Journal of Cardiology 76 (2020) 35–43

Contents lists available at ScienceDirect

Journal of Cardiology
journal homepage: www.elsevier.com/locate/jjcc

Review

Antithrombotic therapy in atrial fibrillation patients with coronary

artery disease: shifting paradigm to a “less is more” concept regimen
Shoji Kawakami (MD, PhD)a,b, Satoshi Yasuda (MD, PhD, FJCC)b,*,
Hisao Ogawa (MD, PhD, FJCC)b
a
Department of Cardiology, Aso Iizuka Hospital, Fukuoka, Japan
b
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Dual antiplatelet therapy (DAPT) reduces the risk of ischemic events, including stent thrombosis, in
Received 1 March 2020 patients undergoing percutaneous coronary intervention (PCI), while oral anticoagulants are superior to
Accepted 2 March 2020 antiplatelet therapy for preventing thromboembolic events, including ischemic stroke, in patients with
Available online 8 May 2020
atrial fibrillation (AF). Reportedly, the AF population accounts for approximately 5 to 10% of patients
undergoing PCI. From a theoretical viewpoint, combination therapy of DAPT and oral anticoagulation was
Keywords: previously recommended in patients with AF undergoing PCI. However, long-term triple therapy carries
Antithrombotic therapy
the risk of major bleeding. Recent clinical trials (WOEST, PIONEER AF-PCI, RE-DUAL PCI, AUGUSTUS, and
Atrial fibrillation
ENTRUST AF-PCI trials) demonstrated the advantage of dual therapy with an oral anticoagulant (warfarin
Coronary artery disease
or direct oral anticoagulant) plus an antiplatelet agent, which decreased the rate of major bleeding in the
acute phase in AF patients who underwent PCI. These results affected guidelines, which now recommend
that the duration of triple therapy should be limited, and dual therapy should be considered an
alternative regimen when considering the bleeding risk. The current guidelines recommend
monotherapy with an oral anticoagulant after 12 months of combination therapy, or in patients with
AF and stable coronary artery diseases not requiring intervention. However, this approach has yet to be
validated by randomized, controlled trials. Recently, the AFIRE trial demonstrated that rivaroxaban
monotherapy was noninferior to dual therapy in terms of efficacy and superior in terms of safety in this
population. Accumulating evidence demonstrates that there has been a paradigm shift in antithrombotic
therapy to a “less is more” regimen. This article reviews current evidence and focuses on the optimal
approach to antithrombotic treatment in patients with AF undergoing PCI in acute and chronic/stable
phases.
© 2020 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.

Contents

Coexistence of atrial fibrillation and coronary artery disease in a sizable population. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Bleeding risk with the combination therapy of oral anticoagulants plus single or dual antiplatelet agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Vitamin K antagonist-based strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Direct oral anticoagulant-based strategies and their clinical advantages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Risk stratification of bleeding and ischemic events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Timing of switching from triple therapy to dual therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Monotherapy with an oral anticoagulant in patients with atrial fibrillation and stable coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . 40
Gaps in evidence and future studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

* Corresponding author at: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan.

https://doi.org/10.1016/j.jjcc.2020.03.001
0914-5087/© 2020 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
36 et al. / Journal of Cardiology 76 (2020) 35–43
Introduction
With the aging of society, the prevalence of atrial fibrillation (AF)
has been increasing [1–3], because AF occurs more frequently in
elderly patients who often have several risk factors for atheroscle-
rotic diseases. Antiplatelets are administered to minimize ischemic
events including stent thrombosis in patients with coronary artery
disease (CAD), while anticoagulants are prescribed in patients with
AF to minimize thrombotic events including stroke. In some patients,
AF and CAD coexist, and such patients require a combination of both
oral anticoagulants and antiplatelet therapies. A multi-targeted,
more antithrombotic-based treatment strategy, addressing both
platelet- and coagulation-mediated mechanisms of thrombosis, is
necessary for ensuring full protection from the risk of ischemia. Such
a therapy, however, carries a greater risk of bleeding events. The
increased bleeding risk identified with triple antithrombotic therapy
[anti-coagulant plus dual anti-platelet therapy (DAPT)] has driven
research on alternative treatment modalities and combination
pharmacological strategies aimed at balancing the benefits and risks
of such therapy in this complex clinical scenario. Over the past
several years, the paradigms surrounding the management of
patients with AF and CAD have substantially evolved. New
antithrombotic regimens based on the concept of “less is more”
have been supported by randomized controlled trials. This article
reviews current evidence and focuses on the optimal approach to
antithrombotic treatment in patients with AF undergoing PCI in
acute and chronic/stable phases.
Coexistence of atrial fibrillation and coronary artery disease in
a sizable population
The relationship between AF and CAD disease has been reported.
In the Fushimi AF registry, which consisted of a community-based
survey of Japanese AF patients, the prevalence of CAD, previous
myocardial infarction and previous percutaneous coronary inter-
vention (PCI) in AF patients was 15.0%, 6.4%, and 7.6%, respectively
[4]. In the PREFER in AF registry (Prevention of thromboembolic
events - European Registry in Atrial Fibrillation), which was designed
as a prospective observational study and enrolled consecutive AF
patients at multiple centers from seven European countries, the
prevalence of CAD, previous myocardial infarction, and prior stenting
in AF patients was 23.4%, 10.7% and 10.2%, respectively [5].
In the CREDO-Kyoto (Coronary REvascularization Demonstrat-
ing Outcome Study in Kyoto) registry Cohort-2, which was a
multicenter registry in Japan, the prevalence of AF was 8.3% in
patients undergoing first coronary revascularization [6]. In the
REACH (Reduction of Atherothrombosis for Continued Health)
registry, which was an international, prospective, observational
registry that enrolled stable outpatients with or at a high risk of
atherothrombosis, AF was found in 12.5% of enrolled patients with
CAD, and was associated with a major increase in cardiovascular
mortality and morbidity [7]. The annual incidence of non-fatal
stroke (AF: 2.4% vs. non-AF: 1.6%, p < 0.01), unstable angina (AF:
6.0% vs. non-AF: 4.0%, p < 0.01) and cardiovascular death (AF: 3.2%
vs. non-AF: 1.4%, p < 0.01) was higher in AF patients as compared to
non-AF patients.
AF and CAD share a number of pathophysiological mechanisms,
particularly in an aging society, which are reflected in the
coexistence of CAD and AF in a sizable proportion of the
population.
Bleeding risk with the combination therapy of oral
anticoagulants plus single or dual antiplatelet agents
Patients undergoing PCI require DAPT, consisting of aspirin and
an inhibitor of P2Y12, a chemoreceptor for adenosine diphosphate,
to reduce the risk of ischemic or atherothrombotic events,
including stent thrombosis, recurrent myocardial infarction, and
cardiovascular death. However, DAPT is less effective in reducing
the incidence of stroke associated with AF [8]. If patients
undergoing PCI are indicated for oral anticoagulation, the
combination therapy of DAPT and an anticoagulant (i.e. triple
therapy) has been theoretically recommended (Table 1).
This triple therapy is reportedly associated with a three- to four-
fold increased risk of bleeding. In Denmark, all citizens have a
unique personal registration number that enables nationwide
cross-linking of data related to hospitalizations, medications, and
death. Using this registry, Hansen et al. studied AF patients
surviving first-time hospitalization between 1997 and 2006. They
found that patients receiving dual therapy of clopidogrel plus a
vitamin K antagonist, i.e. warfarin, and triple therapy with aspirin,
clopidogrel, and warfarin demonstrated a more than three-fold
higher bleeding risk than those receiving warfarin monotherapy
[9]. Sorensen et al. also analyzed this registry between 2000 and
2005 and assessed the risk of hospital admission due to bleeding in
patients with first-time myocardial infarction treated with
antithrombotic agents [10]. With aspirin as a reference, the
adjusted hazard ratios for bleeding were 1.33 for clopidogrel,
1.23 for warfarin, 1.47 for aspirin plus clopidogrel, 1.84 for aspirin
plus warfarin, 3.52 for clopidogrel plus warfarin, and 4.05 for triple
therapy. The risk of bleeding increased with the number of
antithrombotic agents.
The BAT (Bleeding with Antithrombotic Therapy) study was a
multicenter study conducted in Japan between 2003 and 2006 that
enrolled 4009 patients who were treated with oral antithrombotic
agents for stroke and cardiovascular diseases [11]. The annual
incidence of life-threatening or major bleeding risk was 1.21% in
the single antiplatelet agent group, 2.00% in the DAPT group, 2.06%
in the warfarin group, and 3.56% in the dual therapy of warfarin
plus an antiplatelet agent group (p < 0.001). Uchida et al. reported
that triple therapy of warfarin plus DAPT increased hemorrhagic
complications in patients after PCI with drug-eluting stents,
especially in patients with impaired renal function [12].
Dual therapy (antiplatelet plus anticoagulant therapy) and
triple therapy were independently associated with an increased
risk of bleeding events in both Japan and Western countries.
Therefore, the optimal combination, intensity, and duration of
combination antithrombotic therapy still needs determination.
Vitamin K antagonist-based strategies
For AF patients undergoing PCI, two important factors need
consideration. First, the risk of stent thrombosis might increase
due to premature discontinuation of DAPT, especially in the early
phase after coronary stenting. Second, the risk of bleeding with
triple therapy increases with the duration of therapy. Recently, it
has been shown that new-generation drug-eluting stents are
associated with a significant reduction of stent thrombosis in
patients after PCI [13]. Moreover, direct oral coagulants (DOACs)
have shown greater efficacy and safety as compared to the
conventional oral anticoagulant, warfarin, in AF patients [14]. In
view of all these facts, controversy remains on how to balance the
risks and benefits of anti-thrombotic therapy in patients with CAD
Table 1
Pattern of combination therapy with antiplatelet agents and an anticoagulant.
Combination therapy Anticoagulant Aspirin P2Y12 inhibitor
Triple therapy * * *
Dual therapy * *
* *
Dual antiplatelet therapy * *
 et al. / Journal of Cardiology 76 (2020) 35–43 37

and AF for whom multiple therapies might be indicated.
The ‘What is the Optimal antiplatElet and anticoagulant therapy
in patients with oral anticoagulation and coronary StenTing’
(WOEST) trial, which was an open-label, randomized, controlled
trial at 15 sites in the Netherlands and Belgium between 2008 and
2011 (n = 573), showed that dual therapy of clopidogrel plus
warfarin administered to patients taking warfarin who require PCI
was associated with a significantly lower rate of bleeding
complications at 1 year, as compared to triple therapy with aspirin,
clopidogrel, and warfarin (19.4% vs. 44.4%, HR 0.36, 95% CI 0.26–
0.50, p < 0.0001) [15]. Moreover, a composite secondary endpoint
of death, myocardial infarction, stroke, target-vessel revasculari-
zation, and stent thrombosis was reported in 11.1% of patients in
the dual therapy group and 17.6% patients in the triple therapy
group (p = 0.025). Although the bleeding rate in this trial could be
viewed as high compared with other studies because of several
significant reasons, including specific study design to assess
bleeding events as an endpoint [defined as all bleeding events
according to Thrombolysis in Myocardial Infarction (TIMI) criteria],
prolonged duration of clopidogrel therapy, low frequency of
proton-pump inhibitor usage, and the low frequency of radial
access for PCI, what this study indicated to us was that
discontinuation of antiplatelet therapy in response to bleeding
events might instead lead to an increase in the risk of thrombotic
complications and death. Considering the observation that dual
therapy with warfarin and clopidogrel without aspirin did not
significantly increase the thrombotic risk in this study, the authors
suggested that inhibition of thrombin by warfarin and of P2Y12 by
Table 2
Trials that compared triple therapy and dual therapy in patients with atrial fibrillation or other indications for an oral anticoagulant, and undergoing percutaneous coronary
interventions.
clopidogrel would be more beneficial than inhibition of cyclo-
oxygenase-1 by aspirin.
Direct oral anticoagulant-based strategies and their clinical
advantages
Since the WOEST trial with vitamin K antagonist-based
strategies, the efficacy and safety of the regimen of DOAC plus
an antiplatelet agent in place of triple therapy have been
established, because DOACs are associated with the advantages
of decreased risk of stroke and thromboembolic events, as well as
reduced incidence of major bleeding events, as compared to
warfarin in non-valvular AF patients. Four international, random-
ized controlled trials have shown the safety and efficacy of dual
therapy consisting of standard or reduced doses of DOACs plus a
P2Y12 inhibitor in AF patients who underwent PCI (Table 2).
However, these trials focused on bleeding as the primary endpoint
and were underpowered to address the relatively low incidence of
ischemic/thromboembolic events, including stroke, re-infarction,
and stent thrombosis.
The PIONEER AF-PCI (Open-Label, Randomized, Controlled,
Multicenter Study Exploring Two Treatment Strategies of Rivar-
oxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment
Strategy in Subjects with Atrial Fibrillation who Undergo
Percutaneous Coronary Intervention) trial, in which 2124 non-
valvular AF patients who had undergone PCI were enrolled
between 2013 and 2015, showed that either low-dose rivaroxaban
(15 mg oncedaily or 10 mg once daily for patients with renal

WOEST PIONEER AF-PCI RE-DUAL PCI AUGUSTUS ENTRUST-AF PCI

Period of patient 2008-2011 2013-2015 2014-2016 2015-2018 2017-2018

enrollment
Actual number of 573 2124 2725 4614 1506
patients enrolled
Study location Belgium and Netherlands International International International International
Indication for oral Long-term need for oral Non-valvular AF Non-valvular AF Non-valvular AF Non-valvular AF
anticoagulant anticoagulation (AF/atrial
flutter, 69%; mechanical
valve, 10%)
Regimen of (1) Warfarin, clopidogrel, and (1) Warfarin, (1) Warfarin, P2Y12 2
2 factorial design (1) Edoxaban plus
antithrombotic aspirin (2) Warfarin and clopidogrel, and aspirin inhibitor (clopidogrel (1) Warfarin and P2Y12 P2Y12 inhibitor
agents clopidogrel (2) Low dose 90.3%, ticagrelor, 7.8%), inhibitor (clopidogrel, (clopidogrel, 93%)
rivaroxaban (15/10 mg and aspirin (2) Full- 93%) vs. apixaban and (2) Warfarin,
SID) and clopidogrel (3) dose dabigatran P2Y12 inhibitor P2Y12 inhibitor
Very low dose (150 mg BID) and (clopidogrel, 92%) (2) (clopidogrel,
rivaroxaban (2.5 mg P2Y12 inhibitor Warfarin, P2Y12 92%), and aspirin
BID), clopidogrel, and (clopidogrel, 86.9% or inhibitor (clopidogrel,
aspirin ticagrelor, 12.1%) 3) Low 92%) and aspirin vs.
dose dabigatran apixaban, P2Y12
(110 mg BID) and P2Y12 inhibitor (clopidogrel,
inhibitor (clopidogrel, 93%) and placebo
86.4% or ticagrelor,
12.6%)
Timing of <4 hours after PCI <72 hours after PCI <120 hours after PCI <14 days after PCI or 4 hours to 5 days
randomization having an ACS after PCI
Primary endpoint Any bleeding episode Major bleeding or Major or clinically Major or clinically Major or
(TIMI, GUSTO, and BARC minor bleeding (TIMI relevant non-major relevant non-major clinically relevant
criteria) criteria) or bleeding bleeding event (ISTH bleeding (ISTH criteria) non-major
requiring medical criteria) bleeding (ISTH
attention criteria)
PCI performed 100% 100% 100% 76% 100%
ACS 28% 52% 51% 60% 52%
Target range of INR Depended on underlying 2.0-3.0 2.0-3.0 2.0-3.0 2.0-3.0
disease
Time in the - 65% 64% 59% 63%
therapeutic INR range

AF, atrial fibrillation; SID, once daily; BID, twice daily; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction; GUSTO, Global Utilization of
Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; BARC, Bleeding Academic Research Consortium; ISTH, International Society on
Thrombosis and Haemostasis; ACS, acute coronary syndrome; INR, international normalized ratio.
38 et al. / Journal of Cardiology 76 (2020) 35–43
dysfunction defined as creatinine clearance of 30–50 ml/min) plus
a P2Y12 inhibitor for 12 months, or very-low-dose rivaroxaban
(2.5 mg twice daily) plus DAPT for 1, 6, or 12 months was associated
with a lower rate of clinically significant bleeding compared with
triple therapy with warfarin plus DAPT for 1, 6, or 12 months [16].
The rates of clinically significant bleeding, defined as a composite
of major bleeding or minor bleeding according to TIMI criteria, or
bleeding requiring medical attention were 16.8% in the low-dose
rivaroxaban group, 18.0% in the very-low-dose rivaroxaban group,
and 26.7% in the triple therapy group, respectively. The rates of
major adverse cardiovascular events, including death from
cardiovascular causes, myocardial infarction, or stroke, were
similar in the three groups. Although very-low-dose rivaroxaban
in patients with acute coronary syndrome who receive DAPT is
known to be associated with lower rates of death from
cardiovascular causes, myocardial infarction and stroke as
compared to those who receive DAPT alone, this regimen has
not received approval for prescription in Japan.
The RE-DUAL PCI (Randomized Evaluation of Dual Antithrom-
botic Therapy with Dabigatran versus Triple Therapy with Warfarin
in Patients with Nonvalvular Atrial Fibrillation Undergoing
Percutaneous Coronary Intervention) trial was conducted to
compare dual therapy of dabigatran (110 mg or 150 mg twice
daily) plus a P2Y12 inhibitor versus triple therapy with warfarin
plus DAPT among 2725 AF patients who underwent PCI [17]. The
risk of major or clinically relevant non-major bleeding events
[defined as all bleeding events according to International Society
on Thrombosis and Haemostasis (ISTH) criteria] in the dual therapy
group was significantly lower than that with triple therapy with
warfarin (110 mg dual therapy vs. triple therapy, 15.4% vs. 26.9%;
150 mg dual therapy vs. corresponding triple therapy, 20.2% vs.
25.7%). Dual therapy was non-inferior to triple therapy with
respect to the risk of thromboembolic events, including myocardial
infarction and stroke, systemic embolism, death, or unplanned
revascularization.
The AUGUSTUS (A Study of Apixaban in Patients With Atrial
Fibrillation, not Caused by a Heart Valve Problem, who are at Risk
for Thrombosis due to Having had a Recent Coronary Event, Such as
a Heart Attack or a Procedure to Open the Vessels of the Heart) trial,
which was a two-by-two factorial, randomized, controlled clinical
trial, assessed the safety and efficacy of standard-dose apixaban
(5 mg twice daily) compared with warfarin, and of aspirin
compared with a placebo, against a background of concomitant
P2Y12 inhibitor therapy for 6 months in 4614 AF patients with
recent acute coronary syndrome or PCI [18]. The prevalence of
major or clinically relevant non-major bleeding (defined as all
bleeding events according to ISTH criteria) was significantly
decreased in patients receiving apixaban as compared to those
receiving warfarin (10.5% vs. 14.7%) and in patients receiving
placebo as compared to those receiving aspirin (9.0% vs. 16.1%).
Apixaban led to a lower incidence of the composite of death and
hospitalization than warfarin, but had a similar incidence of
ischemic events. Avoiding aspirin resulted in a 47% lower risk of
bleeding as compared to using aspirin, without a significant
increase in the incidence of ischemic coronary events.
The ENTRUST-AF PCI (Edoxaban Treatment Versus Vitamin K
Antagonist in Patients With Atrial Fibrillation Undergoing Percu-
taneous Coronary Intervention) trial showed that dual therapy
with an edoxaban-based regimen (edoxaban 60 mg once daily) was
non-inferior in terms of bleeding compared with warfarin-based
triple therapy in 1506 AF patients who successfully underwent PCI
[19]. The annualized event rate of major or clinically relevant non-
major bleeding events (defined as all bleeding events according to
ISTH criteria) with the edoxaban-based regimen was significantly
smaller than that with a warfarin-based regimen (20.7% vs. 25.6%).
There were no significant differences in the composite outcomes of
cardiovascular death, stroke, systemic embolic events, myocardial
infarction, and definite stent thrombosis between the two groups.
The results of these trials have cumulatively added strength to
the concept that dual therapy of DOAC and a P2Y12 inhibitor
without aspirin might be associated with improved safety in terms
of bleeding in AF patients who undergo PCI. Indeed, the recent
network meta-analysis (n = 10 026) including four randomized
studies (WOEST, PIONEER AF-PCI, RE-DUAL PCI, and AUGUSTUS)
demonstrated that strategies omitting aspirin caused less bleeding,
including intracranial bleeding, without significant difference in
major adverse cardiac events, compared with strategies including
aspirin [20]. A regimen of triple therapy with oral anticoagulant
plus DAPT should be avoided as routine practice.
Risk stratification of bleeding and ischemic events
From the accumulated evidence of prior studies, current
guidelines have suggested risk stratification of bleeding and
ischemic events in patients who are indicated for long-term oral
anticoagulant therapy and undergo PCI.
In the 2017 European Society of Cardiology (ESC) focused
update on DAPT in coronary artery disease, developed in
collaboration with the European Association for Cardio-Thoracic
Surgery (EACTS), in which the AUGUSTUS and ENTRUST trials were
unquoted because the results of these trials were not published,
risk stratification and strategies to improve outcomes after PCI in
patients who are indicated for long-term oral anticoagulants were
described [21]. The update first stated that long-term oral
anticoagulants should be reassessed with respect to their
indications, and should be continued only if a compelling
indication exists. Subsequently, the risk factors associated with
ischemic and bleeding outcomes were evaluated using validated
risk predictors, including the CHADS2 score [22], CHADS2-VASc
score [23], ABC bleeding and stroke risk score [24,25], and HAS-
BLED score [26]. The evaluations showed that ischemic risk scores
could also predict bleeding outcomes in non-valvular AF patients
because considerable overlap exists between the risk factors of
ischemic and bleeding outcomes.
The ESC focused update suggested several strategies to avoid
bleeding complications in patients on antithrombotic therapy,
such as: limiting the duration or avoidance of triple therapy,
setting a target international normalized ratio in the lower part of
the recommended target range and maintaining it in the
therapeutic range for a suitable time when using warfarin, use
of DOACs instead of warfarin, considering the approved lower dose
regimen (if it is available) of rivaroxaban or dabigatran, and
application of other DOAC regimens based on drug-specific criteria
for drug accumulation, use of clopidogrel, and avoidance of
prasugrel and ticagrelor as antiplatelet therapy, low-dose aspirin
(100 mg) usage, and routine use of proton pump inhibitors for
gastric protection. Moreover, short life expectancy, ongoing
malignancy, the expectation of poor adherence, poor mental
status, end stage renal failure, advanced age, prior major bleeding,
or prior hemorrhagic stroke, chronic alcohol abuse, anemia, and
clinically significant bleeding on DAPT were considered as
unfavorable patient profiles for the combination of oral anticoag-
ulant and antiplatelet therapy.
Meanwhile, it is important to simultaneously assess ischemic
risk in these patients. The ESC focused update notes the usefulness
of the PRECISE-DAPT score [27] and DAPT score [28] in evaluating
the benefits and risks of different DAPT durations. In addition,
concern about ischemic risk apply to anatomic [(e.g. the SYNTAX
(Synergy Between PCI With Taxus and Cardiac Surgery)] score [29]
and clinical presentation, such as prior stent thrombosis on
adequate antiplatelet therapy, stenting of the last remaining patent
coronary artery, diffuse multivessel disease especially in diabetic
 et al. / Journal of Cardiology 76 (2020) 35–43 39

Fig. 1. Evaluation of high bleeding and ischemic risks in patients treated with combination antithrombotic therapy. AF, atrial fibrillation; ARC, Academic Research Consortium;
HBR, high bleeding risk; BARC, Bleeding Academic Research Consortium; bAVM, brain arteriovenous malformation; CKD, chronic kidney disease; DAPT, dual antiplatelet
therapy; eGFR, estimated glomerular filtration rate; ICH, intracranial hemorrhage; NSAID, nonsteroidal anti-inflammatory drug; PCI, percutaneous coronary intervention.
*Baseline thrombocytopenia is defined as thrombocytopenia before PCI.
y
Active malignancy is defined as diagnosis within 12 months and/or ongoing
requirement for treatment (including surgery, chemotherapy, or radiotherapy).
z
National Institutes of Health Stroke Scale score 5.

patients, chronic kidney disease, implantation of at least three
stents or treatment of at least three lesions, implantation of two
stents at a bifurcation, total stent length >60 mm, and treatment of
a chronic total occlusion. The CREDO-Kyoto risk score was also
established to predict thrombotic and bleeding events after PCI in
Japanese subjects [30].
The ESC focused update recommended that, when considering
appropriate antithrombotic therapy, it is practical to evaluate DAPT
duration by considering bleeding risk first, prioritizing it over
thrombotic risk. The term “East Asian paradox,” which indicates
that bleeding risk might be higher and ischemic risk lower among
East Asians, including Japanese, compared with Caucasians should
also be noted [31]. This shows that particularly in East Asians,
including Japanese, bleeding risk should be the priority in
determining the use of antithrombotic drugs, and the appropriate
antithrombotic regimen should be determined based on a high
bleeding risk.
A lack of standardization in defining high bleeding risk limits
trial interpretation and clinical decision-making. The Academic
Research Consortium for High Bleeding Risk (ARC-HBR) is a
collaboration among leading research organizations, regulatory
authorities, and physician-scientists from the USA, Asia, and
Europe, focusing on PCI-related bleeding on the basis of a literature
review and clinical consensus [32]. High bleeding risk is defined as
a Bleeding Academic Research Consortium (BARC) type 3 or
5 bleeding risk of 4% at 1 year or the risk of an intracranial
hemorrhage of 1% at 1 year. Major and minor criteria for high
bleeding risk at the time of PCI are shown in Fig. 1. The pragmatic
approach proposed by the ARC-HBR consensus could lead to the
development of quality for evaluating the safety and effectiveness
of antithrombotic regimens in this patient population. The ARC-
HBR criteria were applied in the CREDO-Kyoto registry cohort-2,
that enrolled 13 058 consecutive patients who underwent their
first PCI [33]. There were 5570 (43%) patients in the HBR group.
Timing of switching from triple therapy to dual therapy
The WOEST, PIONEER AF-PCI, RE-DUAL PCI, AUGUSTUS, and
ENTRUST-AF PCI trials revealed that dual therapy with clopidogrel
and an oral anticoagulant after PCI could be an alternative to triple
therapy with DAPT and an oral anticoagulant for patients who are
indicated for long-term oral anticoagulation and undergo PCI, but
40 et al. / Journal of Cardiology 76 (2020) 35–43

Fig. 2. Comparison of the guidelines for patients with AF undergoing PCI.

(Left) Recommendation of the JCS 2018 Guideline on Diagnosis and Treatment of Acute Coronary Syndrome [37] and 2018 Guideline on Revascularization of Stable Coronary
Artery Disease. For patients with a high bleeding risk, triple therapy should be continued for up to 1 month or until discharge. Dual therapy should be continued for up to
6 months. After 6 months of dual therapy, switching from dual therapy to oral anticoagulant monotherapy may be considered. For patients with a high ischemic risk, triple
therapy for longer than 3 months and up to 6 months should be considered. Dual therapy should be continued for up to 12 months and monotherapy with an oral
anticoagulant should be considered thereafter. These guidelines note that choice of prasugrel (Japanese maintenance dose of 3.75 mg once daily) as the antiplatelet drug for
dual therapy is permitted, but there are limited data of prasugrel in this situation.
(Middle) Recommendation of the 2017 ESC focused update on DAPT in coronary artery disease developed in collaboration with EACTS [21]. In patients with a high bleeding
risk, triple therapy or dual therapy (clopidogrel is considered preferable) for 1 month should be considered. In patients with a high ischemic risk, triple therapy for longer than
1 month and up to 6 months should be considered.
(Right) Recommendation of the 2018 North American expert consensus update [38]. A double-therapy regimen should be considered as the default strategy immediately
after hospital discharge. It is reasonable to discontinue dual therapy for 6 months after PCI in patients with a bleeding risk. In patients with a high ischemia risk, on the other
hand, it is reasonable to administer triple therapy for up to 1 month after PCI, with continuation of dual therapy for up to 12 months.
AF, atrial fibrillation; PCI, percutaneous coronary intervention; JCS, Japanese Circulation Society; ESC, European Society of Cardiology; DAPT, dual antiplatelet therapy; EACTS,
European Association for Cardio-Thoracic Surgery.

are considered to have a high bleeding risk. The regimen of
cessation of clopidogrel while maintaining aspirin was evaluated
in the ISAR-TRIPLE (Triple Therapy in Patients on Oral Antic-
oagulation After Drug Eluting Stent Implantation) trial, where
614 patients receiving concomitant aspirin and warfarin were
randomized to either 6-week or 6-month triple therapy of
warfarin, aspirin, and clopidogrel [34]. The primary endpoint of
the trial was a composite of death, myocardial infarction, definite
ST elevation, stroke, or TIMI risk score suggestive of major bleeding
at 9 months after randomization. Six weeks of triple therapy was
not superior to six months of therapy with respect to net clinical
outcomes. These results suggest that physicians should carefully
evaluate the trade-off between ischemic and bleeding risk when
choosing between shorter and longer duration triple therapy.
The current guidelines and statements from Western countries
and Japan recommend a roughly similar duration of triple therapy
(Fig. 2). According to the ESC focused update, triple therapy with
aspirin, clopidogrel, plus an oral anticoagulant for longer than
1 month and up to 6 months should be considered in patients with
a high risk of ischemia (Class IIa, LOE B), while 1-month triple
therapy or dual therapy with an antiplatelet drug (clopidogrel is
considered preferable) and oral anticoagulant should be consid-
ered in those with a high bleeding risk (Class IIa, LOE A) [21]. The
2018 European Heart Rhythm Association (EHRA) Practical Guide
on the use of non-vitamin K antagonist oral anticoagulants in
patients with atrial fibrillation, in which the AUGUSTUS trial and
the ENTRUST trial were also unquoted, recommends that triple
therapy should be continued for 1 to 6 months in patients with a
high ischemic risk, and proposed shortening of triple therapy (1 to
7 days or until hospital discharge) in patients with a low ischemic
risk or high bleeding risk [35]. The 2019 American College of
Cardiology/American Heart Association Task Force on Clinical
Practice Guidelines and the Heart Rhythm Society (AHA/ACC/HRS)
Focused Update of the 2014 AHA/ACC/HRS Guideline for the
Management of Patients With Atrial Fibrillation, in which the
AUGUSTUS trial and the ENTRUST trial were quoted, recommends
that a transition from triple therapy to dual therapy at 4 to 6 weeks
may be considered in patients with high ischemic risk (Class IIb, B-
R) [36]. The Japanese Circulation Society (JCS) Guideline on
Diagnosis and Treatment of Acute Coronary Syndrome recom-
mends that dual therapy with an oral anticoagulant and
clopidogrel should be considered at hospital discharge [37].
It should be noted that the recommended timing of switching
from triple therapy to dual therapy, i.e. aspirin removal, varies
among recent clinical trials. Patients were not immediately
randomized to an aspirin-free strategy following the diagnosis
of acute coronary syndrome or the index PCI procedure (Table 2). A
delay of a maximum 3 days after PCI was allowed before
randomization in the PIONEER AF trial, while a delay of up to
5 days was allowed in the RE-DUAL PCI and ENTRUST AF-PCI trials
[16,17,19]. In the AUGUSTUS trial, the mean interval between the
diagnosis of acute coronary syndrome or the index PCI procedure
and randomization was 6 days [18]. Hence, when switching from
triple therapy to dual therapy, we need to consider the potential
risk of stent thrombosis, particularly in the immediate and early
postprocedural phases of acute coronary syndrome and PCI.
Monotherapy with an oral anticoagulant in patients with atrial
fibrillation and stable coronary artery disease
Several statements and guidelines suggested that following
triple therapy, dual therapy should be continued for up to
 et al. / Journal of Cardiology 76 (2020) 35–43 41

12 months, and that monotherapy with an oral anticoagulant
should be considered thereafter [21]. The JCS guideline, and EHRA
and 2018 North American expert consensus update recommend
that switching from dual therapy to monotherapy with an oral
anticoagulant can be considered after 6 months of dual therapy in
patients with a high bleeding risk [35,38] (Fig. 2). However, these
recommendations were based on a report from the nationwide
Danish registry, which enrolled 8700 patients with AF and stable
CAD, defined as 12 months from an acute coronary event, between
2002 and 2011 [39]. Although the thromboembolic risk was
comparable between dual therapy with warfarin plus aspirin or
clopidogrel and monotherapy with warfarin, the bleeding risk was
significantly increased when aspirin (HR 1.50, 95%CI 1.23–1.82) or
clopidogrel (HR 1.84, 95%CI 1.11–3.06) was added to warfarin.
Moreover, in the WARIS II (Warfarin, Aspirin, Reinfarction Study)
trial, which was a randomized, open-label, multicenter study that
enrolled 3630 survivors of acute myocardial infarction between
1994 and 1998, dual therapy with warfarin plus aspirin or warfarin
monotherapy was superior to aspirin monotherapy in reducing the
incidence of composite events, but was associated with a high
bleeding risk, although the prevalence of AF was not revealed and
the study was performed in the non-PCI era [40]. Importantly,
there has been no randomized controlled trial assessing the
efficacy and safety of oral anticoagulant monotherapy in patients
with AF and stable CAD. The limited evidence might be related to
the fact that there is a gap between guidelines and clinical practice.
Indeed, a survey among fellows of the Japanese College of
Cardiology demonstrated that oral anticoagulant monotherapy is
is not popular one year after stent implantation, and that almost
80% of patients were treated with an oral anticoagulant plus a
single antiplatelet [41].
The OAC-ALONE (Optimizing Antithrombotic Care in Patients
with Atrial Fibrillation and Coronary Stent) trial, which was a
prospective, multicenter, open-label trial in Japan, compared
monotherapy with an oral anticoagulant to dual therapy with an
oral anticoagulant plus an antiplatelet agent in patients with AF
and stable CAD at more than 1 year after stenting [42] (Table 3).
Although this trial was designed to enroll 2000 patients in
12 months, enrollment was prematurely terminated after enrolling
696 patients in 38 months. The primary endpoint, consisting of all-
cause death, myocardial infarction, stroke, or systemic embolism,
occurred in 15.7% of patients in the monotherapy group and 13.6%
in the dual therapy group (HR 1.16, 95%CI 0.79–1.72, p = 0.20 for
noninferiority, p = 0.45 for superiority). The occurrence rate of the
major secondary endpoint, consisting of the primary endpoint or
major bleeding, was 19.5% in the monotherapy group and 19.4% in
the dual therapy group (HR 0.99, 95%CI 0.71–1.39, p = 0.016 for
noninferiority, p = 0.96 for superiority). The OAC-ALONE study did
not establish noninferiority of monotherapy with an oral
anticoagulant to dual therapy with an oral anticoagulant plus an
antiplatelet drug in this population due to premature termination
of enrollment and inclusion of 25% of patients treated with a DOAC.
The AFIRE (Atrial Fibrillation and Ischemic Events with
Rivaroxaban in Patients with Stable Coronary Artery Disease) trial
provided a satisfactory answer to the problem about the lack of
evidence for oral anticoagulant monotherapy in patients with AF
and stable CAD [43] (Table 3). In the AFIRE trial, which was a
multicenter, randomized, open-label, parallel-group trial in Japan,
2240 patients with AF who had undergone PCI or coronary-artery
bypass grafting more than 1 year earlier or who had angiographic-
ally confirmed CAD not requiring revascularization were enrolled
to receive rivaroxaban monotherapy or dual therapy with
rivaroxaban plus an antiplatelet. Rivaroxaban was used at the
dose of 10 mg once daily for patients with a creatinine clearance of
15 to 49 ml per minute, or 15 mg once daily for patients with a
creatinine clearance of 50 ml per minute. The trial was stopped
early because of a high risk of death from any cause in the dual
therapy group. Rivaroxaban monotherapy was found to be
noninferior to dual therapy for the primary efficacy endpoint of
a composite of stroke, systemic embolism, myocardial infarction,
unstable angina requiring revascularization, or death from any
cause (event rate, 4.14% vs. 5.75% per patient-year, respectively; HR
0.72, 95%CI 0.55–0.95, p < 0.001 for noninferiority). In the
assessment of superiority for the primary efficacy endpoint (which
was not a prespecified analysis), the p-value was 0.02. Moreover,
rivaroxaban monotherapy was superior to dual therapy for major
bleeding, defined as the primary safety endpoint (event rate, 1.62%
vs. 2.76% per patient-year, respectively; HR 0.59, 95%CI 0.39–0.89,
p = 0.01 for superiority). The results of the AFIRE trial provide
important evidence on the safety and efficacy of DOAC mono-
therapy with rivaroxaban in the long-term management of AF
patients with stable CAD, including the chronic phase of PCI.
Since bleeding has a strong correlation with subsequent all-
cause mortality and cardiovascular events in CAD patients [44],

Table 3
Trials comparing dual therapy and oral anticoagulant monotherapy in patients with atrial fibrillation and stable coronary artery disease.

OAC-ALONE AFIRE

Period of patient enrollment 2013-2016 2015-2017

Actual enrollment of patients
Study location
Indication for oral anticoagulant
Antithrombotic regimen
Inclusion criteria related to CAD
Exclusion criteria related to ischemia
or bleeding risk
Primary endpoint
PCI performed
Target range of INR
Time in the therapeutic INR range
696 2240
Japan Japan
Non-valvular AF Non-valvular AF
(1) Warfarin (76.3%) or DOAC (23.7%) plus a single (1) Rivaroxaban and single antiplatelet (2) Rivaroxaban
antiplatelet (2) Warfarin (74.1%) or DOAC (25.9%) alone alone
Stable CAD patients who had received coronary stents Stable CAD patients who had undergone PCI or
>1 year earlier CABG > 1 year earlier, or who had angiographically
confirmed CAD not requiring revascularization
History of stent thrombosis History of stent thrombosis, coexisting active tumor,
poorly controlled hypertension
All-cause death, myocardial infarction, stroke, or systemic Efficacy: stroke, systemic embolism, myocardial
embolism infarction, unstable angina requiring revascularization, or
death from any cause Safety: major bleeding (ISTH)
100% 71%
<70years: 2.0–3.0 > = 70years: 1.6–2.6 -
Oral anticoagulant alone group: 75.6% Combined therapy -
group: 73.1%

AF, atrial fibrillation; DOAC; direct oral anticoagulant; CAD, coronary artery disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting;
ISTH, International Society of Thrombosis and Haemostasis; INR, international normalized ratio.
42 et al. / Journal of Cardiology 76 (2020) 35–43
additional analysis of the results of the AFIRE trial was reported
[45]. The rate of cardiovascular events was high in patients with
major bleeding in both the monotherapy group (7 cardiovascular
events following 29 major bleeding events; 24.1%) and combina-
tion group (15 cardiovascular events following 55 major bleeding
events; 27.3%), indicating that major bleeding events are associated
with high morbidity and mortality rates. The following points have
been estimated: (1) reduction of blood volume and oxygen-
carrying capacity resulting in hypotension and inducing ischemia
and severe arrhythmias; (2) discontinuation of antithrombotic
drugs to manage bleeding [46,47]; (3) withdrawal of drugs to treat
hypotension after bleeding, such as beta-blockers and angiotensin-
converting enzyme inhibitors; and (4) blood transfusions that are
associated with systemic vasoconstriction, activation of inflam-
matory pathways, apoptosis, increased platelet aggregation, and
thrombosis [48].
Gaps in evidence and future studies
Certain questions related to antithrombotic therapy in patients
undergoing PCI who also require oral anticoagulation need further
research. First, none of the already-known bleeding or ischemic
risk prediction models have been evaluated in prospective
randomized trials. Whether these predictive models will enable
improvement in patient outcomes remains unclear. Second, as
mentioned above, the duration of triple therapy is not well-
established. Therefore, at this time, we should provide tailor-made
regimens and durations of antithrombotic therapy based on these
evidences and the recommendations of guidelines. Third, the
appropriate choice of antiplatelet agent, whether a P2Y12 inhibitor
or aspirin, for combination therapy remains open. In the WOEST,
PIONEER AF-PCI, RE-DUAL, AUGUSTUS, and ENTRUST-AF PCI trials,
more than approximately 90% of patients were treated with
clopidogrel [15–19]. In the AFIRE trial, 70.2% of patients were
treated with aspirin and 26.8% with clopidogrel, although the
choice of antiplatelet regimen, whether aspirin or the P2Y12
inhibitor, was at the discretion of the treating physicians [43].
Other P2Y12 inhibitors, such as prasugrel and ticagrelor, for dual or
triple therapy have not been sufficiently tested to date. This is
because these potent P2Y12 inhibitors are associated with a
significant increase in bleeding events. When prasugrel was
evaluated as part of a combination triple therapy regimen in
observational studies, the combination was associated with a
three-fold increased risk of major and minor bleeds as compared
with triple therapy using clopidogrel [adjusted HR = 3.2, 95% CI
(1.1–9.1), p = 0.03] [49]. However, further studies are needed to
assess the use of different combinations of anticoagulant and
antiplatelet agents that better match patient-specific risk profiles
for ischemia and bleeding. Fourth, antithrombotic regimens for
patients who underwent PCI and require oral anticoagulation for
reasons other than AF, including mechanical heart valves, venous
thromboembolism, and left ventricular thrombi, have not yet been
evaluated. Fifth, there is lack of sufficient evidence on the efficacy
of dual therapy consisting of DOACs plus a single P2Y12 platelet
inhibition agent. These limitations have driven ongoing efforts to
identify new antithrombotic targets. Impairment of intrinsic
coagulation by selective inhibition of factor XI (FXI) leaves the
extrinsic and common coagulation pathways intact, making FXI a
potential drug target that would attenuate thrombosis with
minimal disruption of hemostasis [50].
Conclusions
Antithrombotic therapy for AF and CAD in the acute and
chronic/stable phase has been shifting to a “less is more” regimen.
Physicians should consider an appropriate antithrombotic
approach based on evaluation of the bleeding and ischemic risks
in individual patients.
Disclosures
Dr Kawakami reports receiving grant support from Fukuda
Foundation for Medical Technology; Dr Yasuda reports receiving
grant support from Takeda Pharmaceutical Company and Abbott
Laboratories and lecture fees from Daiichi Sankyo and Bristol-
Myers Squibb; Dr Ogawa received lecture fees from Towa
Pharmaceutical and honoraria from Novartis Pharma. No other
potential conflicts of interest relevant to this article were reported.
Funding
None.
Acknowledgments
None.
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