Atrial Fibrillation: Classification, Mechanisms, and Triggers

ATRIAL FIBRILLATION
Abnet M , October 30,2017

Harrison’s
INTRODUCTION
 Atrial fibrillation is the most common sustained
arrhythmia
 AF is a supraventricular tachyarrythmia
characterized by disorganized, rapid, and
irregular atrial activation
 The ventricular response to the rapid atrial
activation is also irregular.
 Inan untreated patient, the ventricular rate also
tends to be rapid and is entirely dependent on the
conduction properties of the AV junction.
INTRODUCTION
 AF is the most common sustained cardiac rhythm
disturbance, increasing in prevalence with age.
 AF is often associated with structural heart

disease although a substantial proportion of
patients with AF have no detectable heart
disease.
 Hemodynamic impairment and thromboembolic

events related to AF result in significant
morbidity, mortality, and cost.
INTRODUCTION
 Although typically the rate will vary between 120
and 160 beats per minute, in some patients it can
be >200 beats per minute.
 In other patients, because of heightened vagal

tone or intrinsic AV nodal conduction properties,
the ventricular response is <100 beats per
minute and occasionally even profoundly slow.
CLASSIFICATION
 Paroxysmal AF*: self-terminating within 7 days
 Persistent AF*: one that lasts greater than
seven days or requires termination by a drug or
cardioversion electrically
 Long-standing persistent AF: continuous AF for
12 months or greater
 Permanent AF: should be used when both the
patient and physicians agree to not pursue
strategies to restore or maintain sinus rhythm
CLASSIFICATION
 First detected AF may be either paroxysmal or
persistent.
 These categories are not mutually exclusive*
 One patient may have several episodes of

paroxysmal AF and occasional persistent AF, or
the reverse.
 It is practical to categorize a given patient by

their most frequent presentation.
CLASSIFICATION
 The definition of permanent AF is often
arbitrary, and the duration refers both to
individual episodes and to how long the diagnosis
has been present in a given patient.
 Thus, in a patient with paroxysmal AF, episodes

lasting seconds to hours may occur repeatedly
for years.
 This terminology applies to episodes lasting more
than 30 seconds without a reversible cause
Paroxysmal AF can also be classified clinically on the basis of
the autonomic setting in which it most often occurs.
Approximately 25% of patients with paroxysmal AF have
vagotonic AF, in which AF is initiated in the setting of high
vagal tone, typically in the evening when the patient is relaxing
or during sleep. Drugs that have a vagotonic effect (such as
digitalis) can aggravate vagotonic AF, and drugs that have a
vagolytic effect (such as disopyramide) may be particularly
appropriate for prophylactic therapy. Adrenergic AF occurs in
approximately 10% to 15% of patients with paroxysmal AF in
the setting of high sympathetic tone, for example, during
strenuous exertion. In patients with adrenergic AF, beta
blockers not only provide rate control but can also prevent the
onset of AF. Most patients have a mixed or random form of
paroxysmal AF, with no consistent pattern of onset
CLASSIFICATION
 The term lone AF applies to individuals under 60
years old without clinical or echocardiographic
evidence of cardiopulmonary disease, including
hypertension.
 These patients have a favorable prognosis with
respect to thromboembolism and mortality.
 No need of anticoagulation and can be treated with rate
control
 Over time, patients move out of the lone AF category

due to aging or development of cardiac abnormalities
such as enlargement of the left atrium, and the risks
of thrombo-embolism and mortality rise.
CLASSIFICATION
 The term nonvalvular AF refers to cases without
rheumatic mitral valve disease, prosthetic heart
valve or valve repair.
CLASSIFICATION
 Secondary AF in the setting of acute myocardial
infarction (MI), cardiac surgery, pericarditis,
myocarditis, hyperthyroidism, or acute
pulmonary disease is considered separately.
 Then AF is not the primary problem, and

treatment of the underlying disorder usually
terminates the arrhythmia.
CLASSIFICATION
 Autonomic classification of Paroxysmal AF
 VagotonicAF and
 Adrenergic AF
 Vagotonic AF
~ 25% of paroxysmal AF
 AF is initiated in the setting of high vagal tone,
typically in the evening when the patient is relaxing
or during sleep.
 Drugs that have a vagotonic effect (such as digitalis)
can aggravate vagotonic AF, and drugs that have a
vagolytic effect (such as disopyramide) may be
particularly appropriate for prophylactic therapy.
CLASSIFICATION
 Adrenergic AF
~ 10% to 15% of paroxysmal AF
 For example, during strenuous exertion.
 In patients with adrenergic AF, beta blockers not
only provide rate control but can also prevent the
onset of AF.
 Most patients have a mixed or random form of

paroxysmal AF, with no consistent pattern of
onset.
CLASSIFICATION
 This wide range of presentation is mainly due to
the interaction between triggers and substrates
 AF is initiated by rapid firing (or triggers) from the
pulmonary veins (PV).
 Early in the course of AF the atrium is relatively

healthy and as a result sinus rhythm is
spontaneously restored.
CLASSIFICATION
 As the substrate remodels further over time,
atrial fibrillation no longer terminates
spontaneously and becomes persistent.
 With more extensive remodeling of the atrium it

becomes increasingly difficult to maintain sinus
rhythm and the patient and physician may agree
no longer to attempt to maintain sinus rhythm,
with the AF thereby being considered permanent
MECHANISM: DEFINITIONS OF TERMS
 Trigger ─ a rapidly firing focus often arising the in the
pulmonary veins that can initiate AF
 Triggered activity ─ One of three mechanisms of
cardiac arrhythmias (including automaticity and
reentry).
 Triggered activity refers to additional depolarizations, which
occur during or immediately following a cardiac
depolarization and may cause a sustained cardiac arrhythmia.
 Substrate ─ mechanical and anatomic structure of the
atria in which AF can occur
 Substrate remodeling ─ changes in the mechanical and
anatomic macro, micro, and ultra structure of the atrial
substrate that result from the development of AF and
increase the propensity for the development and
maintenance of AF over time
 Electrical remodeling ─ changes in the atrial
electrical properties (refractoriness and
conduction) that result from the development of
AF and increase the propensity for the
development and maintenance of AF over time
 Dispersion of refractoriness ─ a range of
differences in the refractory period properties
throughout the atrial tissue
 Spatial heterogeneity of refractoriness ─
dispersion of refractoriness manifest as
variability in refractoriness throughout the
atrial anatomy
 Complex fractionated electrograms ─ local
electrograms obtained from areas of the atrium
that are rapid, of low amplitude, and have multiple
components
 Reentry/reentrant mechanism ─ One of three
mechanisms of cardiac arrhythmias (including
automaticity and triggered activity).
 Reentry is the most common mechanism of cardiac
arrhythmias and refers to the presence of one or more
electrical circuit(s) in which electrical activation
proceeds in a circular fashion to complete a self-
sustaining circuit.
 Atrial anisotropy ─ conduction properties related to
directionality of conduction through atrial tissue.
 Normal atrial myocardium has the following
properties:
A short action-potential duration
 Cellular reactivation can occur rapidly due to the
short refractory period (in contrast to Purkinje fibers
and ventricular muscle)
 Very rapid electrical conduction can occur
 The refractory period shortens with increasing rate.
 In the aggregate, these electrophysiologic

properties permit the development of very
complex patterns of conduction and an extremely
rapid atrial rate as seen in AF
MECHANISM
 Conditions associated with AF
 Hypertension (60 to 80 percent)
 Cardiovascular disease, including cardiomyopathy,
valvular and coronary artery disease (25 to 30
percent)
 New York Heart Association class II-IV heart
failure (30 percent)
 Diabetes (20 percent)
 Age
NB. Each of the first three is associated with left atrial
dilatation, which is important in the development of a
substrate for AF and also may increase the probability of
electrical firing from the pulmonary veins
MECHANISM
 The mechanism for AF initiation and maintenance
is still debated
 However, it appears to be a complex interaction

between
 Drivers: responsible for the initiation and
 Substrates: the complex anatomic atrial substrate
that promotes the maintenance of multiple wavelets
of (micro)reentry
MECHANISM: TRIGGERS/DRIVERS
 Currently well established that these originate
predominantly from the atrialized musculature that
enters the pulmonary veins
 It represent either focal abnormal automaticity or
triggered firing that is somewhat modulated by
autonomic influences.
 Additionally, stretch can increase the propensity

for rapid firing from the PVs as a result of
stretch sensitive ion channels.
 It has been speculated that the mechanism of atrial
stretch may help explain the association between AF and
mitral regurgitation as well as various types of heart
failure
MECHANISM: TRIGGERS/DRIVERS
 Sustained forms of microreentry as drivers also
have been documented around the orifice of
pulmonary veins
 Such as other types of supraventricular arrhythmias
including atrioventricular nodal reentrant
tachycardia (AVNRT), orthodromic atrioventricular
(AV) reciprocating tachycardia, and atrial flutter*
 Nonpulmonary vein drivers also have been
demonstrated.
 Such as tissue near the PV, the superior vena cava,
or coronary sinus
MECHANISM:
MAINTENANCE/SUBSTRATE
 In patients with persistent AF, the prevailing
understanding of the mechanism is that, once
triggered, the arrhythmia is maintained
(sustained) by one or more abnormalities in the
atrial tissue.
 This process may explain why the failure rate of

pulmonary vein isolation is as high as 40 to 60
percent at one year:
 The trigger(s) may have been treated but not the
abnormalities that sustain AF once triggered
(initiated).
MECHANISM:
 Factors contributing to the maintenance of AF.
 Atrialremodelling (see slides below)
 Autonimic NS
 Autonomic NS
 Increasingly well recognized cause of maintenance
 Eg.
 Exercise-induced AF may be sympathetically driven
 AF in young patients with no structural heart disease: may
be due to parasympathetic NS
MECHANISM:
 Atrial remodeling*
 Structural remodeling: such as fibrosis
 Contractile Remodeling: Reasons for the post
fibrillatory contractile dysfunction is not clear
 Initial: Atrial stunning due to the shock
 Subsequent persistence often seen: Unclear
 Electricalremodeling: marked shortening of atrial

refractory periods thought to be due to alterations
in the expression of ion channels
MECHANISM:
 Atrial remodeling
 Structural remodelling in atrial myocytes include:
1. Increase in cell size,
2. Perinuclear accumulation of glycogen,
3. Central loss of sarcomeres (myolysis),
4. Alterations in connexin expression,
5. Changes in mitochondrial shape,
6. Fragmentation of sarcoplasmic reticulum,
7. Homogeneous distribution of nuclear chromatin, and
8. Changes in quantity and localization of structural cellular
proteins
MECHANISM: IN SUMMARY
 Rapid discharges from the pulmonary veins are
the most common triggers of AF and may also
play a perpetuating role, more so in paroxysmal
AF than in persistent AF.
 This is why pulmonary vein isolation is

particularly effective for elimination of
paroxysmal AF.
MECHANISM: IN SUMMARY
 In persistent AF, changes in the atrial
substrate, including interstitial fibrosis, which
contributes to slow, discontinuous, and
anisotropic conduction, may give rise to complex
fractionated atrial electrograms (CFAEs) and
reentry.
 Therefore, pulmonary vein isolation is rarely

sufficient to eliminate persistent AF, and
additional ablation of the atrial substrate is
usually necessary.
MECHANISM
 Although AF is common in the adult population, it
is extremely unusual in children unless structural
heart disease is present or there is another
arrhythmia that precipitates the AF, such as
paroxysmal SVT in patients with WPW syndrome
MECHANISMS OF AF AND
PATHOPHYSIOLOGY
EPIDEMIOLOGY
 AF is the most common arrhythmia in clinical
practice, accounting for approximately one-third
of hospitalizations for cardiac rhythm
disturbances.
 The incidence of AF increases with age such

that >5% of the adult population over 70 will
experience the arrhythmia.
EPIDEMIOLOGY
 As many patients are asymptomatic with AF, it is
anticipated that the overall incidence,
particularly that noted in the elderly, may be
more than double previously reported rates
 Occasionally, AF appears to have a well-defined

etiology, such as acute hyperthyroidism, an acute
vagotonic episode, or acute alcohol intoxication
(Holiday Heart).
EPIDEMIOLOGY
 Acute AF is particularly common during the
acute or early recovery phase of major vascular,
abdominal, and thoracic surgery, in which case
autonomic fluxes and/or direct mechanical
irritation potentiate the arrhythmia.
 AF also may be triggered by other

supraventricular tachycardias, such as AV nodal
reentrant tachycardia (AVNRT), and elimination
of these arrhythmias may prevent AF
recurrence.
CLINICAL FEATURES
 AF has clinical importance related to
1. The loss of atrial contractility*
2. The inappropriate fast ventricular response, and
3. The loss of atrial appendage contractility and
emptying leading to the risk of clot formation and
subsequent thromboembolic events.
 Symptoms from AF vary dramatically.

 Many patients are asymptomatic and have no
apparent hemodynamic consequences from the
development of AF.
CLINICAL FEATURES
 Other patients experience only minor
palpitations or sense irregularity of the pulse.
 Many patients, however, experience severe
palpitations
 The hemodynamic effect in patients can be quite

dramatic, depending on the need for normal
atrial contractility and the ventricular response.
 Hypotension,
pulmonary congestion, and anginal
symptoms may be severe in some patients.
CLINICAL FEATURES
 In patients with the LV diastolic dysfunction
that occurs with hypertension, hypertrophic
cardiomyopathy, or obstructive aortic valvular
disease, symptoms may be even more dramatic,
especially if the ventricular rate does not permit
adequate ventricular filling.
 Exercise intolerance and easy fatigability are

the hallmarks of poor rate control with exertion.
CLINICAL FEATURES
 Occasionally, the only manifestation of AF is
severe dizziness or syncope associated with the
pause that occurs upon termination of AF before
sinus rhythm resumes
Syncope can also occur during AF with a rapid
ventricular rate either because of
neurocardiogenic (vasodepressor) syncope that is
triggered by the tachycardia or because of a
severe drop in blood pressure secondary to a
reduction in cardiac output.
The hallmark of AF on physical examination is an
irregularly irregular pulse. Short R-R intervals
during AF do not allow adequate time for left
ventricular diastolic filling, which results in a low
stroke volume and the absence of palpable
peripheral pulse. This leads to a “pulse deficit,”
during which the peripheral pulse is not as rapid as
the apical rate. Other manifestations of AF on
physical examination are irregular jugular venous
pulsations and variable intensity of the first heart
sound
Polyuria can occur because of the release of atrial
natriuretic hormone. Many patients with
symptomatic paroxysmal AF also have
asymptomatic episodes, and some patients with
persistent AF have symptoms only intermittently,
thus making it difficult to accurately assess the
frequency and duration of AF on the basis of
symptoms. It is estimated that approximately 25%
of patients with AF are asymptomatic, more
commonly elderly patients and those with
persistent AF.
Such patients are sometimes erroneously
classified as having asymptomatic AF despite the
presence of fatigue or effort ntolerance. Because
fatigue is a nonspecific symptom, it may not be
clearly due to persistent AF. “Diagnostic
cardioversion” may be helpful by maintaining sinus
rhythm for at least a few days to determine
whether a patient feels better in sinus rhythm.
This can provide a basis to pursue a rhythm-
control versus rate-control strategy
ECG
 The ECG in AF is characterized by the lack of
organized atrial activity and the irregularly irregular
ventricular response.
 Occasionally, one needs to record from multiple ECG

leads simultaneously to identify the chaotic continuous
atrial activation.
ECG
 Features include:-
 Lack of discrete P waves.
 Fibrillatory or f waves are present at a rate that is
generally between 350 and 600 beats/minute; the f
waves vary continuously in amplitude, morphology,
and intervals.
 When the AF is of recent onset, the f waves are often
coarse (>2 mm); by comparison, the f waves are usually fine
(<1 mm) with AF of greater duration.
 When the arrhythmia is of long duration, the fibrillatory
waves may be inapparent
 Variabilityin the intervals between QRS complexes

is often termed “irregularly irregular.”
ECG
 When the ventricular rate during AF is very
rapid (>170 beats/min), the degree of
irregularity is attenuated and the rhythm can
seem regular
ECG
 The ventricular rhythm can be regular during AF
in patients with
A ventricular pacemaker who are fully paced and
 When a third-degree AV block with a regular escape
rhythm is present
 In these cases the diagnosis of AF is based on
the presence of f waves.
 When there is a third-degree AV block with a

junctional escape, a Wenckebach exit block in the AV
junction (as can occur during digitalis toxicity)
results in a regularly irregular ventricular rate
ECG
 Features ctd
 The f waves are of greater amplitude when there is
hypertrophy of left atrial myocardium and become
smaller with increasing atrial scarring and fibrosis.
 The amplitude of the fibrillatory waves does not
correlate with the actual atrial size.
 “Coarse” AF in which the amplitude of the f waves is
large (especially in lead V1) is more common in recent
onset AF and can be confused with atrial flutter or
multifocal atrial tachycardia
ECG
 Features ctd
 The ventricular rate (especially in the absence of AV
nodal blocking agents or intrinsic conduction disease)
usually ranges between 90 to 170 beats/min.
 The QRS complexes are narrow unless AV conduction

through the His Purkinje system is abnormal due to
functional (rate-related) aberration, pre-existing
bundle branch or fascicular block, or ventricular
preexcitation with conduction down the accessory
pathway.
ECG
ECG
 Lead V1 frequently shows the appearance of
organized atrial activity that mimics AFL
 This occurs because the crista terminalis serves as
an effective anatomic barrier to electrical
conduction, and the activation of the lateral right
atrium may be represented by a more uniform
activation wavefront that originates over the roof of
the right atrium
ECG
 ECG assessment of the PP interval (<200 ms) and
the chaotic P-wave morphology in the remaining
ECG leads will confirm the presence of AF.
 Evaluation of a patient with AF should include a

search for a reversible cause of the arrhythmia,
such as hyperthyroidism or anemia.
 An echocardiogram should be performed to

determine whether there is structural heart
disease.
ECG
 Fibrillatory or f waves are present at a rate that
is generally between 350 and 600 beats/minute;
the f waves vary continuously in amplitude,
morphology, and intervals.
 Persistent or labile hypertension should be

identified and treated.
TREATMENT
 Treatment for AF must take into account
 The clinical situation in which the arrhythmia is
encountered,
 The chronicity of the AF,
 The status of the patient's level of anticoagulation,
 Risk factors for stroke,
 The patient's symptoms,
 The hemodynamic impact of the AF, and
 The ventricular rate.
TREATMENT
 Management of patients with AF involves 4, not
mutually exclusive, objectives—
i. Treat underlying cause if present
ii. Rate control
iii. Prevention of thromboembolism/Anticoagulation
iv. Maintenance of sinus rhythm
TREATMENT: ACUTE RATE CONTROL
 Hemodynamically stable:
 Ratecontrol: IV diltiazem or esmolol
 Rhythm control: ?Cardioversion (see slides below)
 Hemodynamically unstable: immediate

transthoracic cardioversion
 Cardioversion should be preceded by TEE rule out a
left atrial thrombus if:-
 The AF > 48 hours duration
 If the duration is unclear and
 The patient is not already receiving an anticoagulant

 Cardioversion for hemodynamically stable
patients: the decision to restore sinus rhythm is
based on several factors, including
 Symptoms,
 Previous AF episodes,
 Age,
 Left atrial size, and
 Current antiarrhythmic drug therapy.
 If cardioversion is decided on for a
hemodynamically stable patient with AF that
does not appear to be self-limited, two
management decisions must be made:
 Early versus delayed cardioversion and
 Pharmacologic versus electrical cardioversion.

 Early versus delayed cardioversion
 Advantages of early cardioversion
 Rapid relief of symptoms,
 Avoidance of the need for TEE or therapeutic

anticoagulation for 3 to 4 weeks before cardioversion if it
is performed within 48 hours of the onset of AF, and
 Possibly a lower risk for early recurrence of AF because of

less atrial remodeling
 Early versus delayed cardioversion
 Reasons to defer cardioversion
 Unavailability of TEE in an unanticoagulated patient with
AF of unclear duration or a duration longer than 48 hours.
 Left atrial thrombus noted on TEE
 A suspicion (based on previous AF episodes) that AF will

convert spontaneously within a few days, or a correctable
cause of AF (e.g., hyperthyroidism).
 Pharmacologic versus electrical cardioversion.
 Advantages of pharmacologic cardioversion
 Not require general anesthesia or deep sedation.
 Lower probability of an immediate recurrence of AF than
with electrical cardioversion.
 Disadvantages of pharmacologic cardioversion

 Associated with a risk for adverse drug effects
 Not as effective as electrical cardioversion.
 Very unlikely to be effective when AF > 7 days

 Pharmacologic versus electrical cardioversion.
 Agents used for pharmacologic cardioversion
 Ibutilide, procainamide, and amiodarone.
 For AF episodes shorter than 2 to 3 days in duration, the

efficacy of these drugs is approximately 60% to 70% for
ibutilide, 40% to 50% for amiodarone, and 30% to 40% for
procainamide.
 To minimize the risk for QT prolongation and polymorphic

ventricular tachycardia (torsades depointes), use of
ibutilide should be limited to patients with an ejection
fraction higher than 35%.
 Pharmacologic versus electrical cardioversion
 Agents used for pharmacologic cardioversion
 Acute pharmacologic cardioversion of AF can also be
attempted with orally administered drugs in patients
without structural heart disease.
 The most commonly used oral agents for acute conversion

of AF are propafenone (300 to 600 mg) and flecainide (100
to 200 mg).
 Efficacy of transthoracic cardioversion= ~95%
 Biphasic waveform shocks convert AF more
effectively than do monophasic waveform shocks
 And allow the use of lower energy shocks, which result in a
lower risk for skin irritation.
 An appropriate first-shock strength using a biphasic
waveform is 150 to 200 J followed by higher output
shocks if needed.
 If a 360-J biphasic shock is unsuccessful, ibutilide
should be infused before another shock is delivered
because it lowers the defibrillation energy
requirement and improves the success rate of
transthoracic cardioversion
 Two types of failure of transthoracic cardioversion
1. Complete failure to restore sinus rhythm.
 An increase in shock strength or infusion of ibutilide
often results in successful cardioversion
2. Immediate recurrence of AF within a few seconds of

successful conversion to sinus rhythm.
 The incidence of this type: ~25% for episodes shorter
than 24 hours in duration and approximately 10% for

episodes longer than 24 hours in duration.
 Here, an increase in shock strength is of no value.
 If the patient has not been receiving an oral rhythm-
control agent, infusion of ibutilide may be helpful for

prevention of an immediate recurrence of AF
 Regardless of whether cardioversion is performed
pharmacologically or electrically, therapeutic
anticoagulation is necessary for 3 weeks or longer
before cardioversion to prevent thromboembolic
complications if the AF has been ongoing for more
than 48 hours.
 If the time of onset of AF is unclear, for the sake of
safety, the duration of AF should be assumed to be
greater than 48 hours
 These patients should receive therapeutic
anticoagulation for 4 weeks after cardioversion to
prevent the thromboembolic complications that may
occur because of atrial stunning.
 Regardless of whether cardioversion is performed
pharmacologically or electrically, therapeutic
anticoagulation is necessary for 3 weeks or longer
before cardioversion to prevent thromboembolic
complications if the AF has been ongoing for more
than 48 hours.
 If the time of onset of AF is unclear, for the sake of
safety, the duration of AF should be assumed to be
greater than 48 hours
 These patients should receive therapeutic
anticoagulation for 4 weeks after cardioversion to
prevent the thromboembolic complications that may
occur because of atrial stunning.
 If the duration of AF is known to be less than 48
hours, cardioversion can be performed without
anticoagulation.
 To improve the safety margin, it may be appropriate

to use a 24-hour cutoff for the AF duration, which
allows safe cardioversion without anticoagulation.
 When the duration of AF is longer than 48 hours or
unclear, an alternative to 3 weeks of therapeutic
anticoagulation before cardioversion is
anticoagulation with heparin and transesophageal
echocardiography to check for a left atrial
thrombus.
 If no thrombi are seen, the patient can safely be

cardioverted but still requires 4 weeks of
therapeutic anticoagulation after cardioversion to
prevent thromboembolism related to atrial stunning
 The rationale for one month of therapeutic
anticoagulation after cardioversion
1. In most of the trials virtually all were kept on it for at
least three weeks
2. Many patients have recurrent episodes of AF.
 Up to 90 percent of these episodes are asymptomatic
 And asymptomatic episodes lasting more than 48 hours
are not uncommon, occurring in 17%.

3. Recovery of atrial mechanical function may be delayed for
several weeks (i.e. atrial stunning)
 The major clinical benefit of the transesophageal
echocardiography–guided approach over the
conventional approach is that sinus rhythm is
restored several weeks sooner.
 When compared with the conventional approach, the

transesophageal echocardiography–guided approach
has not been found to reduce the risk for stroke or
major bleeding or to affect the proportion of
patients still in sinus rhythm at 8 weeks after
cardioversion.
 Urgent Cardioversion
 Clinical
indications for emergent cardioversion of AF
are rare
 However, in the setting of hemodynamic instability

due to rapid AF that is refractory to pharmacologic
support, the need for restoration of sinus rhythm
may take precedence over the need for protection
from thromboembolism.
 Urgent Cardioversion
 If
feasible, the patient should receive precardioversion
heparin bolus.
 Performing a TEE in this setting would be reassuring if no

thrombus is seen; however, in the urgent setting, postponing
cardioversion because of the presence of thrombus may not be
an option.
 Furthermore, a patient who has severe clinical instability due

to AF is less likely to have been in AF for more than 48 hours.
TREATMENT: PREVENTION OF
THROMBOEMBOLISM
 Anticoagulation is of particular importance in
patients who have known risk factors for stroke
associated with AF.
 Because of the risk for hemorrhage during

warfarin therapy, its use should be limited to
patients whose risk for thromboembolic
complications is greater than their risk for
hemorrhage.
 Therefore, it is useful to risk-stratify patients with
AF to identify appropriate candidates for warfarin
therapy.
THROMBOEMBOLISM
 Risk factors are classified into three categories:
Low risk, Moderate risk and High risk
Less validated Moderate risk factors High risk factors

or weaker risk
factors
Female gender Age ≥75 years -Previous stroke, TIA
Age 65-74 years Hypertension or embolism
Coronary artery Heart failure -Mitral stenosis
disease LV ejection fraction -Prosthetic heart
Thyrotoxicosis ≤35% valve
Diabetes mellitus
THROMBOEMBOLISM
Risk Category Recommended Therapy
No risk factors Aspirin, 81-325 mg daily
One moderate risk factor Aspirin, 81-325 mg daily or
Warfarin
(INR 2.0 to 3.0, target 2.5)
Any high risk factor or Warfarin (INR 2.0 to 3.0,
more than 1 moderate risk target 2.5)*
factor
THROMBOEMBOLISM
 Risk factors that predict stroke in patients with
nonvalvular atrial fibrillation include
A history of previous stroke or transient ischemic
attack (relative risk, 2.5),
 Diabetes (relative risk, 1.7),
 History of hypertension (relative risk, 1.6), and
 Increasing age (relative risk, 1.4 for each decade).
 Patients with any of these risk factors have an

annual stroke risk of at least 4 percent if
untreated.
THROMBOEMBOLISM
 When patients with AF and a previous ischemic
stroke are treated with aspirin, the risk for
another stroke is very high, in the range of 10%
to 12% per year.
 At the other end of the risk spectrum are

patients with lone AF, whose cumulative 15-year
risk for stroke was reported to be in the range
of 1% to 2%.
THROMBOEMBOLISM
 Patients with mitral stenosis and atrial fibrillation
have a 4 to 6 percent incidence of embolism per
year.
 Patients whose only stroke risk factor is congestive

heart failure or coronary artery disease have
stroke rates approximately three times higher than
patients without any risk factors.
 Left ventricular (LV) dysfunction and a left atrial

size larger than 2.5cm/m2 on echocardiographic
examination are associated with thromboembolism.
THROMBOEMBOLISM
 Patients with atrial fibrillation who do not have
any of the preceding risk factors have a low
stroke risk (2 percent/year or less) and can be
protected from stroke with aspirin.
 Therefore, the risk of stroke in patients with

lone atrial fibrillation—that is, idiopathic atrial
fibrillation in the absence of any structural
heart disease or any of the risk factors
discussed previously—is relatively low
THROMBOEMBOLISM
 The risk of stroke in patients with nonvalvular
atrial fibrillation is five to seven times greater
than that in controls without atrial fibrillation.
 The CHADS2 (Cardiac Failure, Hypertension,

Age, Diabetes, Stroke [Doubled]) stroke risk
index integrates elements from several of these
schemes.
THROMBOEMBOLISM
 In patients with nonvalvular AF, prior stroke or
TIA is the strongest independent predictor of
stroke, significantly associated with stroke in all
6 studies in which it was evaluated, with
incremental relative risk between 1.9 and 3.7
(averaging approximately 3.0).
 All patients with prior stroke or TIA require

anticoagulation unless contraindications exist in a
given patient.
THROMBOEMBOLISM
 Patient age is a consistent independent predictor
of stroke, but older people are also at increased
risk for anticoagulant-related bleeding
 In patients older than 75 years, anticoagulation

should be used with caution and monitored
carefully to keep the INR less than 3.0 because
of the risk of intracranial hemorrhage
THROMBOEMBOLISM
CHADS2 Risk Criteria Score

Prior stroke or TIA 2
Age >75 years 1
Hypertension 1
Diabetes mellitus 1
Heart failure 1
THROMBOEMBOLISM
 However, recent studies have demonstrated that
the CHA2DS2-VASc score more accurately
discriminates low-risk from intermediate-risk
patients
Risk factor Score
Congestive heart failure/LV dysfunction 1
Hypertension 1
Age ≥75 2
Diabetes mellitus 1
Stroke/TIA/thrombo-embolism 2
Vascular disease* 1
Age 65 to 74 1
Sex category (ie, female sex) 1
Maximum Score 9
THROMBOEMBOLISM
Adjusted stroke rate according to CHA 2 DS 2 -VASc score
Adjusted stroke
CHA 2 DS 2 -VASc Patients
rate
score (n = 7329)
(percent/year) •
0 1 0 percent
1 422 1.3 percent
2 1230 2.2 percent
3 1730 3.2 percent
4 1718 4.0 percent
5 1159 6.7 percent
6 679 9.8 percent
7 294 9.6 percent
8 82 6.7 percent
9 14 15.2 percent
THROMBOEMBOLISM
 The annual risk for stroke is zero or close to
zero when the CHA2DS2-VASc score is 0, as
opposed to approximately 2% when the CHADS2
score is 0.
 A score of 1 is associated with an annual stroke

risk of approximately 3% with the CHADS2
score versus 0.7% with the CHA2DS2-VASc
score
THROMBOEMBOLISM
 Renal Failure
A large-scale study demonstrated that renal failure
is also an independent risk factor for stroke in
patients with AF.
 It may be appropriate to take renal failure into

account in evaluating the risk profile of a patient
with AF.
THROMBOEMBOLISM
 Renal Failure- ATRIA study
THROMBOEMBOLISM
 Paroxysmal vs Persistent AF
 By definition, the burden of AF is greater in patients
with persistent AF than in those with paroxysmal AF.
 It may seem reasonable to assume that the risk for
stroke is lower in patients with occasional episodes
of self-limited AF than in those with AF
continuously.
 However, the data available in fact indicate that the
risk for thromboembolic complications is the same in
patients with paroxysmal and persistent AF.
THROMBOEMBOLISM
 Paroxysmal vs Persistent AF
 Even 15 minutes of AF may be long enough to result
in local cardiac platelet activation and endothelial
dysfunction, which predispose to thrombus formation
during an acute episode of AF
 Therefore, the type of AF should not be taken into

account in risk stratifying AF patients for
thromboembolic risk.
THROMBOEMBOLISM
 Assessing bleeding risk
 The scoring system with the best balance of
simplicity and accuracy is the HAS-BLED score.
 The components are

 Hypertension,
 Abnormal renal or liver function,
 Stroke,
 Bleeding history or predisposition,
 Labile international normalized ratio (INR),
 Older age (>75 years), and
 Concomitant drug (antiplatelet agent or nonsteroidal anti-
inflammatory drug) or alcohol use.

THROMBOEMBOLISM
 Assessing bleeding risk
 Each of these components is worth 1 point.
 As the score increases from 0 to the maximum of 9,

there is a stepwise increase in the risk for bleeding
in patients treated with warfarin.
 For example, in one study the annual rate of major

bleeding was
 1.1% in patients with a HAS-BLED score of 0,
 3.7% with a score of 3, and
 12.5% with a score of 5.

THROMBOEMBOLISM
THROMBOEMBOLISM
 HAS-BLED Score
 Two large-scale cohort studies: the CHA2DS2-VASc
and HASBLED scores were calculated for each
patient.
 In both studies, warfarin was associated with a net clinical
benefit except when the CHA2DS2-VASc score was 0.
 In patients with a CHA2DS2-VASc score of 1 or higher,

the risk for stroke in the absence of warfarin exceeded
the number of bleeding complications during treatment
with warfarin.
THROMBOEMBOLISM
 HAS-BLED Score
 The results of these large cohort studies
notwithstanding, the decision to institute anticoagulation
in a patient in clinical practice should be individualized.
 At times it may be appropriate to not initiate
anticoagulation in a patient with a CHA2DS2-VASc score
of 1 or higher.
 For example, the annual risk for stroke in a patient with
a CHA2DS2-VASc score of 2 is approximately 2%, which
usually justifies the use of warfarin.
 However, if that patient has a HAS-BLED score of 5 or
higher, which is associated with an annual risk for major
bleeding of 12% or higher, it would be imprudent to treat
that patient with warfarin.
THROMBOEMBOLISM
 HAS-BLED Score- Only for Warfarin?
 It should be noted that the HAS-BLED score was
developed and validated in patients in whom warfarin
was used for anticoagulation.
 Except for labile INR, it is likely that the
components of the HAS-BLED score also apply to
patients in whom a direct thrombin inhibitor or
factor Xa inhibitor is used for anticoagulation.
 However, the predictive value of the HAS-BLED
score in patients treated with one of the newer
antithrombotic agents has not yet been determined.
THROMBOEMBOLISM
 Aspirin
 Aspirin does not prevent thromboembolic
complications as effectively as warfarin does in
patients with AF.
 In a meta-analysis of five randomized clinical trials,
aspirin reduced the risk for stroke by only 18%
 In a recent large cohort study of patients with
nonvalvular AF, aspirin had no therapeutic efficacy in
preventing strokes.
 Therefore, if aspirin is used for prophylactic
therapy, it should be used only in patients at lowest
risk for thromboembolic complications (CHA2DS2-
VASc score of 0).
THROMBOEMBOLISM
 Aspirin
 The most recent guidelines of the ESC guidelines
recommend
 No antithrombotic therapy when the CHA2DS2-VASc = 0
and
 An individualized decision regarding no antithrombotic
therapy versus an oral anticoagulant when the CHA2DS2-

VASc score is 1
 This is because of
 The negligible therapeutic effect of aspirin,
 A risk for bleeding complications that is close to the risk
associated with oral anticoagulants, and

 The ability of the CHA2DS2-VASc score to accurately
identify low-risk patients

THROMBOEMBOLISM
 Aspirin + Clopidogrel
 In patients with a CHADS score higher than 1 who
2
are not able to tolerate anticoagulation with

warfarin, combination therapy with aspirin and the
platelet inhibitor clopidogrel is more efficacious than
aspirin alone for prevention of thromboembolic
complications
 ACTIVE-A trial- RCT of ASA vs ASA + Clopidogrel

THROMBOEMBOLISM
 ACTIVE-A trial
 Involved patients who were not suitable candidates for
anticoagulation with warfarin
 The primary outcome was a composite of stroke,

myocardial infarction, systemic embolism, and vascular
death.
 When compared with placebo, clopidogrel reduced the risk

for stroke by 28% and risk for the primary outcome by 11%
but increased the risk for major hemorrhage.
THROMBOEMBOLISM
 ACTIVE-A trial
 For every 1000 patients treated with the combination of
aspirin plus clopidogrel instead of aspirin alone, 28 strokes
(17 fatal or disabling) and 6 myocardial infarctions would
be prevented
 This is at a cost of 20 major bleeding episodes (3 fatal).
 Therefore, in high-risk patients who are not suitable

candidates for warfarin, the benefits of combination
therapy with aspirin plus clopidogrel outweigh the
risk.
THROMBOEMBOLISM
 Warfarin
 Metanalysis: Warfarin vs Placebo 61% risk
reduction
 The target INR should be 2.0 to 3.0.
 Provides the best balance between stroke prevention and
hemorrhagic complications
 Maintaining the INR at a level of 2.0 or higher is
important
 Even a relatively small decrease in the INR from 2.0
to 1.7 more than doubles the risk for stroke.
THROMBOEMBOLISM
 Warfarin
 Furthermore, the data available indicate that the
combination of aspirin and low-intensity
anticoagulation with warfarin is inferior to warfarin
in the standard therapeutic range for stroke
prevention.
 Annual risk for a major hemorrhage: 1% to 2%

 And a strong predictor of major bleeding events is an INR
higher than 3.0.
THROMBOEMBOLISM
 Warfarin- Time in Therapeutic Range (TTR)
 In a retrospective analysis of the SPORTIF III and
V trials, patients assigned to warfarin therapy were
categorized as having poor, moderate, or good
control of anticoagulation (therapeutic INRs less
than 60 percent, 60 to 75 percent, or greater than
75 percent of the time, respectively)
THROMBOEMBOLISM
THROMBOEMBOLISM
 NOACs
 Direct thrombin inhibitors and factor Xa inhibitors
have several advantages over vitamin K antagonists
such as warfarin, the most notable being a fixed
dosing regimen, which eliminates the need for
monitoring of a laboratory test such as the INR*
 Dabigatranand Rivaroxaban were approved by the

FDA in 2010 and 2011, respectively
 Another factor Xa inhibitor, apixaban, was expected

to gain Food and Drug Administration approval in
2013
THROMBOEMBOLISM
 NOACs
 Randomized clinical trials have demonstrated that
each of these three new oral anticoagulants is
noninferior or superior to warfarin in efficacy and
safety.
 Thesestudies included patients with nonvalvular AF

who had risk factors for stroke.
THROMBOEMBOLISM
 NOACs- Major Trials
 Dabigatran RE-LY study
 Rivaroxaban  ROCKET-AF Trial
 Apixaban  ARISTOTLE
M
THROMBOEMBOLISM
 NOACs- Dabigatran
 RE-LY Trial
 18113 patients to Warfarin vs Dabigatran 110mg vs 150mg
 Dabigatran given at a dose of 110 mg was associated with

rates of stroke and systemic embolism that were similar to
those associated with warfarin, as well as lower rates of
major hemorrhage.
 Dabigatran administered at a dose of 150 mg, as compared

with warfarin, was associated with lower rates of stroke
and systemic embolism but similar rates of major
hemorrhage.
THROMBOEMBOLISM
 NOACs- Rivaroxaban
 ROCKET-AF study
 Rivaroxaban at a dose of 20 mg once daily was noninferior
to warfarin for prevention of stroke/systemic embolism
and was associated with a risk for major bleeding that did
not differ from that of warfarin.
 However, intracranial hemorrhage and fatal bleeding were

less common with rivaroxaban.
THROMBOEMBOLISM
 NOACs- Apixaban
 ARISTOTLE study
 Apixaban at a dose of 5 mg twice daily was superior to
warfarin in prevention of stroke/systemic embolism and

was associated with a lower risk for hemorrhagic
complications and lower mortality
THROMBOEMBOLISM
 NOACs prior to Cardioversion?
 An issue that has not been addressed in a
randomized clinical trial is whether the newer oral
anticoagulants provide adequate protection from the
thromboembolic complications of transthoracic
cardioversion.
 Although not studied prospectively, the safety of

dabigatran in patients undergoing cardioversion was
evaluated in a post hoc analysis of the RE-LY study
THROMBOEMBOLISM
A subset of 1336 patients underwent cardioversion
after 3 weeks or more of treatment with dabigatran,
150 mg twice daily, or doseadjusted warfarin with an
INR of 2.0 to 3.0.
 The stroke/systemic embolism rate at 30 days did

not differ significantly between the dabigatran
group (0.3%) and the warfarin group (0.6%).
THROMBOEMBOLISM
 There was also no difference between the two
groups in the rate of major bleeding (0.6% in both
groups).
 These data suggest that dabigatran is a safe and
effective alternative to warfarin in patients
requiring cardioversion.
 However, because patient compliance and a
therapeutic effect of dabigatran cannot be
confirmed by laboratory testing, a precardioversion
transesophageal echocardiogram to rule out a left
atrial thrombus may be appropriate more often in
patients treated with dabigatran than in those
treated with warfarin.
THROMBOEMBOLISM
 X-VeRT trial of Rivaroxaban
 Underpowered o provide statistically rigorous results.
 However, it showed a trend towards lower incidences of
thromboembolic events and major bleeding events in favour

of rivaroxaban
 Thus it appears to be an effective and safe alternative
to VKA and may allow more prompt cardioversion
 Ongoing trials
 EMANATE trial of Apixaban
 ENSURE-AF trial of Edoxaban
THROMBOEMBOLISM
 NOACs- Perioperative bleeding risk
 The onset of action of dabigatran, rivaroxaban, and
apixaban s approximately 1.5 to 2 hours after a dose.
 The half-lives of dabigatran and apixaban range
between 10 and 16 hours, and the half-life of
rivaroxaban is 5 to 9 hours.
 These anticoagulants lose most of their effect by 24
hours after discontinuation.
 The rapid onset of action and washout eliminate the
need for bridging therapy with heparin when
treatment with one of the new anticoagulants is
interrupted for a surgical or invasive procedure.
THROMBOEMBOLISM
 NOACs- Perioperative bleeding risk
 In a recent study
 Dabigatran withheld on the morning of the procedure.
 Warfarin uninterrupted- INR of 2.0 to 3.0
 Major hemorrhagic complications occurred

significantly more often in the dabigatran group (6%)
than in the warfarin group (1%).
 The results of this study demonstrate that

dabigatran should be withheld for at least 24
hours before an invasive or surgical procedure.
THROMBOEMBOLISM
 Low-molecular-weight heparin
 Longer half-life than unfractionated heparin does
and a predictable antithrombotic effect that is
attained with a fixed dosage administered
subcutaneously twice a day.
 Costly for long term use
 Typicallyused as a temporary bridge to therapeutic

anticoagulation
THROMBOEMBOLISM
 Anticoagulation for emergency cardioversion
 Immediate cardioversion should not be delayed to
deliver therapeutic anticoagulation
 But intravenous unfractionated heparin or

subcutaneous injection of a low-molecular-weight
heparin should be initiated before cardioversion by
direct-current countershock or intravenous
antiarrhythmic medication.
THROMBOEMBOLISM
 Anticoagulation for elective cardioversion
 For patients who do not warrant early cardioversion
of AF, anticoagulation should be maintained for at
least 3 weeks with the INR confirmed to be >1.8 on
at least two separate occasions before attempts at
cardioversion.
 Heparin is maintained routinely until the INR is 1.8 with
the administration of warfarin after the TEE.
 Anticoagulation must then be maintained for at least

1 month after restoration of sinus rhythm if the
duration of AF has been prolonged or is unknown
THROMBOEMBOLISM
 The absence of symptoms frequently leads to
stopping anticoagulant therapy, and
asymptomatic AF without anticoagulation
increases stroke risk.
 Any consideration for stopping anticoagulation

therefore must be accompanied by a prolonged
period of ECG monitoring to document
asymptomatic AF.
EXCISION OR CLOSURE OF THE LEFT
ATRIAL APPENDAGE( NOT
APPROVED)
 Approximately 90% of left atrial thrombi form in
the appendage
 Therefore successful excision or closure of the left

atrial appendage should markedly reduce the risk for
thromboembolic complications in patients with AF.
 Rate of successful closure varies
 It is likely that the left atrial appendage closure

device will have its greatest utility in high-risk
patients with AF who cannot tolerate or refuse to
take an oral anticoagulant.
TREATMENT
CHRONIC RATE CONTROL
 Several randomized studies have compared a rate-control
strategy with a rhythm-control strategy in patients with
AF.
 AFFIRM Study
 The largest study by far; N= 4060; Mean age of 70 years who had
AF for 6 hours to 6 months.
 At 5 years of follow-up, the prevalence of sinus rhythm was 35%
in the rate-control arm and 63% in the rhythm-control arm.
 No significant difference was noted between the two study arms
in total mortality, stroke rate, or quality of life.
 The percentage of patients requiring hospitalization was
significantly lower in the rate-control arm (73%) than in the
rhythm-control arm (80%), and the incidence of adverse drug
effects such as torsades de pointes was also significantly lower in
the rate-control arm (0.2% versus 0.8%).
TREATMENT
 The authors of the AFFIRM study concluded
that there is no survival advantage of a rhythm
control strategy over a rate-control strategy
and that a rate-control strategy has advantages
such as a lower probability of hospitalization and
adverse drug effects
TREATMENT
 Post hoc analysis of the AFFIRM study
 Sinus rhythm was found to be independently
associated with lower mortality (hazard ratio, 0.53),
and
 Antiarrhythmic drug therapy was independently
associated with increased mortality (hazard ratio,
1.49).
 Therefore, the potential benefit of maintaining sinus
rhythm with antiarrhythmic drugs was negated by
the adverse effects of the antiarrhythmic drug
therapy.
 This suggested that therapies that maintain sinus
rhythm without major adverse effects may have a
beneficial effect on survival.
TREATMENT
 The results of the AFFIRM study should not be applied
routinely to all patients with AF.
 The decision to pursue a rhythm-control strategy versus a
rate-control strategy should be individualized, with
several factors being taken into account, including
 The nature, frequency, and severity of symptoms;
 The length of time that AF has been present continuously in
patients with persistent AF;
 Left atrial size;
 Comorbid conditions;
 The response to previous cardioversions;
 Age;
 The side effects and efficacy of the antiarrhythmic drugs
already used to treat the patient; and
 The patient’s preference
TREATMENT
 The AFFIRM study convincingly demonstrated that a rate-
control strategy is preferable to a rhythm-control strategy
in asymptomatic or minimally symptomatic patients 65 years
or older.
 In patients with persistent AF, it is reasonable to attempt to

restore sinus rhythm with antiarrhythmic drug therapy or
transthoracic cardioversion at least once in individuals 65
years or younger and in those 65 years or older whose AF is
symptomatic despite adequate heart rate control.
 If the AF has been continuous for longer than 1 year or if

the left atrial diameter is very large (>5.0 cm), there is a
high probability of an early recurrence of AF, and this should
be taken into account in deciding on the best strategy
TREATMENT
 After cardioversion, the decision to maintain the
patient on antiarrhythmic drug therapy to delay the
next episode of AF is based on
 The patient’s preference,
 The perceived risk for early recurrence of AF, and
 The duration of sinus rhythm between previous
cardioversions.
 Treatment by cardioversion without daily
antiarrhythmic drug therapy is acceptable if the
episodes of AF are separated by at least 6 months.
 Treatment with a rhythm-control drug is usually

appropriate when AF recurs within a few months of
cardioversion.
TREATMENT
 A pharmacologic rhythm-control strategy need not
necessarily consist of daily drug therapy.
 Episodic drug therapy (the “pill-in-thepocket” approach) is
useful for patients whose episodes of AF are relatively
infrequent.
 This is reasonable option for patients who are clearly

aware of the onset and termination of the AF episodes and
who have lone AF or only minimal structural heart disease
 A typical drug regimen consists of a class IC drug

(flecainide or propafenone) plus a short-acting beta
blocker (e.g., propranolol) or calcium channel blocker (e.g.,
verapamil) for rate control
TREATMENT
 Many patients with infrequent episodes prefer
this approach because it eliminates the
inconvenience, cost, and possible side effects of
daily prophylactic therapy.
 However, patients who are disabled by severe

symptoms during AF may prefer daily
prophylactic therapy even if the episodes are
infrequent
TREATMENT
 Many patients with symptomatic AF also have
asymptomatic episodes.
 Therefore, daily antithrombotic therapy to
prevent thromboembolic events is appropriate
for all patients being treated for recurrent AF,
whether it is persistent or paroxysmal and
whether a rhythm-control or rate-control
strategy is used.
 The choice of no therapy, an oral anticoagulant,
aspirin, or the combination of aspirin plus
clopidogrel should be dictated by an analysis of
risk factors and drug tolerance.
TREATMENT
 Pharmacologic rate control
 An excessively rapid ventricular rate during AF often
results in uncomfortable symptoms and decreased effort
tolerance and can cause a tachycardia-induced
cardiomyopathy if it is sustained for several weeks to
months.
 Heart rate control must be assessed both at rest and
during exertion.
 Target HR
 At rest: 60 to 75 beats/min.
 Mild to moderate exertion (e.g., rapid walking): 90 to 115bpm
 Strenuous exercise: 120 to 160 beats/min.
 Optimal assessment of the degree of heart rate control

is provided by an ambulatory 24-hour Holter recording
or an exercise test
TREATMENT
 Pharmacologic rate control
 Oral agents available for long-term heart rate control in
patients with AF are digitalis, beta blockers, calcium
channel antagonists, and amiodarone.
 The first-line agents for rate control are beta blockers
and the calcium channel antagonists verapamil and
diltiazem.
 A combination is often used to improve efficacy or to
limit side effects by allowing the use of smaller dosages
of the individual drugs.
 In patients with sinus node dysfunction and tachy-brady
syndrome, use of a beta blocker with intrinsic
sympathomimetic activity (pindolol, acebutolol) may
provide rate control without aggravating the sinus
bradycardia
TREATMENT
 Pharmacologic rate control- Place of Digitalis
 Digitalis may adequately control the rate at rest but
often does not provide adequate rate control during
exertion.
 Its use is appropriate in patients with systolic heart
failure, in whom digitalis has been shown to improve
outcomes such as heart failure and all-cause
hospitalization.
 In patients with the vagotonic form of paroxysmal
AF, the vagotonic effect of digitalis may promote
AF.
 Furthermore, in patients without systolic heart
failure, use of a digitalis glycoside may have a
deleterious effect on survival.
TREATMENT
 Pharmacologic rate control- Place of Digitalis
 In a large anticoagulation trial that compared
warfarin with a direct thrombin inhibitor (SPORTIF
III-IV), digitalis was found to be independently
associated with a 53% higher risk for all-cause
mortality
 Although this was demonstrated by post hoc analysis

and not by a randomized comparison of digitalis
versus placebo, the results are of enough concern to
limit the use of digitalis to patients with heart
failure.
TREATMENT
 Pharmacologic rate control- Place of Amiodarone
 Amiodarone: much less frequently used for rate
control than the others
 This is because of the risk for organ toxicity associated
with long-term therapy.
 Amiodarone may be an appropriate choice for rate

control if the other agents are not tolerated or are
ineffective.
 As an example, amiodarone would be an appropriate choice
for a patient with persistent AF, heart failure, and
reactive airway disease who cannot tolerate either a
calcium channel antagonist or a beta blocker and who has a
rapid ventricular rate despite treatment with digitalis.
TREATMENT
 Strict vs Lenient control- RACE II Trial
 N= 614
 Lenient rate-control strategy: resting rate <110
beats/min
 Strict rate-control strategy: resting heart rate <80
beats/min, rate during moderate exercise <110
beats/min
 Primary composite outcome: cardiovascular death,
heart failure hospitalizations, stroke, embolism,
major bleeding episodes, and major arrhythmic
events.
 The heart rate target was achieved in 98% of
patients in the lenient rate-control group versus 67%
in the strict rate-control group.
Absolute difference of −2.0 percentage points
(90% CI, −7.6 to 3.5)
TREATMENT
 Strict vs Lenient control- RACE II Trial
 The results suggest that strict rate control has no
advantages over lenient rate control.
 However, the study did not present data on the

severity of symptoms, exercise capacity, or left
ventricular ejection fraction, and follow-up was
limited to 3 years.
 Strict rate control is still often an appropriate goal

for relief of symptoms, improvement in functional
capacity, and avoidance of tachycardia-induced
cardiomyopathy during long-term follow-up.
TREATMENT
 Pharmacologic rhythm control
 All antiarrhythmic agents except amiodarone:
 Similar efficacy
 Associated with a 50% to 60% reduction in the odds of
recurrent AF during 1 year of treatment.
 Amiodarone
 Stands out as having higher efficacy than the others is
amiodarone.
 In studies that directly compared amiodarone with sotalol or
class I drugs, amiodarone was 60% to 70% more effective

in suppressing AF.
 However, because of its risk for organ toxicity, amiodarone
is not appropriate first-line drug therapy for many patients

with AF.
TREATMENT
 Pharmacologic rhythm control
 Because the efficacy of rhythm-control agents other
than amiodarone is in the same general range,
selection of an antiarrhythmic drug to prevent AF is
often dictated by the issues of safety and side
effects*
TREATMENT
 Pharmacologic rhythm control- Ventricular
proarrhythmia
 ClassIA agents (quinidine, procainamide,
disopyramide) and class III agents (sotalol,
dofetilide, dronedarone, amiodarone)
 Via QT prolongation and polymorphic ventricular
tachycardia (torsades de pointes).
 Risk factors for this type of proarrhythmia include female

sex, left ventricular dysfunction, and hypokalemia.
 The risk for torsades de pointes appears to be much lower

with dronedarone and amiodarone than with the other class
III drugs.
TREATMENT
 Pharmacologic rhythm control- Ventricular
proarrhythmia
 Class IC agents (flecainide and propafenone)
 Manifested as monomorphic ventricular tachycardia,
sometimes associated with widening of the QRS complex
during sinus rhythm, but not with QT prolongation.
 Published studies indicate that the drugs most likely

to result in ventricular proarrhythmia are quinidine,
flecainide, sotalol, and dofetilide.
 In controlled studies, these agents increased the risk for
ventricular tachycardia by a factor of 2 to 6.
TREATMENT
 Pharmacologic rhythm control- Choice of
antiarrythmics
 The best options for drug therapy to suppress AF
depend on the patient’s comorbid conditions.
 Lone AF or minimal heart disease (e.g., mild left
ventricular hypertrophy)
 First line: Flecainide, propafenone, sotalol, and dronedarone
 Second line: Amiodarone and dofetilide (if the firstline
agents are ineffective or not tolerated)
 SubstantialLVH (LV wall thickness >13 mm) the

hypertrophy heightens the risk for ventricular
proarrhythmia
 The safest choice for drug therapy is amiodarone.
TREATMENT
 Pharmacologic rhythm control- Choice of
antiarrythmics
 Coronary artery disease
 Several of the class I drugs have been found to increase
the risk for death
 Safest 1st line: Dofetilide, sotalol, and dronedarone
 Second line: Amiodarone
 Heart failure
 Several antiarrhythmic drugs have been associated with
increased mortality,
 Only two drugs known to have a neutral effect on survival
are amiodarone and dofetilide

TREATMENT
 Pharmacologic rhythm control- Other agents*
 ACEIs
 Statins
 Omega-3 polyunsaturated fatty acids (PUFAs)
TREATMENT
 NONPHARMACOLOGIC MANAGEMENT OF AF
 P. 974
THANK YOU!
 Ventricular rate control for acute AF is best
established with beta blockers and/or the calcium
channel blocking agents verapamil and diltiazem.
 “Measurement of the heart rate at rest and control of the rate

using pharmacological agents (either a beta blocker or
nondihydropyridine calcium channel antagonist, in most cases)
are recommended for patients with persistent or permanent
AF.”
 The route of administration and dose will be

dictated by the ventricular rate and clinical status.
 In the absence of preexcitation, intravenous administration
of beta blockers (esmolol, metoprolol, or propranolol) or
nondihydropyridine calcium channel antagonists
(verapamil, diltiazem) is recommended to slow the
ventricular response to AF in the acute setting, exercising
caution in patients with hypotension or heart failure (HF).
 Digoxin may add to the rate-controlling benefit

of the other agents but is uncommonly used as a
stand-alone agent, especially in acute AF.
 Intravenous administration of digoxin or
amiodarone is recommended to control the heart
rate in patients with AF and HF who do not have an
accessory pathway.
 In patients with decompensated HF and AF,
intravenous administration of a
nondihydropyridine calcium channel
antagonist may exacerbate hemodynamic
compromise and is not recommended.
 Digoxin is effective following oral administration to

control the heart rate at rest in patients with AF and
is indicated for patients with HF, left ventricular (LV)
 A combination of digoxin and either a beta blocker
or nondihydropyridine calcium channel antagonist is
reasonable to control the heart rate both at rest and
during exercise in patients with AF.
 Intravenous amiodarone can be useful to control the

heart rate in patients with AF when other measures
are unsuccessful or contraindicated.
 Oral amiodarone may be administered as
well.
Classification of antiarrhythmic drugs

Class I—agents that primarily block inward sodium current;
Class IA agents also prolong action potential duration;
Class II—antisympathetic agents;
Class III—agents that primarily prolong action potential duration;
Class IV—calcium channel-blocking agents
Commonly Used Antiarrhythmic Agents—IV Dose Range/Primary Indication
Drug Loading Maintenance Primary Indication Class
Adenosine 6–18 mg (rapid bolus) N/A Terminate reentrant SVT —
involving AV node
Amiodarone 15 mg/min for 10 min, 0.5–1 mg/min AF, AFL, SVT, VT/VF III
1 mg/m for 6 h
Digoxin 0.25 mg q2h until 1 0.125–0.25 mg/d AF/AFL rate control —
mg total
Diltiazem 0.25 mg/kg over 3–5 5–15 mg/h SVT, AF/AFL rate control IV
min (max 20 mg)
Esmolol 500 g/kg over 1 min 50 g/kg per min AF/AFL rate control II
Ibutilide 1 mg over 10 min if N/A Terminate AF/AFL III
over 60 kg
Lidocaine 1–3 mg/kg at 20–50 1–4 mg/min VT IB
mg/min
Metoprolol 5 mg over 3–5 min x 3 1.25–5 mg q6h SVT, AF rate control; II
doses exercise-induced VT; long QT
Procainamide 15 mg/kg over 60 min 1–4 mg/min Convert/prevent AF/VT IA
Quinidine 6–10 mg/kg at 0.3–0.5 N/A Convert/prevent AF/VT IA
mg/kg per min
Verapamil 5–10 mg over 3–5 min 2.5–10 mg/h SVT, AF rate control IV
 The selection of antiarrhythmic agents should be
dictated primarily by the presence or absence of
 CAD,
 Depressed LV function not attributable to a
reversible tachycardia-induced cardiomyopathy,
and/or
 Severe hypertension with evidence of marked LV
hypertrophy
 The presence of any significant structural

heart disease typically narrows treatment to
the use of sotalol, amiodarone, dofetilide, or
dronedarone.
 Severely depressed LV function with heart
failure symptoms precludes the use of
dronedarone and may limit sotalol therapy.
 Owing to the risk of QT prolongation and

polymorphic VT, sotalol and dofetilide have to be
initiated in the hospital in most cases.
 It is reasonable to use ablation of the atrioventricular
(AV) node or accessory pathway to control heart rate
when pharmacological therapy is insufficient or
associated with side effects.
When electrical cardioversion is not necessary in

patients with AF and an accessory pathway,
intravenous procainamide or ibutilide is a reasonable
alternative
 Intravenous administration of digitalis glycosides or
nondihydropyridine calcium channel antagonists to patients
with AF and a preexcitation syndrome may
paradoxicallyaccelerate the ventricular response and is not
recommended
 In patients without evidence of structural heart
disease or hypertensive heart disease without
evidence of severe hypertrophy, the use of the
class IC antiarrhythmic agents flecainide or
propafenone appears to be well tolerated and
does not have significant proarrhythmia risk
 It is important to recognize that no drug is

uniformly effective, and arrhythmia recurrence
should be anticipated in over one-half of the
patients during long-term follow-up regardless
of the type and number of agents tried
 Termination of AF acutely may be warranted on
the basis of clinical parameters and/or
hemodynamic status.
 Pharmacologic cardioversion*
 Direct current transthoracic cardioversion during

short-acting anesthesia is a reliable way to
terminate AF.
 Conversion rates using a 200-J biphasic shock delivered
synchronously with the QRS complex typically are >90%.
 Treatment to achieve strict rate control of
heart rate (80 bpm at rest or 110 bpm during a
6-minute walk) is not beneficial compared to
achieving a resting heart rate 110 bpm in
patients with persistent AF who have stable
ventricular function (LVEF 0.40) and no or
acceptable symptoms related to the arrhythmia,
though uncontrolled tachycardia may over time
be associated with a reversible decline in
ventricular performance.
PHARMACOLOGIC CARDIOVERSION
 Administration of flecainide, dofetilide,

propafenone, or ibutilide is recommended for
pharmacological cardioversion of AF. (Level of
Evidence: A)
 Administration of amiodarone is a reasonable

option for pharmacological cardioversion of AF.
(Level of Evidence: A)
 Administration of amiodarone can be beneficial on an
outpatient basis in patients with paroxysmal or
persistent AF when rapid restoration of sinus
rhythm is not deemed necessary.
 Administration of quinidine or procainamide
might be considered for pharmacological
cardioversion of AF, but the usefulness of these
agents is not well established. (Level of
Evidence: C)
 Digoxin and sotalol may be harmful when used

for pharmacological cardioversion of AF and are
not recommended. (Level of Evidence: A)
 2011 New Recommendation: Dronedarone is
reasonable to decrease the need for
hospitalization for cardiovascular events in
patients with paroxysmal AF or after conversion
of persistent AF. Dronedarone can be initiated
during outpatient therapy. (Level of Evidence: B)
 Dronedarone should not be administered to
patients with class IV heart failure or patients
who have had an episode of decompensated
heart failure in the past 4 weeks, especially if
they have depressed left ventricular function
(left ventricular ejection fraction <35%).
 In using antiarrhythmic agents that slow atrial
conduction, strong consideration should be given
to adding a beta blocker or a calcium channel
blocker (verapamil or diltiazem) to the
treatment regimen.
 This should help avoid a rapid ventricular

response if AF is converted to "slow" AFL with
the drug therapy
DC CARDIOVERSION
 When a rapid ventricular response does not respond
promptly to pharmacological measures for patients with
AF with ongoing myocardial ischemia, symptomatic
hypotension, angina, or HF, immediate R-wave
synchronized direct-current cardioversion is
recommended.
 Immediate direct-current cardioversion is recommended

for patients with AF involving preexcitation when very
rapid tachycardia or hemodynamic instability occurs.
DC CARDIOVERSION
 Cardioversion
is recommended in patients without
hemodynamic instability when symptoms of AF
are unacceptable to the patient.
 Incase of early relapse of AF after

cardioversion, repeated direct-
current cardioversion attempts may
be made following administration of
antiarrhythmic medication.
DC CARDIOVERSION
 Direct-currentcardioversion can be useful to
restore sinus rhythm as part of a long-term
management strategy for patients with AF.
(Level of Evidence: B)
 Patient
preference is a reasonable
consideration in the selection of infrequently
repeated cardioversions for the management
of symptomatic or recurrent AF.
DC CARDIOVERSION
 Frequent repetition of direct-current
cardioversion is not recommended for patients
who have relatively short periods of sinus
rhythm between relapses of AF after multiple
cardioversion procedures despite prophylactic
antiarrhythmic drug therapy.
 Electrical
cardioversion is contraindicated in
patients with digitalis toxicity or hypokalemia
DC CARDIOVERSION
 Pretreatment with amiodarone, flecainide,
ibutilide, propafenone, or sotalol can be useful to
enhance the success of direct-current
cardioversion and prevent recurrent atrial
fibrillation. (Level of Evidence: B)
 In patients who relapse to AF after successful

cardioversion, it can be useful to repeat the
procedure following prophylactic administration
of antiarrhythmic medication. (Level of Evidence:
C)

Atrial Fibrillation: Classification, Mechanisms, and Triggers

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Atrial Fibrillation: Classification, Mechanisms, and Triggers

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ATRIAL FIBRILLATION

Abnet M , October 30,2017

 AF is often associated with structural heart

 Hemodynamic impairment and thromboembolic

 In other patients, because of heightened vagal

 One patient may have several episodes of

 It is practical to categorize a given patient by

 Thus, in a patient with paroxysmal AF, episodes

 Over time, patients move out of the lone AF category

 Then AF is not the primary problem, and

 Most patients have a mixed or random form of

 Early in the course of AF the atrium is relatively

 With more extensive remodeling of the atrium it

 In the aggregate, these electrophysiologic

 However, it appears to be a complex interaction

 Additionally, stretch can increase the propensity

 This process may explain why the failure rate of

 Electricalremodeling: marked shortening of atrial

 This is why pulmonary vein isolation is

 Therefore, pulmonary vein isolation is rarely

 The incidence of AF increases with age such

 Occasionally, AF appears to have a well-defined

 AF also may be triggered by other

 Symptoms from AF vary dramatically.

 The hemodynamic effect in patients can be quite

 Exercise intolerance and easy fatigability are

 Occasionally, one needs to record from multiple ECG

waves may be inapparent

 Variabilityin the intervals between QRS complexes

 When there is a third-degree AV block with a

 The QRS complexes are narrow unless AV conduction

 Evaluation of a patient with AF should include a

 An echocardiogram should be performed to

 Persistent or labile hypertension should be

 Hemodynamically unstable: immediate

 The patient is not already receiving an anticoagulant

 Pharmacologic versus electrical cardioversion.

 Avoidance of the need for TEE or therapeutic

 Possibly a lower risk for early recurrence of AF because of

 Left atrial thrombus noted on TEE

 A suspicion (based on previous AF episodes) that AF will

with electrical cardioversion.

 Disadvantages of pharmacologic cardioversion

 Very unlikely to be effective when AF > 7 days

 For AF episodes shorter than 2 to 3 days in duration, the

 To minimize the risk for QT prolongation and polymorphic

 The most commonly used oral agents for acute conversion

often results in successful cardioversion

2. Immediate recurrence of AF within a few seconds of

than 24 hours in duration and approximately 10% for

 If the patient has not been receiving an oral rhythm-

control agent, infusion of ibutilide may be helpful for

 To improve the safety margin, it may be appropriate

 If no thrombi are seen, the patient can safely be

 And asymptomatic episodes lasting more than 48 hours

are not uncommon, occurring in 17%.

 When compared with the conventional approach, the

 However, in the setting of hemodynamic instability

 Performing a TEE in this setting would be reassuring if no

 Furthermore, a patient who has severe clinical instability due

 Because of the risk for hemorrhage during

Less validated Moderate risk factors High risk factors

 Patients with any of these risk factors have an