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New Horizons in
Atrial Fibrillation
Payal Kohli, MD
TIMI Study Group, Brigham and Women’s Hospital,
Harvard Medical School, Boston, Massachusetts
A REPORT FROM THE 2011 SCIENTIFIC SESSIONS OF THE AMERICAN HEART ASSOCIATION
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1
Disease Burden of Atrial Fibrillation

With an overall prevalence of 0.4%–1%, atrial
fibrillation (AF) is the most common arrhythmia
encountered in clinical practice.1,2

AF also accounts for one third of hospitalizations for
cardiac rhythm disturbances.2

Despite major advances in the diagnosis, risk
stratification, and management of AF over the past
two decades, mortality due to AF remains
unchanged.1

Over the same period, the aging US population has
experienced a 66% increase in hospitalizations for
treatment of AF.1
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2
Disease Burden of Atrial Fibrillation

It is anticipated that 12–15 million patients
worldwide will be diagnosed with AF by the year
2050.2

The global epidemic in the incidence of AF affects
various populations and ethnic groups and carries a
high risk of stroke, all-cause mortality, heart failure,
and associated hospitalizations.

In Chinese patients of the Guangzhou Biobank
Cohort, obesity (as defined by waist circumference or
body mass index) was independently associated with
a substantial risk of developing AF.3

The annual cost to treat AF is $3,600 per patient.2
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3
Disease Burden of Atrial Fibrillation

In a community-based study of 4,618 residents of
Olmstead County, Minnesota, who were diagnosed
with AF between 1980 and 2000, there was no
evidence of improvement in overall mortality, early
or late mortality, or mortality among patients with
no preexisting cardiovascular conditions.1

The reasons for these results are complex and may
be a combination of:
» The increased prevalence of AF, which, in turn, has
increased the overall incidence of stroke.
» The introduction of potent antiplatelet therapies, which
physicians use in place of anticoagulants.
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4
Etiology of Atrial Fibrillation

Atrial fibrillation results from increased ectopic
activity in the atria, which can trigger susceptible
substrates and lead to reentrant arrhythmia.

These triggers and substrates can result from a
variety of causes, including environmental and
genetic factors (eg, ischemic heart disease,
hypertension, alcohol consumption, obstructive
sleep apnea).

The most common risk factors are patient age and a
history of myocardial infarction.
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Etiology of Atrial Fibrillation
Environmental, biologic,
and genetic factors that
contribute to atrial
fibrillation.
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6
Biologic Factors

Age appears to be the strongest risk factor for the
development of AF.4

Both acute and chronic coronary atherosclerotic
disease confers risk. Observational data from a large
cohort (n = 3,983) demonstrated a 3.6-fold increase
in the risk of AF following a myocardial infarction.4

Myocardial ischemia appears to produce both the
trigger and the substrate for ectopic activity. In a
canine model of coronary artery disease affecting the
atria, sustained atrial ischemia/infarction following
ligation of coronary vessels led to persistent ectopic
activity, as well as substrates for reentry.5
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Genetic Factors

Genetic factors may confer significant risk of AF by
altering thresholds for triggers and by altering
substrates.

Mendelian mutations are rare, but their presence
suggests that this mode of inheritance plays a
dominant role in the genetic predisposition for AF.

A mutation on chromosome 4q25 changes the
function of PITX2, a gene involved in cardiac
development, that doubles the risk of developing AF.

Transgenic mice with Pitx2 mutations experience a
loss of myocardial pacemaker cells, increasing their
susceptibility to atrial arrhythmia.6
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Electrophysiologic Mechanisms

Atrial fibrillation results from four principal
electrophysiologic aberrations:
1. Increased arrhythmogenicity related to the pulmonary vein
and other thoracic veins
2. Autonomic dysregulation
3. Fixed and functional reentry substrates, especially
anisotropic high-frequency reentrant sources (“rotors”)
throughout the atria
4. Electroanatomical remodeling of myocardial structures.

One or more mechanisms may be responsible
simultaneously for the generation of AF, making
catheter ablation a more challenging option if the
etiology is multifactorial.
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Electrophysiologic Mechanisms
Atrial fibrillation is a heterogeneous arrhythmia that can result from a variety of
electrophysiologic and electroanatomical mechanisms.
Adapted from a presentation by Hakan Oral, MD, at the 2011 Scientific Sessions of the American Heart Association.
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Catheter Ablation

Most commonly, pulmonary vein arrhythmogenicity
triggers AF. For this reason, ablation efforts focus on
targeting pulmonary vein tissue and the myocardial
tissue cuff adjacent to the pulmonary vein.

Rotors, ganglionated plexi, and other triggers for AF
also may be present. Techniques such as complex
fractionated atrial electrography and isoproterenol
infusions may be used to identify these triggers;
however, their use may trigger passive activation of
foci not responsible for generation and propagation
of AF, resulting in false-positive results.

These diagnostic procedures also may initiate an
arrhythmia or induce contractile dysfunction.
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Catheter Ablation

Isolation of the pulmonary veins followed by
isolation of the superior vena cava and the coronary
sinus and subsequent linear ablation remains the
most commonly used technique for catheter-based
ablation.

Although surgical ablation is an option, the invasive
nature of this procedure makes it less preferable.

Ablation may result in embolic stroke, pulmonary
vein stenosis, atrioesophageal fistula, atrial flutter,
complete heart block, or recurrent arrhythmia.

Risk-prediction tools (eg, the CHADS2 score) may be
used to predict the thromboembolic risk of ablation.7
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Catheter Ablation
Schematic
representation of
pulmonary vein
isolation and linear
ablation, the most
common catheterbased technique
for treating atrial
fibrillation. Yellow
connecting lines
represent the
trajectory for
ablation.
Adapted from a presentation by Hakan Oral, MD, at the 2011 Scientific Sessions of the American Heart Association.
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13
Indications for Ablation
ACC/AHA/HRS indications for ablation:

Symptomatic AF with Wolff-Parkinson-White
syndrome

Symptomatic AF in the presence of persistent
symptoms and failure of antiarrhythmic
medications

Atrial fibrillation in the presence of heart failure or
a decrease in ejection fraction
ACR = American College of Cardiology; AHA = American Heart Association; HRS = Heart Rhythm Society
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Indications for Ablation
Special consideration for ablation should be given to:

Young patients, who have a high likelihood of
needing antiarrhythmic agents and anticoagulants
for the rest of their lives

Patients with tachycardia-mediated cardiomyopathy

Patients with liver or renal disease that may
complicate medical therapy

Patients with structural heart disease
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15
Rate vs Rhythm Control

Physicians who choose not to use ablation for
managing their patients with AF may need to
consider the relative effectiveness of rate control
versus rhythm control.

The choice of whether to control rate or rhythm
should be individualized for each patient and
depends upon the:
» Patient’s age
» Type of symptoms
» Duration of disease
» Presence of additional comorbidities and stroke risk factors
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Rate vs Rhythm Control

Results of the AFFIRM study, in which 4,060
patients with AF were randomized to undergo rate
control or rhythm control, suggested that rhythm
control offered no survival benefit but was linked to a
higher incidence of drug-related side effects.8

The findings of a number of other studies (RACE,
PIAF, HOT CAFE, AF-CHF, and J-RHYTHM) also
demonstrated no benefit of rhythm control over rate
control.9–13

Data from the AF-CHF study even suggested an
increase in hospitalizations due to bradyarrhythmia
in the rhythm-control arm.11
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Rate vs Rhythm Control

Data from the RACE-II trial suggested that rate
control does not need to be as strict as previously
thought necessary and that lenient rate control
(heart rate < 110 beats/min, resting and exercise) is
as effective as strict rate control (resting heart rate
< 80 beats/min; exercise heart rate < 110 beats/min)
and easier to achieve.14

Therefore, rate control likely is the most effective
strategy, especially for elderly patients who have
minimal symptoms.
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When to Use Rhythm Control

In some situations, rhythm control is preferable.

For example, some patients who are especially
susceptible to the long-term adverse effects of
electroanatomical remodeling of the atria may
benefit from maintenance of sinus rhythm. Sinus
rhythm is, indeed, a marker for improved survival.15

For this group, ablation (preferably catheter-based
pulmonary-vein isolation), with or without the use of
adjunctive antiarrhythmic drugs, is recommended.

Because such remodeling is time dependent, this
strategy should be employed early, after the decision
to use rhythm control has been made.
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Anticoagulation Therapy

In addition to providing rate or rhythm control,
anticoagulation is central to the management of AF.

Use of the CHADS2 score to determine which
patients with AF are appropriate candidates for
anticoagulation therapy has been well established.7

Nevertheless, Waldo et al16 reported that 55% of
hospitalized patients with AF at high risk for stroke
were not receiving adequate anticoagulation therapy
with warfarin.
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20
Underutilization of Warfarin

Explanations for the underuse of warfarin in patients
with AF most commonly include advanced age,
which is highly correlated with increased intracranial
hemorrhage, and the presence of preexisting
bleeding diathesis (eg, gastrointestinal bleeding).

However, the most likely explanation relates to the
complex dosing, intensive laboratory monitoring,
and multiple dietary and pharmacologic interactions
associated with warfarin therapy.

For these reasons, great effort has been devoted to
the study of novel oral anticoagulants such as
dabigatran, rivaroxaban, apixaban, and edoxaban to
treat patients with AF.
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Novel Oral Anticoagulants
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Novel Oral Anticoagulants

The results of multiple clinical trials have
emphasized the delicate balance between effective
anticoagulation and the risk of hemorrhagic and
thrombotic complications.

Based on the results of the RE-LY study,17 the FDA
recently approved the use of dabigatran to prevent
stroke in patients with nonvalvular AF, when given
at a dose of 150 mg bid for patients with a creatinine
clearance (CrCl) > 30 mL/min and at a dose of 75 mg
bid for those with a CrCl = 15–30 mL/min.
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Novel Oral Anticoagulants

Likewise, the FDA recently approved the use of
rivaroxaban to reduce the risk of stroke in patients
with AF, based on the results of the ROCKET-AF
trial.18

The recommended dose for this purpose is 20 mg
once daily for patients with a CrCl > 50 mL/min and
10 mg once daily for those with a CrCl = 30–50
mL/min.

In addition, the FDA is giving priority review to the
use of 5 mg of apixaban given twice daily based on
positive results from the phase III AVERROES and
ARISTOTLE trials.19
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Novel Oral Anticoagulants vs Warfarin
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Novel Oral Anticoagulants

These studies have provided a wealth of data that
demonstrate the efficacy of oral anticoagulation
therapy with minimal INR monitoring in patients
with AF and low, medium, and high CHADS2 scores.

Postmarketing surveillance of dabigatran is ongoing.
The FDA has issued warnings about increased
bleeding related to the use of the drug in patients
older than 75 years of age and the risk of rebound
thromboses in patients who are transitioning from
rivaroxaban to warfarin.

Overall, however, dabigatran and other novel oral
anticoagulants appear to be well tolerated.
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Novel Oral Anticoagulants

Concerns persist regarding the usefulness and costeffectiveness of novel anticoagulants in the setting of
excellent control of the INR.2

Potential drug interactions between both dabigatran
and rivaroxaban with P-glycoprotein inhibitors (eg,
dronedarone, ketoconazole) are of concern.

Finally, many questions remain unanswered
regarding the ability to reverse the anticoagulant
effects of these drugs, patient monitoring, and the
risks/benefits of using these agents against a
background of potent antiplatelet therapy and in
patients with AF and acute coronary syndromes.21
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Conclusion

The transition of a new class of drugs from the
clinical trial arena into clinical practice is often
fraught with regulatory and logistic concerns.

Often, safety warnings are issued after FDA
approval.

Further, the addition of a new drug to other drugs a
patient is already taking may compromise
compliance.

Overall, however, the newer oral anticoagulants
provide growing options within the medical arsenal,
which will improve patient care and outcomes.
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References
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developed in partnership with the European Society of Cardiology and in collaboration with the European
Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57:e101–e198.
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Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356:1789–1794.
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References
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16. Waldo AL, Becker RC, Tapson VF, Colgan KJ. Hospitalized patients with atrial fibrillation and a high risk of
stroke are not being provided with adequate anticoagulation. J Am Coll Cardiol. 2005;46:1729–1736.
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