Antithrombotic Management After Transcatheter Aortic Valve Replacement

JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 10, NO. 1, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 1936-8798/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jcin.2016.11.024

EDITORIAL COMMENT

Antithrombotic Management After Transcatheter Aortic Valve Replacement More Questions Than Answers* Lars Søndergaard, MD, DMSC, Fadi J. Sawaya, MD

I

n this issue of JACC: Cardiovascular Interventions,

known AF, as these patients have an indication for

Seeger et al. (1) report on the highly relevant im-

OAC therapy, in the form of either vitamin K antag-

pacts of atrial fibrillation (AF) and oral anticoagu-

onists (VKAs) or 1 of the novel oral anticoagulant

lation (OAC) strategy after transcatheter aortic valve

agents, in combination with antiplatelet therapy for

replacement (TAVR). AF is present in approximately

3 to 6 months according to current practice and

one-third of patients undergoing TAVR (2) and has

guidelines (4). However, recent data indicate that

been shown to be independently associated with late

VKAs alone are as efficient and safe as VKAs in com-

cardiovascular morbidity and mortality, driven by an

bination with antiplatelet therapy after TAVR (5).

increased risk for stroke and bleeding relating to

Indeed, after a median follow-up period of 13 months,

OAC. Thus, 1-year mortality of patients in AF in the

the risk for stroke, major adverse cardiac events, or

PARTNER (Placement of Aortic Transcatheter Valves)

death was similar, with a doubling in major or life-

1B trial was doubled (26.2%) compared with patients

threatening bleeding in patients who received VKAs

in sinus rhythm (12.9%) and quadrupled (48.7%) if

in

these patients experienced major bleeding complica-

(SAPT) or dual-antiplatelet therapy (DAPT), similar

tions within the first year of follow-up (3). Similar to

findings to the WOEST (What Is the Optimal Anti-

previous reports, Seeger et al. show that TAVR patients

platelet and Anticoagulant Therapy in Patients With

with AF have a doubling of mortality (19.1% vs. 7.8%,

Oral Anticoagulation and Coronary Stenting) trial (6).

combination

with

single-antiplatelet

therapy

p < 0.01) and increased life-threatening bleeding

OAC has been associated with a lower rate of

(4.4% vs. 0.9%, p < 0.01) compared with patients in

structural valve deterioration after TAVR (7) and with

sinus rhythm at 1 year after the procedure.

better outcomes after surgical aortic valve replace-

SEE PAGE 66

ment (8). Moreover, with the recent reports and concerns regarding subclinical leaflet thrombosis in

Because the TAVR population is typically older and

bioprosthetic aortic valves, the value of OAC has been

frail, with multiple comorbidities, it can be a chal-

reemphasized (9). Although it has been speculated

lenge to find a balance between prevention of

that leaflet thrombosis and reduced motion may be

thromboembolic events and avoidance of major

related to thromboembolic events and reduced leaflet

bleeding. This is problematic in TAVR patients with

durability, the clinical impact of these abnormalities is

still

unclear.

However,

it

seems

that

anti-

coagulation protects against leaflet thrombosis and *Editorials published in JACC: Cardiovascular Interventions reflect the

may also resolve it. The GALILEO (Global Study

views of the authors and do not necessarily represent the views of JACC:

Comparing

Cardiovascular Interventions or the American College of Cardiology.

Strategy to an Antiplatelet-Based Strategy After

From the Heart Center, Rigshospitalet, Copenhagen University Hospital,

Transcatheter Aortic Valve Replacement to Optimize

Copenhagen, Denmark. Dr. Søndergaard has received research grants

Clinical Outcomes) 4DCT substudy (NCT02833948)

from Medtronic, St. Jude Medical, Boston Scientific, Symetis, and

(n ¼ 300) will evaluate whether a rivaroxaban-based

Edwards Lifesciences; and is a proctor for Medtronic, St. Jude Medical,

a

Rivaroxaban-Based

following

successful

Antithrombotic

Boston Scientific, and Symetis. Dr. Sawaya has reported that he has no

strategy,

relationships relevant to the contents of this paper to disclose.

with an antiplatelet-based strategy is superior in

TAVR,

compared

ARTE

Composite of death, MI, stroke or transient ischemic attack and major bleeding

12 months

No

Aspirin 80 mg for 6 months plus clopidogrel 75 mg/day for 3 months

Aspirin 80 mg/day for 6 months

155

RCT

NCT01559298

The primary outcome is freedom from non-procedure-related bleeding at 1 yr, and the secondary net clinical benefit outcome is freedom from the composite of cardiovascular death, non-procedure-related bleeding, MI, or stroke at 1 yr

12 months

Cohort B: AF

Cohort A: clopidogrel 75 mg for 3 months plus aspirin 100 mg/ day for 1 yr Cohort B: OAC plus clopidogrel 75 mg for 3 months

Cohort A: Clopidogrel 75 mg/day for 3 months Cohort B: OAC

1,010

RCT

NCT02247128

POPULAR-TAVI

AUREA

Occurrence of thromboembolic cerebrovascular events by magnetic resonance imaging

3 months

No

Acenocoumarol

Aspirin 80 mg/day plus clopidogrel 75 mg/day

124

RCT

NCT01642134

AVATAR

Composite outcome of death of any cause, MI, all-cause stroke, valve thrombosis, and hemorrhage

12 months

Yes

OAC plus antiplatelet therapy (aspirin or clopidogrel)

Single OAC therapy

170

RCT

NCT02735902

GALILEO

Composite of all-cause death, stroke, systemic embolism, MI, pulmonary embolism, deep venous thrombosis, and symptomatic valve thrombosis; the primary safety endpoint is the composite of life-threatening, disabling and major bleeding events

Up to 25 months

No

Aspirin 75–100 mg/day long term plus clopidogrel in the first 3 months

Rivaroxaban (10 mg/day long term, coupled with aspirin in the first 3 months)

1,520

RCT

NCT02556203

ATLANTIS

Composite of death, MI, systemic emboli, intracardiac or bioprosthetic thrombus, deep venous thrombosis, pulmonary embolism or major bleeding at 1 yr

Up to 13 months

Both sinus rhythm and AF

VKAs in patients with indications for anticoagulation or SAPT/ DAPT in patients with no indication for OAC

Apixaban (5 mg bid or 2.5 mg bid per renal function)

1,509

RCT

NCT02664649

AF ¼ atrial fibrillation; ARTE ¼ Aspirin Versus Aspirin Clopidogrel Following Transcatheter Aortic Valve Implantation; ATLANTIS ¼ Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis; AUREA ¼ Dual Antiplatelet Therapy Versus Oral Anticoagulation for a Short Time to Prevent Cerebral Embolism After TAVI; AVATAR ¼ Anticoagulation Alone Versus Anticoagulation and Aspirin Following Transcatheter Aortic Valve Interventions; bid ¼ twice daily; DAPT ¼ dual-antiplatelet therapy; GALILEO ¼ Global Study Comparing a Rivaroxaban-Based Antithrombotic Strategy to an Antiplatelet-Based Strategy After Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes; MI ¼ myocardial infarction; OAC ¼ oral anticoagulation; POPULAR-TAVI ¼ Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic Valve Implantation; RCT ¼ randomized controlled trial; SAPT ¼ single-antiplatelet therapy; VKA ¼ vitamin K antagonist.

Primary endpoint

Follow-up

AF

Control arm

Investigational arm

Patients

Study type

ClinicalTrials.gov ID

T A B L E 1 Current Post-TAVR Antithrombotic Management Trials

76

Søndergaard and Sawaya

Antithrombotic Management After TAVR

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 1, 2017 JANUARY 9, 2017:75–8

reducing subclinical valve leaflet thickening and

motion abnormalities, as detected by 4-dimensional

computed tomography.

coagulation is of utmost importance, the question is

Because avoidance of bleeding related to anti-

whether novel oral anticoagulant agents may replace

VKAs when an indication for OAC exists after TAVR. In

the ARISTOTLE (Apixaban for Reduction in Stroke

and Other Thromboembolic Events in Atrial Fibrilla-

tion) trial (10), apixaban was shown to be superior to

VKAs in patients with AF in preventing thromboem-

bolic events, at a lower rate of bleeding events.

Intuitively, apixaban may be a preferred OAC in this

older population, often with impaired renal function,

but it has not previously been evaluated in patients

with AF post-TAVR. Seeger et al. (1) evaluated for

the first time the safety and efficacy of apixaban

compared with VKAs in patients with AF after TAVR

in 617 patients. Despite demonstrating previously

comparable results compared with warfarin in a sub-

group analysis of ARISTOTLE in patients with valvular

stroke rate with apixaban compared with a VKA disease (11), there was a tendency toward a lower

(2.1% vs. 5.3%, p ¼ 0.17) with a significant reduction in

bleeding rate in the apixaban group compared with

the warfarin group (3.5% vs. 5.3%, p < 0.01) in this

study.

apixaban in this study, should an alternative to Despite the reduction of bleeding shown with

OAC in patients with AF post-TAVR be explored?

Recently, left atrial appendage occlusion (LAAO) has

been proposed as an alternative nonpharmacological

treatment for stroke prevention in patients with AF

with increased bleeding risk (12). LAAO to prevent

atrial thrombosis has the potential to become the

preferred strategy to prevent cerebrovascular events

in patients with AF with contraindications to OAC

therapy or at high bleeding risk, criteria that many

ied this hypothesis with simultaneous TAVR and TAVR patients fulfill. Attinger-Toller et al. (13) stud-

LAAO in 1 clinical setting in 52 patients. After a mean

follow-up period of 9.4 months, the investigators

showed that TAVR and LAAO can be combined safely,

with no adverse procedural outcomes. LAAO may be

particularly attractive in patients with AF who un-

dergo coronary revascularization with the use of

drug-eluting stents prior to TAVR, because many of

these patients will be committed on triple therapy

with aspirin, clopidogrel, and oral anticoagulant

agents (14). There is currently no randomized

controlled trial comparing the outcomes of OAC and

LAAO post-TAVR.

what is the best and optimal antithrombotic regimen

This study raises as well the ongoing debate on

Søndergaard and Sawaya

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 1, 2017 JANUARY 9, 2017:75–8

Antithrombotic Management After TAVR

in patients post-TAVR, regardless of whether they are

(NCT01642134) (n ¼ 124) is comparing the fixed

in sinus rhythm or AF. This was reflected in a German

combination of aspirin 80 mg/day and clopidogrel

registry of 1,450 patients showing that 7% of patients

75 mg/day versus OAC with acenocoumarol in pa-

received aspirin or clopidogrel monotherapy, 11%

tients with no indication for OAC, with respect to

received aspirin or clopidogrel with OACs, 66% of

the occurrence of thromboembolic cerebrovascular

patients received DAPT, and 16% received triple

events by magnetic resonance imaging at 3

therapy (15). In the study by Seeger et al. (1), 66% of

months.

patients were on SAPT and 34% on DAPT, although it has been reported that DAPT is associated with higher bleeding risk than SAPT (16). In concordance with

Different strategies are currently being investigated in patients with AF:

this, a shortened period of DAPT of 1 month or SAPT

1. The AVATAR (Anticoagulation Alone Versus Anti-

alone after TAVR has been found to produce a similar

coagulation and Aspirin Following Transcatheter

rate of thromboembolic events and a trend toward a

Aortic Valve Interventions) study (NCT02735902) (n ¼ 170) aims to demonstrate that single–oral

decrease in bleeding risks (5,17). Consequently, what are the optimal treatment

anticoagulant therapy is superior to a combination

strategy and duration for an ideal balance between

of OAC and SAPT with respect to a net clinical

efficacy and bleeding? Several ongoing studies may help define these important questions (Table 1). Different strategies are currently being investi-

1. The ARTE (Aspirin Versus Aspirin Clopidogrel Following Transcatheter Aortic Valve Implantation) study (NCT01559298) (n ¼ 155) is a randomized study of 300 patients not on OAC who will be treated after TAVR with a combination of aspirin for at least 6 months and clopidogrel for 3 months or SAPT therapy with aspirin alone for at least 6 months. 2. Cohort A of the POPULAR-TAVI (Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic Valve Implantation) study (NCT02247128) (n ¼ 1,010) is also a randomized study of 1,010 patients not on OAC who will be treated after TAVR with either clopidogrel 75 mg for 3 months or clopidogrel 75 mg for 3 months plus aspirin 100 mg for a year. 3. The GALILEO trial (NCT02556203) (n ¼ 1,520) will whether

of

the

POPULAR-TAVI

study

plus clopidogrel 75 mg for 3 months. 3. The ATLANTIS (Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis) trial (NCT02664649) (n ¼ 1,509) comprises a broader spectrum of TAVR patients (i.e., those with and without AF) to compare apixaban (5 mg twice daily or 2.5 mg twice daily) versus standard of care (VKAs in patients with indications for OAC or SAPT or DAPT in patients with no indication for OAC). The primary endpoint of ATLANTIS is the composite of death, myocardial infarction, systemic emboli, intracardiac or bioprosthetic thrombus, or major bleeding at 1 year. A wealth of information will be uncovered from this potpourri of trials in the next few years, and one

coagulation strategy compared with an antiplatelet

can foresee a change in the way we approach and

therapy–based strategy is superior in reducing

manage patients after TAVR, both those with AF and

death or thromboembolic events after TAVR.

those in sinus rhythm.

patients

rivaroxaban-based

are randomized to either OAC monotherapy or OAC

anti-

However,

a

B

(NCT02247128) (n ¼ 1,010) is also a randomized study of 1,010 patients, in which patients with AF

gated in patients with sinus rhythm:

assess

benefit endpoint at 1 year. 2. Cohort

with

histories

of

AF

are REPRINT REQUESTS AND CORRESPONDENCE: Dr.

excluded from GALILEO. 4. The AUREA (Dual Antiplatelet Therapy Versus

Lars Søndergaard, The Heart Center, Rigshospitalet,

Oral Anticoagulation for a Short Time to Pre-

Blegdamsvej 9, 2100 Copenhagen, Denmark. E-mail:

vent

[email protected].

Cerebral

Embolism

After

TAVI)

study

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Antithrombotic Management After TAVR

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KEY WORDS antiplatelet, antithrombotic, leaflet thrombosis, stroke, TAVR