Atrial Fibrillation Epidemiology, Prevention, and Treatment

REVIEW
The State of the Art: Atrial Fibrillation

Epidemiology, Prevention, and Treatment
Daniel P. Morin, MD, MPH; Michael L. Bernard, MD, PhD; Christopher Madias, MD;
Paul A. Rogers, MD, PhD; Sudarone Thihalolipavan, MD;
and N.A. Mark Estes III, MD
Abstract
As the most common sustained arrhythmia in adults, atrial fibrillation (AF) is an established and growing
epidemic. To provide optimal patient care, it is important for clinicians to be aware of AF’s epidemiological
trends, methods of risk reduction, and the various available treatment modalities. Our understanding of
AF’s pathophysiology has advanced, and with this new understanding has come advancements in pre-
vention strategies as well as pharmacological and nonpharmacological treatment options. Following
PubMed and MEDLINE searches for AF risk factors, epidemiology, and therapies, we reviewed relevant
articles (and bibliographies of those articles) published from 2000 to 2016. This “state-of-the-art” review
provides a comprehensive update on the understanding of AF in the world today, contemporary thera-
peutic options, and directions of ongoing and future study.
ª 2016 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2016;nn(n):1-33
trial fibrillation (AF) is the most com-
A
EPIDEMIOLOGY AND POPULATION TRENDS From the Department of
Cardiology, Ochsner
mon sustained arrhythmia in adults, Using Einthoven’s string galvanometer in Medical Center, New
and its prevalence is expected to in- 1909, Lewis1 and Rothberger2 separately Orleans, LA (D.P.M.,
crease 3-fold in the next 3 decades. Experts established electrocardiographically that M.L.B., P.A.R., S.T.); Ochs-
now characterize these epidemiological “auricular fibrillation” caused “pulsus irregu- ner Clinical School, The
University of Queensland
trends as an AF epidemic. On the basis of laris perpetuus,” a condition that was noted School of Medicine, New
these considerations and multiple advances years before by the Scottish cardiologist Sir Orleans, LA (D.P.M.);
in prevention and treatment, all clinicians James Mackenzie3 to have lost the jugular Electrophysiology,
Arrhythmia and
should be aware of the current management A wave on his ink-writing polygraph. Pacemaker Program,
of AF. The therapeutic strategies for rate Initially thought of as an insignificant condi- Division of Cardiology,
Department of Medicine,
control or rhythm control have evolved tion, AF is now recognized to have a sub- Rush University Medical
considerably. The risks and benefits of anti- stantial effect on morbidity and mortality, Center, Chicago, IL (C.M.);
coagulant therapy have a more robust evi- along with an increasing burden on health and Cardiac Arrhythmia
dence base to guide decision making about care utilization and cost.4,5 AF is the most Center, Tufts Medical
Center, Boston, MA
anticoagulation. At the same time, options common clinically important arrhythmia, (N.A.M.E.).
for stroke prevention have evolved into with a recent worldwide estimate of up to
novel pharmacological and nonpharmaco- 33.5 million patients (not even including
logical options. There is an important and those with clinically silent disease), and is
growing body of evidence that the burden increasing in prevalence, making this a
of AF can be reduced with lifestyle interven- global epidemic.6
tions that result in weight loss. Following The epidemiology of AF is more clearly
PubMed and MEDLINE searches for AF established in Western developed countries
risk factors (RFs), epidemiology, and thera- than it is in developing nations.7,8 However,
pies, we reviewed relevant articles (and bib- it appears that the incidence of AF in devel-
liographies of those articles) published from oped countries is twice as much as that in
2000 to 2016. This “state-of-the-art” review developing countries.6 The estimated preva-
represents a comprehensive update for all lence in the United States is around 5.2
clinicians, which will ultimately serve to million, with an expected increase to 12.1
improve outcomes in patients with AF. million by the year 2030.9
Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 1

www.mayoclinicproceedings.org n ª 2016 Mayo Foundation for Medical Education and Research
MAYO CLINIC PROCEEDINGS
incidence of AF in African Americans than in

ARTICLE HIGHLIGHTS whites, despite African Americans’ higher
prevalence of RFs for AF.8,16 The Cardiovascu-
d Atrial fibrillation (AF) is an established and growing global
lar Health Study was the first to suggest this
epidemic. paradox, with a 79% lower risk of AF in the
d Several risk factors for AF have been identified, and risk African American population of the study.17
reduction is possible through modification of these factors. The Analysis of the Atherosclerosis Risk in
d The chief strategies for AF treatmentdrate control and rhythm Communities (ARIC) study16 also suggested
that African Americans were at a lower risk
controldare both viable and have different advantages and
of developing AF, with a 41% lower adjusted
disadvantages. risk of developing AF compared with whites.
d Prevention of stroke and systemic embolism, a major aspect of A meta-analysis18 of 10 studies examining
AF treatment, is evolving in the form of new anticoagulant more than 1 million patients reported that Af-
agents and left atrial exclusion techniques. rican American race appeared to be protective
from AF, exhibiting a 49% lower risk. To
d Sinus rhythm maintenance may be accomplished through the
further investigate whether genetic or environ-
use of antiarrhythmic drugs and/or ablative techniques. mental factors contributed to this AF paradox
d Rhythm control via ablation for AF, most often in the form of in African Americans, Marcus et al19 used ge-
pulmonary vein isolation, is constantly improving and now in- netic analysis to determine the degree of Euro-
cludes procedures that are catheter-based, operative, or hybrid. pean ancestry in African Americans in the
Cardiovascular Health Study and ARIC study
and correlated this information with the risk
Age of developing AF. Interestingly, they found
Age is a major RF for AF, with the risk of that for every 10% increase in European
developing AF doubling with each decade of ancestry there was a 10% increased risk of
life.10 For example, in the Framingham popu- incident AF.
lation, the annual incidence of AF per 1000
persons for those younger than 65 years is Sex
1.9 in women and 3.1 in men as compared Sex also affects the incidence and effects of AF.
with 31.4 in women and 38 in men among For example, women have been found to be
those older than 85 years.11 In both men more symptomatic from AF and have longer
and women older than 40 years, the lifetime paroxysmal AF episodes as well as faster ven-
risk of AF in the Framingham population tricular response rates.20 In the ARIC study,16
was estimated to be around 25%.12 Similar women had a 46% lower risk of AF than did
findings were noted in a European cohort, age-matched men. This difference was also
with an incidence of AF of 1.1 per 1000 seen in a Medicare database review from
person-years in patients aged 55 to 59 years, 1993 to 2007, in which men had an incidence
increasing to 20.7 per 1000 person-years in of newly diagnosed AF of approximately 35
those older than 80 years, with a lifetime AF per 1000 person-years as compared with
risk comparable to that seen in the Framing- approximately 25 per 1000 person-years in
ham cohort.13 According to a Medicare data- women.14 However, over that 15-year time
base review, the incidence of AF has period, the incidence of AF more than
remained approximately stable in the US pop- doubled for both sexes, which was related to
ulation older than 65 years over the past the advancing age of the population. Despite
decade, ranging from 27.8 to 28.3 per 1000 their lower incidence of AF, it is well estab-
person-years.14 lished that in the presence of AF, women
have a higher risk of stroke than do
men.21,22 Furthermore, in the Copenhagen
Race City Heart Study,22 a population-based pro-
In the United States, whites appear to have a spective cohort study, women appeared to
higher risk of incident AF than do African have an independent 2.5-fold increased risk
Americans, Hispanics, and Asians.15 An of cardiovascular (CV) mortality related to
apparent paradox is evident in the lower AF as compared with men.
n n
2 Mayo Clin Proc. XXX 2016;nn(n):1-33 http://dx.doi.org/10.1016/j.mayocp.2016.08.022
www.mayoclinicproceedings.org
THE STATE OF THE ART: ATRIAL FIBRILLATION
COMORBID CONDITIONS AND MODIFICA- Congestive HF

TIONS DESIGNED TO REDUCE AF RISK In his 1997 Shattuck lecture, Braunwald24
The genesis and evolution of AF in any 1 predicted that AF and congestive HF would
patient involves many complex and as yet become epidemics in the 21st century. Atrial
incompletely understood mechanisms. We fibrillation and congestive HF often occur in
do know that there are several important the same individuals and share many comor-
comorbid conditions that promote the bidities.25 Atrial fibrillation itself is associated
development and maintenance of AF. with up to a 3-fold increase in the risk of inci-
Understanding potential contributors to AF dent HF.26 In the international Real-life global
is an important area of research that may survey evaluating patients with Atrial Fibrilla-
translate into better treatment and prevention,27 the prevalence of congestive HF was
tion. Some of the most well-described modi- associated with increasing persistence of AF
fiable factors that increase risk of AF are (33% of those with paroxysmal AF had
congestive heart failure (HF), hypertension congestive HF, compared with 44% in those
(HTN), diabetes mellitus (DM), obesity, with persistent AF and 56% in those with
alcohol consumption, and obstructive permanent AF). Regardless of whether systolic
sleep apnea (OSA).23 Risk factor modifica- function is preserved or reduced, the preva-
tion can affect the development and severity lence of AF is directly associated with New
of AF, as illustrated in Figure 1 and York Heart Association (NYHA) functional
discussed below. class: less than 10% in NYHA functional class
Atrial fibrillation
HTN DM Obesity OSA EtOH CHF
risk factors
Target Target Hgb Limit

SBP <140 mm Hg? A1c <7? EtOH: 2
Target at Early drinks/d
OMT
Intervention Role for ARB Role for least 10% diagnosis,
or ACEi? TZDs? weight CPAP
loss adherence
LA pressure Oxidative RAAS

stress HTN activation
Putative RAAS Vagal AF-
Inflammation HTN Oxidative events? LA
effect activation
stress stretch
Advanced Risk of
Sympathetic glycosylation Cardiac LA
EtOH
drive end-products lipoapoptosis size/fibrosis
induced
CHF
LA electrical and structural
remodeling
Desired
outcome AF burden
FIGURE 1. Atrial fibrillation risk factor modification and its putative effects. ACEi ¼ angiotensin-converting
enzyme inhibitor; AF ¼ atrial fibrillation; ARB ¼ angiotensin receptor blocker; CHF ¼ congestive heart
failure; CPAP ¼ continuous positive airway pressure; DM ¼ diabetes mellitus; EtOH ¼ ethyl alcohol
consumption; Hgb A1c ¼ hemoglobin A1c; HTN ¼ hypertension; LA ¼ left atrial; OMT ¼ optimal
medical therapy; OSA ¼ obstructive sleep apnea; SBP ¼ systolic blood pressure; TZD ¼ thiazolidine-
dione; RAAS ¼ renin-angiotensin-aldosterone system.

I have AF compared with up to 55% in NYHA Hypertension

functional class IV.28 Numerous studies have implicated HTN as an
Importantly, patients with combined AF independent RF for incident AF. For example,
and congestive HF have a worse prognosis an analysis10 of the Framingham cohort indi-
than those with either component alone. In cated that HTN independently increased the
an analysis29 of the Framingham population, risk of AF by factors of 1.5 in men and 1.4
development of congestive HF in patients in women. Even pre-HTN range blood pres-
with AF was associated with increased sure has been associated with an increased
mortality in both men (hazard ratio [HR], risk of AF: the Women’s Health Study sug-
2.7; 95% CI, 1.9-3.7) and women (HR, 3.1; gested that the risk of incident AF during their
95% CI, 2.2-4.2). Conversely, in those with 12.4 years of follow-up was greater in those
congestive HF, the subsequent occurrence of with a baseline systolic blood pressure of
AF was associated with increased mortality in 130 mm Hg or higher or a diastolic blood
both men (HR, 1.6; 95% CI, 1.2-2.1) and pressure of 90 mm Hg or higher.38 Similar
women (HR, 2.7; 95% CI, 2.0-3.6).29 A findings were noted in a cohort of middle-
meta-analysis30 reviewing prognosis among aged men followed for 35 years, in which
patients with congestive HF found an adjusted baseline systolic blood pressure of 128 mm
AF-related increase in mortality in 30,248 Hg or higher and diastolic blood pressure of
subjects from randomized controlled trials 80 mm Hg or higher was associated with a
(odds ratio [OR], 1.4; P<.0001) and in 1.5-fold and 1.79-fold higher risk of incident
23,721 subjects from observational studies AF, respectively.39 Hypertension is believed
(OR, 1.14; P<.05). to increase sympathetic output, increase left
Atrial fibrillation and congestive HF are atrial pressure and volume, and activate the
mutual co-conspirators that induce complex RAAS, thereby leading to atrial fibrosis, struc-
structural, electrophysiological, and neuro- tural and electrical atrial remodeling, and pro-
hormonal changes leading to their reciprocal motion of AF.40
evolution and perpetuation. Experimental Conceivably, aggressive treatment of
models have shown that heterogeneity of chronic HTN could help to reduce the risk
repolarization throughout the atria, slowed of AF, and there is some evidence to this ef-
atrial conduction, and a shortened atrial fect. A post hoc analysis41 of the standard vs
refractory period can cause and sustain aggressive blood pressure lowering arms of
AF.31,32 Congestive HF induces atrial tissue the randomized Action to Control Cardiovas-
stretch by way of increased atrial pressure cular Risk in Diabetes trial indicated that tar-
and volume, leading to increased triggered geting a systolic blood pressure of less than
activity and changes in refractoriness, predis- 120 mm Hg compared with the “standard”
posing to AF.33 Furthermore, increased atrial target of less than 140 mm Hg trended toward
automaticity and heterogeneity of depolariza- a lower incidence of AF, though this finding
tion and repolarization result from atrial was not statistically significant.
hypertrophy and chamber enlargement.34 The choice of antihypertensive agent may
Neurohormonal changes occurring in conges- affect the incidence of AF. The effect of
tive HF via renin-angiotensin-aldosterone angiotensin converting enzyme inhibitors
system (RAAS) activation promote extracel- (ACEis) and angiotensin receptor blockers
lular matrix fibrosis, leading to heterogeneity (ARBs) on the prevention of AF is one contro-
of atrial repolarization and predisposing to versial example. A post hoc analysis of 2 large
the development of AF.32,35 Angiotensin II investigations of HTN treatmentdthe Losar-
may also increase the activity of pulmonary tan Intervention For End Point Reduction in
vein (PV) cardiomyocytes, which may lead Hypertension42 and Valsartan Antihyperten-
to AF initiation.36 Atrial fibrillation itself sive Long-Term Use (VALUE)43 trialsd
may lead to RAAS activation and may induce suggested that ACEi or ARB therapy might
tachycardia-mediated cardiomyopathy, again reduce incident AF. In the Losartan Interven-
exemplifying the complex interplay between tion For End Point Reduction in Hypertension
AF and congestive HF.37 trial,42 which enrolled hypertensive patients
n n
with left ventricular (LV) hypertrophy but type 2 DM during follow-up had a nearly
without AF, therapy with losartan had similar 50% increased risk of new-onset AF (HR,
efficacy in lowering blood pressure as atenolol, 1.49; 95% CI, 1.14-1.94). Likewise, a meta-
but was associated with a 33% reduced risk of analysis50 including nearly 1.7 million patients
new-onset AF (relative risk, 0.67; P<.001). In from several case-control and cohort studies
the VALUE trial,43 valsartan was associated indicated a 40% increased risk of AF in
with a lower incidence of AF compared with patients with type 2 DM.
amlodipine (unadjusted HR, 0.843; P¼.046). Currently, there are no convincing pub-
However, a meta-analysis44 evaluating the lished data to support specific upstream ther-
efficacy of ACEi or ARB therapy in preventing apy for AF prevention in patients with DM.
AF revealed a lack of efficacy in the HTN However, a few reports implicate thiazolidine-
subgroup, which included 3 trials and diones (TZDs) as agents that may be associated
26,403 patients. It should be noted that this with AF risk reduction. Thiazolidinediones
meta-analysis44 did not include the VALUE activate peroxisome proliferatoreactivated
trial, that only 2 of the 3 included studies eval- receptor gamma, which decreases peripheral
uated new-onset AF, and that there was signif- insulin resistance in patients with type 2
icant heterogeneity between the 3 studies. A DM. However, the use of these agents is
Danish retrospective nationwide nested 1:1 limited by adverse effects such as weight
matched study45 of individuals with only gain, congestive HF, and potentially bladder
HTN found that the use of ACEi or ARB as cancer.51 A nationwide population-based
monotherapy was associated with a dramati- cohort study52 in Taiwan evaluated 12,065 pa-
cally lower risk of incident AF as compared tients with type 2 DM and observed that the
with the use of b-blockers (ACEi: HR, 0.12; use of TZDs was associated with a 31% lower
95% CI, 0.10-0.15; ARB: HR, 0.10; 95% CI, adjusted risk of new-onset AF. In addition, in
0.07-0.14) or diuretics (ACEi: HR, 0.51; their prospective cohort study of 150 consec-
95% CI, 0.44-0.59; ARB: HR, 0.43; 95% CI, utive patients with type 2 DM undergoing
0.32-0.58), but not compared with the use pulmonary vein isolation (PVI) for drug-
of calcium channel antagonists. A recent refractory paroxysmal AF, Gu et al53 found
meta-analysis46 of 4 randomized controlled that the use of the TZD pioglitazone was asso-
trials found the ARB telmisartan to be more ciated with a higher rate of maintenance of
effective than other antihypertensive drugs in sinus rhythm (SR) without antiarrhythmic
reducing AF recurrence (HR, 0.54; 95% CI, therapy over nearly 23 months of follow-up
0.34-0.86). Overall, these data indicate a po- (86% vs 71%; P¼.034). Animal models sug-
tential role for RAAS blockade in preventing gest that TZDs may prevent electrical and
AF and reducing its recurrence, though more structural atrial remodeling via their anti-
studies are needed. inflammatory and antioxidant properties.54
Diabetes Mellitus Obesity

Diabetes mellitus is found in up to 20% of pa- Like AF, obesity is a growing worldwide
tients with AF.47 The hyperglycemia of DM is epidemic.55 An association between increasing
believed to contribute to oxidative stress, body mass index (BMI; calculated as the
inflammation, and formation of advanced weight in kilograms divided by the height in
glycosylation end products (which infiltrate meters squared) and AF is becoming clear.
the myocardium, causing hypertrophy and Obesity is associated with left atrial dilation,56
interstitial fibrosis), all of which lead to electri- which may be mediated via cardiac lipoapop-
cal and anatomical remodeling of the left tosis57 and impaired autonomic balance.58
atrium (LA) and promotion of AF.48 Indeed, long-term follow-up in the Framing-
Evaluation of the Framingham population ham Heart Study indicated a 4% increase in
implicated DM as an independent contributor incident AF for each unit increase in BMI.59
to new-onset AF in both men (OR, 1.4; 95% However, this association was no longer signif-
CI, 1.0-2.0) and women (OR, 1.6; 95% CI, icant after adjustment for echocardiographic
1.1-2.2).10 Moreover, the VALUE trial49 indi- left atrial diameter, indicating that the link be-
cated that those who were diagnosed with tween AF and obesity may be mediated by left

atrial structural changes. Similar findings link- subjects who underwent CT analysis indicated
ing obesity with an increased risk of AF were that total epicardial fat volume was associated
observed in the Women’s Health Study,60 with AF. Furthermore, the volume of epicar-
the ARIC study,61 and various other commu- dial fat was significantly higher in patients
nity cohort studies.62,63 The Long-Term Effect with persistent AF than in those with parox-
of Goal-directed weight management on an ysmal AF. Potential mechanisms linking
Atrial Fibrillation Cohort study64 of over- epicardial fat and AF include fatty infiltration
weight patients with paroxysmal and persis- potentially leading to anisotropic conduction
tent AF evaluated the effect and magnitude in the atria, profibrotic adipokines leading to
of weight loss on the burden of AF. Remark- remodeling, inflammation, and autonomic
ably, the Long-Term Effect of Goal-directed nervous system dysregulation.70
weight management on an Atrial Fibrillation
Cohort study found a 6-fold greater probabil- Alcohol Consumption
ity of arrhythmia-free survival in patients with The association between alcohol consumption
a durable weight loss of 10% or more than in and AF is well established.71-73 Alcohol intake
those who lost less weight. Furthermore, the is associated with depressed cardiac function,
CARDIOrespiratory FITness on Arrhythmia cardiac conduction abnormalities, and intera-
Recurrence in Obese Individuals With Atrial trial electromechanical conduction delay.73 In
Fibrillation trial65 evaluated how respiratory 1 study,74 alcohol consumption and increased
fitness in obese individuals, defined as BMI vagal activity were found to be independent
of 27 kg/m2 or more, affected the rate of AF triggers for paroxysmal AF. These 2 mecha-
recurrence. Three hundred eight obese pa- nisms were found to coexist in some patients,
tients with symptomatic AF underwent base- raising the possibility of a vagally mediated
line exercise stress testing to determine peak mechanism through which consumption of
metabolic equivalents, and baseline respiratory alcohol increases AF risk. A 34% increased
fitness levels were categorized as low (85%), risk of AF was noted in Framingham partici-
adequate (86%-100%), or high (>100%) ac- pants who consumed more than 3 drinks/
cording to the percentage of predicted meta- d.75 Furthermore, a prospective cohort
bolic equivalents achieved. Subjects were study76 found that consuming more than 14
offered a tailored exercise program. At final drinks/wk was associated with a 39% higher
follow-up (w4 years), those with high cardio- independent risk of AF, and a recent meta-
respiratory fitness levels at baseline and those analysis77 evaluating the “dose-response” rela-
who achieved a fitness gain of 2 metabolic tionship between alcohol intake and AF found
equivalents or more had significantly better a 10% increase in the relative risk of AF for
arrhythmia-free survival with or without a each drink per day beyond the low threshold
rhythm control strategy than did those with of only 1 drink/d. On the basis of these data,
lower baseline fitness levels who did not limiting alcohol consumption could be a perti-
achieve fitness gains. nent strategy for preventing AF.
Recent interest has arisen about the role of
epicardial fat (ie, adipose tissue between the Obstructive Sleep Apnea
myocardium and the visceral pericardium) Obstructive sleep apnea is estimated to exist in
and AF.66,67 Epicardial fat can be evaluated 4% of otherwise healthy adult women and in
via noninvasive imaging techniques, such as 9% of healthy men.78 Repetitive hypopnea
cardiac magnetic resonance and computed to- and apnea, in association with episodes of
mography (CT). Studies have observed an as- hypoxia and subsequent recovery, are associ-
sociation between abundant epicardial fat and ated with increased sympathetic drive and
atrial myocardial adipocyte infiltration.68 A CT parasympathetic withdrawal, increased blood
analysis of subjects in the Framingham Heart pressure, and activation of inflammatory me-
Study68 indicated that total epicardial fat, but diators and reactive oxygen species, all of
not paracardial or intra-abdominal fat, was which may be associated with atrial
independently associated with AF (OR per arrhythmia induction.79,80 Not unexpectedly,
SD increase in pericardial fat volume, 1.28; OSA is frequently associated with AF. Gami
P<.05). Likewise, a separate study69 of 300 et al81 prospectively evaluated 151 consecutive
n n
patients presenting for electrical cardioversion consumption, evaluated the effect of weight
for AF. Compared with 312 consecutive gen- management and control of other RFs for AF
eral cardiology patients without a history of on long-term outcomes after AF ablation.
AF, those with AF had a significantly higher Risk factor management goals in affected indi-
prevalence of OSA, with an OR of 2.19 viduals included an initial weight loss goal of
(P¼.0006). Another study82 revealed a preva- 10% body weight with a subsequent goal of
lence of OSA of 81.6% in patients with achieving a BMI of 25 kg/m2 or less, increased
persistent AF who were referred for exercise activity, achievement of goal lipid
polysomnography as compared with a preva- levels, lifestyle modifications, medical therapy
lence of only 60% in matched subjects as indicated to maintain a glycosylated hemo-
without AF. globin level of 6.5% or less, a target blood
A synergistic effect between treatment of pressure of less than 130/80 mm Hg, use of
OSA and efficacy of AF therapies has been CPAP if indicated for OSA, and counseling
noted. Obstructive sleep apnea is associated to achieve smoking cessation and reduction
with a higher AF recurrence rate after electrical in alcohol intake to 30 g/wk or less. Sixty-
cardioversion,83 a lower rate of response to one patients participated in the RF manage-
antiarrhythmic therapy,84 and an increased ment program, whereas 88 patients did not.
risk of short-term recurrence of AF in patients After catheter ablation (CA), all patients were
undergoing PVI.85 Several single-center evaluated every 3 to 6 months using a Holter
studies have found that OSA therapy with monitoring and clinic visits. Participants in
continuous positive airway pressure (CPAP) the RF management program achieved greater
reduces AF recurrence after electrical cardio- weight and blood pressure reduction as well as
version83 and improves the success rate of improved glycemic and lipid control. As
PVI.86-88 In a large cohort study,88 there was shown in Figure 2, compared with control
a dramatically lower rate of postablation AF subjects, those in the RF management pro-
recurrence in CPAP-treated patients than in gram had far superior arrhythmia-free survival
patients with OSA who did not use CPAP over an average of 3.5 years after a single abla-
(HR, 0.16; P<.001). Another observation of tion procedure (32.9% vs 9.7%; P<.001) and
consecutive patients undergoing PVI, in which also after multiple ablation procedures (87%
approximately 20% had OSA, noted that more vs 17.8%; P<.001). Interestingly, aggressive
than 42 months postablation, patients with RF modification was also associated with car-
OSA who were treated with CPAP had signif- diac structural improvements including a
icantly less AF recurrence than did those with reduction in left atrial volume index, LV septal
untreated OSA (35% vs 68%; P<.0001).89 thickness, and LV end-diastolic diameter.
Although these findings are promising, larger
Risk Factor Modification randomized controlled trials are needed to
Theoretically, intensive targeting of the myriad establish definitively the apparent benefit of
RFs for AF should reduce AF burden. This aggressive RF modification programs for pa-
premise was tested in a randomized controlled tients undergoing AF ablation.
trial90 of 150 overweight or obese patients
who underwent aggressive RF management ECONOMIC AND PUBLIC HEALTH EFFECT
with or without intensive weight management. OF AF
The intervention group reported significant Atrial fibrillation imposes a significant finan-
weight loss (14.3 kg vs 3.6 kg; P<.001), as cial effect on public health. It is estimated to
well as markedly decreased AF frequency account for 1% of the United Kingdom’s Na-
and symptomatic severity. Subsequently, the tional Health Service budget and $16 to $26
Aggressive Risk Factor Reduction Study for billion annually in medical expenditures in
Atrial Fibrillation,91 a single-center observa- the United States.92-96 Compared with
tional cohort study of consecutive patients matched patients, AF is associated with an
with a BMI of 27 kg/m2 or more and at least estimated incremental medical cost of $8705
one other RF including HTN, impaired per patient per year, including inpatient,
glucose tolerance or DM, hyperlipidemia, outpatient, and pharmacy costs.93 The bulk
OSA, smoking, or excessive alcohol of the increased cost of AF includes

1.0 1.0
Single procedure AF-free survival
Multiprocedure AF-free survival

0.8 0.8
0.6 0.6
0.4 0.4
0.2 Group 0.2 Group

Control Control
RFMx RFMx
0.0 0.0
0 180 360 540 720 0 180 360 540 720

Follow-up (d) Follow-up (d)
Time 0 180 360 540 730 0 180 360 540 730

(d)
RFM 61 59 48 33 27 61 55 46 32 25
Control 88 79 51 28 16 88 72 51 36 23
FIGURE 2. Atrial fibrillationefree survival in the Aggressive Risk Factor Reduction Study for Atrial
Fibrillation of adding aggressive risk factor modification to AF ablation. AF ¼ atrial fibrillation; RFM ¼ risk
factor management. Reproduced from J Am Coll Cardiol,91 with permission.
hospitalization, stroke, HF, and loss of eco- AF is evolving. Although a consensus in the
nomic productivity.95,97 Furthermore, evalua- field has not been reached, it seems unlikely
tion of the disability-adjusted life-year metric, that a single mechanism can be implicated in
a means of assessing the effect of chronic AF initiation and maintenance. Almost
disorders combining information on prema- certainly, AF is the ultimate manifestation of
ture death (ie, years of life lost) and disability multiple disease pathways.99,100
caused by the chronic disorder (ie, years lived A significant development in the history of
with disability),95 indicated that over the 20 AF was the identification of focal AF “triggers,”
years spanning 1990 to 2010, the worldwide which usually consist of spontaneous depolar-
burden of disability-adjusted life-year loss ization of atrial cells. The most common
attributable to AF increased from 54 to 65 anatomical sources of ectopic atrial beats that
per 100,000 person-years for men and from trigger AF are the atrial myocardial “sleeves”
39 to 46 per 100,000 person-years for extending onto the PVs. These transient
women.6 These increases reflect a growing ectopic tachycardias initially decrease atrial
global epidemic of AF that not only is an eco- electrical refractoriness, which promotes
nomic burden but also contributes to a AF.101 Later, with repeated firing and atrial
growing disability burden. remodeling, AF is able to sustain itself via
reentry within heterogeneously conducting
PATHOPHYSIOLOGY OF AF atrial tissue.102,103
Electrocardiographically, AF is characterized Once AF is initiated, the mechanisms
by findings including the presence of irregular allowing its maintenance remain disputed.
R-R intervals and the absence of distinct P Among competing theories, the “multiple
waves.98 Mechanically, the chaotic electrical wavelet hypothesis” proposes that there are
activity of AF leads to ineffective atrial contrac- multiple independent reentrant wavelets that
tion as well as further structural (and electri- exist within the fibrillating atria.104,105 Other
cal) changes in the atria, which themselves theories include focal activity within cardiac
potentiate AF.32,99 Our understanding of the ganglionic plexi and untethered macroreen-
exact mechanisms and pathophysiology of trant activity in the form of small spiral
n n
reentrant drivers, often termed rotors.106 Some myocyte depolarization, the atrial cell’s
consider rotors to be analogous to the vortex compensatory response is to down-regulate
of a tornado, giving rise to the surrounding L-type Ca2þ channels to lessen calcium over-
storm of AF. load. However, the reduction in the concentra-
The mechanisms described above are tion of these channels has the untoward
likely involved in various stages of AF. For adverse effect of shortening action potentials,
example, initially when AF is transient (or reducing refractoriness, and further promoting
“paroxysmal”), triggered activity likely is the AF.115
originating mechanism. It is widely observed Increasingly, evidence links AF to inflam-
in the electrophysiology community that if mation.116-119 This relationship has been re-
AF is left untreated, it becomes more difficult ported in the immediate period after cardiac
to suppress (ie, that “AF begets AF”).32 In later surgery.120 In addition, inflammatory markers,
stages of AF, with ongoing structural and elec- such as C-reactive protein levels, tend to be
trical changes in the atrium, more complex more elevated in patients with persistent AF
mechanisms contribute to AF persistence (ie, than in those with paroxysmal AF.121 Further-
AF that continues until it is either chemically more, higher C-reactive protein levels predict
or electrically cardioverted) or permanence AF relapse after cardioversion and have been
(ie, AF that is refractory to all treatments). associated with an increased thromboembolic
Because of this shift in pathophysiology, treat- risk.122
ment of symptomatic patients with parox- Other factors involved in AF initiation and
ysmal AF often focuses on the suppression maintenance include heightened autonomic
of triggers, whereas treatment of persistent nervous system activity and the structural
AF incorporates substrate-based therapeutic fibrosis associated with aging.123 Both para-
strategies.98,106 sympathetic and sympathetic nervous systems
As detailed above, established RFs such as have been implicated. Specifically, when Hol-
HTN, ischemic CV disease, valvular heart dis- ter monitor recordings were analyzed in pa-
ease, HF, obesity, and DM can predispose patients with paroxysmal AF, the initiation of
tients to AF. The mechanisms linking these AF often occurred after an increase in adren-
RFs to AF include structural and electrical ergic (sympathetic) tone, followed by an
changes to the LA, which then promote AF. abrupt parasympathetic predominance imme-
It is hypothesized that atrial histological diately before the initiation of AF.124
remodeling can result from increased left atrial The autonomic nervous system can pro-
pressure and size.107,108 Vulnerability to the mote atrial electrical heterogeneity and is a po-
development of AF correlates with atrial dila- tential trigger of atrial arrhythmias, including
tation, which leads to connective tissue AF.125 In patients with chronic AF, atrial auto-
disruption and eventual interstitial fibrosis. nomic remodeling, including increased atrial
These atrial histological alterations can result sympathetic nerve density, is often present.126
in slowed atrial conduction velocity, local het- Concomitantly, the parasympathetic system
erogeneous conduction, and local block, can contribute by producing spatially hetero-
creating an ideal substrate for AF.35,109,110 geneous atrial refractoriness, promoting
Neurohormonal and electrical atrial remodel- intra-atrial reentry and supporting AF mainte-
ing may also occur, which may further nance.127 In light of the evidence for auto-
encourage the development of AF. For nomic involvement in AF, therapeutic
example, the RAAS can play a contributory applications of neuromodulation are being
role in adverse remodeling via its proinflam- sought to decrease AF’s occurrence and main-
matory and profibrotic properties.111-113 tenance. Currently, ganglionated plexus abla-
As AF progresses, altered calcium tion, renal sympathetic denervation, cervical
handling, including calcium leak from the vagal nerve stimulation, and biological thera-
sarcoplasmic reticulum, can lead to increased pies (including targets for G-protein auto-
automaticity and may also adversely affect nomic effectors) are under active
conduction velocity and tissue refractori- investigation.125
ness.114 Partly because of the increased inward Thus, the development of AF can be a
calcium current that results from frequent multifactorial process, including susceptibility

related to comorbidities that promote early and patient preference should be considered.
atrial enlargement, conduction heterogeneity Experts seem to agree that a trial of rhythm
due to atrial fibrosis, inflammation, ion chan- control should be offered at the first presenta-
nel abnormalities, and autonomic remodeling. tion of AF.98,132 This approach offers patients
with a potentially reversible cause of AF (eg,
RHYTHM CONTROL VS RATE CONTROL hyperthyroidism, pericarditis, or infection) or
Patients and their physicians must coopera- those with an isolated episode of AF the chance
tively make a decision to pursue either a for early control of the arrhythmia. If AF does
“rate control” or a “rhythm control” strategy relapse, the choice is either to continue with a
in the management of their AF. simple rate control strategy or to embark on a
The rate control strategy primarily uses rhythm control strategy if there was symptom-
atrioventricular nodal blockade (often with atic benefit after restoration of SR. Particularly
b-blockers, calcium channel blockers, and/or appropriate patients for the rhythm control
digitalis) to limit the rate of atrioventricular strategy include those who are young (age,
conduction. Every patient with newly detected <50 years), those with “lone” AF, and those
AF should initially receive adequate ventricu- with significant symptoms despite rate
lar rate control (as needed) regardless of the control.132,133
chosen chronic management strategy. A sus- Antiarrhythmic therapy for AF, whether
tained rapid ventricular response to AF over alone or in conjunction with electrical cardio-
even a relatively short time may lead to the version and/or ablation, is currently recom-
development of tachycardia-mediated cardio- mended only for symptom amelioration and
myopathy. Furthermore, significant congestive improvement in quality of life.98 This restric-
HF symptoms can occur in patients who sus- tion exists in part because no mortality benefit
tain rapid ventricular rates, even in the to rhythm control has been established in ran-
absence of overt LV systolic dysfunction.98,128 domized controlled trials. For example, the
The heart rate target for the rate control Atrial Fibrillation Follow-up Investigation of
strategy has evolved over time. In 614 patients Rhythm Management (AFFIRM) study134 was
with permanent AF over at least 2 years of the largest randomized controlled trial to
follow-up, the randomized prospective trial compare the rate control and rhythm control
Rate Control Versus Electrical Cardioversion strategies, and found similar all-cause mortality
II129 established that a lenient rate control strat- at 5 years in the 2 groups (24% vs 21%;
egy (goal resting heart rate, <110 beats/min) is P¼.08). Critics of the AFFIRM study have
as effective as a strict rate control strategy (goal argued that the adverse effects and imperfect ef-
resting heart rate, <80 beats/min). Although ficacy of available antiarrhythmic therapy
the composite end point of death from CV potentially limited the benefit of rhythm con-
causes, hospitalization for HF, and stroke as trol. Supporting this suspicion, a supplemen-
well as systolic embolism, bleeding, and life- tary analysis of the AFFIRM study134 reported
threatening arrhythmic events were similar in a gross mortality benefit to rhythm restoration,
both groups, the lenient rate control group but this effect was neutralized by an increase in
had far fewer total clinical visits than did the mortality associated with antiarrhythmic drug
strict rate control group (75 vs 684; P<.001). (AAD) use. Even among patients with HF, there
Once ventricular rate control is achieved in was no identified difference between the strate-
the short term, the decision must be made to gies in terms of overall survival, CV death,
continue the rate control strategy alone or to worsened HF, or stroke.135 Similarly, in a
pursue SR restoration and maintenance, also study136 of patients who developed new-
termed the rhythm control strategy. Rhythm onset AF after cardiac surgery, there was no dif-
control can be achieved through medical anti- ference between the randomized treatment
arrhythmic therapy, electrical cardioversion, strategies of rate control or rhythm control in
and/or invasive procedures that are either cath- terms of death or other serious adverse events.
eter- or surgery-based.98,130,131 When deciding After discharge, the rate of freedom from AF
among strategies, patient-specific factors such was similarly high between the groups. Thus
as stage of AF (ie, paroxysmal, persistent, or far, the rhythm control strategy including
permanent), symptoms, age, comorbidities, catheter-based therapy has not undergone
n n
randomized controlled trials to assess its effect

on mortality in any population. No structural heart disease Structural heart disease
Improvements in symptoms and quality of
life may occur with rhythm restoration, but
these benefits are not seen in all patients. Dofetlide
CAD CHF
However, after SR restoration there can be sig- dronedarone
flecainide
nificant average symptomatic improve- propafenone
ment.133,135,137 For example, A Randomized sotalol
Dronedarone
Trial to Assess Catheter Ablation Versus Rate Catheter Amiodarone
dofetilide
ablation dofetilide
Control in the Management of Persistent Atrial Catheter sotalol
ablation
Fibrillation in Chronic Heart Failure138 found
in 52 patients with symptomatic AF with LV
ejection fraction less than 35% an objective Amiodarone Amiodarone
improvement in exercise performance after
PVI, including peak oxygen consumption FIGURE 3. A candidate flow diagram for therapy for atrial fibrillation. For
(3.07 mL/kg per min; P¼.02), improved Min- patients without structural heart disease, antiarrhythmic drug therapy with
nesota symptom scores, lower natriuretic pep- any agent except amiodarone is first-line therapy. Dronedarone, dofetilide,
tide levels, and a trend toward improved and sotalol are first-line agents for patients with CAD. Amiodarone and
6-minute walk test (P¼.10) after return to dofetilide are first-line therapy for patients with CHF. Amiodarone is a
SR. Thus, a management strategy of rhythm second-line agent for all patients without CHF. For patients with left ven-
restoration with either AADs or catheter- tricular wall thickness greater than 1.5 cm, only dronedarone and amio-
based ablation is appropriate in symptomatic darone are advised. Catheter ablation before antiarrhythmic drug therapy is
patients with AF, despite a failure to show a a class IIa and IIb indication in patients with paroxysmal and persistent atrial
fibrillation, respectively. CAD ¼ coronary artery disease; CHF ¼ congestive
clear mortality benefit. Finally, it should be
heart failure.
mentioned that diminished frequency of AF
can be seen as an acceptable outcome of the
rhythm control strategy, rather than only contraindicated in patients with creatinine
accepting as success absolute AF suppression. clearance level less than 20 mL/min or baseline
corrected QT interval greater than 440
ANTIARRHYTHMIC DRUG THERAPY ms.142,144-146 Initiation of dofetilide requires
For patients with symptomatic AF, AADs can 3 days of inpatient monitoring of the corrected
be useful for improving symptoms via mainte- QT interval, and similar inpatient monitoring
nance of SR. Also, for patients who develop for sotalol is recommended, but not manda-
cardiomyopathy related to rapidly conducted tory.145,146 Dronedarone is contraindicated in
AF, AADs can be used to restore SR and patients with advanced HF or a recent HF exac-
thereby preserve LV function. In the acute erbation.147-151 Amiodarone and dofetilide are
setting, AADs can be used to facilitate success- the only agents recommended for patients with
ful electrical cardioversion. Antiarrhythmic LV dysfunction.139,146
drugs are not frequently used for patients Amiodarone is a second-line agent for
with asymptomatic AF or for those with per- most patients, but it remains widely used
manent AF. The success of AADs is often because of its high efficacy, its ability to be
limited by contraindications to their use and administered intravenously, and its applica-
by adverse drug effects.139-141 bility in patients with renal impairment and/
As summarized in Figure 3, the choice of or cardiomyopathy. Amiodarone has well-
AAD depends on the presence or absence of known toxicities including adverse effects on
structural heart disease and/or HF, renal insuf- the lung, thyroid, liver, skin, and eye,
ficiency, and LV hypertrophy (ie, LV wall thick- requiring monitoring during long-term use.
ness, 1.5 cm).139 Class Ic agents, such as In addition, amiodarone has a higher risk of
flecainide and propafenone, are restricted to other adverse effects than do other AADs.140
those patients with structurally normal hearts The overall success rates of AADs for
and are contraindicated in patients with previ- maintaining SR range between 30% and
ous myocardial infarction.142,143 Some class III 50%, with amiodarone having the highest effi-
agents, such as sotalol and dofetilide, are cacy.139 For patients with drug-refractory

symptomatic AF, procedural options are rec- incorporates into the model age 65 years, fe-
ommended (see below). male sex, and peripheral vascular disease. In
addition to the CHA2DS2-VASc RFs, other
known factors increasing stroke risk in pa-
STROKE PREVENTION AND BLEEDING RISK
tients with AF include spontaneous echo
Risk Stratification for Stroke and Bleeding contrast, chronic kidney disease, and smok-
Stroke and systemic embolism are significant ing.156-158 The most recent AF guidelines
causes of morbidity and mortality in patients advise oral anticoagulation (OAC) in patients
with AF.152,153 AF increases stroke risk 5- at high risk (ie, CHA2DS2-VASc score, 2).
fold, and strokes that are related to AF lead to For patients with moderate risk (CHA2DS2-
more severe disability and mortality.153 For VASc score, 1), the full gambit of possible pro-
patients with valvular AF, especially AF related phylactic approaches (OAC, aspirin, or even
to mitral stenosis, the stroke risk can reach no therapy) may all be considered, though
20-fold that of a similar patient without AF. expert opinion leans toward full anticoagula-
Stroke prophylaxis in AF must balance a tion (see below). For low-risk patients
patient’s thromboembolic risk with their (CHA2DS2-VASc score, 0), the guidelines
bleeding risk. The most widely accepted risk advise no antithrombotic therapy.98 A HAS-
stratification tools for stroke risk and bleeding BLED score of 3 or more predicts high risk
risk are the CHA2DS2-VASc (Congestive heart of bleeding, but there are no available guide-
failure, hypertension, age 75, diabetes mel- lines on therapy on the basis of this or any
litus, stroke, vascular disease, age 65-74, sex other bleeding risk algorithm.
category [female]) and HAS-BLED (Hyp- In contrast to these epidemiological pre-
ertension, abnormal liver/renal function, diction scores, there also exist both temporal
stroke, bleeding risk, labile INRs, elderly (age and structural determinants of stroke risk in
65), drugs/alcohol) scores, respectively AF. For example, the Asymptomatic Stroke
(Table 1).154,155 In addition to the original and Atrial Fibrillation Evaluation in Pacemaker
CHADS2 score, the CHA2DS2-VASc score Patients (ASSERT) trial reported a roughly 2-
fold increase in stroke rate for patients with
atrial high rate episodes lasting for more than
TABLE 1. CHA2DS2-VASc and HAS-BLED Compo- 6 minutes as detected by their pacemaker or
nents, Scoring Methods, and Risk Calculators defibrillator.159 Interestingly, there was not a
CHA2DS2-VASc Points Score Stroke risk strong temporal association between AF events
CHF 1 0 0% and strokes: only 6 of 59 patients with a stroke
HTN 1 1 1.3% had an atrial high rate event detected within
Age 75 y 2 2 2.2% 30 days of their event.159 In addition, the anat-
DM 1 3 3.2% omy of the left atrial appendage (LAA) can
Stroke/TIA 2 4 4.0%
predict the risk of stroke in AF, with more
Vascular disease 1 5 6.7%
complex morphologies indicating higher
Age 65-75 y 1 6 9.8%
Female sex 1 7 9.6%
thrombotic risk.160
8 6.7%
9 15.2% Choice of Stroke Prophylaxis
For patients at high risk as well as in select pa-
HAS-BLED (1 point each) Score Bleeding risk tients with moderate risk, OAC therapy is
Hypertension 0 0.9% advised for the reduction of stroke and sys-
Abnormal Liver/Renal function 1 3.4% temic embolism.
Stroke 2 4.1%
Bleeding risk 3 5.8%
Aspirin, Antiplatelet Agents, and Warfar-
Labile INRs 4 8.9%
Elderly (age, 65 y) 5 9.1%
in. Early trials examining stroke prevention in
Drugs/alcohol 6-7 Too rare AF focused on warfarin and antiplatelet
agents. Aspirin alone has exhibited essentially
CHF ¼ congestive heart failure; DM ¼ diabetes mellitus;
no meaningful effect on stroke reduction,
HTN ¼ hypertension; INR ¼ international normalized ratio;
TIA ¼ transient ischemic attack.
with only the Stroke Prevention in Atrial
Fibrillation (SPAF) trial reporting any
n n
TABLE 2. Comparison of the Main Trials Leading to Novel Oral Anticoagulant Approval, Including Average CHADS2 Score Among Subjects As
Well As Hazard Ratios With 95% CIs for Stroke and Systemic Embolism, Major Bleeding, and Intracranial Hemorrhagea,b
ENGAGE AF/TIMI 48
RE-LY (N¼18,113): ROCKET-AF (N¼14,264): ARISTOTLE (N¼18,201): (N¼21,105):
Variable dabigatran (150 mg bid) rivaroxaban (20 mg qd) apixaban (5 mg bid) edoxaban (60 mg qd)
CHADS2 score 2.1 3.5 2.1 2.8
Stroke and systemic embolism 0.66 (0.53-0.82)c 0.88 (0.75-1.03)d 0.80 (0.67-0.95)c 0.88 (0.75-1.03)d
Major bleeding 0.93 (0.81-1.07)d 1.04 (0.90-1.20)d 0.69 (0.6-0.8)c 0.80 (0.71-0.91)c
Intracranial hemorrhage 0.40 (0.27-0.60)c 0.67 (0.47-0.93)c 0.42 (0.30-0.38)c 0.47 (0.34-0.67)c
Dose adjustment 75 mg bid if 15 mg qd if Decrease dose to 30 mg qd if
GFR 15-30 mL/min GFR 15-50 mL/min 2.5 mg bid if 2 or GFR 15-50 mL/min
more of Cr >1.5, age
>80 y, or weight
<60 kg are present
a
bid ¼ twice daily; CHADS2 ¼ congestive heart failure, hypertension, age >75 y, diabetes mellitus, stroke, transient ischemic attack, or systemic embolism; GFR ¼ glomerular
filtration rate; qd ¼ daily.
b
Criteria for dose adjustments are also listed.
c
Drug that met superiority criteria for the end point as compared with warfarin.
d
Drug that met noninferiority criteria for the end point as compared with warfarin.
significant benefit.161,162 Despite not having termed novel oral anticoagulants [NOACs] or
been studied in a low-risk population, because direct oral anticoagulants) have been approved
of its low risk, aspirin is an option for patients by the Food and Drug Administration (FDA)
with a CHA2DS2-VASc score of 1 or less. In for stroke and systemic embolism reduction
the Atrial Fibrillation Clopidogrel Trial with in nonvalvular AF.165-168 A summary of the
Irbesartan for Prevention of Vascular Events - outcomes of the major trials leading to each
Aspirin (ACTIVE-A) trial,163 the antiplatelet NOAC’s FDA approval is given in Table 2.
agent clopidogrel plus aspirin reduced strokes Dabigatran (Pradaxa), a direct thrombin
as compared with aspirin alone, at a cost of inhibitor, was the first NOAC approved by
elevated bleeding risk. However, when clopi- the FDA, with the 150 mg dose studied in
dogrel and aspirin were compared with the Randomized Evaluation of Long-Term
warfarin in the Atrial Fibrillation Clopidogrel Anticoagulation Therapy (RE-LY) trial,165
Trial with Irbesartan for Prevention of exhibiting superiority to warfarin therapy for
Vascular Events - Warfarin (ACTIVE-W) stroke reduction (HR, 0.66; 95% CI, 0.53-
trial,164 warfarin produced a 40% further risk 0.82) as well as noninferiority for major
reduction of stroke and systemic embolism. bleeding (HR, 0.93; 95% CI, 0.81-1.07). In
Although warfarin is effective in reducing the Rivaroxaban Once Daily Oral Direct Factor
stroke rates, there are significant limitations to Xa Inhibition Compared with Vitamin K
its use, including the need for frequent Antagonism for Prevention of Stroke and Em-
monitoring of the international normalized bolism Trial in Atrial Fibrillation ARISTOTLE:
ratio, variable time in the therapeutic range Apixaban for Reduction in Stroke and Other
(most often, target international normalized Thromboembolic Events in Atrial Fibrillation
ratio, 2-3), the need for sometimes unaccept- (ROCKET-AF) trial,166 rivaroxaban (Xarelto),
able dietary restrictions, and multiple drug- a factor Xa inhibitor, exhibited noninferiority
drug interactions. The recent advent of non- for reduction of stroke and systemic embolism
warfarin oral anticoagulants has significantly (HR, 0.88; 95% CI, 0.75-1.03) as well as
increased treatment options. bleeding events (HR, 1.04; 95% CI, 0.90-
1.20). Apixaban (Eliquis), a factor Xa inhibi-
Nonwarfarin Oral Anticoagulants (Novel tor, is the only NOAC exhibiting superiority
Oral Anticoagulants/Direct Oral Anti- to warfarin for both stroke reduction (HR,
coagulants). After more than 50 years of 0.80; 95% CI, 0.67-0.95) and major bleeding
warfarin being the only OAC option, since (HR, 0.69; 95% CI, 0.60-0.80), as reported
2010 4 nonwarfarin oral anticoagulants (also in the Apixaban for Reduction in Stroke and

Other Thromboembolic Events in Atrial Fibril- approved for use in patients with prosthetic
lation (ARISTOTLE) trial.167 The Effective heart valves.
Anticoagulation with Factor Xa Next Genera-
tion in Atrial Fibrillation -Thrombolysis in Left Atrial Appendage Closure
Myocardial Infarction 48 (ENGAGE AF-TIMI The most common site of intracardiac
48) trial168 studied edoxaban (Savaysa), the thrombus formation is the LAA.171 Thrombi
newest factor Xa inhibitor, and found nonin- are particularly common in the LAA because
feriority to warfarin for reduction of stroke of the LAA’s dead-end anatomy and because
and systemic embolism (HR, 0.88; 95% CI, of its prominent trabeculations.172 Although
0.75-1.03) and superiority for reducing OAC remains the principal method of prevent-
bleeding events (HR, 0.80; 95% CI, 0.71- ing such thrombi, it does not completely elimi-
0.91). All 4 NOACs exhibited statistically sig- nate stroke risk, and for some patients
nificant reduction in intracranial hemorrhage anticoagulation is contraindicated or undesir-
as compared with warfarin. able. These limitations have generated increased
The choice of NOAC may depend on other interest in mechanical exclusion of the LAA as
factors in addition to efficacy and safety. The an adjunct to, or replacement for, OAC.
NOACs have variable dependence on renal Surgical exclusion of the LAA is commonly
clearance, sometimes leading to specific dose performed at the time of other cardiac surgery,
adjustments (Table 2). Only apixaban has whether that surgery is solely targeted at AF
been approved for patients on dialysis. Edoxa- treatment or is concomitant with other ther-
ban is contraindicated in patients with robust apy (eg, mitral valve repair/replacement).173
renal function (glomerular filtration rate, A number of approaches have been used for
>90 mL/min) because of rapid drug clearance. surgical exclusion. Surgical ligation with
Of note, the only agent to exhibit superiority sutures or staples can be effective in some
to warfarin for ischemic stroke prevention patients. However, when examined with trans-
was dabigatran at the 150 mg dose twice esophageal echocardiography, incomplete
daily.165 Furthermore, only dabigatran has closure or nondurable occlusion has been
an FDA-approved reversal agent, idarucizu- found in a considerable number of patients.174
mab.169 The definition of “nonvalvular” AF Complete excision of the LAA appears to pro-
was somewhat different across the various vide more effective results.175 Newer technol-
NOAC trials, but most often “valvular” AF ogies, such as the AtriClip external closure
included moderate to severe mitral stenosis, device (AtriCure Inc.), make surgical LAA
a prosthetic heart valve, or mitral valve repair. closure technically easier than LAA amputa-
The only available study evaluating dabigatran tion and oversewing and might be more effec-
use in the presence of mechanical heart valves, tive than suture ligation.176 Although
Randomized, Phase II Study to Evaluate the minimally invasive approaches have been
Safety and Pharmacokinetics of Oral Dabiga- described, surgical LAA excision/closure thera-
tran Etexilate in Patients after Heart Valve pies have the inherent disadvantage of being
Replacement (RE-ALIGN),170 reported harm considerably invasive and are not routinely
in the dabigatran arm. To date, there has performed as stand-alone procedures.175 In
been no trial directly comparing NOACs. addition, available data on their effectiveness
As the individual NOAC trials included in stroke prevention are limited, though a
patients with a wide range of mean CHADS2 large randomized controlled trial that seeks
scores, varying from 2.11.1 in the RE-LY to provide more clarity is ongoing (https://
and ARISTOTLE trials to 3.50.9 in the clinicaltrials.gov/ct2/show/NCT01561651). On
ROCKET-AF trial, caution must be exercised the basis of the available data, the 2014
when drawing conclusions about these drugs’ AHA/ACC/HRS guideline for the management
use in patients with much higher or much of patients with AF98 provides a relatively
lower risk scores. Overall, the NOACs as a weak consideration (class IIb; level of evidence
class exhibit favorable efficacy and safety pro- C) for surgical exclusion of the LAA at the time
files in comparison with warfarin. However, of cardiac surgery.
warfarin remains an effective agent for many Percutaneous therapies for LAA exclusion
patients, and it remains the only OAC or closure have gained favor recently.177,178
n n
FIGURE 4. (A) WATCHMAN device, which consists of a metallic frame with fixation barbs and a
polyester fabric that covers the atrial face of the device, as well as a fluoroscopic image of a
WATCHMAN device being deployed. (B) LARIAT system, with its intracardiac (catheter/balloon/magnet)
portion interacting with its epicardially delivered magnetic guidewire and preloaded catheter-delivered
suture, as well as a fluoroscopic image just before LARIAT suture deployment. Reproduced from Prog
Cardiovasc Dis177 and Am Heart J178 with permission.
Among these, the most promising technolo- frequent, likely related to a considerable proce-
gies with supportive data are the intracardiac dural learning curve.180 With continued
WATCHMAN LAA occluder (Boston Scienti- PROTECT-AF follow-up, the WATCHMAN de-
fic) and the LARIAT system (SentreHEART vice was more effective than warfarin for stroke
Inc.), which cinches the LAA closed with a su- reduction (HR, 0.61; 95% CI, 0.38-0.97) and
ture delivered epicardially. These devices are similar in terms of safety.181 Subsequently, the
depicted in Figure 4. Prospective Randomized Evaluation of the
The WATCHMAN device was examined in Watchman LAA Closure Device In Patients
the Watchman Left Atrial Appendage System With Atrial Fibrillation Versus Long Term
for Embolic Protection in Patients With Atrial Warfarin Therapy (PREVAIL) trial182 and REg-
Fibrillation (PROTECT-AF) trial,179 which istry on WATCHMAN Outcomes in Real-Life
enrolled patients with AF who are warfarin Utilization (EWOLUTION) registry183
eligible and compared LAA closure to OAC confirmed WATCHMAN’s high implant suc-
with warfarin and initially found LAA occlusion cess rate and low risk. The WATCHMAN device
to be noninferior to OAC for stroke reduction is FDA approved for stroke risk reduction in
(relative risk, 0.71; 95% CI, 0.44-1.3). patients who are warfarin eligible but for
Although there were concerns about whom anticoagulation is undesirable.
procedure-related adverse events, with subse- In patients with a contraindication to
quent experience these events became less warfarin, the WATCHMAN device has been

FIGURE 5. Pulmonary vein isolation using a standard radiofrequency catheter. (A) Catheters that have
been advanced from the femoral veins to the heart. An intracardiac echocardiography (ICE) catheter is
positioned within the right atrium to guide transseptal puncture as well as mapping and ablation catheter
manipulation. A circular mapping catheter is placed in each pulmonary vein and is used to assess for the
presence of pulmonary vein potentials and to guide ablation. (B) An electroanatomic map of the left
atrium. Encircling ablation lesions (red) placed in a point-by-point fashion around the antrum of each
pulmonary vein. A shadow of the circular mapping catheter is seen in the left inferior pulmonary vein with
the tip of the ablation catheter (gray/green) delivering a lesion along the antrum of the vein. Panel A:
Reproduced from N Engl J Med,192 with permission.
found to be superior to historical controls, as 2.6%.187 Similar to WATCHMAN, the LAR-

well as cost-effective.184,185 To date, no ran- IAT’s rates of success and adverse events also
domized study has been performed comparing show a significant learning curve188: in a more
WATCHMAN device and an inactive control. recent multicenter registry189 of 682 patients,
However, it seems likely that LAA closure complete LAA closure was achieved in 98%,
may be useful for stroke prevention in OAC- with a severe complication rate of only 1.6%.
contraindicated patients. On follow-up, however, incomplete LAA
Originally marketed for use during laparo- closure was detected in approximately 7% of
scopic procedures, the LARIAT suture/snare the examined patients.189
system is FDA approved for soft tissue closure. To date, published trials examining exclu-
In thousands of cases, it has been used “off-label” sion of the LAA have used warfarin as the
to close the LAA via an epicardial approach. Its active control. It remains unclear whether
potential advantage over WATCHMAN is that the future applicability of LAA closure will
LARIAT leaves no foreign material within the be affected by the superior efficacy and safety
heart, which may lessen the need for even of the NOACs in comparison to warfarin.
short-term postprocedure anticoagulation. Its
weakness, however, may be the procedure’s ABLATION OF AF
higher rate of significant procedural complica- Over the past decade, CA of AF has evolved
tions, as well as the risk of incomplete LAA considerably to become safer and more effec-
closure.186 A meta-analysis evaluating a total tive and is now among the most frequently
of 309 patients found a procedural success rate performed cardiac procedures in the United
of 90%, with a rate of severe complications of States.190
n n
As discussed above, PVs are the most exhibited in several clinical trials and has
frequent anatomical sources of ectopic atrial driven the increase in ablation for the manage-
beats that can trigger paroxysms of AF.191 ment of AF.192-195
Left atrial myocardial “sleeves” extending
from the PVs are recognized as the primary Patient Selection for AF Ablation
source of triggers in 82% to 90% of patients The management of AF, including the use of
with paroxysmal AF. Since the initial descrip- CA, should be tailored to each specific patient,
tion of a PV trigger by Haissaguerre et al in taking into account several factors including
1998, electrical isolation of the PVs has been symptom severity and frequency, tolerance of
the primary end point in the catheter-based medical therapy, age, and underlying comor-
treatment of AF.98,191 bidities.190 Patients and physicians should
In PVI, lesions are created in the LA, have a clear understanding of the goals of
around the antrum of each vein, resulting in care, procedural risk, and realistic expectations
nonconducting scar. Most often, this is per- of ablation outcomes. Although CA can be
formed with catheters using radiofrequency effective in individual patients, success rates
energy to deliver point by point, connecting have varied in clinical trials.
lesions around the circumference of the veins Early trials of CA focused on patients with
(Figure 5). Nonconducting tissue around the paroxysmal AF and little or no structural heart
veins’ antra then blocks electrical triggers disease who had failed medical therapy with at
from exiting (and entering) the veins, electri- least 1 AAD. In these trials,192-195 reported 12-
cally isolating them from the LA and thus pre- month success rates ranged from 66% to 86%.
venting the initiation of AF. The superiority of It is clear that AF ablation is most successful in
catheter-based PVI for the maintenance of SR patients with paroxysmal AF.196 Even so,
compared to AAD therapy alone has been many patients with paroxysmal AF require
TABLE 3. AHA/ACC/HRS Practice Guideline for the Management of Patients With Atrial Fibrillation: Recom-
mendations for Catheter Ablation to Maintain Sinus Rhythm
Class I (Benefit >>> Risk; Procedure/treatment SHOULD be performed)
1. Atrial fibrillation catheter ablation is useful for symptomatic paroxysmal AF refractory or intolerant to at least
1 class I or III antiarrhythmic drug when a rhythm control strategy is desired. (Level of evidence: A)
2. Before consideration of AF catheter ablation, assessment of the procedural risks and outcomes relevant to the
individual patient is recommended. (Level of evidence: C)
Class IIa (Benefit >> Risk; IT IS REASONABLE to perform procedure/treatment)

1. Atrial fibrillation catheter ablation is reasonable for some patients with symptomatic persistent AF refractory or
intolerant to at least 1 class I or III antiarrhythmic drug. (Level of evidence: A)
2. In patients with recurrent symptomatic paroxysmal AF, catheter ablation is a reasonable initial rhythm control
strategy before therapeutic trials of antiarrhythmic drug therapy, after weighing the risks and outcomes of
drug and ablation therapy. (Level of evidence: B)
Class IIb (Benefit Risk; Procedure/treatment MAY BE CONSIDERED)

1. Atrial fibrillation catheter ablation may be considered for symptomatic long-standing (>12 mo) persistent AF
refractory or intolerant to at least 1 class I or III antiarrhythmic drug when a rhythm control strategy is desired.
(Level of evidence: B)
2. Atrial fibrillation catheter ablation may be considered before the initiation of antiarrhythmic drug therapy with a
class I or III antiarrhythmic drug for symptomatic persistent AF when a rhythm control strategy is desired.
(Level of evidence: C)
Class III (No benefit, or potential harm; Procedure/treatment IS CONTRAINDICATED)

1. Atrial fibrillation catheter ablation should not be performed in patients who cannot be treated with anticoagulant
therapy during and after the procedure. (Level of evidence: C)
2. Atrial fibrillation catheter ablation to restore sinus rhythm should not be performed with the sole intent of
obviating the need for anticoagulation. (Level of evidence: C)
AF ¼ atrial fibrillation.
Reproduced from J Am Coll Cardiol,98 with permission.

TABLE 4. Randomized Controlled Trials of Catheter Ablation vs Antiarrhythmic Drug Therapy for the Management of AFa
Study % of patients Freedom from AF recurrence

Reference, year Study design size (N) with paroxysmal AF Follow-up CA AAD P value
200 b
Krittayaphong et al, 2003 CA as second-line therapy 30 70% 1y 79% 40% .018
compared to amiodarone
Wazni et al,192 2005 (RAAFT) CA as first-line therapy 70 96% 1y 87% 37% <.001
Stabile et al,201 2005 (CACAF) CA as second-line therapy 137 67% 1y 55.9% 8.7% <.001
Pappone et al,193 2006 (APAF) CA as second-line therapy 198 100% 1y 93% 35% <.001
in paroxysmal AF
Oral et al,202 2006 CA as second-line therapy 146 0% 1y 74% 58% .05
in chronic AF
Jais et al,194 2008 (A4) CA as second-line therapy 112 100% 1y 89% 23% <.0001
in paroxysmal AF
Forleo et al,203 2009 CA as second-line therapy 70 41% 1y 80% 42.9% .001
in patients with paroxysmal
AF with type 2 diabetes
Wilber et al,195 2010 (ThermoCool) CA as second-line therapy 167 100% 9 mo 66% 16% <.001
in paroxysmal AF (after a 3-mo
blanking period)
Packer et al,204 2013 (STOP-AF) Cryoballoon ablation as 245 78% 1y 69.9% 7.3% <.001
second-line therapy in
paroxysmal AF
Cosedis Neilsen et al,205 CA as first-line therapy in 294 100% 2y 85% 71% .004
2012 (MANTRA-PAF) paroxysmal AF
Morillo et al,206 2014 (RAAFT-2) CA as first-line therapy in 127 98% 2y 53% 41% .03
paroxysmal AF
Mont et al,207 2014 (SARA) CA as second-line therapy 146 0% 1y 70.4% 43.7% .002
in persistent AF
a
A4 ¼ Catheter Ablation versus Antiarrhythmic Drugs for Atrial Fibrillation; AAD ¼ antiarrhythmic drug; AF ¼ atrial fibrillation; APAF ¼ Ablate and Pace in Atrial Fibrillation;
CA ¼ catheter ablation; CACAF ¼ Catheter Ablation for the Cure of Atrial Fibrillation; CT ¼ computed tomography; MANTRA-PAF ¼ Medical Antiarrhythmic Treatment
or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation; MRI ¼ magnetic resonance imaging; NA ¼ not applicable; RAAFT ¼ Radiofrequency Ablation for Atrial
Fibrillation Trial; RAAFT-2 ¼ Radiofrequency Ablation versus Antiarrhythmic Drugs as First-Line Therapy of Atrial Fibrillation 2; SARA ¼ Study of Ablation versus anti-
aRrhythmic drugs in persistent Atrial fibrillation; STOP-AF ¼ Sustained Treatment of Paroxysmal Atrial Fibrillation.
b
“Second-line therapy” indicates AF recurrence despite previous management with at least 1 AAD.
more than 1 ablation procedure to produce substantial structural heart disease, the compa-
durable success.197 rably lower success rates of ablation and the
Favorable success rates after CA in patients frequent need for recurrent procedures have
with paroxysmal AF have led to class I recom- led to lower levels of recommendation for
mendations from the Heart Rhythm Society ablation in patients with persistent AF and
and the American College of Cardiology/ long-standing (>12 months) persistent AF
American Heart Association Task Force on (class IIa and class IIb, respectively).98
Practice Guidelines98 for the use of CA to Patients with paroxysmal AF are more
maintain SR in patients with symptomatic likely to achieve maintenance of SR than are
paroxysmal AF who are refractory or intol- those with either persistent or permanent
erant to at least 1 class I or class III AAD. AF.198 For example, recent studies using
Table 3 summarizes societal guideline recom- catheter-based approaches in the treatment of
mendations for AF ablation. Despite the over- paroxysmal AF have reported success rates of
all high levels of recommendation in support more than 80% at 1 year without antiar-
of ablation, it should be stressed that the deci- rhythmic medical therapy. In persistent AF,
sion to pursue ablation needs to be considered however, success rates are not as high, and
on a patient-by-patient basis, weighing indi- ablation typically requires more extensive
vidual factors as described above. In patients lesion sets to address the underlying atrial sub-
with more advanced AF and in those with strate. Among patients with persistent AF,
n n
approximately 40% to 50% require a repeat create more consistent lesions. The use of
procedure, after which the success rate ap- such catheters has been associated with
proaches 70%.199 Table 4 summarizes the re- reduced procedure time and decreased AF
sults of several representative randomized recurrence after CA.
controlled trials examining AF ablation. One technical challenge in point-by-point
Based on the present data, AF ablation PVI is the need for sustained periods of cath-
should be limited to patients with symptom- eter manipulation by a skilled operator to
atic AF, with the goal of improving quality create uninterrupted circumferential lesions.
of life.190 Although AF has been associated To mitigate this challenge, balloon-tipped
with an increased risk of stroke, HF, and catheters have been developed with the objec-
death, the current evidence about whether tive of creating contiguous lesions around the
CA reduces the risk of these outcomes remains antrum of each PV.214 In the most common
insufficient.26,29,134 Ongoing large multicenter current iteration of these procedures, the
randomized controlled trials will assess balloon is advanced toward the PV over an
whether early CA reduces mortality and stroke appropriately placed wire, wedging the
risk as compared with noninvasive therapy balloon into the PV antrum. Through a central
with rate and rhythm control drugs.208,209 lumen, intravenous contrast is injected into
the vein to evaluate for an effective seal of
Innovations in Ablation Catheter Design the PV, indicating circumferential balloon-
Atrial fibrillation ablation is most often per- tissue contact. The balloon is then filled with
formed via the femoral vein, with the LA being liquid nitrous oxide, producing tissue destruc-
accessed via a transseptal approach. Intracar- tion via freezing (cryoablation).214 Cryoabla-
diac echocardiography can be used to guide tion using balloon-based catheters has
transseptal puncture(s) and catheter place- proven effective in large clinical trials.215,216
ment within the LA.210 Electroanatomic map- A recent randomized multicenter trial217
ping systems are then used to create a compared cryoballoon ablation with point-
computerized representation of the LA and by-point RFA in drug-refractory paroxysmal
the PVs.210 Most commonly, a circular map- AF and found that the 2 techniques had
ping catheter is placed within the PVs during similar efficacy and safety.
ablation to record PV electrical potentials and Another balloon-based catheter uses
assess for electrical isolation. An irrigated-tip endoscopy to provide real-time direct tissue
radiofrequency ablation (RFA) catheter is visualization and delivery of laser energy. In
then used to create point-by-point lesions the first multicenter randomized trial218 study-
encircling the antrum of each vein. Although ing this technology, the visually guided laser
ablation using a “simple” RFA catheter can balloon proved noninferior to standard radio-
be successful, it is not the current state of frequency PVI. Novel circular multipoint
the art. Recent innovations in ablation catheter radiofrequency catheters have also been
design have the intention of streamlining the created and have been associated with short
procedure while also improving safety and ef- procedure times and high acute success
ficacy. Some such advancements are depicted rates.211 Further research will be necessary to
in Figure 6 and are discussed below. assess the long-term success of AF ablation
Until recently, information on the quality using these innovative technologies.
of catheter-tissue contact existed only in the
form of tactile feedback from the catheter, im- Substrate Modification: Current and
aging (fluoroscopy and/or intracardiac ultra- Emerging Strategies
sound), and electroanatomic mapping. The etiology of AF relapse despite confirmed
Recent data indicate that effective lesion for- PVI at the time of first ablation can be multi-
mation depends on substantial contact force factorial. Possible causes for recurrence can
between the catheter and the tissue.212,213 include electrical reconnection of PVs, other
Consequently, novel RFA catheters have been (non-PV) anatomical sites functioning as trig-
designed to provide real-time information on gers for AF, progression of atrial myopathy,
the direction and magnitude of catheter- and lack of sufficient arrhythmic substrate
tissue contact force, allowing the operator to modification with PVI alone.190,219 In contrast

FIGURE 6. Novel strategies for pulmonary vein isolation. (A) An artist’s depiction of the cryoballoon. The
balloon is inflated at the antrum of each pulmonary vein. Through a central lumen, a circular mapping
catheter is placed within the vein to assess for pulmonary vein potentials. Through the same central lumen,
intravenous contrast injections are used to evaluate for an effective seal of the pulmonary vein, indicating
circumferential tissue contact around the antrum of the vein. (B) A fluoroscopic image of the cryoballoon
inflated in the antrum of the right superior pulmonary vein. A pacing catheter may be placed high in the
superior vena cava, as shown here. Via that catheter, phrenic nerve pacing allows for monitoring of
phrenic nerve injury during ablation of the right pulmonary veins. (C) A fluoroscopic image of the nMARQ
circular multipoint radiofrequency catheter placed in the antrum of the left inferior pulmonary vein. (D)
Three-dimensional left atrial anatomy with ablation lesions (red) created around each pulmonary vein and
the nMARQ catheter in the antrum of the left inferior pulmonary vein. Panel A: Reproduced from https://
www.medtronicacademy.com, with permission. Panel C and D: J Cardiovasc Electrophysiol. Reproduced
from J Cardiovasc Electrophysiol,211 with permission.
to most ablation procedures performed by car- the appropriate target(s) for substrate modifi-
diac electrophysiologists, in which the cation in AF remain incompletely defined.
arrhythmic circuit or “substrate” is clearly iden- Over time, as PVI evolved from delivery of
tified and directly targeted for ablation (eg, the targeted lesions within the veins themselves to
slow atrioventricular nodal pathway in atrio- wide circumferential lesions enclosing the
ventricular nodal reentrant tachycardia or the veins’ antra, success rates have
cavotricuspid isthmus in typical atrial flutter), improved.190,219 It is believed that moving
n n
FIGURE 7. Strategies for substrate modification. (A) A posterior view of the left atrium. Point-by-point
ablation has been performed using standard radiofrequency catheter ablation. Pulmonary vein isolation
lesions are shown in red. Additional substrate ablation has been performed with an anatomical “roof line”
connecting the 2 superior pulmonary veins and a “mitral annular line” connecting the left inferior pul-
monary vein and the mitral annulus (green lines). Areas of complex fractionated atrial electrograms have
also been ablated (blue lesions). (B) A fluoroscopic image of a 64-pole catheter placed in the left atrium to
guide ablation of focal impulses and left atrial rotors. (C) A minimally invasive subxyphoid approach for
pericardioscopic epicardial ablation of the posterior wall of the left atrium. (D) A representation of the
lesions created by such an approach on the left atrial posterior wall. IVC ¼ inferior vena cava; LA ¼ left
atrium; LPV ¼ left pulmonary vein; LV ¼ left ventricle; PA ¼ pulmonary artery; RA ¼ right atrium; SVC ¼
superior vena cava. Panel B: Reproduced from J Atr Fibrillation,221 with permission. Panel C: Reproduced
from Heart Rhythm,222 with permission. Panel D: Reproduced from EP Lab Digest,223 with permission.
ablation sites into the body of the atrium re- depicted in Figure 7. One strategy attempts
sults in further modification of AF substrate, to emulate surgical approaches to “debulking”
contributing to this success. This theory is the LA by using RFA to create lines of block
supported in studies performed in patients within the LA. The most commonly fashioned
with previous AF ablation who remained free lines include a roof line connecting the left and
of clinical AF despite the identification of elec- right superior PVs and a mitral line connecting
trical reconnection in the PVs.220 In many pa- the left inferior vein to the mitral
tients with paroxysmal AF, it appears that annulus.224,225 Another strategy focuses on
sufficient substrate modification occurs with the mapping and ablation of complex fraction-
antral PVI alone, but patients with more ated atrial electrograms (CFAEs; pronounced
advanced diseasedwith persistent and long- “cafés”) throughout the LA (and sometimes
standing persistent AFdmay require addi- the right atrium).226 It is believed that CFAEs
tional ablation to achieve durable success.190 might represent areas of slowed conduction or
Because the optimal targets for substrate pivot points of wavelets that are critical in the
modification in nonparoxysmal AF remain un- maintenance of AF. The use of these tech-
clear, several different ablation strategies have niques has shown mixed success in clinical tri-
been examined. Some such techniques are als, and over time, additional problems have

been recognized.227 Gaps that result from patients with persistent as opposed to parox-
anatomically noncontiguous lines or from ysmal AF.235 A multicenter prospective study
nondurable lesions can result in recurrence found that in patients with AF undergoing
of AF and can form the substrate for iatrogenic CA, the degree of atrial fibrosis was indepen-
atrial flutters.228 Mapping of CFAEs is rela- dently associated with the likelihood of
tively nonspecific, and 1 disadvantage of this recurrent arrhythmia postablation.236 The vari-
approach is that extensive single point ablation ability in the degree and distribution of fibrosis
can result in a proarrhythmic substrate.227,229 might help to explain why PVI can fail in pa-
Mechanistic insights into AF have led to tients with clinically paroxysmal AF but exten-
novel catheter-based techniques focusing on sive atrial fibrosis and why PVI alone might be
the identification and targeting of specific elec- effective in some patients with persistent AF
trical substrates that could be central to the and only mild atrial fibrosis. Patients with a
perpetuation of AF.129 Despite the traditional diffuse, extensive pattern of atrial fibrosis
description of AF as a disorganized rhythm, appear less likely to respond favorably to CA.237
growing evidence points to focal impulses
and organized sources of functional reentry, Surgical and Hybrid Approaches to AF
termed rotors, that might play a key role in Management
the perpetuation of the arrhythmia.230 A rela- The theory that the atrial substrate sustains AF
tively novel strategy for AF ablation attempts by supporting multiple wandering electrical
to identify these localized, focal drivers of AF. wavelets heavily affects the surgical approach
The Focal Impulse and Rotor Modulation to ablation. The objective of most surgical AF
(FIRM) ablation technique uses a 64-pole “bas- management is the creation of strategically
ket” catheter placed in the atria, together with a fashioned lines of scar in an attempt to debulk
computational mapping approach, to identify the atrial substrate and interrupt the possibility
localized rotors and focal impulses.106 Target- of wavelet propagation.219 A cut-and-sew tech-
ing the electrical substrate using FIRM ablation nique known as the Cox maze procedure was
in combination with PVI was more successful first described in the late 1980s.238 Subse-
than conventional PVI alone in case series and quently, the procedure has evolved, with
early trials.106,231 Randomized controlled trials changes in the location of the lesion sets in
assessing the short- and long-term success of the left and right atria, and replacement of inci-
FIRM ablation are ongoing. sional lesions with RFA and cryoablation.238
Noninvasive mapping of rotors and focal Although success rates for surgical approaches
impulses also has been described recently.232 to AF management can be high, because of the
Electrical data obtained from a 252-electrode invasive nature of the procedure and the asso-
vest are combined with atrial anatomical ge- ciated morbidity, a stand-alone surgical
ometry obtained from a cardiac CT scan to approach is infrequently used. Surgical ablation
create a noninvasive map of AF drivers.233 for AF is performed most often in patients un-
These data, obtained in the electrophysiology dergoing concomitant cardiac surgery (eg,
laboratory or just before ablation, can be valve replacement) or in those symptomatic pa-
used to guide electrical substrate ablation.232 tients who have had 1 or more unsuccessful
An ongoing prospective multicenter trial is percutaneous CA procedures.98
investigating these techniques to guide local- Recently, a combined surgical and percuta-
ized electrical substrate ablation in patients neous approach, which has come to be known
with persistent AF. as hybrid ablation or the convergent procedure,
There is some evidence supporting the has gained traction.239 In hybrid ablation, a
notion that the substrate for AF stems from an surgeon uses a closed-chest, minimally inva-
underlying fibrotic atrial cardiomyopathy.234 sive approach to deliver transmural linear
Using delayed enhancement magnetic resolu- ablation lesions guided by direct visualization
tion imaging, the degree of atrial remodeling of the epicardial surface of the atrium. An elec-
can be quantified by identifying the total vol- trophysiologist then performs percutaneous
ume of atrial tissue fibrosis.210 The extent and endocardial ablation, either immediately after
location of atrial fibrosis can vary, but on the surgical ablation or at a later time (ie, in
average it appears to be more advanced in a “staged” approach). The addition of the
n n
percutaneous approach to the surgical proced- models, radiotherapy has been used for the
ure allows for the direct electrophysiological noninvasive delivery of lesions to the
assessment of isolation of the PVs and poste- heart,245 and noninvasive carbon ion radia-
rior LA, often with limited endocardial lesions tion for ablation of AF specifically is currently
necessary to achieve successful electrical isola- under investigation.246 In the future, radio-
tion. In addition, any postsurgical atrial flut- therapy might offer a noninvasive approach
ters can be targeted from an endocardial for the management of cardiac arrhythmias,
approach. Several centers have published their including AF.247
experience with hybrid ablation, reporting
relatively high success rates, with most
studies240,241 including a fairly large propor- Practical Considerations
tion of patients with persistent and long- Atrial fibrillation ablation is often performed
standing persistent AF. Although further study under general anesthesia, though some centers
is needed to optimize patient selection and to do use conscious sedation.190 In most centers,
assess clinical success, the hybrid ablation patients after ablation remain under observa-
approach may provide an effective strategy tion overnight and, barring any complications,
for the management of AF in patients for are discharged the next morning.
whom 1 or more percutaneous attempts Given the established periprocedural
have failed. Hybrid procedures may also be stroke risk, a careful anticoagulation strategy
useful for those with persistent or long- must be established before ablation. The usual
standing persistent AF, or for those with practice is to rule out left atrial thrombus pre-
substantial structural heart disease, in whom procedurally, most often via transesophageal
standard CA techniques are unlikely to be echocadiography performed within 24 hours
successful.239 of ablation.210 There also are data supporting
the use of intracardiac echocardiography or
Future Directions cardiac CT to exclude thrombus.248,249 The
Although RFA has been used effectively for presence of left atrial thrombus is a contraindi-
several decades, it does have limitations. Radio- cation to proceeding with ablation.
frequency can cause collateral heat damage to Standard practice during left atrial ablation
tissues around ablation sites. In addition, the includes continuous anticoagulation with hep-
cooling effects of blood flow can limit lesion cre- arin, and OAC is maintained for a minimum of
ation. Other ablation modalities are currently 2 months postprocedure.190 Data suggest that
being explored, including nonthermal irrevers- AF ablation can be more safely performed with
ible electroporation.242 In porcine studies, a cir- uninterrupted therapeutic warfarin therapy, as
cular electroporation catheter has been used to opposed to periprocedural bridging anticoagu-
create ablation lesions inside PVs. Compared lation with intravenous or low-molecular-
with standard radiofrequency, electroporation weight heparin.250 The periprocedural use of
lesions effectively ablated myocardial sleeves NOACs also has been used safely in some se-
without causing surrounding connective tissue ries.251 Novel oral anticoagulants are often
damage that can result in intimal proliferation, held the day of, and sometimes the day before,
scar tissue formation, and ultimately PV the procedure and reinitiated the night of abla-
stenosis.243 Although further study is required, tion, after access site hemostasis has been
irreversible electroporation is a promising tech- confirmed.98 Recent data suggest that ablation
nology that might develop into an important might be safely performed under uninter-
modality for treatment of cardiac arrhythmias, rupted NOAC therapy, though this is
including AF.244 controversial.252,253
Although CA has revolutionized the field Ablation of AF should not be performed
of electrophysiology, it remains an invasive with the sole principal objective of discontinu-
technique that can be associated with ing long-term OAC.98 Standard practice
serious complications, which has stimulated dictates that postablation, long-term use of
exploration of alternative modalities. One OAC is driven by individual risk of thrombo-
such method currently under investigation embolism and bleeding, regardless of heart
is catheter-free radiotherapy. In animal rhythm.190

24
TABLE 5. Potential Complications of Catheter Ablation of Atrial Fibrillation

Complication Prevention strategy Symptoms Management
Cardiac tamponade Intracardiac echocardiography to guide transseptal Hypotension; often abrupt Percutaneous drainage and reversal of anticoagulation; if bleeding
puncture; use of contact force catheters to continues, surgical drainage and repair
direct catheter manipulation
Pulmonary vein stenosis Avoidance of ablation within the pulmonary Dyspnea, chest pain, cough, CT or MRI if stenosis is suspected; for severe symptomatic
veins with targeted ablation toward the hemoptysis, recurrent stenosis, angioplasty or stenting of the pulmonary vein; surgery
antrum lung infections can be considered for restenosis
Vascular access complications
Hematoma/retroperitoneal bleed Meticulous access technique; ultrasound Groin/leg pain, swelling, Manual compression of hematomas; pseudoaneurysm often
Arteriovenous fistula guidance can be helpful; careful pulsatile mass, hypotension, managed with ultrasound-guided compression or ultrasound-
Pseudoaneurysm manual compression postprocedure and shock if large guided local injection of thrombin; surgery might be required to
to achieve complete hemostasis retroperitoneal bleed manage large pseudoaneurysms, atrioventricular fistulas, or
retroperitoneal bleed
Phrenic nerve injury More common with ablation of Dyspnea, hiccups, cough Nerve function usually recovers with time
right-sided (especially superior)
pulmonary veins; avoid distal vein
placement of cryoballoon or
ablation catheter; phrenic nerve pacing
Mayo Clin Proc.
during ablation to monitor for injury

Esophageal injury
Atrial-esophageal fistula Temperature probe for esophageal thermal Fever, chills, sepsis, neurologic CT or MRI if suspected; urgent surgical correction or esophageal
monitoring; modifying energy delivery near events (septic emboli) stent
the esophagus; use of proton pump inhibitor
n
XXX 2016;nn(n):1-33
for several weeks postablation

Esophageal injury Nausea, vomiting, bloating, Usually recovers with time; small meals low in fat and fiber; rarely
abdominal pain metoclopramide or other interventions needed
Stroke Careful intra- and periprocedural Varying manifestations Management based on severity and location of thromboembolism
anticoagulation management; depending on the site
heparin during ablation and oral of thromboembolism
n
anticoagulation for at least 2-3 mo

http://dx.doi.org/10.1016/j.mayocp.2016.08.022
postablation

Iatrogenic atrial flutter Limiting ablation strategy to pulmonary Palpitations Cardioversion; antiarrhythmic therapy;
vein isolation in paroxysmal atrial catheter ablation
fibrillation; for additional ablation

lines, electrical completeness of the
line should be established by mapping
or pacing maneuvers
Mitral valve injury Careful manipulation of circular mapping Symptoms can vary depending Gentle attempts to free catheter;
catheters near the mitral valve to on the extent of trauma and echocardiography to confirm entrapment;
avoid entrapment and trauma underlying comorbidities surgical management/repair might be necessary
Continued on next page
Early postablation recurrence of AF is not

uncommon, possibly because of indirect ef-
fects of cardiac ablation including myocardial
inflammation and pericarditis. Although early
recurrence of AF has been associated with a
higher long-term arrhythmic risk, some such
patients still show a favorable long-term
response. For this reason, an early recurrence
Management
“blanking period” of 3 months has been used

Nonsteroidal anti-inflammatory drugs;
in most clinical trials, and recurrences during

this time are not counted as procedure fail-
colchicine; corticosteroids
ures.190 Patients should be made aware of

the potential for early AF recurrence. Antiar-
rhythmic drugs taken before ablation is
therefore often continued for 3 months posta-
blation or may be instituted to suppress early
recurrences in those previously not taking
NA
AADs.98
The most common cause of recurrence of
AF (>3 months postablation) is reconnection
Acute or subacute skin burn
of 1 or more PVs.190 Although the decision

to pursue repeat ablation after documented
Symptoms
recurrence should be made on an individual

Chest pain/pressure
basis, repeat procedures are associated with

improvements in long-term success rates.
Standard practice for repeat procedures is to
reassess for electrical isolation of PVs and to
NA
reisolate veins with electrical reconnection. In

patients without PV reconnection undergoing
a repeat ablation procedure, targeting of non-
Minimizing extent of ablation when possible
PV triggers and substrate modification might

adjustment of fluoroscopy frame rates
be necessary.190 Commonly observed non-PV

Minimizing fluoroscopy with the use of
triggers include the superior vena cava, coro-

Prevention strategy
3-dimensional mapping systems;
nary sinus, LAA, and other aspects of the LA

including the posterior wall.254
As noted earlier, cardiac RFs such as
obesity, OSA, HTN, and DM have been associ-
CT ¼ computed tomography; MRI ¼ magnetic resonance imaging.
ated with atrial structural and electrical

remodeling and an increased incidence of
AF. Aggressive RF modification, including
weight management, blood pressure control,
NA
OSA therapy, lipid and glucose control, and

smoking and alcohol cessation can improve
clinical outcomes. In a trial91 assessing the ef-
fect of RF reduction on ablation outcomes, the
aggressive RF reduction cohort exhibited
Complication
marked improvements in ablation outcomes,

TABLE 5. Continued
with concomitant reductions in left atrial size

Radiation injury
and LVH. Patients should be educated on

the importance of lifestyle and RF manage-
Pericarditis
ment as they relate to AF.

Death
Although the safety of catheter-based AF

ablation has improved with time, the procedure

is associated with serious risks. Table 5 lists honoraria from Biotronik and Medtronic, and has received
several potential complications of AF ablation. research grants from Boston Scientific and Medtronic. Dr
Bernard serves on the speaker’s bureau for Janssen. Dr Estes
An analysis of more than 93,000 procedures
serves as a consultant to Boston Scientific, Medtronic, and
performed in the United States between 2000 St. Jude Medical.
and 2010 revealed an overall procedural
complication rate of 6.3%.255 Cardiac compli- Correspondence: Address to Daniel P. Morin, MD, MPH,
Department of Cardiology, Ochsner Medical Center, 1514
cations including tamponade were the most
Jefferson Hwy, New Orleans, LA 70121 (dmorin@
frequent (2.5%), followed by vascular (1.5%), ochsner.org).
respiratory (1.3%), and neurological (1.0%)
complications. Advanced age and female sex REFERENCES
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Atrial Fibrillation Epidemiology, Prevention, and Treatment

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REVIEW

The State of the Art: Atrial Fibrillation

trial ﬁbrillation (AF) is the most com-

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 1

incidence of AF in African Americans than in

COMORBID CONDITIONS AND MODIFICA- Congestive HF

Target Target Hgb Limit

LA pressure Oxidative RAAS

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 3

I have AF compared with up to 55% in NYHA Hypertension

Diabetes Mellitus Obesity

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 5

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 7

Single procedure AF-free survival

Multiprocedure AF-free survival

0.2 Group 0.2 Group

0 180 360 540 720 0 180 360 540 720

Time 0 180 360 540 730 0 180 360 540 730

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 9

randomized controlled trials to assess its effect

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 11

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 13

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 15

found to be superior to historical controls, as 2.6%.187 Similar to WATCHMAN, the LAR-

Class IIa (Beneﬁt >> Risk; IT IS REASONABLE to perform procedure/treatment)

Class IIb (Beneﬁt Risk; Procedure/treatment MAY BE CONSIDERED)

Class III (No beneﬁt, or potential harm; Procedure/treatment IS CONTRAINDICATED)

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 17

Study % of patients Freedom from AF recurrence

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 19

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 21

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 23

TABLE 5. Potential Complications of Catheter Ablation of Atrial Fibrillation

during ablation to monitor for injury

for several weeks postablation

anticoagulation for at least 2-3 mo

MAYO CLINIC PROCEEDINGS

ﬁbrillation; for additional ablation

Early postablation recurrence of AF is not

“blanking period” of 3 months has been used

in most clinical trials, and recurrences during

ures.190 Patients should be made aware of

of 1 or more PVs.190 Although the decision

recurrence should be made on an individual

basis, repeat procedures are associated with

reisolate veins with electrical reconnection. In

PV triggers and substrate modiﬁcation might

be necessary.190 Commonly observed non-PV

triggers include the superior vena cava, coro-

3-dimensional mapping systems;

nary sinus, LAA, and other aspects of the LA

ated with atrial structural and electrical

OSA therapy, lipid and glucose control, and

marked improvements in ablation outcomes,

with concomitant reductions in left atrial size

and LVH. Patients should be educated on

ment as they relate to AF.

Although the safety of catheter-based AF

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 25

Mayo Clin Proc. n XXX 2016;nn(n):1-33 n http://dx.doi.org/10.1016/j.mayocp.2016.08.022 27