Trends in Cardiovascular Medicine 28 (2018) 469–480

Contents lists available at ScienceDirect

Trends in Cardiovascular Medicine

journal homepage: www.elsevier.com/locate/tcm

Contemporary approach to stroke prevention in atrial fibrillation:

Risks, benefits, and new options

✩

Jonathan Stock

a , Brian J. Malm

a , b , ∗

a Yale University, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States b Department of Cardiology, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT, United States

a r t i c l e i n f o

Keywords:

Atrial fibrillation

Stroke

Anti-coagulation

Warfarin

Direct oral anticoagulants

Left atrial appendage

a b s t r a c t

Atrial fibrillation is a common diagnosis affecting nearly 3 million adults in the United States. Morbid-

ity and mortality in these patients is driven largely by the associated increased risk of thromboembolic

complications, especially stroke. Atrial fibrillation is a stronger risk factor than hypertension, coronary dis-

ease, or heart failure and is associated with an approximately five-fold increased risk. Mitigating stroke

risk can be challenging and requires accurate assessment of stroke risk factors and careful selection of

appropriate therapy. Anticoagulation, including the more recently introduced direct oral anticoagulants,

is the standard of care for most patients. In addition, emerging non-pharmacologic mechanical interven-

tions are playing an expanding role in reducing stroke risk in select patients. In this review we highlight

the current approach to stroke risk stratification in atrial fibrillation and discuss in detail the mechanism,

risks, and benefits of current and evolving therapies.

© 2018 Elsevier Inc. All rights reserved.

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bbreviations glossary

CC American College of Cardiology

HA American Heart Association

CTIVE Atrial Fibrillation \ Clopidogrel Trial With Irbesar-

tan for Prevention of Vascular Events

FASAK Copenhagen Atrial Fibrillation, Aspirin and Anti-

coagulation

FFIRM Atrial Fibrillation Follow-Up Investigation of

Rhythm Management

F Atrial Fibrillation

FI Atrial Fibrillation Investigators

RISTOTLE Apixaban for Reduction in Stroke and Other

Thromboembolic Events

FNET Atrial Fibrillation Network

NNEXA-A Andexanet Alpha a Novel Antidote to the Antico-

agulant Effects of Factor Xa Inhibitor Apixaban

NNEXA-R Andexanet Alpha a Novel Antidote to the Anti-

coagulant Effects of Factor Xa Inhibitor Rivarox-

aban

VERROES Apixaban Versus Acetylsalicylic Acid [ASA] to

Prevent Stroke in Atrial Fibrillation Patients

AATAF Boston Area Anticoagulation Trial for Atrial Fib-

rillation

✩ Disclosures : The authors have no conflicts of interest and received no funding

elated to this manuscript. ∗ Corresponding author.

E-mail address: brian.malm@yale.edu (B.J. Malm).

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ttps://doi.org/10.1016/j.tcm.2018.03.004

050-1738/© 2018 Elsevier Inc. All rights reserved.

AFTA Birmingham Atrial Fibrillation Treatment of the

Aged

A Catheter Ablation

AD Coronary Artery Disease

AFA Canadian Atrial Fibrillation Anticoagulation

Study

NS Central Nervous System

TI Cavotricuspid Isthmus

APT Dual Anti-Platelet Therapy

OAC Direct Oral Anti Coagulants

NGAGE AF Effective Anticoagulation With Factor XA Next

Generation in Atrial Fibrillation

SC European Society of Cardiology

SRD End Stage Renal Disease

DA Food and Drug Administration

RACTAL Fibrillation Registry Assessing Costs, Therapies,

Adverse Events and Lifestyle

I Gastro-Intestinal

RS Heart Rhythm Society

NR International Normalized Ratio

SI International Sensitivity Index

SAR-TRIPLE Intracoronary Stenting and Antithrombotic Regi-

men: TRIPLE Therapy in Patients on Oral Antico-

agulation After Drug Eluting Stent Implantation

AA left Atrial Appendage

ARM-AF Mechanical and Rheumatic Mitral Valvular Atrial

Fibrillation

I Myocardial Infarction

470 J. Stock, B.J. Malm / Trends in Cardiovascular Medicine 28 (2018) 469–480

Fig. 1. Left atrial appendage thrombus seen on TEE (arrow). LA = left atrium. LV =

left ventricle.

Table 1

CHA 2 DS 2 -VASc score and risk of stroke.

Risk factor Value CHA 2 DS 2 -VASc

score

Adjusted stroke

rate (%/year)

0 0%

C HF/LV dysfunction 1 1 1.3%

Hypertension 1 2 2.2%

Age ≥75 2 3 3.2%

Diabetes mellitus 1 4 4.0%

Stroke 2 5 6.7%

Vascular disease 1 6 9.8%

Age 65–74 1 7 9.6%

Sex category (female) 1 8 6.7%

9 15.2%

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NT-pro-BNP N-Terminal B-Type Natriuretic Peptide

OAC-ALONE Optimizing Antithrombotic Care in Patients With

Atrial Fibrillation and Coronary Stent

PCI Percutaneous Coronary Intervention

PINNACLE Practice Innovation and Clinical Excellence

PIONEER AF-PCI Study Exploring Two Strategies of Rivaroxaban

and One of Oral Vitamin K Antagonists in Pa-

tients With Atrial Fibrillation Who Undergo Per-

cutaneous Coronary Intervention

PROTECT-AF Watchman Left Atrial Appendage System for Em-

bolic Protection in Patients With AF

PREVAIL Prospective Randomized Evaluation of the

Watchman LAA Closure Device in Patients With

Atrial Fibrillation Versus Long Term Warfarin

Therapy

RE-DUAL PCI Evaluation of Dual Therapy With Dabigatran VS.

Triple Therapy With Warfarin in Patients With

AF That Undergo A PCI With Stenting

RE-LY Randomized Evaluation of Long-Term Anticoagu-

lant Therapy

REWRAPS Registry for Estimation of Warfarin and Rivarox-

aban in Atrial Fibrillation Patients with Coronary

Stent Implantation

ROCKET-AF Rivaroxaban Once Daily Oral Direct Factor XA In-

hibition Compared With Vitamin K Antagonism

For Prevention of Stroke and Embolism Trial in

Atrialfibrillation

SPAF Stroke Prevention and Atrial Fibrillation

SPINAF Stroke Prevention in Atrial Fibrillation Study

SPORTIF III Stroke Prevention Using Oral Thrombin Inhibitor

in Atrial Fibrillation

TEE Transesophageal Echocardiography

WOEST What is the Optimal Antiplatelet and Anticoagu-

lant Therapy in Patients With Oral Anticoagula-

tion and Coronary Stenting

Introduction

Atrial fibrillation (AF) is a common diagnosis affecting nearly

3 million adults in the United States with a projected doubling in

prevalence by the year 2050 [1] . The incidence of AF increases dra-

matically with age in both men and women with greater than 10%

of individuals over 80 years old having the disease [1] . Morbidity

and mortality in patients with AF is driven largely by the asso-

ciated increased risk of thromboembolic complications, especially

stroke. AF is a stronger risk factor than hypertension, coronary dis-

ease, or heart failure and is associated with an approximately five-

fold increased risk of stroke [2] . In addition, strokes occurring in

patients with AF tend to be more debilitating, are more likely to

recur, and are associated with poorer survival compared to strokes

in patients without AF [3] . Most thromboembolic events in AF are

due to emboli arising from left atrial appendage (LAA) thrombi

caused by blood flow stasis in a fibrillating atrium which is best

diagnosed by transesopheageal echocardiography ( Fig. 1 ).

As will be discussed in this review, managing stroke risk in pa-

tients with AF can be challenging and requires accurate assess-

ment of risk factors and careful selection of appropriate therapy.

The mainstay of therapy is anticoagulation with warfarin being the

standard agent until the more recent introduction of direct oral an-

ticoagulants (DOACs). Emerging non-pharmacologic mechanical in-

terventions also play an important role in mitigating stroke risk in

select patients with AF.

isk stratification

The risk of stroke in patients with AF is highly variable rang-

ng from < 2% per year to > 10% per year. This heterogeneity re-

ults from variation in clinical predictors across patient subpop-

lations. Because the relative risk reduction in thromboembolism

ith current antithrombotic therapies are consistent across these

ifferent patient subpopulations, the absolute benefit of antithrom-

otic therapy in each patient depends on their individual stroke

isk weighed against the risks of the proposed therapy. Classifica-

ion schemes employed at the point of care can aid in estimat-

ng risk and assigning appropriate therapies. Two early approaches

ncluded the AFI (atrial fibrillation investigators) and SPAF (stroke

revention and atrial fibrillation) schemes which characterized pa-

ients as low, moderate, or high risk based on the presence or ab-

ence of validated stroke risk factors including age, hypertension,

iabetes, and prior ischemia [4] . These were later combined into

he simpler CHADS 2 score which was validated in the National

egistry of Atrial Fibrillation and showed improved predictive

ccuracy.

Despite the development and use of these risk classification

chemes, subsequent studies demonstrated limitations in these ap-

roaches and the need for further improvement in our ability to

stimate stroke risk in AF [5] . A refinement of the CHADS 2 score,

he CHA 2 DS 2 -VASc score ( Table 1 ) , provides a more accurate esti-

ate of stroke risk in AF and is especially useful in patients clas-

ified as low risk using prior schemes [6,8] . This was well studied

n the German AFNET registry of 8847 patients with non-valvular

F [7] . In this prospective registry, more than one-third of the

trokes or other thromboembolic events during the 5-year follow-

p period occurred in patients assigned a CHADS score of ≤1 and

2

J. Stock, B.J. Malm / Trends in Cardiovascular Medicine 28 (2018) 469–480 471

Fig. 2. Echocardiographic predictors of thromboembolism in AF. Spontaneous echo contrast (arrow); complex aortic plaque (asterisk). LA = left atrium. Ao = aorta lumen.

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herefore not considered high risk and often not anticoagulated

ased on clinical guidelines. In contrast, using the CHA 2 DS 2 -VASc

core reclassified more than half of these patients to a CHA 2 DS 2 -

ASc score of ≥2 which would generally warrant anticoagulation.

urrent guidelines from the ACC/AHA and ESC support the use of

he CHA 2 DS 2 -VASc score in the management of patients with AF

8,48] . Although widely used in contemporary medicine, the pre-

ictive value of the CHA 2 DS 2 -VASc score differs amongst patient

opulations. In Japanese AF patients, for example, female gender

as not been shown to be an independent predictor of stroke risk

100] .

It is important to bear in mind that these schemes include clin-

cal variables which can and will likely change overtime, there-

ore it is essential to serially modify a given patients risk score as

t may impact their candidacy for appropriate therapies. In addi-

ion, these risk estimators should not be applied to patients with

ignificant left-sided valvular disease, especially rheumatic mitral

tenosis and prosthetic valves, as well as hypertrophic cardiomy-

pathy as these conditions are generally considered high risk for

hromboembolism and warrant anticoagulation regardless of their

isk score. Anticoagulation use should also be based on clinical risk

ssessment irrespective of the pattern of AF (i.e. paroxysmal, per-

istent, or permanent) as these carry similar risks of thromboem-

olism. In the ACTIVE-W sub-study, the annual rate of stroke or

on-CNS systemic embolism, as well as the benefit of oral antico-

gulation, was similar in patients with paroxysmal and persistent

r permanent AF [18] . Societal guidelines have also reinforced this

rinciple of anticoagulation based on risk rather than burden of AF.

cho/imaging predictors

In addition to the clinical variables incorporated in commonly

sed risk calculators, certain echocardiographic findings are also

ssociated with increased stroke risk in AF. These are best demon-

trated on TEE and provide further insight into the mechanism of

hromboembolism ( Fig. 2 ). Markers of blood flow stasis including

pontaneous ultrasound contrast or “smoke” and low pulse-wave

oppler outflow velocities in the LAA are associated with increased

isk of thrombus formation [9] . In addition to atrial stasis, the pres-

nce of complex aortic arch atheromatous plaque can differentiate

atients with AF at high risk from those at moderate risk of throm-

oembolism [9] . Left atrial volume enlargement, commonly seen in

atients with chronic AF, has also been associated with increased

isk of ischemic stroke [10] . Although not incorporated in current

ractice guidelines, these findings should be taken into consider-

tion when managing patients with AF and may impact decisions

egarding anticoagulation in certain circumstances.

iomarkers

In addition to clinical and echocardiographic predictors, some

iomarkers have also been associated with an increased risk of

troke in AF. High sensitivity troponin-I and troponin-T, both mark-

rs of myocyte injury, and N-terminal b-type natriuretic peptide

NT-pro-BNP) are associated with increased stroke risk and may

mprove risk stratification beyond clinical predictors alone [11–13] .

he recently devised ABC (age, biomarkers, clinical history) score,

ncorporating these biomarkers in addition to age and prior stroke,

utperformed the CHA 2 DS 2 -VASc score in predicting the risk of

troke in a large cohort of AF patients [14] . Although promising,

he role of these novel approaches to risk assessment in routine

linical practice remains undefined.

ntithrombotic therapy

For decades, the standard of care for stroke prophylaxis in AF

ad been aspirin or warfarin for most patients. Both reduce the

isk of stroke with warfarin being approximately three times more

ffective than aspirin. More recently, DOACs have largely replaced

arfarin in most patients with non-valvular AF at increased risk.

hich strategy to use depends on careful assessment of the com-

eting risks of thromboembolism, as discussed in the previous sec-

ion, and bleeding related to antithrombotic therapy.

arfarin

Warfarin inhibits the production of the vitamin K-dependent

oagulation factors II, VII, IX and X. Its efficacy in preventing stroke

n nonvalvular AF was demonstrated in multiple randomized clin-

cal trials including SPAF- I, SPAF- II, AFASAK, BAATAF, SPINAF, and

AFA. A meta-analysis of the 6 major trials showed a 62% rela-

ive risk reduction with adjusted-dose warfarin versus placebo for

revention of all stroke (both ischemic and hemorrhagic) [15] . The

tandard laboratory parameter for evaluating warfarin’s anticoagu-

ation efficacy is the INR (International Normalized Ratio). The INR

s the ratio of a patient’s prothrombin (PT) time to a normal con-

rol sample, raised to the power of the ISI value for the analyt-

cal system being used, providing standardization for monitoring.

he goal INR for most patients with AF is 2–3 as this range is as-

ociated with optimal reduction in stroke risk without an unac-

eptably high risk of bleeding [16] . The benefit of warfarin may

472 J. Stock, B.J. Malm / Trends in Cardiovascular Medicine 28 (2018) 469–480

Fig. 3. Coagulation cascade and the mechanism of action of DOACs.

Table 2

HAS-BLED score and bleeding risk.

Clinical feature Value HAS-BLED

score

Bleeds per

100 patient-years

Hypertension 1 0 1.13

Abnormal renal or liver function 1 or 2 1 1.02

Stroke 1 2 1.88

Bleeding 1 3 3.74

Labile INR 1 4 8.7

Elderly 1

Drugs or alcohol 1 or 2

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in fact be underestimated in patients who maintain a consistently

therapeutic INR. In pooled clinical trial data, for example, patients

spend only 61% of the time in a therapeutic INR. Unfortunately,

one of the major disadvantages of warfarin is this relatively nar-

row therapeutic index with INR values < 2 being associated with

significantly increased risk of ischemic events (up to five-fold) and

supratherapeutic INRs carrying an increased risk of major bleed-

ing complications [17] . As a result, warfarin therapy is challenging

and impractical for many patient’s due to the need for INR mon-

itoring and dose adjustment as well as significant food and drug

interactions.

The efficacy of warfarin in clinical practice has generally mir-

rored the findings from early randomized trials. An observational

study of more than 11,0 0 0 patients with non-valvular AF found a

64% reduction in thromboembolism and a 31% reduction in all-

cause mortality [19] . Unfortunately, this benefit occurs at the ex-

pense of significantly increased bleeding risk including a two-

fold increased risk of intracranial hemorrhage with warfarin [19] .

Pooled data from primary prevention trials also revealed a 1.2%

annual risk of major bleeding with warfarin [20] . It is therefore

imperative to carefully assess a patient’s bleeding risk prior to pre-

scribing anticoagulation. Like current tools used to assess stroke

risk, there are useful algorithms to assist in estimating bleeding

risk. The most commonly used is the HAS-BLED score which as-

signs points for clinical features associated with bleeding risk in-

cluding hypertension, abnormal kidney and liver function, prior

stroke, bleeding history, labile INR, elderly status, and use of illicit

drugs or alcohol [21] ( Table 2 ). The sum of the points for each risk

factor is the patient’s HAS-BLED score and those with a score of

≥3 are generally considered high risk for bleeding. Mobile device

applications such as the American College of Cardiology’s Antico-

agEvaluator have been developed to provide anticoagulation deci-

c

ion support to clinicians by performing an individualized risk as-

essment using both the CHA 2 DS 2 -VASc and HAS-BLED scores.

spirin

In a meta-analysis of 6 randomized trials, aspirin conferred

modest non-dose-dependent 22% relative stroke risk reduction

ompared with placebo [15] . Warfarin is superior to aspirin in pre-

enting stroke with a 30% relative risk reduction seen in a meta-

nalysis of 5 trials [15] . Like all antithrombotic medications, as-

irin is associated with an increased risk of bleeding, particularly

astrointestinal bleeding [22] . Given the superiority of anticoagu-

ation for most patients at increased risk of stroke, the role of as-

irin in contemporary AF management is controversial, especially

n lieu of advances in pharmacotherapy to be discussed later. De-

pite this, nearly one third of patients with AF and increased risk

f stroke who would otherwise benefit from anticoagulation are

reated with aspirin alone as demonstrated in a large outpatient

ohort in the PINNACLE registry [23] .

J. Stock, B.J. Malm / Trends in Cardiovascular Medicine 28 (2018) 469–480 473

Table 3

DOAC clinical trials in AF ∗ .

TRIAL Drug/dose Total #

patients

Stroke/ systemic embolism

(%patients/year)

Hemorrhagic Stroke

(% patients/ year)

Bleeding (% patients/year) Mortality (%

patients/ year)

Major Intracranial GI

RELY Dabigatran 150 mg twice daily 18,113 1.1 vs 1.7 0.1 vs 0.4 3.1 vs 3.4 0.3 vs 0.7 1.5 vs 1.0 3.6 vs 4.1

Dabigatran 110 mg twice daily 1.5 vs 1.7 0.1 vs 0.4 2.7 vs 3.4 0.2 vs 0.7 1.1 vs. 1.0 3.8 vs 4.1

ROCKET-AF Rivaroxaban 20 mg daily 14,264 1.7 vs 2.2 0.3 vs 0.4 3.6 vs 3.4 0.5 vs 0.7 3.2 vs 2.2 4.5 vs 4.9

ARISTOTLE Apixaban 5 mg twice daily 18,201 1.3 vs 1.6 0.2 vs 0‘.5 2.1 vs 3.1 0.3 vs 0.8 0.8 vs 0.9 3.5 vs 3.9

ENGAGE-TIMI 48 Edoxaban 30 mg daily 21,105 1.6 vs 1.5 0.2 vs 0.5 1.6 vs 3.4 0.3 vs 0.9 0.8 vs 1.2 3.8 vs 4.4

Edoxaban 60 mg daily 1.2 vs 1.5 0.3 vs 0.5 2.8 vs 3.4 0.4 vs 0.9 1.5 vs 1.2 4 vs 4.4

∗Results are reported as DOAC vs warfarin, statistically significant differences in bold.

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ractice trends

Anticoagulation use in AF has been shown to decrease with ad-

ancing age, especially > 80 years, despite the increased risk of is-

hemic stroke in the elderly population. In a large patient cohort

ith nonvalvular AF and no contraindication to anticoagulation,

arfarin use increased with age peaking at 61% in patients aged

5–74 years while decreasing to 57% in those aged 75–84 years

nd 35% in patients greater than 85 years old [24] . A recent retro-

pective cohort study of elderly patients with AF hospitalized with

schemic stroke found 44% were not prescribed oral anticoagula-

ion at discharge [25] . In addition to anticoagulation underutiliza-

ion, there is also a problem of inappropriate discontinuation. In

he FRACTAL registry of patients with new-onset AF, 70% were ini-

iated on warfarin with only 50% prescribed warfarin at 30-month

ollow-up [26] . Of more concern, the relationship between AF re-

urrence and warfarin use was stronger than any individual stroke

isk factor reflecting the erroneous assumption that maintenance

f sinus rhythm is associated with reduced stroke risk. This issue

as underscored in the AFFIRM randomized trial of rate vs. rhythm

ontrol in AF, whereby most strokes in both groups occurred in

atients who discontinued anticoagulation or had sub-therapeutic

NR [27] .

Concerns regarding compliance, safety, food and drug inter-

ctions with warfarin have spearheaded effort s to develop safer,

ore effective and more practical strategies for anticoagulation in

F. An early attempt in the SPAF III trial found the combination

f aspirin and a fixed low dose of warfarin inferior to adjusted-

ose warfarin [28] . The ACTIVE-W trial compared dual anti-platelet

herapy with aspirin and clopidogrel to warfarin in patients with

F and ≥1 stroke risk factor. Again, warfarin was superior in pre-

enting the primary end-point of stroke, non-CNS embolism, MI,

r vascular death [29] .

irect oral anti-coagulants ( Fig. 3 )

In recent years, there has been a paradigm shift in the ap-

roach to stroke prevention in non-valvular AF with the introduc-

ion of DOACs following a series of landmark non-inferiority tri-

ls comparing them to warfarin ( Table 3 ). In the SPORTIF III trial

imelagatran, a direct oral thrombin inhibitor, demonstrated non-

nferiority compared to warfarin for stroke prevention in patients

ith non-valvular AF and ≥1 stroke risk factor with lower rate of

ll-cause bleeding [30] . Unfortunately, increased risk of hepatotox-

city prompted the FDA to deny its application for approval and

ventual withdrawal from the non-US market in 2006.

Dabigatran, another oral direct thrombin inhibitor, was the first

ovel agent approved for use in the US based on the findings from

he RE-LY trial which randomized patients with non-valvular AF

nd ≥1 stroke risk factor to dabigatran 110 mg twice daily, 150 mg

wice daily or dose-adjusted warfarin [31] . The primary endpoint

as stroke or systemic embolism and mean follow-up was 2 years.

abigatran 110 mg twice daily was non-inferior to warfarin with

ower rates of major hemorrhage while dabigatran 150 mg twice

aily was superior to warfarin with a 35% relative risk reduction

n the primary endpoint and comparable risk of major hemor-

hage. Importantly, both doses of dabigatran were associated with

ower risks of hemorrhagic stroke. Gastrointestinal bleeding, how-

ver, was more common with dabigatran likely attributable to tar-

aric acid which lowers the gastric pH to assist with drug absorp-

ion [32] .

Dabigatran 150 mg twice daily was FDA approved in 2010 for

troke prevention in non-valvular AF and the ACC/AHA guidelines

33] were updated to include a Class I recommendation for use

f dabigatran as an alternative to warfarin in the absence of se-

ere renal failure or advanced liver disease as the drug is renally

xcreted and is a pro-drug requiring hepatic activation. The up-

ated 2012 American College of Chest Physicians guidelines rec-

mmended dabigatran rather than dose-adjusted warfarin for non-

alvular AF [34] .

Rivaroxaban, an oral factor Xa inhibitor, was studied in ROCKET-

F which randomized patients with non-valvular AF and a CHADS 2 core of ≥2 to rivaroxaban 20 mg daily or dose-adjusted warfarin

35] . Rivaroxaban was non-inferior to warfarin for the composite

rimary end-point of stroke or non-CNS systemic embolism, and

tatistically superior in the on-treatment analysis for patients who

ook rivaroxaban for 40 weeks. Although there was no difference

n overall bleeding, there was less fatal bleeding and a nearly 30%

ower risk of intracranial hemorrhage in patients treated with ri-

aroxaban. Like dabigatran, GI bleeding was more common with

ivaroxaban. One criticism of this trial was the lower proportion of

ime in the therapeutic INR range in the warfarin arm (mean, 55%)

han was seen in prior studies. The efficacy of rivaroxaban, how-

ver, was as favorable in centers with the best INR control as in

hose with poorer control.

The ARISTOTLE trial randomized patients with non-valvular AF

nd ≥ 1 additional stroke risk factor to the oral factor Xa inhibitor

pixaban 5 mg twice daily or dose-adjusted warfarin. Apixaban

emonstrated superiority to warfarin with regards to the primary

ndpoint of stroke or systemic embolism with a relative risk re-

uction of 21%, including a 49% lower rate of hemorrhagic stroke

36] . In addition, there was a significant 11% relative risk reduc-

ion in all-cause mortality with apixaban. Major bleeding, clinically

elevant non-major bleeding, and intracranial hemorrhage were all

ignificantly lower in apixaban treated patients. Although not sta-

istically significant, there was also numerically less GI bleeding in

atients treated with apixaban compared to warfarin, in contrast

o dabigatran and rivaroxaban in RELY and ROCKET-AF, respectively.

n a pre-specified secondary analysis, the composite risk of stroke,

ortality and major bleeding were lower with apixaban regardless

f the pattern of AF [37] .

Apixaban was also compared to aspirin in the AVERROES trial

hich randomized patients with non-valvular AF and increased

troke risk (mean CHADS 2 = 2) who were deemed unsuitable for

474 J. Stock, B.J. Malm / Trends in Cardiovascular Medicine 28 (2018) 469–480

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warfarin, for reasons including difficulty maintaining therapeutic

INR and patient refusal [38] . Compared to aspirin, apixaban sig-

nificantly reduced the primary endpoint of stroke or systemic em-

bolism with a relative risk reduction of 55% and no difference in

fatal or clinically relevant non-major bleeding.

Edoxaban, the most recently approved oral factor Xa inhibitor,

was studied in patients with AF and a CHADS 2 score of ≥ 2 in

ENGAGE AF-TIMI 48 [39] . Patients were randomized to edoxaban

30 mg or 60 mg daily compared to dose-adjusted warfarin over a

median follow-up of 2.8 years. Both doses of edoxaban were non-

inferior to warfarin in preventing stroke and systemic embolism

and were associated with lower annualized risk of major and mi-

nor bleeding. An increased risk of gastrointestinal bleeding, how-

ever, was observed in patients randomized to 60 mg of edoxaban.

Although there are no direct head-to-head trials comparing

DOACs, an indirect comparison of dabigatran, rivaroxaban, and

apixaban in patients with a CHADS 2 ≥ 3 from their respective

trials revealed comparatively similar efficacy for thromboembolic

prophylaxis with apixaban having a lower risk of major bleeding

[40] . This finding supports the use of apixaban as the preferred

DOAC in patients at higher risk for bleeding as assessed by a clini-

cal tool such as the HAS-BLED score.

The lower occurrence of significant drug-drug and food inter-

actions is another major advantage of DOACs over warfarin. This

was underscored in a sub-analysis of amiodarone-treated patients

from ARISTOTLE which showed a significantly increased risk of

stroke, bleeding and a trend toward increased mortality in those

treated with warfarin compared to apixaban, a finding likely due

to drug-drug interactions [41] . This issue is especially relevant in

contemporary medicine given the growing age and medical com-

plexity of our patient population and the potential for polyphar-

macy and associated risks. Additional practical advantages include

no requirement for routine blood monitoring or dose adjustments

and shorter half-lives. There are some disadvantages with DOACs,

however, including twice daily dosing for dabigatran and apixaban,

the lack of widely available antidotes for all agents, the restric-

tion to patients with non-valvular AF, and their relatively high cost.

Regarding cost effectiveness, apixaban, dabigatran and rivaroxaban

have all been shown to be cost effective alternatives to warfarin

based on clinical trial data, however, this is dependent on pricing

of the individual agents as well as bleeding events [42] . Concerning

reversal agents, the monoclonal antibody idarucizumab has proven

efficacy in rapidly reversing the effects of dabigatran in patients

with serious bleeding or requiring an urgent procedure and is FDA-

approved for this purpose [43] . Andexanet, a recombinant modi-

fied factor Xa protein, has greater binding affinity for factor Xa in-

hibitors than native factor Xa and effectively reversed the action of

apixaban and rivaroxaban in the ANNEXA-A and ANNEXA-R trials

[44] . Even without specific reversal agents, most serious bleeding

in patients receiving DOACs can be successfully treated and man-

agement strategies have been published [45] .

Meta-analyses of pooled data from RE-LY, ROCKET-AF, ARISTO-

TLE and ENGAGE AF-TIMI 48 have confirmed the superior efficacy

of DOACs compared to warfarin for stroke prophylaxis in AF in-

cluding a 19% reduced risk of stroke and systemic embolism, driven

largely by reduction in the risk of hemorrhagic stroke, and lower

all-cause mortality. In addition, overall major bleeding, including

intracranial bleeding, was lower in DOAC-treated patients, although

GI bleeding was more common. Importantly, the relative efficacy

and safety benefits of DOACs were consistent across a wide range

of patient subgroups [46] . A more recent study also demonstrated

a small but significant reduction in mortality for DOAC-treated

patients compared to warfarin driven primarily by reduced fatal

bleeding [47] .

Despite the relative efficacy and safety profile favoring DOACs,

the updated 2014 AHA/ACC/HRS guidelines recommend oral anti-

oagulation with either warfarin (INR 2.0–3.0) or a DOAC in pa-

ients with non-valvular AF and prior stroke/transient ischemic at-

ack (TIA), or a CHA 2 DS 2 -VASc ≥2 [48] . The guidelines do, however,

ecommend DOACs in patients unable to maintain a therapeutic

NR on warfarin. The 2016 ESC guidelines go so far as to prefer use

f DOACs over warfarin in eligible patients [49] . It is important to

ote that existing guidelines define non-valvular AF as occurring in

he absence of moderate to severe rheumatic mitral valve stenosis,

itral valve repair, or prosthetic heart valves as such patients were

xcluded from the aforementioned clinical trials.

pecial populations

atients at low risk for stroke

For patients with a CHA 2 DS 2 -VASc score ≥2, it is generally

greed that anticoagulation therapy should be offered as the risks

utweigh the benefits in the absence of a contraindication. In pa-

ients with a CHA 2 DS 2 -VASc score = 0, the 2014 AHA/ACC guide-

ines and the 2016 ESC guidelines both recommend against treat-

ent with anticoagulation [4 8,4 9] . The guidelines for patients with

CHA 2 DS 2 -VASc score = 1 are less clear with the AHA/ACC rec-

mmending either no treatment, anticoagulation or aspirin and

he ESC recommending anticoagulation in male patients. Although

HA 2 DS 2 -VASc score = 1 corresponds to an annual stroke risk of

.3%, a retrospective Swedish health registry study suggests women

ith CHA 2 DS 2 -VASc = 1 have an annual stroke risk as low as 0.1–

.2% and men as low as 0.5–0.7% [50] . The reason for this dis-

repancy lies in the heterogeneity of risk conferred by the differ-

nt factors weighted at 1 point in the CHA 2 DS 2 -VASc scheme with

ge 65–74 conferring significantly more risk than the others [51] .

t would therefore be reasonable to consider withholding anticoag-

lation in patients < 65 years of age with a CHA 2 DS 2 -VASc score = and offering it to older patients with the same score.

alvular atrial fibrillation

As discussed previously, DOACs are currently approved for use

n patients with non-valvular AF, which excludes patients with sig-

ificant mitral valve stenosis, prior mitral valve repair or a pros-

hetic heart valve. An analysis from ENGAGE AF-TIMI 48 showed

alvular heart disease including moderate aortic and mitral re-

urgitation, aortic stenosis, prior valve repair, prior valvuloplasty

nd bioprosthetic valve replacement to be independently associ-

ted with an increased risk of death, major cardiovascular events

nd bleeding; however, these factors did not influence the efficacy

r safety of edoxaban [52] . A meta-analysis of phase III DOAC tri-

ls also concluded the presence of comorbid valvular heart disease

ther than moderate to severe rheumatic mitral valve stenosis or

echanical heart valves did not affect the efficacy or safety of the

OACs, including patients with bioprosthetic valves [53] . The supe-

iority of warfarin in patients with AF and mechanical heart valves

as evident in the RE-ALIGN trial which was terminated early

ue to a significantly increased incidence of stroke and bleeding

ith dabigatran compared to dose-adjusted warfarin [54] . Given

his emerging evidence, perhaps the recently proposed acronym

ARM-AF standing for “mechanical and rheumatic mitral valvular

trial fibrillation” would be a more accurate way to identify pa-

ients in whom warfarin would be preferred rather than the non-

pecific term “valvular-atrial fibrillation” [55] .

lderly patients

Although age ≥75 years is the single strongest risk factor for

troke in patients with AF [56] , the risk of bleeding complications

J. Stock, B.J. Malm / Trends in Cardiovascular Medicine 28 (2018) 469–480 475

Table 4

DOAC dosing in CKD based on FDA-approved labelling.

DOAC Renal impairment category Dose

Dabigatran CrCl 15–30 mL/min 75 mg twice daily

CrCl < 15 mL/min or HD Not defined, avoid use

Rivaroxaban CrCl 15–50 mL/min 15 mg daily

CrCl < 15 mL/min (not HD) Not defined, avoid use

HD 15 mg daily (efficacy not established)

Apixaban Cr > 1.5 mg/dL (in addition to age > 80 years or weight < 60 kg) 2.5 mg twice daily

CrCl < 15 mL/min (not on HD) Not defined, avoid use

HD 5 mg twice daily (efficacy not established)

HD (in addition to age > 80 years or weight < 60 kg) 2.5 mg twice daily (efficacy not established)

Edoxaban CrCl > 95 mL/min Avoid use

CrCl 15–50 mL/min 30 mg daily

CrCl < 15 mL/min or HD Not defined, avoid use

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lso increases with age [57] . Historically, physicians have underuti-

ized anticoagulation in the elderly due to the perceived increased

isk of bleeding, particularly related to falls and intracranial hem-

rrhage, as well as concerns regarding adherence to warfarin and

aintenance of therapeutic INR [58,59] . For these reasons, some

linicians may choose to treat an elderly patient with aspirin rather

han anticoagulation to reduce their perceived bleeding risk. How-

ver, the BAFTA trial showed that warfarin was superior to aspirin

n preventing stroke in patients with AF age ≥75 with no differ-

nce in major bleeding events [60] .

Concerning falls and intracranial hemorrhage, a retrospective

nalysis of elderly medicare beneficiaries with AF at high risk for

alls found warfarin to be associated with increased mortality from

ntracranial hemorrhage but not increased occurrence. In addition,

arfarin use was shown to be protective against the composite

nd-point of stroke, intracranial hemorrhage, myocardial infarction

nd death [61] . Furthermore, a meta-analysis of elderly patients

ith AF at increased risk for falls showed that quality-adjusted life

xpectancy was higher with warfarin use than with aspirin use or

o therapy unless the patient’s annual risk of stroke was < 2% per

ear [62] . The authors asserted that risk of falling should not be

n important factor in determining candidacy for anticoagulation

nd that one would have to fall 300 times/year for the risk of fall-

elated bleeding complications to outweigh the benefits of antico-

gulation [62,63] .

As discussed earlier, DOACs have a lower risk of hemorrhagic

troke and do not share the disadvantages of therapeutic drug

onitoring and narrow therapeutic index with warfarin. These dif-

erences make them potentially attractive for use in the elderly. In

he RE-LY trial, patients < 75 years of age had lower major bleed-

ng with dabigatran, however, there was a trend toward increased

ajor bleeding in patients ≥75 years of age receiving the 150 mg

wice daily dose currently approved in the US [64] . ROCKET-AF

atients ≥75 years of age on rivaroxaban had a lower risk of in-

racerebral and fatal hemorrhages but a higher risk of non-major

leeding. [65] . Patients ≥75 years of age on apixaban in the AVER-

OES and ARISTOTLE trials had a risk of major bleeding compara-

le to aspirin and lower than warfarin respectively [36,38] . Based

n the available evidence, DOACs, apixaban in particular, are rea-

onable alternatives to warfarin in elderly patients with AF.

atients with renal failure

The anticoagulation strategy for patients with AF at increased

isk for stroke with concomitant chronic kidney disease (CKD)

eserves special consideration. The randomized controlled trials

omparing DOACs versus warfarin excluded patients with ad-

anced CKD (CrCl < 30 ml/min in RELY, ROCKET-AF, ENGAGE-

IMI48, serum Cr > 2.5 mg/dl or CrCl < 25 ml/min in ARISTOTLE)

ince all DOACs, dabigatran in particular, are renally cleared to

ome degree requiring dose adjustment based on creatinine clear-

nce. Table 4 summarizes DOAC dose adjustments in CKD based

n approved labelling by the U.S. Food and Drug Administration.

n general, DOACs should be avoided in patients with severe re-

al impairment (i.e. CrCl < 15–30) or ESRD on hemodialysis. Dose-

djusted warfarin remains the preferred anticoagulant in these

ettings.

There is conflicting evidence regarding the benefit of warfarin

n patients with ESRD on hemodialysis. Patients with severe renal

mpairment have been shown to require decreased maintenance

oses of warfarin due in part to vitamin K deficiency [66] . Pa-

ients on hemodialysis also spend more time outside the therapeu-

ic window and are more likely to have supratherapeutic INRs [67] .

n observational cohort study from Taiwan comparing patients on

emodialysis with new onset AF to hemodialysis patients without

F showed a modest increased risk of stroke which was statis-

ically insignificant after considering in-hospital death as a com-

eting risk [68] . A retrospective Canadian cohort study compar-

ng patients on hemodialysis with AF receiving warfarin to those

ho were not found no significant association with reduction in

troke risk but a higher risk of bleeding [69] . Although these re-

ults may caution the use of anticoagulation in hemodialysis pa-

ients with AF, other observational studies have shown a reduction

n stroke risk and a trend toward improved mortality in patients

reated with warfarin [70,71] . Guideline recommendations for anti-

oagulation in this setting are also not in agreement. The Canadian

ardiovascular Society 2012 and Kidney Disease: Improving Global

utcomes 2011 guidelines both advise against anticoagulation for

troke prevention in hemodialysis patients. The European Society

f Cardiology 2016 guidelines do not make a definitive recommen-

ation on this matter. The ACC/AHA/HRS 2014 guidelines, however,

ive a class IIb recommendation for warfarin in patients with ESRD

nd a CHA 2 DS 2 -VASc score of ≥2. Until a randomized controlled

rial is performed, as some have called for [72] , the decision to ini-

iate warfarin therapy should be a shared one with the patient on

n individual basis.

atients with coronary artery disease

Estimates of the prevalence of CAD in patients with AF vary

rom 18 to 47% [73,74] . Thrombosis in acute coronary syndrome

iffers mechanistically from thromboembolism in AF, and there-

ore the mainstay of therapy in this setting is antiplatelet ther-

py, including prolonged dual antiplatelet therapy (DAPT) follow-

ng percutaneous coronary intervention (PCI) with aspirin and a

2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) for at least 12

onths, a class I recommendation in current guidelines [75] . In pa-

ients with AF undergoing PCI with stent placement, older guide-

ines suggested the use of DAPT plus oral anticoagulation with war-

arin (commonly referred to as triple therapy) for prevention of

tent thrombosis as well as stroke and systemic thromboembolism

hich, until recently, has been the standard of care [76] .

476 J. Stock, B.J. Malm / Trends in Cardiovascular Medicine 28 (2018) 469–480

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Observational studies reporting increased risk of bleeding com-

plications [77–79] , however, has prompted clinical trials to eval-

uate alternatives to long term triple therapy. WOEST randomized

patients with an indication for anticoagulation undergoing PCI to

warfarin and clopidogrel with or without aspirin and revealed less

bleeding complications and a reduction in the combined secondary

endpoint of death, MI, revascularization, stroke and stent throm-

bosis in the double therapy group [80] . The 2014 AHA/ACC/HRS

guidelines were subsequently updated to include a Class IIb rec-

ommendation for clopidogrel monotherapy in addition to oral an-

ticoagulation in patients with AF undergoing PCI [81] . ISAR-TRIPLE

randomized patients undergoing PCI with an indication for antico-

agulation to triple therapy for 6 months versus 6 weeks and found

no significant difference in net clinical benefit or the secondary

outcomes of cardiac death, MI, stroke, stent thrombosis or major

bleeding [82] .

More recent studies have investigated the role of DOACs in

this setting as well. PIONEER AF-PCI randomized patients with

AF undergoing PCI to rivaroxaban 15 mg daily plus a P2Y12 in-

hibitor (clopidogrel or ticagrelor), rivaroxaban 2.5 mg twice daily

plus DAPT or warfarin plus DAPT and demonstrated fewer bleed-

ing complications in both rivaroxaban groups and no difference in

major cardiovascular events (death, MI, stroke), though the trial

was underpowered to detect a difference in efficacy [83] . The RE-

DUAL PCI trial similarly randomized patients with AF undergoing

PCI to warfarin plus DAPT, dabigatran 110 mg twice daily plus a

P2Y12 inhibitor, or dabigatran 150 mg twice daily plus a P2Y12

inhibitor. Both dabigatran arms demonstrated significantly lower

rates of major and non-major clinically relevant bleeding and non-

inferiority with respect to efficacy in preventing thromboembolic

events [84] . Taken together, these recent trials provide compelling

evidence against the routine use of triple therapy in favor of dou-

ble therapy with a DOAC and a P2Y12 inhibitor to reduce bleed-

ing complications and prevent thrombosis in most patients with

AF undergoing PCI.

Uncertainty also exists regarding the long-term anticoagulation

strategy for patients with AF and stable CAD (defined as > 12

months since the last acute coronary event). The 2012 ESC guide-

lines recommend oral anticoagulation as monotherapy for patients

with stable CAD and AF supported by evidence for reduced re-

current cardiovascular events in patients treated with warfarin

[85,86] . The 2011 AHA/ACC guidelines, however, continue to rec-

ommend antiplatelet therapy in addition to anticoagulation [87] .

Unfortunately, there are no randomized controlled trials comparing

anticoagulation alone against double therapy (anticoagulation plus

aspirin or P2Y12 inhibitor) in patients with AF and comorbid CAD.

However, a recent Danish cohort study of patients with AF and sta-

ble CAD treated with warfarin and antiplatelet therapy showed no

reduction in coronary or thromboembolic events although bleeding

risk was increased compared to warfarin alone [88] . The ongoing

OAC-ALONE trial in Japan comparing warfarin with warfarin plus

aspirin in patients with AF and stable CAD should help illuminate

this issue further [89] . The currently enrolling REWRAPS registry

comparing rivaroxaban and warfarin in patients with stable CAD

will also shed light on the role of DOACs in this setting [90] .

Post-ablation

Radiofrequency catheter ablation (CA) of AF is often performed

for rhythm management in symptomatic patients who fail or de-

cline anti-arrhythmic medications. Although there is an increased

risk of cardioembolic complications, peri–procedural anticoagula-

tion strategies vary including the decision of whether to con-

tinue or interrupt oral anticoagulation prior to the procedure. For

patients undergoing CA who have been therapeutically anticoag-

ulated with warfarin, dabigatran, or rivaroxaban, the 2017 HRS

xpert Consensus Statements recommends performing the proce-

ure without interruption [104] . In addition, recent clinical tri-

ls have demonstrated less major bleeding with both dabigatran

nd rivaroxaban compared to warfarin in patients undergoing CA

105,106] , making DOACs attractive options in this setting. It is

lso recommended that patients continue to receive oral antico-

gulation for at least 2 months following CA and long-term anti-

oagulation, especially if CHA 2 DS 2 -VASc > 1, be continued based

n stroke risk rather than procedural success. Long-term antico-

gulation following successful CA remains controversial as non-

andomized studies suggest that anticoagulation can be safely dis-

ontinued [107] , there is currently no evidence that CA reduces

troke risk in patients with AF. In general, discontinuation of an-

icoagulation in this setting should be based on patient prefer-

nces and guidelines recommend considering continuous or fre-

uent ECG monitoring to screen for AF recurrence.

Cavotricuspid isthmus (CTI) CA of typical atrial flutter is a

ighly effective treatment and although current guidelines recom-

end managing anticoagulation similarly to AF, it is occasionally

iscontinued following successful CTI ablation given the low risk

or atrial flutter recurrence. In a recent study of 364 patients with

trial flutter who underwent successful CTI ablation, however, AF

eveloped in 22% of those with no prior history of AF during a

ean follow-up of 22 months [108] . Providers should therefore ex-

rcise caution when discontinuing anticoagulation in this setting.

ryptogenic stroke

Paroxysmal AF is often asymptomatic and is being identified

ub-clinically in a growing number of patients with cryptogenic

troke. In a randomized study of 512 patients, 30 days monitor-

ng detected AF in 16% patients compared to 3% with conventional

4-hour Holter monitoring [101] . A smaller cohort study of 51 pa-

ients using the Reveal XT implantable loop recorder (Medtronic)

dentified AF in 25% patients [102] . In addition, smartphone appli-

ations have demonstrated accuracy in rhythm identification and

ill likely play an expanded role in screening for AF in the future

103] . Diagnosis of subclinical AF in this setting can identify appro-

riate candidates for anticoagulation to reduce future thromboem-

olic risk.

on-pharmacologic approaches

In a recent study, 12.4% patients with AF had a contraindication

o oral anticoagulation including 43% having CHA 2 DS 2 -VASc ≥ 4

91] . We know from imaging and autopsy studies that the LAA

s the source of thrombus in > 90% of patients with AF [92] . Sev-

ral devices and techniques have therefore been developed to ex-

lude the LAA and reduce the risk of thromboembolism in patients

eemed unsuitable for anticoagulation ( Table 4 ) including those

ith contraindications, prohibitively high bleeding risk or patients

ith prior stroke or TIA despite anticoagulation.

The AMPLATZER cardiac plug (St. Jude Medical, St. Paul, Min-

esota, USA) is an endovascular device placed via a trans-septal ap-

roach under fluoroscopic and transesophageal echocardiographic

uidance. Although not evaluated in a randomized controlled trial,

multi-center European study demonstrated a 59% relative risk re-

uction in the rate of CVA or TIA in patients treated with the AM-

LATZER device [93] . Acute periprocedural complications, including

troke and pericardial tamponade, occurred in 5% of patients. The

MPLATZER device is not currently approved for use in the United

tates.

The WATCHMAN device (Boston Scientific, Natick, Mas-

achusetts, USA) is another endovascular device deployed via an

maging-guided trans-septal approach to occlude the LAA ( Fig. 4 ).

he efficacy and safety of this device has been evaluated in two

J. Stock, B.J. Malm / Trends in Cardiovascular Medicine 28 (2018) 469–480 477

Fig. 4. WATCHMAN LAA closure device. (A-B) image provided courtesy of Boston Scientific. ©2017 Boston Scientific Corporation or its affiliates. All rights reserved.

Table 5

Indications for LAA closure.

Common indications for percutaneous LAA closure

• Thrombocytopenia/coagulopathy

• Recurrent bleeding, including GI, GU, pulmonary

• Prior severe bleeding, including intracranial hemorrhage

• Combined use of dual antiplatelet and anticoagulant therapy

• Poor compliance with or intolerance to anticoagulant therapy

• High bleeding risk (i.e. HAS-BLED score > 3) outweighs benefit of

anticoagulation

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andomized trials leading to FDA approval in 2015 for use in pa-

ients with non-valvular AF at increased risk of stroke with an ap-

ropriate reason to seek a non-pharmacologic alternative to anti-

oagulation. In the PROTECT-AF trial, patients with non-valvular AF

nd ≥1 stroke risk factor were randomized to LAA closure with the

ATCHMAN device or dose-adjusted warfarin [94] . Although the

evice was non-inferior to warfarin for efficacy, there was a higher

ncidence of adverse safety events primarily due to periprocedu-

al complications in the device group. Due to concerns regarding a

ignificant number of patients in the trial with CHA 2 DS 2 -VASc = 1,

second trial, PREVAIL, was conducted. In PREVAIL, patients with

HA 2 DS 2 -VASc ≥ 2 were randomized to WATCHMAN device or

ose-adjusted warfarin. After 18 months of follow-up, the trial

ailed to show non-inferiority of the WATCHMAN device mostly

ue to low overall event rates. The WATCHMAN device did, how-

ver, achieve non-inferiority for the prevention of ischemic stroke

7 days post-procedure. The device was also successful in meet-

ng pre-specified safety outcomes with events occurring in 2.2% of

atients [95] .

Another device used off-label for percutaneous LAA closure is

he LARIAT (SentreHeart Inc. Redwood City, CA USA), which ligates

he LAA via suture through an epicardial approach guided by flu-

roscopy, transesophageal echocardiography and a magnet-based

ndovascular guide rail. Although there are no randomized trials

ssessing its efficacy or safety, a prospective US multicenter eval-

ation of 712 patients treated with the LARIAT device showed a

6% success rate with complete occlusion of the LAA occurring in

8% of cases with 10 cardiac perforations requiring surgical repair

nd 1 death [96] . An advantage of this approach over endovascular

losure is the avoidance of short-term post-procedure anticoagu-

ation which is challenging in patients with absolute contraindica-

ions (such as those with recent intracranial hemorrhage). Table 5

Surgical LAA closure is another option in patients with AF un-

ergoing cardiothoracic surgery with complete excision being gen-

rally more effective than suture ligation [97] . Although efficacy

ata is limited, retrospective studies have demonstrated a reduced

ncidence of embolic events in patients treated in this manner [98] .

oth the 2014 ACC/AHA/HRS and 2016 ESC Guidelines give a class

Ib recommendation for surgical LAA excision at the time of car-

iothoracic surgery in patients with AF [48,99] .

ummary

Atrial fibrillation is a common disease in contemporary

edicine with an increasing prevalence. Thromboembolic events,

rimarily stroke, are the major cause of morbidity and mortality

n patients with AF and prevention of these complications requires

areful risk assessment incorporating clinical, echocardiographic,

nd biological risk factors. The CHA 2 DS 2 -VASc score is currently

he most useful clinical risk stratification tool and is recommended

y current guidelines. The standard therapy for reducing the risk

f thromboembolism in most patients with AF is anticoagula-

ion, which is highly effective in appropriately selected patients.

lthough dose-adjusted warfarin had been the mainstay of an-

icoagulation for decades, it has been largely replaced by newer

irect oral anticoagulants due to their favorable pharmacology

nd superior safety and efficacy profiles. Mechanical devices used

o occlude the LAA are under active investigation and are now

vailable for clinic use. These promising interventions offer a non-

harmacologic alternative in carefully selected patients deemed

nsuitable for anticoagulation.

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