Therapeutic Advances in Hematology Review

The role of oral anticoagulant therapy in

Ther Adv Hematol

2017, Vol. 8(12) 353–366

patients with acute coronary syndrome DOI: 10.1177/

2040620717733691
© The Author(s), 2017.
Reprints and permissions:
Jae Youn Moon, Deepa Nagaraju, Francesco Franchi, Fabiana Rollini http://www.sagepub.co.uk/
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and Dominick J. Angiolillo

Abstract: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor antagonist
represents the current standard of care to prevent atherothrombotic recurrences in patients
with acute coronary syndrome (ACS). However, despite the use of DAPT, the recurrence
rate of cardiovascular ischemic events still remains high. This persistent risk may be in part
attributed to the sustained activation of the coagulation cascade leading to generation of
thrombin, which may continue to play a key role in thrombus formation. The use of vitamin
K antagonists (VKAs) as a strategy to reduce atherothrombotic recurrences after an ACS
has been previously tested, leading to overall unfavorable outcomes due to the high risk of
bleeding complications. The recent introduction of non-VKA oral anticoagulants (NOACs),
characterized by a better safety profile and ease of use compared with VKA, has led to
a reappraisal of the use of oral anticoagulant therapy for secondary prevention in ACS
patients. The present article provides an overview of the rationale and prognostic role of oral
anticoagulant therapy in ACS patients as well as recent updated clinical data, in particular
with NOACs, in the field and future perspectives on this topic.

Keywords: acute coronary syndrome, coagulation cascade, non-vitamin K antagonist oral

anticoagulants, thrombin

Received: 23 May 2017; revised manuscript accepted: 4 September 2017.

Introduction patients with non-ST-segment elevation ACS

Cardiovascular disease in general and the devel- (NSTE-ACS) are more commonly characterized
opment of an acute coronary syndrome (ACS) in by partial vessel occlusion.2
Correspondence to:
particular is among the leading causes of morbid- Dominick J. Angiolillo
ity and mortality.1 The main pathophysiological These pathophysiological considerations under- University of Florida
College of Medicine –
mechanism leading to an ACS is represented by score how inhibition of both platelets and coagu- Jacksonville, 655 West 8th
thrombus formation in the coronary artery fol- lation factors are essential for the treatment and Street, Jacksonville, FL
32209, USA
lowing erosion or rupture of an atherosclerotic secondary prevention of ACS patients. Dual anti- dominick.angiolillo@jax.
plaque.2 After initial plaque erosion/rupture, a platelet therapy (DAPT) including aspirin and a ufl.edu

cascade of events driven by cellular (i.e. platelets) P2Y12 receptor antagonist represents the gold Jae Youn Moon
Division of Cardiology,
and plasma (i.e. coagulation factors) components standard antithrombotic treatment regimen to pre- University of Florida
leading to thrombus formation has a pivotal role vent atherothrombotic recurrences.5,6 Currently, College of Medicine
– Jacksonville, FL, USA
in this process. Thrombus formation in the coro- three oral P2Y12 receptor inhibitors including Department of Cardiology,
nary artery ultimately culminates in complete or clopidogrel, prasugrel and ticagrelor are approved CHA Bundang Medical
Center, CHA University,
partial vessel occlusion contributing to the con- for clinical use in ACS patients.7–9 Prasugrel and Seongnam, Korea
stellation of signs and symptoms that characterize ticagrelor are characterized by enhanced potency Deepa Nagaraju
Francesco Franchi
patients presenting with an ACS. 2–4 In particular, over clopidogrel and better net clinical outcomes Fabiana Rollini
most patients presenting with an ST-segment- in ACS patients.7,8 Accordingly, guidelines sup- Division of Cardiology,
elevation myocardial infarction (STEMI) have a port their preferential use in ACS settings.10–13 University of Florida
College of Medicine –
completely occluded coronary artery, while Anticoagulant therapy, typically parenteral Jacksonville, FL, USA

journals.sagepub.com/home/tah 353
Therapeutic Advances in Hematology 8(12)
agents, is commonly used in the acute phase of
ACS presentations. However, following the intro-
duction of DAPT, the use of oral anticoagulant
therapy, in particular vitamin K antagonists
(VKAs), for long-term management of ACS
patients has been largely abandoned. Nonetheless,
the recent introduction of non-VKA oral antico-
agulants (NOACs), characterized by a better
safety profile and ease of use compared with
VKAs, has led to a reappraisal of the option of
using oral anticoagulant therapy for secondary
prevention in ACS patients.14
The present manuscript will present an overview
of the rationale and potential role of oral antico-
agulant therapy in patients with ACS, as well as
the available clinical data in the field and future
perspectives on this topic. The use of oral anti-
coagulants for other indications, including atrial
fibrillation (AF), among patients with coronary
artery disease (CAD) will not elaborated in this
manuscript and is described in details
elsewhere.15,16
Platelet activation and coagulation cascade
Thrombus formation after rupture or erosion of
an atherosclerotic plaque in the arterial wall is
known to be the main pathophysiological mecha-
nism leading to the development of an ACS. 2–4
After plaque rupture or superficial erosion, a cas-
cade of events consisting of platelet adhesion,
activation and aggregation in conjunction with
thrombin formation contributes to thrombus for-
mation and vascular occlusion.2–4 In particular,
von Willebrand factor (vWF) that binds to the
collagen on the exposed extracellular matrix at
the site of plaque rupture or erosion interacts with
the glycoprotein (GP) Ib/V/IX receptor complex
on the platelet surface.3,4,17,18 Subsequently, col-
lagens from the subendothelium at the site of vas-
cular injury bind to GP VI on the platelet surface.
This leads to conformational changes in platelet
structure and release of various factors which pro-
mote platelet activation, including thromboxane
A2 (TxA2), adenosine diphosphate (ADP) and
thrombin.3,4,18 The final process of platelet activa-
tion is represented by the conformational change
of the platelet GP IIb/IIIa receptor to its active
form, which allows it to bind to fibrinogen, pro-
moting platelet aggregation and contributing to
final thrombus formation (Figure 1).
In parallel with the platelet cascade described
above, the exposed extracellular matrix also
354
induces activation of the coagulation cascade
which leads to thrombin generation.4,19 Tissue
factor (TF), locally exposed to the plasma at the
site of plaque rupture, binds to Factor VIIa
(FVIIa) to form an activated TF/FVIIa complex.
This complex activates Factor IX and Factor X
into Factor IXa and Factor Xa. The following
combination of Factor IXa and Factor VIIIa form
the intrinsic tenase (FVIIIa/FIXa), which con-
tributes to the conversion of Factor X to Factor
Xa (FXa). FXa and Factor Va lead to formation
of the prothrombinase complex (FVa/FXa),
which cleaves Factor II (prothrombin) to gener-
ate Factor IIa (thrombin).20,21 In the propagation
phase of the coagulation cascade, both the FVIIIa/
FIXa and FVa/FXa complexes gather on the acti-
vated platelet surface and promote the burst in
thrombin generation (Figure 2). Thrombin is a
serine protease and has multifunctional proper-
ties in thrombus formation. Thrombin mediates
the conversion of fibrinogen to fibrin, which is
essential to form a thrombus. In particular, fibrin
monomers polymerize to form a fibrin-rich clot
and this clot is stabilized by crosslinking with
Factor XIIIa. In addition, thrombin plays an
essential role in platelet activation via binding to
protease activator receptors (PARs)-1 on the
platelet membrane.22,23
Rationale for anticoagulation therapy in ACS
patients
Thrombin generation plays a key role in the
pathophysiology of ACS. In particular, thrombin
contributes to platelet activation, enhancing acti-
vation of the coagulation cascade, overall favoring
thrombus formation and its associated complica-
tions.22 Therefore, anticoagulant therapy is criti-
cal in the acute care of ACS patients. Currently,
various parenteral anticoagulant agents are avail-
able for clinical use in the acute setting of ACS.
These include heparin (unfractionated form and
low molecular-weight heparin), bivalirudin (a
direct thrombin inhibitor) and fondaparinux (a
direct Factor Xa inhibitor).24 However, these
agents are used only for a short period of time,
essentially for the in-hospital phase of care of
ACS patients. Conversely, the use of oral antico-
agulant drugs has not traditionally been part of
the long-term management of ACS patients, par-
ticularly after the introduction of current regi-
mens of standard DAPT.
The rationale for supporting the use of DAPT in
patients experiencing an ACS is represented by
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 J Y Moon, D Nagaraju et al.

Figure 1. The process of platelet adhesion and aggregation.

The interactions between the GP Ib/V/IX receptor complex in platelet surface and vWF that immobilized on the collagen of
exposed extracellular matrix lead to subsequent binding between GP VI and exposed collagen. This interaction contributes
to the conformational change in platelet structure and release of TxA2, ADP and thrombin. TF locally triggers thrombin
formation, which bind to the platelet PAR-1 and this leads to enhance platelet activation. The released mediators carry
out their role in the activation of platelets via their platelet activation pathway. The final process of platelet activation is
the conformal change of platelet GP IIb/IIIa receptor to its active form, which binds to fibrinogen and contributes to final
thrombus formation. Reproduced with permission from Circulation Journal.4
ADP, adenosine diphosphate; GP, glycoprotein; PAR-1, protease activated receptor-1; thromboxane prostanoid receptor; TF,
tissue factor; TP receptor; TxA2, thromboxane A2; vWF, von Willebrand factor.

Figure 2. The cell surface-based coagulation process.

In the initiation phase, TF exposed to plasma at the plaque rupture site binds to Factor VIIa. Platelets are activated by vessel injury
simultaneously. The TF/Factor VIIa (TF/FVIIa) complex activates Factor X and Factor IX into Factor Xa and Factor IXa, and small
amounts of thrombinare generated by Factor Xa. In the amplification phase, thrombin activates Factor V, Factor VIII and Factor
XI, located on the platelets’ surfaces. In the propagation phase of the coagulation cascade, both Factor VIIIa/Factor IXa (FVIIIa/
FIXa) complex and Factor Va/Factor Xa (FVa/FXa) complex gather on activated platelet surfaces and leads to the burst of thrombin,
which is sufficient for fibrin monomers to polymerize to form a fibrin-rich clot. Finally, this clot is stabilized by crosslinking with
Factor XIIIa; thereafter, a thrombus is formed. Reproduced with permission from Thrombosis and Haemostasis (2012).21
GP, glycoprotein; PAR-1, protease activated receptor-1; TF, tissue factor; vWF, von Willebrand factor.

journals.sagepub.com/home/tah 355
Therapeutic Advances in Hematology 8(12)
the fact that thrombotic complications after an
ACS have been primarily considered a platelet-
mediated process.5,6 Currently, three oral P2Y12
receptor inhibitors – clopidogrel, prasugrel and
ticagrelor – are approved for clinical use in ACS
patients.7–9 Prasugrel and ticagrelor are character-
ized by enhanced potency over clopidogrel and
better net clinical outcomes in ACS patients.7,8
Accordingly, guidelines support their preferential
use in ACS settings.10–13 However, regardless of
the use of optimal DAPT regimens including
prasugrel and ticagrelor, recurrence rates of car-
diovascular ischemic events still remain high. 1
This persistent risk may be in part attributed to
the sustained generation of thrombin, which play
a key role in thrombus formation. Several studies
in fact support that thrombin generation is persis-
tently high in ACS patients after an acute epi-
sode.25–27 Biomarkers of persistent activation of
the coagulation system, such as prothrombin
fragment 1 + 2, D-dimer have been shown to be
associated with worse clinical outcomes.28 These
findings indicate that thrombotic complications
may not be prevented by antiplatelet therapy
alone and support the potential need for long-
term oral anticoagulant therapy to inhibit throm-
bin generation. The use of anticoagulant therapy
for long-term management of ACS patients, in
particular VKA, has been largely abandoned with
the use of DAPT. However, the recent introduc-
tion of NOACs, characterized by a better safety
profile and ease of use compared with VKA, has
led to a reappraisal of the need for using oral anti-
coagulant therapy for secondary prevention in
ACS patients, as described below.14
Vitamin K antagonists for the patients of
ACS
In the 1940s, intravenous unfractionated heparin
was used for the treatment of patients with myo-
cardial infarction (MI). Then VKAs were used as
oral anticoagulant therapy and had represented
the only oral agents for several decades.29
Warfarin, a representing drug of the VKA class,
inhibits multiple enzyme in the coagulation cas-
cade, including Factor II (prothrombin), Factor
VII, Factor IX, Factor X, protein C and protein
S. However, warfarin has several limitations
including drug–drug and food–drug interactions,
need for frequent monitoring, delayed onset and
offset of action (due to indirect action and long
half-life), and genetic variability in liver enzyme
metabolism.30 Although warfarin has been the
cornerstone of oral anticoagulation therapy for
356
the prevention of stroke in patients with AF for
several decades, its role in the treatment of ath-
erosclerotic events such as ACS is not clear.31–33
The AFTER (aspirin and anticoagulation follow-
ing thrombolysis with eminase in recurrent
infarction) study did not show any benefit of war-
farin monotherapy compared with aspirin 150
mg monotherapy in post-MI patients.34
Thereafter, warfarin monotherapy without aspi-
rin in post-MI patients was largely abandoned.35
There were several large-scale randomized clini-
cal trials comparing aspirin monotherapy with
dual therapy of aspirin plus warfarin. Among
these, the CARS (the Coumadin aspirin reinfarc-
tion study) and CHAMP (the combination
hemotherapy and mortality prevention) studies
were conducted in a relatively large number of
participants. The CARS study evaluated the role
of warfarin among 8803 patients with recent MI
(3–21 days after index MI). Patients were ran-
domly assigned to three groups: 160 mg of aspi-
rin monotherapy, 80 mg of aspirin and 1 mg of
warfarin, 80 mg of aspirin and 3 mg of warfarin. 31
After a median of 14 months, the addition of
warfarin to aspirin did not provide any benefit in
the reduction of rates of cardiovascular events
beyond that achieved from 160 mg of aspirin
monotherapy (one year estimated event rate,
8.6% in 160 mg of aspirin monotherapy, 8.8% in
80 mg of aspirin + 1 mg of warfarin, and 8.4% in
80 mg of aspirin + 3 mg of warfarin) and showed
increased rates of major bleeding. The CHAMP
study also compared a combination therapy of
warfarin and aspirin (81 mg) to aspirin mono-
therapy (162 mg) in 5059 patients with a recent
MI for a median follow up of 2.7 years. 32
Combination therapy did not demonstrate a
reduction of cardiovascular events compared to
aspirin monotherapy and the addition of warfarin
was significantly associated with an increased risk
of bleeding (1.28 versus 0.72 events, per 100 per-
son years, p < 0.001). In a meta-analysis includ-
ing 14 studies enrolling 25,307 MI patients, as
compared with aspirin monotherapy, combina-
tion of warfarin and aspirin was associated with a
27% relative risk reduction in the rates of all-
cause death, non-fatal MI or stroke only when
INR targets were between 2.0 and 3.0; however,
this occurred at the expense of increased major
bleeding.36
Overall, the addition of warfarin to aspirin mono-
therapy does not provide the clinical benefits
desired for the prevention of secondary events in
ACS patients, largely due to the increased risk of
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bleeding complications. There are no available
data of combined therapy with warfarin and
clopidogrel as well as with newer-generation
P2Y12 receptor inhibitors such as ticagrelor and
prasugrel. There is also limited evidence on the
use of ‘triple therapy’ (combination of warfarin
with DAPT), which, however, has shown to be
associated with a high risk of major bleeding in
registry data and thus is not recommended for
secondary prevention of ACS.35
Non-vitamin K antagonist oral
anticoagulants
Since VKAs inhibit the synthesis of coagulation
factors which are dependent on vitamin K, VKAs
are called indirect oral anticoagulants. On the
other hand, NOACs act directly on their target
(i.e. FXa or thrombin) and are thus called direct
oral anticoagulants.37 Because of these properties,
their anticoagulation effect is more prompt and
they also have more rapid offset of action com-
pared with warfarin. Direct thrombin inhibitors
directly bind to thrombin and prevent conversion
of fibrinogen into fibrin.38 Ximelagatran and
dabigatran etexilate were tested in clinical trials,
and currently dabigatran etexilate is the only oral
direct thrombin inhibitor used in clinical practice
for prevention of stoke in AF patients, as well as
treatment and prevention of venous thromboem-
bolism (VTE).39 The other group of NOACs is
represented by the direct FXa inhibitors. FXa is
upstream to prothrombin and its inhibition con-
tributes to the down-regulation of thrombin gen-
eration. The role of FXa inhibition in ACS
patients is supported by the result from paren-
teral use of the indirect FXa inhibitor fonda-
parinux in two large studies in the acute care
setting.40,41 Contrary to indirect agents, cofac-
tors, like antithrombin III, are not required for
the action of the direct FXa inhibitors which
directly target FXa activity.21 The oral direct
FXa inhibitors, including apixaban, rivaroxaban
and edoxaban, are currently used for the preven-
tion of stoke in AF patients and prevention/treat-
ment of VTE.39 Other oral FXa inhibitors
including darexaban, letaxaban and betrixaban
have been investigated in phase II clinical trials.
However, of all the clinically available NOACs,
only rivaroxaban has successfully completed
phase III investigation meeting its primary end-
point in ACS patients and has received approval
for clinical use for this indication. The individual
results of clinical trials for anticoagulation in
CAD are be described in detail below (Table 1).
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J Y Moon, D Nagaraju et al.
Ximelagatran
Ximelagatran, an oral direct thrombin inhibitor,
is the first NOAC that has been studied for the
reduction of ischemic recurrences in ACS
patients. After oral administration, ximelagatran
is rapidly converted to its active form, mela-
gatran.42 The ESTEEM trial (The efficacy and
safety of the oral direct thrombin inhibitor ximel-
agatran in patients with recent myocardial dam-
age trial) explored the safety and efficacy of
ximelagatran in ACS patients.43 A total of 1883
ACS patients (within 14 days of the index event)
were randomly assigned to ximelagatran [at twice
daily doses (BID) of 24 mg, 36 mg, 48 mg or 60 mg]
or placebo. Approximately, two-thirds of the total
study population were STEMI and about half of
these were treated with thrombolytic therapy.
Almost all patients received 160 mg of aspirin.
However, this study does not reflect current prac-
tice. For example, percutaneous coronary inter-
vention (PCI) performed in the past four months
or planned within two months of randomization
were excluded. Patients needing adjunctive oral
antiplatelet therapy, including P2Y12 receptor
inhibitors, and anticoagulants were excluded. In
the trial, the combination of ximelagatran and
aspirin significantly reduced the primary end-
point (defined by composite all-cause death, non-
fatal MI and severe recurrent ischemia) compared
with aspirin alone (HR 0.76, 95% CI 0.59–0.98,
p = 0.036) with a 3.6% absolute risk reduction of
the primary endpoint (12.7%, ximelagatran versus
16.3%, placebo). The frequency of major bleed-
ing was numerically higher in the ximelagatran
group (1.8% versus 0.9%, HR 1.97, 95% CI
0.80–4.84). However, elevation in liver enzymes
occurred with ximelagatran (about 12.2–13.0%
on the higher dose of ximelagatran). Because of
liver toxicity, ximelagatran was withdrawn from
commercialization.
Dabigatran
Dabigatran is the only oral direct thrombin inhib-
itor available for clinical use.39 After oral adminis-
tration of the pro-drug of dabigatran etexilate, the
serum esterase rapidly converts dabigatran etex-
ilate into dabigatran. The efficacy and safety of
dabigatran in ACS patients was investigated in
the phase II, dose-ranging RE-DEEM (rand-
omized dabigatran etexilate dose finding study in
patients with acute coronary syndromes post
index event with additional risk factors for cardio-
vascular complications also receiving aspirin and
clopidogrel) trial.44 A total of 1861 patients with
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Therapeutic Advances in Hematology 8(12)

Table 1. Phase II dose-escalation, clinical trials for the safety and efficacy of NOAC in ACS patients.
Ximelagatran Dabigatran Apixaban Rivaroxaban Darexaban (YM150) Letaxaban

Study name ESTEEM RE-DEEM APPRAISE ATLAS ACS-TIMI 46 RUBY-1 AXIOM ACS
Number of 1883 1861 1715 3491 1279 2753
patients
Baseline Aspirin 160 mg monotherapy Dual antiplatelet: Dual antiplatelet: Stratum 1: aspirin (75–100 Dual antiplatelet: Dual antiplatelet:
antiplatelet aspirin (<100 mg) + aspirin (<162 mg) + mg) monotherapy aspirin (75–325 mg) + aspirin + clopidogrel in 75.6%
therapy clopidogrel in 99.2% clopidogrel in 75.6% stratum 2: aspirin (75–100 clopidogrel in 97%
mg) + clopidogrel
Study duration 6 months 6 months 6 months 6 months 6 months 6 months
Daily dosage 24 mg BID 50 mg BID 2.5 mg BID 2.5 mg BID, 5 mg BID, 7.5 5 mg BID Stage 1: 10 mg BID, 20 mg BID,
36 mg BID 75 mg BID 10 mg QD mg BID (stratum 2 only), 10 10 mg QD 40 mg QD;
48 mg BID 110 mg BID 10 mg BID mg BID, 15 mg BID Stage 2: 40 mg BID, 80 mg QD,
60 mg BID 150 mg BID 20 mg QD 5 mg QD, 10 mg QD, 15 mg 30 mg QD 80 mg BID;
QD (stratum 2 only), 20 mg 30 mg BID Stage 3: 160 mg QD, 120 mg BID
QD 60 mg QD
Safety endpoint Major bleeding (its own ISTH major and ISTH major and TIMI major, TIMI minor, or ISTH major and clinically TIMI major bleeding
and bleeding definition) or bleeding clinically relevant non- clinically relevant non- requiring medical attention relevant non-major bleeding
definition leading to discontinuation. major bleeding major bleeding
Safety 24 mg: 3.57 (1.80–7.09) 50 mg: 1.82 (0.77–4.29) 2.5 mg BID: 1.78 2.5 mg BID: 1.71 (0.76–3.85) 10 mg QD: 1.78 (0.68–4.60) *TIMI major + minor bleeding
outcome, HR 36 mg: 1.63 (0.71–3.72) 75 mg: 2.44 (1.05–5.65) (0.91–3.48) 5 mg BID: 3.36 (2.21–5.09) 30 mg QD: 1.83 (0.71–4.75) Placebo: 0.9%
(95% CI) 48 mg: 4.37 (2.25–8.47) 110 mg: 3.56 (1.60–7.91) 10 mg QD: 2.45 7.5 mg BID: 3.41 (1.97–5.89) 60 mg QD: 2.43 (0.98–5.97) 10 mg BID: 0.4%
60 mg: 3.80 (1.94–7.46) 150 mg: 3.88 (1.73–8.74) (1.31–4.61) 10 mg BID: 4.80 (3.09–7.45) 5 mg BID: 2.05 (0.81–5.15) 20 mg BID: 1.6%
5 mg QD: 2.73 (1.38–5.37) 15 mg BID: 2.27 (0.92–5.59) 40 mg QD: 0.4%
10 mg QD: 3.35 (2.21–5.09) 30 mg BID: 3.80 (1.66–8.68) 40 mg BID: 3.7% (p < 0.01)
15 mg QD: 3.69 (2.17–6.29) 80 mg QD: 3.6% (p < 0.01)
20 mg QD: 5.32 (3.46–8.18) 80 mg BID: 2.8%
160 mg QD: 1.2%
120 mg BID: 3.2% (p < 0.05)
Efficacy Ximelagatran reduced the No significant difference Showing the tendency Rivaroxaban non-significantly No significant difference in No significant differences in CV
outcome death, non-fatal MI and in cardiovascular in reduction of CV reduced death, MI, stroke, death, non-fatal MI, non-fatal death, non-fatal MI, non-fatal
HR (95% CI) severe recurrent ischemia: ischemic events death, MI, severe severe recurrent ischemia stroke or severe recurrent stroke or myocardial ischemia
0.76 (0.59–0.98, p = 0.036) recurrent ischemia or requiring revascularization: ischemia requiring hospitalization
ischemic stroke 0.79 (0.60–1.05, p = 0.10)
Other findings Liver enzyme elevation Reduced D-dimer 10 mg BID and 20 mg Rivaroxaban reduced death, The rate of efficacy endpoint was
(about 12.2–13.0% on the concentrations in QD arms were stopped MI or stroke: 0.69 (0.50–0.96, numerically higher than placebo
higher dose of ximelagatran) dabigatran groups because of bleeding p = 0.027) in daily 30 mg and 60 mg.
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*The incidences of the primary bleeding endpoint, TIMI major bleeding, in each dose were low, so we present the composite of TIMI major and minor bleeding.
ACS, acute coronary syndrome; BID, twice daily; CI, confidence intervals; CV, cardiovascular; HR, hazard ratio; ISTH, International Society of Thrombosis and Haemostasis; MI, myocardial infarction; NOAC, non-
vitamin K antagonist oral anticoagulants; QD, once daily.

recent STEMI or NSTEMI were randomly
assigned to different doses of dabigatran (dabi-
gatran 50 mg BID, 75 mg BID, 110 mg BID, 150
mg BID) or placebo. At the time of randomiza-
tion, 99.2% of patients were already on DAPT
with aspirin plus clopidogrel and 83.8% of
patients continued DAPT until the end of the
study. The primary endpoint of this study was the
rate of major and clinically relevant minor bleed-
ing. The assessment of major bleeding was based
on the International Society of Thrombosis and
Haemostasis (ISTH) definition. There was a
dose-dependent increase in the rate of the pri-
mary endpoint compared to placebo (2.2% in
placebo group, 3.5% in 50 mg BID group, 4.3%
in 75 mg BID, 7.9% in 110 mg BID and 7.8% in
150 mg BID). Dabigatran was not associated
with any ischemic benefit. It significantly reduced
coagulation activity, such as D-dimer concentra-
tion.44 Further investigations, including phase III,
of dabigatran in ACS patients have not been con-
ducted after the RE-DEEM trial.
Apixaban
Apixaban is a selective direct-acting FXa inhibitor
which affects both free and prothrombinase-bound
FXa.39 The half-life of apixaban is approximately
12 h and it is eliminated through multiple path-
ways, including hepatic metabolism, renal clear-
ance and biliary secretion.39 The safety and efficacy
of apixaban in ACS patients were explored in the
phase II, dose-ranging APPRAISE trial.45
APPRAISE enrolled 1715 patients with recent
STEMI or NSTE-ACS. Aspirin was used in almost
all patients and clopidogrel was used in 76% of
cases. Patients were randomly allocated to receive
apixaban [one of four different doses; 2.5 mg BID,
10 mg QD (once daily), 10 mg BID, 20 mg QD] or
placebo. The primary outcome was major bleeding
(by ISTH definition) and clinically relevant non-
major bleeding during 6-month clinical follow up.
Apixaban 2.5 mg BID demonstrated a non-signifi-
cant increase in the primary outcome compared to
placebo (HR 1.78, 95% CI 0.91–3.48, p = 0.09)
and the 10 mg QD dose resulted in a significant
increase in the primary outcome (HR 2.45, 95%
CI 1.31–4.61, p = 0.005). Both the 10 mg BID
and 20 mg QD arms were stopped due to excess
bleeding. Although apixaban showed dose-
dependent increased bleeding, a trend in reducing
ischemic events was also demonstrated. Overall,
the addition of apixaban to ACS patients treated
with DAPT was associated with dose-related
increase in bleeding events, with modest benefit in
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J Y Moon, D Nagaraju et al.
the reduction of ischemic events (rate of ischemic
event; 7.6% in 2.5 mg BID, 6.0% in 10 mg QD,
8.7 % in placebo).
Based on the result of the APPRAISE trial, a 5 mg
BID dose of apixaban was investigated in addition
to DAPT after an ACS event in the large-scale,
phase III APPRAISE-2 trial.46 Among the base-
line characteristics of study participants, 59% of
patients were ⩾ 65 years old, 47.8% of patients
had diabetes mellitus, 10.0% of patients had a
prior stroke and 28.9% of patients had impaired
renal function. With a median follow up of
approximately 8 months, TIMI major bleeding
(primary safety outcome) occurred in 1.3% and
0.5% of patients in the apixaban and placebo
groups, respectively (HR 2.59, 95% CI 1.50–4.46,
p = 0.001). In addition, apixaban was associated
with an increase in fatal bleeding events and
intracranial bleeding (ICH) compared to placebo.
There was no reduction in ischemic events with
the primary efficacy outcome, defined as a com-
posite of cardiovascular death, MI or ischemic
stroke, occurring in 7.5% and 7.9% in the apixa-
ban and placebo groups, respectively. After
recruitment of 7392 participants, the APPRAISE-2
trial terminated prematurely because of increased
bleeding without clinical benefits.
Rivaroxaban
Rivaroxaban is a highly selective, direct FXa
inhibitor.39 Similarly to apixaban, it inhibits both
free FXa activity and prothrombinase-bound
FXa activity. Rivaroxaban has a half-life of 5–9 h,
and is eliminated through the renal (66%) and
fecal/biliary systems (28%). The safety and effi-
cacy of rivaroxaban in ACS patients (1–7 days
after the index event) was explored in the phase
II, dose-escalation ATLAS ACS-TIMI 46 trial.47
This trial had two strata based on the antiplatelet
treatment regimen used (stratum I: monotherapy
of aspirin 75–100 mg; stratum II: dual therapy of
aspirin 75–100 mg and clopidogrel). Patients (n =
3491) were randomized to placebo or different
doses (5–20 mg) of rivaroxaban (2.5 mg BID, 5 mg
BID, 7.5 mg BID, 10 mg BID, 5 mg QD, 10 mg
QD, 15 mg QD, 20 mg QD). During the 6-month
follow-up period, rivaroxaban showed a dose-
dependent increase in clinically significant bleed-
ing with a non-significant reduction in the primary
efficacy endpoint (death, MI, stroke or severe
recurrent ischemia requiring revascularization).
However, the secondary efficacy endpoints
(death, MI or stroke) was significantly decreased
359
Therapeutic Advances in Hematology 8(12)

Figure 3. The survival benefit of rivaroxaban 2.5 mg BID from the ATLAS ACS2 TIMI 51 trial.
(a) The efficacy of rivaroxaban 2.5 mg BID in reduction of the cardiovascular death, MI or stroke (the primary efficacy
endpoints) compared with placebo is presented (mITT p = 0.02, ITT p = 0.007). (b) There is a significant reduction in the rate
of CV death by 34% compared with placebo (mITT p = 0.002, ITT p = 0.005). (c) All-cause death reduced by 32% compared
with placebo (mITT p = 0.002, ITT p = 0.004). Reproduced with permission from Thrombosis and Haemostasis (2016).35
CV, cardiovascular; mITT, modified intention to treat; NNT, number needed to treat.

with rivaroxaban (HR 0.69, 95% CI 0.50–0.96, p
= 0.027). A dose of 2.5 mg BID was the only
regimen that did not show a statistically signifi-
cant increase in bleeding risk (HR 1.71, 95% CI
0.76–3.85), while this was significantly increased
with all other doses.
The findings from the ATLAS ACS-TIMI 46 trial
identified the most suitable dosing regimens of
rivaroxaban to be used in combination with DAPT,
which were applied in the phase III, ATLAS ACS
2-TIMI 51 study.48 In this trial, 15,526 patients
with a recent ACS were randomized to either rivar-
oxaban (2.5 mg BID or 5 mg BID) or placebo. 46
Among the baseline characteristics of study partici-
pants, 36.5% of patients were ⩾ 65 years old,
32.0% had diabetes mellitus and 50.3% of patients
were STEMI. Patients with a prior stroke were
excluded. The median time from the index event
to randomization was 4.7 days. Thienopyridines
(clopidogrel or ticlopidine) were used as a back-
ground antiplatelet therapy in 93% of the patients.
The trial showed a significant reduction in the pri-
mary efficacy endpoint (a composite of cardiovas-
cular death, MI or stroke) with rivaroxaban
compared with placebo after mean treatment
duration of 13.1 months (8.9%, rivaroxaban versus
10.7%, placebo; HR 0.84, 95% CI 0.74–0.96, p =
0.008). In particular, both dosing regimens showed
a significant reduction in the primary efficacy end-
point (8.8% in 5 mg BID and 10.7% in placebo,
p = 0.03; 9.1% in 2.5 mg BID dose and 10.7% in
placebo, p = 0.02). Most importantly, a survival
benefit was achieved with the 2.5 mg BID regi-
men; in particular, there was a significant reduc-
tion in cardiovascular death (2.7% in 2.5 mg BID
and 4.1% in placebo, p = 0.002) and death from
any cause (2.9% in 2.5 mg BID dose and 4.5% in
placebo, p = 0.002) (Figure 3). However, no sur-
vival benefit compared to placebo was demon-
strated with the 5 mg BID regimen. Rivaroxaban
was associated with a significant increase in non-
coronary artery bypass grafting (CABG)-related
major bleeding (2.1% in rivaroxaban and 0.6% in
placebo, p < 0.001) and ICH (0.6% in rivaroxa-
ban and 0.2% in placebo, p = 0.009). The rate of
TIMI bleeding requiring medical attention was also
increased with rivaroxaban (14.5% versus 7.5%, p <
0.001). Overall, the 5 mg BID dose was associated
with more bleeding, including fatal bleeding (5 mg
BID: 0.4% versus 2.5 mg BID: 0.1%, p = 0.004)
compared with the 2.5 mg BID dose. The lower
rate of fatal bleeding with the 2.5 mg BID dose
may indeed have contributed to its survival bene-
fit. Overall, the ATLAS ACS 2 trial demonstrated
that the addition of low-dose rivaroxaban (2.5 mg
BID regimen) to DAPT with aspirin and clopi-
dogrel reduced recurrent cardiovascular events,
including mortality, in patients with a recent
ACS at the expense of three-fold increased
major bleeding, but with no increase in fatal
bleeding. To date, the only reported subgroup

360 journals.sagepub.com/home/tah

analysis of the ATLAS ACS 2 trial is that on
patients with STEMI (n = 7817). In this analy-
sis, rivaroxaban reduced the incidence of the
primary efficacy endpoint consistently with the
overall trial results (8.7% with 2.5 mg BID,
8.2% with 5 mg BID and 10.6% with placebo).49
Rivaroxaban was also associated with an increase
of major bleeding rate, but there was no signifi-
cant increase in fatal bleeding in the STEMI
subgroup.
The result of the two phase III trials, ATLAS
ACS 2 and APPRAISE-2, which investigated the
long-term use of NOACs in post-ACS patients
are discordant. One probable reason for the con-
flicting results may be attributed to the character-
istics of the study population. The study
participants of APPRAISE-2 were older and had
more comorbidities, including more diabetes and
renal dysfunction. Importantly, patients with
prior stroke who were excluded in ATLAS ACS 2
were enrolled in the APPRAISE-2 trial. The
higher risk profile of patients enrolled in the
APPRAISE-2 trial is also supported by the higher
ischemic event rate. The second possible reason
is the level of anticoagulant effects achieved in the
two studies. The APPRAISE-2 trial tested 5 mg
BID of apixaban, which is the same dose used for
stroke prevention in AF patients. On the con-
trary, in ATLAS ACS 2 there was a survival ben-
efit with the 2.5 mg BID daily dose, which is
one-quarter of the total daily dose of rivaroxaban
used in AF.14 Therefore, the high levels of antico-
agulant effect when added to DAPT in ACS
patients may not provide benefits due to the high
risk of bleeding complications.
Given the survival benefit presented in the
ATLAS ACS 2 trial, the 2.5 mg BID regimen of
rivaroxaban with aspirin alone or with DAPT
obtained regulatory approval from the European
Medicines Agency (EMA) for secondary preven-
tion in ACS patients with elevated cardiac bio-
markers.50 However, rivaroxaban has not been
approved by the Food and Drug Administration
(FDA) for the ACS indication due to concerns
regarding missing data in the pivotal trial. The
addition of low-dose rivaroxaban (2.5 mg BID for
one year) is now considered within the European
Society of Cardiology guidelines on NSTE-ACS
and STEMI.11,12 In particular, in NSTEMI
patients without history of prior stroke/TIA and
at high ischemic risk as well as low bleeding risk
receiving aspirin and clopidogrel, low-dose rivar-
oxaban (2.5 mg BID) may be considered after
journals.sagepub.com/home/tah
J Y Moon, D Nagaraju et al.
discontinuation of parenteral anticoagulation
(Class IIb, level of evidence B);12 in selected
STEMI patients who receive aspirin and clopi-
dogrel, low-dose rivaroxaban (2.5 mg BID) may
be considered if the patient is at low bleeding risk
(Class IIb, level of evidence B).11
The observations from the ATLAS ACS 2 trial
have led to questions on how to enhance the safety
profile of rivaroxaban while maintaining efficacy.
Recently, there has been emerging interest in
exploring whether withdrawing aspirin from novel
antithrombotic treatment regimens could be a
potential approach to reaching this goal.51,52 The
rationale behind this is that in the presence of
other antithrombotic agents, aspirin may not pro-
vide further ischemic benefit, but simply enhance
the risk of bleeding complications, in particular
gastrointestinal. The bleeding risk of low-dose
rivaroxaban (in addition to a P2Y12 receptor
inhibitor) without aspirin was evaluated in the
phase II, GEMINI-ACS-1 (A study to compare
the safety of rivaroxaban versus acetylsalicylic acid
in addition to either clopidogrel or ticagrelor ther-
apy in participants with acute coronary syn-
drome-1) trial.53 A total of 3037 ACS patients
were randomly assigned to 2.5 mg BID rivaroxa-
ban versus 100 mg aspirin (1:1 ratio) in addition to
a P2Y12 receptor inhibitor in a double-blind fash-
ion. The choice of the P2Y12 receptor inhibitor
(ticagrelor or clopidogrel) was not randomized,
and was left at the discretion of the investigator.
TIMI non-CABG-related clinically significant
bleeding, the primary endpoint of this trial, was
similar in both groups at 12-month follow up
(rivaroxaban: 5% versus aspirin: 5%, p = 0.584).
The rates of TIMI major bleeding and ICH were
very low and not significantly different between
groups (TIMI major bleeding, rivaroxaban 1%
versus aspirin 1%; ICH, rivaroxaban <1% versus
aspirin 0%). The rate of the primary endpoint was
similar between the two groups both in the tica-
grelor stratum (rivaroxaban 7% versus aspirin 6%)
and in the clopidogrel stratum (rivaroxaban 3%
versus aspirin 3%). There was a significant increase
in bleeding with ticagrelor compared to clopi-
dogrel (p = 0.0006). The exploratory ischemic
endpoint (CV death, MI, stroke or definite stent
thrombosis) was also similar between groups
(rivaroxaban 5% versus aspirin 5%, p = 0.73).
Overall, the findings from the GEMINI-ACS-1
trial suggest that the use of low-dose rivaroxaban
with ticagrelor without aspirin was associated with
an acceptable safety profile compared with DAPT
with aspirin and ticagrelor.
361
Therapeutic Advances in Hematology 8(12)
Darexaban (YM150)
The tolerability and safety of darexaban (YM150),
another direct FXa inhibitor, in ACS patients was
tested in the phase II, RUBY-1 [A randomized,
double-blind, placebo controlled trial of the safety
and tolerability of the novel oral Factor Xa inhibitor
darexaban (YM150) following ACS] trial.54 In this
trial, a total of 1279 patients with recent NSTEMI
or STEMI were enrolled and randomly assigned to
different doses of darexaban (5 mg BID, 10 mg
QD, 15 mg BID, 30 mg QD, 30 mg BID, 60 mg
QD) or placebo. There were higher rates of major
(by ISTH definition) and clinically relevant non-
major bleeding in a dose-dependent manner with all
dosing regimens of darexaban compared to placebo
without any improvement in efficacy endpoints (the
composite of death, MI, stroke, systemic thrombo-
embolism and severe recurrent ischemia). After the
RUBY-1 trial, the development of darexaban for
ACS patients was halted.
Letaxaban (TAK-442)
The safety and tolerability of letaxaban were tested
in the AXIOM ACS (Safety and efficacy of TAK-
442 in subjects with acute coronary syndromes)
trial.55 The AXIOM ACS trial was a dose-ranging,
phase II trial that enrolled 2753 ACS patients.
This trial explored a wide range of letaxaban doses
(from 10 mg BID to 120 mg BID). The rate of
TIMI major bleeding, the primary endpoint of this
study, was not significantly different between
groups (0.9% in letaxaban versus 0.5% in placebo,
p = 0.47). However, the composite rate of TIMI
major and minor bleeding was more frequent with
letaxaban (2.1% versus 0.9%, p = 0.025). The effi-
cacy endpoint was similar between letaxaban and
placebo. There has not been further testing for
ACS patients with letaxaban.
Edoxaban
Edoxaban is a direct oral Factor Xa inhibitor used
for the prevention of ischemic stroke in AF
patients as well as for the prevention/treatment of
VTE.39 However, there have not been any studies
assessing edoxaban in ACS patients.
Clinical trial update
Large randomized trials have either been recently
completed or are completing enrollment which are
assessing the safety and efficacy of oral anticoagu-
lant therapy, in particular rivaroxaban, in patients
with atherosclerotic disease manifestations, albeit
362
not selectively in patients with an ACS. The
COMPASS trial [Cardiovascular outcomes for
people using anticoagulation strategies trial
(ClinicalTrials.gov identifier: NCT01776424)]
was designed to evaluate the efficacy and safety of
low-dose rivaroxaban plus aspirin compared to
aspirin monotherapy for the prevention of
ischemic events in patients with CAD or periph-
eral artery disease (PAD). Patients were randomly
assigned to one of three groups (rivaroxaban
2.5 mg BID plus aspirin 100 mg; rivaroxaban
5 mg BID alone; or aspirin 100 mg alone). The
trial was stopped one year ahead of its scheduled
completion date after enrollment of 27,402
patients because rivaroxaban was shown to meet
its efficacy endpoint. In particular, rivaroxaban
plus aspirin showed better cardiovascular out-
comes, including reduced mortality, than with
aspirin alone, with consistent findings in the
CAD and PAD populations. Although the com-
bination group showed more major bleeding than
aspirin alone, there was no significant difference
in rate of ICH or fatal bleeding between these
two groups. Rivaroxaban monotherapy (5 mg
BID) did not result in better cardiovascular out-
comes than aspirin alone and showed more major
bleeding events.56 It is important to note that
only 62% of patients enrolled in COMPASS had
a prior ACS, and the mean time from this event
to randomization was 7.1 years. Therefore, the
observations from the COMPASS trial suggest
that there may be a role for adjunctive use of a
very low dose of rivaroxaban for secondary pre-
vention of ischemic events in the patients with
stable atherosclerotic disease, and should not be
considered as a post-ACS management strategy
until further information is available. The
VOYAGER PAD trial [Efficacy and safety of
rivaroxaban in reducing the risk of major throm-
botic vascular events in subjects with sympto-
matic peripheral artery disease undergoing
peripheral revascularization procedures of the
lower extremities trial (ClinicalTrials.gov identi-
fier: NCT02504216)] is investigating the role of
rivaroxaban in addition to the standard care of
PAD. This ongoing trial will enroll 6500 partici-
pants undergoing successful revascularization
procedure for symptomatic PAD, and rand-
omized to rivaroxaban 2.5 mg BID or placebo.
The use of clopidogrel is kept to the minimum
necessary in accordance with international prac-
tice guidelines. The primary endpoint is a first
occurrence of MI, ischemic stroke, CV death,
acute limb ischemia and major amputation for 2
years; results are anticipated in 2019.
journals.sagepub.com/home/tah

Future perspectives
Despite the use of standard of care DAPT with
aspirin and a P2Y12 receptor antagonist, the risk of
ischemic recurrences in ACS patients remains
high. The persistence of thrombin generation after
an ACS event may contribute to these observa-
tions, prompting investigators to reappraise the
role of long-term oral anticoagulant therapy in
these patients. Indeed, the introduction of the
NOACs, which have a more favorable safety pro-
file and ease of use compared with VKA, have
stimulated interest in this field of investigation. A
multitude of NOACs have been tested in the con-
text of ACS settings. However, only rivaroxaban
successfully completed phase III clinical investiga-
tion meeting its primary endpoint and has received
approval for clinical use in most parts of the world
(not in the United States) for patients with ACS.
However, despite the survival benefit observed
with rivaroxaban when used at a 2.5 mg BID regi-
men, in addition to standard of care therapy
including DAPT, the uptake of the drug for the
ACS indication has been very limited. Indeed, the
increased bleeding risk as well as the need to con-
sider a third antithrombotic agent contribute to
the lack of enthusiasm of physicians and patients
embracing this approach in clinical practice.
Encouraging data from recent trial results suggest
that withdrawal of aspirin therapy may be a safe
approach in patients treated with low-dose rivar-
oxaban plus ticagrelor. These investigations have
been prompted based on studies that have sug-
gested that there is limited antithrombotic efficacy
associated with aspirin therapy in the presence of
potent P2Y12 blockade, which has been associated
with modulation of other key platelet signaling
pathways, including thromboxane generation.57–59
Indeed larger investigations are warranted to sup-
port the efficacy of this strategy. Moreover, a bet-
ter understanding is needed to define the interplay
between NOACs and antiplatelet agents. In fact,
to date there is very limited data on this topic and
it is also unclear how NOACs with different tar-
gets (anti-FII versus anti-FX) impact the effects of
different classes of antiplatelet agents (COX-1
versus P2Y12 inhibitors).60,61 These studies will
indeed provide important insights on the safety
and efficacy findings from clinical trial data associ-
ated with their combined use. Ultimately, how to
bridge from acute to long-term care with oral anti-
coagulant therapy among patients who experi-
enced an ACS is also needed. Indeed, the results
from patients with a more recent ACS who were
enrolled in the COMPASS trial will provide fur-
ther insights on this topic.
journals.sagepub.com/home/tah
J Y Moon, D Nagaraju et al.
Conclusions
Over recent years there has been a reappraisal of
the use of oral anticoagulant therapy for secondary
prevention of ischemic recurrences in ACS
patients. This has been indeed facilitated by the
introduction of the NOACs, which have a favora-
ble safety profile and ease of use compared with
VKAs, which were tested in the same context a
few decades ago, leading to disappointing out-
comes due to the high risk of bleeding. Of the
clinically available NOACs, only rivaroxaban
when used at a 2.5 mg BID regimen, which is sub-
stantially lower than that used for stroke preven-
tion in AF patients, has shown to be associated
with an ischemic benefit, including a reduction in
mortality and has received regulatory approval for
clinical use in most countries across the globe.
However, risks of bleeding complications still
remain high when this regimen is added to stand-
ard DAPT, underscoring the need to define
antithrombotic treatment regimens that maintain
efficacy but minimize bleeding complications. A
current wave of investigations is evaluating
whether withdrawing aspirin therapy may repre-
sent a potential option to reach this goal. Indeed,
a number of ongoing pharmacodynamic and clini-
cal investigations will provide more insights on the
role of using long-term oral anticoagulant therapy
for secondary prevention in patients with cardio-
vascular disease manifestations.
Funding
This research received no specific grant from any
funding agency in the public, commercial or not-
for-profit sectors.
Conflict of interest statement
Dr. Angiolillo reports receiving payments as an indi-
vidual for: (a) consulting fee or honorarium from
Amgen, Aralez, AstraZeneca, Bayer, Biosensors,
Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli
Lilly, Janssen, Merck, PLx Pharma, Pfizer, Sanofi,
and The Medicines Company; (b) participation
in review activities from CeloNova and St. Jude
Medical. Institutional payments for grants from
Amgen, AstraZeneca, Bayer, Biosensors, CeloNova,
CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly,
Gilead, Janssen, Matsutani Chemical Industry Co.,
Merck, Novartis, Osprey Medical, and Renal Guard
Solutions; in addition, Dr. Angiolillo is recipient of
a funding from the Scott R. MacKenzie Foundation
and the NIH/NCATS Clinical and Translational
Science Award to the University of Florida UL1
TR000064 and NIH/NHGRI U01 HG007269,
outside the submitted work.
363
Therapeutic Advances in Hematology 8(12)
References
1. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart
disease and stroke statistics – 2017 update: a
report from the American Heart Association.
Circulation 2017; 135: e146–e603.
2. Libby P. Mechanisms of acute coronary
syndromes and their implications for therapy. N
Engl J Med 2013; 368: 2004–2013.
3. Davi G and Patrono C. Platelet activation and
atherothrombosis. N Engl J Med 2007; 357:
2482–2494.
4. Angiolillo DJ, Ueno M and Goto S. Basic
principles of platelet biology and clinical
implications. Circ J 2010; 74: 597–607.
5. Franchi F and Angiolillo DJ. Novel antiplatelet
agents in acute coronary syndrome. Nat Rev
Cardiol 2015; 12: 30–47.
6. Franchi F, Rollini F and Angiolillo DJ.
Antithrombotic therapy for patients with STEMI
undergoing primary PCI. Nat Rev Cardiol 2017;
14: 361–379.
7. Wiviott SD, Braunwald E, McCabe CH, et al.
Prasugrel versus clopidogrel in patients with acute
coronary syndromes. N Engl J Med 2007; 357:
2001–2015.
8. Wallentin L, Becker RC, Budaj A, et al.
Ticagrelor versus clopidogrel in patients with
acute coronary syndromes. N Engl J Med 2009;
361: 1045–1057.
9. Yusuf S, Zhao F, Mehta SR, et al. Effects of
clopidogrel in addition to aspirin in patients with
acute coronary syndromes without ST-segment
elevation. N Engl J Med 2001; 345:
494–502.
10. O’Gara PT, Kushner FG, Ascheim DD, et al.
2013 ACCF/AHA guideline for the management
of ST-elevation myocardial infarction: a report of
the American College of Cardiology Foundation/
American Heart Association Task Force on
Practice Guidelines. Circulation 2013; 127:
e362–e425.
11. Steg PG, James SK Atar D, et al. ESC Guidelines
for the management of acute myocardial
infarction in patients presenting with ST-segment
elevation. Eur Heart J 2012; 33: 2569–2619.
12. Roffi M, Patrono C, Collet JP, et al. 2015 ESC
Guidelines for the management of acute coronary
syndromes in patients presenting without
persistent ST-segment elevation: Task Force for
the Management of Acute Coronary Syndromes
in Patients Presenting without Persistent
ST-Segment Elevation of the European Society
of Cardiology (ESC). Eur Heart J 2016; 37:
267–315.
364
13. Amsterdam EA, Wenger NK, Brindis RG, et al.
2014 AHA/ACC guideline for the management
of patients with non-ST-elevation acute coronary
syndromes: a report of the American College of
Cardiology/American Heart Association Task
Force on Practice Guidelines. J Am Coll Cardiol
2014; 64: e139–e228.
14. De Caterina R, Husted S, Wallentin L, et al. New
oral anticoagulants in atrial fibrillation and acute
coronary syndromes: ESC Working Group on
Thrombosis-Task Force on Anticoagulants in
Heart Disease position paper. J Am Coll Cardiol
2012; 59: 1413–1425.
15. Angiolillo DJ, Goodman SG, Bhatt DL, et al.
Antithrombotic therapy in patients with atrial
fibrillation undergoing percutaneous coronary
intervention: a North American perspective –
2016 update. Circ Cardiovasc Interv 2016; 9.
16. Lip GY, Windecker S, Huber K, et al.
Management of antithrombotic therapy in
atrial fibrillation patients presenting with
acute coronary syndrome and/or undergoing
percutaneous coronary or valve interventions:
a joint consensus document of the European
Society of Cardiology Working Group on
Thrombosis, European Heart Rhythm
Association (EHRA), European Association
of Percutaneous Cardiovascular Interventions
(EAPCI) and European Association of Acute
Cardiac Care (ACCA) endorsed by the Heart
Rhythm Society (HRS) and Asia-Pacific Heart
Rhythm Society (APHRS). Eur Heart J 2014; 35:
3155–3179.
17. Brass LF. Thrombin and platelet activation. Chest
2003; 124: 18s–25s.
18. Varga-Szabo D, Pleines I and Nieswandt B. Cell
adhesion mechanisms in platelets. Arterioscler
Thromb Vasc Biol 2008; 28: 403–412.
19. Monroe DM, Hoffman M and Roberts HR.
Transmission of a procoagulant signal from tissue
factor-bearing cell to platelets. Blood Coagul
Fibrinolysis 1996; 7: 459–464.
20. Tanaka KA, Key NS and Levy JH. Blood
coagulation: hemostasis and thrombin regulation.
Anesth Analg 2009; 108: 1433–1446.
21. De Caterina R, Husted S, Wallentin L, et al.
General mechanisms of coagulation and targets
of anticoagulants (Section I). Position Paper
of the ESC Working Group on Thrombosis –
Task Force on Anticoagulants in Heart Disease.
Thromb Haemost 2013; 109: 569–579.
22. Angiolillo DJ, Capodanno D and Goto S.
Platelet thrombin receptor antagonism and
atherothrombosis. Eur Heart J 2010; 31:
17–28.
journals.sagepub.com/home/tah

23. Coughlin SR. Protease-activated receptors in
hemostasis, thrombosis and vascular biology. J
Thromb Haemost 2005; 3: 1800–1814.
24. Angiolillo DJ and Ferreiro JL. Antiplatelet and
anticoagulant therapy for atherothrombotic
disease: the role of current and emerging agents.
Am J Cardiovasc Drugs 2013; 13: 233–250.
25. Ardissino D, Merlini PA, Bauer KA, et al.
Coagulation activation and long-term outcome
in acute coronary syndromes. Blood 2003; 102:
2731–2735.
26. Merlini PA, Bauer KA, Oltrona L, et al.
Persistent activation of coagulation mechanism
in unstable angina and myocardial infarction.
Circulation 1994; 90: 61–68.
27. Christersson C, Oldgren J, Bylock A, et al.
Long-term treatment with ximelagatran, an oral
direct thrombin inhibitor, persistently reduces the
coagulation activity after a myocardial infarction.
J Thromb Haemost 2005; 3: 2245–2253.
28. Christersson C, Oldgren J, Bylock A, et al. Early
decrease in coagulation activity after myocardial
infarction is associated with lower risk of
new ischaemic events: observations from the
ESTEEM Trial. Eur Heart J 2007; 28: 692–698.
29. Ebert RV. Use of anticoagulants in acute
myocardial infarction. Circulation 1972; 45:
903–910.
30. De Caterina R, Husted S, Wallentin L, et al.
Vitamin K antagonists in heart disease: current
status and perspectives (Section III). Position
paper of the ESC Working Group on Thrombosis
– Task Force on Anticoagulants in Heart Disease.
Thromb Haemost 2013; 110: 1087–1107.
31. Coumadin Aspirin Reinfarction Study (CARS)
Investigators. Randomised double-blind trial
of fixed low-dose warfarin with aspirin after
myocardial infarction. Lancet 1997; 350: 389–
396.
32. Fiore LD, Ezekowitz MD, Brophy MT, et al.
Department of Veterans Affairs Cooperative
Studies Program Clinical Trial comparing
combined warfarin and aspirin with aspirin
alone in survivors of acute myocardial infarction:
primary results of the CHAMP study. Circulation
2002; 105: 557–563.
33. Rothberg MB, Celestin C, Fiore LD, et al.
Warfarin plus aspirin after myocardial infarction or
the acute coronary syndrome: meta-analysis with
estimates of risk and benefit. Ann Intern Med
2005; 143: 241–250.
34. Julian DG, Chamberlain DA and Pocock SJ.
A comparison of aspirin and anticoagulation
following thrombolysis for myocardial infarction
journals.sagepub.com/home/tah
J Y Moon, D Nagaraju et al.
(the AFTER study): a multicentre unblinded
randomised clinical trial. BMJ 1996; 313:
1429–1431.
35. De Caterina R, Husted S, Wallentin L, et al. Oral
anticoagulants in coronary heart disease (Section
IV). Position paper of the ESC Working Group
on Thrombosis – Task Force on Anticoagulants
in Heart Disease. Thromb Haemost 2016; 115:
685–711.
36. Andreotti F, Testa L, Biondi-Zoccai GG, et al.
Aspirin plus warfarin compared to aspirin alone
after acute coronary syndromes: an updated and
comprehensive meta-analysis of 25,307 patients.
Eur Heart J 2006; 27: 519–526.
37. Husted S, de Caterina R, Andreotti F, et al.
Non-vitamin K antagonist oral anticoagulants
(NOACs): no longer new or novel. Thromb
Haemost 2014; 111: 781–782.
38. Eisert WG, Hauel N, Stangier J, et al.
Dabigatran: an oral novel potent reversible
nonpeptide inhibitor of thrombin. Arterioscler
Thromb Vasc Biol 2010; 30: 1885–1889.
39. Chan NC, Eikelboom JW and Weitz JI. Evolving
treatments for arterial and venous thrombosis:
role of the direct oral anticoagulants. Circ Res
2016; 118: 1409–1424.
40. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects
of fondaparinux on mortality and reinfarction
in patients with acute ST-segment elevation
myocardial infarction: the OASIS-6 randomized
trial. JAMA 2006; 295: 1519–1530.
41. Yusuf S, Mehta SR, Fifth Organization to Assess
Strategies in Acute Ischemic Syndromes, et al.
Comparison of fondaparinux and enoxaparin in
acute coronary syndromes. N Engl J Med 2006;
354: 1464–1476.
42. Eriksson UG, Bredberg U, Hoffmann KJ, et al.
Absorption, distribution, metabolism, and
excretion of ximelagatran, an oral direct thrombin
inhibitor, in rats, dogs, and humans. Drug Metab
Dispos 2003; 31: 294–305.
43. Wallentin L, Wilcox RG, Weaver WD, et al.
Oral ximelagatran for secondary prophylaxis
after myocardial infarction: the ESTEEM
randomised controlled trial. Lancet 2003; 362:
789–797.
44. Oldgren J, Budaj A, Granger CB, et al.
Dabigatran versus placebo in patients with acute
coronary syndromes on dual antiplatelet therapy:
a randomized, double-blind, phase II trial. Eur
Heart J 2011; 32: 2781–2789.
45. APPRAISE Steering Committee and
Investigators, Alexander JH, Becker RC, et al.
Apixaban, an oral, direct, selective Factor Xa
365
Therapeutic Advances in Hematology 8(12)
inhibitor, in combination with antiplatelet
therapy after acute coronary syndrome: results of
the Apixaban for Prevention of Acute Ischemic
and Safety Events (APPRAISE) trial. Circulation
2009; 119: 2877–2885.
46. Alexander JH, Lopes RD, James S, et al. Apixaban
with antiplatelet therapy after acute coronary
syndrome. N Engl J Med 2011; 365: 699–708.
47. Mega JL, Braunwald E, Mohanavelu S, et al.
Rivaroxaban versus placebo in patients with acute
coronary syndromes (ATLAS ACS-TIMI 46): a
randomised, double-blind, phase II trial. Lancet
2009; 374: 29–38.
48. Mega JL, Braunwald E, Wiviott SD, et al.
Rivaroxaban in patients with a recent acute
coronary syndrome. N Engl J Med 2012; 366: 9–19.
49. Mega JL, Braunwald E, Murphy SA, et al.
Rivaroxaban in patients stabilized after a
ST-segment elevation myocardial infarction:
results from the ATLAS ACS-2-TIMI-51 trial
(Anti-Xa Therapy to Lower Cardiovascular
Events in Addition to Standard Therapy in
Subjects with Acute Coronary Syndrome –
Thrombolysis In Myocardial Infarction-51). J Am
Coll Cardiol 2013; 61: 1853–1859.
50. Xarelto (rivaroxaban). Summary of product
characteristics. www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Product_Information/
human/000944/WC500057108.pdf (accessed
April 2017).
51. Miyazaki Y, Suwannasom P, Sotomi Y, et al.
Single or dual antiplatelet therapy after PCI. Nat
Rev Cardiol 2017; 14: 294–303.
52. Gargiulo G, Windecker S, Vranckx P, et al.
A critical appraisal of aspirin in secondary
prevention: is less more? Circulation 2016; 134:
1881–1906.
53. Ohman EM, Roe MT, Steg PG, et al. Clinically
significant bleeding with low-dose rivaroxaban
Visit SAGE journals online
versus aspirin, in addition to P2Y12 inhibition,
journals.sagepub.com/ in acute coronary syndromes (GEMINI-ACS-1):
home/tah a double-blind, multicentre, randomised trial.
SAGE journals Lancet 2017; 389: 1799–1808.
366
54. Steg PG, Mehta SR, Jukema JW, et al. RUBY-1:
a randomized, double-blind, placebo-controlled
trial of the safety and tolerability of the novel oral
factor Xa inhibitor darexaban (YM150) following
acute coronary syndrome. Eur Heart J 2011; 32:
2541–2554.
55. Goldstein S, Bates ER, Bhatt DL, et al. Phase 2
study of TAK-442, an oral factor Xa inhibitor,
in patients following acute coronary syndrome.
Thromb Haemost 2014; 111: 1141–1152.
56. Eikelboom JW, Connolly SJ, Bosch J, et al.
Rivaroxaban with or without aspirin in stable
cardiovascular disease. N Engl J Med. Epub
ahead of print 27 August 2017. DOI: 10.1056/
NEJMoa1709118.
57. Warner TD, Armstrong PC, Curzen NP, et al.
Dual antiplatelet therapy in cardiovascular
disease: does aspirin increase clinical risk in the
presence of potent P2Y12 receptor antagonists?
Heart 2010; 96: 1693–1694.
58. Armstrong PC, Dhanji AR, Tucker AT,
et al. Reduction of platelet thromboxane A2
production ex vivo and in vivo by clopidogrel
therapy. J Thromb Haemost 2010; 8: 613–615.
59. Franchi F, Rollini F, Aggarwal N, et al.
Pharmacodynamic comparison of prasugrel
versus ticagrelor in patients with type 2 diabetes
mellitus and coronary artery disease: the
OPTIMUS (Optimizing Antiplatelet Therapy
in Diabetes Mellitus)-4 study. Circulation 2016;
134: 780–792.
60. Franchi F, Rollini F, Cho JR, et al. Effects of
dabigatran on the cellular and protein phase
of coagulation in patients with coronary artery
disease on dual antiplatelet therapy with aspirin
and clopidogrel: results from a prospective,
randomised, double-blind, placebo-controlled
study. Thromb Haemost 2016; 115: 622–631.
61. Perzborn E, Heitmeier S and Laux V. Effects of
rivaroxaban on platelet activation and platelet-
coagulation pathway interaction: in vitro and in
vivo studies. J Cardiovasc Pharmacol Ther 2015;
20: 554–562.
journals.sagepub.com/home/tah