypotension (systolic pressure, ⬍ 90
mm Hg); history of transient ischemic attack (with significantly
marked vascular pathology requiring surgical intervention); history of hemorrhagic stroke; ischemic stroke during the 3 months
preceding entrance into the trial; any mitral stenosis or other
valvular disease suitable for surgical treatment; R-R intervals
exceeding 3 s; ventricular response to AF of ⬍ 90 beats/min
(unrelated to drugs used to reduce ventricular rate); bundle
branch block or QT-segment prolongation (ie, corrected QT
interval of ⬎ 480 ms or uncorrected QT interval of ⬎ 500 ms);
alcoholism; contraindications to anticoagulation therapy; liver,
kidney, or CNS damage; advanced chronic lung disease, malignancy; or any noncardiac illness associated with a life expectancy
of ⬍ 1 year; or participation in another study. In addition,
premenopausal women who were still capable of procreation and
had not undergone tubal ligation or hysterectomy also were
excluded from the study.
Randomization, Therapy, and Follow-up
Participating patients were randomly assigned to one of the two
groups following a predefined sequential management (Fig 1).
The randomization of eligible patients was performed by permuted block design with equal allocation and was stratified
centrally by a steering center of the Chair and Department of
Cardiology. The trial was conducted on an intention-to-treat
basis. All patients were seen in the outpatient department at least
once a month during the first 6 months of follow-up and every 3
months until the end of the study. All patients enrolled in the trial
were potentially eligible for either rate control or rhythm control
therapy at entrance into the study.
Rate Control Group: The therapeutic strategy in the rate
control group was rate control and chronic thromboembolic
prophylaxis, with heart rate as the therapeutic target. Heart rate
was considered to be adequately controlled when the ventricular
response ranged between 70 and 90 beats/min during rest
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CHEST / 126 / 2 / AUGUST, 2004
477
Clinical and biochemical symptoms of hyperthyroidism and AF recurrence were observed in 1 of 59
study patients receiving long-term amiodarone therapy. One patient had decreased thyroid-stimulating
hormone levels without clinical symptoms.
Bleeding Complications: Oral acenocoumarol
was used as thromboembolic prophylaxis in 74.3%
patients in the rate control arm. Aspirin and ticlopidine were used in 19.8% and 1.0% of patients,
respectively. At total of 4.9% of study patients
received no anticoagulant agents because of a perceived low risk of systemic embolization.13 All patients assigned to sinus rhythm restoration received
anticoagulation therapy (mean INR, 2.43 ⫾ 0.72) at
least 3 weeks before and 4 weeks after undergoing
cardioversion. In 15.6% of patients in whom cardioversion was successful, oral anticoagulants were prescribed for ⬎ 4 weeks after the procedure. In 62.2%
of study subjects, thromboembolic prophylaxis was
continued with aspirin, and one patient (0.9%) received ticlopidine. Nineteen patients (21.1%) who
maintained sinus rhythm for ⬎ 1 month were prescribed no additional antithrombotic agents.13 Thirteen patients, all of whom were receiving acenocoumarol at the time, had minor bleeding complications
outside the CNS (rate control group, 5 patients
[5.0%]; rhythm control group, 8 patients [7.7%]).
Hospitalization: Five patients (4.8%; 0.05 hospitalizations per person) who were assigned to ventricular rate control required hospitalization (mean
length of hospital stay, 12.3 ⫾ 4.2 days). There were
211 hospitalizations in the group in which sinus
rhythm restoration was attempted (mean length of
hospital stay, 2.5 ⫾ 1.1 days). Excluding 104 hospitalizations required by protocol for cardioversion,
there were 1.03 hospitalizations per person in the
sinus rhythm group. The most frequent cause of
hospital admission was recardioversion (94 cases;
87.9%). Thirteen patients (12.1%) required inpatient
care due to treatment side effects and/or new or
worsening concomitant disease. Clinical outcomes of
the follow-up period in both study groups are presented in Table 2.
Congestive Heart Failure: Both therapeutic strategies prevented the development and/or progression
of heart failure (NYHA functional class). In the rate
control group, heart failure regression was observed
during the first 2 months of observation (p ⬍ 0.02),
but no further improvement in NYHA functional
class occurred during follow-up. Almost 2 years of
observation revealed statistically significant heart
failure regression in the rate control arm of the study
(p ⬍ 0.05). In the rhythm control group, a similar
improvement of hemodynamic status (NYHA functional class) was observed during follow-up
(p ⬍ 0.001) [Fig 2]. No difference in NYHA functional class between patients initially randomized to
the two strategies was found at the end of the
follow-up period.
Exercise Tolerance: The rate control strategy did
not result in a statistically significant difference in
mean maximal workload during the treadmill test
(5.3 ⫾ 1.1 vs 4.8 ⫾ 2.5 metabolic equivalents, respectively; p ⬎ 0.42). Conversely, in the rhythm
control arm, exercise tolerance improvement and a
significant increase in maximal workload or were
observed (from 5.2 ⫾ 5.1 to 7.6 ⫾ 3.3 metabolic
equivalents, respectively; p ⬍ 0.001). Both treatment strategies led to significantly increased exercise
duration, but much more so in the rhythm control
group (rate control group: 118.0 ⫾ 87.5 vs
157.8 ⫾ 126.2 s; p ⬍ 0.03; rhythm control group:
125.3 ⫾ 115.7 vs 294.7 ⫾ 216.7 s; p ⬍ 0.001). At the
end of follow-up, both maximal workload and exercise duration were higher in the rhythm control arm
(p ⬍ 0.001 and p ⬍ 0.001, respectively).
Echocardiographic Parameters: In the rate control group, both right atrial enlargement (22.1 ⫾ 4.1 vs
23.3 ⫾ 3.8 cm2, respectively; p ⬍ 0.001) and left atrial
enlargement (25.7 ⫾ 5.0 vs 26.4 ⫾ 5.0 cm2, respectively; p ⬍ 0.05) were observed during the follow-up
period. Our observation demonstrated a significant
decrease in right atrial size (21.8 ⫾ 4.1 vs 20.3 ⫾ 3.4
cm2, respectively; p ⬍ 0.01) and left atrial size
(26.2 ⫾ 4.7 vs 25.4 ⫾ 5.0 cm2, respectively; p ⬍ 0.02)
in the rhythm control arm. A significant increase in left
ventricular fractional shortening (29.9 ⫾ 6.9% vs
34.5 ⫾ 8.9%, respectively; p ⬍ 0.001) was found in
patients assigned to the sinus rhythm restoration group,
while the rate control strategy failed to significantly
affect left ventricular fractional shortening (32.8 ⫾ 6.6
vs 35.6 ⫾ 7.4%, respectively).
Discussion
The results of the HOT CAFE study have provided data that are relevant to the management of
patients with AF. Our study demonstrated that the
rate control of AF is as acceptable as sinus rhythm
restoration and maintenance. Despite the relatively
small number of enrolled patients and the short
observation period, our study suggests that, at least
with currently available pharmacologic therapy,
there is no distinct advantage associated with the
rhythm control strategy. Moreover, the control of
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Clinical Investigations
above, with cardioversion attempted again. Patients in whom
sinus rhythm was restored continued their amiodarone treatment
in daily maintenance doses. The amiodarone therapy started at
the hospital was continued on an outpatient basis with subjects
being assessed at least weekly.
In patients in whom there was no response to the first and
second cardioversions, with the second cardioversion preceded
by amiodarone loading, or there was a recurrence of AF without
an identifiable cause while receiving amiodarone, the arrhythmia
was considered permanent, and rate control became the goal of
therapy. Only electrocardiographically confirmed episodes lasting
⬎ 12 h despite additional antiarrhythmic drug therapy were
considered to be clinically significant. Patients experiencing such
episodes received anticoagulation prophylaxis, with ventricular
rhythm control as additional therapy. Patients who required
pacing for rate support and/or to maintain normal sinus rhythm
remained in the study. Current guidelines15 were followed when
pacing was used.
In the rhythm control arm of the study, thromboembolic
prophylaxis (with acenocoumarol) titrated to achieve an INR of
2.0 to 3.0 was started 4 weeks before cardioversion.13 Therapy
was continued in all patients until normal sinus rhythm had been
maintained for at least 4 weeks. Decisions regarding prolonged or
chronic anticoagulation or antiplatelet therapy were left to the
discretion of the local clinical teams but had to be reported.13
Assessment and Follow-up
A physician and a nurse coordinator assessed patients initially
and then at least monthly for 6 months, and every 3 months
thereafter. Twelve-lead ECGs were obtained at each visit. Chest
radiograph examinations were obtained at the first follow-up
appointment and were repeated annually thereafter. The level of
serum thyroid-stimulating hormone was measured every 6
months in patients receiving amiodarone. All study patients had
their exercise tolerance estimated by a stress test that was
performed at study entry, 2 months after randomization, and then
annually. In addition, atrial and ventricular morphology and
function were echocardiographically assessed during the followup period.
The primary end point was a composite of death from any
cause, thromboembolic complications (especially disabling ischemic stroke), and intracranial or other major hemorrhage. Disabling stroke was defined as an acute neurologic deficit for ⬎ 24
h that affected the ability to perform activities of daily life or
resulted in death. Cerebrovascular events required diagnosis by
CT scan and neurology consultation. Major bleeding was defined
as a drop in hemoglobin levels of ⬎ 2 g/L, requiring a blood
transfusion, needing surgical intervention, or resulting in death.
All events occurring between randomization and the end of the
study were recorded. All deaths were considered to be due to
cardiovascular causes unless an unequivocal noncardiac cause
could be identified. Secondary end points included rate control,
sinus rhythm maintenance, discontinuation of therapy (especially
if due to a potential proarrhythmic effect), hemorrhage, hospitalization, new or worsening congestive heart failure, or changes
in exercise tolerance.
measurements were averaged for more than five cardiac cycles
recorded during relaxed expiration. Echocardiography was performed at study entry, 2 months after randomization, and at the
end of the study. In patients assigned to rhythm control, echocardiographic examination was performed prior to and 30 days
after successful cardioversion, and at the end of the observation
period.
Exercise Testing
On entry into the study, all patients underwent a treadmill
exercise stress test, which was performed according to the
symptom-related modified Bruce I protocol. This was repeated at
2, 12, and 24 months after randomization, and at the end of the
study. In addition, in the rhythm control arm, this testing was
performed prior to and 30 days after successful cardioversion.
Exercise was continued until the patient was exhausted or
developed progressive angina, hypotension, or ventricular arrhythmia. Age-predicted maximal heart rate, shifts in ST segments, the emergence of ventricular ectopic beats, or the development of atrial arrhythmia did not constitute end points of the
treadmill test. Heart rate during AF was determined by measuring the average heart rate for a period of 60 s. Maximal workload
and exercise duration also were considered. An exercise stress
test was repeated as needed in the rate control group to achieve
optimal heart rate control.
24-h ECG Holter Monitoring
The circadian pattern and the mean 24-h heart rate were
monitored with an ECG Holter recording performed at the study
entry, at 1 and 3 months after randomization, and every 6 months
thereafter. In addition, 24-h ECG monitoring was performed in
patients assigned to the rhythm control strategy 7 and 30 days
after successful cardioversion or after every antiarrhythmic drug
change.
Statistical Analysis
Summary data are expressed as the mean ⫾ SD or as the
numbers and percentages of patients. Analyses were performed
using the intention-to-treat principle. Continuous variables were
tested by analysis of variance for between-group comparisons
(with the baseline value as the covariable). Dependent on analysis
of variance results, the Student t test (in modification for paired
measurements if necessary) was used to compare mean parameter values in each group on one visit or in one group on each
visit. The Bonferroni correction was used to avoid multipletesting problems. The change in time of NYHA functional class
was tested using the Wilcoxon test, and between-group comparisons were tested using the Kruskal-Wallis test on each visit. All
pair comparisons, if needed, were made by the Dunn test. The
cumulative risk of AF recurrence was estimated by the KaplanMeier product-limit method. Data were censored if the patient
died, reached the end of the follow-up period, or was lost to
follow-up without the occurrence of a primary end point. The
difference between treatment groups was assessed with the
log-rank test with a p value of ⬍ 0.05 considered to be statistically
significant.
Echocardiography
M-mode echocardiographic measurements including left atrial
diameter and left ventricular diameter, were made at enddiastole in the parasternal long-axis view using standard techniques.16 Left ventricular fractional shortening was determined
on two-dimensional imaging. The left atrial long axis was measured at end-diastole from the apical four-chamber view. All
Results
Baseline Characteristics
Of 738 screened patients with AF from March
1997 to December 2000, 205 patients (134 men and
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479
71 women) met the inclusion criteria and were
enrolled into the study. Valvular heart disease (21%),
thyrotoxicosis (13%), and advanced stages of concomitant diseases influencing the natural history of
AF (11%) were the main exclusion criteria limiting
enrollment. One hundred one consecutive patients
were randomly assigned to the heart rate control
group. The restoration and maintenance of sinus
rhythm for a period of at least 12 months was
attempted in 104 patients. Patients were followed up
for a mean of 1.7 ⫾ 0.4 years (maximum follow-up,
2.5 years). There were no significant differences in
the duration of follow-up between the two study
groups. The mean age was 60.8 ⫾ 11.2 years. The
mean arrhythmia duration prior to enrollment was
273.7 ⫾ 112.4 days. The characteristics of the study
patients were typical of a population of subjects
affected by persistent AF. There were no significant
differences in baseline characteristics between the
rate control group and the rhythm control group. A
comparison of the clinical and echocardiographic
characteristics of study patients on enrollment is
shown in Table 1.
Primary End Point
None of the patients was lost to follow-up. Allcause mortality, and the number of thromboembolic
and major bleeding complications, the primary composite end point of the study, were not significantly
different between the rate control group and the
rhythm control group (odds ratio, 1.98; 95% confidence interval, 0.28 to 22.3; p ⬎ 0.71). One patient
(1.0%) assigned to the rate control group died due to
leukemia diagnosed 6 months after enrollment.
Three patients (2.9%) died in the rhythm control
Table 1—Baseline Characteristics of the Study Groups*
Parameter
Age, yr
Gender
Female
Male
AF duration
7 d–1 mo
1 mo–2 yr
Mean AF duration, d
AF etiology
Ischemic heart disease
Myocardial infarction
CABG
Hypertension
Valvular heart disease
Lone AF
Diabetes
Congestive heart failure, NYHA scale
I
II
III
Echocardiographic parameters
LAsax, mm
LAlax, mm
LVEDD, mm
FS, %
Pharmacologic therapy, %
␤-adrenolitics
Verapamil/diltiazem
Digoxin
␤-adrenolitics ⫹ digoxin
ACE-I
Amlodipine
Nitrates
Diuretics
Rate Control
(n ⫽ 101)
Rhythm Control
(n ⫽ 104)
Significance
61.4 ⫾ 17.6
60.4 ⫾ 7.9
NS
38 (37.6)
63 (62.4)
33 (31.7)
71 (68.3)
NS
NS
17 (16.8)
84 (83.2)
243.2 ⫾ 137.3
16 (15.4)
88 (84.6)
220.4 ⫾ 148.6
NS
NS
NS
38 (37.6)
7 (6.9)
0 (0.0)
60 (59.4)
15 (14.8)
25 (24.8)
18 (17.8)
52 (50.0)
7 (6.7)
1 (1.0)
72 (69.2)
16 (15.4)
18 (17.3)
15 (14.4)
NS
NS
NS
NS
NS
NS
NS
48 (47.5)
48 (47.5)
5 (5.0)
30 (28.8)
59 (56.7)
15 (14.4)
NS
NS
NS
48.0 ⫾ 4.7
64.0 ⫾ 6.8
50.8 ⫾ 5.9
32.8 ⫾ 6.6
47.4 ⫾ 5.3
62.5 ⫾ 7.9
52.2 ⫾ 6.8
29.9 ⫾ 6.9
NS
NS
NS
NS
49.5
7.9
3.0
39.6
71.2
12.1
9.1
16.1
52.1
7.7
6.5
31.7
69.2
14.4
8.7
14.4
NS
NS
NS
NS
NS
NS
NS
NS
*Values given as mean ⫾ SD or No. (%), unless otherwise indicated. NS ⫽ not significant; CABG ⫽ coronary artery bypass grafting;
ACE ⫽ angiotensin-converting enzyme; LAsax ⫽ left atrial anteroposterior axis; LAlax ⫽ left atrial longitudinal axis; LVEDD ⫽ left ventricular
end diastolic diameter; FS ⫽ left ventricular fractional shortening.
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group, two (1.9%) from strokes. One female patient
(1.0%) from the rhythm control arm died in a motor
vehicle accident in which she was a passenger, in the
10th month of observation. Three patients (2.9%)
assigned to the rhythm control group developed
massive cerebral strokes. Two of the strokes (1.9%),
both resulting in death, were observed on the third
day following successful cardioversion despite appropriate anticoagulant therapy (INR, 2.8 ⫾ 0.7) during
a sufficient period of time (35.3 ⫾ 11.2 days) prior to
the procedure. In both cases, a cardiogenic etiology
was supported by the exclusion of all other possible
causes. The third stroke (0.9%), which was not
disabling, affected a patient with AF recurrence
during amiodarone therapy. The patient was receiving long-term aspirin therapy.
Pulmonary embolism occurred despite oral anticoagulation in one patient (1.0%) in the rate control
group. One patient from the rhythm control arm
withdrew his consent after 6 months of observation.
Secondary End Points
Rate Control and Maintenance of Sinus Rhythm:
The treatment goal in the rate control group was an
optimal heart rate, as defined by 24-h Holter monitoring. Calcium antagonists (7.9%), ␤-blockers
(49.5%), ␤-blockers plus digoxin (39.6%), or digoxin
alone (3.0%) were used. Two patients (2.0%) in this
study arm developed symptomatic, sustained tachycardia despite receiving pharmacologic therapy, and
ultimately underwent atrioventricular node ablation
with pacemaker implantation. One patient (1.0%) in
the rate control arm required a pacemaker due to
symptomatic bradycardia and pauses of ⬎ 3.5 s.
Planned electrical cardioversion was performed in
all 104 patients assigned to receive rhythm control.
Following the first electrical cardioversion, sinus
rhythm was restored in 56 patients (53.8%). Fortyeight patients failed to convert and received loading
doses of amiodarone prior to the next cardioversion
attempt. Sinus rhythm recovery occurred in 10 patients (20.8%) during amiodarone loading. The second electrical cardioversion, preceded by amiodarone loading, restored sinus rhythm in 24 of 38
patients (63.2%). The first and second cardioversions, the latter preceded by amiodarone loading,
enabled sinus rhythm restoration in 90 patients
(86.5%).
Sixty-six patients (63.5%) in the rhythm control
arm were in sinus rhythm at the end of the study. In
27 patients, sinus rhythm was successfully maintained with the first antiarrhythmic compound following the initial effective cardioversion. Sequential
electrical cardioversion and antiarrhythmic treatment resulted in sinus rhythm maintenance in an
additional 15 patients who previously had been
subjected to a successful initial procedure. Amiodarone administered in loading doses prior to the
second cardioversion and maintenance therapy following the successful procedure prevented AF recurrence in the remaining 24 subjects whose initial
cardioversion had failed. Altogether, 37 patients
(56.0%) received amiodarone as AF prophylaxis following sinus rhythm restoration. Two patients (1.9%)
in the rhythm control arm required pacemaker
placement due to bradycardia. In both patients,
antiarrhythmic therapy was continued.
There was a continuous decline in heart rate
during the follow-up period in patients who were
assigned to receive rhythm control. The mean heart
rate measured 30 days after electrical cardioversion
was significantly lower than that at randomization
(86.0 ⫾ 11.6 vs 77.8 ⫾ 12.6 beats/min, respectively;
p ⬍ 0.001). There were no other significant differences in measured parameters during further observation. However, the mean heart rate during subsequent visits was significantly lower than that at entry
in the sinus rhythm group. The mean heart rate in
24-h Holter monitoring was significantly lower during rhythm control (79.1 ⫾ 8.6 beats/min) than during rate control (85.8 ⫾ 7.5 beats/min; p ⬍ 0.003).
There were no significant changes in mean heart rate
in the rate control arm of the study during the
follow-up. Rate control therapy maintained the ventricular response rate within satisfactory ranges during the follow-up (at randomization 86.2 ⫾ 7.8 beats/
min; at the end of follow-up, 83.1 ⫾ 4.3 beats/min;
p ⬎ 0.093).
Discontinuation of Therapy: Two of 25 patients
who had received sotalol in the sinus rhythm group
required drug withdrawal due to abdominal pain,
diarrhea, or eczema, all of which disappeared on
drug termination. One patient experienced torsade
de pointes during a routine 24-h Holter monitoring
session, and another patient had QT prolongation (ie,
QTc ⬎ 0.6). Two of the 38 patients treated with
propafenone experienced drug intolerance (ie, headaches, nausea, and vomiting). One patient presented
with complex ventricular arrhythmias during routine
Holter monitoring after 3 weeks of propafenone
therapy. Another patient treated with propafenone
presented with atrial flutter requiring electrical cardioversion. One of 10 patients receiving disopyramide demonstrated dyspeptic symptoms, and another patient who experienced a dry mouth and
urination difficulties refused to change drugs. Potential proarrhythmic effects were noted in 4 of 83
patients (4.8%) receiving drugs other than amiodarone.
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481
Clinical and biochemical symptoms of hyperthyroidism and AF recurrence were observed in 1 of 59
study patients receiving long-term amiodarone therapy. One patient had decreased thyroid-stimulating
hormone levels without clinical symptoms.
Bleeding Complications: Oral acenocoumarol
was used as thromboembolic prophylaxis in 74.3%
patients in the rate control arm. Aspirin and ticlopidine were used in 19.8% and 1.0% of patients,
respectively. At total of 4.9% of study patients
received no anticoagulant agents because of a perceived low risk of systemic embolization.13 All patients assigned to sinus rhythm restoration received
anticoagulation therapy (mean INR, 2.43 ⫾ 0.72) at
least 3 weeks before and 4 weeks after undergoing
cardioversion. In 15.6% of patients in whom cardioversion was successful, oral anticoagulants were prescribed for ⬎ 4 weeks after the procedure. In 62.2%
of study subjects, thromboembolic prophylaxis was
continued with aspirin, and one patient (0.9%) received ticlopidine. Nineteen patients (21.1%) who
maintained sinus rhythm for ⬎ 1 month were prescribed no additional antithrombotic agents.13 Thirteen patients, all of whom were receiving acenocoumarol at the time, had minor bleeding complications
outside the CNS (rate control group, 5 patients
[5.0%]; rhythm control group, 8 patients [7.7%]).
Hospitalization: Five patients (4.8%; 0.05 hospitalizations per person) who were assigned to ventricular rate control required hospitalization (mean
length of hospital stay, 12.3 ⫾ 4.2 days). There were
211 hospitalizations in the group in which sinus
rhythm restoration was attempted (mean length of
hospital stay, 2.5 ⫾ 1.1 days). Excluding 104 hospitalizations required by protocol for cardioversion,
there were 1.03 hospitalizations per person in the
sinus rhythm group. The most frequent cause of
hospital admission was recardioversion (94 cases;
87.9%). Thirteen patients (12.1%) required inpatient
care due to treatment side effects and/or new or
worsening concomitant disease. Clinical outcomes of
the follow-up period in both study groups are presented in Table 2.
Congestive Heart Failure: Both therapeutic strategies prevented the development and/or progression
of heart failure (NYHA functional class). In the rate
control group, heart failure regression was observed
during the first 2 months of observation (p ⬍ 0.02),
but no further improvement in NYHA functional
class occurred during follow-up. Almost 2 years of
observation revealed statistically significant heart
failure regression in the rate control arm of the study
(p ⬍ 0.05). In the rhythm control group, a similar
improvement of hemodynamic status (NYHA functional class) was observed during follow-up
(p ⬍ 0.001) [Fig 2]. No difference in NYHA functional class between patients initially randomized to
the two strategies was found at the end of the
follow-up period.
Exercise Tolerance: The rate control strategy did
not result in a statistically significant difference in
mean maximal workload during the treadmill test
(5.3 ⫾ 1.1 vs 4.8 ⫾ 2.5 metabolic equivalents, respectively; p ⬎ 0.42). Conversely, in the rhythm
control arm, exercise tolerance improvement and a
significant increase in maximal workload or were
observed (from 5.2 ⫾ 5.1 to 7.6 ⫾ 3.3 metabolic
equivalents, respectively; p ⬍ 0.001). Both treatment strategies led to significantly increased exercise
duration, but much more so in the rhythm control
group (rate control group: 118.0 ⫾ 87.5 vs
157.8 ⫾ 126.2 s; p ⬍ 0.03; rhythm control group:
125.3 ⫾ 115.7 vs 294.7 ⫾ 216.7 s; p ⬍ 0.001). At the
end of follow-up, both maximal workload and exercise duration were higher in the rhythm control arm
(p ⬍ 0.001 and p ⬍ 0.001, respectively).
Echocardiographic Parameters: In the rate control group, both right atrial enlargement (22.1 ⫾ 4.1 vs
23.3 ⫾ 3.8 cm2, respectively; p ⬍ 0.001) and left atrial
enlargement (25.7 ⫾ 5.0 vs 26.4 ⫾ 5.0 cm2, respectively; p ⬍ 0.05) were observed during the follow-up
period. Our observation demonstrated a significant
decrease in right atrial size (21.8 ⫾ 4.1 vs 20.3 ⫾ 3.4
cm2, respectively; p ⬍ 0.01) and left atrial size
(26.2 ⫾ 4.7 vs 25.4 ⫾ 5.0 cm2, respectively; p ⬍ 0.02)
in the rhythm control arm. A significant increase in left
ventricular fractional shortening (29.9 ⫾ 6.9% vs
34.5 ⫾ 8.9%, respectively; p ⬍ 0.001) was found in
patients assigned to the sinus rhythm restoration group,
while the rate control strategy failed to significantly
affect left ventricular fractional shortening (32.8 ⫾ 6.6
vs 35.6 ⫾ 7.4%, respectively).
Discussion
The results of the HOT CAFE study have provided data that are relevant to the management of
patients with AF. Our study demonstrated that the
rate control of AF is as acceptable as sinus rhythm
restoration and maintenance. Despite the relatively
small number of enrolled patients and the short
observation period, our study suggests that, at least
with currently available pharmacologic therapy,
there is no distinct advantage associated with the
rhythm control strategy. Moreover, the control of
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Table 2—Side Effects*
Side Effect
Mean follow-up, yr
Deaths
From cardiovascular causes
Total No.
Total bleeding complications
Major bleeding
Minor bleeding
Nasal cavity bleeding
Urinary tract bleeding
Oral cavity bleeding
Epitaxis
Ecchymosis
Intracranial bleeding
Thromboembolic complications
Ischemic stroke
Pulmonary embolism
Antiarrhythmic therapy
Proarrhythmia
Ventricular tachycardia
Bigeminy/trigeminy
QTc prolongation
Atrial flutter
Somatic symptoms
Headache
Abdominal pain/dyspeptic symptoms
Oral cavity dryness
Urination difficulties
Hyperthyroidism
Others
Impotence (during atenolol therapy)
Invasive therapy
Implantation of pacemaker
AV nodal ablation
Hospitalizations
Total
Rate Control
(n ⫽ 101)
Rhythm Control
(n ⫽ 104)
Significance
1.6 ⫾ 0.9
1.8 ⫾ 0.3
NS
1 (1.0)
5
2 (2.0)
3 (2.9)
8
NS
NS
NS
NS
1 (1.0)
3 (2.9)
1 (1.0)
1 (1.0)
2 (1.9)
NS
NS
NS
NS
NS
3 (2.9)
NS
NS
4 (3.8)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
8 (7.7)
1 (1.0)
3 (2.9)
1 (1.0)
1 (1.0)
2 (1.9)
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
3 (3.0)
2 (2.0)
1 (1.0)
1 (1.0)
3 (3.0)
2 (2.0)
0.05/person
8
NS
2 (1.9)
1.03/person
32
NS
NS
0.001
0.05
*Values given as mean ⫾ SD or No. (%), unless otherwise indicated. AV ⫽ atrioventricular. See Table 1 for other abbreviations not used in the
text.
ventricular response was easily achieved, and thus
allowed for the good management of symptoms and
exercise tolerance.
One noted advantage of rate control is the obviation of antiarrhythmic drug therapy and its potential
side effects. Furthermore, whereas antiarrhythmic
drug prophylaxis must often be initiated at a hospital,
this is not mandatory when the aim is rate control.
Successful arrhythmia suppression leads to the significant improvement of hemodynamic parameters,
exercise tolerance, and congestive heart failure relief. In the HOT CAFE study, patients in the rhythm
control group had better rate control and a significant decrease in mean heart rate during follow-up.
Ventricular response to the pharmacologic therapy
protocol in the rate control group remained within
satisfactory ranges during follow-up, although there
were no significant differences in ventricular rate
frequency between the following visits. Our results
support those of the Pharmacological Intervention in
Atrial Fibrillation (PIAF) study.10
In our Polish study, both the rhythm control and
rate control strategies, which were monitored by
exercise testing and Holter recordings, resulted in
symptomatic improvement. Exercise tolerance improvement and congestive heart failure relief in both
arms of the study reemphasizes the point that the
careful control of ventricular response in patients
with AF can result in a substantial benefit for the
patient. However, while similar at baseline, patients
in the rhythm control arm had a higher maximal
workload and could exercise longer than patients in
the rate control arm at the end of follow-up.
The outcomes of our trial revealed that the rhythm
control strategy resulted in an increase in left ventricular fractional shortening, which has been found
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483
Figure 2. Congestive heart failure intensity estimated by NYHA functional class in both groups during
the follow-up period.
in other studies.17 The right and left atria increased
their dimensions during follow-up in the rate control
group, while the opposite was found in the rhythm
control group, suggesting a partial reversal of atrial
remodeling and, possibly, a better chance to maintain sinus rhythm.
On the other hand, the strategy of rate control was
associated with significantly fewer hospital admissions. Cardioversion, AF recurrence, and the side
effects arising from therapeutic strategy in our study
group have significant economic implications. This is
particularly relevant given the number of people
with AF.
Besides the benefits of sinus rhythm restoration
(eg, the elimination of AF symptoms and improved
hemodynamics), the risk of thromboembolism occurrence also was expected to be reduced. Interestingly, so far no studies have shown that the restoration of normal sinus rhythm eliminates the risk of
thromboembolic complications.9,18 In our study,
strokes occurred in the sinus rhythm restoration
group, but thromboembolic prophylaxis seemed to
effectively protect rate control group patients. Longterm anticoagulation therapy, both in AF patients
and in all patients with successfully restored sinus
rhythm, as was proposed in the PIAF study,10 is not
an attractive alternative. Oral anticoagulant therapy
decreases the appeal of a rhythm control strategy,
and not only in high-risk patients. Other factors,
including more hospitalizations and more frequent
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new arrhythmias in the rhythm control group, also
indicated that rate control is at least as useful as sinus
rhythm restoration in the management of patients
with AF.
Our results are similar to those of the Atrial
Fibrillation Follow-up Investigation of Rhythm
Management (AFFIRM) trial9 and the Rate Control
vs Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) trial,11 however, the patient populations included in those studies differed slightly
from that in ours. Our study population comprised
younger patients, with a lower risk of systemic embolization, and mostly with the first episode of AF.
The AFFIRM trial,9 the largest study to evaluate
rate control vs rhythm control for AF found no
differences between the two strategies. All-cause
mortality, the primary end point of the study, did not
differ significantly between the two groups
(p ⫽ 0.056), although the survival curves separated
at around 1.5 to 2 years in favor of the rate control
strategy. The AFFIRM trial revealed no differences
in several of the secondary end points, including
functional status, quality of life, or major bleeding.
The rate of ischemic stroke over the average 3.5-year
follow-up period showed a trend favoring the rate
control group. Also, hospitalization and new arrhythmia rates were higher in the rhythm control group.
The RACE trial11 was the second study to address
the issue of a rate control vs a rhythm control
strategy in recurrent persistent AF patients. The
RACE protocol was based on the hypothesis that
rate control with medical therapy would prove inferior to rhythm control using cardioversion in tandem
with therapy using antiarrhythmic drugs. The primary composite end point of the study was a combination of cardiovascular death, hospitalization for
heart failure, thromboembolic complications, severe
bleeding, pacemaker implantation, and severe drug
side effects. Over an average of 3 years of follow-up,
Van Gelder and colleagues11 found no differences in
mortality rate between the study groups, although
the incidence of the composite primary end point
was higher in the rhythm control group. The difference also lay in some nonfatal end points (eg, more
thromboembolic complications, more frequent heart
failure, and more adverse drug effects in the rhythm
control group).
The results of these studies have major implications for the way that persistent AF is managed.
Above all, the decision to restore and maintain
normal sinus rhythm should be driven by patient
symptoms. Some patients remain symptomatic even
after the ventricular response was well-controlled.
For example, there is a small subgroup of patients
with reduced left ventricular compliance in whom
atrial systole is important for ventricular filling. In
these patients, the restoration and maintenance of
normal sinus rhythm may be an important strategy
for symptom control. In any case, when we elect to
use a rate control and anticoagulation strategy, it is
important to document (with ambulatory ECG recordings) that rate control remains satisfactory during everyday activities.
Considering the results of these studies,9 –11,19 we
consider rate control in AF to be an acceptable
primary therapy. The two strategies seem equal in
terms of mortality rate as well as thromboembolic
and hemorrhagic risk. A rhythm control strategy
without long-term anticoagulation therapy might result in a higher stroke rate, which implies that
anticoagulation therapy should be extended after
cardioversion, even in patients with a stable sinus
rhythm.
Our study has several limitations, one of which is
the relatively small number of patients. This was due
to the restrictive selection criteria that we applied in
order to achieve a homogenous group of patients.
This could have affected our results and prevented
the detection of more differences between the two
treatment strategies. Also, the number of our patients receiving anticoagulation therapy after sinus
rhythm restoration and maintenance was relatively
low. Yet, only a single ischemic stroke, unrelated to
cardioversion, occurred in this subgroup of patients.
Thus, rhythm control may still be a valid option for
patients with persistent AF and relative contraindications to long-term anticoagulation therapy. Despite the limited number of patients, our findings are
similar to those reported in other trials.9 –11,19 The
HOT CAFE trial, being a randomized trial with
well-defined end points and an almost 2-year
follow-up period, may be a useful element in a future
meta-analysis. We hope that our results will contribute to the discussion on rate control vs rhythm
control to the benefit of patients with AF.
Conclusions
The HOT CAFE study suggests that the rate
control of persistent AF is equivalent to rhythm
control in terms of mortality rate, stroke, and thromboembolic and severe bleeding complications.
Therefore, our trial supports the results of other
studies, although our population was younger and
possibly had AF relatively longer than other populations (for up to 2 years). The HOT CAFE trial, like
the PIAF, AFFIRM, RACE, and other trials, showed
no significant differences in the two proposed treatment strategies for AF, so we still have to choose the
best therapeutic approach based on an individual
patient’s needs.9 –11,19 A meta-analysis of all random-
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ized trials might offer the possibility of subgroup
analysis and might help to optimize treatment procedures in everyday clinical practice.
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