Propensity-Matched Comparison of Oral Anticoagulation Versus Antiplatelet Therapy After Left Atrial Appendage Closure With WATCHMAN

Propensity-Matched Comparison of Oral Anticoagulation Versus Antiplatelet Therapy After Left Atrial Appendage Closure With WATCHMAN

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 11, 2019 ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER Propensity-M...

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JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 12, NO. 11, 2019

ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

Propensity-Matched Comparison of Oral Anticoagulation Versus Antiplatelet Therapy After Left Atrial Appendage Closure With WATCHMAN Lars Søndergaard, MD, DMSC,a Yam-Hong Wong, MBBS,a,b Vivek Y. Reddy, MD,c Lucas V.A. Boersma, MD, PHD,d Martin W. Bergmann, MD, PHD,e Shephal Doshi, MD,f Saibal Kar, MD,g Horst Sievert, MD,h Scott Wehrenberg, MS,i Kenneth Stein, MD,i David R. Holmes, JR, MDj

ABSTRACT OBJECTIVES In this propensity-matched analysis of post–left atrial appendage closure antithrombotic therapy, the safety and effectiveness of oral anticoagulation (OAC) and antiplatelet therapy (APT) were compared. BACKGROUND Left atrial appendage closure with the WATCHMAN device is an alternative to OAC in patients with nonvalvular atrial fibrillation, who are at high bleeding risk. Initial trials included 45 days of post-implantation OAC, but registry data suggest that APT may suffice. METHODS Patients from the PROTECT-AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation), PREVAIL (Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy), CAP (Continued Access to PROTECT-AF), CAP2 (Continued Access to PREVAIL), ASAP (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology), and EWOLUTION (Registry on WATCHMAN Outcomes in Real-Life Utilization) trials receiving either OAC or APT post-implantation were matched and compared for nonprocedural bleeding and stroke or systemic thromboembolism over 6 months following implantation. Each patient on APT was matched with 2 patients on OAC, with propensity scores derived from age, sex, congestive heart failure, hypertension, diabetes, prior transient ischemic attack or stroke, peripheral vascular disease, left ventricular ejection fraction, renal impairment, and different atrial fibrillation subtypes. RESULTS The cohort on OAC (n ¼ 1,018; 95% receiving warfarin and 5% receiving nonwarfarin OAC) was prescribed 45-day OAC post-implantation (92% also received single APT), followed by 6-month single or dual APT. The cohort on APT (n ¼ 509; 91% receiving dual APT and 9% receiving single APT) received APT for variable durations. Six-month freedom from nonprocedural major bleeding was similar (OAC, 95.7%; APT, 95.5%; p ¼ 0.775) despite more early bleeds with OAC. Freedom from thromboembolism beyond 7 days was similar between groups (OAC, 98.8%; APT, 99.4%; p ¼ 0.089). However, device-related thrombosis was more frequent with APT (OAC, 1.4%; APT, 3.1%; p ¼ 0.018). CONCLUSIONS After left atrial appendage closure with the WATCHMAN, although device-related thrombosis was more common with APT, both APT and OAC strategies resulted in similar safety and efficacy endpoints. (J Am Coll Cardiol Intv 2019;12:1055–63) © 2019 by the American College of Cardiology Foundation.

From the aRigshospitalet, University of Copenhagen, Copenhagen, Denmark; bMedicine and Geriatric Department, Tuen Mun Hospital, Hong Kong, China; cIcahn School of Medicine at Mount Sinai, New York, New York; dSt. Antonius Hospital, Nieuwegein, the Netherlands; eCardiologicum Hamburg, Hamburg, Germany; fProvidence St. John’s Health Center, Santa Monica, California; g

Cedars-Sinai Medical Center, Los Angeles, California; hCardioVascular Center Frankfurt, Frankfurt am Main, Germany; iBoston

Scientific, Minneapolis, Minnesota; and the jMayo Clinic, Rochester, Minnesota. Dr. Søndergaard has received consulting fees and institutional research grants from Boston Scientific. Dr. Reddy has received consulting fees and research grants from Boston Scientific, Coherex, SentreHEART, and St. Jude Medical; has conflicts with other companies not related to this manuscript; and his wife is employed by Boston Scientific but has no connection with Mount Sinai Hospital and receives no direct financial benefit from any LAAC procedures performed at Mount Sinai. Dr. Boersma has received personal fees from Boston Scientific and Medtronic outside the submitted work. Dr. Bergmann has received personal fees from Boston Scientific, St. Jude Medical, Biosense

ISSN 1936-8798/$36.00

https://doi.org/10.1016/j.jcin.2019.04.004

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Anticoagulation Versus Antiplatelet Therapy After LAAC

P

atients with nonvalvular atrial fibril-

recommended to continue OAC in case of incom-

lation are at increased risk for throm-

plete

boembolic complications, and oral

Because LAAC in other countries is used mainly in

anticoagulation (OAC) is recommended if

patients with strong contraindications to OAC, the

this risk is considered high as usually

most common post-procedural therapy is APT rather

assessed by the CHA2DS2-VASc score. How-

than OAC. Although OAC may be a better therapy to

ever, OAC by its very nature confers an

protect against device-related thrombosis (DRT)

ongoing bleeding risk, and patients and

during endothelialization in the initial phase after

closure

physicians need to carefully weigh these

LAAC, it may associate with a higher bleeding rate

OAC = oral anticoagulation

risks against the benefits in deciding whom

than APT. However, the relative merits of these 2

SAPT = single APT

to

Because

alternative treatment strategies remain uncertain.

thrombus formation in most cases is located

Accordingly, the aim of the present study was to

in the left atrial appendage (1), an alterna-

assess the safety and effectiveness of limited early

tive treatment is to exclude the appendage

OAC (45 days) versus APT post-LAAC with the

from the blood circulation. One option is left atrial

WATCHMAN device using propensity score match-

appendage closure (LAAC) by implantation of a de-

ing of patients from the available prospective trials

vice in the proximal part of the appendage. The 2

and registries.

ABBREVIATIONS AND ACRONYMS APT = antiplatelet therapy DAPT = dual-antiplatelet therapy

DRT = device-related thrombosis

LAAC = left atrial appendage

TEE = transesophageal echocardiography

treat

with

long-term

OAC.

closure

with

a

peridevice

leak

>5

mm.

landmark trials, PROTECT-AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients

With

Atrial

Fibrillation)

and

METHODS

PREVAIL

(Watchman LAA Closure Device in Patients With

The study included all patients who underwent LAAC

Atrial Fibrillation Versus Long Term Warfarin Ther-

with the WATCHMAN device in the randomized

apy), compared this concept using the WATCHMAN

PROTECT-AF and PREVAIL trials (2–5) as well as the

device (Boston Scientific, Marlborough, Massachu-

CAP (Continued Access to PROTECT-AF), CAP2

setts) against warfarin in patients who were other-

(Continued Access to PREVAIL), ASAP (ASA Plavix

wise candidates for long-term OAC (2–5). These

Feasibility

trials have led to U.S. Food and Drug Administration

Appendage Closure Technology), and EWOLUTION

approval of the WATCHMAN in this patient cohort.

(Registry on WATCHMAN Outcomes in Real-Life Uti-

In contrast to the United States, in all other coun-

lization) registries (6–8). Table 1 summarizes the trials

tries, LAAC is reserved mainly for patients who are

and registries.

Study

With

Watchman

Left

Atrial

The immediate post-procedural antithrombotic

deemed unsuitable for OAC (6).

therapy was OAC with warfarin (on top of aspirin) for

SEE PAGE 1064

at least 45 days in PROTECT-AF, PREVAIL, CAP, and was

CAP2, followed by dual APT (DAPT) after documen-

continued for at least 45 days after LAAC, followed

tation of satisfactory closure (peridevice leak <5 mm)

by transesophageal echocardiography (TEE). OAC

of the LAA. In ASAP, 6 months of DAPT was followed

was replaced by anti-platelet therapy (APT) after

by lifelong single APT (SAPT). In EWOLUTION, DAPT

echocardiographic

effective

was used in most patients (60%), while other patients

closure of the appendage, whereas patients were

received OAC, direct OAC, or SAPT for variable

In

PROTECT-AF

and

PREVAIL,

documentation

OAC

of

Webster, and Johnson & Johnson outside the submitted work. Dr. Doshi has received consulting fees and research grants from Boston Scientific, St. Jude Medical, Coherex, and SentreHEART; and is the national principal investigator of CAP2 (Continued Access to PREVAIL). Dr. Kar has received research grants from Boston Scientific, St. Jude Medical, and Abbott Vascular; is a member of the advisory board for LAAC; is the national principal investigator of CAP (Continued Access to PROTECT-AF) and CAP2; and has served as a proctor for Boston Scientific. Dr. Kar also has received honorarium from Abbott Vascular, Boston Scientific, Medtronic, and W.L. Gore. Dr. Seivert has received personal fees from Abbott, Aptus, Atrium, Biosense Webster, Boston Scientific, Carag, Cardiac Dimensions, CardioKinetix, CardioMEMS, Cardiox, Celonova, CGuard, Coherex, Comed, Contego, Covidien, CSI, CVRx, ev3, FlowCardia, Gardia, Gore, GTIMD Medical, Guided Delivery Systems, Hemoteq, InSeal Medical, InspireMD, Kona Medical, Lumen Biomedical, Lifetech, Lutonix, Maya Medical, Medtronic, Occlutech, pfm Medical, Recor, Trireme, Trivascular, Valtech, Vascular Dynamics, Venus Medical, Veryan, and Vessix outside the submitted work; and holds stock options in Cardiokinetix, Access Closure, Coherex, and SMT outside the submitted work. Mr. Wehrenberg is an employee and a shareholder at Boston Scientific. Dr. Stein is an employee and a shareholder at Boston Scientific. Dr. Holmes, Jr. and the Mayo Clinic have financial interests in technology related to this research. That technology has been licensed to Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received December 21, 2018; revised manuscript received March 6, 2019, accepted April 3, 2019.

Søndergaard et al.

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Anticoagulation Versus Antiplatelet Therapy After LAAC

T A B L E 1 Trials and Registries Included in the Present Study

Study

Purpose

Sample Size (Number of Patients Included in Analysis)*

Design

Antithrombotic Therapy Immediately Post-LAAC

PROTECT-AF Determine noninferiority of WATCHMAN to warfarin in patients with NVAF

Multicenter, prospective RCT

463 (408)

45 days of warfarin plus aspirin, then DAPT up to 6 months, then aspirin for life

PREVAIL

Assess safety and efficacy of WATCHMAN compared with warfarin, even with new operators

Multicenter, prospective RCT

269 (252)

45 days of warfarin plus aspirin, then DAPT up to 6 months, then aspirin for life

CAP

Assess long-term safety and effectiveness following the PROTECT-AF trial

Multicenter, prospective registry

566 (534)

See PROTECT-AF trial

CAP2

Assess long-term safety and effectiveness following the PREVAIL trial

Multicenter, prospective registry

578 (545)

See PREVAIL trial

ASAP

Assess safety and efficacy of WATCHMAN in patients with NVAF contraindicated for warfarin

Multicenter, prospective registry

150 (142)

6 months of clopidogrel or ticlopidine plus lifelong aspirin

Multicenter, prospective registry

1,025 (931)

EWOLUTION Assess real-world safety and efficacy of WATCHMAN

Warfarin 16%, DOAC 11%, DAPT 60%, SAPT 7%, no antithrombotic therapy 6%

*Sample size includes the total number in each study, enrolled or randomized to WATCHMAN, while patients who did not undergo successful WATCHMAN implantation were excluded from the present analysis. ASAP ¼ ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology; CAP ¼ Continued Access to PROTECT-AF; CAP2 ¼ Continued Access to PREVAIL; DAPT ¼ dual-antiplatelet therapy; DOAC ¼ direct oral anticoagulation; EWOLUTION ¼ Registry on WATCHMAN Outcomes in Real-Life Utilization; LAAC ¼ left atrial appendage closure; NVAF ¼ Nonvalvular atrial fibrillation; PREVAIL ¼ 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; RCT ¼ randomized controlled trial; SAPT ¼ singleantiplatelet therapy.

durations at the implanting physician’s discretion.

F I G U R E 1 Antithrombotic Regimens Before Matching

Patients in PROTECT-AF, PREVAIL, CAP, CAP2, and ASAP studies were followed up with TEE at 45 days, while in EWOLUTION, TEE was performed per local practice. Patients in these studies were divided into OAC and APT groups according to the choice of immediate post-procedural antithrombotic regimen (Figure 1). Baseline characteristics for the OAC and APT groups were compared using standardized differences instead of p values (9). Next, patients were propensity-matched on the following baseline characteristics: age, sex, presence of congestive heart failure, hypertension, diabetes, history of transient ischemic attack or stroke, peripheral vascular disease, different ranges of left ventricular ejection fraction (<30%, 30% to 50%, or >50%), renal impairment, and different types of AF (persistent, paroxysmal, or permanent). Propensity scores were obtained for all subjects using a logistic regression

model

of

post-implantation

medical

therapy (OAC vs. APT) on the aforementioned baseline characteristics. Missing data were imputed using bootstrap samples from the subjects within the same group with known data. OAC subjects were matched

Choice of immediate post-procedural antithrombotic regimen. DAPT ¼ dual-

2:1 to APT subjects using a greedy nearest neighbor

antiplatelet therapy; DOAC ¼ direct oral anticoagulation.

algorithm. Baseline risk factors were considered

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Anticoagulation Versus Antiplatelet Therapy After LAAC

T A B L E 2 Baseline Demographics Before Propensity Score Matching

Age at enrollment (yrs) Female CHF Hypertension

Overall (N ¼ 2,812)

APT (n ¼ 808)

OAC (n ¼ 2,004)

73.5  8.6 (33.0–95.0) (2,755)

74.5  8.2 (47.0–94.0) (794)

73.1  8.7 (33.0–95.0) (1,961)

0.1576

36.5 (1,005/2,755)

39.7 (316/795)

35.2 (873/2,144)

0.0928

Standardized Difference

27.9 (770/2,755)

33.2 (264/795)

25.8 (506/2,144)

0.1638

89.3 (2,460/2,755)

89.9 (714/795)

89.0 (1,746/2,144)

0.0290

Diabetes

29.4 (810/2,755)

32.5 (258/795)

28.1 (552/2,144)

0.0946

History of TIA or stroke

32.1 (884/2,755)

38.5 (306/795)

29.5 (578/2,144)

0.1922

Vascular disease

46.1 (1,271/2,755)

45.2 (359/795)

46.5 (912/2,144)

0.0259

LVEF <30% 30%–50% >50%

1.0 (25/2,545) 23.4 (596/2,545) 75.6 (1,924/2,545)

2.2 (14/795) 21.5 (139/795) 76.4 (495/795)

0.6 (11/2,144) 24.1 (457/2,144) 75.3 (1429/2,144)

0.1363 0.0630 0.0248

AF type Persistent Paroxysmal Permanent

25.4 (701/2,755) 47.3 (1,303/2,755) 27.3 (751/2,755)

20.7 (164/794) 42.1 (334/794) 37.3 (296/794)

27.4 (537/1,961) 49.4 (969/1,961) 23.2 (455/1,961)

0.1580 0.1479 0.3102

Values are mean  SD (range) (n) or % (n/N). AF ¼ atrial fibrillation; APT ¼ antiplatelet therapy; CHF ¼ congestive heart failure; LVEF ¼ left ventricular ejection fraction; OAC ¼ oral anticoagulation; TIA ¼ transient ischemic attack.

balanced across the OAC and APT groups in the

stroke as defined by the Bleeding Academic Research

matched sample if the absolute difference of the

Consortium (10) up to 6 months post-procedure and

standardized difference was #0.2.

device-related thrombus beyond 7 days after the

The efficacy endpoint was freedom from ischemic

procedure and up to 6 months.

stroke or systemic embolism beyond 7 days from the procedure and up to 6 months. Strokes within 7 days

STATISTICAL ANALYSIS. The efficacy and safety

were excluded, to avoid any confounding effect of

endpoints, as well as freedom from DRT, were

periprocedural strokes, which likely reflect a different

compared across the propensity-matched groups us-

mechanism unrelated to the post-implantation drug

ing a long-rank test stratified by propensity score

regimen. Safety endpoints included non-procedure-

quintile. All analyses were performed using SAS

related

version 9.4 (SAS Institute, Cary, North Carolina).

major

bleeding,

including

hemorrhagic

T A B L E 3 Baseline Demographics After Propensity Score Matching

Overall (N ¼ 1,527)

Age at enrollment (yrs)

APT (n ¼ 509)

OAC (n ¼ 1,018)

73.8  8.4 (39.0–95.0) (1,527) 73.8  8.5 (47.0–94.0) (509) 73.7  8.4 (39.0–95.0) (1,018)

Standardized Difference

0.0072

Female

37.4 (571/1,527)

38.1 (194/509)

37.0 (377/1,018)

0.0223

CHF

28.3 (432/1,527)

29.1 (148/509)

27.9 (284/1,018)

0.0261

89.8 (1,371/1,527)

89.2 (454/509)

90.1 (917/1,018)

0.0290

Diabetes

31.2 (476/1,527)

30.8 (157/509)

31.3 (319/1,018)

0.0106

History of TIA or stroke

32.9 (503/1,527)

32.2 (164/509)

33.3 (339/1,018)

0.0230

Vascular diseases

Hypertension

45.7 (698/1,527)

45.6 (232/509)

45.8 (466/1,018)

0.0039

LVEF <30% 30%–50% >50%

0.6 (9/1,527) 23.4 (358/1,527) 76.0 (1,160/1,527)

0.8 (4/509) 24.0 (122/509) 75.2 (383/509)

0.5 (5/1,018) 23.2 (236/1,018) 76.3 (777/1,018)

0.0185 0.0252 0.0232

AF type Persistent Paroxysmal Permanent

23.1 (353/1,527) 50.9 (777/1,527) 26.0 (397/1,527)

23.8 (121/509) 50.1 (255/509) 26.1 (133/509)

22.8 (232/1,018) 51.3 (522/1,018) 25.9 (264/1,018)

0.0045 0.0072 0.0223

Values are mean  SD (range) (n) or % (n/N). Abbreviations as in Table 2.

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Anticoagulation Versus Antiplatelet Therapy After LAAC

C ENTR AL I LL U STRA T I O N Efficacy Endpoint: Ischemic Stroke or Systemic Embolism Beyond 7 Days

Ischemic Stroke Systemic Embolism Beyond 7 Days Propensity Score Matching by First Nine Variables

Event Free Probability

1.00

0.90

0.80

0.70

509

499

491

483

476

471

468

APT

1018

1012

1007

1000

996

987

982

OAC

0

1

2

5

6

3 4 Time (Months)

Treatment

APT

OAC

Log-Rank p-value = 0.3240 Søndergaard, L. et al. J Am Coll Cardiol Intv. 2019;12(11):1055–63.

No significant difference was observed. APT ¼ antiplatelet therapy; OAC ¼ oral anticoagulation.

RESULTS

(interquartile range: 68 to 80 years), and 62% of the patients were male. In the OAC group, 95% were on

There were 2,812 patients who successfully under-

vitamin K antagonists and 5% on direct OAC.

went WATCHMAN implantation in the aforemen-

Furthermore, 92% of the patients received SAPT in

tioned trials and registries. Baseline demographics of

addition to OAC. In the APT group, 91% were treated

the unmatched groups receiving post-procedural

with DAPT and 9% with SAPT.

OAC or APT are given in Table 2. Patients in the

EFFICACY ENDPOINT. There was no significant dif-

APT group were generally older, with higher rates of

ference in freedom from ischemic stroke or systemic

congestive heart failure, previous stroke, permanent

embolism beyond 7 days and up to 6 months between

rather than paroxysmal or persistent atrial fibrilla-

the 2 groups (OAC, 98.8%; APT, 99.4%; hazard ratio:

tion, low left ventricular ejection fraction, and renal

0.82; 95% confidence interval: 0.45 to 1.50; p ¼ 0.3240)

impairment.

(Central Illustration).

After propensity score matching, a total of 1,527

So as not to miss the possibility of a different result,

patients (1,018 patients in the OAC group and 509

total ischemic stroke or systemic embolism including

patients in the APT group) were included in the ana-

the initial 7 days after LAAC was also analyzed. Again,

lyses (Table 3). The median age was 75 years

there was no significant difference between 2 groups

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Anticoagulation Versus Antiplatelet Therapy After LAAC

(OAC, 98.3%; APT, 99.4%; p ¼ 0.0887) (Figure 2,

F I G U R E 2 Efficacy Endpoint: Ischemic Stroke or Systemic Embolism

Table 4).

(Including Initial 7 Days)

SAFETY ENDPOINTS. Similarly, accumulated 6-month

freedom from hemorrhagic stroke or other non-

Ischemic Stroke Systemic Embolism Propensity Score Matching by First Nine Variables

procedural major bleeding was similar between the

Event Free Probability

1.00

OAC and APT groups (95.7% and 95.5%, respectively; hazard ratio: 1.00; 95% confidence interval: 0.65 to 1.52; p ¼ 0.775), despite a larger number of early

0.90

bleeds with OAC (Figure 3). Freedom from hemorrhagic stroke or nonprocedural major bleeding at 45 days was 98.2% in the APT group and 98.0% in the

0.80

OAC group (p ¼ 0.456). Details of the bleeding events 509

499

491

483

476

471

468

APT

0.70 1018

1007

1002

995

991

983

978

OAC

1

2

3

4

5

6

0

are presented in Tables 5 and 6. Device-related thrombus was significantly more frequent in the APT group than in the OAC group

Time (Months)

Treatment

APT

(OAC, 1.4%; APT, 3.1%; p ¼ 0.014; hazard ratio not

OAC

constant from 0 to 6 months and therefore not pre-

Log-Rank P-value = 0.0887

sented) (Figure 4). When patients on post-procedural SAPT were excluded, this comparison still resulted

No significant difference was observed. APT ¼ antiplatelet therapy; OAC ¼ oral

in significant difference (OAC, 1.1%; APT, 3.3%;

anticoagulation.

p ¼ 0.0048) (Figure 5). The same conclusion was reached if patients (from EWOLUTION) who did not undergo follow-up TEE (13%) were excluded from the analysis (OAC, 1.3%; APT, 2.9%; p ¼ 0.0419)

T A B L E 4 Thromboembolism With and Without Events Occurring Within 7 Days

(Figure 6, Table 7).

6-Month Survival (%) Event

OAC

APT

p Value

Ischemic stroke or SE

98.3

99.4

0.0887

Ischemic stroke or SE >7 days

98.8

99.4

0.3240

In the OAC group, 21.4% of subjects with DRT (3 of 14) experienced ischemic stroke or systemic embolism beyond 7 days and up to 6 months, compared with 0% (0 of 16) in the APT matched group. The difference was not statistically significant (p ¼ 0.09).

SE ¼ systemic embolism; other abbreviations as in Table 2.

There were no hemorrhagic strokes in subjects experiencing DRT. F I G U R E 3 Safety Endpoint: Accumulated Freedom From Hemorrhagic Stroke or

Nonprocedural Major Bleeding

The major findings of this study are that although

Hemorrhagic Stroke or Non-procedure related Major Bleeding Propensity Score Matching by First Nine Variables

antithrombotic therapy with APT as an immediate therapy after LAAC with the WATCHMAN device is

1.00 Event Free Probability

DISCUSSION

associated with a slightly higher rate of devicerelated thrombus, thromboembolic event rates are 0.90

similar compared with immediate post-implantation OAC, and bleeding complications are the same for the 2 post-procedural regimens.

0.80

APT and OAC seem to be comparably effective 509

497

483

473

465

457

453

APT

antithrombotic options in the immediate period after

0.70 1017

998

986

976

970

961

952

OAC

LAAC with the WATCHMAN device. This supports

1

2

3

4

5

6

0

Treatment

APT

the recent change in instruction for use in Conformité Européenne mark countries, where both

Time (Months

OAC

Log-Rank P-value = 0.7749

therapeutic regimens are included. How this will translate into clinical practice may vary among institutions and on a patient-by-patient basis. A prag-

No significant difference was observed. APT ¼ antiplatelet therapy; OAC ¼ oral anticoagulation.

matic approach could be to continue OAC until efficient closure has been confirmed in patients with no contraindications, whereas patients with strong

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Anticoagulation Versus Antiplatelet Therapy After LAAC

T A B L E 5 Nonprocedural Major Bleeding Breakdown at 45 Days

APT Number of Events (% of All Events)

Adverse Event Classification

OAC

Number of Patients Experiencing Events (% of All Patients)

Number of Events (% of All Events)

Number of Patients Experiencing Events (% of All Patients)

12 (1.2)

Gastrointestinal bleeding

2 (20.0)

2 (0.4)

14 (56.0)

Hematuria

0 (0.0)

0 (0.0)

1 (4.0)

1 (0.1)

Other causes of blood transfusion

7 (70.0)

6 (1.2)

8 (32.0)

7 (0.7)

Stroke (hemorrhagic)

1 (10.0)

1 (0.2)

1 (4.0)

1 (0.1)

Subdural hematoma

0 (0.0)

0 (0.0)

1 (4.0)

1 (0.1)

10 (100.0)

9 (1.8)

25 (100.0)

21 (2.1)

Number of Events (% of All Events)

Number of Patients Experiencing Events (% of All Patients)

Number of Events (% of All Events)

Number of Patients Experiencing Events (% of All Patients)

Epistaxis

0 (0.0)

0 (0.0)

5 (9.1)

2 (0.2)

Gastrointestinal bleeding

5 (19.2)

5 (1.0)

34 (61.8)

28 (2.8)

Total Values are n (%). Abbreviations as in Table 2.

T A B L E 6 Nonprocedural Major Bleeding Breakdown at 6 Months

APT

Adverse Event Classification

Hematuria Other causes of blood transfusion

OAC

0 (0.0)

0 (0.0)

1 (1.8)

1 (0.1)

17 (65.4)

13 (2.6)

12 (21.8)

10 (1.0) 2 (0.2)

Stroke (hemorrhagic)

1 (3.8)

1 (0.2)

2 (3.6)

Subdural hematoma

3 (11.5)

3 (0.6)

1 (1.8)

1 (0.1)

26 (100.0)

22 (4.3)

55 (100.0)

43 (4.2)

Total Values are n (%). Abbreviations as in Table 2.

F I G U R E 4 Freedom From Device-Related Thrombosis

Device Thrombus Propensity Score Matching by First Nine Variables

Event Free Probability

1.00

0.90

0.80

509

499

480

472

465

459

457

APT

0.70 1018

1015

1002

996

993

984

979

OAC

1

2

3

4

5

6

0

Time (Months) Treatment

APT

OAC

Log-Rank P-value = 0.0148

Significantly more device-related thrombosis was seen in the antiplatelet therapy (APT) group. OAC ¼ oral anticoagulation.

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JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 11, 2019 JUNE 10, 2019:1055–63

Anticoagulation Versus Antiplatelet Therapy After LAAC

Nonwarfarin OACs were used in only 5% of the

F I G U R E 5 Freedom From Device-Related Thrombosis, With

patients in the OAC group. This reflects that

Single-Antiplatelet Therapy Patients Excluded

PROTECT-AF and PREVAIL were conducted before the widespread introduction of those agents. At pre-

Device Thrombus Propensity Score Matching by First Nine Variables

sent, only nonrandomized retrospective data exist on

1.00

the outcomes using direct OAC as post-procedural

Event Free Probability

therapy (11), although this will be tested in the upcoming PINNACLE FLX (Investigational Device Eval-

0.90

uation of the WATCHMAN FLX LAA Closure Technology) trial (NCT02702271). Similarly, outcomes in the population deemed unsuitable for OAC and

0.80

treated with short-course DAPT post-implantation are 0.70

461

451

433

425

421

415

413

APT

922

919

910

906

903

894

889

OAC

0

1

2

3

4

5

6

APT

being studied in the ongoing randomized ASAP-TOO (Assessment of the WATCHMAN Device in Patients Unsuitable for Oral Anticoagulation) trial.

Time (Months) Treatment

Although DRT was seen more frequently in the APT OAC

group, the overall incidence was low (3.1%). Importantly, it is still controversial whether DRT is directly

Log-Rank P-value = 0.0048

associated with increased risk for stroke, transient Significantly more device-related thrombosis was seen in the antiplatelet

ischemic attack, or systemic embolization. In a pre-

therapy (APT) group. OAC ¼ oral anticoagulation.

vious analysis of PROTECT-AF, PREVAIL, CAP, and CAP2, DRT was associated with higher rate of stroke

contraindications for OAC may be on APT immediately after LAAC. Because the majority of the patients in the APT group were on dual therapy, the present study does not provide robust evidence for the outcome of SAPT during

the

immediate

post-procedural

period.

Comparative studies are warranted before one can specifically comment on the efficacy as well as safety of SAPT in particular, after LAAC.

and systemic embolism (12). A similar finding was noted in a retrospective analysis (n ¼ 469) (13). But in EWOLUTION, this was not the case. And in this focused analysis comparing short-term OAC and APT, the elevated DRT rate with APT also did not translate into significantly more clinical events, though it should be noted that the overall sample size was still small, despite the fact that this is the most comprehensive analysis to this date. STUDY LIMITATIONS. There are challenges in using

F I G U R E 6 Freedom From Device-Related Thrombosis, With Patients Who

Did Not Undergo Transesophageal Echocardiography Excluded

a DRT endpoint. First, it may be difficult to diagnose DRT, particularly on transthoracic echocardiography. Second, there is no standardized definition of

Device Thrombus Propensity Score Matching by First Nine Variables

DRT. For instance, EWOLUTION identified DRT through site reporting, on-site monitoring, and

1.00

sponsor classification of events, while the clinical Event Free Probability

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events committee adjudicated these events for 0.90

other studies. Similarly, as discussed earlier, the availability, frequency, and timing of TEE to identify DRT were not

0.80

necessarily uniform among trials. In particular, trans0.70

415

414

401

397

393

390

388

APT

esophageal

830

827

817

813

811

804

800

OAC

available in 87% of the patients in EWOLUTION, per

0

1

2

3

4

5

6

APT

assessments

were

local practice, with an average time to first TEE of 77 days and an average time to last TEE of 225 days. In

Time (Months) Treatment

echocardiographic

OAC

Log -Rank P-value = 0.0419

contrast, in PROTECT-AF and PREVAIL, TEE was performed regularly in all patients at 45 days, 6 months, and 12 months after WATCHMAN implantation.

Significantly more device-related thrombosis was seen in the antiplatelet therapy (APT) group. OAC ¼ oral anticoagulation.

Furthermore, in this study only LAAC cases using the WATCHMAN device were evaluated. Whether the results can be generalized to all other LAAC devices

Søndergaard et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 12, NO. 11, 2019 JUNE 10, 2019:1055–63

Anticoagulation Versus Antiplatelet Therapy After LAAC

T A B L E 7 Device Thrombus Rates After Excluding Subsets of Subjects*

6-Month Device Thrombus Rate Subset

OAC

APT

Odds Ratio for APT vs. OAC (95% CI)

p Value

All subjects (N ¼ 1,018 OAC and N ¼ 509 APT)

1.4

3.1

2.3 (1.12–4.76)

0.0148

Excluding subjects on single APT (n ¼ 922 OAC and n ¼ 462 APT)

1.1

3.3

3.1 (1.4–6.9)

0.0048

Excluding EWOLUTION subjects without FU TEE (n ¼ 830 OAC and n ¼ 415 APT)

1.3

2.9

2.2 (1.0–5.1)

0.0419

*All subjects who are propensity matched to subjects in the subset of interest are also excluded. FU ¼ follow-up; TEE ¼ transesophageal echocardiography; other abbreviations as in Tables 1 and 2.

remains uncertain. This study also had limitations

PERSPECTIVES

inherent to all retrospective and not pre-defined analyses. Last, risk factors such as renal function and alcohol consumption were not included in the propensity score, as these were not captured in all 6 trials and registries.

higher DRT rate with APT, both APT and OAC therapies resulted in similar safety and efficacy endpoints. This study suggests that APT might be a reasonable post-LAAC antithrombotic alternative in patients with high bleeding risk. CORRESPONDENCE:

Blegdamsvej

rate of DRT, thromboembolic event rates were similar compared with immediate post-implantation OAC, and bleeding complications were the same for the 2 post-procedural regimens. APT might be a reasonable post-LAAC antithrombotic therapy in patients at high bleeding risk. WHAT IS NEXT? Further studies are warranted to clarify

Dr.

Lars

Søndergaard, Rigshospitalet, Section 2011, University of Copenhagen,

suffice.

antithrombotic therapy with APT was associated with a higher

After LAAC with the WATCHMAN device, despite a

FOR

post-implantation OAC, but registries suggested that APT may

WHAT IS NEW? This study demonstrates that although

CONCLUSIONS

ADDRESS

WHAT IS KNOWN? Initial trials of LAAC included 45 days of

9,

2100

Copenhagen,

efficacy and safety of DAPT versus SAPT and to address controversies concerning the association between DRT and clinical outcomes of embolization.

Denmark. E-mail: [email protected].

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6. Boersma LV, Schmidt B, Betts TR, et al. Implant success and safety of left atrial appendage closure with the WATCHMAN device: peri-procedural outcomes from the EWOLUTION registry. Eur Heart J 2016;37:2465–74. 7. Reddy VY, Holmes D, Doshi SK, et al. Safety of percutaneous left atrial appendage closure: results from the WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation 2011;123:417–24. 8. Reddy VY, Möbius-Winkler S, Miller MA, et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013;61:2551–6. 9. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med 2009;28:3083–107. 10. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical

trials—a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123: 2736–47. 11. Enomoto Y, Gadiyaram VK, Gianni C, et al. Use of non-warfarin oral anticoagulants instead of warfarin during left atrial appendage closure with the Watchman device. Heart Rhythm 2017;14: 19–24. 12. Dukkipati SR, Kar S, Holmes DR, et al. Devicerelated thrombus after left atrial appendage closure—incidence, predictors, and outcomes. Circulation 2018;138:874–85. 13. Fauchier L, Cinaud A, Brigadeau F, et al. Device-related thrombosis after percutaneous left atrial appendage occlusion for atrial fibrillation. 1528–36.

J

Am

Coll

Cardiol

2018;71:

KEY WORDS antiplatelet therapy, antithrombotic therapy, atrial fibrillation, direct oral anticoagulation, left atrial appendage closure, oral anticoagulation, stroke

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