412 Review in depth
Novel oral anticoagulants in the management of coronary
artery disease
Sean R. McMahona, Kathleen Brummel-Ziedinsb and David J. Schneidera
Despite advances in interventional and pharmacologic
therapy, survivors of myocardial infarction remain at an
increased risk of subsequent cardiovascular events. Initial
pharmacological management includes both platelet
inhibition and parenteral anticoagulation, whereas long-
term pharmacological therapy relies on antiplatelet therapy
for prevention of thrombotic complications. Biomarkers
showing ongoing thrombin generation after acute coronary
syndromes suggest that anticoagulants may provide
additional benefit in reducing cardiovascular events. We
review the pharmacokinetics of novel anticoagulants,
clinical trial results, the role of monitoring, and future
directions for the use of novel oral anticoagulants in the
treatment of coronary artery disease. Clinical trials have
shown that long-term use of oral anticoagulants decreases
the risk of cardiovascular events, but they do so at a cost of
Introduction
Despite advancements in cardiac revascularization and
pharmacologic therapy, survivors of myocardial infarction
(MI) remain at significant risk of subsequent cardiovas-
cular events. Pharmacological treatment of acute coronary
syndromes (ACSs) includes an initial strategy that com-
bines antiplatelet therapy and parenteral anticoagulation.
This early strategy frequently includes revascularization.
Subsequent thrombotic risk is limited most commonly
with antiplatelet therapy alone. Despite advances in
antiplatelet therapy, the risk of cardiovascular death,
stroke, or MI is ∼ 10% during the first year. Although an
elevated risk of cardiovascular events is apparent through
12 months, the greatest burden of risk is observed during
the first 30 days (∼50% of the events that will occur after
1 year are observed during the first month) [1,2]. The
beneficial effects of antiplatelet therapy [1,2] indicate the
importance of platelets in thrombotic complications;
however, evidence of ongoing thrombin generation and
activity suggests that thrombotic complications are not
solely mediated by platelet activation [3,4]. Consistent
with this observation, biochemical markers of ongoing
thrombin generation have been linked to an increased
risk of subsequent cardiovascular events [5]. These
observations suggest that anticoagulants may be effective
in reducing subsequent risk after an ACS. This review
will focus on our current understanding of the pharma-
cokinetics, recent trial results, the role of monitoring, and
future directions for the use of novel oral anticoagulants
in the treatment of coronary artery disease (CAD).
0954-6928 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
an increased risk of bleeding. Future studies will need to
identify optimal treatment combinations for selected
patients and conditions that address both the appropriate
combination of therapy and the appropriate dosage of each
agent when used in combination. Coron Artery Dis
27:412–419 Copyright © 2016 Wolters Kluwer Health, Inc.
All rights reserved.
Coronary Artery Disease 2016, 27:412–419
Keywords: coronary artery disease, novel oral anticoagulants, thrombosis
a
Cardiology Unit, Department of Medicine, Cardiovascular Research Institute and
b
Department of Biochemistry, University of Vermont, Burlington, Vermont, USA
Correspondence to Sean R. McMahon, MD, Cardiology Unit, Department of
Medicine, Cardiovascular Research Institute, University of Vermont, 111
Colchester Avenue, Burlington, VT 05401, USA
Tel: + 1 802 847 3734; fax: + 1 802 847 8818;
e-mail: sean.mcmahon@uvmhealth.org
Pharmacokinetics of selected novel oral
anticoagulants
Clinical trials assessing the efficacy of novel antic-
oagulants in patients with CAD have been conducted
with ximelagatran, darexaban, dabigatran, rivaroxaban,
and apixaban. The mechanistic and pharmacokinetic
characteristics of agents that are available for clinical use
(dabigatran, rivaroxaban, edoxaban, and apixaban) will be
reviewed.
Dabigatran is a prodrug whose metabolite is a reversible
competitive direct-acting inhibitor of thrombin.
Dabigatran has a bioavailability of 3–7%. Peak plasma
concentrations are observed within 2 h and the active
metabolite has a clearance half-life of ∼ 12–17 h.
Dabigatran is excreted 80% unchanged in the urine.
Clearance is facilitated by P-glycoprotein cell membrane
pumps that are susceptible to inhibition by medications
such as amiodarone and verapamil [6,7].
Rivaroxaban is a highly selective direct-acting inhibitor of
factor Xa. The parent compound has anticoagulant
properties and peak plasma concentrations are observed
2–4 h after ingestion. The clearance half-life is 7–11 h in
the young and 11–13 h in elderly patients. Absorption is
not affected by food intake and no first-pass metabolism
has been observed. The bioavailability is 80–100%.
Clearance is mediated predominantly by metabolism
(approximately two-thirds) in the liver by CYP3A4 and
the rest is excreted unchanged in the urine [8].
DOI: 10.1097/MCA.0000000000000387

Apixaban is another highly selective direct-acting inhi-
bitor of factor Xa. The parent compound has antic-
oagulant properties and a bioavailability of ∼ 50%. Peak
plasma concentrations are achieved in ∼ 3.5 h and the
clearance half-life is ∼ 12 h. More than 50% of apixaban is
excreted unchanged in feces or urine. The rest is cleared
primarily by oxidative metabolism that is catalyzed by
CYP3A4/5 [9,10].
Edoxaban is a factor Xa inhibitor that has not been
evaluated in the treatment of patients with CAD. The
parent compound has anticoagulant properties and peak
plasma concentrations are observed 1–2 h after ingestion.
Absorption is not affected by food intake and bioavail-
ability is ∼ 62%. Clearance half-life is 10–14 h.
Elimination is mediated by the kidneys (50%) as well as
by biliary and intestinal excretion. Because an increased
incidence of ischemic stroke was observed in patients
with a creatinine clearance greater than 95 ml/min,
edoxaban is not recommended in these patients [11,12].
Direct-acting anticoagulants exert more consistent antic-
oagulant effects because they are not dependent on
endogenous cofactors for their anticoagulant properties.
Their direct effect on activated coagulation factors may
enable them to exert pleiotropic effects [13] (Fig. 1).
Direct-acting anticoagulants inhibit clot-bound factor Xa
and prothrombinase more effectively than heparins.
Because thrombus may persist up to 30 days after plaque
rupture [14], the inhibition of clot-bound thrombin may
reduce cardiac events. Direct-acting anticoagulants may
provide benefits independent of the prevention of
thrombosis. Both thrombin and factor Xa activate inflam-
matory mediators and promote fibrosis. Proinflammatory
and fibrotic effects have been found in cardiac, renal, and
lung tissue exposed to ischemia [15–17]. Direct thrombin
inhibition has been shown to improve organ survival in
experimental renal preparations exposed to ischemia and
to reduce inflammation/fibrosis in bleomycin-induced
pulmonary fibrosis [18,19]. Thus, treatment with direct-
acting anticoagulants after ACS may reduce postischemic
injury and fibrosis, and thereby enhance survival by pre-
serving cardiac function.
Trials of long-term anticoagulation in the
management of CAD
The use of long-term treatment with anticoagulants for
the prevention of thrombotic cardiovascular events in
CAD was first studied with the use of vitamin K
antagonists (VKAs). Their use has been investigated with
mixed results in studies dating back to the 1980s [20]. A
meta-analysis of these trials suggested benefit in ACS
patients with a low or an intermediate risk for bleeding.
However, because these trials were completed before
coronary stents were commonly used, they do not include
patients who underwent coronary stenting [21]. These
studies were plagued by variable international normal-
ized ratio (INR) values that likely increased the risk of
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NOACs in the management of CAD McMahon et al. 413
major bleeding. The lack of considerable numbers of
patients treated with percutaneous coronary intervention
(PCI) prevents assessment of an effect on stent throm-
bosis or restenosis. Treatment with VKA carried a sig-
nificant risk of bleeding complications, but this treatment
reduced the incidence of ischemic events [22,23].
Treatment of CAD with coronary stents in patients with
atrial fibrillation has led to the combination of VKA with
dual antiplatelet therapy. Observational studies have
identified a marked increase in the risk of bleeding
complications in this setting [24]. One large observational
study found that the combination of VKA with dual
antiplatelet therapy led to a four-fold increased risk of
bleeding requiring hospitalization with a number needed
to harm of 12.5 [25].
The use of clopidogrel with or without aspirin in patients
receiving oral anticoagulant therapy and undergoing a
percutaneous coronary intervention trial (WOEST) was
the first prospective randomized trial to challenge the
necessity of ASA after coronary stenting in patients
treated with clopidogrel and VKA [26]. The WOEST trial
was a single-center open-label multicenter randomized
control trial with 573 patients on VKA undergoing PCI.
Patients were randomized to clopidogrel alone (double
therapy) or ASA and clopidogrel (triple therapy). After a
1-year follow-up, the study showed a marked and highly
significant reduction in the incidence of bleeding com-
plications (the primary endpoint). In the triple-therapy
arm, there was a significant increase in all bleeding epi-
sodes driven by thrombolysis in myocardial infarction
(TIMI) minor bleeding [14.4 vs. 44.4%, hazard ratio
(HR): 0.36, confidence interval (CI): 0.26–0.50].
Surprisingly, the incidence of thrombotic complications
was lower with dual therapy than with triple therapy. The
incidence of the combined secondary endpoint that
included death, MI, target-vessel revascularization,
stroke, or stent thrombosis was lower in the double-
therapy group (11.1 vs. 17.6%, HR: 0.60, CI: 0.38–0.94;
number needed to treat 15).
At this time, the FDA has not approved the use of novel
anticoagulants in the treatment of CAD. The optimal
treatment strategy for patients with atrial fibrillation who
require dual antiplatelet therapy after coronary stenting
has not been defined. The most common treatment
strategy used in these patients is to combine VKA with
dual antiplatelet therapy (triple therapy) and attempt to
limit the duration of triple therapy. Several ongoing trials
seek to evaluate the efficacy and risk of selected com-
binations of antiplatelet therapies and anticoagulants in
patients with and without atrial arrhythmia.
Ximelagatran: the ESTEEM trial
Ximelagatran, a direct thrombin inhibitor that was not
approved for clinical use by the FDA, was the first novel
oral anticoagulant studied in the prevention of cardio-
vascular events after ACS. The Oral ximelagatran for
414 Coronary Artery Disease 2016, Vol 27 No 5
Fig. 1
Intrinsic pathway
XII
XIIa
XI XIa
VIIIa
IX IXa
TF VIIa
Extrinsic pathway
Exposure or expression
of tissue factor (TF)
II
Fibrinogen
The coagulation cascade and pleiotropic interactions.
secondary prophylaxis after myocardial infarction trial
(ESTEEM trial) was a phase II multicenter, multi-
national, randomized-controlled trial assessing the effi-
cacy and safety of four doses of ximelagatran in addition
to ASA in patients with ACS [27]. The primary outcome
was a composite of death, MI, and recurrent ischemia.
Patients were treated with ASA 75–160 mg daily and
excluded if they were treated with thienopyridines. Of
the 1900 patients with biomarker evidence of MI enrol-
led, 61% had ST-elevation myocardial infarction
(STEMI) and 51% of those patients were treated with
lytic therapy.
The results indicated that ximelagatran combined with
aspirin compared with placebo plus aspirin was associated
with a reduction in the composite endpoint of death,
nonfatal MI, and severe recurrent ischemia. There was a
3.6% (12.7 vs. 16.3%, HR: 0.71, CI: 0.55–0.90) absolute
risk reduction and a 24% relative risk reduction. There
was no evidence of greater benefit with higher or lower
doses among the four doses of ximelagatran studied. The
reduction in thrombotic risk was apparent during the first
month maintained through the treatment period.
Treatment with ximelagatran led to a consistent and
persistent reduction in prothrombin fragment 1.2 (F1.2, a
marker released when thrombin is formed) and D-dimer
(a marker produced when plasmin cleaves fibrin).
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Endothelial and
smooth muscle cell
proliferation
X Platelet activation
Xa Inflammation
Xa Va
Coagulation promotion
IIa
Fibrin clot formation
Consistent with the occurrence of thrombotic events, the
extent of reduction was not greater with higher doses of
drug [28].
Major bleeding was infrequent, but doubled in the
ximelagatran group compared with placebo [23 patients
(1.8%) vs. six patients (0.9%), HR: 1.97, CI: 0.80–4.84].
Bleeding that led to the discontinuation of study medi-
cation was increased [83 (8%) vs. 13 (2%) HR: 3.35, CI:
1.87–6.01] as was total bleeding [273 (22%) vs. 83 (13%)
HR: 1.76, CI: 1.38–2.25] in those treated with ximela-
gatran. Unlike the effect on the risk of thrombosis, a
greater incidence of bleeding was observed with higher
doses of ximelagatran. Accordingly, the results from the
ESTEEM trial were consistent with those found with
VKA, suggesting that greater intensity anticoagulation
does not add benefit, but clearly increases the risk of
bleeding.
Dabigatran: the RE-DEEM trial
Dabigatran was the second of the novel oral antic-
oagulants studied in patients with MI and the first in
which all patients were treated with dual antiplatelet
therapy. The dabigatran vs. placebo in patients with
ACSs on dual antiplatelet therapy trial (RE-DEEM trial)
was a phase II trial that assessed the safety and efficacy of
dabigatran for long-term (6 months) treatment after ACS
 NOACs in the management of CAD McMahon et al. 415

[29]. RE-DEEM was a double-blind, placebo-controlled, Fig. 2

dose-escalation trial that enrolled a total of 1861 patients
Placebo APPRAISE 2
who were treated, on average, 7.5 days after STEMI or
RE-DEEM ATLAS 2
non-ST-elevation myocardial infarction (NSTEMI) (60
9%
and 40%, respectively). Patients were randomized to
dabigatran (dose-escalation plan, randomized to 50, 75, 8%
110, or 150 mg) plus standard therapy of thienopyridine 7%
and aspirin (no dose limits) or placebo plus standard 6%
therapy. A total of 99% of patients were on dual anti- 5%
platelet treatment at randomization. The primary out-
4%
come was clinically relevant minor bleeding and major
3%
bleeding. The secondary outcomes included the con-
centration of D-dimer and the incidence of cardiovascular 2%
ischemic events. Cardiovascular ischemic events inclu- 1%
ded a composite of death, nonfatal MI, nonhemorrhagic 0%
stroke, MI, and recurrent ischemia. Of those enrolled, Dabigatran Apixaban Rivaroxaban Rivaroxaban
54.5% of patients underwent PCI for the index event. (combined doses) 5 mg BID 2.5 mg BID 5 mg BID

The study indicated that dabigatran compared with pla- Major bleeding among patients receiving novel oral anticoagulants in
cebo resulted in significantly increased rates of clinically addition to dual antiplatelet therapy. BID, twice daily.
relevant minor and major bleeding as defined by the
International Society of Thrombosis and Hemostasis
(ISTH) [30], with a four-fold increase [7.8 (110 mg), 7.9% Fig. 3
(150 mg)] in the high-dose group compared with placebo
(2.2%). Higher doses of dabigatran were associated with Placebo APPRAISE 2
more bleeding events. When the results from the two RE-DEEM ATLAS 2
lower dose groups were combined, the absolute risk of 12%
major bleeding was increased by 1%.
10%
Treatment with dabigatran decreased the concentration
of D-dimer in a non-dose-dependent manner by an 8%
average of 37 and 45% at weeks 1 and 4, respectively
(P < 0.001). Patients treated with dabigatran and showing 6%
a reduction in the D-dimer concentration at week 1 had a
significantly lower incidence of the composite endpoint 4%
of cardiovascular death, nonfatal MI, or nonhemorrhagic
2%
stroke (HR: 0.47, CI: 0.26–0.82). Cardiovascular ischemic
events were less common in patients treated with the 0%
higher doses of dabigatran (110 and 150 mg), but this was Dabigatran Apixaban Rivaroxaban Rivaroxaban
at the cost of an observed four-fold increased incidence of (combined doses) 5 mg BID 2.5 mg BID 5 mg BID
bleeding (Figs 2 and 3). Consistent with the results from
Combined endpoints of cardiovascular death, nonfatal myocardial
the ESTEEM trial, these results support lower intensity infarction, or stroke. BID, twice daily.
therapy to reduce the risk of bleeding. Further, these
results suggest that suppression of a biomarker of
thrombosis (D-dimer) may predict benefit.
clinically relevant nonmajor bleeding events as defined by
Darexaban: the RUBY-1 trial the modified version of the ISTH [30]. The secondary
The RUBY-1: a randomized, double-blind, placebo- efficacy outcome was a composite of death, stroke, MI,
controlled trial of the safety and tolerability of the severe recurrent ischemia, and systemic thromboembolism.
novel oral factor Xa inhibitor darexaban (YM150) fol-
lowing ACS trial (RUBY-1 trial) was a phase II rando- As anticipated, the results showed a higher incidence of
mized, double-blind, placebo-controlled trial of the safety bleeding in the treatment group that was dose dependent
and tolerability of the factor Xa inhibitor darexaban (HR: 2.28, CI: 1.13–4.60). Cumulative bleeding events
(YM150) after ACSs [31]. RUBY-1 enrolled 1279 patients were 6.2, 6.5, and 9.3% in the 10, 30, and 60 mg dose
with either high-risk NSTEMI (29%) or STEMI (71%) group, respectively, compared with 3.9% in the placebo
to receive one of six doses of darexaban or placebo in group. The range of major and clinically relevant minor
addition to clopidogrel plus ASA (ASA dose 75–325 daily) bleeding was 5.6% for the lowest dose (HR: 1.78, CI:
for 6 months. The primary outcome was major and 0.68–4.60) and 11.3% for the high-dose group (HR: 3.8,

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416 Coronary Artery Disease 2016, Vol 27 No 5
CI: 1.66–8.68) compared with placebo (2.8%). Consistent
with previous results, a decrease in composite efficiency
events was observed with the lowest dose tested. Rates
of instent thrombosis were low, but more common in
those receiving darexaban (1.1 vs. 0.4%).
Apixaban: the APPRAISE-2 trial
The apixaban with antiplatelet therapy after acute cor-
onary syndrome trial (APPRAISE-2 trial) is a randomized,
double-blind, placebo-controlled trial that sought to
evaluate the efficacy and safety of long-term treatment
with apixaban after ACS for the prevention of acute
ischemic events [32]. The APPRAISE-2 trial enrolled
7392 patients and randomized them to received apixaban
5 mg twice daily or placebo in addition to the P2Y12
receptor antagonist and low-dose aspirin. A dose of
2.5 mg twice daily was used in patients with an estimated
creatinine clearance of less than 40 ml/min. Enrolled
patients had ACS including NSTEMI (42%), STEMI
(40%), and unstable angina with the presence of dynamic
ST-segment changes (18%). Patients were enrolled at a
median of 6 days after the index event and followed for
up to 240 days. The primary efficacy outcome was a
composite of cardiovascular death, MI, or ischemic
stroke. The primary safety outcomes were defined as
TIMI major and minor bleeding, major, or clinically
relevant nonmajor bleeding as defined by the ISTH and
GUSTO [30,33,34]. Approximately 52% of the patients
enrolled underwent angiography and 44% had PCI.
The study was stopped because of an increase in major
bleeding without evidence of decreased ischemic events.
After a median follow-up of 241 days, there was a similar
distribution of the primary outcome of cardiovascular
death, MI, or ischemic stroke between the apixaban
group and placebo (7.5 vs. 7.9% respectively, HR: 0.95,
CI: 0.80–1.11). The primary safety outcome of TIMI
major bleeding occurred in 1.3% of the patients receiving
apixaban and 0.5% of those receiving placebo (HR: 2.59,
CI: 1.50–4.46). In addition, in the treatment group, sig-
nificantly more patients had fatal bleeding, intracranial
hemorrhage, ISTH major or clinically relevant nonmajor
bleeding, bleeding requiring transfusion, and total
bleeding. The results of this large trial were not con-
sistent with previous results. An increased risk of
bleeding was not offset by a reduction in the incidence of
thrombotic complications.
Rivaroxaban: the ATLAS ACS 2 TIMI 51 trial
The rivaroxaban in patients with a recent acute coronary
syndrome trial (ATLAS-2 TIMI 51 trial) was a rando-
mized, double-blind, placebo-controlled phase 3 trial that
assessed thrombotic risk reduction with rivaroxaban in
addition to standard medical therapy after ACS [35]. All
patients took low-dose aspirin (75–100 mg daily) and a
thienopyridine [clopidogrel (93%) or ticlopidine]. The
trial included three treatment arms; 15 526 patients were
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
randomized to rivaroxaban 5 mg twice daily, rivaroxaban
2.5 twice daily, or placebo. Patients were excluded if they
had a history of intracranial hemorrhage, ischemic cere-
brovascular accident, or transient ischemic attack. All
patients were treated with a proton pump inhibitor.
Patients were randomized within 7 days of admission for
ACS that included unstable angina (24%), NSTEMI
(26%), or STEMI (50%).
The results indicated a lower incidence of ischemic
events, but again at the cost of a higher rate of bleeding
complications. The primary endpoint, a composite of
cardiovascular death, MI, or stroke, was achieved in 8.9%
of patients randomized to any dose of rivaroxaban com-
pared with 10.7% in the placebo group (relative risk
reduction: 16%, HR: 0.84, CI: 0.74–0.96). A similar
reduction in the incidence of ischemic events was
observed in patients treated with the 2.5 mg dose (9.1%,
P = 0.02 vs. placebo) compared with the 5 mg dose (8.8%,
P = 0.03 vs. placebo).
The low-dose (2.5 mg twice daily) rivaroxaban group
showed a significant reduction in the incidence of car-
diovascular death and overall death that was not observed
in the high-dose group. Cardiovascular death occurred in
2.7% of those on 2.5 of rivaroxaban compared with 4.1%
in the placebo group (HR: 0.66, CI: 0.51–0.86) and the
overall incidence of death was 2.9 and 4.5%, respectively
(HR: 0.68, CI: 0.53–0.87). The incidence of stent
thrombosis was 21% lower in patients treated with riv-
aroxaban (2.3 vs. 2.9%, HR: 0.69, CI: 0.51–0.93).
Rivaroxaban decreased the concentrations of biomarkers
that reflect ongoing thrombosis (D-dimer and PF1.2) that
were assessed 180 days after enrollment [4].
TIMI major bleeding not related to coronary artery
bypass grafting and intracranial hemorrhage were
increased in patients treated with rivaroxaban. When the
results with both doses were combined, the rate of TIMI
major bleeding was increased four-fold in those treated
with rivaroxaban (2.1 vs. 0.6%, HR: 3.96, CI: 2.46–6.38)
and the rate of intracranial bleeding was increased three-
fold (0.6 vs. 0.2%, P = 0.009). As would be expected on
the basis of previous trials, a lower incidence of bleeding
was found with the 2.5 mg dose (Table 1). The rate of
TIMI major bleeding was nonsignificantly lower in the
2.5 mg dose group (1.8 vs. 2.4, P = 0.12). However, the
rates of TIMI minor bleeding (0.9 vs. 1.6%, P = 0.046),
TIMI bleeding requiring medical attention (12.9 vs.
16.2%, P < 0.001), and fatal bleeding (0.1 vs. 0.4%,
P = 0.04) were all significantly lower in the 2.5 mg group
compared with the 5 mg group.
The results from the ATLAS-2 trial and the APPRAISE
trial were quite different (Table 1). In particular, the
ATLAS trial showed a significant reduction in events and
the lower dose (2.5 mg twice daily) was associated with a
significant reduction in mortality. The ATLAS trial
excluded patients with previous stroke, whereas this

Table 1 Clinical trials and major findings of oral anticoagulants studied in coronary artery disease with monitoring and reversal strategies
Medication Dose Antiplatelets
Dabigatran (mg) 50, 75, 110, or 150 DAPT
Apixaban (mg b.i.d.) 5.0 DAPT
Rivaroxaban (mg b.i.d.) 2.5 DAPT
5.0 DAPT
Coumadin (%) INR adjusted Plavix alone
b.i.d., twice daily; DAPT, dual antiplatelet therapy; FFP, fresh-frozen plasma; INR, international normalized ratio; MI, myocardial infarction; PCC, prothrombin complex
concentrate; PT, prothrombin time; VK, vitamin K.
exclusion was not applied to patients enrolled in the
APPRAISE trial. In addition, the ATLAS enrolled a
higher percentage of patients with STEMI than the
APPRAISE trial (50 vs. 39%, respectively). Rivaroxaban
and apixaban have similar mechanisms of action. The
lower dose of rivaroxaban yielded the greatest net benefit
(combination of a lower risk of ischemic/thrombotic
events plus a lower risk of bleeding events). This dosage
would be expected to result in a less anticoagulant effect
than the dosage of apixaban used in APPRAISE.
Accordingly, the ATLAS-2 trial suggests that the pre-
vention of cardiovascular events after MI in patients who
are treated with dual antiplatelet therapy and low-dose
anticoagulation may be more effective than dual anti-
platelet therapy alone. In addition, the low-dose rivar-
oxaban (2.5 mg twice daily) was associated with a lower
risk of bleeding.
Anticoagulation monitoring and reversal of
anticoagulant effects
The prothrombin time (PT) and the INR that was
developed to standardize measurements have been used
to enhance prevention of thrombosis and limit the
occurrence of bleeding in patients treated with a VKA.
Because novel oral anticoagulants are direct acting and
have predictable pharmacokinetic and pharmacodynamic
profiles, they were developed to be used without regular
monitoring. The predictable pharmacokinetic and phar-
macodynamic profiles are likely to be offset, to some
extent, by the considerable interindividual variability in
the concentration of coagulation factors and the stimulus
driving their activation. Accordingly, monitoring may be
useful under circumstances where substantial inter-
individual variability would be expected.
Inhibitors of factor Xa
Rivaroxaban and apixaban exert their anticoagulation
effects by inhibiting coagulation factor Xa. Tests of coa-
gulation that are affected by the inhibition of factor Xa
include PT, activated partial thromboplastin time
(aPTT), and chromogenic assays that directly measure
the activity of factor Xa. Both factor Xa inhibitors prolong
the PT and have a direct linear correlation with the
plasma concentration of the anticoagulant [36,37].
However, thromboplastin reagents are not specific to
factor Xa and vary widely in their sensitivity. One
laboratory found a 2.6- to eight-fold difference in the
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
NOACs in the management of CAD McMahon et al. 417
Death, MI, stroke (placebo) Major bleeding (placebo) Monitoring Reversal
4.0% (3.8%) 7.9% (2.2%) Ecarin clotting time Idarucizumab
7.5% (7.9%) 1.3% (0.5%) Factor Xa assay PCC
9.1% (10.7%) 1.8% (0.6%) Factor Xa assay PCC
8.8% (10.7%) 2.4% (0.6%)
11.1 vs. 17.6 19.4 vs. 44.4 PT/INR VK, PCC, FFP
concentration of factor Xa inhibitor that led to doubling
of the PT [38]. Thus, the PT cannot be used to deter-
mine the concentration of rivaroxaban or apixaban, but
this test may be used in emergent situations to qualita-
tively assess hemostatic function. In contrast, when
appropriate calibration is performed, chromogenic anti-
factor Xa assays can quantify the concentration of rivar-
oxaban and apixaban [38,39].
Although there is no commercially available direct-acting
(specific) reversal agent for rivaroxaban and apixaban,
administration of the prothrombin complex concentrate
has been shown to exert a rapid reversal effect on bio-
chemical tests [40]. Reversal was quantified by mea-
surement of the PT and endogenous thrombin potential
and noted to be immediate, with an effect that persisted
for more than 24 h. Administration of prothrombin com-
plex concentrate did not effectively reverse biochemical
tests in blood from patients treated with dabigatran.
Two specific reversal agents have been evaluated.
Andexanet-α has been shown to rapidly reduce antifactor
Xa activity by 97% [41,42]. Andexanet-α is a modified
inactive factor Xa protein with a high affinity for factor Xa
inhibitors that has been shown to reverse the effects of
both apixaban and rivaroxaban as well as other Xa inhi-
bitors. Antifactor Xa activity was reduced within 2–5 min
of administration. A continuous infusion was necessary to
sustain the reversal of antifactor Xa activity. Ciraparantag
is another agent under evaluation for the reversal of
anticoagulants [43,44]. Ciraparantag is a synthetic mole-
cule with a high affinity for factor Xa inhibitors as well as
the oral thrombin inhibitor dabigatran. Ciraparantag has
been referred to as a universal reversal agent because of
its ability to reverse unfractionated heparin, low-
molecular-weight heparin, and the direct-acting antic-
oagulants. After injection, ciraparantag binds rapidly and
inhibits anticoagulants. Ciraparantag decreases clotting
time within 10 min and its effects are sustained for 24 h.
Inhibitors of thrombin
Similar to rivaroxaban and apixaban, the anticoagulant
effect and hence the concentration of dabigatran cannot
be reliably measured with the use of traditional assays.
The PT and its derived INR are insensitive to the effects
of dabigatran and provide an imprecise assessment of the
effect of this agent on clotting. Similar to its effect on the
PT, dabigatran exerts a nonlinear effect on the aPTT.
418 Coronary Artery Disease 2016, Vol 27 No 5
Accordingly, the aPTT may be used as a qualitative
measurement to inform clinicians of the presence or
absence of dabigatran, but not as a quantitative mea-
surement. Alternative methods that can assess the effect
of direct-acting antithrombins include the ecarin clotting
time (ECT) and the thrombin time (TT). Both the TT
and ECT show a linear response to dabigatran and pro-
vide an accurate quantitative assessment of thrombin
inhibition. The ECT has been shown to be the most
accurate and specific [45]. A promising alternate assay
under evaluation is the HEMOCLOT Thrombin
Inhibitor assay, which has been shown to be highly
sensitive [46].
Recently, the FDA approved a specific reversal agent for
dabigatran. Idarucizumab is a monoclonal antibody frag-
ment that binds dabigatran with an affinity 350 times
higher than thrombin [47]. The idarucizumab for dabi-
gatran reversal (RE-VERSE AD) clinical trial assessed
the efficacy of Idarucizumab [48]. Treatment with
Idarucizumab produced rapid reversal of the dilute TT
and ECT – effects were observed within minutes and
sustained for at least 24 h. Idarucizumab is administered
as two 2.5 g (50 ml) bolus infusions within 15 min and
does not require repeated dosing or a continuous infu-
sion. Idarucizumab has not found to exert a pro-
thrombotic effect [49].
Future directions
Biochemical testing on blood from patients who have
experienced a MI has shown that patients have variable
extents of ongoing thrombin generation. Greater ongoing
thrombin generation and activity is associated with an
increased risk of subsequent cardiovascular events.
Clinical trials have shown that long-term treatment with
oral anticoagulants decreases the risk of cardiovascular
events, but the treatment does so at a cost of an increased
risk of bleeding. Strategies that suppress thrombin gen-
eration without markedly increasing the risk of bleeding
would improve patient care. The results from clinical
trials suggest two options. The ATLAS trial suggests that
the combination of very low doses of anticoagulants with
antiplatelet agents may achieve this end. The WOEST
trial suggests that one component of therapy; aspirin in
this case, may contribute a substantial component of the
increased risk of bleeding without markedly reducing the
risk of thrombotic events when an anticoagulant is com-
bined with P2Y12 inhibition. Comparison of the ATLAS-
2 and APPRAISE trials also suggests that clinical char-
acteristics may be useful to guide therapy. Specifically,
patients with a previous stroke appear to be at a higher
risk of intracranial hemorrhage when anticoagulants are
combined with antiplatelet therapy. Because the
ATLAS-2 trial also included more patients with STEMI
than the APPRAISE trial, the efficacy of selected thera-
pies may be impacted by the clinical syndrome.
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Results from trials that used anticoagulants for long-term
treatment after ACS suggest that when antiplatelet
therapy and anticoagulant therapy are combined, the
dosage of each agent may require adjustment. Results
from the ATLAS-2 trial showed that a reduction in
thrombotic risk can be achieved with low-dose antic-
oagulation, allowing for a relatively lower risk of bleed-
ing. The effect on clinical events shown in ATLAS-2 was
evident with biochemical marker testing when higher
doses of anticoagulant did not have greater effect on
thrombosis biomarkers in the RE-DEEM trial and
ESTEEM trial. Similarly, lower doses of darexaban
appeared to be more effective in the phase II RUBY-1
trial. The results from the ATLAS-2 trial were most
compelling, showing a survival benefit with the low-dose
therapy that was not apparent with the high dose. A
difference in the intensity of anticoagulant effect could
be a determinant of the apparent discrepancy between
the results from ATLAS-2 compared with the
APPRAISE-2 trial.
The results from the WOEST trial suggest a different
paradigm. Rather than simply adding new therapy to
existing treatment strategies, the WOEST trial results
suggest that treatment strategies may need to be tailored
to specific clinical situations. Identification of optimal
treatment combinations and the ability to tailor therapy
to the needs of an individual would be supported greatly
by the availability of biochemical tests that have been
validated to predict clinical outcomes.
Conclusion
Despite advances in therapies that reduce cardiovascular
events after ACS, continued opportunities for improve-
ment remain. Novel oral anticoagulants may be an
important adjunct in selected patients. Trials suggest that
long-term anticoagulant therapy prevents ischemic com-
plications at a cost of a higher risk of bleeding. Continued
research to develop novel treatment strategies that use
optimal combinations and dosages is necessary. Research
in this area will be aided by the development of clinically
validated biochemical testing that can be used to tailor
therapies to the needs of individual patients.
Acknowledgements
Conflicts of interest
Dr Schneider reports grant funding from Bristol Myers
Squib and Janssen Pharmaceuticals as well as honorarium
from Janssen Pharmaceuticals. For the remaining authors
there are no conflicts of interest.
References
1 Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W,
Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary
syndromes. N Engl J Med 2007; 357:2001–2015.
2 Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al.
Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
N Engl J Med 2009; 361:1045–1057.

3 Merlini PA, Bauer KA, Oltrona L, Ardissino D, Cattaneo M, Belli C, et al.
Persistent activation of coagulation mechanisms in unstable angina and
myocardial infarction. Circulation 1990; 90:61–68.
4 Gibson M, Mega J, Jennings LK, Mohanavelu S, Misselwitz F, Plotnikov A,
et al. Effect of rivaroxaban on markers of coagulation in patients with acute
coronary syndromes: an ATLAS ACS-TIMI 46 substudy. Circulation 2009;
120:S1035.
5 Christersson C, Oldgren J, Bylock A, Siegbahn A, Wallentin L. 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.
6 Stangier J, Stahle H, Rathgen K, Fuhr R. Pharmacokinetics and
pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy
elderly subjects. Clin Pharmacokinet 2008; 47:47–59.
7 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral
direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008;
47:285–295.
8 Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban.
Fundam Clin Pharmacol 2012; 26:27–32.
9 Bhanwra S, Ahluwalia K. The new factor Xa inhibitor: apixaban. J Pharmacol
Pharmacother 2014; 5:12–14.
10 Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG, et al.
Apixaban metabolism and pharmacokinetics after oral administration
to humans. Drug Metab Dispos 2009; 37:74–81.
11 Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M,
et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of
the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol
2010; 50:743–753.
12 Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL,
et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med
2013; 369:2093–2104.
13 Schneider DJ. Potential contribution of pleiotropic effects of direct
anticoagulants to clinical benefits. Drug Dev Res 2013; 74:472–477.
14 Van Belle E, Lablanche JM, Bauters C, Renaud N, McFadden EP,
Bertrand ME. Coronary angioscopic findings in the infarct-related vessel
within 1 month of acute myocardial infarction: natural history and effect of
thrombolysis. Circulation 1998; 97:26–33.
15 Mackman N. The role of tissue factor-thrombin pathway in cardiac ischemia-
reperfusion injury. Semin Vasc Med 2003; 3:193–198.
16 Grandaliano G, Di Paolo S, Monno R, Stallone G, Ranieri E, Pontrelli P, et al.
Protease-activated receptor 1 and plasminogen activator inhibitor 1
expression in chronic allograft nephropathy: the role of coagulation and
fibrinolysis in renal graft fibrosis. Transplantation 2001; 72:1437–1443.
17 Ramachandran R, Hollenberg MD. Proteinases and signaling:
pathophysiological and therapeutic implications via PARs and more. Br J
Pharmacol 2008; 153:S263–S282.
18 Favreau F, Thuillier R, Cau J, Milin S, Manguy E, Mauco G, et al. Anti-thrombin
therapy during warm ischemia and cold preservation prevents chronic kidney
graft fibrosis in a DCD model. Am J Transplant 2010; 10:30–39.
19 Bogatkevich GS, Ludwicka-Bradley A, Nietert PJ, Akter T, Van Ryn J,
Silver RM. Anti-inflammatory and antifibrotic effects of the oral direct
thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung
disease. Arthritis Rheum 2011; 63:1416–1425.
20 EPSIM RESEARCH GROUP. A controlled comparison of aspirin and oral
antocoagulants in prevention of death after myocardial infarction. N Engl J
Med 1982; 307:701–708.
21 Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. 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.
22 Van Es RF, Jonker JJ, Verheugt FW, Deckers JW, Grobbee DE. Aspirin and
coumadin after acute coronary syndromes (the ASPECT-2 study): a
randomized controlled trial. Lancet 2002; 360:109–113.
23 Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or
both after myocardial infarction. N Engl J Med 2002; 347:969–974.
24 Faxton DP, Eikelboom JW, Berger PB, Holmes DR, Bhatt DL, Moliterno DJ,
et al. Antithrombotic therapy in patients with atrial fibrillation undergoing
coronary stenting: a North-American perspective. Circ Cardiovasc Interv
2011; 4:522–534.
25 Sørensen R, Hansen ML, Abildstrom SZ, Hvelplund A, Andersson C,
Jørgensen C, et al. Risk of bleeding in patients with acute myocardial
infarction treated with different combinations of aspirin, clopidogrel, and
vitamin K antagonists in Denmark: a retrospective analysis of nationwide
registry data. Lancet 2009; 374:1967–1974.
26 Dewilde WJ, Oirbans T, Verheught FW, Kelder JC, de Smet BJ, Herrman JP,
et al. Use of clopidogrel with or without aspirin in patients taking oral
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
NOACs in the management of CAD McMahon et al. 419
anticoagulant therapy and undergoing percutaneous coronary intervention:
an open-label, randomized, controlled trial. Lancet 2013; 381:1107–1115.
27 Wallentin PL, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A,
Nyström P, et al. Oral ximelagatran for secondary prophylaxis after myocardial
infarction: the ESTEEM randomized controlled trial. Lancet 2003; 362:9386.
28 Christersson C, Oldgren J, Bylock A, Wallentin L, Siegbahn A. Long-term
treatment with ximelagatran, an oral direct thrombin. J Thromb Haemost
2005; 3:2245–2253.
29 Oldgren J, Budaj A, Granger C, Khder Y, Roberts J, Siegbahn A, et al.
Dabigatran vs. 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.
30 Schulman S, Kearon C. Definition of major bleeding in clinical investigations
of antihemostatic medicinal products in non-surgical patients. J Thromb
Haemost 2005; 3:692–694.
31 Steg PG, Mehta SR, Jukema JW, Lip GY, Gibson CM, Kovar F, 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.
32 Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, et al. Apixaban
with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;
635:699–708.
33 Rao SV, Eikelboom JA, Granger CB, Harrington RA, Califf RM, Bassand JP.
Bleeding and blood transfusion issues in patients with non-ST-segment
elevation acute coronary syndromes. Eur Heart J 2007; 28:1193–1204.
34 THE GUSTO INVESTIGATORS. An international randomized trial
comparing four thrombolytic strategies for acute myocardial infarction.
N Engl J Med 1993; 329:673–682.
35 Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt D, Bode C, et al.
Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J
Med 2012; 366:9–19.
36 Samama MM, Contant G, Spiro TE, Perzborn E, le Flem L, Gourmelin Y, et al.
Laboratory assessment of rivaroxaban: a review. Thromb J 2013; 11:11.
37 Samama MM, Martinoli JL, le Flem L, Guinet C, Plu-Bureau G, Depasse F,
et al. Assessment of laboratory assays to measure rivaroxaban – an oral,
direct factor Xa inhibitor. Thromb Haemost 2010; 103:815–825.
38 Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of
direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin
time assay. Thromb Haemost 2010; 104:1263–1271.
39 Samama MM, Contant G, Spiro TE. Evaluation of the anti-factor Xa
chromogenic assay for the measurement of rivaroxaban plasma concentrations
using calibrators and controls. Thromb Haemost 2012; 107:379–387.
40 Eerenberg ES, Kamphuisen PW, Sijpkens MK. Reversal of rivaroxaban and
dabigatran by prothrombin complex concentrate. Circulation 2011;
124:1573–1579.
41 Crowther M, Gold A, Levy GG, Lu G, Leeds J, Wiens BL, et al. ANNEXA-A
part 2: a phase 3 randomized, double-blind, placebo-controlled trial
demonstrating sustained reversal of apixaban-induced anticoagulation in
older subjects by andexanet alfa, a universal antidote for factor Xa inhibitors.
J Thromb Hemost 2015; 13:84–85.
42 Siegal DM, Curnette JT, Connolly SJ, Lu G, Conley P, Wiens BL, et al.
Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med
2015; 373:2413–2424.
43 Bakhru S, Laulicht B, Jiang X, Chen L, Grosso M, Morishima Y, et al. Reversal
of anticoagulant-induced bleeding in external and internal bleeding models
by PER977, a small molecule anticoagulant antidote. Circulation 2014; 130:
A19361.
44 Ansell JE, Bakhru S, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use
of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med
2014; 339:2141–2142.
45 Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics,
pharmacodynamics, and tolerability of dabigatran etexilate, a new oral direct
thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007;
64:292–303.
46 Samoš M, Stančiaková L, Ivanková J, Staško J, Kovář F, Dobrotová M, et al.
Monitoring of dabigatran therapy using hemoclot thrombin inhibitor assay in
patients with atrial fibrillation. J Thromb Thrombolysis 2015; 39:95–100.
47 Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, et al. A
specific antidote for dabigatran: functional and structural characterization.
Blood 2013; 121:3554–3562.
48 Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al.
Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373:511–520.
49 Glund S, Stangier J, Schmohl M, Gansser D, Norris S, van Ryn J, et al.
Safety, tolerability, and efficacy of idarucizumab for the reversal of the
anticoagulant effect of dabigatran in healthy male volunteers: a randomized,
placebo-controlled, double-blind phase 1 trial. Lancet 2015; 386:680–690.