-
2018 Joint European consensus document on
the management of antithrombotic therapy in
atrial fibrillation patients presenting with acute
coronary syndrome and/or undergoing
percutaneous cardiovascular interventions: a
joint consensus document of the European
Heart Rhythm Association (EHRA), European
Society of Cardiology Working Group on
Thrombosis, European Association of
Percutaneous Cardiovascular Interventions
(EAPCI), and European Association of Acute
Cardiac Care (ACCA) endorsed by the Heart
Rhythm Society (HRS), Asia-Pacific Heart
Rhythm Society (APHRS), Latin America
Heart Rhythm Society (LAHRS), and Cardiac
Arrhythmia Society of Southern Africa
(CASSA)
Gregory Y.H. Lip (Chair)1,2,3*, Jean-Phillippe Collet
(Co-Chair)4, Michael Haude
(Co-Chair)5, Robert Byrne6,7, Eugene H. Chung8, Laurent
Fauchier9,
Sigrun Halvorsen10, Dennis Lau11, Nestor Lopez-Cabanillas12,
Maddalena Lettino13,
Francisco Marin14, Israel Obel15, Andrea Rubboli16, Robert F.
Storey17,
Marco Valgimigli18, and Kurt Huber (Co-Chair)19
* Corresponding author. Tel: þ44 121 5075080. E-mail address:
[email protected] on behalf of the European Society of
Cardiology. All rights reserved. VC The Author(s) 2018. For
permissions, please email: [email protected].
Europace EHRA CONSENSUS DOCUMENTdoi:10.1093/europace/euy174
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ESC Scientific Document Group: Tatjana Potpara (Review
Coordinator)20,
Carina Blomström Lundqvist21, Harry Crijns22, Jan Steffel23,
Hein Heidbüchel24,
Goran Stankovic25, Juhani Airaksinen26, Jurrien M. Ten Berg27,
Davide Capodanno28,
Stefan James29, Hector Bueno30,31, Joao Morais32, Dirk
Sibbing33, Bianca Rocca34,
Ming-Hsiung Hsieh35, Nazem Akoum36, Deborah J. Lockwood37,
Jorge Rafael Gomez Flores38, Ronald Jardine39
1Institute of Cardiovascular Sciences, University of Birmingham,
UK; 2Liverpool Centre for Cardiovascular Science, University of
Liverpool and Liverpool Heart & Chest Hospital,Liverpool, UK;
3Department of Clinical Medicine, Aalborg Thrombosis Research Unit,
Aalborg University, Aalborg, Denmark; 4Sorbonne Université Paris
6, ACTION StudyGroup (www.action-coeur.org), Institut de
Cardiologie Hôpital Pitié-Salpêtrière (APHP), INSERM UMRS,
Paris, France; 5Städtische Kliniken Neuss Lukaskrankenhaus
GmbhKardiologie, Nephrologie, Pneumologie, Neuss, Germany;
6Deutsches Herzzentrum Muenchen, Munich, Germany; 7DZHK (German
Centre for Cardiovascular Research),partner site Munich Heart
Alliance, Munich, Germany; 8University of North Carolina at Chapel
Hill, Medicine, Cardiology, Electrophysiology, Chapel Hill, NC,
USA; 9CentreHospitalier Universitaire Trousseau et Faculté de
Médecine—Université François Rabelais, Tours, France;
10Department of Cardiology, Oslo University Hospital Ulleval,
andInstitute of Clinical Medicine, University of Oslo, Oslo,
Norway; 11Centre for Heart Rhythm Disorders, South Australian
Health and Medical Research Institute, University ofAdelaide and
Royal Adelaide Hospital, Adelaide, Australia; 12Clinica Adventista
Belgrano, Instituto Del Corazon, Buenos Aires, Argentina;
13Cardiology Department, HumanitasResearch Hospital, Rozzano, MI,
Italy; 14Department of Cardiology, Hospital Universitario Virgen de
la Arrixaca, Murcia, Spain; 15Milpark Hospital, Cardiology Unit,
Johannesburg,South Africa; 16Division of Cardiology, Laboratory of
Interventional Cardiology, Ospedale Maggiore, Bologna, Italy;
17Department of Infection, Immunity and Cardiovascular
Disease,University of Sheffield, Sheffield, UK; 18Inselspital,
Cardiology, Bern, Switzerland; 193rd Department of Medicine,
Cardiology and Intensive Care Medicine, Wilhelminenhospital
Vienna,Vienna, Austria; 20School of Medicine, Belgrade University,
Cardiology Clinic, Clinical Centre of Serbia, Belgrade, Serbia;
21Department of Medical Science and Cardiology, UppsalaUniversity,
Uppsala, Sweden; 22Cardiology Department, Maastricht UMCþ,
Maastricht, Netherlands; 23University Heart Center Zurich, Zurich,
Switzerland; 24Antwerp Universityand University Hospital, Antwerp,
Belgium; 25Department of Cardiology, Clinical Center of Serbia,
Belgrade, Serbia; 26Turku University Hospital, Cardiology,
Department of InternalMedicine, Turku, Finland; 27St. Antonius
Hospital, Cardiology Department, Nieuwegein, Netherlands;
28Ferrarotto Hospital, Azienda Ospedaliero-Univ,
Policlinico-VittorioEmanuele, University of Catania, Cardiologia
Department, University of Catania, Catania, Italy; 29Department of
Medical Sciences and Uppsala Clinical Research Center,
UppsalaUniversity, Senior Interventional Cardiologist, Uppsala
University Hospital, Uppsala, Sweden; 30Centro Nacional de
Investigaciones Cardiovasculares (CNIC), Melchor FernandezAlmagro,
Madrid, Spain; 31Department of Cardiology, Hospital Universitario
12 de Octubre, Madrid, Spain; 32Department of Cardiology, Leiria
Hospital Centre, Portugal;33Oberarzt, Medizinische Klinik und
Poliklinik I, Ludwig-Maximilians-Universität (LMU), Campus
Großhadern, München, Germany; 34Department of Pharmacology,
Catholic UniversitySchool of Medicine, Rome, Italy; 35Taipei
Medical University, Taipei, Taı̈wan; 36Cardiology Department,
University of Washington, Seattle, USA; 37OU Heart Rhythm
Institute, OUHealth Sciences Center, Oklahoma, USA; 38Instituto
Nacional de Cardiologia I. Chavez, Electrofisiologia, Mexico, DF
Mexico; and 39Linmed Hospital, Benoni, South Africa
Received 25 June 2018; editorial decision 28 June 2018; accepted
28 June 2018
In 2014, a joint consensus document dealing with the management
of antithrombotic therapy in atrial fibrillation(AF) patients
presenting with acute coronary syndrome (ACS) and/or undergoing
percutaneous coronary or valveinterventions was published, which
represented an effort of the European Society of Cardiology Working
Group onThrombosis, European Heart Rhythm Association (EHRA),
European Association of Percutaneous CardiovascularInterventions
(EAPCI), and European Association of Acute Cardiac Care (ACCA)
endorsed by the Heart RhythmSociety (HRS) and Asia-Pacific Heart
Rhythm Society (APHRS). Since publication of this document,
additional datafrom observational cohorts, randomized controlled
trials, and percutaneous interventions as well as new
guidelineshave been published. Moreover, new drugs and
devices/interventions are also available, with an increasing
evidencebase. The approach to managing AF has also evolved towards
a more integrated or holistic approach. In recognizingthese
advances since the last consensus document, EHRA, WG Thrombosis,
EAPCI, and ACCA, with additionalcontributions from HRS, APHRS,
Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia
Society ofSouthern Africa (CASSA), proposed a focused update, to
include the new data, with the remit of comprehensivelyreviewing
the available evidence and publishing a focused update consensus
document on the management ofantithrombotic therapy in AF patients
presenting with ACS and/or undergoing percutaneous coronary or
valveinterventions, and providing up-to-date consensus
recommendations for use in clinical practice.
...................................................................................................................................................................................................
Keywords European Heart Rhythm Association • Consensus document
• Position paper • Atrial fibrillation • Acutecoronary syndrome •
Coronary artery disease • Myocardial infarction • Percutaneous
coronaryintervention • Stent • Antithrombotic therapy •
Antiplatelet agents • Anticoagulation • Vitamin Kantagonists •
Non-vitamin K antagonist oral anticoagulants • Low molecular weight
heparin • Parenteralanticoagulants • Left atrial appendage
occlusion • Stroke • Thromboembolism • Thrombosis • Bleeding
Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3Evidence review . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . 3
An overview of new data since last version of the document . . .
. . . . . . . . 3
Observational cohorts . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . 3New randomized
controlled trials on antithrombotic therapy . . . . . . . 4
Oral anticoagulants . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . 4Antiplatelet drugs .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . 5Parenteral anticoagulants . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
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Stents in patients with increased bleeding risk . . . . . . . .
. . . . . . . . . . . . . . . 7Other data in structural
interventions, i.e. valve interventions(TAVI, mitral), LAA closure
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 8
Assessing stroke and bleeding risks . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . 10Optimizing management . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 11
Elective PCI . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . 11Acute
management . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . 12
Post-procedural and post-discharge therapy . . . . . . . . . . .
. . . . . . . . 16Long-term management . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . 18
Areas for future research . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . 22
Introduction
In 2014, a joint consensus document dealing with the management
ofantithrombotic therapy in atrial fibrillation (AF) patients
presentingwith acute coronary syndrome (ACS) and/or undergoing
percutane-ous coronary (PCI) or valve interventions was published,
which rep-resented an effort of the European Society of Cardiology
WorkingGroup on Thrombosis, European Heart Rhythm
Association(EHRA), European Association of Percutaneous
CardiovascularInterventions (EAPCI), and European Association of
Acute CardiacCare (ACCA) endorsed by the Heart Rhythm Society (HRS)
andAsia-Pacific Heart Rhythm Society (APHRS).1 Since publication
ofthis document, additional data from observational
cohorts,randomized trials, and percutaneous interventions have been
pub-lished. New guidelines on AF from the ESC2 and APHRS,3
andEuropean ST-elevation myocardial infarction (STEMI)
management4
as well as a focused update on dual antiplatelet therapy
(DAPT)5
have been published.This year, we saw publication of the 2018
update of the EHRA
practical guide on the use of non-vitamin K antagonist oral
anticoagu-lants (NOACs) in patients with AF6 and we expect new AF
guidelinesfrom North America from the American College of Chest
Physicians(ACCP) and American College of Cardiology
(ACC)/AmericanHeart Association (AHA)/Heart Rhythm Society
(HRS).
We also recognized that the approach to managing AF has
evolvedtowards an integrated or holistic approach, with the three
essentialcomponents of the patient management pathway as follows:7
(i)Avoid stroke with Anticoagulation therapy; (ii) Better symptom
man-agement, with a patient-centred, symptom-directed decision
makingwith regard to rate or rhythm control; and (iii)
Cardiovascular andcomobidity risk factor management, i.e.
addressing lifestyle changesand associated risks including
hypertension, sleep apnoea, cardiac is-chaemia, etc. This has been
referred to as the ABC (Atrial fibrillationBetter Care)
pathway.7
In recognizing these advances since the last consensus
document,EHRA, WG Thrombosis, EAPCI, and ACCA, with additional
contri-butions from HRS, APHRS, Latin America Heart Rhythm
Society(LAHRS), and Cardiac Arrhythmia Society of Southern
Africa(CASSA), proposed a focused update to include the new data,
withthe remit of comprehensively reviewing the available evidence
andpublishing a focused update consensus document on the
manage-ment of antithrombotic therapy in AF patients presenting
with ACSand/or undergoing PCI or valve interventions (e.g.
transcatheteraortic valve replacement), and providing up-to-date
consensus rec-ommendations for use in clinical practice. However,
the ultimate
decision on management must be made between the healthcare
pro-vider and the patient in light of all individual factors
presented.
Evidence reviewThis document was prepared by the Task Force with
representationfrom EHRA, WG Thrombosis, EAPCI, and ACCA, with
additionalcontributions from HRS, APHRS, LAHRS and CASSA, and
peer-reviewed by official external reviewers representing all these
bodies.Their members made a detailed literature review, weighing
thestrength of evidence for or against a specific treatment or
procedure,and including estimates of expected health outcomes where
data ex-ist. In controversial areas, or with respect to issues
without evidenceother than usual clinical practice, a consensus was
achieved by agree-ment of the expert panel after thorough
deliberation.
We opted for an easier and user-friendly system of ranking
using‘coloured hearts’ that should allow physicians to easily
assess the cur-rent status of the evidence and consequent guidance
(Table 1). ThisEHRA grading of consensus statements does not have
separate defi-nitions of the level of evidence. This
categorization, used for consen-sus statements, must not be
considered as directly similar to thatused for official society
guideline recommendations, which apply aclassification (Class
I-–III) and level of evidence (A, B, and C) to rec-ommendations
used in official guidelines.
Thus, a green heart indicates a ‘should do this’ consensus
state-ment or indicated treatment or procedure that is based on at
leastone randomized trial, or is supported by strong observational
evi-dence that it is beneficial and effective. A yellow heart
indicates gen-eral agreement and/or scientific evidence favouring a
‘may do this’statement or the usefulness/efficacy of a treatment or
procedure. A‘yellow heart’ symbol may be supported by randomized
trials basedon a small number of patients or which is not widely
applicable.Treatment strategies for which there is scientific
evidence of poten-tial harm and should not be used (‘do not do
this’) are indicated by ared heart.
An overview of new data since lastversion of the document
Observational cohortsSince the publication of the previous
consensus document, at least30 observational reports on patients on
oral anticoagulation (OAC)presenting with ACS and/or undergoing PCI
have been published8–37
(Supplementary material online, Table Sw1).A total of 171 026
patients have been included, with AF being the
most frequent, albeit not the only, indication for OAC. For 29
418patients, information on the different antithrombotic strategies
wasprovided: 7656 (26%) received triple antithrombotic therapy
(TAT)of OAC, aspirin and a P2Y12-receptor inhibitor (generally
clopidog-rel), 21 279 (72%) DAPT of aspirin and P2Y12-receptor
inhibitor(generally clopidogrel), and 483 (2%) dual antithrombotic
therapy(DAT) of OAC and either aspirin or clopidogrel. In all
studies, exceptthree14,15,21 where approximately 50%, 39%, and 8%
of patients, re-spectively, received a NOAC as part of the
antithrombotic regimen,OAC consisted of a vitamin K-antagonist
(VKA), generally warfarin(Supplementary material online, Table
Sw1). Indication for PCI
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included, in most cases, either ACS or stable coronary artery
disease(CAD). The majority were retrospective analyses of either
small-sizedatabases or large, multicentre nationwide registries
that had gener-ally been set up for other purposes. In only a few
cases, the data werederived from prospective, observational
registries specificallydesigned to evaluate the management
strategies and outcomes ofOAC patients undergoing PCI. Length of
follow-up was variable,ranging from in-hospital to 6 years
(Supplementary material online,Table Sw1) between 1999 and
2015.
Overall, TAT was consistently associated with a significantly
in-creased risk of total and/or major bleeding compared with
otherantithrombotic regimens. The risk of (major) bleeding may be
in-versely related to the quality of OAC, measured as time in
therapeu-tic range (TTR) for patients receiving a VKA.8 The
bleeding riskprofile may impact on the occurrence of major bleeding
more thanthe antithrombotic combination.10 The rates of major
adverse car-diovascular and cerebrovascular events (MACCE) were
similar irre-spective of the antithrombotic regimen and/or use of
OAC.
The limitations of these studies include the lack of
randomizationand associated selection bias in the prescription of
the various antith-rombotic regimens, as well as the lack of
systematic bleeding risk as-sessment, incomplete information on
adherence to treatment andTTR values, the independent contribution
of periprocedural manage-ment on the occurrence of MACCE and
bleeding, and the alterationsin the prescribed antithrombotic
therapy subsequent to an ischaemicor haemorrhagic event.
In patients with CHA2DS2-VASc [congestive heart failure,
hyper-tension, age >_75 (doubled), diabetes, stroke
(doubled)-vascular dis-ease, age 65–74 and sex category (female)]
score 1 when comparedwith >_2, the efficacy of TAT in the
prevention of stroke and/or sys-temic embolism was not
statistically superior to DAPT22
(Supplementary material online, Table Sw1). In general, these
data
have to be interpreted with caution as this registry study was
smalland not randomized. The use of the newer, more potent
P2Y12-receptor inhibitors, prasugrel and ticagrelor as part of a
TAT regime,has been associated with an increased risk of bleeding
events. Nospecific information on the relative efficacy and safety
of NOACs, ei-ther as a category or as individual agents, can be
derived from avail-able observational data. Further data are
expected to come from theobservational, multicentre AVIATOR 2
registry.38 This study wascapped after including 500 (of the
originally planned 2500) AFpatients undergoing PCI and evaluates
MACCE and bleeding rates.
New randomized controlled trials onantithrombotic therapyOral
anticoagulants
Since publication of the 2014 consensus document, two
randomizedcontrolled trials on NOAC vs. VKA in combination with
antiplateletsfor patients with AF undergoing PCI have been
published primarily in-vestigating safety,39,40 and at least two
large trials are ongoing.
In the randomized PIONEER AF PCI trial (Open-Label,Randomized,
Controlled, Multicenter Study Exploring TwoTreatment Strategies of
Rivaroxaban, and a Dose-Adjusted OralVitamin K Antagonist Treatment
Strategy in Subjects with AtrialFibrillation who Undergo
Percutaneous Coronary Intervention),2124 participants with
non-valvular AF who had undergone PCI withstenting (about 30% of
patients had a troponin-positive ACS andabout 20% had unstable
angina as index event) were randomlyassigned to DAT with ‘low-dose’
rivaroxaban [15 mg od (once daily)]plus a P2Y12 inhibitor for 12
months (Group 1), novel TAT with‘very-low-dose’ rivaroxaban [2.5 mg
bid (twice daily)] plus DAPT for1, 6, or 12 months (Group 2), or
standard therapy with a dose-adjusted VKA (od) plus DAPT for 1, 6,
or 12 months (Group 3).39
....................................................................................................................................................................................................................
Table 1 Scientific rationale of recommendationsa
Definitions where related to a treatment or
procedure
Consensus statement
instruction
Symbol
Scientific evidence that a treatment or procedure is
beneficial and effective. Requires at least one ran-
domized trial or is supported by strong observa-
tional evidence and authors’ consensus (as indicated
by an asterisk).
‘Should do this’
General agreement and/or scientific evidence favour
the usefulness/efficacy of a treatment or procedure.
May be supported by randomized trials based on a
small number of patients or which is not widely
applicable.
‘May do this’
Scientific evidence or general agreement not to use or
recommend a treatment or procedure.
‘Do not do this’
aThis categorization for our consensus document should not be
considered as being directly similar to that used for official
society guideline recommendations which apply aclassification
(I–III) and level of evidence (A, B, and C) to recommendations.
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Text: (Deleted Text: twice daily)Deleted Text: once daily
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The primary endpoint of the trial was clinically-significant
bleeding.The rates of clinically-significant bleeding were lower in
the twogroups receiving rivaroxaban than in the group receiving
standardtherapy (16.8% in Group 1, 18.0% in Group 2, and 26.7% in
Group 3;P < 0.001 for both comparisons). There were no
statistically signifi-cant differences in the rates of death from
cardiovascular causes,myocardial infarction (MI), or stroke,
although the study was notpowered for efficacy and the observed
broad confidence intervals(CIs) diminish the surety of any
conclusions. No power calculation inthis exploratory trial,
recruitment was not event-driven, and thatprior stroke was an
exclusion criteria (which led to the selection oflow risk
patients).
In the Randomized Evaluation of Dual Antithrombotic TherapyWith
Dabigatran vs. Triple Therapy With Warfarin in Patients
WithNonvalvular Atrial Fibrillation Undergoing Percutaneous
CoronaryIntervention (RE-DUAL PCI) study,39,40 DAT with dabigatran
etexi-late (110 or 150 mg bid) and a P2Y12 inhibitor (either
clopidogrel orticagrelor) was compared with TAT with warfarin, a
P2Y12 inhibitor(either clopidogrel or ticagrelor), and low-dose
aspirin (for 1 or3 months, depending on stent type) in 2725
non-valvular AF patientswho had undergone PCI with stenting. The
primary endpoint wasmajor or clinically-relevant non-major bleeding
during follow-up, asdefined by the International Society on
Thrombosis and Hemostasis(ISTH). The trial also tested for the
non-inferiority of dual therapywith dabigatran (both doses
combined) to TAT with warfarin withrespect to the incidence of a
composite efficacy Endpoint of throm-boembolic events (MI, stroke,
or systemic embolism), death, orunplanned revascularization.
Approximately half of the patients hadan ACS. Most of the patients
received clopidogrel as the P2Y12 inhibi-tor; only 12.0% received
ticagrelor. Drug-eluting stents alone wereused in 82.6% of the
patients.
In RE-DUAL PCI, the incidence of the primary endpoint was
15.4%in the 110-mg DAT group when compared with 26.9% in the
TATgroup [hazard ratio (HR) 0.52, 95% CI 0.42–0.63; P < 0.001
for non-inferiority; P < 0.001 for superiority] and 20.2% in the
150-mg DATgroup when compared with 25.7% in the corresponding TAT
group,which did not include elderly patients outside the United
States (HR0.72, 95% CI 0.58–0.88; P < 0.001 for
non-inferiority). The incidenceof the composite efficacy endpoint
was 13.7% in the two DAT groupscombined when compared with 13.4% in
the TAT group (HR 1.04,95% CI 0.84–1.29; P = 0.005 for
non-inferiority). When looking at thetwo dabigatran groups
separately, there was a non-significant excessin the number of
ischaemic events (i.e. stent thrombosis and MI) withthe 110 mg bid
dose compared with TAT.
Apixaban has been shown to have similar beneficial effects
onstroke or systemic embolism and major bleeding compared
withwarfarin, irrespective of concomitant aspirin use.41 However,
nocompleted trial has studied apixaban as part of dual or triple
therapyin patients with AF and ACS or PCI. The ongoing AUGUSTUS
study(NCT02415400) is an open-label, 2 � 2 factorial, randomized,
con-trolled non-inferiority clinical trial to evaluate the safety
of apixaban(standard dosing) vs. VKA and aspirin vs. aspirin
placebo in patientswith AF and ACS (the only trial including ACS
patients treated con-servatively or by PCI).42 The primary focus is
a comparison of thebleeding risk of apixaban, with or without
aspirin, vs. a VKA such as
warfarin, with or without aspirin. This study will include 4600
patientsand enrolment was completed in April 2018 (Table 2). The
EdoxabanTreatment vs. Vitamin K Antagonist in Patients With
AtrialFibrillation Undergoing Percutaneous Coronary
Intervention(ENTRUST-AF-PCI, 1500 patients are planned) study is
designed toevaluate the safety and to explore the efficacy of an
edoxaban-based(standard dosing) antithrombotic regimen vs. a
VKA-based antith-rombotic regimen in subjects with AF following PCI
with stent place-ment.43 In both the AUGUSTUS and the
ENTRUST-AF-PCI study(again, both being safety studies not
sufficiently powered for ischae-mic outcomes), standard dosing of
NOAC is used in combinationwith antiplatelets, with dose reduction
only in selected patients fulfill-ing NOAC specific dose reduction
criteria.
In a systematic review and meta-analysis of four randomized
clini-cal trials including 5317 patients [3039 (57%) received
DAT],Thrombolysis in Myocardial Infarction (TIMI) major or minor
bleed-ing showed a reduction by 47% in the DAT arm compared with
theTAT arm (4.3% vs. 9.0%; HR 0.53, 95% CI 0.36–0.85).44 There was
nodifference in the major adverse cardiac events (MACE) (10.4%
vs.10.0%, HR 0.85, 95% CrI 0.48–1.29), or in individual outcomes of
all-cause mortality, cardiac death, MI, stent thrombosis, or stroke
be-tween DAT and TAT.
Antiplatelet drugs
The WOEST study initially tested the concept of dropping aspirin
af-ter PCI and using a combination of clopidogrel and warfarin
alone,suggesting that this approach is effective and safe in terms
of throm-botic events, and reduced overall bleeding risk.45 As
discussed above,the PIONEER and RE-DUAL trials39,40 further
reinforce the conceptof potential redundancy of aspirin and its
associated bleeding hazardin AF patients treated with anticoagulant
and P2Y12 inhibitor.
Although in a non-AF population, the GEMINI-ACS-1 study
hasreinforced the concept that oral anticoagulation may substitute
foraspirin in patients who are stable early after PCI, showing that
rivar-oxaban combined with either clopidogrel or ticagrelor
provided simi-lar efficacy in prevention of ischaemic events
compared with aspirinwith either of these P2Y12 inhibitors.
46 The COMPASS study demon-strated higher efficacy of
rivaroxaban 2.5 mg bid plus aspirin 100 mgod in long-term
prevention of ischaemic events vs. aspirin alone, in anon-AF
vascular disease population. This was accompanied by higherbleeding
complications when compared with aspirin alone, and doesnot support
the suggestion that aspirin can be substituted by anOAC.47 The
GLOBAL-LEADERS study is assessing, amongst otherconcepts, whether
ticagrelor monotherapy from 1 month after PCI issuperior to
standard DAPT and will further define the necessity of as-pirin
from this timepoint in a non-AF population.48 TWILIGHT is
thelargest study to date that is designed and powered in order to
dem-onstrate a lower bleeding rate with ticagrelor monotherapy vs.
tica-grelor plus acetylsalicylic acid (ASA) beyond 3 months
post-procedure in a high-risk patient population undergoing PCI
withdrug-eluting stents (DES).49
Overall, limited numbers of patients have been studied with
thecombination of an anticoagulant and either prasugrel or
ticagre-lor.23,28,50 Because of the greater platelet inhibition
with approveddoses of prasugrel or ticagrelor compared with
clopidogrel, the risk
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of spontaneous bleeding is higher when used in combination
withaspirin.51,52
The PEGASUS-TIMI 54 study assessed a lower dose of ticagrelor(60
mg bid) in addition to the 90 mg bid dose licensed for use in ACSin
combination with aspirin (75–150 mg od) in non-AF patients
within1–3 years of MI and at higher risk of recurrent
atherothromboticevents.53 Both doses of ticagrelor had similar
efficacy and safety al-though there were numerical trends
suggesting less minor bleedingand better tolerability with
ticagrelor 60 mg bid.54 Interestingly, theextent of platelet
inhibition with ticagrelor 60 mg bid was similar tothat achieved
with ticagrelor 90 mg bid.55 The TROPICAL-ACS studysuggested that
guided de-escalation from prasugrel to clopidogrel (inclopidogrel
responders) after PCI is non-inferior to continuing prasu-grel in a
DAPT strategy.56 Another de-escalation trial (TOPIC) com-pared a
switch from DAPT (aspirin plus a new P2Y12-inhibitor)
withconservative DAPT (aspirin plus clopidorel) 1 month after ACS
or tocontinue their initial drug regimen (unchanged DAPT).57
Theseauthors reported that switched DAPT is superior to an
unchangedDAPT strategy to prevent bleeding complications without
increase inischaemic events following ACS, although these studies
were notpowered to compare ischaemic event rates However, the
implica-tions of poor response to clopidogrel in patients treated
with clopi-dogrel and an anticoagulant, rather than aspirin, are
not wellcharacterized.
Parenteral anticoagulants
Recent meta-analysis of 2325 VKA-treated AF patients
undergoingcoronary angiography with or without PCI showed that
bothbleeding and 30-day major adverse cardiovascular event rates
weresimilar between those with interrupted or uninterrupted
VKA.58
However, those who received parenteral bridging anticoagulants
oninterruption of VKA had higher major bleeding rates.58 The
abovedata confirm recommendations of uninterrupted anticoagulation
forelective PCI.1 At present, little is known regarding the
bleedingand MACCE rates with continuation or interruption of NOAC
dur-ing PCI.
Limited data exists to guide the choice of and the dose of
paren-teral anticoagulants, whether unfractionated heparin (UFH),
bivaliru-din, or enoxaparin and their optimal dosages, specific to
AF patientsalready taking OAC when undergoing PCI for ACS.
Additional paren-teral anticoagulants may not be needed,
particularly if the interna-tional normalized ratio (INR) is more
than 2.5 at the time of electivePCI.1,59 On the other hand, the
usage of parenteral anticoagulantsduring PCI is recommended in AF
patients on NOAC regardless ofthe timing of the last NOAC
dose.59
Stents in patients with increasedbleeding riskDrug-eluting and
bare-metal stents
Since December 2014, three large-scale trials, comparing
differentstents, have enrolled relatively high proportions of
patients with AFrequiring treatment with OAC. One trial enrolled
patients regardedas being uncertain candidates for DES at the
time.60 About 12% hadOAC at discharge. This pre-specified post hoc
analysis of the ZEUStrial demonstrated that the use of the Endeavor
zotarolimus-elutingstent is superior to bare-metal stents in terms
of the composite of
death, MI and target vessel revascularization (TVR) (HR 0.76,
95% CI0.61–0.95; P = 0.011) in patients at high bleeding risk
(mainly triggeredby TVR).60 The median duration of DAPT was 1
month.
Another prospective randomized trial enrolled patients at
highbleeding risk and randomly allocated treatment with a
polymer-freebiolimus A9-DES vs. a bare-metal stent (LEADERS FREE
trial).61 Themain finding was that the primary safety endpoint of
death, MI, andstent thrombosis was reduced with the biolimus A9-DES
(HR 0.71,95% CI 0.56–0.91; P < 0.001 for non-inferiority and P =
0.005 for su-periority). In line with expectations, the primary
efficacy endpoint oftarget lesion revascularization was reduced by
half with the biolimusA9-DES (HR 0.50, 95% CI 0.37–0.69; P <
0.001), while death as singleendpoint was not reduced. Treatment
effects were consistent inpatients with planned OAC therapy at
discharge for efficacy andsafety endpoints.
Subgroup analysis demonstrated similar outcome data for the
biol-imus A9-DES vs. bare-metal stents in elderly patients; there
was evi-dence of interaction with regard to treatment effect and
diagnosis ofACS at baseline in relation to the primary safety
endpoint (P = 0.04)with greater benefit for patients treated with
the biolimus A9-DES.62
Safety and efficacy were maintained during an extended
follow-upout to 2 years, even amongst the subgroup of patients who
were can-didates for long term OAC.63,64
A more recent clinical trial compared the outcomes of
elderlypatients (>75 years) undergoing PCI with a new generation
DES (bio-degradable polymer everolimus-eluting stents) compared
with bare-metal stents (SENIOR trial), where 17.6% had AF at
enrolment.65
DAPT was recommended in both groups for the same duration:1
month in patients with stable angina and 6 months in patients
withACS. The composite of death, MI, stroke, or target
lesionrevascularization was significantly reduced in patients
treated withDES (relative risk 0.71, 95% CI 0.52–0.94; P = 0.02).
Bleeding was sim-ilar in both groups, in line with the identical
recommendations forantithrombotic treatment in both groups.
Results with new-generation DES are generally excellent
acrossthe spectrum of patient and lesion subgroups. A recent
systematic re-view of 158 trials—conducted as part of a ESC-EAPCI
task force onthe evaluation of coronary stents—reported low rates
of both reste-nosis and stent thrombosis at 9–12 months with
new-generationDES (less than 5% and 1%, respectively), with lower
rates comparedwith both bare-metal stents and early-generation
DES.66 Large-scaleregistries support the generally high efficacy
and safety of new-generation DES. Convincing data to support
different durations ofDAPT according to stent type are lacking and
the general recommen-dation for 1-month DAPT after bare-metal
stenting in stable patientsis not well supported. More recently,
drug-eluting balloons can be analternative for stenting in special
lesions (e.g in patients with in-stentrestenosis).
The 2017 ESC Focused Update on Antiplatelet Therapy recom-mends
that choice of duration of DAPT in patients should no longerbe
differentiated on basis of device used, i.e. whether the
stentimplanted at time of PCI is a DES or bare-metal stent, or
whether adrug eluting balloon is used.5 In view of the superior
antirestenotic ef-ficacy and no signal of higher thrombotic risks
even after short termDAPT duration of new generation DES when
compared with BMS, itis recommended that patients with AF
undergoing PCI should betreated with new generation DES.
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Bioresorbable scaffolds
Bioresobable scaffolds (BRS) are rarely used in clinical
practice at pre-sent,67 due to an increased risk of target lesion
failure and devicethrombosis at 2–3 year follow-up and an excess of
1-year target ves-sel MI and stent thrombosis in comparison with
conventional DES.68
Consensus statements
Other data in structural interventions,i.e. valve interventions
(TAVI, mitral),left atrial appendage closureTranscatheter aortic
valve implantation
Cerebral embolization is one of the major complications that
mightoccur in the very early phase of valve placement. New
periproceduralcerebral ischaemic defects have been reported in more
than 60% ofpatients, and clinically-apparent stroke occurs in
around 3% of caseson average (range 0–6%).69
Despite a higher incidence of cerebrovascular events with the
firstdevices in the PARTNERS trials,70,71 there seems to be a
similar riskof stroke in patients undergoing TAVI compared with
patients receiv-ing the surgical aortic valve replacement
(SAVR).72–75 Parenteralantithrombotic treatment during TAVI aims to
prevent thrombo-embolic complications related to large catheter
manipulation, guide-wire insertion, balloon aortic valvuloplasty,
and valve prosthesis im-plantation, while minimizing the risk of
bleeding, particularly at thevascular access site. Based on
retrospective studies and randomizedtrials,72,73,76,77 the most
commonly used anticoagulant is UFH atdoses of 50–70 IU/kg with a
target activated clotting time (ACT) of250–300 s, although no
optimal ACT has been defined, even in guide-lines.78–82 Given the
higher cost and similar efficacy of bivalirudinwhen compared with
UFH, the latter should remain the standard ofcare for patients
undergoing TAVI unless contra-indications to UFH,such as known
heparin-induced thrombocytopenia, exist.83
Subacute cerebrovascular events associated with TAVI occur
be-tween 24 h and 30 days, while all the episodes occurring after
30 daysare defined as late. Stroke rate at 30 days reported by
randomizedclinical trials and registries ranges from 0% to 9%.84
Factors poten-tially involved in such cerebrovascular events
development are:thrombogenicity of the valve apparatus, exposure of
the stent struts(expanded together with the valve), persistence of
the perivalvularspace occupied by the native valve and the
development of paroxys-mal atrial arrhythmias.69,82 Moreover, the
baseline risk for ischaemicand thromboembolic complications is
further increased by comor-bidities including concomitant CAD,
which is present in 20–70% ofpatients and requires PCI in 20–40% of
patients. Furthermore, AF isfound in about one-third of patients
referred for TAVI.70,71,85–87
Prospective data on antithrombotic therapy after TAVI are
stillscarce and recommendations regarding choice and optimal
durationof antiplatelet or antithrombotic therapy are largely based
on experi-ence from PCI and open-heart aortic valve
replacement.
Among patients without CAD and without AF, the current stan-dard
of care is still DAPT consisting of low-dose aspirin (75–100 mgper
day) and clopidogrel 75 mg od (after loading dose of 300–600 mg),
both started within 24 h prior to the intervention, and con-tinued
for 3–6 months followed by indefinite aspirin monotherapy.Patients
receiving single antiplatelet therapy soon after TAVI tendedto have
a lower rate of major adverse events after the interventionwhen
compared with patients on DAPT, with a significant reductionof
major and life-threatening bleeding complications at three
monthsfollow-up.88 A meta-analysis of the pooled results of this
trial andother minor studies showed no benefit of DAPT in early
stroke re-duction with a trend towards an increase in major
bleeding, thus sug-gesting the opportunity to adopt an antiplatelet
monotherapy soonafter the intervention for all patients without
indication foranticoagulation.89
Other clinical trials are currently ongoing. The
AntiplateletTherapy for Patients Undergoing Transcatheter Aortic
ValveImplantation (POPular TAVI, n = 1000) trial is currently
exploringwhether it is possible to skip clopidogrel in a larger
population ofpatients undergoing TAVI with or without an indication
for OACprior to the procedure. Patients are randomized to aspirin
alone vs.aspirin plus clopidogrel for the first 3 months after the
procedure andevaluated for the primary safety endpoint of freedom
of non-procedure-related bleeding complications at 1 year
follow-up. Thecohort of patients for whom OAC is indicated (AF,
mechanical valveprostheses) is randomized to clopidogrel plus OAC
vs. OAC alone(NCT02247128).
The Global Study Comparing a rivAroxaban-basedAntithrombotic
Strategy to an antiplatelet-based Strategy afterTranscatheter
aortic vaLve rEplacement to Optimize ClinicalOutcome (Galileo, n =
1520) study is an open-label, multicentre, ran-domized controlled
trial actively recruiting patients undergoing TAVIwith no
indication to permanent anticoagulant therapy. Patientsassigned to
the OAC arm are randomly assigned to receive 10 mg odrivaroxaban up
to 25 months plus low-dose aspirin during the first 3months in
order to assess whether this strategy is superior to DAPTwith
aspirin plus clopidogrel (for 3 months) followed by aspirin alonein
reducing death or first clinical thromboembolic events with no
in-crease in bleeding complications (NCT02556203).90
.................................................................................................References
• In view of the superior anti-reste-notic efficacy and no
signal of higher
thrombotic risk of new-generation
DES it is recommended that patients
with AF undergoing PCI should be
treated with new generation DES
5,66
• Choice of DAPT duration should notbe differentiated based on
whether
the stent implanted at time of PCI is
a DES or bare-metal stent
5
• Patients requiring oral anticoagula-tion should not receive
BRS
63,64
DES, drug-eluting stent; DAPT, dual antiplatelet therapy; BRS,
biovascularscaffold.
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Third, the Anti-Thrombotic Strategy after Trans-Aortic
ValveImplantation for Aortic Stenosis (ATLANTIS, n = 1509) trial is
evalu-ating whether an anticoagulant-based strategy with apixaban 5
mg bidis superior to standard-of-care therapy in preventing death,
MI,stroke, systemic embolism, intracardiac or bioprosthesis
thrombusformation, or life-threatening/major bleeding complications
at 1 yearfollow-up in patients successfully treated with a TAVI
procedure. TheATLANTIS trial will include two different
populations: patients withan indication for anticoagulation, where
standard of care is repre-sented by a VKA and patients for whom an
antiplatelet regimen withaspirin plus clopidogrel is the
first-choice antithrombotic treatment.Randomization is consequently
stratified according to the need (orno need) for anticoagulation
for clinical reasons other than TAVI it-self (NCT02664649).
Finally, another study that aims at demonstrating the
superiority ofa single anticoagulant vs. the combination of an
anticoagulation plusaspirin with respect to a net clinical benefit
endpoint at 1 year (theAVATAR trial, NCT02735902) has been
announced (n = 170).
Among TAVI patients with AF but without CAD, OAC is recom-mended
in accordance with recommendations for AF alone.1
Whether the addition of antiplatelet therapy to OAC is required
inthis context remains to be determined. The existing experience
withpatients receiving biological aortic valve replacement suggests
thatOAC alone may be sufficient to prevent thrombotic events.79
Indeed, OAC (essentially VKA) use in surgically-implanted
biologicalaortic valves is generally recommended for only 3 months
and can bestopped thereafter, except where patients have other
reasons forprolonged or life-long OAC.
The POPular TAVI trial, which is currently recruiting patients,
willprovide information regarding the safety and the net clinical
benefitof a VKA alone vs. the combination of clopidogrel plus a VKA
inpatients undergoing TAVI who have an indication to
permanentOAC.91 With reference to the life-long use of a NOAC
comparedwith VKA, beyond the reported ATLANTIS trial, the
EdoxabanCompared to Standard Care after Heart Valve Replacement
Using aCatheter in Patients with Atrial Fibrillation (ENVISAGE-TAVI
AF)trial recently started recruiting a planned population of 1400
AFpatients undergoing TAVI. The study will compare the two
anticoag-ulant drugs (warfarin vs. edoxaban) in terms of overall
side effectsand major bleeding during 3 years follow-up
(NCT02943785).
In summary, TAVI patients taking OAC (e.g. for AF) and recentPCI
should be treated similarly to patients receiving a stent
withoutTAVI. While awaiting results of controlled randomized
trials, patientsundergoing TAVI without concomitant need for OAC
should receivean antiplatelet regimen consisting of lifelong
aspirin monotherapy oraspirin and clopidogrel for 3–6 months
followed by aspirin mono-therapy, depending on bleeding risk, and
concomitant treated oruntreated coronary artery disease. The use of
prasugrel or ticagrelorin combination with aspirin or NOAC after
TAVI has not been inves-tigated and cannot be recommended at this
time.
Mitral intervention
No study has addressed the optimal antithrombotic regimen
afterpercutaneous edge-to-edge transcatheter mitral valve repair
(e.g.MitraClip system, Abbott, Abbott Park, IL, USA92) Pivotal
studieshave mandated the use of aspirin for at least 6 months in
combination
with clopidogrel for 1–3 months in patients without AF while
patientswith AF are treated with OAC plus aspirin.93
Transcatheter mitral valve implantation (TMVI) with a
transcath-eter mitral valve prosthesis has been performed in
patients with sur-gical degenerated bioprostheses [valve-in-valve
(ViV)] or withrecurrent MR following mitral repair annuloplasty
[valve-in-ring(ViR)].94 There is currently limited evidence that
adding a single anti-platelet therapy or DAPT to OACs further
decreases the risk ofsymptomatic or asymptomatic valve
thrombosis.
Left atrial appendage closure
The left atrial appendage (LAA) is implicated in approximately
90% ofstrokes in patients with AF.95 Left atrial appendage
occlusion, eitherpercutaneous or surgical, is a rapidly-emerging
option for patientswho cannot take long-term OAC.96 Of the
percutaneous options,the WATCHMAN (Boston Scientific) device is so
far the only testedLAA closure device in a randomized controlled
fashion. It is currentlythe only percutaneous device approved in
both Europe and the US.
In the PROTECT-AF trial, patients were treated with warfarin
andaspirin 81 mg for 45 days post-procedure, then with aspirin and
clopi-dogrel for 6 months, and then with aspirin indefinitely.97 In
thePREVAIL study, patients were on warfarin plus aspirin 81 mg for
thefirst 45 days, then on aspirin 325 mg plus clopidogrel until
post-opera-tive month 6 (in the absence of any clot), then on
aspirin 325 mgalone.98 Thus, PROTECT and PREVAIL did not enroll
patients unableto take OACs, but patients who were at least able to
take warfarinfor 45 days post-procedure. This contradicts the
current suggestedindication to use a LAA closure device in patients
with contraindica-tions against OACs. Moreover, the efficacy and
safety of using aNOAC instead of warfarin was not assessed in these
two majortrials.
These trials have been subject to much debate,99 with reports
ofdevice related thrombus that can lead to thromboembolism.100
Inthe absence of clinically relevant LAA leaks, OAC can be
discontin-ued and the patient treated with DAPT or a single
antiplatelet ther-apy for at least 6 months after the procedure,
although somecardiologists continue single antiplatelet therapy
long term. Thereare also no data to suggest the optimal management
of an AF patientwith left atrial appendage occlusion who requires a
cardioversion. Atransoesophageal echocardiogram (TOE) assessment
for thrombusmay be performed, and a shorten duration of
anticoagulation similarto TOE-guided cardioversion protocol may be
considered.
AmplatzerThe data on Amplatzer Cardiac Plug (now Amulet), are
largely basedon registry studies.101,102 The most recent study had
18.9% patientson either a VKA or NOAC immediately
post-procedure.101 In astudy of 52 Canadian patients receiving this
device, there was an only1.9% rate of stroke when antiplatelets
alone were used post-procedure during a mean follow-up of 20 ± 5
months.103
LariatThe LARIAT device (SentreHeart) ligates off the LAA via a
combinedtrans-septal and epicardial approach. It received FDA
approval forsoft tissue closure but not specifically for LAA
closure. It has notbeen tested in a randomized controlled trial, so
efficacy data are
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derived from prospective registries.104 Since the US FDA
released asafety alarm communication in July 2015 due to reports of
adversepatient outcomes, the use of LARIAT in the US has dropped
signifi-cantly
(https://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm454501.htm).
In summary, LAA occlusion may be considered in selected
AFpatients with absolute contraindications to any OAC. Trial data
sup-porting use of shorter duration TAT or even DAT in these
patientsin general (as discussed above), as well as the
recommendation forshort duration OAC after the procedure in
patients treated withWatchman device, makes the rationale for
implanting these devicessolely for the reason that the AF patient
requires PCI unclear.
Assessing stroke and bleedingrisks
The CHA2DS2-VASc has been widely used worldwide for stroke
riskstratification in AF,105 even in patients with coronary artery
diseasetreated with coronary stenting.106,107 Other less
established risk fac-tors for stroke include unstable INR and low
TTR in patients treatedwith a VKA; previous bleed or anaemia;
alcohol excess and othermarkers for decreased therapy adherence;
chronic kidney disease;elevated high-sensitivity troponin; and
elevated N-terminal pro-B-type natriuretic peptide.2 Some have been
incorporated into morerecent stroke scores proposed for AF, such as
the ATRIA(AnTicoagulation and Risk factors In Atrial fibrillation),
QStroke, andABC-stroke scores.108–110 Biomarker-based stroke risk
scores (e.g.ABC score) do not appear to confer long-term benefit
over simpleclinical scores such as CHA2DS2-VASc.
111,112 In addition, stroke riskis not static, and regular
review and reassessment of risk is neededduring
follow-up.113,114
In the CHA2DS2-VASc score, the V criterion for ‘vascular
disease’is defined as ‘previous MI, peripheral artery disease, or
aortic plaque’,since these are factors, which are more validated to
confer anexcess of stroke risk in patients with AF. Patients with
mild coronaryatheroma alone, or simply a history of angina, have
not been defini-tively shown to have an excess of stroke risk if no
other CHA2DS2-VASc risk factors are present (hence do not score a
point for theV criterion). Patients with a CHA2DS2-VASc score of
>_1 for menor >_2 for women are likely to benefit from stroke
preventionwith specific treatment decisions for type and duration
of associa-tions of antithrombotic agents based on the clinical
setting and pa-tient profile (elective PCI or ACS, risk factor for
CAD progression,and coronary events, risk of bleeding) possibly
incorporating patientpreferences.
Clinical risk scores for bleedingSeveral bleeding risk scores
have been developed, mainly in patientson VKAs. These include
HAS-BLED [hypertension, abnormal renal/liver function (1 point
each), stroke, bleeding history or predisposi-tion, labile INR,
elderly (>65 years), drugs/alcohol concomitantly(1 point each)],
ATRIA, ORBIT (Outcomes Registry for BetterInformed Treatment of
Atrial Fibrillation), and more recently, theABC (age, biomarkers,
clinical history) bleeding score, which includesselected
biomarkers.115–118 While stroke and bleeding risks correlatewith
each other, the HAS-BLED score is a superior predictor of
bleeding risk compared with the CHADS2 [congestive heart
failure,hypertension, age, diabetes, stroke (doubled)] or
CHA2DS2-VAScscores.119,120
The simple HAS-BLED score has similar or a superior bleeding
riskassessment to other proposed scores, some of which are more
com-plex.121–123 This is particularly evident amongst VKA users,
given thatother scores (HEMORRH2AGES, ATRIA, ORBIT) do not
considerquality of anticoagulation control, i.e. labile INR as a
bleedingrisk.124,125 In another trial cohort, the ORBIT score
demonstratedthe best discrimination and calibration when tested in
the RE-LY(Randomized Evaluation of Long-term anticoagulant therapY
withdabigatran etexilate) trial, whereby all the scores
demonstrated, to avariable extent, an interaction with bleeding
risk associated with dabi-gatran or warfarin.126 On the other hand,
the biomarker-based ABCbleeding risk score did not appear to confer
long-term benefit over amore simple clinical score such as
HAS-BLED.112,127 Similarly, thePRECISE DAPT score has been
developed to assess the out-of-hospital bleeding risk in patients
in whom DAPT but not OAC is indi-cated; however, this score
currently does not provide useful informa-tion on the additional
bleeding risk in patients in whom both OACand DAPT are
concomitantly indicated.128
Of note, the HAS-BLED, ORBIT, and ABC scores have also
beenvalidated in patients on NOACs.126,129 The HAS-BLED score
hasbeen validated in patients with CAD treated with coronary
sten-ting.130,131 A high bleeding risk score should generally not
result inwithholding OAC, and is appropriately used to ‘flag up’
patients athigh risk of bleeding (HAS-BLED score >_3) for more
regular reviewand earlier follow-up.
Of importance, modifiable bleeding risk factors (e.g.
uncontrolledblood pressure, concomitant antiplatelet or NSAID use,
alcohol ex-cess) should always be identified and corrected at every
patient con-tact. In addition, bleeding risk is not static, and
regular review andreassessment of risk is needed during follow-up,
especially since anadverse change in (say) HAS-BLED score is
associated with excessivebleeding risk particularly in the initial
3 months.132
When managing patients with AF undergoing PCI/stenting, it is
rec-ommended to concomitantly assess stroke, bleeding, and
ischaemicevent risks (using validated tools such as the REACH,
Syntax, andGRACE scores6,133–135) A recent retrospective analysis
confirmedthe value of the Syntax and GRACE scores for identifying
higher risksof coronary events and mortality, respectively, in AF
patients withcoronary stenting.106
What is the practical application of formal bleeding risk
assess-ment? An approach based only on modifiable bleeding risk
factorsalone is an inferior assessment compared with a formal
bleeding riskscore.119,136,137 A high (uncorrectable) bleeding risk
may flag up thepatient for earlier review and follow-up (e.g. 4
weeks rather than 4–6 months), as well as lead to shortening of TAT
with earlier switch toDAT in case of estimated low atherothrombotic
risk as calculatedwith the Syntax or REACH score, although
prospective validation ismissing in such combination scenarios. A
similar clinical setting maylead to the decision to discontinue all
antiplatelets and provide anti-coagulation as monotherapy earlier
(e.g. after 6 months instead of1 year).2,6 In the small subset of
AF patients undergoing PCI with ele-vated bleeding risk and a
relatively low stroke risk (CHA2DS2-VAScof one in males or two in
females), one option would be to treat withonly DAPT, without OACs,
from the onset (although in ACTIVE-W,
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there were numerically more MIs with aspirin plus clopidogrel
com-pared with warfarin).138
The TIMI-AF score has recently been proposed in
VKA-naivepatients with AF to assist in the prediction of a poor
composite out-come and guide selection of anticoagulant therapy by
identifying a dif-ferential clinical benefit with a NOAC or VKA.139
This complexscore includes 11 items (including a history of MI)
with a maximum in-teger score of 17 and needs to be more
specifically validated in AFpatients with ACS and/or undergoing
percutaneous coronary orvalve interventions. In a ‘real world’
cohort of VKA-experienced AFpatients, the TIMI-AF score was found
to have limited usefulness inpredicting net clinical outcomes over
a long-term period of follow-upand was not superior to CHA2DS2-VASc
and HAS-BLED for identify-ing low-risk AF patients.140 Another
simple score, the 2MACE [twopoints for Metabolic Syndrome and Age
>_75; one point for MI/revas-cularization, Congestive heart
failure (ejection fraction 2.0, in whom total and major BARC
bleed-ing and need for transfusions was significantly lower with
radial whencompared with femoral approach.150
Limited data are available for AF patients undergoing PCI while
onNOAC. In the phase IIa, multicentre D-fine clinical trial, 50
patientsundergoing elective PCI were randomized to either
pre-proceduraldabigatran 110 or 150 mg bid or standard
intra-procedural UFH.151
Following PCI, dabigatran appeared to provide insufficient
anticoagu-lation, as shown by significantly higher values compared
with UFH ofprothrombin fragment 1þ 2 and thrombin-antithrombin
complex-es.152 Clinical outcomes tended to be higher in the
dabigatran group,where 5 out of 40 (12.5%) required bail-out
anticoagulation whencompared with 1 out of 10 (10%) in the standard
UFH group.151
No significant bleeding was observed in either group.151
In a phase IIa, multicentre trial (X-plorer), 108 patients
undergoingelective PCI and on stable dual antiplatelet therapy of
aspirin and clo-pidogrel were randomized to a single dose of either
rivaroxaban10 mg, rivaroxaban 20 mg, rivaroxaban 10 mg plus
intravenous bolusof UFH, or standard UFH.152 Patients with an
indication for OACwere excluded. Following PCI, in all groups
receiving rivaroxaban co-agulation was effectively suppressed,
comparably to standard UFH, asshown by the low plasma levels of the
fragment 1þ 2 and thrombin-antithrombin complex.152 No patients in
the three rivaroxaban armsrequired bail-out antithrombotic
medication and/or had clinical signsof catheter-related
thrombosis.152 No significant bleeding was ob-served in either
group up to 30 days after PCI.152
Because of the inconsistency of the results reported with the
twodifferent NOACs (dabigatran and rivaroxaban), performing
elective
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PCI in patients with stable CAD on ongoing uninterrupted
NOACmonotherapy is currently not recommended. Also, uncertainty
onthe true level of anticoagulation with NOAC raises uncertainty
whenthe treatment of a thrombotic complication is needed, e.g.
adminis-tration of glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors153
or the optimaluse of additional UFH.
Whereas intra-procedural anticoagulation with UFH should
becarried out as per usual practice in AF patients on NOAC,
uncer-tainty exists on whether additional UFH should be given to
patientson OAC with VKA undergoing PCI while the INR is >2.0. In
a case–control study on 336 patients undergoing transradial
coronary angi-ography either on therapeutic warfarin or standard,
intra-proceduralUFH, the incidence of both early (24-h) and late
(30-day) radial arteryocclusion was significantly higher in the
ongoing warfarin group,154
thereby supporting the addition of UFH also in VKA patients.
Giventhat doses as low as 30–50 U/kg have been shown effective in
pre-venting ischaemic complications related to PCI,155 they should
bepreferred with the aim of limiting the risk of bleeding. When
coro-nary angiography is performed through the femoral approach,
(low-dose) UFH should likely be added only if PCI is carried out,
given theuncertainty on the degree of protection provided by
ongoing, thera-peutic VKA.156
Whether bivalirudin, which in both stable and ACS patients
hasbeen shown to be associated with a significantly lower rate of
bleed-ing than UFH plus glycoprotein (GPI),157 may be a preferable
optionfor intra-procedural anticoagulation on ongoing effective VKA
is un-certain. Limited, observational data suggest that bivalirudin
may in-deed be preferred, given that the 30-day occurrence of
majorbleeding and MACCE was shown to be lower in 51 patients
receivingbivalirudin (stable CAD in 47%) when compared with 87
treatedwith UFH plus GPI (stable CAD in 15%), who were identified
out of1104 on warfarin undergoing PCI in two study
protocols.158
While there is a general agreement on the need for, at least
initial,TAT of OAC plus DAPT of aspirin and clopidogrel in most
AFpatients undergoing PCI, the optimal timing and schedule for
antipla-telet agents administration is not established. In patients
not on OAC
and stable aspirin therapy, clopidogrel may be administered
eitherprior to or during PCI with no apparent differences in
outcomes withthe two strategies.159 Given that TAT is associated
with an increasedrisk of bleeding, it may be considered to withhold
the additional anti-platelet agent until indication for PCI arises
from diagnostic coronaryangiography.
The time required to reaching effective platelet inhibition with
oralloading of clopidogrel is approximately 2 to 6–8 h, depending
onwhether a 600 or 300 mg dose, respectively, is given,160 as
opposedto either intravenous or oral aspirin, which has a nearly
immediateantiplatelet effect.161 When carried out, pre-treatment
with both as-pirin and clopidogrel should preferably include
loading with 300 mg,given that the slower and less intense platelet
inhibition comparedwith 600 mg162 may reduce the initial risk of
bleeding in patients naiveto antiplatelet therapy and on ongoing
OAC.
No additional data are available on GPI use in AF patients
treatedwith OAC undergoing PCI. As for non-OAC patients with
stableCAD, indication for GPI remains essentially limited to
bail-out situa-tions where however, further care is advised, given
the previouslyreported substantial risk of major bleeding in the
absence of a signifi-cant benefit on MACCE.153 When abciximab is
used, bolus only, ei-ther intracoronary or intravenous, may be
considered because ofpossible superior safety compared with
conventional intravenous bo-lus plus infusion strategy.163 Use of
GPI as per standard practice canbe considered for patients on NOAC
when timely discontinuationbefore PCI has been carried out.
Acute managementNo randomized trials have specifically studied
periprocedural man-agement in anticoagulated patients developing an
ACS and undergo-ing acute angiography with or without PCI. The
following suggestionsare based on observational studies and expert
opinion and are in ac-cordance with recent ESC guidelines.5,164,165
All AF patients takingOAC developing an ACS should receive aspirin
immediately [150–300 mg oral loading dose or 75–150 mg i.v.
(intravenous)].164 To re-duce the risk of bleeding, one option is
to postpone the
....................................................................................................................................................................................................................
Table 3 Summary of main recommendations in recent guidelines
ESC myocardial
revascularization
2017143
ESC
AF 20162ACC/AHA
2016 combined
OAC/APT144
ESC 2017
DAPT
update5
Use of periprocedural aspirin and clopidogrel � � � þþPreferred
use of DES þþ � þþRecommendations according to the type of platform
(DES vs. BMS) n/a � þþ n/aUse of ticagrelor or prasugrel � � � �Use
of specific score for ischaemic or bleeding risks þþ n/a n/a
n/aDAPT as an alternative to TAT in CHA2DS2-VASc score
-
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Tab
le4
Su
mm
ary
ofth
ean
tith
rom
bo
tic
man
agem
en
td
iffe
ren
ces
betw
een
aV
KA
an
dN
OA
Cin
pati
en
tsu
nd
erg
oin
gele
cti
ve
PC
I
VK
AN
OA
C
Peri
proc
edur
alm
anag
emen
t
Ant
icoa
gula
tion
(see
Figu
re1)
Beca
use
ofth
ere
duce
dri
skof
blee
ding
,VK
Ash
ould
not
bein
terr
upte
d(o
r
brid
ged
with
hepa
rin)
.
Elec
tive
PCI
•Be
caus
eof
the
unde
fined
intr
a-pr
oced
ural
prot
ectio
nag
ains
tth
rom
-
botic
even
tsof
NO
AC
,tim
ely
(12–
24h
inad
vanc
e,ba
sed
onre
nal
func
tion
and
agen
t)in
terr
uptio
nis
pref
erre
d.•
Dep
endi
ngon
rena
lfun
ctio
nan
dag
ent
used
(e.g
.Dab
igat
ran
has
high
rena
ldep
ende
ncy
for
itsex
cret
ion)
,ces
satio
nfo
r24
–48
hm
aybe
cons
ider
ed.
•N
obr
idgi
ngis
reco
mm
ende
d.
Emer
genc
yPC
I•
NO
AC
sne
edno
tto
bein
terr
upte
d.
Vas
cula
rac
cess
Beca
use
ofth
ere
duce
dri
skof
acce
ss-s
itebl
eedi
ngco
mpl
icat
ions
,the
radi
alap
proa
chsh
ould
bepr
efer
red.
Add
ition
alin
tra-
proc
edur
alU
FHT
opr
even
tra
dial
arte
ryoc
clus
ion,
and
poss
ibly
limit
the
occu
rren
ceof
intr
a-
proc
edur
alth
rom
botic
com
plic
atio
ns,U
FHsh
ould
bead
min
iste
red.
Whe
ther
NO
AC
isin
terr
upte
dor
not,
UFH
shou
ldbe
adm
inis
tere
das
per
usua
lpra
ctic
e
Dos
eof
addi
tiona
lint
ra-p
roce
dura
l
UFH
To
limit
the
risk
ofbl
eedi
ng(in
ongo
ing
VK
A),
redu
ced
dose
(30–
50U
/kg)
shou
ldbe
give
n.
Stan
dard
dose
UFH
(70–
100
U/k
g)sh
ould
begi
ven
Use
ofbi
valir
udin
Beca
use
ofth
eob
serv
atio
nof
supe
rior
safe
ty,a
ndpo
ssib
lyal
soef
ficac
y,it
may
beco
nsid
ered
inac
cord
ance
with
pres
crib
ing
labe
l.Spe
cific
data
in
patie
nts
onO
AC
are
limite
d.
P2Y
12-r
ecep
tor
inhi
bito
rBe
caus
eof
pote
ntia
linc
reas
edri
skof
blee
ding
with
pras
ugre
land
ticag
relo
rin
stab
leC
AD
patie
nts
onO
AC
,clo
pido
grel
isge
nera
llyre
com
men
ded.
•C
onsi
der
pre-
trea
tmen
tw
ithat
leas
ton
ean
tipla
tele
tag
ent
inm
ost
case
s.•
Whe
reco
rona
ryan
atom
yis
know
nor
inem
erge
ncy
case
s,w
here
bya
de-
cisi
onfo
rPC
Iis
likel
y,pr
e-tr
eatm
ent
with
aP2
Y12-
rece
ptor
inhi
bito
rca
n
beco
nsid
ered
.•
Smal
lnum
bers
ofpr
asug
relw
ere
used
inth
ePI
ON
EER
-AF
tria
l.In
RED
UA
L-PC
I,12
%w
ere
pres
crib
edtic
agre
lor,
whi
chdi
dno
tsh
owex
cess
blee
dsw
hen
used
with
dabi
gatr
anas
DA
T.
Dos
eof
P2Y
12-r
ecep
tor
inhi
bito
rBe
caus
ecl
opid
ogre
lsho
uld
begi
ven
inad
vanc
eof
PCI,
300
mg
load
ing
shou
ld
gene
rally
bepr
efer
red
tolim
itth
eri
skof
blee
ding
(with
ongo
ing
VK
A).
Whe
ther
NO
AC
isin
terr
upte
dor
not,
300
or60
0m
glo
adin
gdo
se
shou
ldbe
sele
cted
aspe
rus
ualp
ract
ice
due
tolim
ited
data
.
Use
ofG
PIBe
caus
eof
the
obse
rved
incr
ease
inm
ajor
blee
ding
,with
nobe
nefit
inis
chae
-
mic
outc
omes
,GPI
shou
ldno
tbe
used
,exc
ept
for
bail-
out,
inlif
e-th
reat
en-
ing
situ
atio
ns.
Beca
use
ofth
eob
serv
edin
crea
sein
maj
orbl
eedi
ng,w
ithno
bene
fitin
is-
chem
icou
tcom
es,G
PIsh
ould
not
beus
ew
here
NO
AC
sar
eun
inte
r-
rupt
ed,e
xcep
tfo
rba
ilou
t,in
life-
thre
aten
ing
situ
atio
ns.
Use
ofG
PIas
per
stan
dard
prac
tice
can
bem
ade
for
patie
nts
onN
OA
Cw
hen
timel
ydi
scon
tinua
tion
befo
rePC
Ihas
been
carr
ied
out.
Cont
inue
d
EHRA Consensus Document Page 13 of 27D
ownloaded from
https://academic.oup.com
/europace/advance-article-abstract/doi/10.1093/europace/euy174/5056658
by guest on 16 September 2018
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Tab
le4
Conti
nued
VK
AN
OA
C
Post
-pro
cedu
ralm
anag
emen
t
Ant
ithro
mbo
ticre
gim
en
Inte
nsity
ofO
AC
Inpa
tient
son
TA
T,I
NR
atth
elo
wer
end
ofth
erap
eutic
rang
e(2
.0–2
.5)
shou
ld
beta
rget
ed,w
ithhi
ghT
TR
(>65
–70%
).
With
DA
T,c
onve
ntio
nalt
hera
peut
icra
nge
(2.0
–3.0
)m
aybe
targ
eted
,with
high
TT
R(>
65–7
0%).
Low
dose
dabi
gatr
an11
0m
gbi
dan
dfu
lldo
seap
ixab
an5
mg
bid
and
edox
-
aban
60m
god
shou
ldbe
sele
cted
toop
timiz
eri
sk-b
enefi
tra
tio,i
fpar
tof
aT
AT
regi
me.
With
DA
T,d
abig
atra
n15
0m
gpl
usP2
Y12
ispr
efer
red,
unle
ssdo
sere
duc-
tion
crite
ria
for
dabi
gatr
anar
epr
esen
tin
acco
rdan
cew
ithits
labe
l.
Red
uced
Low
dose
riva
roxa
ban
15m
god
rath
erth
anfu
lldo
se20
mg
od
may
beco
nsid
ered
tore
duce
the
risk
ofbl
eedi
ng.
Pend
ing
furt
her
data
inth
ePC
Iset
ting,
redu
ced
dose
apix
aban
and
edox
a-
ban
are
only
used
inac
cord
ance
with
thei
rre
spec
tive
appr
oved
labe
ls.
Inte
nsity
ofO
AC
duri
ngsu
bseq
uent
antit
hrom
botic
regi
men
afte
r12
mon
ths
Tar
get
INR
shou
ldbe
2.0–
2.5
afte
rw
ithdr
awal
ofon
ean
tipla
tele
tag
ent,
with
high
TT
R(>
65–7
0%).
Aft
erw
ithdr
awal
ofon
ean
tipla
tele
tag
ent,
full
dose
apix
aban
5m
gbi
dan
d
edox
aban
60m
god
shou
ldbe
used
,whe
reas
redu
ced
dose
riva
roxa
ban
15m
god
s
