2. Eagle et al Atrial Fibrillation Management 5
activation, obesity, the use of stimulants, inflammation fibrillation.8 Electrical remodeling, which begins soon after
caused by pericarditis or other disorders, and pulmonary arrhythmia onset, is characterized by a shortening of the atrial
disease. refractory period. This process may be reversible upon resto-
Hospitalizations for atrial fibrillation have increased signif- ration of sinus rhythm. Structural remodeling, which is likely
icantly in recent years, primarily due to the increased avail- more permanent than electrical remodeling, occurs weeks to
ability and utilization of hospital- months after the onset of the ar-
based therapeutic options including rhythmia and includes changes at
drugs and nonpharmacologic inter- both the cellular and tissue lev-
CLINICAL SIGNIFICANCE STATEMENT
ventions (eg, cardioversion).13 The els.8,19,20 Together, these pro-
escalating prevalence of atrial fi- ● Many established options for the treat- cesses result in contractile remod-
brillation and the need for re- ment of atrial fibrillation have limited eling that may facilitate atrial
peated hospitalizations and long- efficacy and safety/tolerability issues, fibrillation persistence and the de-
term pharmacologic treatment of velopment of negative sequelae
but newer therapies attempt to address
these patients make the condition (eg, thrombus formation and atrial
costly; one recent European sur-
these issues and have promising out- dilation). Recovery of contractility
vey showed that the mean in- comes from clinical trials and postmar- after restoration of sinus rhythm is
creased annual cost of caring for a keting surveillance. typically slow.
patient with atrial fibrillation is ● Customized atrial fibrillation manage- The pathophysiology of atrial fi-
approximately €3200 ($5000) ment, assessing individual patient char- brillation in patients with underly-
compared with a matched popula- acteristics and comorbidities, should ing congestive heart failure seems
tion without atrial fibrillation.14 to be somewhat different. In con-
guide the optimal treatment selection.
Indeed, it has been estimated that gestive heart failure, interstitial fi-
the direct cost of managing atrial brosis is found to be increased in the
fibrillation to the United Kingdom atria, leading to heterogeneity of
National Health Service accounts for 2.4% of their annual atrial conduction and regions of slow electrical conduction,
expenditure, amounting to more than £450 million.15 Atrial predisposing to the occurrence of atrial fibrillation.21,22 The
fibrillation is associated with a significant economic burden in atrial fibrosis in congestive heart failure seems to be due to
the US as well. Several studies have shown that health care upregulation of the renin-angiotensin-aldosterone system
costs in the US are approximately 5 times higher for patients and dysregulation of intracellular Ca2 homeostasis in cells
with atrial fibrillation than for those without it, and hospital- of the atrial myocardium.23
14,16
izations are a key contributor. Thorough clinical evaluation of patients who present
Early detection and intervention potentially could de- with certain conditions (eg, hypertension/hypertensive heart
crease the burden of atrial fibrillation on the individual and disease, congestive heart failure, CAD, ischemic cardiomy-
society by preventing progression and related conse- opathy, valvular [rheumatic] heart disease, diabetes, hyper-
quences. The purpose of this review was to briefly describe thyroidism, obesity, and obstructive sleep apnea)9,24,25 can
the pathophysiology of atrial fibrillation and associated se- facilitate early atrial fibrillation detection and timely inter-
quelas, review the goals of atrial fibrillation therapy, and vention. Of course, clinicians should remain mindful that
provide a practical management guide for internists based atrial fibrillation can occur even in the absence of predis-
on recent guidelines and current clinical data. posing factors. Typically, the term “lone atrial fibrillation”
is used to describe younger patients ( 60 years of age) who
have atrial fibrillation in the absence of underlying cardio-
PATHOPHYSIOLOGY AND BURDEN OF pulmonary disease.3
ATRIAL FIBRILLATION Up to 40% of patients in whom atrial fibrillation is found
The pathophysiology of atrial fibrillation remains incom- on a baseline electrocardiogram (ECG) do not experience or
pletely understood; however, it is clear that its occurrence recognize symptoms.1 Even among those that do manifest
requires a triggering factor and an appropriate substrate to symptoms, clinical presentation is highly variable. When
sustain re-entry.3,17 In the majority of patients, the under- present, symptoms can include palpitations, chest pain, dys-
lying triggering mechanism is thought to involve the inter- pnea, fatigue, lightheadedness, syncope, and polyuria. The
action of rapidly firing ectopic foci in the pulmonary veins, hemodynamic consequences of loss of atrial contraction
into which the atrial muscle is known to extend.18 The with resultant loss of atrioventricular (AV) synchrony, heart
mechanism for aberrant impulse origin in pulmonary veins rate irregularity, and rapid ventricular response that are
is uncertain but may involve automaticity, triggered activ- typically found in atrial fibrillation may each contribute in
ity, and/or re-entry.18 varying degrees to the manifestations of these symptoms.1
If atrial fibrillation has been sustained for a period of Regardless of presentation, improperly managed atrial
time, physical and molecular changes in the electrical and fibrillation is associated with significant morbidity and mor-
structural properties of the atria (“remodeling”) occur and tality, including a 5-fold increased risk of stroke (in the
facilitate the conversion from transient to persistent atrial absence of anticoagulation) and a 1.5-fold to 1.9-fold in-
4. Eagle et al Atrial Fibrillation Management 7
Figure 2 American College of Cardiology (ACC)/American Heart Association (AHA)/Euro-
pean Society of Cardiology (ESC) algorithm for the selection of maintenance anti-arrhythmic
drug therapy.3 It can be seen that catheter ablation for atrial fibrillation is considered second-line
therapy after failure of an anti-arrhythmic drug. For the clinician, the decision is made after
careful consideration and discussion with the patient about the risks and benefits of either
approach. Reprinted from Fuster et al.,3 with permission from Oxford University Press.
ization of therapy based on the specific clinical character- tions, the potential for drug-drug and drug-food interactions,
istics of the patient. The guidelines recognize the impor- and the need for ongoing monitoring.41 Current guidelines
tance of concomitant anticoagulation therapy in the advocate more liberal use of warfarin, while full-dose aspi-
management of atrial fibrillation. rin may be useful for patients at low risk for stroke.3,36,37
Data from recently completed and ongoing studies of Stroke risk and the identification of atrial fibrillation
newer atrial fibrillation management therapies will likely patients who may benefit most from antithrombotic therapy
play a major role in shaping future guidelines. Several can be assessed by the Congestive heart failure, Hyperten-
studies are investigating important clinical endpoints that sion, Age, Diabetes, prior Stroke risk index by assigning
more closely reflect practical treatment goals, such as the numerical values to accepted risk factors (advanced age of
prevention of cardiovascular hospitalization and death. 75 years old; concomitant congestive heart failure, hyper-
tension, or diabetes; and history of stroke or TIA).27 Bleed-
BENEFITS/RISKS OF MANAGEMENT OPTIONS ing risk should also be determined and weighed against the
potential benefit before anticoagulant initiation. Factors that
Antithrombotic Treatment may influence risk include patient characteristics (eg, in-
Current guidelines recommend long-term anticoagulation in creased age, history of bleeding, presence of treated hyper-
patients with atrial fibrillation and risk factors for thrombo- tension, cerebrovascular disease, ischemic stroke, serious
embolism, regardless of atrial fibrillation management ap- heart disease, diabetes, renal insufficiency, alcoholism, liver
proach.3,36,37 Even patients who seem to be in normal sinus disease, or malignancy; or genetic factors affecting drug
rhythm after atrial fibrillation remain at considerable risk for metabolism), concomitant medications (eg, antiplatelet
stroke. For this reason, longer-term risk-based anticoagula- drugs), and proposed intensity and length of therapy.42
tion should be prescribed even in patients receiving anti- The protective effects of anticoagulants have been dem-
arrhythmic drug therapy and also in patients who have onstrated repeatedly and are generally greater than those
undergone electrical cardioversion or radiofrequency (RF) associated with antiplatelet therapy.43 Results of the Atrial
ablation.26,38 Fibrillation Clopidogrel Trial with Irbesartan for Prevention
Despite a strong body of evidence supportive of the of Vascular Events44 and Birmingham Atrial Fibrillation
benefits of antithrombotic therapy, it is widely underutilized Treatment of the Aged45 studies provide evidence of the
in the atrial fibrillation population.39,40 The reluctance of protective effects of warfarin therapy over clopidogrel plus
clinicians to prescribe, and patients to use, warfarin likely aspirin, and aspirin alone, respectively. However, for pa-
arises from fear of increased risk for bleeding complica- tients unable or unwilling to assume the risks of warfarin
5. 8 The American Journal of Medicine, Vol 124, No 1, January 2011
therapy, clopidogrel plus aspirin may reduce the risk of except amiodarone and propafenone, were associated with
major vascular events over aspirin alone.46 significant pro-arrhythmia risk.52 Rates of withdrawal due
Other alternatives for reducing thromboembolism risk to adverse effects ranged from 9% to 23% and rates of
(eg, direct thrombin inhibitors) are in various stages of withdrawal due to pro-arrhythmia ranged from 1% to 7%.
clinical evaluation. The direct thrombin inhibitor ximelagat- Withdrawals due to both pro-arrhythmia and adverse events
ran was shown to be at least as effective as adjusted-dose were lower with amiodarone than with sodium channel
warfarin therapy for stroke/TIA prevention in noninferiority blockers.
trials (Stroke Prophylaxis Using an Oral Thrombin Inhibitor Because of the pro-arrhythmia risk, maintenance therapy
in Atrial Fibrillation III and V)47,48 but was not approved in with any of these agents generally should be initiated at
the United States because of concern about hepatotoxicity. relatively low doses and while the patient is hospitalized.
Another direct thrombin inhibitor, dabigatran, has been Clinicians should seek to identify at-risk patients via com-
shown to be at least as safe and effective as warfarin therapy plete medical history, physical examination, and/or electro-
in a large-scale, international, multicenter trial (Randomized cardiographic monitoring (Table provides typical doses of
Evaluation of Long-Term Anticoagulant Therapy).49 Al- anti-arrhythmic drugs used to maintain normal sinus rhythm
though this was an open-label study, its other methodologic in atrial fibrillation).3 Established predisposing factors in-
strengths were significant; application for regulatory ap- clude QT interval 440 msec for men and 460 msec for
proval in the United States, Canada, and Europe is antici- women, left ventricular ejection fraction (LVEF) 40%,
pated soon. Two direct factor Xa inhibitors (apixaban and hypokalemia/hypomagnesemia, female sex, renal dysfunc-
rivaroxaban) are currently listed at clinicaltrials.gov in tion, bradycardia, concomitant drugs that prolong the QT
phase III trials designed to determine noninferiority to war- interval (eg, antifungals) or drugs associated with torsades
farin as a stroke prevention strategy. Although vitamin K de pointes, previous pro-arrhythmic response to anti-ar-
antagonists present challenges, such as a narrow therapeutic rhythmics, and concomitant ventricular tachycardia or rapid
index and numerous drug/dietary interactions, the conve- ventricular response rate.53
nience and safety of warfarin therapy can be increased with Generally, doses of anti-arrhythmic drugs are titrated to
access to a dedicated anticoagulation management service heart rate and electrocardiographic response. Changes in
and or both patient home measurement of international patient status also should be monitored, as changes in car-
normalized ratio values.50,51 diac function, plasma electrolytes, or renal function could
affect drug response and pro-arrhythmia risk. Patients
Maintenance of Normal Sinus Rhythm should be counseled regarding potential signs of arrhythmia
(Pharmacologic Therapies) such as syncope, angina, or dyspnea.
A number of agents are effective for the maintenance of Potential drug-drug interactions need to be considered as
normal sinus rhythm in patients with atrial fibrillation. a number of anti-arrhythmics are cytochrome P enzyme
ACC/AHA/ESC guidelines describe amiodarone, disopyr- substrates (eg, quinidine, disopyramide, lidocaine, mexil-
amide, flecainide, propafenone, and sotalol as agents with etine, flecainide, and propafenone) or inhibitors (amioda-
proven efficacy for this use (Table).3 However, meta-anal- rone). Others undergo active tubular secretion (procain-
ysis of data from 44 clinical trials revealed high rates of amide), and are, therefore, influenced by inhibitors of this
atrial fibrillation recurrence (55% to 67%) with maintenance route of elimination (eg, cimetidine, trimethoprim).54 In
anti-arrhythmic therapy, and all atrial fibrillation therapies, some instances, dose adjustment for concomitant medica-
Table Anti-arrhythmic agents used to maintain sinus rhythm in patients with atrial fibrillation.
Drug* Daily Dose Potential Adverse Effects
Amiodarone† 100-400 mg Photosensitivity, pulmonary toxicity, polyneuropathy, gastrointestinal upset, bradycardia,
torsades de pointes (rare), hepatic toxicity, thyroid dysfunction, eye complications
Disopyramide 400-750 mg Torsades de pointes, heart failure, glaucoma, urinary retention, dry mouth
Dofetilide‡ 500-1000 g Torsades de pointes
Flecainide 200-300 mg Ventricular tachycardia, heart failure, conversion to atrial flutter with rapid conduction
through the atrioventricular node
Propafenone 450-900 mg Ventricular tachycardia, heart failure, conversion to atrial flutter with rapid conduction
through the atrioventricular node
Sotalol‡ 160-320 mg Torsades de pointes, heart failure, bradycardia, exacerbation of chronic obstructive or
bronchospastic lung disease
Modied from Fuster et al., with permission from Oxford University Press.
*Drugs are listed alphabetically.
†A loading dose of 600 mg/d is usually given for 1 month, or 1000 mg/d for 1 week.
‡Dosage should be adjusted for renal function and QT interval response during in-hospital initiation phase.
6. Eagle et al Atrial Fibrillation Management 9
tions should be made before beginning anti-arrhythmics. mortality rate in the dronedarone-treated patients (16% risk
For example, doses of warfarin and digoxin should be reduction; P .18).58 Adverse event rates were higher in
halved before amiodarone administration in anticipation of the dronedarone group than in the placebo group, and more
amiodarone-associated cytochrome P enzyme inhibition. patients in the dronedarone group discontinued from the
Despite amiodarone (Wyeth Pharmaceuticals Inc.,/ study prematurely due to adverse events (12.7% vs 8.1%;
Pfizer, Philadelphia, Penn) being widely considered the P .001). Approximately one-fourth of patients (26.2%)
most effective of the available anti-arrhythmic drugs for treated with dronedarone reported gastrointestinal events
maintenance of sinus rhythm in atrial fibrillation pa- compared with 22% of patients who received a placebo
tients,55,56 it lacks the US Food and Drug Administration (P .001). Bradycardia (3.5% vs 1.2%), QT prolongation
(FDA) approval for this indication. Additionally, its long- (1.7% vs 0.6%), and increased serum creatinine (4.7% vs
term use has been associated with serious adverse effects, 1.3%) were also more common in the dronedarone treat-
including pulmonary and hepatic toxicity, thyroid dysfunc- ment group (all P .001 vs placebo). The results of
tion, and eye complications.57 Therefore, there is a pressing ATHENA provide evidence of the morbidity and mortality
unmet need for maintenance therapies with improved effi- benefits of dronedarone in appropriate populations. The
cacy/safety profiles. early discontinuation of one nonatrial fibrillation trial Anti-
In contrast to these older agents, a newly approved ben- arrhythmic Trial with Dronedarone in Moderate to Severe
zofuran derivative, dronedarone (Multaq [dronedarone]; Congestive Heart Failure Evaluating Morbidity Decrease
sanofi-aventis US LLC, Bridgewater, NJ), was recently ap- (ANDROMEDA) conducted in high-risk patients with ad-
proved (July 2009) by the FDA to reduce the risk of hos- vanced congestive heart failure and recent decompensation
pitalization in patients with atrial fibrillation or atrial flutter leading to hospitalization (regardless of the absence or pres-
and associated cardiovascular risk factors (ie, age 70 years ence of atrial fibrillation), led to concern regarding the effects
old, hypertension, diabetes, prior cerebrovascular accident, of dronedarone on mortality in this high-risk group.62
left atrial diameter 50 mm or LVEF 40%), who are in The ATHENA investigators suggested that the difference
sinus rhythm or will be cardioverted. Its use is contraindi- in outcomes between ATHENA and ANDROMEDA may
cated in patients with New York Heart Association (NYHA) be a reflection of the disparate populations studied (ie,
class IV heart failure, or NYHA class II to III heart failure ANDROMEDA enrolled only patients with advanced heart
with a recent decompensation requiring hospitalization or failure and recent decompensation leading to hospitalization;
specialist referral. Dronedarone has characteristics of all 4 ATHENA specifically excluded patients who had either hemo-
Vaughan–Williams classes and a short half-life (of approx- dynamic instability or severe [NYHA class IV] heart failure).58
imately 24 hours), which reduces its accumulation in tissue. A “pill-in-pocket” approach has been advocated for
Lacking an iodine moiety, dronedarone is expected to offer some patients with paroxysmal or persistent atrial fibrilla-
reduced risk of thyroid and pulmonary toxicity.58 tion.3 This approach, in which patients are instructed to
In clinical studies,59,60 dronedarone 400 mg twice daily self-administer a single dose of a Vaughan–Williams Class
was effective for preventing the recurrence of atrial fibril- IC agent, such as flecainide or propafenone, upon the onset
lation or atrial flutter (prolonged time to recurrence relative of atrial fibrillation symptoms, may terminate the episode or
to placebo) and was well tolerated (no serious side effects). prevent recurrence in patients with paroxysmal atrial fibril-
Perhaps even more importantly, it has demonstrated bene- lation and reduce the risk for toxicity associated with pro-
ficial effects with respect to cardiovascular morbidity and longed anti-arrhythmic therapy. This method is associated
mortality in the atrial fibrillation population. Data from the with few adverse effects in patients with no structural heart
recent A Placebo-Controlled, Double-Blind, Parallel Arm disease. All patients using this method should receive on-
Trial to Assess the Efficacy of Dronedarone 400 mg twice a going beta-blockers or nondihydropyridine calcium channel
day for the Prevention of Cardiovascular Hospitalization or blocker therapy for rate control to prevent rapid AV con-
Death from Any Cause in Patients with Atrial Fibrillation/ duction. In addition to being rapidly effective and safe, the
Atrial Flutter (ATHENA) trial in patients with moderate- pill-in-pocket approach has been associated with improved
risk to high-risk paroxysmal or persistent atrial fibrillation quality of life,63 reduced emergency department and hospi-
or atrial flutter (N 4628; 29% with history of class I, II, or tal admissions,63,64 and lower costs.63
III heart failure and 12% with LVEF 45%) demonstrated
significantly reduced cardiovascular morbidity and mortal- Rate Control
ity in the dronedarone group.58 Compared with a placebo, Generally, beta-blockers and nondihydropyridine calcium
treatment with dronedarone in ATHENA reduced the com- channel blockers are appropriate for most patients with
posite endpoint of “time to first cardiovascular hospitaliza- persistent or permanent atrial fibrillation for whom control
tion or death from any cause” by 24% (P .001), time to of their ventricular rate is desired.3 (Digoxin or amiodarone
first cardiovascular hospitalization by 26% (P .001), car- should be considered in patients with heart failure and no
diovascular mortality by 29% (P .03), and stroke by 34% accessory pathway.) All of these agents can be administered
(P .027).58,61 Unlike other rhythm-control agents which intravenously in the acute setting and orally for maintenance
may be associated with an increase in noncardiovascular therapy. For most patients, a target heart rate of 60 to 80
mortality, there was a trend toward improvement in the total beats per minute at rest and 90 to 115 beats per minute
7. 10 The American Journal of Medicine, Vol 124, No 1, January 2011
during moderate exercise is appropriate. The selection of cess rates with single procedures are approximately 60% in
appropriate rate-control therapy for each patient should in- patients with paroxysmal atrial fibrillation and 30% in
clude consideration of the drug’s potential impact on co- patients with persistent atrial fibrillation, up to 70% and
morbid conditions such as hypertension, ischemic heart 50% with a second or third attempt, respectively.68 How-
disease, and hypertrophic cardiomyopathy. ever, there are no large well-designed trials to support wide-
Generally, beta-blockers and nondihydropyridine cal- spread use of RF ablation. RF ablation is associated with a
cium channel blockers are well tolerated; however, they are 6% risk of major complications69 and should not be used in
not always effective at controlling heart rate nor always the presence of left atrial thrombus.68 This approach is best
titrated to suitable levels, possibly because up-titration is performed early in the course of the disease, as longer
associated with the increased occurrence of adverse durations are associated with poorer outcomes.70
events.65 In at-risk patients, these agents may contribute to Surgical maze procedures are usually optional add-on
the development of decreased blood pressure, heart block,
procedures in patients undergoing other open-heart surgical
and/or heart failure.3,66 Beta-blockers should be used with
operations.71 Similarly, AV node ablation is not recom-
caution in patients with asthma. Amiodarone may cause
mended as a primary strategy, but is typically reserved for
bradycardia, hypotension, visual disturbances, and gastroin-
symptomatic patients who have a rapid ventricular rate and
testinal events (oral route), or phlebitis (peripheral intravenous
route).3 Long-term use of amiodarone may result in end-organ who are refractory to pharmacologic treatment.3 AV node
toxicity (pulmonary, hepatic, thyroid, neurologic, and/or ablation is warranted in patients with a rapid ventricular
skin).57 When digoxin is used, patients should be monitored response to atrial fibrillation who cannot be controlled with
for signs of digoxin toxicity, especially in those with reduced medication. It is associated with improved symptoms and
renal function, advanced age, acute or chronic hypoxia, or quality of life and reduced health care resource utilization.72
thyroid disease.67 Because this technique results in complete heart blockage,
permanent pacing and long-term continuous anticoagulation
are required.3
Cardioversion
Conversion to normal sinus rhythm may be attempted using
electrical or pharmacologic measures and may be appropri- OTHER TREATMENT OPTIONS
ate for patients with persistent atrial fibrillation, symptom-
atic atrial fibrillation, or atrial fibrillation-induced acute Renin-angiotensin System Blockade
heart failure, hypotension, or worsening of angina pectoris Several lines of evidence suggest that angiotensin-convert-
(in persons with CAD).3,36 Regardless of approach (electri-
ing enzyme inhibitors and angiotensin receptor blockers
cal or pharmacologic), appropriate anticoagulation prophy-
(ARBs) can retard or reverse atrial fibrosis and structural
laxis should be implemented before cardioversion whenever
remodeling of the atria.73,74 These agents have been shown
possible.
to decrease atrial pressure, reduce the frequency of prema-
The efficacy of direct-current cardioversion is widely
accepted; however, limitations include the need for the ture atrial beats, reduce fibrosis, and may lower atrial fibril-
patient to receive conscious sedation or anesthesia along lation relapse rates after cardioversion. These actions have
with risks of thromboembolism and proarrhythmia.3,36 promoted interest in their potential use for primary preven-
Pharmacologic cardioversion does not require sedation or tion or treatment of recurrent episodes of atrial fibrillation,
anesthesia; however, it is likely less effective and still poses particularly when associated with hypertension, myocardial
thromboembolic and pro-arrhythmia risks. The ACC/AHA/ infarction, congestive heart failure, or diabetes mellitus.3
ESC guidelines identify dofetilide, ibutilide, and amioda- Renin-angiotensin system inhibitors also may be useful in
rone as agents with efficacy for pharmacologic cardiover- patients receiving maintenance anti-arrhythmic drug ther-
sion of atrial fibrillation of 7 days’ duration and apy. The combination of amiodarone plus an angiotensin-
disopyramide, flecainide, procainamide, propafenone, and converting enzyme inhibitor or ARB has been shown to
quinidine as less effective or incompletely studied.3 result in better control of sinus rhythm in several
studies.75-77
Ablation Although the impact of renin-angiotensin system block-
Patients failing first-line anti-arrhythmic treatment should ers on morbidity and mortality in patients with atrial fibril-
be considered candidates for amiodarone or RF ablation, lation has not been well studied, ARB therapy was associ-
which is considered to be a second-line option for paroxys- ated with a reduction in the risk of the primary composite
mal or persistent atrial fibrillation, or may be useful in endpoint (cardiovascular mortality, stroke, and myocardial
patients with highly symptomatic lone atrial fibrillation.3 infarction), stroke, and cardiovascular death relative to beta-
Good candidates for RF ablation include individuals who blocker therapy in patients with hypertension, left ventric-
are 70 years of age, with highly symptomatic paroxysmal ular hypertrophy, and atrial fibrillation in the Losartan In-
atrial fibrillation, who have never cardioverted, and have a tervention For Endpoint study.78 Additional studies are
left atrial size 5 cm and ejection fraction 40%.68 Suc- needed to confirm these findings.
8. Eagle et al Atrial Fibrillation Management 11
Statins, Steroids, and Polyunsaturated early reversible neutropenia86 have been identified and
Fatty Acids complicated the clinical development of this agent.
Cardiac inflammation seems to play a role in the pathogen- Tedisamil is an anti-ischemic agent currently being eval-
esis of atrial fibrillation in some patients, and evidence uated for use in patients with atrial fibrillation. In patients
with recent-onset symptomatic atrial fibrillation or atrial
suggests that statins, steroids, and polyunsaturated fatty
flutter, intravenous tedisamil has demonstrated rapid (within
acids may have beneficial anti-inflammatory and anti-ar-
30-40 minutes), dose-related effects (cardioversion); how-
rhythmic properties.73 The prevalence of atrial fibrillation is
ever, pro-arrhythmic effects were evident in the high-dose
reportedly lower among patients with reduced LVEF taking
group (1 case each of torsades de pointes and monomorphic
lipid-lowering drugs (fibric-acid derivatives, bile-acid se-
ventricular tachycardia).87
questrants, statins, ezetimibe, or niacin) than among patients
Vernakalant has demonstrated consistent conversion
with similar levels of ventricular function who are not rates (as high as 61% with intravenous administration) and
taking these drugs.79 low pro-arrhythmia risk.88-90 Orally administered ver-
nakalant reduced short-term recurrence (39%) relative to
Management of Concomitant Conditions placebo (57%) in a phase II clinical trial.91 Adverse events
Hypertension,80 heart failure,9,81 and diabetes82 all com- that occurred more frequently in the active treatment groups
monly coexist with atrial fibrillation and may contribute to than with placebo were bradycardia, sinus bradycardia, and
its development and progression. Therefore, strategies for first-degree AV block (rates not provided). Torsades de
the management of these conditions should be part of the pointes did not occur.
overall treatment plan. The ACC/AHA/ESC guidelines pro- Additional studies are needed to determine if these
vide specific recommendations for maintenance of sinus agents will have a role in the management of atrial fibril-
rhythm in patients with recurrent paroxysmal or persistent lation in the future.
atrial fibrillation plus hypertension, CAD, or heart failure
(Figure 2).3 When no (or minimal) heart disease or uncom-
plicated hypertension is present, flecainide, propafenone, or
SUMMARY
sotalol are recommended as first-line agents. However, fur- Atrial fibrillation is an increasingly common supraventric-
ular arrhythmia which, if not managed appropriately, results
ther clinical assessments should be made as, for example,
in significant consequences in terms of patient morbidity
the choice of sotalol would not be recommended if the
and mortality. The primary goals of atrial fibrillation ther-
patient has underlying bradycardia or a prior sensitivity to
apy should be to reduce such consequences and minimize
beta-blockers. If hypertension is complicated with substan-
symptoms (if present). To ensure the best possible outcome,
tial left ventricular hypertrophy, amiodarone or catheter
atrial fibrillation management should be individualized
ablation is recommended. In patients with CAD, it is rec-
based on patient characteristics and comorbidities that could
ommended that treatment be initiated using dofetilide or
influence response to specific management approaches. The
sotalol, followed by amiodarone or ablation. In the case of importance of adequate anticoagulation concomitant with
heart failure, amiodarone or dofetilide are first-choice anti-arrhythmic therapy should not be overlooked. Histori-
agents, followed by catheter ablation if pharmacologic- cally, anti-arrhythmic drugs have provided suboptimal effi-
based treatment is not successful. Again, choosing between cacy and have had safety/tolerability issues, resulting in an
amiodarone or catheter ablation also would need to take into unmet clinical need for atrial fibrillation drug therapies with
account the prospective patient’s age and comorbidities that improved benefit/risk profiles and demonstrable benefits on
could exclude drug therapy. clinically meaningful outcomes. Newer drugs, such as
dronedarone and several other agents in later stages of
Investigational Agents clinical development may potentially address this need by
New atrial fibrillation therapies being investigated that show providing greater efficacy, reduced cardiovascular morbid-
particular promise include safer multi-ion channel blockers ity and mortality, and an improved safety profile.
or atrial-selective/preferential ion channel blockers such as
azimilide, tedisamil, and vernakalant. Other agents in earlier References
stages of development include new rate-control agents (eg, 1. Rho RW, Page RL. Asymptomatic atrial fibrillation. Prog Cardiovasc
tecadenoson, selodenoson), stretch-activated ion channel Dis. 2005;48:79-87.
blockers (eg, GsMTx-4), and gap junction modifiers (eg, 2. Cohen M, Naccarelli GV. Pathophysiology and disease progression of
atrial fibrillation: importance of achieving and maintaining sinus
rotigaptide, AAP10). rhythm. J Cardiovasc Electrophysiol. 2008;19:885-890.
The investigational agent azimilide has demonstrated 3. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guide-
mixed results in clinical trials conducted in patients with lines for the management of patients with atrial fibrillation-executive
atrial fibrillation.83-85 Although its potential role remains to summary: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines and the European
be established, the benefit of azimilide may be greater in Society of Cardiology Committee for Practice Guidelines (Writing
patients with a history of ischemic heart disease or heart Committee to Revise the 2001 Guidelines for the Management of
failure. An increased risk of torsades de pointes and, rarely, Patients with Atrial Fibrillation). Eur Heart J. 2006;27:1979-2030.
9. 12 The American Journal of Medicine, Vol 124, No 1, January 2011
4. Tsang TS, Miyasaka Y, Barnes ME, Gersh BJ. Epidemiological profile 26. Crijns HJ. Rate versus rhythm control in patients with atrial fibrilla-
of atrial fibrillation: a contemporary perspective. Prog Cardiovasc Dis. tion: what the trials really say. Drugs. 2005;65:1651-1667.
2005;48:1-8. 27. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical
5. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation classification schemes for predicting stroke: results from the National
begets atrial fibrillation. A study in awake chronically instrumented Registry of Atrial Fibrillation. JAMA. 2001;285:2864-2870.
goats. Circulation. 1995;92:1954-1968. 28. Dorian P, Jung W, Newman D, et al. The impairment of health-related
6. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial quality of life in patients with intermittent atrial fibrillation: implica-
pacing. Structural, functional, and electrophysiological characteristics tions for the assessment of investigational therapy. J Am Coll Cardiol.
of a new model of sustained atrial fibrillation. Circulation. 1995;91: 2000;36:1303-1309.
1588-1595. 29. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control
7. Ausma J, Wijffels M, Thoné F, et al. Structural changes of atrial and rhythm control in patients with atrial fibrillation. N Engl J Med.
myocardium due to sustained atrial fibrillation in the goat. Circulation. 2002;347:1825-1833.
1997;96:3157-3163. 30. Opolski G, Torbicki A, Kosior DA, et al. Rate control vs rhythm
8. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural control in patients with nonvalvular persistent atrial fibrillation: the
remodeling during atrial fibrillation. Cardiovasc Res. 2002;54:230- results of the Polish How to Treat Chronic Atrial Fibrillation (HOT
246. CAFE) Study. Chest. 2004;126:476-486.
9. Schoonderwoerd BA, Van Gelder IC, Van Veldhuisen DJ, et al. 31. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial
Electrical and structural remodeling: role in the genesis and mainte- fibrillation--Pharmacological Intervention in Atrial Fibrillation (PIAF): a
nance of atrial fibrillation. Prog Cardiovasc Dis. 2005;48:153-168. randomised trial. Lancet. 2000;356:1789-1794.
10. Manning WJ, Silverman DI, Katz SE, et al. Impaired left atrial me- 32. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate
chanical function after cardioversion: relation to the duration of atrial control and rhythm control in patients with recurrent persistent atrial
fibrillation. J Am Coll Cardiol. 1994;23:1535-1540. fibrillation. N Engl J Med. 2002;347:1834-1840.
11. Franz MR, Karasik PL, Li C, et al. Electrical remodeling of the human 33. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-
atrium: similar effects in patients with chronic atrial fibrillation and control versus rhythm-control in persistent atrial fibrillation: the Strat-
atrial flutter. J Am Coll Cardiol. 1997;30:1785-1792. egies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll
12. Brundel BJ, Van Gelder IC, Henning RH, et al. Ion channel remod- Cardiol. 2003;41:1690-1696.
eling is related to intraoperative atrial effective refractory periods in 34. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control
patients with paroxysmal and persistent atrial fibrillation. Circulation.
for atrial fibrillation and heart failure. N Engl J Med. 2008;358:2667-
2001;103:684-690.
2677.
13. Miyasaka Y, Barnes ME, Gersh BJ, et al. Changing trends of hospital
35. Steinberg JS, Sadaniantz A, Kron J, et al. Analysis of cause-specific
utilization in patients after their first episode of atrial fibrillation. Am J
mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm
Cardiol. 2008;102:568-572.
Management (AFFIRM) study. Circulation. 2004;109:1973-1980.
14. Le Heuzey JY, Paziaud O, Piot O, et al. Cost of care distribution in
36. Snow V, Weiss KB, LeFevre M, et al. Management of newly detected
atrial fibrillation patients: the COCAF study. Am Heart J. 2004;147:
atrial fibrillation: a clinical practice guideline from the American
121-126.
Academy of Family Physicians and the American College of Physi-
15. Thrall G, Lane D, Carroll D, Lip GY. Quality of life in patients with
cians. Ann Intern Med. 2003;139:1009-1017.
atrial fibrillation: a systematic review. Am J Med. 2006;119:448.e1-
37. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in
448.e19.
atrial fibrillation: American College of Chest Physicians Evidence-
16. Wu EQ, Birnbaum HG, Mareva M, et al. Economic burden and
Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6
co-morbidities of atrial fibrillation in a privately insured population.
Suppl):546S-592S.
Curr Med Res Opin. 2005;21:1693-1699.
17. Shiroshita-Takeshita A, Brundel BJ, Nattel S. Atrial fibrillation: basic 38. Calkins H, Brugada J, Packer DL, et al. HRS/EHRA/ECAS expert
mechanisms, remodeling and triggers. J Interv Card Electrophysiol. consensus statement on catheter and surgical ablation of atrial fibril-
2005;13:181-193. lation: recommendations for personnel, policy, procedures and follow-
18. Wit AL, Boyden PA. Triggered activity and atrial fibrillation. Heart up. A report of the Heart Rhythm Society (HRS) Task Force on
Rhythm. 2007;4(3 Suppl):S17-S23. Catheter and Surgical Ablation of Atrial Fibrillation developed in
19. Xu J, Cui G, Esmailian F, et al. Atrial extracellular matrix remodeling partnership with the European Heart Rhythm Association (EHRA) and
and the maintenance of atrial fibrillation. Circulation. 2004;109:363- the European Cardiac Arrhythmia Society (ECAS); in collaboration
368. with the American College of Cardiology (ACC), American Heart
20. Nakano Y, Niida S, Dote K, et al. Matrix metalloproteinase-9 contrib- Association (AHA), and the Society of Thoracic Surgeons (STS).
utes to human atrial remodeling during atrial fibrillation. J Am Coll Endorsed and approved by the governing bodies of the American
Cardiol. 2004;43:818-825. College of Cardiology, the American Heart Association, the European
21. Wongcharoen W, Chen SA. Management of atrial fibrillation in pa- Cardiac Arrhythmia Society, the European Heart Rhythm Association,
tients with heart failure: from drug therapy to ablation. Expert Rev the Society of Thoracic Surgeons, and the Heart Rhythm Society.
Cardiovasc Ther. 2009;7:311-322. Europace. 2007;9:335-379.
22. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by 39. Go AS, Hylek EM, Borowsky LH, et al. Warfarin use among ambu-
heart failure in dogs: atrial remodeling of a different sort. Circulation. latory patients with nonvalvular atrial fibrillation: the anticoagulation
1999;100:87-95. and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med.
23. Ohkusa T, Ueyama T, Yamada J, et al. Alterations in cardiac sarco- 1999;131:927-934.
plasmic reticulum Ca2 regulatory proteins in the atrial tissue of 40. Waldo AL, Becker RC, Tapson VF, Colgan KJ. Hospitalized patients
patients with chronic atrial fibrillation. J Am Coll Cardiol. 1999;34: with atrial fibrillation and a high risk of stroke are not being provided
255-263. with adequate anticoagulation. J Am Coll Cardiol. 2005;46:1729-
24. Lévy S, Maarek M, Coumel P, et al. Characterization of different 1736.
subsets of atrial fibrillation in general practice in France: the ALFA 41. Mitchell AR. Will this be the end of the anticoagulation clinic for
study. The College of French Cardiologists. Circulation. 1999;99: patients with atrial fibrillation? Curr Drug Targets Cardiovasc
3028-3035. Haematol Disord. 2005;5:405-408.
25. Kannel WB, Benjamin EJ. Current perceptions of the epidemiology of 42. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic compli-
atrial fibrillation. Cardiol Clin. 2009;27:13-24. cations of anticoagulant and thrombolytic treatment: American Col-
10. Eagle et al Atrial Fibrillation Management 13
lege of Chest Physicians Evidence-Based Clinical Practice Guidelines 62. Køber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality
(8th Edition). Chest. 2008;133(6 Suppl):257S-298S. after dronedarone therapy for severe heart failure. N Engl J Med.
43. Aguilar MI, Hart R, Pearce LA. Oral anticoagulants versus antiplatelet 2008;358:2678-2687.
therapy for preventing stroke in patients with non-valvular atrial fi- 63. Capucci A, Villani GQ, Piepoli MF, Aschieri D. The role of oral 1C
brillation and no history of stroke or transient ischemic attacks. Co- antiarrhythmic drugs in terminating atrial fibrillation. Curr Opin Car-
chrane Database Syst Rev. 2007;Issue 3. Art. No.: CD006186. DOI: diol. 1999;14:4-8.
10.1002/14651858.CD006186.pub2. 64. Alboni P, Botto GL, Baldi N, et al. Outpatient treatment of recent-
44. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, onset atrial fibrillation with the “pill-in-the-pocket” approach. N Engl
Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for J Med. 2004;351:2384-2391.
atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbe- 65. Van Gelder IC, Wyse DG, Chandler ML, et al. Does intensity of
sartan for prevention of Vascular Events (ACTIVE W): a randomised rate-control influence outcome in atrial fibrillation? An analysis of
controlled trial. Lancet. 2006;367:1903-1912. pooled data from the RACE and AFFIRM studies. Europace. 2006;8:
45. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke 935-942.
prevention in an elderly community population with atrial fibrillation
66. Singh BN. -blockers and calcium channel blockers as antiarrhythmic
(the Birmingham Atrial Fibrillation Treatment of the Aged Study,
drugs. In: Zipes DP, Jalife J, editors. Cardiac Electrophysiology: From
BAFTA): a randomised controlled trial. Lancet. 2007;370:493-503.
Cell to Bedside, 4th edition. Philadelphia: W.B. Saunders, 2004 p
46. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopi-
918-931.
dogrel added to aspirin in patients with atrial fibrillation. N Engl
67. DiMarco JP. Adenosine and digoxin. In: Zipes DPJalife J, editors
J Med. 2009;360:2066-2078.
Cardiac Electrophysiology: From Cell to Bedside, 4th edition. Phila-
47. Olsson SB; Executive Steering Committee of the SPORTIF III Inves-
delphia: W.B. Saunders, 2004 p 942-949.
tigators. Stroke prevention with the oral direct thrombin inhibitor
ximelagatran compared with warfarin in patients with non-valvular 68. Calkins H. New ACC/AHA/ESC guidelines for the management of
atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. atrial fibrillation: highlighting stroke prevention and catheter ablation.
2003;362:1691-1698. 2006. Available at: http://cme.medscape.com/viewarticle/543645_
48. Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for print. Accessed April 2009.
stroke prevention in patients with nonvalvular atrial fibrillation: a 69. Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the
randomized trial. JAMA. 2005;293:690-698. methods, efficacy, and safety of catheter ablation for human atrial
49. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus war- fibrillation. Circulation. 2005;111:1100-1105.
farin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139- 70. Kobza R, Hindricks G, Tanner H, et al. Late recurrent arrhythmias
1151. after ablation of atrial fibrillation: incidence, mechanisms, and treat-
50. Ansell J, Jacobson A, Levy J, et al. Guidelines for implementation of ment. Heart Rhythm. 2004;1:676-683.
patient self-testing and patient self-management of oral anticoagula- 71. Padanilam BJ, Prystowsky EN. Atrial fibrillation: goals of therapy and
tion. International consensus guidelines prepared by International Self- management strategies to achieve the goals. Med Clin North Am.
Monitoring Association for Oral Anticoagulation. Int J Cardiol. 2005; 2008;92:217-235.
99:37-45. 72. Wood MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clinical
51. Garcia DA, Witt DM, Hylek E, et al. Delivery of optimized antico- outcomes after ablation and pacing therapy for atrial fibrillation: a
agulant therapy: consensus statement from the Anticoagulation Forum. meta-analysis. Circulation. 2000;101:1138-1144.
Ann Pharmacother. 2008;42:979-988. 73. Goldstein RN, Stambler BS. New antiarrhythmic drugs for prevention
52. Lafuente-Lafuente C, Mouly S, Longás-Tejero MA, et al. Antiarrhyth- of atrial fibrillation. Prog Cardiovasc Dis. 2005;48:193-208.
mic drugs for maintaining sinus rhythm after cardioversion of atrial 74. Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibril-
fibrillation: a systematic review of randomized controlled trials. Arch lation with angiotensin-converting enzyme inhibitors and angiotensin
Intern Med. 2006;166:719-728. receptor blockers: a meta-analysis. J Am Coll Cardiol. 2005;45:1832-
53. Roden DM, Anderson ME. Proarrhythmia. Handb Exp Pharmacol. 1839.
2006;73-97. 75. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to
54. Trujillo TC, Nolan PE. Antiarrhythmic agents: drug interactions of maintain sinus rhythm in patients with long-lasting persistent atrial
clinical significance. Drug Saf. 2000;23:509-532. fibrillation: a prospective and randomized study. Circulation. 2002;
55. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Mainte- 106:331-336.
nance of sinus rhythm in patients with atrial fibrillation: an AFFIRM
76. Ueng KC, Tsai TP, Yu WC, et al. Use of enalapril to facilitate sinus
substudy of the first antiarrhythmic drug. J Am Coll Cardiol. 2003;42:
rhythm maintenance after external cardioversion of long-standing per-
20-29.
sistent atrial fibrillation. Results of a prospective and controlled study.
56. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for
Eur Heart J. 2003;24:2090-2098.
atrial fibrillation. N Engl J Med. 2005;352:1861-1872.
77. Yin Y, Dalal D, Liu Z, et al. Prospective randomized study comparing
57. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects
amiodarone vs. amiodarone plus losartan vs. amiodarone plus perin-
of low dose amiodarone: a meta-analysis. J Am Coll Cardiol. 1997;
30:791-798. dopril for the prevention of atrial fibrillation recurrence in patients with
58. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone lone paroxysmal atrial fibrillation. Eur Heart J. 2006;27:1841-1846.
on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360: 78. Wachtell K, Hornestam B, Lehto M, et al. Cardiovascular morbidity
668-678. and mortality in hypertensive patients with a history of atrial fibrilla-
59. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of tion: The Losartan Intervention For End Point Reduction in Hyperten-
atrial fibrillation: a dose-ranging study. Eur Heart J. 2003;24:1481- sion (LIFE) study. J Am Coll Cardiol. 2005;45:705-711.
1487. 79. Hanna IR, Heeke B, Bush H, et al. Lipid-lowering drug use is asso-
60. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance ciated with reduced prevalence of atrial fibrillation in patients with left
of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007; ventricular systolic dysfunction. Heart Rhythm. 2006;3:881-886.
357:987-999. 80. Lombardi F, Terranova P. Hypertension and concurrent arrhythmias.
61. Connolly SJ. ATHENA: the effect of dronedarone on cardiovascular Curr Pharm Des. 2003;9:1703-1713.
outcomes and stroke in patients with atrial fibrillation. Presented at the 81. Savelieva I, John Camm A. Atrial fibrillation and heart failure: natural
European Society of Cardiology Congress 2008, Munich, Germany, history and pharmacological treatment. Europace. 2004;5(Suppl 1):
August 30-September 3, 2008. S5-S19.
11. 14 The American Journal of Medicine, Vol 124, No 1, January 2011
82. Movahed MR, Hashemzadeh M, Jamal MM. Diabetes mellitus is a 87. Hohnloser SH, Dorian P, Straub M, et al. Safety and efficacy of intrave-
strong, independent risk for atrial fibrillation and flutter in addition to nously administered tedisamil for rapid conversion of recent-onset atrial
other cardiovascular disease. Int J Cardiol. 2005;105:315-318. fibrillation or atrial flutter. J Am Coll Cardiol. 2004;44:99-104.
83. Pritchett EL, Kowey P, Connolly S, et al. Antiarrhythmic efficacy of 88. Roy D, Rowe BH, Stiell IG, et al. A randomized, controlled trial
azimilide in patients with atrial fibrillation. Maintenance of sinus rhythm of RSD1235, a novel anti-arrhythmic agent, in the treatment of
after conversion to sinus rhythm. Am Heart J. 2006;151:1043-1049. recent onset atrial fibrillation. J Am Coll Cardiol. 2004;44:2355-
84. Pratt CM, Singh SN, Al-Khalidi HR, et al. The efficacy of azimilide in 2361.
the treatment of atrial fibrillation in the presence of left ventricular 89. Roy D, Pratt C, Wyse G, et al. RSD1235 for conversion of atrial
systolic dysfunction: results from the Azimilide Postinfarct Survival fibrillation, the phase III atrial arrhythmia conversion trial. Heart
Evaluation (ALIVE) trial. J Am Coll Cardiol. 2004;43:1211-1216. Rhythm. 2005;2:1035. Abstract LBA– 6098.
85. Lombardi F, Borggrefe M, Ruzyllo W, Lüderitz B. Azimilide vs. 90. Pratt C, Roy D, Juul-Moller S, et al. Efficacy and tolerance of
placebo and sotalol for persistent atrial fibrillation: the A-COMET-II RSD1235 in the treatment of atrial fibrillation or atrial flutter: results
(Azimilide-CardiOversion MaintEnance Trial-II) trial. Eur Heart J. of a phase III, randomized, placebo-controlled, multicenter trial. J Am
2006;27:2224-2231. Coll Cardiol. 2006;47:10A. Abstract 804-803.
86. VerNooy RA, Mangrum JM. Azimilide, a novel oral class III antiar- 91. Pratt CM, Navratil J, Nagy A, et al. Oral vernakalant (RSD1235-SR)
rhythmic for both supraventricular and ventricular arrhythmias. Curr prevents recurrence of atrial fibrillation following cardioversion. Heart
Drug Targets Cardiovasc Haematol Disord. 2005;5:75-84. Rhythm. 2007;4(Suppl):S176. Abstract PO2-92.
![Eagle et al Atrial Fibrillation Management 5
activation, obesity, the use of stimulants, inflammation fibrillation.8 Electrical remodeling, which begins soon after
caused by pericarditis or other disorders, and pulmonary arrhythmia onset, is characterized by a shortening of the atrial
disease. refractory period. This process may be reversible upon resto-
Hospitalizations for atrial fibrillation have increased signif- ration of sinus rhythm. Structural remodeling, which is likely
icantly in recent years, primarily due to the increased avail- more permanent than electrical remodeling, occurs weeks to
ability and utilization of hospital- months after the onset of the ar-
based therapeutic options including rhythmia and includes changes at
drugs and nonpharmacologic inter- both the cellular and tissue lev-
CLINICAL SIGNIFICANCE STATEMENT
ventions (eg, cardioversion).13 The els.8,19,20 Together, these pro-
escalating prevalence of atrial fi- ● Many established options for the treat- cesses result in contractile remod-
brillation and the need for re- ment of atrial fibrillation have limited eling that may facilitate atrial
peated hospitalizations and long- efficacy and safety/tolerability issues, fibrillation persistence and the de-
term pharmacologic treatment of velopment of negative sequelae
but newer therapies attempt to address
these patients make the condition (eg, thrombus formation and atrial
costly; one recent European sur-
these issues and have promising out- dilation). Recovery of contractility
vey showed that the mean in- comes from clinical trials and postmar- after restoration of sinus rhythm is
creased annual cost of caring for a keting surveillance. typically slow.
patient with atrial fibrillation is ● Customized atrial fibrillation manage- The pathophysiology of atrial fi-
approximately €3200 ($5000) ment, assessing individual patient char- brillation in patients with underly-
compared with a matched popula- acteristics and comorbidities, should ing congestive heart failure seems
tion without atrial fibrillation.14 to be somewhat different. In con-
guide the optimal treatment selection.
Indeed, it has been estimated that gestive heart failure, interstitial fi-
the direct cost of managing atrial brosis is found to be increased in the
fibrillation to the United Kingdom atria, leading to heterogeneity of
National Health Service accounts for 2.4% of their annual atrial conduction and regions of slow electrical conduction,
expenditure, amounting to more than £450 million.15 Atrial predisposing to the occurrence of atrial fibrillation.21,22 The
fibrillation is associated with a significant economic burden in atrial fibrosis in congestive heart failure seems to be due to
the US as well. Several studies have shown that health care upregulation of the renin-angiotensin-aldosterone system
costs in the US are approximately 5 times higher for patients and dysregulation of intracellular Ca2 homeostasis in cells
with atrial fibrillation than for those without it, and hospital- of the atrial myocardium.23
14,16
izations are a key contributor. Thorough clinical evaluation of patients who present
Early detection and intervention potentially could de- with certain conditions (eg, hypertension/hypertensive heart
crease the burden of atrial fibrillation on the individual and disease, congestive heart failure, CAD, ischemic cardiomy-
society by preventing progression and related conse- opathy, valvular [rheumatic] heart disease, diabetes, hyper-
quences. The purpose of this review was to briefly describe thyroidism, obesity, and obstructive sleep apnea)9,24,25 can
the pathophysiology of atrial fibrillation and associated se- facilitate early atrial fibrillation detection and timely inter-
quelas, review the goals of atrial fibrillation therapy, and vention. Of course, clinicians should remain mindful that
provide a practical management guide for internists based atrial fibrillation can occur even in the absence of predis-
on recent guidelines and current clinical data. posing factors. Typically, the term “lone atrial fibrillation”
is used to describe younger patients ( 60 years of age) who
have atrial fibrillation in the absence of underlying cardio-
PATHOPHYSIOLOGY AND BURDEN OF pulmonary disease.3
ATRIAL FIBRILLATION Up to 40% of patients in whom atrial fibrillation is found
The pathophysiology of atrial fibrillation remains incom- on a baseline electrocardiogram (ECG) do not experience or
pletely understood; however, it is clear that its occurrence recognize symptoms.1 Even among those that do manifest
requires a triggering factor and an appropriate substrate to symptoms, clinical presentation is highly variable. When
sustain re-entry.3,17 In the majority of patients, the under- present, symptoms can include palpitations, chest pain, dys-
lying triggering mechanism is thought to involve the inter- pnea, fatigue, lightheadedness, syncope, and polyuria. The
action of rapidly firing ectopic foci in the pulmonary veins, hemodynamic consequences of loss of atrial contraction
into which the atrial muscle is known to extend.18 The with resultant loss of atrioventricular (AV) synchrony, heart
mechanism for aberrant impulse origin in pulmonary veins rate irregularity, and rapid ventricular response that are
is uncertain but may involve automaticity, triggered activ- typically found in atrial fibrillation may each contribute in
ity, and/or re-entry.18 varying degrees to the manifestations of these symptoms.1
If atrial fibrillation has been sustained for a period of Regardless of presentation, improperly managed atrial
time, physical and molecular changes in the electrical and fibrillation is associated with significant morbidity and mor-
structural properties of the atria (“remodeling”) occur and tality, including a 5-fold increased risk of stroke (in the
facilitate the conversion from transient to persistent atrial absence of anticoagulation) and a 1.5-fold to 1.9-fold in-](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)