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Atrial
fibrillation is the most common sustained arrhythmia encountered
in the clinical practice. Its prevalence and incidence
increase with age. The mortality rate of patients with
AF is about double that of patients in normal sinus rhythm
and is linked with the severity of the underlying heart
disease. The rate of ischemic stroke among patients with
non-rheumatic AF averages 5 % per year, 2-7 times that
of people without AF. (1,2)
The
major issues in the management of patients with AF are
related to the arrhythmia itself and to prevent thromboembolism,
in patients with AF there are two fundamental ways to
manage the arrhythmia; to restore and maintain sinus rhythm
or to allow AF to continue with controlling the ventricular
rate. The relative merits of rhythm versus rate control
is the subject of our study.
The
aim of this work is to compare the effect of therapy intended
to maintain sinus rhythm versus therapy intended to control
the heart rate on the composite endpoint of mortality,
stroke, myocardial infarction, major hemorrhage and systemic
embolism.
The
second objective of this study was to compare whether
optimized antiarrhythmic drug therapy administered to
attempt to maintain sinus rhythm has an impact on the
cost and quality of life when compared to optimized therapy
which merely control the heart rate.
Patients
and Methods
Eighty-four
patients with atrial fibrillation were randomly assigned
for heart control and anticoagulation or rhythm control
with antiarrhythmic drugs and anticoagulation.
All
of the following criteria had to be met for a patient
with documented atrial fibrillation to be included in
the study:
Patients
under the age of 65 years had to have at least one clinical
risk factor for stroke (Hypertension, Diabetes mellitus,
Congestive heart failure, a left atrial dimension of 50
mm or more by M-mode echocardiography and a fractional
shortening of 25% or less, an ejection fraction of 45%
or less by any form of investigation, prior cerebrovascular
accident, or other systemic embolus.
To
qualify for enrollment in the study, the patient had to
have at least two episodes of sustained atrial fibrillation
in the six months prior to the study, one of them being
in the last six weeks prior to the study and documented
by ECG; sustained atrial fibrillation being defined as
an attack that lasted for more than one hour. The total
attack time had to equal or exceed six hours.
Maintenance
of sinus rhythm for at least one hour after cardioversion
was required for eligibility for randomisation. The patients
had to be eligible for therapy with two antiarrhythmic
drugs, or both dose levels of amiodarone, or one antiarrhythmic
drug in addition to one amiodarone dose. Likewise, the
patients had to be eligible for therapy with at least
two of rate-controlling drugs. Both rate and rhythm control
strategies were initiated immediately after randomization
or within a maximum of five days.
Patients
with reversible causes of atrial fibrillation were excluded
(thyrotoxicosis, severe electrolyte balance, infection,
pericarditis, acute alcohol intoxication, excessive use
of B- adrenergic stimulants or patients who suffered AF
within seven days of a major surgical procedure, electrocution,
trauma or myocardial infarction). Likewise we excluded
patients in whom valve surgery or valvuloplasty was scheduled
within one year. Patients suffering from hypertrophic
cardiomyopathy, long QT syndrome, WPW syndrome and lone
AF with no clinical risk factors for stroke were also
not enrolled. Patients were excluded if they underwent
ablation, Maze or Corridor surgery or ICD implantation
Other
medical exclusions were renal failure requiring dialysis,
contraindication to warfarin and women of childbearing
potential.
Study
Design
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All
patients in the study were subjected to history and
physical examination. Functional status was measured
by the Six-Minute walk test.
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Laboratory
Studies: This included Blood urea, creatinine, sodium,
potassium, glucose, INR, and T3,T4 and TSH.
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Standard
12 lead electrocardiography.
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Standard
two-dimensional and M- mode echocardiography for measurement
of left atrial size and the presence or absence of
thrombus. Ejection fraction was recorded qualitatively
and estimated as normal, mildly, moderately or severely
reduced.
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Cardioversion:
Atrial fibrillation of less than 48 hours duration
was treated by cardioversion without prior anticoagulation.
Atrial fibrillation of 48 hours or more duration cardioversion
was postponed for at least 3 weeks during which the
patient was anticoagulated with warfarin. Anticoagulation
continued for at least 12 weeks. At least 3 weeks
of anticoagulation were required before cardioversion
if thrombus was noted.Cardioversion was attempted
prior to randomization; and patients were entered
into the study only if cardioversion was successful
(normal sinus rhythm for at least 1 hour).
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Randomization
Performed by permuted block design with equal allocation
and stratified only by clinical site. Treatment started
immediately after randomization, or as soon as possible,
but no later than 5 days after randomization.
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Intervention:
I)
To maintain sinus rhythm one of the following regimens
was used:
Quinidine,
600 mg/ day of quinidine base plus atrioventricular blockers.
Propafenone,
150 mg TDS plus atrioventricular blockers.
Amiodarone-a
minimum cumulative loading dose of 10 gm over a period
of several weeks prior to the first maintenance dose.
The first maintenance dose was 100- 200 mg per day . A
higher dose of 300 - 400 mg per day if necessary
Sotalol
120 mg BID
Combinations
of the above drugs.
The
patient was considered to be controlled if he had no more
than 1 episode of atrial fibrillation in a 6 month period.
II)
Therapeutic approach to rate control:
Patients
were assessed of heart rate control both at
rest
and at a six minute walk test.
The
approved drugs were:
Digoxine.
Verapamil.
Amiodarone.
Propranolol.
Combination
of the above drugs.
Proper
control of heart rate was defined as a resting heart rate
of less than 80 beats per minute in addition to a heart
rate of less 110 beats per minute during a six minute
walk test.
Antithrombotic
therapy was given as follows:
All
patients who had at least one risk factor for stroke were
given warfarin.
The
target INR for warfarin was 2.5
Patients
follow-up:
Patients
were evaluated at 2 and at 12 months following randomization.
At
each visit, angina and heart failure, were assessed by
the Canadian and New York Heart classifications. The six-
minute walk functional status test was performed
Cost was
assessed by counting:
The number of
days of relevant hospitalizations.
The
number of major cardiac procedures and device implantation
and
Number
of emergency room and short stay visits
Events
during follow-up:
Death
(including mode of death).
CVA
(embolic, thrombotic, hemorrhagic).
Cardiac
arrest with disabling anoxic encephalopathy.
Systemic
embolism.
Myocardial
infarction.
Major
and minor bleeding.
Resuscitated
cardiac arrest, including VF, sustained VT, and torsade
de pointes.
Analysis
Baseline
characteristics of patients in the two groups were compared.
Covariates were examined by graphical methods, descriptive
statistics, and tables, and were compared by Chi-square
tests, t- tests. Subsequent analyses were adjusted for
covariates, which were found to be significantly different
between the groups.
Results
Population
Characteristics
A)
Clinical Characteristics
The
study consisted of eighty-four patients, forty-three patients
were randomized to the rhythm control group and forty-one
patients were randomized to the rate control group. Both
groups were similar as concerns the baseline clinical
characteristics. See Table 1
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2.
Echocardiography
The
cardiac dimensions, mitral valve disease, aortic valve
disease, regional wall motion abnormality, cardiac thrombi,
and fractional shortening were comparable in both groups.
The baseline echocardiographic data are summarized in
table 2.
C)
Laboratory findings
Regarding laboratory tests, both groups were comparable.
D)
Baseline Six-Minute walk test
The distance covered was longer and the resting and peak
heart rate were slower in the rate control group. The
data of
six-minute walking test are summarized in table 3.
E)
Baseline ECG characteristics
Left axis deviation was more frequent in the rate control
and
right bundle branch block in the rhythm control group.
F)
Drugs used to maintain sinus rhythm
Thirteen patients were maintained on propfenone
(450mg/day), three patients were maintained on quinidine
(600mg / day), four patients were maintained on amiodarone
large dose (400mg /day) and twenty three were maintained
on amiodarone small dose (200mg/day).
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End
points of the study
As
regards composite endpoint of the study of mortality,
cerebrovascular stokes, major bleeding, systemic embolism,
there was no statistical difference between the to groups
(p = 0.8).
Cumulative
Secondary endpoint
Cost
of the therapy
Cost
of therapy in both treatment strategies were assessed
by days of hospitalization and number of ER visits. During
one year of follow up, there was no statistical difference
between the two groups. Data are summarized in table 5.
Functional
capacity
Functional
capacity in both treatment strategies during one year
of follow up was assessed subjectively by New York Heart
classification of dyspnea and objectively by six- minute
walking test. In both groups, there was no difference
regarding dyspnea at the time of randomization, and at
the first visit after two months. After six months, seven
patients in the rate control group remained in NYHA III
while in the rhythm control group none of the patients
exceeded NYHA II, indicating marked improvement in the
symptomatology in this group, which persisted for twelve
months.
Both
groups were assessed by the six- minute walk test. In
both groups, there was marked improvement of their effort
tolerance in comparison with the baseline status, (walking
distance from160 + 80 meters to 230 +101
meters in the rate control group and from 130 +75 meters
to 243+ 100 meters in the rhythm control group). However
there was no statistically significant difference between
both groups during one year follow up.
Atrial
fibrillation recurrence
Most
of the recurrences occurred in the 1st two
months, with no statistically significant difference between
both groups (14 patients in the rate control group versus
16 in the rhythm control group) see table 6
Recurrence
of atrial fibrillation in the rate control group was related
to hypertension, smoking, and diabetes, (r =0.5, p = 0.001,
r =0.3, p = 0.03, r = 0.3, p = 0.03 respectively), while
Rhythm control group, in the 1st two months, the only
factor related to recurrence was age (r = 0.3, p =0.03),
At
the last visit after 12 months, hypertension became the
only factor that was related to recurrence of atrial fibrillation
in the rate control group, (r = 0.4, p = 0.03), while
female gender and left atrial diameter were related to
recurrence (r = 0.4, p = 0.02) in the rhythm control group.
Further
analysis of recurrence rates in the rhythm control group
revealed that only 20% of the patients could be maintained
on sinus rhythm for one year (see table 7)
Of the drug regimens
used to maintain sinus rhythm, only Amiodarone in the
larger dose appeared to be promising, with a success rate
of 47% (see table 8).
Discussion
Rate
versus rhythm control in cases of atrial fibrillation
is still a controversial issue. In this study we randomized
84 Egyptian patients suffering from recent onset atrial
fibrillation, and successfully cardioverted by direct
current cardioversion into two groups, a rhythm control
group in which the goal was to maintain sinus rhythm medically
using profafenone, quinidine and amiodarone and to attempt
cardioversion after each recurrence, and a rate control
group in which no attempt was made to restore sinus rhythm
after the 1st recurrence.
Most
of the recurrences occurred in the 1st two
months, with no statistically significant difference between
both groups (14 patients in the rate control group versus
16 in the rhythm control group) , which is similar to
results reported in the literature (3, 4, 5)
Recurrence
of atrial fibrillation in both groups was similar and
showed in either groups only very weak relation to risk
factors. (hypertension, smoking, and diabetes, in the
rate control group(r =0.5, p = 0.001, r =0.3, p = 0.03,
r = 0.3, p = 0.03 respectively), while Rhythm control
group, in the 1st two months, the only factor related
to recurrence was age (r = 0.3, p =0.03), This seems to
indicate that the role of antiarrhythmic agents here is
to balance the effect of hypertension , smoking and diabetes.
However, at the last visit after 12 months, hypertension
became the only factor that was related to recurrence
of atrial fibrillation in the rate control group, (r =
0.4, p = 0.03), while female gender and left atrial diameter
were related to recurrence (r = 0.4, p = 0.02) in the
rhythm control group.
Further
analysis of recurrence rates in the rhythm control group
revealed that only 20% of the patients could be maintained
on sinus rhythm for one year .Of the drug regimens used
to maintain sinus rhythm, only Amiodarone in the larger
dose appeared to be promising, with a success rate of
47%. Also this is in accordance with findings of the AFFIRM
trial, where Amiodarone was more effective at one year
than either sotalol or class I agents for the strategy
of maintenance of sinus rhythm without cardioversion.
(6)
As
regards composite endpoint of the study of mortality,
cerebrovascular strokes, major bleeding, systemic embolism,
there was no statistical difference between the to groups
(14 patients in the rate versus 15 patients in the rhythm
control group, p = 0.8). Although some studies such as
AFFIRM and PIAF had similar results, others such as RACE
showed an increased mortality in their rhythm control
limb (7,8,9,10) Functional capacity as assessed by the
6 minute walk test improved to a similar degree in both
groups, although the rhythm control group subjectively
reported to be in a slightly better functional class.
There
was also no difference in terms of duration of hospital
stay or number of admissions. In a polish study, (11),
the number of hospital admissions was significantly greater
in the rhythm than in the rate control group, with similar
endpoints and quality of life outcome. When considering
the cost of antiarrhythmic therapy, and the similar outcome
in all respects between both rate and rhythm controlled
groups in our study, the recommendation for Egyptian patients
is the same as that of the American college of physicians,
namely that rate control is preferable to rhythm control
in patient suffering from recent onset persistent atrial
fibrillation. (12)
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