Left Atrial Appendage Closure as an Alternative to Warfarin for Stroke Prevention in Atrial Fibrillation

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 24, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.

ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2015.04.025

Left Atrial Appendage Closure as an Alternative to Warfarin for Stroke Prevention in Atrial Fibrillation A Patient-Level Meta-Analysis David R. Holmes, JR, MD,* Shephal K. Doshi, MD,y Saibal Kar, MD,z Matthew J. Price, MD,x Jose M. Sanchez, MD,k Horst Sievert, MD,{ Miguel Valderrabano, MD,# Vivek Y. Reddy, MD**

ABSTRACT BACKGROUND The risk-benefit ratio of left atrial appendage closure (LAAC) versus systemic therapy (warfarin) for prevention of stroke, systemic embolism, and cardiovascular death in nonvalvular atrial fibrillation (NVAF) requires continued evaluation. OBJECTIVES This study sought to assess composite data regarding left atrial appendage closure (LAAC) in 2 randomized trials compared to warfarin for prevention of stroke, systemic embolism, and cardiovascular death in patients with nonvalvular AF. METHODS Our meta-analysis included 2,406 patients with 5,931 patient-years (PY) of follow-up from the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the Watchman LAA Closure Device In Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trials, and their respective registries (Continued Access to PROTECT AF registry and Continued Access to PREVAIL registry). RESULTS With mean follow-up of 2.69 years, patients receiving LAAC with the Watchman device had significantly fewer hemorrhagic strokes (0.15 vs. 0.96 events/100 patient-years [PY]; hazard ratio [HR]: 0.22; p ¼ 0.004), cardiovascular/ unexplained death (1.1 vs. 2.3 events/100 PY; HR: 0.48; p ¼ 0.006), and nonprocedural bleeding (6.0% vs. 11.3%; HR: 0.51; p ¼ 0.006) compared with warfarin. All-cause stroke or systemic embolism was similar between both strategies (1.75 vs. 1.87 events/100 PY; HR: 1.02; 95% CI: 0.62 to 1.7; p ¼ 0.94). There were more ischemic strokes in the device group (1.6 vs. 0.9 and 0.2 vs. 1.0 events/100 PY; HR: 1.95 and 0.22, respectively; p ¼ 0.05 and 0.004, respectively). Both trials and registries identified similar event rates and consistent device effect in multiple subsets. CONCLUSIONS In patients with NVAF at increased risk for stroke or bleeding who are candidates for chronic anticoagulation, LAAC resulted in improved rates of hemorrhagic stroke, cardiovascular/unexplained death, and nonprocedural bleeding compared to warfarin. (J Am Coll Cardiol 2015;65:2614–23) © 2015 by the American College of Cardiology Foundation.

From the *Mayo Clinic, Rochester, Minnesota; ySt. John’s Health Center, Santa Monica, California; zCedars Sinai Medical Center, Los Angeles, California; xScripps Clinic, La Jolla, California; kMercy Hospital, St. Louis, Missouri; {Cardiovascular Center Frankfurt, Sankt Katharinen, Frankfurt, Germany; #Methodist Hospital, Houston, Texas; and the **Mount Sinai School of Medicine, New York, New York. Dr. Holmes and the Mayo Clinic have a financial interest in technology related to this research; the technology has been licensed to Boston Scientific. Dr. Doshi has received research grants and consultant fees from Boston Scientific, St. Jude Medical, Coherex, and SentreHeart; and is the national principal Investigator of the Continuous Access Registry (CAP2). Dr. Kar has received research grants from Boston Scientific, St. Jude Medical, and Abbott Vascular; is a member of the advisory board for left atrial appendage closure; is the national principal investigator of the Continuous Access Registries (CAP and CAP2) has served as a proctor for Boston Scientific; owns equity in Coherex; and is a consultant for Abbott Vascular. Dr. Price has received consulting honoraria from Boston Scientific, St. Jude Medical, Janssen Pharmaceuticals, Daiichi-Sankyo, Terumo, and W.L. Gore; and his institution receives research support from Boston Scientific, St. Jude Medical, and SentreHeart. Dr. Sanchez has received consulting fees from Boston Scientific. Dr. Sievert has received study honoraria, travel expenses, consulting fees

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L

eft atrial appendage closure (LAAC) has been

and noninferiority of 1 of 2 coprimary efficacy

ABBREVIATIONS

investigated intensely for stroke prevention

endpoints; an 18-month rate ratio (RR) for

AND ACRONYMS

as an alternative to systemic oral anticoagula-

primary efficacy, and an 18-month rate ratio

tion in selected patients with high-risk nonvalvular

difference for post-procedure ischemic stroke

atrial fibrillation (NVAF) (1–11). The PROTECT AF (Pro-

and systemic embolism. After review of these

spective Randomized Evaluation of the Watchman

data in December 2013, the FDA panel

LAA Closure Device In Patients With Atrial Fibrilla-

returned a positive vote for safety, efficacy,

tion Versus Long Term Warfarin Therapy) trial was a

and benefit/risk. However, after this panel,

multicenter, randomized controlled trial in NVAF pa-

an updated data set to FDA as part of routine

tients comparing the Watchman device to warfarin

regulatory filings raised further efficacy con-

for a composite primary endpoint of stroke, systemic

cerns, resulting in a third panel to evaluate

embolism, and cardiovascular (CV) death (1,9). Non-

the totality of data.

inferiority to warfarin was documented early and long term (2,621 patient-years [PY]), LAAC demonstrated a significant (40%) relative risk reduction to warfarin for the primary efficacy endpoint (1,5), an 85% relative risk reduction in hemorrhagic stroke, a 60% relative reduction in CV mortality (absolute annual risk reduction of 1.4%), and a 34% relative reduction in all-cause mortality (absolute annual risk reduction of 1.6%) (5). Despite a positive vote from the Center for Devices and Radiological Health (CDRH) Panel in 2009, the U.S. Food and Drug Administration (FDA) issued a nonapprovable letter on the basis of concerns of procedural complications, the risk profile of patients, and the confounding use and effect of clopidogrel following implant. To address these,

2615

Stroke Prevention in Nonvalvular Atrial Fibrillation

the

device

manufacturer

worked

with

SEE PAGE 2624

To evaluate the totality of data, this patient level meta-analysis was performed in which: 1) all randomized patients from the

CI = confidence interval CV = cardiovascular HR = hazard ratio INR = international normalized ratio

LAA = left atrial appendage LAAC = left atrial appendage closure

NOAC = new oral anticoagulant agent

NVAF = nonvalvular atrial fibrillation

PY = patient-years RR = rate ratio

PROTECT AF and PREVAIL trials are combined and the data analyzed using “traditional” frequentist statistical methods; and 2) patients from 2 nonrandomized registries of LAAC with the device (the CAP [Continued Access to PROTECT AF registry] and the CAP2 [Continued Access to PREVAIL registry]) are included. (3) By including these data from over 2,200 patients and w6,000 PY of follow-up, we provide the most comprehensive assessment to date of the efficacy of Watchman LAAC for stroke prevention.

METHODS

the FDA for a confirmatory randomized trial (PREVAIL [Prospective Randomized Evaluation of the

Local institutional review board approval was ob-

Watchman LAA Closure Device In Patients With Atrial

tained for each dataset. All clinical trials were re-

Fibrillation Versus Long Term Warfarin Therapy]

gistered on ClinicalTrials.gov (1,3,4). The specific

trial) comparing LAAC with the Watchman device to

Watchman device was identical throughout; a self-

warfarin, which mandated inclusion of new opera-

expanding nitinol framed structure positioned at

tors, slight modifications in inclusion criteria, and

LAA ostium with diameter ranges from 20 to 33 mm

elimination of clopidogrel 7 days before implant.

and fixation barbs to prevent embolization (9).

Bayesian statistical methodology was agreed upon

Implant protocols were identical. As previously

using informative prior data from the PROTECT AF

described (1,4,9), after implantation, patients were

trial (see Methods section). At the pre-defined evalu-

treated with warfarin with an international normal-

ation time point, the PREVAIL trial demonstrated

ized ratio (INR) goal of 2.0 to 3.0 and aspirin

improved safety compared to the PROTECT AF trial,

(81 mg) for 45 days; at that time, transesophageal

<25,000 V from Abbott, Access Closure, AGA, Angiomed, Aptus, Atrium, Avinger, Bard, Biosense Webster, Boston Scientific, Bridgepoint, Carag, Cardiac Dimensions, CardioKinetix, CardioMEMS, Cardiox, Celonova, CGuard, Coherex, Contego, Covidien, CSI, CVRx, EndoCross, ev3, FlowCardia, Gardia, Gore, GTIMD Medical, Guided Delivery Systems, Hemoteq, InSeal Medical, InspireMD, Lumen Biomedical, HLT, Lifetech, Lutonix, Maya Medical, Medtronic, NDC, Occlutech, Osprey, Ostial, PendraCare, pfm Medical, Recor, ResMed, Rox Medical, SentreHeart, Spectranetics, SquareOne, Svelte Medical Systems, Tendyne, Trireme, Trivascular, Valtech, Vascular Dynamics, Venus Medical, Veryan, and Vessix; has received research grant support <25,000 V from Cook, and St. Jude Medical; and owns stock options <25,000 V from Cardiokinetix, Access Closure, Velocimed, Lumen Biomedical, Coherex, and SMT. Dr. Valderrabano has received consulting fees from Boston Scientific, St. Jude Medical, Biosense Webster, Hansen Medical, and SentreHeart. Dr. Reddy has received research grant support from and has been a consultant for Atritech/Boston Scientific. Noel Boyle, MD, PhD, served as Guest Editor for this paper. Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. Manuscript received January 24, 2015; revised manuscript received March 17, 2015, accepted April 15, 2015.

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Stroke Prevention in Nonvalvular Atrial Fibrillation

echocardiography was performed. If there was com-

excluding the first 7 days post-randomization, which

plete LAAC or if residual peridevice flow was <5 mm

aimed to isolate the mechanism of LAAC and its

in width, warfarin was discontinued and the patient

potential effect on outcomes without the con-

was treated with clopidogrel 75 mg and aspirin 81 to

founding influence of procedural complications;

325 mg until 6 months following implantation, at

and 3) a composite of early safety—death, ischemic

which time clopidogrel was discontinued and 325 mg

stroke, systemic embolization, device-/procedural-

of aspirin was used indefinitely. In the control

related events requiring open CV surgery or a major

(warfarin) limb, INR was monitored every 2 weeks to

endovascular intervention between randomization

achieve an INR of 2 to 3. All patients had follow-up

and 7 days post-procedure or during the index

visits at 45 days, and at 6, 9, and 12 months, and

hospitalization.

then twice yearly.

Inclusion of new operators was mandated to assess

All 4 datasets included a primary efficacy com-

procedural performance. Trial design recognized

posite of all cause stroke (both hemorrhagic and

the utility of the available efficacy data from the

ischemic), systemic embolization, and CV death. Any

PROTECT AF trial, and used Bayesian statistical

death of unknown origin was included as CV. Safety

methodology that allowed “borrowing” some data on

endpoints varied slightly between the 2 randomized

PREVAIL-eligible PROTECT AF trial patients at 1,500

trials and included bleeding as well as all cause stroke

PY of follow-up as an informative prior. Incorporation

(ischemic and hemorrhagic). To be a candidate for the

of the informative prior allowed for a smaller confir-

device, all patients had to be able to take warfarin for

matory PREVAIL trial, but results in the fact that the

45 days following implantation.

confirmatory trial by itself is not powered to reach

Because of the identical efficacy endpoint defini-

robust conclusions. The PROTECT AF trial results

tions in both randomized trials, the data from both

were combined with the small sample size of the

trials were pooled for this meta-analysis (1,4).

PREVAIL trial to confirm device safety and collect

PROTECT

criteria included

additional efficacy data on LAAC. The resulting study

$18 years of age with paroxysmal persistent or per-

requirements were such that follow-up with the new

manent AF with a CHADS2 risk score $1. Exclusion

PREVAIL trial patients was limited to 6 months min-

criteria

to

imum in order for the endpoint to occur using the

warfarin, LAA thrombus, a patent foramen ovale with

modeled 18-month event rates against pre-specified

an atrial septal aneurysm and right to left shunt,

performance boundaries.

AF

STUDY. Eligibility

included

absolute

contraindications

mobile aortic atheroma, or symptomatic carotid dis-

REGISTRIES. The registries (3) were designed to treat

ease. The primary composite safety endpoint included

patients with similar baseline characteristics ac-

excessive bleeding or procedural-related complica-

cording to the same protocols after the specific trial

tions (e.g., pericardial effusion requiring interven-

enrollment

tion, device embolization, or procedural-related

PROTECT AF and CAP2 following the PREVAIL trial.

stroke). A Bayesian statistical model (12) was used for

Procedural performance and adjunctive medications

noninferiority trial design, and pre-specified endpoint

were identical in each registry and the respective

analysis of observed event rates after 600 follow-up

randomized trials except registries did not mandate

PY and after each additional 150 PY, up to 1,500.

1-year neurological assessment required in both

PREVAIL TRIAL. Selection criteria were modified to

randomized trials.

include higher risk patients: a CHADS2 score $2 or a

DEFINITIONS. For all data sets, the CHADS2 score

CHADS 2 score $1 with more than 1 of the following

(1,4) was used for patient entry. Because the

had

been

completed—CAP

following

higher risk characteristics; female $75 years of age,

CHA 2DS2-VASc score has largely supplanted CHADS2

baseline ejection fraction $30% but <35%, 65 to

(13–16), risk prediction was reported using both.

74 years of age with either diabetes or coronary artery

Assessment of bleeding risk was a clinical site deter-

disease, and $65 years of age with heart failure. Ex-

mination. Though not prospectively captured in

clusion criteria were similar to the PROTECT AF trial,

the Watchman studies, many components of the

except patients in whom clopidogrel therapy was

HAS-BLED (13,15) score were captured as a part of

indicated were excluded because of the potential con-

routine data collection. A conservative bleeding score

founding influence of this drug on efficacy outcome.

was determined using the available case report form

There were 3 coprimary endpoints: 1) a composite

data and points were assigned per the HAS-BLED

efficacy endpoint identical to the PROTECT AF

score. Abnormal liver function and labile INR were

trial; 2) a second, “late ischemic efficacy endpoint”— a

not captured and were consequently assigned a score

composite of ischemic stroke or systemic embolization

of zero. An independent Clinical Events Committee

Holmes, Jr. et al.

JACC VOL. 65, NO. 24, 2015 JUNE 23, 2015:2614–23

Stroke Prevention in Nonvalvular Atrial Fibrillation

adjudicated strokes in all trials and registries.

of recruitment, the PROTECT AF trial patients have

Ischemic stroke was defined as sudden onset of a

the longest follow-up, but registry patients provide

focal neurological deficit with symptoms and/or signs

the largest number of patients.

persisting >24 h, or symptoms <24 h with computed

Analyses were intent-to-treat, censoring data from

tomography or magnetic resonance imaging evidence

patients without events at the time of the last

of tissue loss without hemorrhage. Although hemor-

known status. A Cox proportional hazards model with

rhagic stroke definitions varied slightly from the

confidence intervals (CIs) was used for comparison

PROTECT AF trial to the PREVAIL trial, they included

of event rates. For the analysis including the ran-

sudden onset of a focal neurological deficit with

domized trials, this model was stratified by study

computed tomography or magnetic resonance imag-

(PROTECT AF or PREVAIL) in order to account for

ing evidence of tissue loss with evidence of blood

differences in risk profiles. For the analysis including

vessel and/or intracranial hemorrhage with symp-

all 4 data sets, studies were treated as “clusters” in

tomatic focal neurological deficit. Subdural hema-

order to account for correlation among patients

tomas with evidence of parenchymal involvement

within studies. The Kaplan-Meier method was used

such as parenchymal extensions or contusion were

for graphical assessment of time-dependent events.

adjudicated as a hemorrhagic stroke, unless confined

Results are presented using frequentist statistics and

exclusively to the subdural space.

2-sided p values nominally significant at p < 0.05

STATISTICAL ANALYSIS FOR META-ANALYSIS. This

patient level meta-analysis had 3 components: 1) as-

with no adjustments for multiple comparisons.

RESULTS

sessment of the device outcomes including all primary efficacy components, all-cause mortality, and major

PATIENT

bleeding versus warfarin control in patients random-

enrolled 2,406 patients from 2005 to 2014; 1,877 were

CHARACTERISTICS. Four

ized in both the PROTECT AF and PREVAIL trials; 2)

treated with Watchman (1,145 Registry patients) and

the primary composite efficacy rates of patients

382 (the control limbs in the 2 randomized clinical tri-

receiving the Watchman device in both randomized

als) received warfarin. Mean follow-up depended on

controlled trials and registries; and 3) comparison of

when the patients were enrolled; there were a total of

the device performance in each of the 4 trials.

5,931 PY follow-up available (Table 1). Patient follow-

clinical

trials

Both randomized trials were designed to establish

up for CAP2 was the shortest by virtue of enrollment

noninferiority of a device-based strategy versus

initiation (mean follow-up of 0.58 years vs. 4.0 for the

warfarin for a composite primary efficacy endpoint.

PROTECT AF trial and 3.7 years for CAP). There was a

To evaluate benefit-risk ratio, the PROTECT AF and

progressive increase in patient risk over the course of

PREVAIL data sets were combined with all available

these data sets (Table 2); mean patient age ranged from

follow-up and analyzed as a traditional patient-level

72.0  8.9 years of age in the PROTECT AF trial to

meta-analysis. Fully utilizing the data from both tri-

75.3  8.0 years of age in CAP2. The CHADS2 score

als while accounting for the fact that they are

similarly ranged from 2.2  1.2 to 2.7  1.1 (p < 0.0001)

different studies facilitates more robust exploration

as did the CHA 2DS2-VASc score 3.5  1.6 to 4.5  1.3

of the role of covariates.

(p < 0.0001). On the basis of these scores, the total

This meta-analysis of these 2 studies is appropriate because both studies randomized subjects to the same

predicted annualized risk for stroke, if untreated with anticoagulation, ranged from 5.7% to 7.6% annually.

treatment strategies (Watchman vs. warfarin) and

The distribution of both CHADS2 and CHA2 DS2-

primary efficacy endpoint definitions. The baseline

VASc scores documented the majority of patients

risk profile in the combined the PROTECT AF and

were high risk for stroke and all were eligible for

PREVAIL trial population included a somewhat higher

warfarin (Figures 1A and 1B). Conversely, 90% of pa-

risk profile for the PREVAIL trial; subgroup analyses by

tients were moderate to high risk of bleeding using

CHADS 2 and CHA2 DS2-VASc scores were performed to

the estimated HAS-BLED score; 61% had a moderate

assess differences in outcome by baseline risk profile.

risk of increased bleeding. The PROTECT AF trial had

Further, results were stratified with Cox proportional

the highest prevalence of a low-risk HAS-BLED score,

hazards modeling, adjusting for potential baseline risk

but even in this study, this only constituted 6.4% of

differences. In addition, the device patients from the

the study. Between 93.2% and 98.7% of patients were

registry data were combined with all randomized data

able to discontinue warfarin at 1 year.

in the same fashion. Though registries had no control

LAAC

group, the same criteria around device and primary

RANDOMIZED CLINICAL TRIALS. Both the PROTECT

efficacy definitions apply. Given the variable initiation

AF and PREVAIL trials shared the primary efficacy

VERSUS

WARFARIN—META-ANALYSIS

OF

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Stroke Prevention in Nonvalvular Atrial Fibrillation

(1.6 vs. 0.9 events/100 PY; HR: 1.95; p ¼ 0.05) once

T A B L E 1 PROTECT AF and CAP: Largest Data Sets to Evaluate Totality of Data

Enrollment

PROTECT AF

PREVAIL

CAP

CAP2

2005–2008

2010–2012

2008–2010

2012–2014

procedure-related strokes were excluded, the rates of Total

ischemic stroke were no longer significantly different between the device and warfarin (HR: 1.40 [95% CI:

Enrolled

800

461

566

579

2,406

707

407

—

—

1.10 to 1.78] and HR: 0.89 [95% CI: 0.50 to 1.61];

Randomized

1,114

463:244

269:138

566

579

1,877:382

HR: 1.56; 95% CI: 0.78 to 3.09; p ¼ 0.21). In contrast,

Watchman:warfarin (2:1) Mean follow-up, yrs Patient-years

4.0

2.2

3.7

0.58

N/A

2,717

860

2,022

332

5,931

hemorrhagic

stroke

occurred

significantly

less

frequently in the LAAC treated patients at a rate of 0.15 per 100 PY (95% CI: 0.07 to 0.4) for device versus 0.96

CAP ¼ Continued Access to PROTECT AF registry; CAP2 ¼ Continued Access to PREVAIL registry; N/A ¼ not applicable; PREVAIL ¼ Prospective Randomized Evaluation of the Watchman LAA Closure Device In Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy; PROTECT AF ¼ Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation.

(95% CI: 0.55 to 1.70) for warfarin (HR: 0.22; 95% CI: 0.08 to 0.61; p ¼ 0.004). There were also significantly fewer CV deaths in the LAAC cohort (HR: 0.48; 95% CI: 0.28 to 0.81; p ¼ 0.006). Subgroup

endpoint of stroke, systemic embolism, and CV death.

analysis

of

the

composite

efficacy

The meta-analysis of the randomized clinical trial co-

endpoint revealed no significant interaction with cli-

horts reveals that the hazard ratio (HR) for this com-

nical characteristics such as age dichotomized at

posite efficacy endpoint was 0.79 (95% CI: 0.53 to 1.2;

75 years of age, sex, or the CHADS2 and CHA2DS 2-

p ¼ 0.22) (Figure 2) meeting noninferiority of LAAC

VASc risk scores (Figure 3). The p value for interaction

versus warfarin. Event rates per 100 PY were 2.72 (95%

of the estimated HAS-BLED score was 0.098. Finally,

CI: 2.29 to 3.24) and 3.50 (95% CI: 2.60 to 4.72) for de-

the presence or absence of a history of transient

vice and warfarin, respectively. But for the individual

ischemic attack or stroke before entering the clinical

endpoint components, there were significant differ-

trial also failed to affect outcomes.

ences. Although all-cause stroke or systemic embolism

Beyond the composite efficacy endpoint and its

rates per 100 PY were virtually identical between the 2

individual components, 2 additional analyses were

strategies (device: 1.75; 95% CI: 1.41 to 2.17; warfarin:

performed: all-cause mortality and major bleeding

1.87; 95% CI: 1.41 to 2.17; HR: 1.02; 95% CI: 0.62 to 1.7;

(Figure 2). Consistent with CV mortality, the HR for

p ¼ 0.94), there were differences when strokes were

all-cause mortality also favored LAAC, but did not

subdivided into ischemic versus hemorrhagic. Though

reach statistical significance (HR: 0.73; 95% CI: 0.52 to

there were more ischemic strokes in the device group

1.00; p ¼ 0.07). For total major bleeding including the index implantation period, there was no significant difference between LAAC and warfarin (HR: 1.00;

T A B L E 2 Patient Demographics Across Trials

95% CI: 0.69 to 1.40; p ¼ 0.95). However, for non–

PROTECT AF (N ¼ 707)

PREVAIL (N ¼ 407)

CAP (N ¼ 566)

CAP2 (N ¼ 579)

72.0  8.9

74.3  7.4

74.0  8.3

75.3  8.0

70.3

70.0

65.5

61.0

Asian

0.7

0.5

1.6

0.7

LAAC

Black/African American

1.6

1.7

1.9

1.2

RANDOMIZED CLINICAL TRIALS AND NONRANDOMIZED

White/Caucasian

91.5

94.4

91.9

94.1

REGISTRIES. In addition to 732 and 382 patients ran-

Hispanic/Latino

5.7

2.7

3.5

2.1

Other

0.6

0.7

1.1

1.0

2.2  1.2

2.6  1.0

2.4  1.2

Age, yrs Male

first 7 days post-implantation, there was a highly significant reduction in events in the LAAC arm (HR: 0.51; 95% CI: 0.33 to 0.77; p ¼ 0.02).

Ethnicity/race

CHADS2 score

procedure-related major bleeding occurring after the

2.7  1.1

CHADS2 risk factors

VERSUS WARFARIN:

META-ANALYSIS

OF

domized to either LAAC or warfarin, respectively, the 2

registries

enrolled

1,145

patients

undergoing

Watchman implantation. Despite the fact that the

CHF

26.9

19.1

23.3

27.1

average risk score for the patients in the registries

Hypertension

89.8

88.8

91.4

92.5

was higher than that of the patients enrolled in the 2

$75 yrs of age

43.1

51.8

53.6

59.7

randomized clinical trials, the composite efficacy

Diabetes

26.2

24.9

32.4

33.7

event rates were consistent. Kaplan-Meier analysis

Stroke/transient ischemic attack

18.5

30.4

27.8

29.0

revealed similar rates of events between the LAAC

3.5  1.6

4.0  1.2

3.9  1.5

4.5  1.3

arms of the randomized clinical trials and registry

CHA2DS2-VASc

6.4

1.7

2.8

2.8

patients (Central Illustration), even though the latter

HAS-BLED ¼ 1–2 (moderate risk)

73.7

68.6

61.0

69.9

had higher baseline risk. The meta-analysis of all

HAS-BLED ¼ 3þ (high risk)

19.9

29.7

36.2

28.3

4 clinical trials was entirely consistent with the

HAS-BLED ¼ 0 (low risk)

Values are mean  SD or %. CHF ¼ congestive heart failure; other abbreviations as in Table 1.

balanced comparison of the randomized clinical trials alone: 1) the overall composite efficacy endpoint was similar between groups; 2) the increase in ischemic

Holmes, Jr. et al.

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Stroke Prevention in Nonvalvular Atrial Fibrillation

stroke seen in the LAAC group is counterbalanced by a highly significant reduction in hemorrhagic stroke;

F I G U R E 1 Majority of Watchman Patients at High Risk of Stroke and

Moderate-to-High Bleeding Risk

3) there were significantly fewer CV deaths with LAAC; 4) all-cause mortality favored LAAC, but was not statistically significant; and 5) major bleeding was

50%

similar between groups, but non–procedure-related

PROTECT AF 93% 96% CAP PREVAIL 100% CAP2 100%

bleeds occurred with significantly greater frequency

40%

with warfarin treatment.

DISCUSSION

Patients (%)

In patients with NVAF, the totality of the Watchman data from 2 randomized clinical trials and 2 non-

CHA2DS2-VASc Score ≥2

Anticoagulation Eligible High Risk

A

30% 20% 10%

randomized registries demonstrates: 1) local therapy with LAAC provides similar benefit to warfarin for the

0% 0

composite efficacy endpoint of stroke, systemic em-

1

bolism, or CV death; 2) compared with long-term warfarin, patients randomized to LAAC have a significant

improvement

in

survival,

particularly

freedom from CV death; 3) although all-cause stroke rates are identical between groups, the pathophysiology of stroke was significantly different; more warfarin patients experiencing hemorrhagic strokes and more device patients experiencing ischemic strokes; 4) by 1 year, approximately 95% of device patients discontinued warfarin; 5) although all-cause bleeding was similar between groups, when periprocedural bleeding was excluded, bleeding rates

2 3 4 CHA2DS2-VASc Score

5

6–9

B

100% 90% 80% 70% 60% Patients 50% (%) 40% 30% 20% 10% 0% 0

were significantly higher in patients treated with

1–2 3+ HAS BLED Score

chronic warfarin; 6) device performance was consistent over the entire data set—both randomized clin-

(A) The majority of Watchman patients are high risk. CHA2DS2-VASc score is increasingly used

ical trials and registries, the latter of which are likely

to estimate stroke risk in patients with nonvalvular atrial fibrillation. In all 4 data sets, patients

to more closely resemble real world experience.

were at increased risk for stroke per American College of Cardiology/American Heart Asso-

The relationship between the increasing incidence

ciation/Heart Rhythm Society (ACC/AHA/HRS) 2014 guidelines, particularly in the PREVAIL (Prospective Randomized Evaluation of the Watchman LAA Closure Device In Patients With

of NVAF and consequent stroke is well described:

Atrial Fibrillation Versus Long Term Warfarin Therapy) trial and Continued Access to PREVAIL

stroke rates are increased 4- to 5-fold, larger and more

registry. (B) Most Watchman patients have moderate to high HAS-BLED scores. Patients

debilitating with hemorrhagic conversion, and higher

in all 4 data sets also had increased risk of bleeding. CAP ¼ Continued Access to PROTECT

recurrence rates (13,17–20). In patients >80 years of age, AF is believed to be responsible for 15% to 30% of

AF registry; CAP2 ¼ Continued Access to PREVAIL registry; PROTECT AF ¼ Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation.

strokes (20). Although warfarin has been the mainstay for stroke prevention, reducing it by approximately

relative contraindications, as perceived by patients or

65%, its disadvantages are well appreciated including

physicians (10,13,22–24).

drug-drug interactions, the need for frequent moni-

Warfarin limitations have led to the development

toring and dose adjustment, and the potential for

of new oral anticoagulant agents (NOACs), such as

bleeding. In addition, when a stroke occurs in the

Factor II and Xa inhibitors, which have now been

setting of anticoagulant therapy, mortality rates

studied in comparison to warfarin in large randomized

approximate 50%. In the National Electronic Injury

trials (25–30). In a meta-analysis of trials randomizing

Surveillance System project that included 99,682

NOACs to warfarin, NOACs were associated with a

emergency hospitalizations, warfarin was the most

significant decrease in stroke (RR: 0.81; 95% CI: 0.73 to

commonly implicated medication, constituting 33%

0.91), primarily driven by a reduction in hemorrhagic

of cases (21). Combined with the anxiety provoked by

stroke (RR: 0.48; 95% CI: 0.39 to 0.59). There was also

the fear of bleeding, these reasons have led to the fact

a significant decrease in all-cause mortality (RR: 0.90;

that over 40% of patients with NVAF at risk for stroke

95% CI: 0.85 to 0.95), but a significant increase in

do not receive warfarin, either because of absolute or

gastrointestinal bleeding (RR: 1.25; 95% CI: 1.01 to

Holmes, Jr. et al.

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Stroke Prevention in Nonvalvular Atrial Fibrillation

The LAA has been implicated as the source of

F I G U R E 2 PROTECT AF/PREVAIL Combined: Meta-Analysis Shows Comparable

emboli in w90% of patients with NVAF (7); strategies

Primary Efficacy Results to Warfarin

to isolate or occlude the LAA have been developed HR

p Value

with initial studies demonstrating feasibility and

0.79

0.22

safety. LACC may have competing influences on

1.02

0.94

Ischemic stroke or SE

1.95

0.05

Hemorrhagic stroke

0.22

0.004

Ischemic stroke or SE >7 days

1.56

0.21

0.48

0.006

All-cause death

0.73

0.07

benefit ratio of local therapy, the PROTECT AF and

Major bleed, all

1.00

0.98

PREVAIL trials were performed. Taken together, the 2

Major bleeding, non procedure-related

0.51

0.002

randomized trials included 1,114 randomized patients

Efficacy All stroke or SE

CV/unexplained death

Favors Watchman 0.01

would not attenuate stroke arising from other vascular sources such as aortic atheroma or carotid disease, but on the other hand, truncating exposure to anticoagulant agents should minimize the risk for hemorrhagic complications, including stroke. To evaluate the risk/

with 3,577 PY of follow-up. By virtue of trial enroll-

Favors warfarin

0.1 1 Hazard Ratio (95% Cl)

stroke rates: on the one hand, local therapy with LAAC

ment dates, the PROTECT AF data represents 75% of

10

all of the available follow-up. Although not dictated by trial design, the majority of patients enrolled in these

The combined data set of all PROTECT AF and PREVAIL Watchman patients versus chronic

trials were at moderate to high risk for bleeding on the

warfarin patients documented: 1) similarity in overall stroke or systemic embolism;

basis of the estimated HAS-BLED score.

2) ischemic stroke slightly increased with Watchman but hemorrhagic stroke significantly decreased with warfarin; and 3) all-cause mortality and major nonprocedural bleeding both significantly improved with Watchman. CI ¼ confidence interval; CV ¼ cardiovascular; HR ¼ hazard ratio; SE ¼ systemic embolism; other abbreviations as in Figure 1.

For this meta-analysis of the randomized clinical trials, the composite efficacy endpoint favored the Watchman patients (HR: 0.79), albeit without reaching statistical significance (p ¼ 0.22). The individual com-

1.55) (30). These new agents have not become dominant in the field of stroke prevention for several reasons, including cost, lack of antidotes, need for twice daily dosing (with 2 of the agents), and side effects. In addition, by 2 years, 21% to 33% of patients discontinued the NOAC, and the major bleeding rate per year was 2 to 3.5%, both of which are similar to that reported for conventional warfarin (26–28).

ponents of this composite endpoint, however, were quite different between groups. The 3 most striking differences were in hemorrhagic stroke (HR: 0.22; p

¼ 0.004),

CV/unexplained

p

¼

and

0.006),

major

death

(HR:

0.48;

non–procedural-related

bleeding (HR: 0.51; p ¼ 0.002). The reduction in hemorrhagic stroke and major nonprocedural bleeding could have been anticipated because device patients were not chronically exposed to a continued incremental bleeding risk from anticoagulation. Between

F I G U R E 3 Pooled Watchman Efficacy Performance in Randomized Clinical Trials

(PROTECT AF/PREVAIL)

93.2% and 98.7% of patients had been able to discontinue warfarin after 1 year. The reduction in hemorrhagic stroke with LAAC was

Subgroup Age Sex CHADS2 Score CHA2D S2VASc Score HA S-BLED History of TIA Stroke

–

<75 ≥75 Female Male ≤2 >2 ≤3 >3 ≤2 >2 No Yes

–

balanced by a relative increase in ischemic stroke or

0.910

systemic embolism with rates per 100 years for device

0.679

and warfarin of 0.15 and 0.96 (hemorrhagic), respectively, and 1.62 and 0.89 (ischemic, including proce-

0.316

dure related), respectively. As mentioned this may

0.176

relate to the fundamental observation that local device therapy does not prevent strokes from other causes.

0.098 0.623

–

Favors Watchman 0.1

p Value

relate to possible technical failures of the device: failure to completely obliterate LAA flow, anatomical

Favors warfarin

1.0 Hazard Ratio

Alternatively, the higher ischemic stroke rate may

remodeling of the LAA ostium over time resulting in 10.0

more leaks, or the development of thrombus on the device. Although small series have raised questions about the embolic potential of these small leaks

Documentation of the effect of Watchman versus chronic warfarin on the different subsets of patients enrolled. There was no significant difference in Watchman effect by patient subset. TIA ¼ transient ischemic attack; other abbreviations as in Figure 1.

(<5 mm), the only large patient dataset evaluated to address this question indicated that small residual leaks are not associated with increased stroke rates (31).

Holmes, Jr. et al.

JACC VOL. 65, NO. 24, 2015 JUNE 23, 2015:2614–23

CENTRAL I LLU ST RAT ION

Stroke Prevention in Nonvalvular Atrial Fibrillation

Stroke Prevention in Nonvalvular Atrial Fibrillation With LAA Closure

Holmes, Jr., D.R. et al. J Am Coll Cardiol. 2015; 65(24):2614–23.

(Upper Panel) Combination of PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the Watchman LAA Closure Device In Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trial patients receiving the Watchman device, compared with patients receiving chronic warfarin for overall stroke, ischemic stroke, and all-cause death. (Bottom Panel) Watchman performance consistent across all 4 data sets. Although the duration of follow-up varied by trial enrollment periods, being shortest for the Continued Access to PREVAIL registry (CAP2), overall freedom from event was similar in all 4 groups treated with Watchman. CAP ¼ Continued Access to PROTECT AF registry; CI ¼ confidence interval; CV ¼ cardiovascular; HR ¼ hazard ratio; LAA ¼ left atrial appendage; SE ¼ systemic embolism.

The dramatic reduction in CV/unexplained death

out the possibility that a small amount of bleeding in a

with Watchman (HR: 0.48; p ¼ 0.006) is one of the most

warfarin-treated patient could have had significant

significant findings. This mortality benefit may be

clinical implications, or resulted in discontinuation of

multifactorial, but is likely at least in part a result of

other beneficial medications because of postulated

the reduced rate of hemorrhagic stroke and is

drug-drug interactions. Also, some of the deaths in

completely consistent with the w10% to 15% mortality

the warfarin arm may have resulted from undetected

benefit that NOACs confer over warfarin—a benefit

ischemic stroke with hemorrhagic transformation.

also driven by the reduction in hemorrhagic stroke

The addition of the CAP and CAP2 registries to the

with NOACs (26–28). However, it should also be noted

meta-analysis added important information to the to-

that the PROTECT AF and PREVAIL trial patients had

tality of the Watchman data. In these registries, 1,145

multiple comorbidities. In this setting, one cannot rule

patients were enrolled and the procedural performance

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JACC VOL. 65, NO. 24, 2015 JUNE 23, 2015:2614–23

Stroke Prevention in Nonvalvular Atrial Fibrillation

and follow-up schedules were similar. The absence of

noted that the Watchman trials were randomized in a

trial randomization in these registries was associated

2-to-1 fashion, thus resulting in a limited number of

with a patient cohort at somewhat higher risk for both

warfarin patients with whom to compare the device,

stroke and hemorrhage. Although a warfarin control

and the majority of device patients in this analysis

cohort for the registries was also not available for in-

(62%) were registry patients.

clusion into the meta-analysis, this additional bias favoring the warfarin group did not appreciably alter any of the conclusions derived from the randomized clinical trial—alone meta-analysis. The LAAC and warfarin groups performed similarly for the composite efficacy endpoint; the advantage seen with warfarin for ischemic stroke was counterbalanced by improved rates of hemorrhagic stroke and CV death with LAAC, and major non–procedure-related bleeding was significantly less frequent with LAAC. Thus, device performance was consistent across all 4 clinical trial datasets. An important consideration revolves around pa-

CONCLUSIONS In the setting of NVAF with increased stroke risk, systemic embolism, or CV death, patients who are treated with the Watchman device for LAAC have marked reduction in hemorrhagic stroke, CV death, and major non–procedural-related bleeding compared to patients treated with chronic warfarin. This is balanced by a smaller magnitude increase in ischemic stroke in device treated patients that may reflect the diverse etiology of stroke in this population.

tient selection criteria. With that in mind, the risk

ACKNOWLEDGMENT The authors thank Nicole Gor-

benefit of an invasive procedure must be balanced

don (Boston Scientific) for her assistance in the

against the longer term issues of continued exposure

preparation of the manuscript.

to anticoagulation and bleeding. In patients who are excellent candidates for an anticoagulant agent, or

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

who have uncomplicated success with anticoagulant

David R. Holmes, Jr., Mayo Clinic, 200 First Street

agents for stroke prevention, an LAAC device may not

Southwest, Rochester, Minnesota 55905. E-mail:

be needed. In other patients, careful consideration of

[email protected].

LAAC versus long-term anticoagulant agents warrants an individualized discussion between physician and

PERSPECTIVES

patient. COMPETENCY IN MEDICAL KNOWLEDGE: CarSTUDY LIMITATIONS. There are important considera-

dioembolic strokes in patients with nonvalvular atrial

tions that these analyses do not address. By trial

fibrillation typically arise from the left atrial

design, all device patients were treated with aspirin

appendage, and are associated with high rates of

and warfarin until the 45 day transesophageal echo-

recurrence, morbidity, and mortality. Although sys-

cardiogram, and thereafter acetylsalicylic acid and

temic anticoagulation can reduce the risk of stroke in

Plavix for 6 months followed by acetylsalicylic acid

patients with atrial fibrillation, this form of therapy

alone. An important question relates to the population

carries a risk of bleeding and a large proportion of

of “contraindicated” patients, those with NVAF at risk

patients are undertreated.

of stroke but who are either not prescribed, or do not take, oral anticoagulation. Although all 4 Watchman

COMPETENCY IN PATIENT CARE AND PROCEDURAL

studies excluded these contraindicated patients, in the

SKILLS: In patients at elevated risk of stroke and

Aspirin Plavix Registry (8), the device was implanted in

bleeding with suitable anatomy, occlusion of the left

150 NVAF patients ineligible for warfarin. As compared

atrial appendage with the catheter-deployed

to the expected stroke rates in this population, there

Watchman device is associated with lower risks of

were 77% fewer ischemic strokes observed with device.

major bleeding post procedure, hemorrhagic stroke,

Another question not answered by these analyses is the relative effect of the device compared to currently approved NOACs. Currently, there are no data comparing LAAC to any of the NOACs. It must be remembered that even in the randomized NOAC trials, the 2-year drug discontinuation rates ranged between 21% and 33%, and for these patients, the protective effect of the drug would accordingly be lost (26–28). Though warfarin has been extensively studied and has well-characterized efficacy rates, it should be

and mortality than long-term warfarin therapy. TRANSLATIONAL OUTLOOK: Further studies are needed to define risk thresholds for thromboembolism and bleeding at which patients with atrial fibrillation benefit from left atrial appendage occlusion therapy for stroke prevention and to compare the safety and efficacy of this strategy with targetspecific oral anticoagulant agents.

Holmes, Jr. et al.

JACC VOL. 65, NO. 24, 2015 JUNE 23, 2015:2614–23

Stroke Prevention in Nonvalvular Atrial Fibrillation

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preferences in anticoagulant therapy; discrete choice experiment. Circ Cardiovasc Qual Outcomes 2014;7:912–9. 25. Baker WL, Phung OJ. Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012;5:711–9. 26. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. 27. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. 28. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrrillation. N Engl J Med 2009;361:1139–51. 29. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369: 2093–104. 30. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials. Lancet 2014;383:955–62. 31. Viles-Gonzalez JF, Kar S, Douglas P, et al. The clinical impact of incomplete left atrial appendage closure with the WATCHMAN device in patients with atrial fibrillation: a PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients with Atrial Fibrillation) substudy. J Am Coll Cardiol 2012;59:923–9.

KEY WORDS appendage occlusion, long-term warfarin, stroke prevention, thromboembolism, warfarin alternative

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