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1. What are the differences between lone, paroxysmal, persistent and permanent atrial
fibrillation (AF)?
A joint task force met in 2001 to develop guidelines for the management of AF and
proposed a clinically relevant classification system [1]. Episodes of AF that occur on
more than one occasion are called recurrent. Paroxysmal AF is used to identify AF that
generally last less than or equal to 7 days and may be recurrent. Persistent AF refers to
episodes that last longer than 7 days. If AF continues for over a year, with or without
failed cardioversion, it is called Persistent. The presence or absence of symptoms do not
affect the classification of AF. This system of classification excludes AF that lasts less
than 30 seconds or that is secondary to a precipitating condition, such as surgery or
myocardial infarction. The term “Chronic AF” is not used in this classification, but is
generally what is thought of as Permanent AF. Lone AF refers to AF that occurs in the
absence of echocardiographic or clinical evidence of cardiopulmonary disease and
generally applies to patients less than 60 years old and implies a group of patients at low
risk of thromboembolic events. Lone AF can be paroxysmal, persistent or permanent.
2. What diagnostic tests should be done in patients with a new diagnosis of atrial
fibrillation?
There are multiple risk factors and disease processes that have been associated with atrial
fibrillation. A study of the Framingham cohort, for example, revealed that diabetes,
hypertension, myocardial infarction and age are strong risk factors of AF[2]. Tests
should be directed at determining underlying etiology or an associated, treatable
condition. A thorough history may reveal symptoms of cardiopulmonary disease or
expose risk factors such as binge drinking. Physical exam can assess blood pressure and
heart murmurs and signs of heart failure. The electrocardiogram can help establish the
diagnosis of AF and assess for ventricular hypertrophy and acute myocardial infarction.
Echocardiography should be performed to rule out ventricular dysfunction, valvular
disease, rheumatic heart disease and hypertrophic cardiomyopathy. Patients should also
be screened for diabetes, if not already established, with fasting blood sugars. Although
TSH is routinely checked, a Canadian study revealed that fewer than 1% of patients with
newly diagnosed AF were found by two years to have clinical hyperthyroidism and that
checking TSH routinely is of low yield[3]. Further targeted testing should be performed if
clinical suspicion exists for acute myocardial infarction, obstructive sleep apnea, COPD
or pulmonary embolism.
3. What are the indications for hospitalization in a patient with atrial fibrillation?
Under appropriate conditions, it is safe to manage even new onset AF as an outpatient.
Admission to the hospital is often considered in order to rule out acute myocardial
infarction. In one study of 109 patients who were admitted with new onset AF to rule out
myocardial infarction, only 5.5% ruled in[4]. In this study, all patients who lacked ST
depressions > 2mm or ST elevations ruled out for a myocardial infarct. It would be
reasonable to treat those patients at low risk for an acute coronary syndrome as
outpatients. If the patient, however, demonstrates hemodynamic instability, signs or
symptoms of heart failure, persistent rapid ventricular response or symptoms that can not
be controlled in the emergency room, he or she should be admitted for further
management and potential inpatient cardioversion. Although not yet validated for these
purposes, a model for calculating risk of stroke or death, such as the one based on the
Framingham cohort [5], could potentially be used to help decide which patients would
best be served as inpatients.
4. Is rhythm control better than rate control?
It was formerly believed that maintenance of AV synchrony was beneficial and was often
attained at considerable cost. The largest randomized controlled trial that challenged this
assumption was the AFFIRM trial[6]. 4060 patients with asymptomatic AF were
randomized to rate control with nodal agents versus rhythm control with pharmacologic
or electrical cardioversion. There were no statistically significant differences in stroke or
death between the two groups. However, patients in the rhythm control group had more
hospitalizations and adverse drug reactions and many deaths in the rhythm control group
may have been attributed to the antiarrhythmic drugs themselves. Similar findings were
noted in the RACE trial, a randomized controlled trial with 522 participants[7]. It is
reasonable, however, to aim for rhythm control in patients who either can not achieve
adequate rate control or are symptomatic from AF, especially in the younger population
that was not well represented in these trials. As newer, potentially safer approaches to
rhythm control become available, such as catheter ablation techniques, the benefits of one
approach over the other will need to be readdressed.
5. Are beta blockers better than calcium channel blockers for rate control?
Although rate control has been established as an appropriate approach to the management
of AF in older, asymptomatic patients, the choice of which nodal agent to use is in
question. The goals for patients randomized to rate control in the AFFIRM trial was a
heart rate below 80 at rest and below 110 during a six minute walk test[6]. In a sub-study
of the AFFIRM trial, the medical approach to rate control was evaluated[8]. Patients
whose first drug was a beta-blocker, with or without digoxin, were able to achieve rate
control in 70% of cases whereas those whose first drug was a calcium channel blocker,
with or without digoxin, were successful in 54% of cases. Calcium channel blockers
may, however, be more beneficial in selected groups, such as those prone to
bronchospasm or who develop other adverse reactions to beta blockers or younger
patients who may have diminished exercise capacity with beta blockers. Six minute walk
tests or Holter monitoring during activities of daily living may be necessary to assess
adequate rate control.
6. Which patients benefit from treatment with digoxin?
Among its many mechanisms of action, digoxin increases vagal tone and can have a
direct sympathoinhibitory effect. Because it has been available for a long time, it is
relatively inexpensive and requires only once a day administration, it remains a popular
therapeutic agent. Alone, it is effective at rate control as a first-line agent in only 58% of
patients, which is comparable to calcium channel blockers but worse than beta blockers
alone[8]. In combination, it can help reduce the dose of calcium channel blocker or beta
blocker required to achieve rate control and together with carvedilol, can lower the heart
rate better than either agent alone in patients with systolic heart failure[9]. In the absence
of heart failure, digoxin is not effective at converting patients in AF to sinus rhythm[10],
but may reduce the frequency of symptomatic episodes in paroxysmal AF. In summary,
digoxin may benefit patients already on calcium channel blockers or beta blockers who
have not achieved adequate rate control, especially those with heart failure, and patients
with frequent episodes of symptomatic paroxysmal AF.
7. Is pharmacologic cardioversion better than electrical cardioversion in patients who
need rhythm control?
There are no trials that have randomized patients undergoing acute rhythm control to
pharmacologic versus electrical cardioversion. The decision remains primarily the
preference of the patient and health care provider. Electrical cardioversion with a
biphasic waveform is effective in 80-90% of cases[11], but requires conscious sedation.
A small group of patients may be at risk of developing VT, particularly in the setting of
hypokalemia or digitalis intoxication. The efficacy of pharmacologic therapy varies
depending on the agent chosen, but is generally not as high as electrical cardioversion.
Pharmacologic cardioversion tends to be tolerated, but the risk of torsade de pointes can
range from 1% – 8% , depending on the agent and dose used as well as any underlying
susceptibilities, such as bradycardia and hypokalemia[12]. The primary risk of
cardioversion with either approach remains thromboembolism or stroke and can be as
high as 7% in those not adequately anticoagulated. The risk does not differ significantly
between these two approaches.
8. How should electrical cardioversion be performed?
Unless the patient is hemodynamically unstable or there is another indication for
emergent cardioversion, the patient should undergo conscious sedation. A recent
multicenter controlled trial randomized 203 patients to either biphasic or monophasic
shock waveforms and found that biphasic shocks were more efficacious, requiring fewer
shocks and resulted in less dermal injury[11]. The amount of energy necessary for
cardioversion varies depending on the waveform used, duration of AF and size of patient.
For monophasic waveforms, the minimal therapy should be 100J for < 48h, 150J for < 7
days and 200J for >1 year. For biphasic waveforms, the minimal initial therapy should
be 50J for < 48h, 100J for < 7 days and 150J for > 1year. This can be titrated up to the
maximum energy of 360J for monophasic and 200J for biphasic waveforms. Anteriorposterior paddle positioning, over the sternum and left scapula, is more effective than the
anterior-lateral approach[13]. Cardioversion in patients with pacemakers and
defibrillators is safe, but devices should be interrogated immediately before and after
external discharge. Long-term success improves if the cardioversion is performed after
the inciting cause, if any, of AF has resolved and after initiation of therapy for
maintenance of sinus rhythm.
9. Which antiarrhythmic agents should be used for acute conversion to and maintenance
of sinus rhythm?
The choice of antiarrhythmic agent depends primarily on the presence or absence of any
underlying cardiovascular disease, the side effect profile and the experience of the
clinician with certain agents. There are few studies that have randomized patients to the
different available drugs. In a meta-analysis of clinical trials measuring efficacy of
pharmacologic cardioversion, it was found that ibutilide, dofetilide and flecainide were
24-29 times more likely to lead to cardioversion than standard therapy with calcium
channel or beta blockers[14]. Although amiodarone and propafenone were moderately
effective, sotalol was generally ineffective at inducing sinus rhythm. In this metaanalysis, all agents were approximately equally efficacious in the maintenance of normal
sinus rhythm. Given the propensity of certain agents to induce ventricular arrhythmias in
the presence of cardiovascular disease, guidelines from the joint task force recommend
that for maintenance of sinus rhythm, flecainide, propafenone and sotalol be used as firstline agents in patients with no or minimal cardiovascular disease[1]. According to these
guidelines, patients with heart failure can be started on amiodarone or dofetilide, patients
with coronary disease can begin with sotalol and patients with hypertension can be
started on amiodarone.
10. How is amiodarone used in the management of AF?
Amiodarone is a class III agent whose use in AF, although not FDA approved for this
indication, has become exceedingly common primarily because of its low risk of
ventricular arrhythmias compared with other antiarrhythmics and lack of negative
ionotropic effects. The major deterrent is that its long-term use is associated with
multiple toxicities, namely pulmonary, hepatic and thyroid toxicities and its use in
younger populations should be limited. Although there is no standardized dosing
regimen, consensus guidelines recommend an initial loading of approximately 10 grams
of amiodarone and subsequent titration down to 200mg daily[1]. One approach is to
begin an oral load with 400mg twice daily for one week, followed by 200mg twice daily
for two weeks, then titrated down to 200mg po daily for maintenance. Another approach
proven to be safe[15] is to load with 600mg daily for four weeks, followed by
maintenance of 200mg daily. When used intravenously, amiodarone can be bolused at
150mg, followed by a drip of 1mg per hour for 6 hours and then maintained at 0.5mg per
hour until the load can be completed orally. Toxicities from long-term use should be
monitored with baseline and regular pulmonary function, liver function thyroid
stimulating hormone tests.
11. Can antiarrhythmic agents be started as an outpatient?
Because of the risk of torsade de pointes associated with these medications, almost all
studies of antiarrhythmics were performed during inpatient observation with careful
monitoring for QT prolongation. In one study of 597 drug trials, 13.7% of patients
suffered adverse cardiac events, including bradyarrhythmias in 8%, significant QT
prolongation in 1.5% requiring drug discontinuation and ventricular arrhythmias in 1.3%
of trials[16]. Some antiarrhythmics, such as dofetilide, are additionally restricted to
prescribers who have completed appropriate educational forums[17]. In one study of 129
patients with AF or flutter, subjects were given 600mg daily of amiodarone for 4 weeks
and none of the patients suffered ventricular arrhythmias[15]. Given this and similar
observations, it is considered that amiodarone can be started safely on an outpatient basis.
12. What is the pill-in-pocket approach?
There are a group of patients with paroxysmal AF who have relatively mild or well
tolerated symptoms during their episodes. If the episodes are infrequent enough, there
may be a reluctance to initiate daily use antiarrhythmic agents. These patients may be
managed with the “pill-in-the-pocket” approach, which consists of asking this group of
patients to take a single dose of an antiarrhythmic when they become symptomatic
instead of coming to the emergency room. In a study evaluating the safety of this
approach[18], 268 patients presenting with mild or no heart disease were converted to
sinus rhythm with either flecainide or propafenone in the hospital. The patients who did
not have an adverse event were then followed as outpatients and advised to selfadminister a single dose of flecainide or propafenone after the onset of heart palpitations.
These patients had a significant fall in the number of emergency room visits and hospital
admissions compared to the year prior. Only one patient experienced atrial flutter with
rapid ventricular rate and 11 patients reported non-cardiac side effects. This approach is
a safe option for the management of a select group of patients who would prefer not to
endure long-term standing use of antiarrhythmic therapy.
13. Do angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor
blockers (ARB) prevent recurrence of atrial fibrillation?
On retrospective examination of several trials, it was observed that the use of ACEI and
ARBs were associated with the prevention of AF and the maintenance of sinus rhythm in
patients with AF. Several potential mechanisms have been proposed and this effect is
likely related to atrial remodeling as well as the modification of diseases that are
associated with AF such as hypertension and congestive heart failure. In one study of
186 patients with persistent AF, participants were randomized to amiodarone versus
amiodarone plus irbesartan followed by electrical cardioversion[19]. After 2 months, the
group treated with irbesartan had fewer recurrences of AF. In a recent meta-analysis that
reviewed 11 randomized trials of ACEI and ARBs that also reported new onset of AF, it
was found that ACEI and ARBs reduced the relative risk of developing AF by 28%[20].
This effect was greatest in patients with heart failure. At this point there is not sufficient
prospective evidence to support the empiric use of ACEI or ARBs in the treatment of AF,
however, this may influence the choice of therapy in someone who also has hypertension
or congestive heart failure. Larger, more definitive trials to address this question are
underway.
14. Who should receive anticoagulation?
Whether or not a patient is anticoagulated depends on their risk of suffering a
thromboembolic event, which is related to age and coexisting cardiovascular disease. In
a large Danish cohort of patients with AF, the incidence of stroke rose from 1.3% per
year in those aged 50-59 to 5.1% per year in those aged 80-89[21]. The stroke rate in
those with lone AF, defined as younger than 60 without evidence of cardiopulmonary
disease, remains at 1.3% per year [22]. Stroke rates can be reduced significantly with the
use of oral anticoagulation and, to a lesser degree, with aspirin. A meta-analysis of
sixteen trials, including Stroke Prevention in Atrial Fibrillation, revealed that adjusteddose warfarin reduced stroke by 62% while ASA reduced stroke by only 22%[23].
Similar multi-trial analysis suggests that patients who are below 65 and without a history
of transient ischemic attacks, diabetes mellitus and hypertension have a stroke risk of less
than 1% per year without warfarin[24]. Based on these studies, it is strongly
recommended that patients with AF be treated with warfarin at a goal INR 2-3. Aspirin
alone may be acceptable in patients younger than 60 years who have no hypertension,
diabetes or evidence of cardiovascular disease.
15. Is immediate cardioversion with TEE better than delayed cardioversion after
anticoagulation?
Immediately after either electrical or pharmacological cardioversion, there is transient left
atrial dysfunction known as stunning. Depending on how long the patient has been in AF,
stunning can last for several weeks and predisposes patients to thromboembolism.
Patients with evidence of a thrombus in the left atrial appendage seen on transesophageal
echocardiogram are at a particularly high risk of thromboembolic events. The risk of an
embolic event without anticoagulation has been reported to vary from 1-5% in patients
with persistent AF, but is closer to 0.8% in those who have been in AF for less than 48
hours[25]. In a multicenter, randomized prospective trial, 1222 patients with AF of
greater than 48 hours duration were either anticoagulated for 3 to 4 weeks before
cardioversion or had earlier cardioversion guided by transesophageal
echocardiography[26]. There were no significant differences in rates of embolic events,
however, the group guided by transesophageal echo had a greater rate of successful
restoration of sinus rhythm and fewer hemorrhagic events. The decision of one approach
over the other may be guided primarily by patient preference, but this study suggested
that both approaches are equally effective in reducing stroke rates.
16. Do patients with paroxysmal atrial fibrillation need to be anticoagulated for life?
Anticoagulation can be burdensome because of the close monitoring that is necessary and
bruising associated with the therapy. Many patients understandably request that
anticoagulation be stopped, especially patients with paroxysmal AF who have not felt any
symptoms over a long period of time. The stroke risk, however, is equivalent between
patients with persistent and patients with chronic AF[27]. When patients were recorded
with continuous electrocardiograms over a 28 day period, however, most patients with
paroxysmal AF experienced asymptomatic episodes of AF[28]. Patients will experience
asymptomatic episodes even when they claim to know exactly when they are in the
arrhythmia. There is no easy way to identify patients who will stay in sinus rhythm and
no longer be at risk for thromboembolic events. Although it is not known definitively if
asymptomatic episodes of AF are associated with increased risk of stroke, at this moment
there is no evidence to suggest that stopping anticoagulation after maintenance of sinus
rhythm is safe.
17. What should be the goal INR in patients with atrial fibrillation and is it safe to hold
anticoagulation for surgery?
Anticoagulation is a balance between prevention of embolic strokes and avoidance of
hemorrhagic events. Although major gastrointestinal bleeding can be life-threatening,
hemorrhagic strokes can be equally devastating. In patients being anticoagulated for AF,
it is important to minimize the risk of over-anticoagulation with careful monitoring of
INR. The risk of stroke rises significantly when the INR is below 2.0 and the risk of
intracranial bleeding begins to rise above an INR of 3.0[29]. It is therefore recommended
that patients be kept on warfarin with a goal INR between these two values. With the
understanding that the 1-5% stroke risk is estimated over the course of a year, it was
deemed safe by the joint committee to recommend that in patients undergoing surgery or
other invasive procedures, it is acceptable to hold anticoagulation for up to one week
without the use of heparin[1]. If interruption of warfarin is necessary for a period longer
than one week, it has been recommended that either intravenous unfractionated heparin
or subcutaneous low molecular weight heparin be administered.
18. What can be done when patients do not respond adequately to medical therapy?
Most patients with atrial fibrillation will be adequately managed with anticoagulation and
rate control. Patients who have symptomatic AF or can not be adequately rate controlled
are often exposed to numerous antiarrhythmic agents. There is a group of patients,
however, who remain symptomatic despite antiarrhythmic therapy or who can not
tolerate these agents due to side effects. These are the patients who often seek nonpharmacologic approaches to the prevention of recurrent AF. There are multiple
approaches that have been studied in this setting, including surgical incision of the
atrium, atrial pacing and implantable atrial defibrillators. An emerging therapy is
catheter based ablation. After the discovery that ectopic stimuli from the veins can
induce AF[30], techniques to electrically isolate the pulmonary veins from the atrium
have been developed. In one study of 251 patients who underwent pulmonary vein
isolation, after 10 months, 85% of patients with paroxysmal and 68% of patients with
permanent AF maintained sinus rhythm based on serial Holter monitoring[31]. The
major risk of this procedure is pulmonary vein stenosis and cardiac tamponade which was
observed in 0.8% of patients in this study.
19. When is atrioventricular node (AVN) ablation necessary?
Many untreated patients with AF can mount ventricular response rates to 170 beats per
minute. The major disadvantage of these rapid rates is that most patients become
symptomatic and can, over time, develop tachycardia-mediated cardiomyopathy. Based
on the AFFIRM trial, a reasonable goal in the rate control strategy is a heart rate below
80 at rest and below 110 during a six minute walk test[6]. In patients who can not
achieve rate control, become excessively bradycardic or are symptomatic with medical
therapy, AV nodal ablation followed by pacemaker implantation is an option. In the
AIRCRAFT trial, 99 highly symptomatic patients with persistent AF were randomized to
AVN ablation plus pacemaker versus aggressive pharmacologic approach[32]. The
patients randomized to the AVN ablation plus pacemaker approach were less
symptomatic at one year. Although an increasing number of patients with AF refractory
to medical therapy will undergo ablation for pulmonary vein isolation (PVI), the AVN
ablation plus pacemaker approach may be reserved for those with sick sinus syndromes
or those who fail PVI.
20. Are there genetic tests for patients with lone atrial fibrillation?
The genetics of atrial fibrillation is an emerging field. Thus far only two genes, including
KCNQ1 which encodes a potassium channel, have been identified as the cause of lone
atrial fibrillation in certain families[33]. There are probably multiple, yet unidentified
genes that cause lone atrial fibrillation in other families. AF that is acquired later in life,
on the other hand, is likely multifactorial and is probably due to a combination of
different susceptibility genes and exposures to environmental factors. The genetic studies
are essential in helping us understand the pathophysiology of atrial fibrillation, which
although is the most common arrhythmia in adults, is the least well understood. At the
moment, genetic testing in patients with AF is not routinely recommended. As more
genes are discovered in the future, especially in families with lone atrial fibrillation, it
may become routine to perform genetic tests and treat prophylactically for the prevention
of development of AF.
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