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Credits:William G. Stevenson, M.D., Usha B.Tedrow, M.D., and Jens Seiler, M.D.
From:The Cardiovascular Division,Department of Medicine,Brigham and Women’s Hospital,Harvard Medical School,Boston, Massachusetts
Address for Correspondence:William G. Stevenson, M.D.,Cardiovascular Division,Brigham and Women’s Hospital,75 Francis St, Boston, MA 02115
doi : 10.4022/jafib.v1i1.401
Atrial fibrillation is common in heart failure
patients and is associated with increased mortality. Pharmacologic trials have
not shown any survival benefit for a rhythm control over a rate control
strategy. It has been suggested that sinus rhythm is associated with a
survival benefit, but that the risks of anti-arrhythmic drug treatment and poor
efficacy offset the beneficial effect. Catheter ablation for atrial
fibrillation can establish sinus rhythm without the risks of anti-arrhythmic
drug therapy. Data from randomized trials demonstrating a survival benefit for
patients undergoing an ablation procedure for atrial fibrillation are still
lacking. Ablation of the AV junction and permanent pacing remain a treatment
alternative in otherwise refractory cases. Placement of a biventricular system
may prevent or reduce negative consequences of chronic right ventricular
pacing. Current objectives and options for treatment of atrial fibrillation in
heart failure patients are reviewed.
Keywords:
atrial fibrillation, heart failure, anticoagulation, antiarrhythmic drugs,
ablation
Atrial fibrillation and heart failure
are epidemics of contemporary cardiovascular medicine. In the US, more than 2
million people are suffering from atrial fibrillation and more than 5 million
have heart failure.[1-3]
Atrial fibrillation and heart failure often coexist, and patients with one
condition, who subsequently develop the other, have an increased mortality.[4]
Heart failure is associated with a 4.5 to 5.9-fold risk for atrial
fibrillation.[5]
The prevalence of atrial fibrillation increases with the severity of heart
failure from ≤ 5% in patients with functional class NYHA I to nearly 50%
in patients with functional class NYHA IV.[6]
Approximately 40-50% of heart failure patients have preserved left ventricular
function, which is often associated with older age, female gender and a history
of hypertension.[7-9]
In these patients, atrial fibrillation is even more prevalent than in patents
with reduced ejection fraction.[7,
9,
10]
Atrial fibrillation may lead to
further hemodynamic deterioration in heart failure patients. An
inappropriately fast or slow ventricular response, ventricular rhythm
irregularity and loss of mechanical atrial function can have negative
hemodynamic consequences and may elicit an increase in sympathetic tone.[6,
11, 12]
A chronic fast ventricular response may lead to tachycardia-induced
cardiomyopathy causing exacerbation or aggravation of heart failure.[13]
This article focuses on clinical
management of atrial fibrillation in heart failure patients. Treatment options
to prevent thromboembolism, control heart rate and maintain sinus rhythm will
be discussed.
Data from the National Registry for
Atrial Fibrillation suggest an overall stroke risk of 4.4% per year in patients
with non-rheumatic atrial fibrillation aged 65 to 95 years. The annual stroke
risk ranges from 1.9% in the absence of, to 18.2% per year in the presence of
all of the following risk factors, recent congestive heart failure, history of
hypertension, age ≥ 75 years, diabetes mellitus and prior stroke or
history of prior thromboembolism.[14]
Data from the Framingham Heart Study suggest that the risk of stroke is
increased by 4.8-fold in atrial fibrillation and by 4.3-fold in heart failure.
The presence of atrial fibrillation in patients with heart failure almost
doubles the risk of stroke in men and triples the risk of stroke in women.[15]
Recent meta-analyses showed, that dose-adjusted warfarin reduces the risk of
stroke by 64% to 67%, but antiplatelet agents (i.e. aspirin and dipyridamole) are
less effective, reducing stroke by only by 22%. [16,
17] Heart
failure and left ventricular ejection fraction ≤ 35% are both considered
moderate risk factors for thromboembolic events in patients with atrial
fibrillation. Anticoagulation with dose-adjusted warfarin should be maintained
in all patients with heart failure and a history of atrial fibrillation unless
contraindicated.[18,
19]
Data from the AFFIRM trial shows that
major bleeding during anticoagulation with warfarin in patients at risk of
stroke occurs in approximately 2% of patients per year. Congestive heart
failure increases the risk of major bleeding by 43%. However, the rate of
major bleeding in patients with atrial fibrillation at risk of stroke is
usually lower than the expected rate of a thromboembolic event.[20]
Thus, anticoagulation is still favored.
In prior randomized trials (AFFIRM,
RACE and STAF) comparing rhythm control and rate control with antiarrhythmic
drugs, neither strategy demonstrated a survival benefit over the other.[21-23]
The recently completed AF-CHF study addressed this issue specifically in heart
failure patients. A total of 1,376 patients with heart failure symptoms, a
left ventricular ejection fraction of ≤ 35% and at least one episode of
atrial fibrillation within 6 months preceding enrollment were included. Mean
left-ventricular ejection fraction was 27%; 31% of patients were in functional
class NYHA III to IV and atrial fibrillation was persistent in 69% of
patients. After a mean follow-up of 37 months, there was no difference between
rate and rhythm control groups in the primary endpoint of cardiovascular
mortality. Secondary outcomes including total mortality, worsening heart
failure and stroke were also not different between groups.[24,
25] Patients
included in these studies are likely different from those usually considered
for catheter ablation of atrial fibrillation. It is conceivable, that patients
with severe symptomatic episodes of atrial fibrillation would not have been
considered as optimal participants. In the AFFIRM study, only patients of at
least 65 years of age or with other risk factors for stroke or death could be
enrolled.[21]
The mean age of the participants in the AFFIRM, RACE, STAF and AF-CHF studies
was 66 to 70 years.[21-23,
25] In contrast,
the mean age of patients undergoing catheter ablation for atrial fibrillation
was 60 years in a recent large multicenter registry.[26]
The AFFIRM, RACE and other studies have
shown that maintenance of sinus rhythm is associated with improved survival and
less hospitalizations, but in AFFIRM, antiarrhythmic drug use was associated
with a worse outcome.[27-30]
Thus, whether sinus rhythm is only a marker of less severe illness or causative
for a better outcome remains controversial.[27]
In the absence of data clearly
favoring one strategy over the other, therapy has to be individualized. Our
practice is to consider rhythm control in patients with a first episode of
persistent atrial fibrillation, for symptomatic paroxysms of atrial
fibrillation, and when adequate rate control is difficult to achieve.[31]
Amiodarone or dofetilide, both class
III antiarrhythmic drugs, are the major pharmacologic considerations for
attempted maintenance of sinus rhythm in patients with heart failure.[18]
Amiodarone was shown to be safe in heart failure patients in the CHF-STAT trial
with a trend to a better survival in patients with non-ischemic cardiomyopathy.[32]
In the SCD-HeFT trial, amiodarone did not significantly influence overall
mortality, but subgroup analysis showed an increased mortality in patients with
NYHA III heart failure. Whether this result is biologically plausible was
questioned by the authors of the study, but the findings do raise concern as to
drug toxicity.[33]
Amiodarone has a high efficacy in maintaining sinus rhythm, and it can safely
be initiated in an outpatient setting.[29,
34] Major
concerns early during therapy include drug-induced bradycardia necessitating
adjustment of concomitant drug therapy or pacemaker implantation in up to one
third of the patients.[34]
Noncardiac lung, liver, neurologic and thyroid toxicities are major concerns
during long-term treatment. Amiodarone has to be discontinued in approximately
8% of patients per year due to extracardiac side effects.[35]
Dofetilide was shown to be relatively
safe in heart failure patients, provided that several precautions are taken in
its use.[36]
In this patient group, it has efficacy in converting atrial fibrillation to
sinus rhythm and maintaining sinus rhythm.[30,
36] As an IKr
blocker, dofetilide prolongs the QT interval. It caused torsade de pointes in
approximately 3% of patients in the DIAMOND trial, even after dose-adjustment
according to renal function and attention to following the QT interval. The
peak increase in the QT interval was seen within the first 2 days, and 76% of cases
of torsades de pointes occurred within the first 3 days of dofetilide therapy.
In-hospital monitored initiation of dofetilide for 3 days is warranted.[36]
ICDs may provide protection from death due to this arrhythmia. There is no
head-to-head comparison of amiodarone and dofetilide in heart failure patients.
Sotalol is another class III
antiarrhythmic drug that is an IKr blocker and also a non-selective
beta-blocker. It may be considered as a therapeutic alternative. Data from
the CTAF and SAFE-T trials show, that amiodarone is superior to sotalol in
maintenance of sinus rhythm, but sotalol is still superior to placebo.[37,
38] In patients
with coronary artery disease, sotalol and amiodarone are similarly efficacious.[38]
Of note, the minority of patients in both trials had abnormal left ventricular
function.[37,
38] Sotalol has
a proarrhythmic potential similar to that of dofetilide. This effect may have
been the cause of excess mortality that led to premature termination of the
SWORD trial in which the d-isomer of sotalol was administered to patients with
a history of prior myocardial infarction and an ejection fraction ≤ 40%.
Excess in total mortality was driven by arrhythmic cardiac deaths. However,
torsade de pointes were reported in only 0.2% of patients receiving sotalol.[39]
The proarrhythmic effect of sotalol warrants in-hospital initiation of the
drug.
The CAST trial showed an excess of
mortality with use of class I antiarrhythmic drugs (sodium channel blockers,
including flecainide) in patients with structural heart disease.[40]
Heart failure patients may be prone to suffer from arrhythmogenic and
cardiodepressant side effects of class I antiarrhythmic drugs. Accordingly,
these drugs should be avoided in heart failure patients.[19]
Over the last 20 years, surgical and
catheter ablation techniques for treatment of atrial fibrillation have been
developed and improved, with most of the trials in populations with no or
little heart failure. The Cox maze III procedure, which was introduced into
surgical treatment in 1988, is regarded as the gold standard for surgical
treatment of atrial fibrillation. Long-term success in over 90% of patients,
most of them off drugs, has been reported.[41,
42] A review of
recent publications on radiofrequency catheter ablation for atrial fibrillation
shows consistently success rates in approximately 80% of patients, most of them
off drugs, although more than one procedure is required in a significant
number.[43]
It is difficult to extrapolate these results for heart failure patients, since
patients in these trials are selected to be reasonable ablation candidates,
often with no or minimal structural heart disease. As for most therapies,
lower success rates would be anticipated in patients with heart failure. Left
atrial scarring, decreased left ventricular function, persistent atrial
fibrillation and age were identified as predictors of procedural failure in catheter
ablation for atrial fibrillation.[44,
45]
Surgical and catheter ablation
procedures in patients with depressed left ventricular function were
investigated in several recent studies. In a retrospective study of 37
patients with a left ventricular ejection fraction < 55% (mean, 44%), who
underwent a Cox maze procedure for paroxysmal and chronic atrial fibrillation
and flutter, there was no perioperative mortality, and 3 patients required
placement of a permanent pacemaker. During a median follow-up of 48 months,
atrial arrhythmias recurred in 4 patients. Mean left ventricular ejection
fraction improved significantly to 54%. Improvement in functional capacity was
noted in 56% of patients, deterioration of functional capacity was not
observed.[46]
Surgical risks are an important consideration. A recent review of 48 studies
on surgical treatment of atrial fibrillation including the classical Cox maze
III procedure, most performed with concomitant valve or bypass procedures,
reported a 30-day mortality of 2 to 4%, major complications in 8% and the need
for pacemaker implantation in 5 to 6% of cases.[47]
Hsu and coworkers studied 58 patients
with congestive heart failure and a left ventricular ejection fraction < 45%
(mean, 35%), who underwent radiofrequency catheter ablation for atrial
fibrillation. One patient died 3 months after the procedure of heart failure.
After a follow-up period of 12 months, 78% of patients remained in sinus
rhythm, 69% off antiarrhythmic drugs. To achieve this result, a second
procedure was required in 50% of patients. Success rates in a control group
were 84% and 71%, respectively. Mean left ventricular ejection fraction improved
to 56%, and left ventricular dimensions decreased. This translated into better
functional capacity and quality of life.[48]
Similar results were seen in another study on catheter ablation for atrial
fibrillation, which included 90 patients with a reduced left ventricular
ejection fraction of < 40% (mean, 36%). After a follow-up of 14 months, 73%
of patients were free of atrial fibrillation, compared to 87% of patients in a
control group. The increase in left ventricular ejection fraction to 41% was
not significant, but quality of life improved significantly. In 22% of
patients a second procedure was successful.[45]
Major complications of catheter ablation for atrial fibrillation occur in 4 to
6% of patients, and it can be anticipated that heart failure patients will
generally be at greater risk.[26,
49]
These reports from highly experienced
centers with selected patients are promising, but controlled data confirming a
prognostic benefit for patients undergoing these procedures are still lacking.
The ongoing CABANA trial, which compares catheter ablation for atrial
fibrillation with current state-of-the-art medical therapy, addresses this
issue with a primary outcome measure of total mortality, but does not focus
solely on a heart failure population.[50]
At present, catheter ablation for atrial fibrillation in heart failure is
warranted in selected symptomatic patients with atrial fibrillation refractory
to at least one antiarrhythmic drug. Surgical ablation for atrial fibrillation
is usually considered for symptomatic patients undergoing other cardiac
surgery, such as mitral valve repair. Patients may also be considered for
surgical ablation, when they prefer a surgical approach, have failed one or
more catheter ablation procedures or are not candidates for catheter ablation.[18,
42]
Atrial fibrillation with a fast
ventricular response may have immediate adverse hemodynamic effects and places
the patient at risk for tachycardia-mediated cardiomyopathy, particularly if
the chronic heart rate exceeds 100 beats per minute.[6,
13] Digoxin is
recommended for rate control in patients with heart failure, but it slows
atrioventricular conduction more effective at rest than during exercise.
Beta-blockers are usually indicated in all symptomatic patients with systolic
heart failure, but in heart failure initiation should be at a low dose followed
by a gradual increase, because negative inotropic effects may cause fluid
retention and worsening of heart failure. Combination of beta-blockers and
digoxin may be more effective than beta-blockers alone. Amiodarone is an
alternative for pharmacologic rate control in patients, where the
abovementioned medications are contraindicated or fail, but it has a
considerable potential of adverse drug effects and is usually avoided for rate
control alone. Non-dihydropyridine calcium channel blockers verapamil and
diltiazem slow heart rate during exercise, but should be avoided due to their
negative inotropic effect, which increases the risk of exacerbation of heart failure.[18,
19]
Pharmacologic rate control with
atrioventricular nodal blocking agents is chosen either as first line strategy
or when attempts to establish and maintain sinus rhythm fail. Heart rate goals
are 60 to 80 beats per minute at rest and 90 to 115 beats per minute during
moderate exercise, but may vary according to patient age.[18]
Radiofrequency
catheter ablation of the atrioventricular junction and pacemaker placement may
be warranted in medically refractory atrial fibrillation where sinus rhythm
cannot be maintained and adequate rate control is not possible. Limitations of
this approach include the persistent need for anticoagulation, loss of
atrioventricular synchrony and pacemaker dependency.[18]
A
meta-analysis of 21 studies showed, that ablation and pacing reduces symptoms
and healthcare use and improves left ventricular function, exercise duration
and quality of life, with a one year total and sudden death mortality of 6.3%
and 2.0%, respectively.[51]
However,
right ventricular apical pacing may be detrimental by worsening heart failure
and increasing mortality.[52]
Right ventricular pacing induces electrical and mechanical dyssynchrony, which
can adversely influence contraction and relaxation, ultimately causing
unfavorable ventricular remodeling. It may be less well tolerated in patients
with pre-existing systolic heart failure and mitral regurgitation.[53,
54] Consistent
with this consideration is the observation that atrioventricular node ablation
and permanent pacing for refractory atrial fibrillation leads to hemodynamic
deterioration in certain patients. Ozcan and coworkers studied this approach
in patients with left ventricular dysfunction with a mean left ventricular
ejection fraction of 26% before the procedure.[55]
Mean ejection fraction increased to 34% after ablation. The twenty-nine
percent of patients with near normalization of the left ventricular ejection
fraction to ≥ 45% had a survival comparable to that of normal subjects.
However, the majority of patients had a persistent low ejection fraction and a
poor prognosis with a mortality of 48% during a mean follow-up of 40 months.[55]
In some patients with heart failure, ablation and pacing is followed by
aggravation of mitral regurgitation.[56]
Vanderheyden and coworkers found hemodynamic deterioration in 7% of patients
undergoing ablation and pacing therapy, which was related to worsening mitral
regurgitation. Of note, baseline echocardiograms in patients with hemodynamic
deterioration showed left ventricular dilation and subnormal fractional
shortening.[57]
The
PAVE study compared conventional right ventricular with biventricular pacing in
patients undergoing atrioventricular node ablation for the management of atrial
fibrillation.[58]
Biventricular pacing was associated with improvement in functional capacity at
6 months. Left ventricular ejection fraction remained unchanged after
implantation of a biventricular system in contrast to right ventricular pacing,
where a slight but significant decline in ejection fraction was observed.
Patients with a baseline ejection fraction of ≤ 45% or NYHA functional
class II / III symptoms had a greater improvement in functional capacity than
patients with normal left ventricular function or class I symptoms.[58]
In another study of patients with severe heart failure after atrioventricular
node ablation and right ventricular pacing for management of chronic atrial
fibrillation, upgrade to a biventricular system was followed by improvement in
left ventricular dimensions and function, and quality of life and a decrease in
hospitalizations.[59]
The HOBIPACE study compared bi-ventricular to right ventricular pacing for 3
months in a randomized cross-over design trial in 30 patients. Biventricular
pacing was superior to conventional right ventricular pacing with regard to
left ventricular function, exercise capacity and quality of life in patients
with left ventricular dysfunction and standard indication for pacemaker implantation.[60]
Accordingly,
implantation of a biventricular pacemaker is a reasonable consideration for
patients who are undergoing atrioventricular node ablation for drug-refractory
atrial fibrillation with heart failure or depressed left ventricular function.
An upgrade to a biventricular system should be contemplated in patients with
persistent heart failure, who have undergone atrioventricular junctional
ablation and have only right ventricular pacing.[18]
Polymorphic
ventricular tachycardia, ventricular fibrillation and sudden death were not
uncommonly observed early after ablation of the atrioventricular junction and
pacemaker implantation. These complications occurred in 6% of cases in a
larger study of Geelen and coworkers. Ventricular arrhythmias mostly occurred
during slow ventricular escape rhythms or slow pacing rates of ≤ 60 beats
per minute. Bradycardia and pacing-related prolongation of repolarization,
change in ventricular activation, increased dispersion of repolarization,
increased sympathetic tone and individual factors like heart failure,
hypokalemia and female gender may increase the vulnerability to these
arrhythmias. Pacing at 90 beats per minute for 1 to 3 months after the
procedure appears to prevent this complication.[61,
62]
The
recently completed PABA CHF trial compared catheter ablation for atrial
fibrillation with atrioventricular node ablation and biventricular pacing.
Preliminary results showed a significantly greater ejection fraction in the
catheter ablation group at 6 months post procedure.[63]
Perhaps the best way to deal with
atrial fibrillation and its negative consequences is through prevention.
Angiotensin converting enzyme inhibitors, angiotensin receptor blockers and
beta-blockers belong to the standard pharmacologic armamentarium for treatment
of heart failure.[19]
There is strong evidence of participation of the renin-angiotensin system in
electrical and structural atrial remodeling, involved in the pathogenesis of
atrial fibrillation.[64]
Both angiotensin converting enzyme inhibitors and angiotensin receptor blockers
reduce atrial fibrillation in patients with heart failure or hypertension, as
supported by meta-analysis.[65]
The benefit was similar between these two classes of drugs and greatest in
patients with heart failure with a 44% relative risk reduction.[65]
A recent meta-analysis on the efficacy of beta-blockers in heart failure trials
showed a significant prevention of atrial fibrillation by use of beta-blockers
with a 27% relative risk reduction.[66]
The protective effect of cardiac
resynchronization therapy is still unclear. Although a small study showed a
significantly lower incidence of atrial fibrillation in patients with cardiac
resynchronization therapy, data from the CARE-HF study did not support this
hypothesis.[67,
68]
Atrial fibrillation is common in
heart failure. Patients with one condition who subsequent develop the other
have an increased mortality. Treatment has to be individualized in these
complex patients and the risks and benefits of the different therapeutic
options carefully considered. Anticoagulation and rate control are crucial in
all patients with atrial fibrillation and heart failure. Pharmacologic rhythm
control offers no survival benefit over rate control, and may be used in
selected symptomatic patients. Catheter ablation of atrial fibrillation in
selected patients can be successful, but also has risks. Atrioventricular node
ablation and placement of a biventricular pacemaker for drug-refractory atrial
fibrillation is an option when rate control and sinus rhythm can not be
maintained. The important question, of whether catheter ablation for atrial
fibrillation has the potential to prolong life, is still unresolved. The
answer may have substantial impact on our approach to treat atrial
fibrillation in the future.
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