REVIEWS

Oral factor Xa inhibitors for the long-term

management of ACS
James W. Wisler and Richard C. Becker
Abstract | Despite considerable reductions in cardiovascular events in patients with an acute coronary
syndrome (ACS) receiving dual antiplatelet therapy (DAPT), substantial residual risk persists. This unmet
need has stimulated the development of anticoagulant drugs that target specific coagulation factors involved
in the pathogenesis of thrombosis after atheromatous plaque disruption. Factor Xa is an attractive target
for inhibition because of both its integral role in coagulation and its recognized participation in cellular
proliferation and inflammation. Several oral, direct factor Xa inhibitors are undergoing investigation and large,
phase III clinical trials of two agents, apixaban and rivaroxaban, in patients with an ACS have been completed.
On the basis of the known pathobiology of ACS, one might anticipate that drugs in this class of anticoagulant
would beneficially reduce ischemic and thrombotic events; however, a strategy of combined anticoagulant
therapy and DAPT is likely to increase concomitant bleeding complications. The balance of benefit and risk will
ultimately determine uptake in clinical practice. We review the available data on factor Xa inhibitors in the
long-term management of patients with an ACS.
Wisler, J. W. & Becker, R. C. Nat. Rev. Cardiol. 9, 392–401 (2012); published online 21 February 2012; doi:10.1038/nrcardio.2012.18

Introduction
The development and clinical investigation of platelet
antagonists and their combined administration, referred
to as dual antiplatelet therapy (DAPT), has successfully
reduced ischemic and thrombotic events in patients
with an ST-segment or non-ST-segment elevation acute
coronary syndrome (ACS). Despite the benefit of DAPT,
substantial residual risk of ischemic complications per-
sists over time.1–3 One potential strategy to reduce this
risk is the addition of an anticoagulant to aspirin mono-
therapy or DAPT after initial hospital-based manage-
ment. Randomized clinical trials, have shown that the
addition of a vitamin K antagonist, such as warfarin, to
aspirin monotherapy reduces recurrent ischemic and
thrombotic events.4–6 To date, no clear benefit has been
identified from the addition of an oral anticoagulant to
DAPT, and increased bleeding seems likely with multi-
target antithrombotic strategies—both warfarin added
to aspirin monotherapy,4,6 and warfarin combined with
DAPT (aspirin and clopidogrel).7,8 Furthermore, the
use of vitamin K antagonists in patients with an ACS is
compli­cated by various inherent and well-recognized
limita­tions of this class of drugs—their narrow thera-
Division of Cardiology peutic index, variable dose–response relationships, inter­
(J. W. Wisler), Duke
Clinical Research actions with other drugs and food, and high propensity
Institute (R. C. Becker), for bleeding complications.9
Duke University
Medical Center,
Box 3850, 2400 Pratt Competing interests
Street, Durham, R. C. Becker declares associations with the following
NC 27705, USA.
companies: AstraZeneca, Bayer Pharmaceuticals, Bristol–Myers
Squibb, Daiichi Sankyo, Eli Lilly, Johnson & Johnson, The
Correspondence to:
R. C. Becker Medicines Company, Merck, Momenta, Regado Biosciences,
richard.becker@ and Schering–Plough. See the article online for full details of the
duke.edu relationships. J. W. Wisler declares no competing interests.
Novel anticoagulants that target specific coagula-
tion factors, such as thrombin and factor Xa, have been
developed in an attempt to overcome the limitations of
oral vitamin K antagonists. Factor Xa has emerged as an
attractive target for inhibition because of its prominent
role in the initiation, amplification, and propagation
phases of coagulation,10 as well as its participation in cel-
lular proliferation,11 apoptosis,12 matrix-metalloprotein
integrity,13 and inflammation.14
Preclinical studies of several oral, direct factor Xa
inhibitors have identified favorable characteristics of
these agents, which include a predictable dose–response
effect, rapid onset and relatively rapid offset of action, low
potential for interactions with other drugs and with food,
and a low risk of off-target effects.15 In addition, several of
these agents have demonstrated clinical efficacy to reduce
the incidence of various thrombotic disorders such as
venous thromboembolism (VTE) in patients undergoing
hip-replacement 16,17 or knee-replacement surgery,18,19 and
stroke or systemic embolism in patients with nonvalvu-
lar atrial fibrillation20–22 (the latter is separately reviewed
in this focus issue on anticoagulation therapies23). These
results, together with the recognized role of factor Xa
in the pathobiology of ACS, have sparked consider-
able interest in the potential use of factor Xa inhibitors
as an adjunct to monotherapy or DAPT for secondary
prevention after an ACS.
Cell-based model of coagulation
According to the cell-based model, coagulation occurs
in three overlapping phases.10 The first phase, ‘initia-
tion’ (Figure 1a), begins with vascular injury, such as

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 FOCUS ON ANTICOAGULATION THERAPIES

disruption of an atherosclerotic plaque, which exposes Key points

the subendothelial proteins collagen, tissue factor (Tf),
and collagen-bound von Willebrand factor (vWf ) to
circulating blood and Tf-bearing extravascular cells.10,24
Exposed collagen subsequently triggers adhesion and
activation of platelets, whereas exposed Tf forms a
complex with factor VIIa.25 The Tf–factor VIIa complex
activates both factor IX and factor X. If it leaves the cell
surface, factor Xa is rapidly inhibited by Tf pathway
inhibitor. However, any factor Xa molecules that remain
on the cell surface can combine with factor Va to produce
a small, but sufficient, amount of thrombin for platelet
activation.26 The process of platelet binding to exposed
extracellular-matrix proteins at the site of vascular injury
activates platelets and brings them into proximity with a
site of Tf exposure.10
In the second phase of coagulation, termed ‘ampli-
fication’ or ‘priming’ (Figure 1b), the initial proco-
agulant signal is amplified by the small amount of
thrombin generated on Tf-bearing cells via enhanced
platelet adhesion,27 full activation of platelets, and acti-
vation of factors V, VII, and XI. 26 During activation,
platelets release factor V from alpha granules onto their
surfaces in a partially active form.28 Factor V is then acti-
vated by either thrombin or factor Xa.29 Thrombin also
activates factor VIII and releases it from vWf by cleaving
platelet-bound vWf–factor VIII.30 Factor VIIIa remains
bound to the cell surface. Once platelets have been acti-
vated and factors Va and VIIIa have bound to the platelet
surface, assembly of coagulation proteins, formation of
enzymatically active protein complexes, and thrombin
generation begins.
The final phase of coagulation, ‘propagation’
(Figure 1c), begins with the assembly of the proco-
agulant ‘tenase’ and ‘prothrombinase’ complexes on the
cell surface.10 The tenase complex, which consists of
■■ Factor Xa is an attractive target for inhibition in patients with an acute coronary
syndrome (ACS) because of its roles in coagulation, cellular proliferation,
apoptosis, matrix-metalloprotein stability, and inflammation
■■ Four oral, competitive factor Xa inhibitors (apixaban, darexaban, letaxaban,
and rivaroxaban) have been investigated in patients with an ACS; only apixaban
and rivaroxaban have progressed to phase III clinical trials
■■ In the APPRAISE‑2 trial, addition of apixaban to standard therapy in patients
with an ACS showed no clinical benefit, and increased the risk of major and
intracranial bleeding
■■ In ATLAS ACS 2–TIMI 51, addition of rivaroxaban to dual antiplatelet therapy
(aspirin plus clopidogrel) reduced cardiovascular events and mortality, which
outweighed the increased bleeding risk
factor VIIIa and factor IXa, is formed when factor IX
reaches the cell surface. The tenase complex activates
factor X on the platelet surface. Factor Xa then binds
to factor Va, and forms the prothrombinase complex.
This complex subsequently initiates the conversion of pro-
thrombin to thrombin, and produces the burst of throm-
bin necessary for fibrin-clot formation. Factor Xa thus
serves as a participant and key mediator in each stage of
coagulation, and ultimately leads to thrombin generation.
Targeting factor Xa in ACS
In addition to having a vital role in each phase of coagu-
lation, factor Xa also exhibits a variety of cellular effects.
Binding of factor Xa to vascular endothelial cells is
associated with several events, including Tf expression,
release of plasminogen activator inhibitor 1, expression of
E‑selectin, intercellular adhesion molecule 1, and vascular
cell adhesion protein 1, and release of several inflamma-
tory cytokines, such as IL‑6 and IL‑8.11,31 Furthermore,
macrophages localized within atheromatous plaques can
synthesize factor Xa,32 which in turn stimulates leukocyte
chemotaxis and proliferation.33

a b c
Endothelial cell
Fibrin
Tf
Xa Va Xa Va
VIIa
Prothrombin
IX X Fibrinogen

X Thrombin Thrombin
IXa
VIII XIa Xa Va
V
VIIIa
Activated
VIIIa IXa platelet Prothrombin
Va IXa
Platelet Activated
platelet IX

Figure 1 | Cell-based model of coagulation, in which coagulation occurs in three overlapping phases. a | ‘Initiation’ begins
with endothelial injury. Exposed collagen and subendothelial proteins trigger adhesion and activation of platelets. Exposed Tf
forms a complex with factor VIIa. Tf–factor VIIa activates factor IX and factor X. Factor V is slowly activated by factor Xa.
Factor Xa then binds to factor Va and forms the prothrombinase complex, which generates small amounts of thrombin.
b | In the second phase, ‘amplification’ or ‘priming’, the initial procoagulant signal is amplified by small amounts of thrombin
generated on Tf-bearing cells. During activation, platelets release factor V, which is activated by either thrombin or factor Xa.
Thrombin also activates factor VIII. Upon platelet activation, factors Va and VIIIa bind to the platelet surface. c | The final
phase of coagulation, ‘propagation’, begins with assembly of procoagulant complexes on the cell surface. The tenase
complex (factor VIIIa and factor IXa) activates factor X on the platelet surface. Factor Xa then rapidly binds to factor Va
(generated by thrombin in the amplification phase), forming the prothrombinase complex, which initiates conversion of
prothrombin to thrombin, producing the thrombin burst necessary for fibrin-clot formation. Abbreviation: Tf, tissue factor.

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Table 1 | Pharmacokinetic and pharmacodynamic profiles of oral factor Xa inhibitors under development
Drug Dosing Time to Ki (nmol/l) Half-life (h) CYP Clearance Possible drug–drug Antidote
Cmax (h) metabolism interactions
Apixaban15,53,78 Twice daily 1–3  0.08 Once daily: 14  CYP3A4, 25% fecal Potent CYP3A4 Possibly recombinant
Twice daily: 9  CYP3A5 25% renal inhibitors* factor Xa derivative
(PRT 064445)
Betrixaban15,78,79 Once daily NR 0.12 19–20  None Almost entirely Low potential Possibly recombinant
unchanged in bile reported factor Xa derivative
<5% renal (PRT 064445)
Darexaban15,46,80,81 Once daily 1–1.5  0.03 14–18  NR Equally via fecal Minimal food NR
and renal routes interactions and no
reported drug–drug
interaction
Edoxaban15 Once daily 1–2  0.56 9–11  NR 65% fecal Potent CYP3A4 NR
35% renal inhibitors
P‑glycoprotein
inhibitors‡
Eribixaban48 Once daily NR 0.32 NR NR NR NR NR
Letaxaban Once daily 1–2  1.8 9–13  NR 30% renal NR NR
(TAK‑442)85,86
LY515711749,82 Once daily 0.5–4  4.6–6.6 25  NR Gastrointestinal NR NR
tract
Rivaroxaban83,84 Twice daily 2–4  0.4 Healthy: 5–9  CYP3A4, 66% renal Potent CYP3A4 Possibly recombinant
Elderly: 9–13  CYP2J2 34% fecal inhibitors factor Xa derivative
P‑glycoprotein (PRT 064445)
inhibitors‡
*Potent CYP3A4 inhibitors include ketoconazole, macrolides, verapamil, and protease inhibitors. 15 ‡Inhibitors of CYP3A4 and P‑glycoprotein include ketoconazole, itraconazole, voriconazole,
posaconazole, and ritonavir.15 Abbreviations: Cmax, peak plasma concentration; CYP, cytochrome P450; Ki, inhibitor dissociation constant; NR, not reported.

Factor Xa might be a more-attractive target for inhi-
bition than thrombin for several reasons. Coagulation
occurs in an amplified manner,34 with factor Xa func-
tioning at the confluence of several early steps (the initi­
ation and amplifi­cation phases) of coagulation on both
Tf-bearing cells and platelets.10 In addition, factor Xa is
more thrombo­genic than thrombin on a molar basis.35
Consequently inhibition of factor Xa might be a more-
efficient means to reduce fibrin formation than inhibi­
tion of thrombin. By contrast with direct thrombin
inhibitors, factor Xa inhibitors decrease endogenous
thrombin potential 36–38 and prolong the lag phase
of thrombin generation in a dose-dependent fashion.37
Direct inhibition of factor Xa has also been shown to
allow small amounts of thrombin generation and acti-
vation of vitamin K-dependent protein C, an important
contribution to vascular thromboresistance.38,39 This dif-
ferential effect might be at least partially responsible for
the rebound thrombophilia observed with some direct
thrombin inhibitors.40,41
For these reasons, targeting factor Xa in patients with
an ACS offers the potential to attenuate or modulate the
pluripotent effects of factor Xa. An illustration of benefit
from factor Xa inhibition, albeit in the acute management
of ACS, is found in the Organization to Assess Strategies
in Ischemic Syndromes trials, OASIS‑542 and OASIS‑6.43
The indirect, parenteral factor Xa inhibitor fondaparinux
demonstrated a significant reduction in bleeding compli-
cations, but no improvement in efficacy, compared with
enoxaparin in OASIS‑5,42 and superior efficacy with a con-
comitant reduction in bleeding complications compared
with unfractionated heparin in OASIS‑6.43
Clinical trials of factor Xa inhibitors in ACS
Several oral, direct factor Xa inhibitors (apixaban, 44
betrixaban, 45 darexaban, 46 edoxaban, 47 eribixaban, 48
letaxaban,49 LY5157117,50 and rivaroxaban51) have entered
clinical development for various indications, including
prevention of VTE after orthopedic surgery, treatment of
established VTE, stroke prevention in patients with non-
valvular atrial fibrillation, and secondary prevention after
an ACS. The pharmacokinetic and pharma­codynamic
characteristics of these drugs are summarized in Table 1.
Of these agents, apixaban, darexaban, letaxaban, and riva-
roxaban have been evaluated in phase II clinical trials in
patients with an ACS, but only apixaban and riva­roxaban
have progressed to phase III trials in these patients
(Table 2). The other agents have not been assessed in
patients with an ACS.
Apixaban
Apixaban is an oral, highly selective, direct-acting, revers-
ible inhibitor of factor Xa.52 The drug is rapidly absorbed
after oral administration, with a peak plasma concentra-
tion achieved after approximately 1 h.53 The half-life of
apixaban is 8–14 h,53 with approximately 25% of the drug
excreted in urine, 25% excreted in feces, and the remain-
ing portion metabolized by liver enzymes, including
cytochrome P450 3A4 and cytochrome P450 3A5.53–55
The phase  II Apixaban for Prevention of Acute
Ischemic and Safety Events (APPRAISE) trial44 was
an international, multicenter, double-blind, random-
ized, placebo-controlled, dose-finding study of apixa-
ban in patients with an ACS. Patients were eligible for
enrollment if they presented with an ACS (myocardial

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Table 2 | Features of the phase III trials of oral factor Xa inhibitors in patients with an ACS
Characteristics ATLAS ACS 2–TIMI 51 trial62,87
Inclusion criteria Patients aged ≥18 years with symptoms of ACS
(ST-segment MI, non-ST-segment MI, or unstable
angina) in past 7 days
Receiving standard medical therapy with either
aspirin or aspirin plus any thienopyridine
Patients aged 18–54 years also had to have
diabetes mellitus or previous MI
Key exclusion criteria Active bleeding
Platelet count <90,000/mm3
Hemoglobin <10 g/dl
Creatinine clearance <30 ml/min
History of intracranial bleeding
Clinically significant gastrointestinal bleeding in past
12 months
Ischemic stroke or TIA in patients who were taking
both aspirin and a thienopyridine
Key patient Mean age: 61 years
characteristics Aged ≥65 years: 36.5%
Previous MI: 26.9%
Diabetes mellitus: 32.0%
History of stroke or TIA: 2.7%
Concomitant aspirin only: 6.8%
Concomitant aspirin plus a thienopyridine: 93.2%
Treatment duration Rivaroxaban, mean 13.1 months
Abbreviations: ACS, acute coronary syndrome; APPRAISE‑2, Apixaban for Prevention of Acute Ischemic and Safety Events 2; ATLAS ACS 2–TIMI 51, Anti‑Xa
Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome 2—Thrombolysis in Myocardial Infarction 51;
MI, myocardial infarction; TIA, transient ischemic attack.
infarction [MI] with or without ST-segment elevation, or
unstable angina) in the past 7 days, were clinically stable,
were receiving standard treatment for ACS (including
aspirin alone or DAPT with aspirin and a thieno­pyridine),
and had at least one additional risk factor for recurrent
ischemic events (such as diabetes mellitus, cerebral or
peripheral vascular disease, congestive heart failure,
or a left ventricular ejection fraction <40%). The study
was conducted in two phases. In the first phase, patients
were assigned in a 1:1:1 fashion to placebo, apixaban
2.5 mg twice daily, or apixaban 10 mg once daily. After
approximately 25% of the patients had received the study
drug for 30 days, an independent data and safety moni-
toring committee recommended the inclusion of two
planned higher doses, 10 mg twice daily and 20 mg once
daily, in an attempt to gain more information on safety at
those doses. In the second phase, patients were assigned
in a 3:1:1:2:2 ratio to placebo, and apixaban 2.5 mg twice
daily, 10 mg once daily, 10 mg twice daily, and 20 mg
once daily, respectively.
The primary study outcome was occurrence of major
bleeding and clinically relevant nonmajor (CRNM) bleed-
ing as defined by the International Society on Thrombosis
and Haemostasis (ISTH).56 A secondary end point was the
composite of cardiovascular death, MI, severe recurrent
ischemia, or ischemic stroke. In total, 99.7% of patients
enrolled were treated with aspirin and 75.6% were receiv-
ing DAPT with aspirin and clopidogrel. Compared with
placebo, apixaban showed a significant, dose-dependent
increase in ISTH major and CRNM bleeding at both
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FOCUS ON ANTICOAGULATION THERAPIES
APPRAISE‑2 trial57
ACS in past 7 days
Clinically stable
Receiving standard medical therapy with either aspirin
or aspirin plus any thienopyridine
Two or more of the following high-risk characteristics:
age ≥65 years, diabetes mellitus, MI in past 5 years,
cerebrovascular disease, peripheral vascular disease,
clinical heart failure or ejection fraction <40% in
association with index event, creatinine clearance
<60 ml/min, no revascularization after index event
Active bleeding
Platelet count <100,000/mm3
Hemoglobin <9 mg/dl
Creatinine clearance <20 ml/min
History of intracranial bleeding
Persistent, severe hypertension
Median age: 69 years
Aged ≥65 years: 58.9%
Previous MI (in past 5 years): 26.2%
Diabetes mellitus: 47.8%
History of stroke or TIA: 10.0%
Concomitant aspirin only: 16%
Concomitant aspirin plus a thienopyridine: 81%
Apixaban, mean 175 days
2.5 mg twice daily (5.7% versus 3.0%; HR 1.78, 95% CI
0.91–3.48, P = 0.09) and 10 mg once daily (7.9% versus
3.0%; HR 2.45, 95% CI 1.31–4.61, P = 0.05). Substantially
higher rates of ISTH major bleeding and total bleeding
were also observed in patients taking apixaban 10 mg
twice daily and 20 mg once daily compared with patients
taking either of the lower doses. The rates of ISTH major
or CRNM bleeding were also more pronounced in
patients on DAPT plus apixaban compared with those
on DAPT who received a placebo.
The incidence of cardiovascular death, MI, severe
recurrent ischemia, or ischemic stroke was numerically,
but not significantly, decreased in patients who received
apixaban 2.5 mg daily (7.6% versus 8.7%; HR 0.73, 95% CI
0.44–1.19, P = 0.21) or 10 mg daily (6.0% versus 8.7%;
HR 0.61, 95% CI 0.35–1.04, P = 0.07) compared with
placebo. The dose-related reduction in ischemic events
in patients taking apixaban versus placebo was less pro-
nounced in those patients receiving concomitant DAPT.
The investigators concluded that, when comparing ISTH
major bleeding with the reduction in clinically important
ischemic events, apixaban 2.5 mg twice daily and apixa-
ban 10 mg once daily resulted in absolute net reductions
in clinical events in the overall study population of 0.3%
and 1.6%, respectively.
On the basis of the results of the APPRAISE trial,44
apixaban was investigated in the phase III APPRAISE‑2
study.57 APPRAISE‑2 was a multicenter, prospective,
randomized, double-blind, placebo-controlled trial in
which the efficacy and safety of apixaban in patients with
REVIEWS
an ACS were investigated. The key inclusion and exclu-
sion criteria are listed (Table 2). Patients were randomly
assigned in a 1:1 ratio to apixaban 5 mg twice daily or
a matched placebo. Those with an estimated creati-
nine clearance <40 ml/min were randomly assigned to
apixaban 2.5 mg twice daily or a matched placebo.
The primary efficacy outcome was the composite of
cardiovascular death, MI, or ischemic stroke, and the
primary safety outcome was major bleeding according
to the Thrombolysis in Myocardial Infarction (TIMI)
definition.58 Of 7,392 patients, 97% were taking aspirin
and 81% were receiving DAPT at the time of random-
ization. The trial was discontinued prematurely by the
data and safety monitoring committee because of an
increase in major bleeding events with apixaban in the
absence of a significant reduction in recurrent ischemic
events. The primary efficacy outcome was observed in
7.5% and 7.9% of patients receiving apixaban or placebo,
respectively (HR 0.95, 95% CI 0.80–1.11, P = 0.51). The
primary safety outcome occurred in 1.3% of patients
who received at least one dose of apixaban, and 0.5%
of patients who received at least one dose of placebo
(HR 2.59, 95% CI 1.50–4.46, P = 0.001). A greater
number of intracranial (0.3% versus 0.1%; HR 4.06,
95% CI 1.15–14.38, P = 0.03) and fatal (0.1% versus 0.0%)
bleeding events occurred with apixaban than placebo.
These findings were consistent across all subgroups,
including those defined by antiplatelet strategy (aspirin
monotherapy versus DAPT) and by ACS-management
strategy (revascularization versus noninvasive manage­
ment). The investigators concluded that the addition of
apixaban at a dose of 5 mg daily to antiplatelet therapy
after an ACS event increased the number of bleed-
ing events without a significant reduction in recurrent
ischemic events.
Rivaroxaban
Rivaroxaban is an oral, reversible, direct-acting factor Xa
inhibitor that is rapidly absorbed and reaches a maximum
plasma concentration in 2–4 h.59 In healthy and elderly
patients, the half-life is approximately 5–13 h.15 Rivaroxaban
has a dual mode of elimination. Approximately two-thirds
is degraded metabolically in the liver by pathways cata-
lyzed by cytochrome P450 enzymes (predominately cyto-
chrome P450 3A4 and cytochrome P450 2J2), with half
of the degradation products eliminated renally and half via
the fecal route.59–61 The other one-third is excreted renally
as the unchanged, active substance.
The phase II Anti‑Xa Therapy to Lower Cardiovascular
Events in Addition to Standard Therapy in Subjects with
Acute Coronary Syndrome—Thrombolysis in Myocardial
Infarction 46 (ATLAS ACS–TIMI 46) study 51 was a multi-
center, prospective, randomized, double-blind, placebo-
controlled, dose-escalation trial in which the efficacy
and safety of rivaroxaban were evaluated in approxi-
mately 3,500 patients with an ACS (ST-segment or non-
ST-­segment elevation MI, or unstable angina) event in
the past 7 days. In this study, all patients received stan-
dard antiplatelet therapy of either aspirin monotherapy
or aspirin and a thienopyridine at the discretion of the
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© 2012 Macmillan Publishers Limited. All rights reserved
physician. Patients were then randomly allocated to
receive either rivaroxaban or a matching placebo for
6 months. Escalating dose regimens from 5 mg to 20 mg
per day were administered once or twice daily. The
primary efficacy outcome was the composite of death,
MI, stroke, or severe recurrent ischemia that required
revasculari­zation. The primary safety end point was clini-
cally significant bleeding (TIMI major, TIMI minor, or
requiring medical attention).
Overall, treatment with rivaroxaban was associated
with a nonsignificant reduction in the primary compos-
ite efficacy outcome compared with placebo (5.6% versus
7.0%; HR 0.79, 95% CI 0.60–1.05, P = 0.10). A significant
reduction was observed for the main secondary efficacy
outcome, a composite of death, MI, or stroke, compared
with placebo (3.9% versus 5.5%; HR 0.69, 95% CI 0.50–
0.96, P = 0.027). A dose-dependent increase in the primary
safety end point was observed with rivaroxaban compared
with placebo (HR 2.21, 95% CI 1.25–3.91; HR 3.35, 95% 
CI 2.31–4.87; HR 3.60, 95% CI 2.32–5.58; HR 5.06, 95% CI
3.45–7.42, for rivaroxaban 5 mg, 10 mg, 15 mg, and 20 mg
given once daily or the same total dose given twice daily,
respectively; P <0.0001).
Because of the favorable efficacy rates observed with
rivaroxaban and the dose-dependent incidence in bleed-
ing, doses of 2.5 mg twice daily and 5 mg twice daily
were chosen for further assessment in the phase III
ATLAS ACS 2–TIMI 51 trial (Table 2).62 Researchers
investigated the use of rivaroxaban in addition to stan-
dard antiplatelet therapy (either aspirin monotherapy or
DAPT with aspirin and either clopidogrel or ticlopidine)
for the prevention of long-term adverse cardiovascular
events after an ACS. In total, 15,526 patients with an ACS
<7 days before enrollment were stratified according to
background antiplatelet therapy (aspirin or DAPT) and
randomly allocated within those strata in a 1:1:1 ratio to
receive rivaroxaban 2.5 mg twice daily, rivaroxaban 5 mg
twice daily, or a matched placebo. The primary efficacy
end point was a composite of cardiovascular death, MI,
or stroke. The primary safety end point was TIMI major
bleeding not associated with CABG surgery.
Rivaroxaban significantly reduced the rate of the
primary efficacy end point compared with placebo (8.9%
versus 10.7%; HR 0.84, 95% CI 0.74–0.96, P = 0.008;
Figure 2). The 2.5 mg twice-daily dose also resulted in
a significant reduction in death from cardiovascular
causes (2.7% versus 4.1%; HR 0.66, 95% CI 0.51–0.86,
P = 0.002) and death from any cause (2.9% versus 4.5%;
HR 0.68, 95% CI 0.53–0.87, P = 0.002) compared with
placebo. No survival benefit was observed with the 5 mg
twice-daily dose compared with placebo. Rivaroxaban
was associated with an increase in the primary safety
end point (2.1% versus 0.6%; HR 3.96, 95% CI 2.46–6.38,
P <0.001) and intracranial hemorrhage (0.6% versus
0.2%; HR 3.28, 95% CI 1.28–8.42, P = 0.009), without an
increase in fatal bleeding (0.3% versus 0.2%; HR 1.19,
95% CI 0.54–2.59, P = 0.66) compared with placebo.
The 2.5 mg twice-daily dose was associated with fewer
episodes of TIMI bleeding requiring medical atten-
tion (12.9% versus 16.2%; P <0.001) and fatal bleeding

(0.1% versus 0.4%; P = 0.04) than rivaroxaban 5 mg
twice daily. The investigators concluded that in patients
with a recent ACS event, treatment with rivaroxaban
reduced the risk of the composite end point of cardio­
vascular death, MI, or stroke, but resulted in a signifi-
cant increase in the risk of intracranial hemorrhage
without increasing fatal bleeding.
Darexaban
Darexaban (formerly YM‑150) is an oral, direct factor Xa
inhibitor with a rapid onset of action and a plasma half-
life of approximately 14–20 h.46,63 Upon absorption, the
drug is extensively metabolized to its main active metabo­
lite, YM‑222714, and reaches peak plasma concentrations
within 2 h of an oral dose.46 The Study Evaluating Safety,
Tolerability, and Efficacy of YM‑150 in Subjects with Acute
Coronary Syndromes (RUBY‑1)46 was a phase II, dose-
finding, randomized, double-blind, placebo-­controlled
trial of the safety and tolerability of darexaban in patients
with an ACS. In this study, 1,279 patients with a high-
risk non-ST-segment or ST-segment elevation ACS event
within 7 days of presentation were randomly allocated
in a 1:1:1:1:1:1:2 ratio to one of six darexaban regimens
(5 mg twice daily, 10 mg once daily, 15 mg twice daily,
30 mg once daily, 30 mg twice daily, or 60 mg once
daily) or a matched placebo, respectively, in addition to
DAPT with aspirin and clopidogrel. The primary outcome
was the incidence of ISTH-defined major or CRNM
bleeding. The primary efficacy end point was a compos-
ite of death, stroke, MI, systemic thromboembolism, or
severe recurrent ischemia.
Overall, bleeding rates were significantly higher in
all darexaban arms compared with placebo (pooled
HR 2.275, 95% CI 1.13–4.60, P = 0.022). No decrease was
observed in the primary efficacy event rates with darexa-
ban; however, the study was primarily designed to evalu-
ate safety, and was underpowered to assess efficacy. The
investigators concluded that darexaban, when added to
standard DAPT after an ACS, produced a twofold to four-
fold increase in bleeding with no other safety concerns,
but with no signal for efficacy. Citing the increased bleed-
ing risk and lack of efficacy observed with darexaban,
the manufacturer announced the discontinuation of the
development of darexaban for all indications.64
Letaxaban
Letaxaban (formerly TAK‑442) is an oral, direct
factor Xa inhibitor with a bioavailability of approxi-
mately 50% 65 and a plasma half-life of 9–13 h. 66,67
Letaxaban was investi­gated in patients with an ACS in
the phase II Safety and Efficacy of TAK‑442 in Subjects
with Acute Coronary Syndromes (AXIOM‑ACS) trial.49
In this prospective, multicenter, randomized, double-
blind, three-stage adaptive trial, 2,753 patients were
randomly allocated to receive either placebo or letaxa-
ban in addition to usual care (including aspirin and a
thienopyridine) after an ACS. In stage 1, patients were
randomly allocated to one of three doses of letaxaban
(10 mg twice daily, 20 mg twice daily, or 40 mg once
daily) or a matched placebo for up to 24 weeks. In stage 2,
NATURE REVIEWS | CARDIOLOGY VOLUME 9  |  JULY 2012  |  397
© 2012 Macmillan Publishers Limited. All rights reserved
FOCUS ON ANTICOAGULATION THERAPIES
12
HR 0.84, 95% Cl 0.74–0.96, P = 0.008
Death from cardiovascular causes,
myocardial infarction, or stroke (%)
Placebo
10
8
6
Rivaroxaban
4
2
0
0 90 180 270 360 450 540 630 720
Time (days)
Number at risk
Rivaroxaban 10,229 8,817 7,797 6,324 5,137 3,967 2,830 1,747 831
Placebo 5,113 4,437 3,974 3,253 2,664 2,059 1,460 878 421
Figure 2 | Reduction in adverse cardiovascular events associated with rivaroxaban
treatment. When added to standard (aspirin or dual) antiplatelet therapy after an
acute coronary syndrome, rivaroxaban significantly reduced the risk of the primary
efficacy end point (a composite of death from cardiovascular causes, myocardial
infarction, or stroke) in the ATLAS ACS 2–TIMI 51 trial. Reproduced with permission
from Mega, J. L. et al. Rivaroxaban in patients with a recent acute coronary
syndrome. N. Engl. J. Med. 366 (1), 9–19 © 2012, with permission from the
Massachusetts Medical Society.
patients were randomly allocated to one of three doses of
letaxaban (40 mg twice daily, 80 mg once daily, or 80 mg
twice daily) or a matched placebo for up to 24 weeks. In
stage 3, patients were randomly allocated to one of two
doses of letaxaban (160 mg once daily or 120 mg twice
daily) or a matched placebo for up to 24 weeks. At the
end of stage 1, an independent data and safety moni-
toring board assessed the incidence of major bleeding
and other safety findings before random allocation into
stage 2 or 3. The primary end point was the incidence of
TIMI major bleeding. Secondary end points included a
more-sensitive bleeding scale consisting of a composite
of major and clinically significant nonmajor bleeding
and the incidence of expanded major adverse cardiac
events (defined in this study as cardiovascular death,
nonfatal MI, nonfatal stroke, or myocardial ischemia
that required hospitalization).
The overall incidence of TIMI-major bleeding
observed with letaxaban was low and was numerically,
but not significantly, higher at larger doses compared
with placebo. A significant, dose-dependent increase
in the secondary bleeding scale was observed with
letaxaban compared with placebo. No positive trend for
a reduction in expanded major adverse cardiac events
was observed. Importantly, the investigators reported
an increase in adverse events (although details were
not provided) in stages 2 and 3 compared with placebo,
which resulted in discontinuation of the trial; however,
no hepatotoxicity was observed with letaxaban.
Why might factor Xa inhibitors fail in ACS?
The role of factor Xa in coagulation, as described above,
is incontrovertible. Why then might factor Xa inhibition
not yield generally favorable results, including efficacy,
REVIEWS
in patients with an ACS? Several biology-based hypo­
theses are worthy of consideration. Arterial thrombosis
is highly platelet-dependent, occurs after the presen-
tation of Tf predominantly from local, intravascular
sites,68 and is characterized by flow under high shear
stress. Tf-induced blood coagulation yields approxi-
mately 2 nmol/l thrombin during the initiation phase,
with the majority (96%) of the thrombin being gener-
ated long after clotting occurs through bioamplification
and resupply of coagulation subtrates.68,69 Platelet activa-
tion occurs with approximately 0.5 nmol/l thrombin.69 In
high-shear-stress environments, aspirin reduces throm-
bin generation and reactions catalyzed by this enzyme.70
Under conditions of flow, the cleavage of prothrombin
yields meizothrombin—a protein intermediate with
anticoagulant properties achieved through activated
vitamin K-dependent protein C. Therefore, a significant
proportion of thrombin generated at the vessel-wall
surface under flow conditions is, in fact, anticoagulant
in nature.
The impact of flow on thrombin generation from
prothrombinase (factor Xa and factor Va) has been
summarized previously.71 Prothrombin arrives at pro-
thrombinase anchored to the vessel wall primarily by
diffusion from adjacent blood. Under flow conditions,
vessel-wall thrombin is diluted and neutralized by the
arrival of antithrombin. The boundary-layer concen-
trations of substrates required for thrombin generation
under flow conditions can be predicted by computational
fluid dynamics.72 The importance of platelets in throm-
bus growth under flow conditions is well illustrated in
hypothetical estimates of vessel occlusion in proximity to
anchored prothrombinase—in coronary arteries at high
shear rates, platelet accumulation is required to alter flow
sufficiently for thrombin generation, thrombus growth,
and vessel occlusion.
Conceptually, the role of prothrombinase activity and
thrombin generation in the natural history of an ACS
would decrease with platelet inhibition, particularly in
the setting of increasingly potent DAPT strategies and
nonocclusive thrombus, as is commonly encountered
with unstable angina and non-ST-segment elevation MI.
By contrast, prothrombinase and thrombin are always
vital for hemostasis. This might not be the case with a
more-moderate strategy of inhibition with aspirin and
clopidogrel. Indeed, stent thrombosis was reduced with
the addition of rivaroxaban in the ATLAS ACS 2–TIMI 51
trial,62 which underscores the dynamic nature of coronary
arterial thrombosis in contemporary ACS.
Some patients with an ACS might have thrombin-
dependent (or factor  Xa-dependent), rather than
platelet-­dependent, arterial thrombosis. Similarly, in
speci­fic populations, the response to either aspirin mono-
therapy or DAPT with clopidogrel can be sub­optimal
because of highly prevalent loss-of-function genotypes
or drug–drug interactions. Further investi­gation employ-
ing novel biomarkers, including the coagu­lation pro-
teome and pathways-based analyses, will be required to
test these important hypotheses. The potential impact of
attenuating the pluripotent activity of factor Xa, including
398  |  JULY 2012  |  VOLUME 9  www.nature.com/nrcardio
© 2012 Macmillan Publishers Limited. All rights reserved
its effects on inflammation, apoptosis, cellular prolif-
eration, and matrix-metalloprotein stability might be
demonstrable at relatively low levels of inhibition, where
the overriding negative effects of bleeding are also less
likely to be operative.
Future role of factor Xa inhibitors in ACS
To date, only two oral factor Xa inhibitors, apixaban44,57
and rivaroxaban,51,62 have been evaluated in phase III
clinical trials for secondary prevention in patients with
an ACS (Table 2). In both the ATLAS ACS–TIMI 4651
and APPRAISE‑1 studies,44 a trend towards a reduction
in cardiovascular events was observed. However, in the
APPRAISE‑2 trial,57 the addition of apixaban 5 mg twice
daily to standard DAPT resulted in an increase in major
and fatal bleeding events, without a reduction in recurrent
ischemic events. Whereas in the ATLAS ACS 2–TIMI 51
trial, 62 significant reductions in recurrent ischemic
events, cardiovascular death, and all-cause mortality were
observed with rivaroxaban 2.5 mg twice daily, in addition
to increases in both bleeding unrelated to CABG surgery
and intracranial bleeding.
The exact reasons for the discrepancies in efficacy and
safety observed in the APPRAISE‑2 and ATLAS ACS 2–
TIMI 51 trials are unclear; however, differences between
the patient populations enrolled in the trials might
have contributed. For example, patients with a history
of stroke or transient ischemic attack who were treated
with aspirin in addition to a thienopyridine were
excluded from the ATLAS ACS 2–TIMI 51 trial, but
not the APPRAISE‑2 study. This group of patients in
particular does not seem to benefit from an increased
intensity of antithrombotic therapy.2,73 Fundamentally,
one could argue that some very high-risk patients, with
multiple comorbid characteristics, might be beyond
a threshold to derive benefit from increased intensity
antithrombotic therapy, and receive only an increased
risk of bleeding.
Another possible explanation for the differing results
between drugs and trials might be related to dose selec-
tion. In both the Apixaban for Reduction in Stroke and
Other Thromboembolic Events in Atrial Fibrillation
(ARISTOTLE) study 21 and the APPRAISE‑2 trial,57 a
dose of 5 mg twice daily was selected. In trials of riva-
roxaban for stroke prevention in patients with atrial
fibrillation or treatment of VTE, most patients received
20 mg per day.22,74 In the ATLAS ACS 2–TIMI 51 study,62
a dose of one-quarter to one-half of the 20 mg dose was
tested, and survival benefits were observed with the
lower dose of rivaroxaban (2.5 mg twice daily). This
inverse dose–response relationship with cardiovascular
events was also observed in the ATLAS ACS–TIMI 46
trial44 and RUBY‑1,46 which suggests that low doses of a
factor Xa inhibitor might be preferred in this particular
patient population. Whether even lower doses of rivar-
oxaban than those tested in the ATLAS ACS 2–TIMI 51
trial would be equally efficacious and cause less bleed-
ing than higher doses is unclear. In preclinical studies of
rivaroxaban, single doses of 1.25 mg in healthy volun-
teers produced no significant inhibition of factor Xa.75
 FOCUS ON ANTICOAGULATION THERAPIES

These results suggest that 2.5 mg of rivaroxaban might Conclusions

represent the lowest efficacious dose.
We are, therefore, left with the question of whether
the results of the ATLAS ACS 2–TIMI 51 trial represent
a drug-specific effect or are an example of selecting the
appropriate dose for the right patient population—a tenet
of drug development that underscores the importance of
early phase clinical trials and a critical need for parallel
investigations designed to provide signals for both on-
target and off-target drug effects. On the basis of a cumu-
latively large experience from clinical trials, one might
conclude that the therapeutic window for factor Xa inhi-
bition in patients with an ACS is narrow, particularly in
the context of ‘triple therapy’, and in patients at high risk
of bleeding complications, such as the elderly or those
with multiple medical comorbidities.76 The propensity
for intracranial hemorrhage in this high-risk patient
population when treated with combined anti­coagulant
and antiplatelet therapy or triple antithrombotic therapy
is striking and requires further investigation.77 This
undertaking must proceed without delay and take full
advantage of the large repositories of clinical data and
collections of blood samples.
Importantly, oral factor Xa inhibitors have not been
studied in combination with new-generation antiplatelet
agents, such as prasugrel or ticagrelor. Given the increased
rates of major bleeding observed with prasugrel 2 and
major bleeding unrelated to CABG surgery observed with
ticagrelor,1 one would anticipate the therapeutic window
to be even narrower for factor Xa inhibition in combi-
nation with these potent antiplatelet agents than with
clopidogrel. Whether the addition of a factor Xa inhibi-
tor, such as rivaroxaban, to ticagrelor could improve upon
the mortality benefits previously observed with ticagrelor
and aspirin in the PLATO study 1 is unclear.
Factor Xa has an important role in coagulation and exhi­
bits several cellular effects thought to contribute to the
progression and clinical expression of athero­thrombosis.
Targeting factor Xa in patients with an ACS has numer-
ous biologically supported benefits over current anti­
coagulation strategies; however, the available data suggest
that the risk-to-benefit relationship might be prohibi-
tive with some agents, at least at the doses tested and in
very high-risk patients, when used in combination with
DAPT. The results of the ATLAS ACS 2–TIMI 51 trial62
support the ‘factor Xa hypothesis’ in ACS and underscore
the delicate balance between risk and benefit with triple
anti­t­hrombotic therapy. This narrow therapeutic window
might, in turn, attenuate enthusiasm for the develop-
ment of oral, competitive, active-site factor Xa inhibitors
designed specifically for secondary prevention in patients
with an ACS. Existing agents need to be tested in combi-
nation with novel antiplatelet regimens, such as prasugrel
or ticagrelor in addition to aspirin. Rivaroxaban seems to
represent a novel addition to DAPT with aspirin and clopi-
dogrel after an ACS event, but its place in clinical prac-
tice, if approved for this indication, will depend on very
careful consideration of all the available treatment options,
risk–benefit relationships, patient-specific needs, and cost.
Review criteria
The initial literature search was performed using
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“factor Xa acute coronary syndrome”, “factor Xa
inhibitors”, “rivaroxaban”, “ATLAS ACS”, “apixaban”, and
“APPRAISE apixaban”. All manuscripts identified were
English-language, full-text articles. The reference lists
of comprehensive Review articles were examined for
additional references.

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Author contributions
J. W. Wisler researched the data for this article. Both
authors contributed substantially to discussion of its
contents and to writing, reviewing, and editing the
manuscript before submission.