Education in Heart
Triple antithrombotic therapy after ACS and PCI in
1
Division of Cardiology, Cardio-
Thoracic-Vascular Department,
Azienda Ospedaliero-
Universitaria “Policlinico-Vittorio
Emanuele”, Catania, Italy
2
Department of General Surgery
and Medical-Surgical Specialties,
University of Catania, Catania,
Italy
Correspondence to
Professor Davide Capodanno,
Department of General Surgery
and Medical-Surgical Specialties, these indications. AF is the most common scenario
University of Catania, Catania
95100, Italy; ​dcapodanno@​
gmail.c​ om
To cite: Capodanno D.
Heart Epub ahead of
print: [please include Day
Month Year]. doi:10.1136/
heartjnl-2017-312228
patients on chronic oral anticoagulation: update
Davide Capodanno1,2
Introduction
Oral anticoagulation (OAC) with vitamin K antag-
onists (VKAs) is indicated for the prophylaxis and
treatment of venous thrombosis and pulmonary
embolism as well for the prophylaxis and treat-
ment of thromboembolic complications associated
with atrial fibrillation (AF), cardiac valve replace-
ment and myocardial infarction. Non-vitamin K
antagonist oral anticoagulants (NOACs), which are
safer alternatives to VKAs and do not require labo-
ratory monitoring, are also available for many of
where chronic OAC is required for the prevention
of stroke or systemic embolism, with a prevalence
of about 3% in adults aged 20 years or older, and
greater prevalence in elderly and patients with
predisposing factors.1 In the European guidelines
for the management of AF, OAC is recommended
(class I) for all male AF patients with a CHA2DS2-
VASc (Congestive Heart Failure, Hypertension, Age
≥75 [Doubled], Diabetes Mellitus, Prior Stroke
or Transient Ischemic Attack [Doubled], Vascular
Disease, Age 65-74, Female) score of 2 or more and
all female AF patients with a CHA2DS2-VASc score
of 3 or more, but should be also considered (class
IIa) in male and female AF patients with CHA2DS2-
VASc scores of 1 and 2, respectively.2 NOACs are
regarded as first-line drug options for thromboem-
bolic prevention in eligible patients with AF (eg,
in preference to VKAs) but are not recommended
for AF patients with mechanical heart valves and
moderate-to-severe mitral stenosis.
The cornerstone of chronic antithrombotic
prophylaxis in patients undergoing percutaneous
coronary intervention (PCI), presenting with or
without an acute coronary syndrome (ACS), is dual
antiplatelet therapy (DAPT) with low-dose aspirin
and a P2Y12 inhibitor.3 Coronary artery disease
(CAD) coexist in 20%–30% of patients with AF, and
approximately 5%–7% of PCI patients present with
AF or other indications for chronic OAC.4 When
indications for DAPT and OAC coexist, the optimal
management of antithrombotic therapy becomes a
clinical dilemma, because prescribing a triple anti-
thrombotic therapy regimen is known to increase
the chance of bleeding by four times compared with
prescribing aspirin alone.5 Unfortunately, none of
the two antithrombotic strategies (ie, anticoagulant
and antiplatelet) can be easily discounted: OAC is
superior to DAPT or single antiplatelet therapy for
preventing cardioembolic events, but DAPT is supe-
rior to OAC for preventing stent thrombosis and
recurrent coronary events.6 Indeed, stent throm-
bosis and coronary events are typically caused by
platelet-rich thrombi that develops in the setting
Capodanno D. Heart 2018;0:1–8. doi:10.1136/heartjnl-2017-312228
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Learning objectives
►► To describe the clinical risks and benefits
associated with triple antithrombotic therapy.
►► To provide a state-of-the-art exposition of
clinical studies in the field, including recent
studies of non-vitamin K antagonist oral
anticoagulants.
►► To explore clinically oriented scenarios and
master the theory and practice of using
combinations of anticoagulant and antiplatelet
drugs.
of high shear stress, while low shear stress thrombi
develop in the left atrium of patients with AF, which
is a less platelet-dependent process.
For years, the optimal management of triple anti-
thrombotic therapy has been empirical, with expert
consensus documents providing some sort of direc-
tion in a guideline-free zone. Patients on chronic
OAC were generally excluded from landmark trials
of antiplatelet therapy for ACS,7 8 but the use of
antiplatelet agents was only partly restricted or left
to the discretion of the treating physician in trials
of NOACs for AF and represented the background
therapy in ACS trials of NOACs. Subgroup analyses
from these studies provide some indirect evidence
on the risk–benefit balance of triple antithrom-
botic therapy in the era of NOACs. More recently,
randomised controlled trials have been published
that compare directly antithrombotic strategies for
patients on OAC in need of antiplatelet therapy and
seriously challenge the concept of full-dose triple
antithrombotic therapy. A focused guideline update
on DAPT has been issued in 2017 by the European
Society of Cardiology that partly incorporates the
new evidence and inform clinical practice.3 The
scope of this review is to provide the reader with an
update on the current status, evidence and recom-
mendations regarding the field of antithrombotic
therapy after PCI and/or ACS in patients on chronic
OAC. The primary focus will be on patients with
AF, because data for patients who may have other
indications for OAC are extremely limited, and no
dedicated randomised clinical studies are available.
Triple or dual antithrombotic therapy in
the era of VKAs
Two randomised trials explored antithrombotic
strategies to improve the safety of triple antithrom-
botic therapy with warfarin and DAPT (ie, with-
drawing aspirin or reducing the duration of triple
therapy). The What is the Optimal antiplatElet &
  1
Education in Heart
Anticoagulant Therapy in Patients With Oral Anti-
coagulation and Coronary StenTing (WOEST)
trial investigated the hypothesis that dual anti-
thrombotic therapy with warfarin and clopidogrel
(ie, without aspirin) reduces the risk of bleeding
episodes within 1 year from PCI in comparison
with a triple antithrombotic therapy regimen.9 The
trial randomised in an open-label fashion 573 OAC
patients (69% with AF, 65% treated with drug-
eluting stents and 27.5% with ACS) and found a
64% relative decrease in bleeding episodes with
dual antithrombotic therapy, driven by a reduced
rate of minor bleeding episodes (table 1). There
was no increase in the risk of thrombotic events
with the lower intensity regimen, and all-cause
mortality was significantly lower, but the study
was underpowered for efficacy endpoints. Addi-
tional caveats of WOEST included the prolonged
period of triple antithrombotic therapy in the
control group, which does not reflect contem-
porary guideline recommendations (figure 1),10
and the relatively low proportion of patients with
ACS, which makes the data less generalisable.
Still, the WOEST trial was the first important
piece of evidence that dropping aspirin achieves
superior safety outcomes in candidates to triple
antithrombotic therapy, leading to the initiation
of multiple trials of aspirin-free strategies.
In the Triple Therapy in Patients on Oral Anti-
coagulation After Drug Eluting Stent Implanta-
tion (ISAR-TRIPLE) trial, 614 PCI patients treated
with drug-eluting stents on OAC (one-third with
ACS) were randomised to 6 weeks or 6 months of
clopidogrel on top of aspirin and OAC use.11 The
study can be considered as a trial of shorter versus
longer DAPT duration in OAC patients, because
clopidogrel was stopped earlier in the investigational
group (figure 1). The primary endpoint, comprising
a combination of ischaemic and bleeding events,
did not differ at 9 months between the two groups,
and no differences were also noted in secondary
events (table 1). In a landmark analysis of events
between 6 weeks and 6 months, the risk of bleeding
was higher in the group on clopidogrel. Notably,
the same power issues noted in WOEST, including
the small proportion of ACS patients, also apply to
the ISAR-TRIPLE study, challenging the interpre-
tation. However, a consistent message from these
studies, which is consistent with the findings from a
nationwide registry,5 is the clinical need to minimise
the duration of triple antithrombotic therapy as
much as possible and take patient-by-patient deci-
sions on using triple or dual antithrombotic therapy
depending on the balance of the individual bleeding
and ischaemic risks.
Triple or dual antithrombotic therapy in
the era of NOACS
Lessons from studies of NOACs in AF
In pivotal trials of NOACs versus VKAs for AF, the
concomitant use of aspirin ranged between 29%
and 37%, and the concomitant use of a thienopy-
ridine (alone or in combination with aspirin) was
2 Capodanno D. Heart 2018;0:1–8. doi:10.1136/heartjnl-2017-312228
excluded by study protocol or occurred in a negli-
gible proportion of patients.4 In none of these trials
an interaction was noted between the treatment
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effect and outcome according to clinical presenta-
tion (ie, ACS at presentation), which suggests that
the clinical benefit of NOACs may be preserved
in patients with CAD. Substudies on treatment
effect interactions for use of antiplatelet agents
versus no use come from the Long-term Antico-
agulation Therapy  (RE-LY), Apixaban for Reduc-
tion in Stroke and Other Thromboembolic Events
in Atrial Fibrillation (ARISTOTLE)  and Effective
anticoagulation with factor Xa next generation in
AF (ENGAGE-AF) trials of dabigatran, apixaban
and edoxaban, respectively.12–14 In these post hoc
analyses, the risk of major bleeding was consistently
increased with concomitant use of antiplatelet
therapy, while the relative efficacy and safety
profiles of the NOACs over warfarin were not
significantly modified. These results are informa-
tive on the risk of combining OAC and antiplatelet
agents and support a role of NOACs in decreasing
bleeding complications relative to VKAs but should
be interpreted with caution because the use of anti-
platelet agents was not stratified and only a minority
of patients was using an antiplatelet agent contin-
uously throughout the studies. In addition, most
patients on antiplatelet agents were taking aspirin,
whereas the use of clopidogrel or DAPT was infre-
quent, and prasugrel or ticagrelor was not used.
Lessons from studies of NOACs for ACS
In three phase II trials of patients with ACS, the
addition of dabigatran, apixaban or rivaroxaban
to DAPT was associated with a dose-dependent
increase in bleeding events.15–17 The efficacy and
safety of selected doses of apixaban and rivarox-
aban were further investigated in two larger trials
of patients with ACS. The  Apixaban for Preven-
tion of Acute Ischemic Events 2 (APPRAISE 2)
study was terminated prematurely due to evidence
of an increase in major bleeding events with apix-
aban in the absence of a counterbalancing reduc-
tion in ischaemic events.18 Conversely, in the
Anti-Xa Therapy to Lower Cardiovascular Events
in Addition to Standard Therapy in Subjects
with Acute Coronary Syndrome  (ATLAS-ACS-2)
study, a very low-dose of rivaroxaban (2.5 mg
twice daily) resulted in significantly less ischaemic
events at the price of increased major and intra-
cranial bleeding.19 In further scrutiny of a safer
rivaroxaban-based strategy for patients with ACS,
a phase II study recently reported the same risk of
clinically significant bleeding with very low-dose
rivaroxaban and a P2Y12 inhibitor (ie, without
aspirin) compared with DAPT, but whether this
strategy is also similarly effective remains uncer-
tain.20 Rivaroxaban is currently indicated by the
European Medical Agency for the prevention of
atherothrombotic events in patients with ACS
and elevated cardiac biomarkers and is given by
clinical practice guidelines a class IIb recommen-
dation for combination therapy with DAPT.21
 Table 1  Randomised studies of dual or triple antithrombotic therapy in patients on chronic OAC in need of antiplatelet therapy
Study Year Patients (N) ACS (%) DES (%) Intervention(s)* Control* Primary outcome Follow-up Key findings
WOEST 2013 573 patients receiving 27 64 Clopidogrel 75 mg daily for 1–12 months Aspirin 80–100 mg daily Any bleeding episode 12 months ►► Bleeding episodes were observed in 19.4% of
VKA and undergoing and clopidogrel 75 mg patients receiving DAT and 44.4% of patients
PCI with stenting daily for 1–12 months receiving TAT (HR 0.36, 95% CI 0.26 to 0.50,
p<0.0001).
►► The combined secondary endpoint of death, MI,
stroke, target-vessel revascularisation and stent
thrombosis was observed in 11.1% of patients
receiving DAT and 17.6% of patients receiving TAT
(adjusted HR 0.56, 95% CI 0.35 to 0.91).
ISAR-TRIPLE 2015 614 patients receiving 32 100 Aspirin 75–200 mg daily and clopidogrel 75 mg daily Aspirin 75–200 mg daily Death, MI, definite stent 9 months ►► The primary endpoint was observed in 9.8% of
VKA and undergoing for 6 weeks and clopidogrel 75 mg thrombosis, stroke or TIMI patients receiving shorter TAT and 8.8% of patients
PCI with DES daily for 6 months major bleeding receiving longer TAT (HR 1.14, 95% CI 0.68 to 1.91,
p=0.63).
►► The combined secondary endpoint of cardiac death,
MI, ischaemic stroke and definite stent thrombosis

Capodanno D. Heart 2018;0:1–8. doi:10.1136/heartjnl-2017-312228

was observed in 4.0% of patients receiving shorter
TAT and 4.3% of patients receiving longer TAT (HR
0.93, 95% CI 0.43 to 2.05).
►► The secondary safety endpoint of TIMI major
bleeding was observed in 5.3% of patients receiving
shorter TAT and 4.0% of patients receiving longer
TAT (HR 1.35, 95% CI 0.64 to 2.84).
PIONEER-AF 2016 2124 patients with 52 68 ►► Rivaroxaban 10–15 mg once daily and clopidogrel VKA-, aspirin 75–100 mg Clinically significant TIMI 12 months ►► The primary endpoint was observed in 16.8% in
NVAF undergoing PCI 75 mg daily (or ticagrelor 90 mg twice daily or once daily and clopidogrel bleeding group 1, 18.0% in group 2 and 26.7% in group 3
with stenting prasugrel 10 mg once daily) for 12 months (group 1). 75 mg once daily (or (HR for group 1 vs group 3, 0.59, 95% CI 0.47 to
►► Rivaroxaban 2.5 mg twice daily (10–15 mg if ticagrelor at a dose of 0.76; HR for group 2 vs group 3, 0.63, 95% CI 0.50
clopidogrel discontinuation at 1 or 6 months), 90 mg twice daily or to 0.80).
aspirin 75–100 mg once daily and clopidogrel 75 mg prasugrel at a dose of ►► The combined secondary rates of death from
daily (or ticagrelor 90 mg twice daily or prasugrel 10 mg once daily) for 1, 6 cardiovascular causes, MI or stroke were similar in
10 mg once daily) for 1, 6 or 12 months (group 2). or 12 months (group 3) the three groups (6.5% in group 1, 5.6% in group 2
and 6.0% in group 3).
RE-DUAL PCI 2017 2725 patients with 51 83 ►► Dabigatran etexilate 110 mg twice daily plus VKA, aspirin ≤100 mg Major or clinically relevant 14 months ►► The primary endpoint was observed in (A) 15.4%
NVAF undergoing PCI clopidogrel 75 mg once daily or ticagrelor 90 mg daily for 1–3 months and non-major bleeding (mean) of patients in the 110 mg DAT group and 26.9%
with stenting twice daily (110 mg DAT group). clopidogrel 75 mg once of patients in the TAT group (HR 0.52, 95% CI 0.42
►► Dabigatran etexilate 150 mg twice daily plus daily or ticagrelor 90 mg to 0.63); (B) 20.2% of patients in the 150 mg DAT
clopidogrel 75 mg once daily or ticagrelor 90 mg twice daily (TAT group). group and 25.7% of patients in the TAT group,
twice daily (150 mg DAT group). which did not include elderly patients outside the
USA (HR 0.72, 95% CI 0.58 to 0.88).
►► The combined secondary endpoint of death,
MI, stroke, systemic embolism and unplanned
revascularisation was observed in 13.7% of patients
receiving DAT (two dabigatran doses combined) and
13.4% of patients receiving TAT (HR 1.04, 95% CI
0.84 to 1.29).
*Where not otherwise specified, the intended length of therapy corresponds to the latest follow-up.
ACS, acute coronary syndromes; CI, confidence interval; DAT, dual antithrombotic therapy; DES, drug-eluting stents; HR, hazard ratio; ISAR-TRIPLE, Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation; MI, myocardial infarction; NVAF, non-valvular
atrial fibrillation; OAC, oral anticoagulation; PCI, percutaneous coronary intervention; RE-DUAL PCI, Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Non-valvular Atrial Fibrillation Undergoing Percutaneous
Coronary Intervention; TAT, triple antithrombotic therapy; TIMI, thrombolysis in myocardial infarction; VKA, vitamin K antagonist; WOEST, What is the Optimal antiplatElet & Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary StenTing.
Education in Heart

3
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 Education in Heart

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Figure 1  Treatment strategies in trials of dual or triple antithrombotic therapy. The x axis depicts drug durations in months for each strategy.
AF, atrial fibrillation; ASA, acetylsalicylic acid; DAT, double antithrombotic therapy; ISAR TRIPLE, Triple Therapy in Patients on Oral Anticoagulation
After Drug Eluting Stent Implantation; PCI, percutaneous coronary intervention; PIONEER AF, Open-Label, Randomized , Controlled, Multicenter
Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial
Fibrillation; RE-DUAL PCI, Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with
Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; TAT, triple antithrombotic therapy; VKA, vitamin K antagonist; WOEST,
What is the Optimal antiplatElet & Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary StenTing.

This recommendation cannot be generalised to
ACS patients with AF because the dose of rivar-
oxaban approved for stroke prevention (20 mg
once daily) is fourfold higher than the dose tested
in the ATLAS-ACS-2 trial. Overall, the results of
ACS studies of NOACs are poorly generalisable
to patients with AF, but points again towards the
bleeding risk associated with triple antithrom-
botic therapy.
Lessons from dedicated studies of NOACs in
patients with AF undergoing PCI: PIONEER-AF
and RE-DUAL PCI
The Open-Label, Randomized, Controlled, Multi-
center Study Exploring Two Treatment Strategies of
Rivaroxaban and a Dose-Adjusted Oral Vitamin K
Antagonist Treatment Strategy in Subjects with Atrial
Fibrillation who Undergo Percutaneous Coronary
Intervention  (PIONEER AF-PCI) trial compared
three treatment strategies after PCI in 2124 patients
with AF: a WOEST-like strategy of low-dose rivarox-
aban (15 mg once daily) plus a single P2Y12 inhibitor,
the ATLAS ACS 2-like regimen of very low dose rivar-
oxaban (2.5 mg twice daily) plus DAPT and standard
triple antithrombotic therapy with a VKA plus DAPT
(figure 1).22 Randomised patients were stratified by
the intended duration of DAPT (1, 6 or 12 months)
and the intended P2Y12 inhibitor (clopidogrel, prasu-
grel or ticagrelor). Compared with the standard triple
antithrombotic therapy group, the primary endpoint
of clinically significant bleeding at 12 months was
reduced by both the WOEST-like and ATLAS-ACS 2
strategies, driven by lower rates of bleeding requiring
medical attention (table 1). There were no differences
in major adverse cardiovascular events, but the power
was low for ischaemic endpoints, as previously noted
in the WOEST trial. PIONEER-AF and WOEST
differed in that the first included almost only patients
with AF and maintained triple antithrombotic therapy
at 1 year in the control arm in only 22% of patients.

4 Capodanno D. Heart 2018;0:1–8. doi:10.1136/heartjnl-2017-312228


The Randomzsed Evaluation of Dual Anti-
thrombotic Therapy with Dabigatran versus
Triple Therapy with Warfarin in Patients with
Non-valvular Atrial Fibrillation Undergoing
Percutaneous Coronary Intervention (RE-DUAL
PCI) trial compared in 2725 patients with AF
who had undergone PCI (half of them in the
setting of an ACS) two regimens of dual anti-
thrombotic therapy that included dabigatran and
mostly clopidogrel (ticagrelor in 12%) versus
a regimen of triple antithrombotic therapy
with warfarin.23 In the triple antithrombotic
therapy group, aspirin was discontinued after
1 month in patients who received a bare-metal
stent (17%) and after 3 months in patients who
received a drug-eluting stent (83%) (figure 1).
At a mean of 14 months, the risk of the primary
endpoint in the 110 mg dabigatran dual-therapy
group (major or clinically relevant non-major
bleeding) was non-inferior (and superior) to
the risk observed in the triple antithrombotic
therapy group (table 1). The 150 mg dabigatran
dual therapy group also met the non-inferiority
objective compared with the triple therapy
group but did not show superiority. The risk of
thromboembolic events was non-inferior in the
two dual therapy groups combined as compared
with the triple therapy group. Notably, the
protocol was amended to enrol a smaller than
anticipated number of patients, with reflections
on the power of the trial to examine efficacy
according to dabigatran dose. However, other
study findings were consistent with the hypoth-
esis of a net clinical benefit of each of the two
dual antithrombotic therapy regimens. Overall,
the RE-DUAL PCI study validated the WOEST
hypothesis (ie, less bleeding with dual therapy)
with greater power. These results are even more
important given the shorter length of triple
antithrombotic therapy in the control arm of
RE-DUAL PCI compared with WOEST.
Table 2  Ongoing trials of NOACs in patients undergoing percutaneous coronary intervention
AUGUSTUS
Study type Open label (apixaban vs warfarin) and blinded (aspirin vs placebo),
randomised, factorial design
Investigational drug(s) Apixaban
Clinicaltrials.gov identifier NCT02415400
Patients ~4600 patients with atrial fibrillation, and ACS or PCI or both
Experimental arm(s) Apixaban 5 mg twice daily (or reduced dose of 2.5 mg twice daily)
plus clopidogrel. 2×2 factorial plan for aspirin.
Control arm Warfarin plus clopidogrel 75 mg
Primary safety endpoint International Society of Thrombosis and Haemostasis Major or
clinical relevant non-major bleeding event
Primary efficacy endpoint Death, MI, stroke or stent thrombosis
Follow-up 6 months
ACS, acute coronary syndromes; AUGUSTUS, A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis (Blood
Clots) Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart; ENTRUST-AF PCI, Edoxaban Treatment Versus Vitamin
K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; MI, myocardial infarction; NOACs, non-vitamin K antagonist oral anticoagulants;
od, once daily; PCI, percutaneous coronary intervention.
Capodanno D. Heart 2018;0:1–8. doi:10.1136/heartjnl-2017-312228
Education in Heart
Two more trials of NOACs in patients under-
going PCI are ongoing with apixaban and edox-
aban, respectively (table 2). In the A Study of
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Apixaban in Patients With Atrial Fibrillation, Not
Caused by a Heart Valve Problem, Who Are at
Risk for Thrombosis (Blood Clots) Due to Having
Had a Recent Coronary Event, Such as a Heart
Attack or a Procedure to Open the Vessels of the
Heart (AUGUSTUS) trial, about 4600 patients will
be randomised to apixaban 5 mg twice daily plus
clopidogrel or warfarin plus clopidogrel. Interest-
ingly, a 2×2 factorial plan is envisaged to investi-
gate whether aspirin should also be part of these
combinations. In the Edoxaban Treatment Versus
Vitamin K Antagonist in Patients With Atrial Fibril-
lation Undergoing Percutaneous Coronary Inter-
vention (ENTRUST-AF PCI) trial, edoxaban 60 mg
once daily will be tested against standard triple anti-
thrombotic therapy in about 1500 patients. In both
trials, the primary endpoint will be a combined
safety endpoint.
Recommendations on the management
of patients on OAC undergoing PCI with
or without an ACS
The focused update on DAPT from the European
Society of Cardiology is so far the most updated
document providing clinicians with recommen-
dations on antiplatelet therapy duration in PCI
patients with indication for OAC, but it does not
include the results of RE-DUAL PCI, which were
released after the guidelines were published.3 The
document emphasises the need for implementing
strategies to minimise PCI-related complications
including (1) risk stratification for ischaemic and
bleeding with a focus on modifiable risk factors,
(2) keeping triple antithrombotic therapy to the
shortest possible duration with dual antithrom-
botic therapy as an alternative, (3) using NOACs
whenever possible instead of VKAs, at the lowest
approved dose effective for stroke prevention
ENTRUST-AF PCI
Open label, randomised
Edoxaban
NCT02866175
~1500 patients with atrial fibrillation that undergo a PCI with
stenting
Edoxaban 60 mg od (or reduced dose of 30 mg od)
Warfarin plus clopidogrel 75 mg od or prasugrel 10 mg od or
ticagrelor 90 mg twice daily plus aspirin ≤100 mg od
International Society of Thrombosis and Haemostasis Major or
clinical relevant non-major bleeding event
Cardiovascular death, stroke, systemic embolism, MI or stent
thrombosis
12 months
5
 Education in Heart

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Figure 2  Practical algorithm for the use of antithrombotic therapy in patients with non-valvular atrial fibrillation on oral anticoagulation with
NOACs. The proposed dabigatran 110 mg and dabigatran 150 mg strategies are based on the design and results of the RE-DUAL PCI trial. The
proposed rivaroxaban 15 mg strategy is based on the design and results of the PIONEER-AF PCI trial. A strategy of rivaroxaban 20 mg (with reduction
based on renal function) plus dual (or single) antiplatelet therapy as long as necessary is also supported by clinical practice guidelines. The apixaban
and edoxaban-based strategies are currently empirical, with trials ongoing (ie, AUGUSTUS and ENTRUST-AF PCI), but are also supported by clinical
practice guidelines. *Rivaroxaban 15 mg OD if CrCl 30–49 mL/min; **apixaban 2.5 mg twice daily if at least two of the following: age ≥80 years,
body weight ≤60 kg or serum creatinine level ≥1.5 mg/d; ***edoxaban 30 mg OD if any of the following: CrCl of 30–50 mL/min, body weight ≤60 kg,
concomitant use of verapamil, quinidine or dronedarone; ****ticagrelor 90 mg twice daily in selected cases based on risk–benefit considerations;
*****clopidogrel (or ticagrelor, if applicable) can be removed instead of ASA if a dual therapy regimen is adopted. AUGUSTUS, A Study of Apixaban
in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis (Blood Clots) Due to Having Had a Recent
Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart; ASA, acetylsalicylic acid; DES, drug-eluting stent; ENTRUST-
AF PCI, Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; mo,
month(s); NOACs, non-vitamin K antagonist oral anticoagulants; NSAID, non-steroidal anti-inflammatory drugs; NVAF, non-valvular atrial fibrillation;
od, once daily; PCI, percutaneous coronary intervention; PIONEER-AF PCI, Open-Label, Randomized, Controlled, Multicenter Study Exploring Two
Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who
Undergo Percutaneous Coronary Intervention; PPI, proton pump inhibitor; RE-DUAL PCI, Randomized Evaluation of Dual Antithrombotic Therapy with
Dabigatran versus Triple Therapy with Warfarin in Patients with Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

tested in AF trials when combined with antiplatelet
drugs, (4) considering an INR in the lowest part of
the therapeutic range in case of VKAs use and (5)
using proton pump inhibitors routinely.
In patients where concerns about the risk of isch-
aemic complications prevail, 1 month of triple anti-
thrombotic therapy with OAC, aspirin and clopidogrel
is recommended irrespective of the type of stent used
but may be considered up to 6 months in patients at
high ischaemic risk due to ACS or other anatomical/
procedural characteristics that outweigh the risk of
bleeding. When the period of triple antithrombotic
therapy is concluded, a dual antithrombotic regimen
with OAC and aspirin or clopidogrel is recommended
up to 12 months, followed by OAC alone. The safety
of using OAC alone after 12 months is supported by
large registries,24 but dual antithrombotic therapy can
still be considered beyond that timeframe in selected
patients at very high risk of thrombotic events. In
patients where concerns about the risk of bleeding
complications prevail, triple antithrombotic therapy
should not be prolonged beyond 1 month and can be
even avoided using dual antithrombotic therapy with
OAC and clopidogrel as an alternative. All the above
recommendations are now class IIa with varying levels
of evidence. When rivaroxaban is used in combina-
tion with aspirin and/or clopidogrel, the 15 mg once
daily dose of rivaroxaban may be used instead of the
conventional 20 mg once daily dose (class IIb), based
on the design and results of the PIONEER-AF study.
The regimens of dabigatran 110 mg and 150 mg
investigated in the RE-DUAL PCI study can be easily
implemented in clinical practice by addition of clopi-
dogrel to OAC for 12 months. The use of ticagrelor
or prasugrel is not recommended as part of triple anti-
thrombotic therapy (class III) as the consequence of
the low use in randomised clinical trials (ie, only 6%
in PIONEER-AF) and the worrying signals of unac-
ceptable bleeding risk in a small registry.25 Based on
the above and the results of recent trials, figures 2 and
3 provide practical algorithms for the management of
combination therapy with NOACs and antiplatelet
drugs in two increasingly common scenarios: patients
with AF undergoing PCI (presenting with or without
ACS) and patients with ACS/PCI who develop newly
onset AF. Case-by-case decisions are necessary for

6 Capodanno D. Heart 2018;0:1–8. doi:10.1136/heartjnl-2017-312228

 Education in Heart

Heart: first published as 10.1136/heartjnl-2017-312228 on 25 April 2018. Downloaded from http://heart.bmj.com/ on 26 April 2018 by guest. Protected by copyright.
Figure 3  Practical algorithm for the use of antithrombotic therapy in patients with indications to antiplatelet therapy and newly onset non-valvular
atrial fibrillation with indication for oral anticoagulation. The same considerations may apply to any new indication to NOAC therapy. *Or maintain
prasugrel or ticagrelor in selected cases based on risk–benefit considerations. **With NOAC and ASA or clopidogrel. ***With considerations on the
type of stents implanted and complexity of treated and residual coronary artery disease. ASA, acetylsalicylic acid; BMS, bare metal stent; DAPT, dual
antiplatelet therapy; NOAC, non-vitamin K antagonist oral anticoagulant; NVAF, non-valvular atrial fibrillation; OAC, oral anticoagulation.

patients with new or recent ACS/PCI who are on with AF at an unacceptably high bleeding risk with
OAC due to causes other than AF (ie, recurrent triple or dual antithrombotic therapy may benefit
thromboembolic events and mechanical prostheses). from a third option for stroke prevention that is left
Finally, it should be considered that selected patients atrial appendage closure.

Key messages
►► Prescribing triple antithrombotic therapy is known to increase the chance of
bleeding compared with prescribing dual antiplatelet therapy, aspirin alone
or the combination of an oral anticoagulant and an antiplatelet drug.
►► Studies of non-vitamin K antagonist oral anticoagulants are available (ie,
dabigatran and rivaroxaban) or will be available (ie, apixaban and edoxaban)
to guide physicians towards the optimal use of these drugs in the setting of
percutaneous coronary intervention.
►► Patient-by-patient decision after definition of individual bleeding and
ischaemic risk characteristics is the essential step for achieving a net benefit
in efficacy and safety with combination therapies of anticoagulant and
antiplatelet drugs.
CME credits for Education in Heart
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credits, click on the ‘Take the Test’ link on the online version of the article.
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Summary/conclusions
Combination of anticoagulant and antiplatelet drugs
increases the risk of bleeding but is requested by rela-
tively common clinical scenarios in daily practice.
A term of triple antithrombotic therapy is recom-
mended for patients with AF presenting with PCI
and/or ACS, but there is consensus that this should
be as short as possible and that it should be avoided
in patients where the concern of bleeding prevails
over the concern of ischaemic complications. The
introduction of NOACs and their clinical testing
in the PCI setting may encourage the shift towards
safer dual antithrombotic therapy strategies. Whether
these ‘less-is-more’ combinations are also effective
remains a matter of uncertainty due to the small size
of the available studies and will likely be the objective
of future study-level meta-analyses of the RE-DUAL
PCI, PIONEER AF, AUGUSTUS and ENTRUST-AF
PCI trials. Incorporation of ticagrelor and prasugrel
into these schemes is challenging in a field where data
are limited. Ultimately, patient-by-patient decision
after characterisation of the individual ‘bleeding and
ischaemic risk profile’ is the best strategy to achieve a
net benefit in efficacy and safety.
Funding  The authors have not declared a specific grant for this
research from any funding agency in the public, commercial or
not-for-profit sectors.

Capodanno D. Heart 2018;0:1–8. doi:10.1136/heartjnl-2017-312228 7

Education in Heart
Competing interests  Speaker’s and consulting fees from
AstraZeneca, Bayer and Sanofi-Aventis.
Patient consent  Not required.
Provenance and peer review  Commissioned; externally peer
reviewed.
Author note  References that include an asterisk (*) are
considered to be key references.
© Article author(s) (or their employer(s) unless otherwise stated in
the text of the article) 2018. All rights reserved. No commercial use
is permitted unless otherwise expressly granted.
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