Circulation

IN DEPTH
Combination Antiplatelet and Oral
Anticoagulant Therapy in Patients With
Coronary and Peripheral Artery Disease
Focus on the COMPASS Trial

ABSTRACT: Antiplatelet therapy is the mainstay for the treatment of Paul A. Gurbel, MD
acute and chronic arterial disease involving the coronary and peripheral Keith A.A. Fox, MB ChB
beds. However, questions remain about optimal antithrombotic therapy Udaya S. Tantry, PhD
for long-term treatment of chronic vascular disease. The observation Hugo ten Cate, MD, PhD
that dual antiplatelet therapy with acetylsalicylic acid and clopidogrel Jeffrey I. Weitz, MD
was associated with lower thrombotic event rates than acetylsalicylic
acid monotherapy in patients with acute coronary syndromes and those
undergoing percutaneous coronary intervention changed the treatment
paradigm. Moreover, the demonstration that more pharmacodynamically
potent P2Y12 inhibitors than clopidogrel were associated with fewer
thrombotic event occurrences further solidified the dual antiplatelet
therapy approach. However, recurrent thrombotic events occur in ≈1 in
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10 patients in the first year following an acute coronary syndrome event,

despite treatment with the most potent P2Y12 inhibitors, a limitation that
has stimulated interest in exploring the efficacy and safety of approaches
using anticoagulants on top of antiplatelet therapy. These investigations
have included treatment with very-low-dose oral anticoagulation, and
even its replacement of acetylsalicylic acid in the presence of a P2Y12
inhibitor, in patients stabilized after an acute coronary syndrome event.
Recent basic and translational studies have suggested noncanonical
effects of coagulation factor inhibition that may further modulate
clinical benefits. This in-depth review will discuss developments in our
understanding of the roles that platelets and coagulation factors play
in atherothrombosis and review the rationale and clinical evidence for
combining antiplatelet and oral anticoagulant therapy in patients with
coronary and peripheral artery disease.

Key Words: anticoagulants ◼ aspirin

◼ blood coagulation ◼ blood platelets
◼ coronary artery disease ◼ factor Xa
inhibitors◼ peripheral arterial disease
◼ rivaroxaban

© 2019 American Heart Association, Inc.

https://www.ahajournals.org/journal/circ

2170 April 30, 2019 Circulation. 2019;139:2170–2185. DOI: 10.1161/CIRCULATIONAHA.118.033580

 Gurbel et al
P
atients with coronary artery disease (CAD) and pe-
ripheral artery disease (PAD) are at high risk of fu-
ture cardiovascular events.1 Despite implementa-
tion of contemporary secondary prevention strategies,
there was an ≈25% 3-year cumulative risk of cardio-
vascular death, myocardial infarction (MI), or stroke in
patients with prior MI.2 Among patients with symptom-
atic PAD and no history of stroke or transient ischemic
attack, the rate of cardiovascular death, nonfatal MI,
or stroke was 17.6% by year 4 and was driven mainly
by cardiovascular mortality (11.1%). Systemic (com-
posite of cardiovascular death, MI, or stroke) and limb
ischemic event (composite of lower limb amputation,
peripheral bypass graft, and percutaneous intervention
for PAD) occurrence was 11.9% at 2 years.3 Consistent
with the systemic atherosclerotic process, atherothrom-
botic event rates involving coronary or cerebral arteries
are higher in those with polyvascular bed involvement
than patients with PAD alone.4
A critical component of the treatment strategy for
patients with CAD and PAD is antiplatelet therapy. De-
spite evidence of clinical event reduction associated
with potent P2Y12 inhibitors plus acetylsalicylic acid
(ASA) in large-scale trials, residual ischemic risk persists
along with risks for bleeding that are proportional to
the intensity of the antiplatelet regimen.5–8 Therefore,
there is a need for better therapies. Recent attention has
focused on the efficacy and safety of combination an-
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tiplatelet and anticoagulant therapy with non–vitamin
K antagonist direct oral anticoagulants. In this review,
we will discuss the developments in our understand-
ing of the roles that platelets and coagulation factors
play in atherothrombosis with a focus on the results of
the recent COMPASS trial (Cardiovascular Outcomes for
People Using Anticoagulation Strategies) that imple-
mented a very low dose of rivaroxaban on top of ASA in
patients with chronic CAD and PAD.9 Mechanisms that
may underlie the results of COMPASS are described.
MECHANISTIC RATIONALE FOR
COMBINING ANTIPLATELETS AND
ANTICOAGULANTS
Atherosclerosis is the common pathophysiological pro-
cess underlying both CAD and PAD. As initially described
in the injury-repair hypothesis by Ross10, platelet adhe-
sion, activation, and aggregation (both platelet-platelet
and platelet-monocyte) play pivotal roles in the initia-
tion and progression of atherosclerotic lesions and the
final manifestation of thrombotic complications (athero-
thrombosis) following atherosclerotic plaque erosion or
rupture.10,11 Coronary atherosclerotic disease progression
from a stable to an unstable state has been character-
ized as a pathophysiological condition associated with
heightened platelet activation, hypercoagulability, and
Circulation. 2019;139:2170–2185. DOI: 10.1161/CIRCULATIONAHA.118.033580
Antiplatelet and Oral Anticoagulant Therapy
inflammation, a thromboinflammatory syndrome.12,13
Vascular injury exposes the subendothelial matrix, and
STATE OF THE ART
platelets adhere to newly exposed collagen and von Wil-
lebrand factor, interactions mediated by specific platelet
receptors. The von Willebrand factor-glycoprotein Ib/
IX/V interactions play a major role in initial platelet ad-
hesion and activation in the high-shear environment of
coronary arteries, whereas this process has been less ex-
plored in peripheral arteries. Following activation, ADP
is released from platelet dense granules, and Throm-
boxane A2 is generated by the activity of thromboxane
synthase on prostaglandin H2, an intermediate formed
by cyclooxygenase-1 (COX-1). Although both ADP and
thromboxane A2 amplify platelet activation and aggre-
gation, continuous ADP-P2Y12 receptor signaling is es-
sential for sustained activation of the glycoprotein IIb/
IIIa receptor and stable platelet thrombus generation.5
The contribution of coagulation in the initiation of
acute arterial thrombosis is less well established than
platelet function. Only femtomolar (1×10–15) levels of
thrombin are generated during the initial stages of clot
formation, whereas the major amount of thrombin is
generated after clot formation, suggesting that throm-
bin is primarily important for clot stability but not initia-
tion.14 Nonetheless, elevated procoagulant activity and
thrombin generation were reported during the acute
phases of unstable angina and MI and persisted for
months after presentation.15–20 Thrombin generation,
marked by prothrombin fragment 1+2, was heightened
in the first 12 hours of acute MI, and was higher in
patients with acute coronary syndrome (ACS) who de-
veloped in-hospital recurrent ischemia despite nearly 72
hours of intravenous heparin infusion.16 In addition, an
association between in vivo thrombin generation and
severity of coronary vessel disease defined by angiog-
raphy21 or coronary calcification by computed tomogra-
phy has been reported.22
The latter fundamental construct provides the ratio-
nale for pharmacological strategies that have focused
on platelet inhibition and anticoagulation to prevent
ischemic events in patients with cardiovascular disease.
Targets for inhibition include COX-1, P2Y12, and the
thrombin pathway (Figure 1).5 At this time, the relative
importance of these individual pathways in the initial
genesis of thrombus formation in the coronary and pe-
ripheral arterial vascular beds remains elusive.
CROSS-TALK BETWEEN PLATELETS
AND COAGULATION
Exposed tissue factor (TF), derived from macrophages,
vascular smooth muscle cells, and microvesicles at the
site of vascular injury,23 initiates the coagulation cas-
cade, triggering thrombin generation. Thrombin ac-
tivates platelet protease-activated receptor (PAR)–1
April 30, 2019 2171
 Gurbel et al Antiplatelet and Oral Anticoagulant Therapy
STATE OF THE ART

Figure 1. Canonical mechanistic concept of atherothrombosis and potential therapeutic targets.

Platelet activation and coagulation are stimulated by the interaction of flowing blood with injured vessel wall. There are 3 major pathways amplifying platelet
activation that are inhibited by currently available oral agents: 1, the COX-1 pathway; 2, the ADP-P2Y12 pathway; and 3, the thrombin pathway. Activity of the
thrombin pathway can be inhibited by direct inhibition of thrombin, inhibition of thrombin generation by targeting FXa, and inhibition of the platelet protease
activated receptor (PAR)-1, the thrombin receptor. ASA indicates acetylsalicylic acid; EC, endothelial cell; FVIIa, factor VIIa; FXa, factor Xa; GPIIb/IIIa, glycoprotein IIb/
IIIa; TF, tissue factor; and TxA2, thromboxane A2. Modified from Gurbel and Tantry5 with permission. © 2010, the American Heart Association.

and PAR-4, the latter in a dynamic manner and prob-
ably mostly during thromboinflammatory conditions,24
causing further platelet activation. Concurrently, the
phosphatidylserine-rich surface of activated platelets
supports the assembly of clotting factor complexes that
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platelets is in a partially activated state, and factor Xa
is 50 to 100 times more effective than thrombin in ac-
tivating platelet-released factor V. The activated factor
V on the platelet surface is well positioned to combine
with factor Xa and form the potent prothrombin acti-

amplify thrombin generation. In addition to activating
platelets, thrombin converts fibrinogen to fibrin and
activates factor XIII, and enhances its own generation
through feedback activation of factors V, VIII, and XI.
Therefore, activated platelets and hypercoagulability
play important roles in occlusive thrombus formation at
the site of vascular injury, and atherothrombosis under-
lies the ultimate clinical manifestations of MI, ischemic
stroke, and a substantial proportion of acute limb isch-
emic events in PAD.11,12,25 Multiple studies have dem-
onstrated elevated markers of platelet activation and
coagulation, and evidence of inflammation and en-
dothelial activation, as well, in patients with CAD and
PAD.26–29
A recent murine transgenic model suggested that
platelet-derived factor V is a critical mediator of in
vivo arterial thrombosis involving platelet activation
and coagulation. Platelet-derived factor V significantly
contributed to localized assembly of the prothrombi-
nase complex with factor Xa at the site of plaque rup-
ture. The latter process leads to the generation of sig-
nificant amounts of thrombin on the activated platelet
surface and early feedback loop stimulation of coagu-
lation pathways. The direct thrombin inhibitors may
not have the same influence in attenuating thrombin
generation in this setting as do factor Xa inhibitors.30
In support of this concept, it has been shown that hu-
man factor V released from α-granules of activated
vation complex. The activity of this complex is attenu-
ated by direct factor Xa inhibitors but not by throm-
bin inhibitors. Platelet prothrombinase may produce
too much thrombin to be effectively controlled with
thrombin inhibitors.31,32 Therefore, platelet activation
and the formation of the initial prothrombinase com-
plex play important roles in the early genesis of arterial
thrombosis.
In support of the cross-talk between platelets and
coagulation and the modulation of this cross-talk by
platelet inhibitors, ex vivo inhibition of the P2Y12 recep-
tor by clopidogrel diminished the rapid exposure of TF in
a mouse model and attenuated TF-dependent factor Xa
activity of platelet-neutrophil suspensions.33 Clopidogrel
markedly and rapidly inhibited platelet annexin-binding
activity34 and prolonged the time to platelet-fibrin clot
formation measured by thromboelastography, a marker
of the rate of thrombin generation.35 Other studies sup-
port the attenuation of platelet procoagulant activity by
the in vitro addition of P2Y12 inhibitors.36,37
However, coronary thrombosis may still occur despite
the presence of potent P2Y12 blockade, suggesting the
importance of mechanisms beyond platelet function
driving thrombus occurrence.5 Thromboelastography
studies in stented patients who were pharmacodynam-
ically responsive to dual antiplatelet therapy (DAPT),
and who had recurrent ischemic events, revealed rapid
times to platelet-fibrin clot generation and formation of

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 Gurbel et al Antiplatelet and Oral Anticoagulant Therapy

STATE OF THE ART

Figure 2. Potential noncanonical pathways involved in atherothrombosis and their inhibition by FXa inhibitors and ASA.
The role of FXa in atherosclerosis has been attributed to direct activation of PAR-2 signaling or indirect activation of PAR-1 through the generation of thrombin
with resultant release of proinflammatory cytokines and expression of cell adhesion molecules. Resultant vascular effects include modulation of inflammation,
plaque progression, and fibrosis. ASA has been reported to modulate clot porosity through non–COX-1–mediated effects. Activated platelets generate thrombin
on their surface, an event that is attenuated by antiplatelet therapy. ASA indicates acetylsalicylic acid; EC, endothelial cell; FXa, factor Xa; PAR, protease activated
receptor; and WBC, white blood cell.

clots with high tensile strength, findings that support a
hypercoagulable phenotype.38
Another potentially relevant thromboinflammatory
network involves a platelet-localized factor XI–depen-
dent mechanism of thrombin generation that impacts
vascular tone, blood pressure, and endothelial func-
tion in an angiotensin-dependent manner.39 Factor XI
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thrombotic effects beyond the inhibition of aggrega-
tion (Figure 2). In a human microvascular injury model,
in addition to reducing thrombin generation and atten-
uating factor XIII activation, ASA also enhanced fibrin
clot permeability and clot lysis by acetylating lysine resi-
dues in fibrin.41,42 Therefore, very-low-dose rivaroxaban
combined with ASA may act synergistically to inhibit

is a component of the intrinsic pathway of coagulation,
which is activated by factor XIIa or by thrombin. It has
been shown that activated factor XI can activate coagu-
lation factors IX, V, and VIII, and inhibit the anticoagu-
lant TF pathway inhibitor. In addition, the role of factor
XI as an independent risk factor for deep vein throm-
bosis, ischemic stroke, and MI has been demonstrat-
ed.40 Taken together, the above data provide evidence
of substantial cross-talk between platelet function and
coagulation and provide the supportive mechanistic ra-
tionale for potential synergistic antithrombotic effects
derived from the inhibition of platelet activation and
thrombin generation by combination therapy with an
antiplatelet agent and a factor Xa inhibitor. Finally, non-
canonical effects of factor Xa inhibition together with
noncanonical effects of ASA and P2Y12 receptor inhibi-
tors may also modulate clinical outcomes in patients
with arterial diseases.
thrombosis through multiple pathways, including direct
effects of ASA on the clot and the effects mediated by
the inhibition of platelet activation and resultant inhibi-
tion of activated coagulation factor generation. In an
in vitro study, enhanced inhibition of thrombin gen-
eration was observed when ticagrelor and ticagrelor
plus ASA were combined with rivaroxaban in com-
parison with when the agents were not combined.43
Also, in an arteriovenous shunt model, low doses of
rivaroxaban combined with ASA or ASA plus clopi-
dogrel resulted in an increased antithrombotic effect
in comparison with the effects observed when these
agents were not combined.43 The above potentiation
of the inhibition of thrombin generation and throm-
bus formation by the combination of rivaroxaban with
antiplatelet agents suggests potential mechanisms for
the reduction of ischemic effects that were observed in
the COMPASS trial.9

NONCANONICAL EFFECTS OF P2Y12 Inhibitors

ANTITHROMBOTIC AGENTS
Acetylsalicylic Acid
In addition to the antithrombotic properties of ASA
classically attributed to platelet COX-1 inhibition and
resultant inhibition of aggregation, ASA exhibits anti-
P2Y12 is a G-protein–coupled receptor consisting of
a single polypeptide chain with 7 transmembrane α-
helices associated with multiple functionally different
G proteins that elicit specific intracellular responses to
ADP resulting in the activation of the glycoprotein IIb/
IIIa receptor.44 Active metabolites of thienopyridines (ti-

Circulation. 2019;139:2170–2185. DOI: 10.1161/CIRCULATIONAHA.118.033580 April 30, 2019 2173

 Gurbel et al
clopidine, clopidogrel, and prasugrel) irreversibly bind
to the ADP binding site and thereby prevent intracel-
STATE OF THE ART
lular signaling and ADP-induced platelet aggregation.
In addition, P2Y12 receptor mRNA expression and ADP-
induced vasoconstriction have been reported in human
vascular smooth muscle cells.45 Animal studies have
also shown that the P2Y12 receptor may participate
in atherogenesis by promoting the proliferation and
migration of vascular smooth muscle cells and by in-
ducing endothelial dysfunction. In an apolipoprotein
E–deficient mice model, clopidogrel reduced levels of
p-selectin, e-selectin, monocyte chemoattractant pro-
tein-1, and platelet-derived growth factor β, and mac-
rophage and T-cell infiltration in atherosclerotic lesions,
and delayed the development and progression of de
novo atherosclerosis.46 In addition to potent inhibition
of the P2Y12 receptor, ticagrelor, a cyclopentyl-triazolo-
pyrimidine, inhibits adenosine reuptake in erythrocytes
and other cells. The latter effect has been attributed to
improved platelet inhibition and coronary blood flow
and reduced infarct size.47–49 These noncanonical ef-
fects of ticagrelor may account for some of the clini-
cal benefits associated with ticagrelor observed in the
PLATO trial (Platelet Inhibition and Patient Outcomes).7
Factor Xa Inhibitors
There is growing evidence that factor Xa and throm-
bin play critical roles in various cellular processes50 (Fig-
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ure 2). In addition to its main role in triggering thrombin
generation, factor Xa is involved in inflammation, vas-
cular remodeling, atherosclerotic plaque progression,
and tissue fibrosis.51,52 The role of factor Xa in the ath-
erosclerosis process has been attributed to direct activa-
tion of PAR-2 signaling, or indirect activation of PAR-1
via thrombin generation with resultant release of proin-
flammatory cytokines and the expression of cell adhe-
sion molecules.50 Both PAR-1 and PAR-2 have been im-
plicated in atherosclerosis development.53 In addition to
factor Xa and thrombin, other agonists including metal-
loproteinases have been implicated in PAR activation.54
In in vitro studies, factor Xa induced interleukin-6, in-
terleukin-8, and monocyte chemoattractant protein-1
expression in endothelial cells and leukocytes,51,52,55 re-
sponses that are more efficient when factor Xa forms a
complex with TF-VIIa.50,56
Factor Xa inhibition attenuates some of the pleiotro-
pic effects of factor Xa, reduces proinflammatory cyto-
kine expression, and attenuates restenosis after balloon
angioplasty in rabbits.57,58 Moreover, ex vivo–measured
high-tensile platelet fibrin-clot strength occurring after
the generation of thrombin was associated with the
development of 6-month ischemic events after elective
coronary stenting and in-stent restenosis.59,60 These ob-
servations suggest that prothrombotic and mitogenic
phenotypes may be identified by the tensile property
2174 April 30, 2019
Antiplatelet and Oral Anticoagulant Therapy
of the platelet-fibrin clot that marks the robustness of,
and the response to, thrombin generation.
Rivaroxaban has been shown to decrease proinflam-
matory cytokine expression in primary cultures of hu-
man umbilical vein endothelial cells, and its effect was
comparable to PAR-1 and direct thrombin inhibition.61
In apolipoprotein E–deficient mice with atherosclerotic
lesions, rivaroxaban reduced the expression of pro-
inflammatory cytokines such as interleukin-6, tumor
necrosis factor-α, and monocyte chemoattractant pro-
tein-1, and was suggested to enhance plaque stability.62
Thrombin increases the activation of leukocytes and
surface expression of adhesion molecules. The pleiotro-
pic effects of factor Xa and thrombin are described in
detail elsewhere.50,63 In summary, the data above sug-
gest that noncanonical mechanisms underlying the po-
tential vascular protective effects of very-low-dose riva-
roxaban include modulation of cellular function either
directly by inhibiting the effects of factor Xa on PAR-2,
or indirectly by inhibiting thrombin generation and its
effects on PAR-1.
CLINICAL RATIONALE
COMBINING ANTIPLATELETS AND
ANTICOAGULANTS
DAPT with ASA and a P2Y12 receptor blocker is indicat-
ed acutely and for up to 12 months in the high-risk pa-
tient with ACS and in those undergoing coronary stent-
ing. For long-term secondary prevention, ASA remains
the cornerstone of therapy.5 Various strategies have
been investigated to improve the long-term outcomes
of ASA therapy but with limited success (Table 18,64–70).
In patients with stable cardiovascular disease, there
was only a marginal benefit of clopidogrel over ASA
in major adverse cardiovascular events (MACE) reduc-
tion and no difference in cardiovascular or all-cause
mortality.64 Among patients with symptomatic stable
cardiovascular disease or multiple risk factors, DAPT
with clopidogrel added to ASA did not lower MACE
or all-cause mortality in comparison with ASA alone.65
In patients with prior MI, the combination of ticagre-
lor and ASA modestly reduced MACE but increased
bleeding in comparison with ASA monotherapy, with-
out an effect on cardiovascular or all-cause mortality.8
However, in patients with stable PAD, ticagrelor alone
did not lower MACE in comparison with the weaker
P2Y12 inhibitor, clopidogrel.66 Blockade of PAR-1 with
vorapaxar in patients with stable cardiovascular disease
on top of single or dual antiplatelet therapy reduced
MACE, but increased bleeding and did not reduce mor-
tality.67 However, a benefit of vorapaxar on reducing the
rates of hospitalization for acute limb ischemia and pe-
ripheral artery revascularization in patients with stable
cardiovascular disease has been reported.68
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 Gurbel et al Antiplatelet and Oral Anticoagulant Therapy

Table 1. Oral Antiplatelet and Anticoagulant Therapy Trials in Patients With Stable Coronary and Peripheral Artery Diseases

STATE OF THE ART

Clinical Trial (n)Ref Patient Population (n) Treatment End Points Outcomes
PEGASUS-TIMI 54 Patients with MI 1–3 y 90 mg twice daily TIG vs Primary efficacy end Primary efficacy end point=7.85% vs 7.77%
(n=21 162)8 earlier 60 mg twice daily TIG point=composite of vs 9.04%.
vs ASA for a median of cardiovascular mortality, MI, HR for 60 mg TIG vs placebo=0.85; P=0.008
33 mo or stroke.
HR for 60 mg TIG vs placebo=0.84; P=0.004
Primary safety end point=TIMI
TIMI major bleeding=2.60% with 90 mg and
major bleeding
2.30% with 60 mg TIG vs 1.06% placebo
(P<0.001 for each dose vs placebo)
CAPRIE Patients with 75 mg CLP vs 325 mg First occurrence of ischemic Primary end point=5.32% vs 5.83%
(n=19 185)64 atherosclerotic vascular ASA for median of 1.9 y stroke, MI, or vascular RRR=8.7%; P=0.043
disease manifested as mortality
Safety=no significant difference in bleeding
either recent ischemic
(9.28% vs 9.27%); ASA group greater
stroke, recent MI, or
gastrointestinal bleeding (2.66% vs 1.9%;
symptomatic PAD
P=0.05
No difference in cardiovascular or all-cause
mortality
CHARISMA CVD, or PAD or ≥3 75–162 mg ASA+75 mg Primary end point=composite Primary end point: RR=0.93; P=0.22;
(n=15 603)65 atherothrombotic risk CLP vs 75–162 mg/d of MI, stroke, or death from Secondary end point: RR=0.92; P=0.004
factors ASA+ placebo median for cardiovascular causes;
Increase in GUSTO severe bleeding
28 mo Secondary end
(RR=1.25; P=0.09) and moderate bleeding
point=hospitalization for UA,
(RR=1.62; P=0.001)
TIA, or revascularization
No difference in all-cause mortality
procedure
EUCLID (n=13 885) 66
Patients with 90 mg twice daily TIG vs Primary efficacy end Primary efficacy end point= 0.8% vs 10.6%,
symptomatic PAD 75 mg once daily CLP for point=composite of adjudicated HR=1.02; P=0.65
median of 30 mo cardiovascular mortality, MI,
Primary safety end point=1.6% each,
or ischemic stroke
HR=1.10; P=0.49
Primary safety end point =
major bleeding
TRAP2P-TI MI 50 Patients with a history 2.5 mg once daily Primary efficacy end Primary efficacy end point=9.3% vs 10.5%,
(n=26 449)67 of MI, ischemic stroke, vorapaxar or matching point=composite of HR=0.87; P<0.001
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or PAD placebo for a median of cardiovascular mortality, MI,

Primary safety end point=4.2% vs 2.5%,
30 mo or stroke
HR=1.66; P<0.001
Primary safety end
point=GUSTO moderate or
severe bleeding
Meta-analysis of Patients with established VKAs with and without Total mortality, MI, and stroke VKAs with INR>2.8 significantly reduced
randomized trials CAD antiplatelet therapy cardiovascular complications and increased
(n=20 000)69 bleeding in comparison with controls
VKAs with INR 2–3 and ASA is more effective
and as equally as safe as ASA alone
WAVE Patients with PAD Antiplatelet agent+oral First coprimary outcome=MI, First coprimary outcome=12.2% vs 13.3%,
(n=2161)70 anticoagulant agent stroke, cardiovascular RR=0.92; P=0.48
(target INR=2.0–3.0) or to mortality; Second coprimary outcome=15.9% vs 7.4%.
antiplatelet therapy alone Second coprimary RR=0.91; P=0.37
outcome=MI, stroke, severe Life-threatening bleeding=4.0% vs 1.2%,
ischemia of the peripheral RR=3.41; P<0.001
or coronary arteries leading
to urgent intervention, or
cardiovascular mortality

ASA indicates acetylsalicylic acid; CAD, coronary artery disease; CAPRIE, A Randomised, Blinded, Trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischemic
Events; CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CLP, clopidogrel; EUCLID, Examining Use of
Ticagrelor in Peripheral Artery Disease; GUSTO, Global Utilization Of Streptokinase And Tpa For Occluded Arteries; HR, hazard ratio; INR, international normalization
ratio; MI, myocardial infarction; PAD, peripheral arterial disease; PEGASUS-TIMI 54, Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using
Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54; RR, relative risk; TIG, ticagrelor; TIMI, thrombolysis in
myocardial infarction; TRAP2P-TI MI 50, Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial
Infarction 50; VKA, vitamin K antagonist; and WAVE, The Warfarin Antiplatelet Vascular Evaluation.

Earlier studies used vitamin K antagonists as an anti- tional normalized ratio, vitamin K antagonists reduced
coagulant in an attempt to improve clinical outcomes in cardiovascular events in patients with stable CAD but
patients with stable CAD and PAD. When administered increased bleeding.69 In contrast, no benefit was ob-
in doses sufficient to produce a therapeutic interna- served for low-dose vitamin K antagonists that did not

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 Gurbel et al Antiplatelet and Oral Anticoagulant Therapy

Table 2. Clinical Trials of Rivaroxaban in Patients With Coronary and Peripheral Artery Diseases
STATE OF THE ART

Patients
Population (Days
Clinical Trial (n)Ref From Index Event) Treatment End Points Outcomes
COMPASS Stable CAD and After a 30-day run in period, Primary efficacy end point: Primary efficacy end point=
(n=27 395)9 PAD, RIV 2.5 mg twice daily+ASA MI, stroke, or cardiovascular 2.5 mg RIV+ASA vs 5 mg RIV vs ASA alone; 4.1%
MI in the past 20 y (100 mg once daily), RIV death vs 4.9% vs 5.4%
alone (5 mg twice daily), or Primary safety end point: 2.5 mg RIV+ASA vs ASA alone: HR=0.76; P<0.001
ASA alone (100 mg once
major bleeding 5 mg RIV+ASA alone: HR=0.90, P=0.12
daily) for 1.95 y
Primary safety end point=2.5 mg RIV+ASA vs 5
mg RIV vs ASA alone: 3.1% vs 2.8% vs 1.9%.
2.5 mg RIV+ASA vs ASA alone: HR=1.70; P<0.001
5 mg RIV+ASA vs ASA alone: HR=1.51; P<0.001
ATLAS ACS-TIMI 46 Stabilized ACS RIV (5–20 mg) once or twice Primary safety end point: Primary safety end point: 5 mg HR=2.21, 10 mg
(n=3491)76 (2–7) daily vs placebo; ASA only clinically significant bleeding RIV HR=3.35, 15 mg RIV HR=3.60, and 20 mg RIV
vs ASA plus thienopyridine (TIMI major, TIMI minor, or HR=5.06; P<0.0001.
for 6 mo requiring medical attention). Primary efficacy end point: HR=0.79, P=0.$1$2s
Primary efficacy end Secondary efficacy end point: HR=0.69; P=0.027
point=death, MI, stroke, or
severe recurrent ischemia
requiring revascularization
Secondary efficacy end
point=death, MI, or stroke
ATLAS ACS-2 TIMI Stabilized ACS Rivaroxaban (2.5 or 5 mg Primary efficacy end Primary efficacy end point=2.5 mg RIV HR=0.84;
51 (n=15 526)77 (1–7) twice daily) vs placebo for a point=cardiovascular death, P=0.02 and 5 mg RIV HR=0.85; P=0.03
mean of 13 mo MI, or stroke Non-CABG TIMI bleeding=2.5 mg RIV HR=3.46;
P<0.001, 5 mg RIV HR=4.47; P<0.001
ICH=2.5 mg RIV HR=2.83, P=0.04; 5 mg RIV
HR=3.47, P=0.005
Fatal bleeding=2.5 mg RIV HR=0.67, P=0.45; 5
mg RIV HR=1.72, P=0.20
COMPASS-Stable Stable CAD, After a 30-day run in period, Primary efficacy end point: Primary efficacy end point=2.5 mg RIV +ASA vs 5
Downloaded from http://ahajournals.org by on June 29, 2023

CAD MI in the past 20 y RIV (2.5 mg twice daily)+ASA
(n=24 824)78 (100 mg once daily),
rivaroxaban alone (5 mg twice
daily), or ASA alone (100 mg
once daily) for 1.95 y
COMPASS-Stable Stable PAD After a 30-day run in period,
PAD (n= 7470)79 RIV 2.5 mg twice daily + ASA
100 mg once daily, RIV alone
(5 mg twice daily), or ASA
alone (100 mg once daily)
for 1.95 y
GEMINI-ACS-1 ACS (<10) RIV 2.5 mg twice daily vs
(n=3037)80 100 mg ASA once daily, in
addition to clopidogrel (44%)
or ticagrelor (56%) (chosen at
investigator discretion before
randomization), continued for
median of 291 days
MI, stroke, or cardiovascular
death
Primary safety end point:
major bleeding
Primary efficacy end point:
MI, stroke, or cardiovascular
death
Primary safety end point:
major bleeding
Primary end point= TIMI non-
CABG clinically significant
bleeding
CV death, MI, stroke, or
definite stent thrombosis
mg RIV vs ASA alone; 4% vs 5% vs 6%
2.5 mg RIV+ASA vs ASA alone: HR=0.74;
P<0.0001
5 mg RIV+ASA alone: HR=0.89; P=0.094
Primary safety end point: 2.5 mg RIV +ASA vs 5
mg RIV vs ASA alone; 3% vs 3% vs 2%
2.5 mg RIV+ASA vs ASA alone: HR=1.66;
P<0.0001
5 mg RIV vs ASA alone: HR=1.51; P<0.0001
Primary efficacy end point: 2.5 mg RIV+ASA vs 5
mg RIV vs ASA alone: 5% vs 6% vs 7%
2.5 mg RIV+ASA vs ASA alone: HR=0.72; P=0.0047
5 mg RIV+ASA alone: HR=0.86; P=0.19
Primary safety end point=2.5 mg RIV +ASA vs 5
mg RIV vs ASA alone: 3% vs 3% vs 2%
2.5 mg RIV+ASA vs ASA alone: HR=1.61; P=.0089
5 mg RIV+ASA vs ASA alone: HR=1.68; P=0.0043
TIMI non-CABG clinically significant bleeding=5%
vs 5%, HR=1.09; P=0.58
Cardiovascular death, MI, stroke, or definite stent
thrombosis=5% vs 5%, HR=1.06; P=0.73

ACS indicates acute coronary syndrome; ASA, acetylsalicylic acid; ATLAS, Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects
with Acute Coronary Syndrome; ATLAS ACS-TIMI 46, 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-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; CAD, coronary artery disease; COMPASS, Cardiovascular Outcomes for People Using
Anticoagulation Strategies; COMPASS-Stable CAD, Cardiovascular Outcomes for People Using Anticoagulation Strategies- Stable Coronary Artery Disease; COMPASS-
Stable PAD, Cardiovascular Outcomes for People Using Anticoagulation Strategies- Stable Peripheral Artery Disease; CV, cardiovascular; GEMINI-ACS 1, Clinically significant
bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes; HR, hazard ratio; ICH, intracranial hemorrhage; MI,
myocardial infraction; non-CABG, non–coronary artery bypass grafting; PAD, peripheral arterial disease; RIV, rivaroxaban; and TIMI, thrombolysis in myocardial infarction.

2176 April 30, 2019 Circulation. 2019;139:2170–2185. DOI: 10.1161/CIRCULATIONAHA.118.033580

 Gurbel et al
prolong the international normalized ratio to therapeu-
tic levels, but increased bleeding in comparison with
ASA alone.69 There is no documented evidence of the
long-term benefit of therapeutic levels of vitamin K an-
tagonist therapy in patients with PAD.70 Smaller studies
have demonstrated the potential benefits of warfarin
plus ASA versus ASA in patients with ACS.71,72 A meta-
analysis including 25 307 patients with ACS reported
that combination therapy of ASA plus warfarin therapy
(irrespective of international normalized ratio) versus
ASA therapy alone was not associated with less MACE
(all-cause death, nonfatal MI, and nonfatal thrombo-
embolic stroke), but was associated with more major
bleeding (P<0.00001).73 In an analysis of studies with
international normalized ratio values between 2 and 3,
long-term warfarin plus ASA therapy was associated
with fewer major adverse events (P=0.0001) and an
increased risk of major bleeding (P<0.00001) in com-
parison with ASA alone.73 The unfavorable net clinical
outcome (balancing ischemic events and bleeding) of
full-dose warfarin in combination with ASA has led to
its disfavor in the long-term treatment of CAD and PAD.
The inhibition of a single downstream coagulation
factor, such as factor Xa, rather than multiple factors
(for example, warfarin) is a new therapeutic strategy
for long-term therapy for patients with arterial diseas-
es. Some of the advantages of factor Xa inhibitors over
warfarin include a lower risk of intracranial bleeding,
the absence of any significant reported interactions
Downloaded from http://ahajournals.org by on June 29, 2023
with food, fewer interactions with medications, and the
absence of the need for frequent laboratory monitoring
and dose adjustments. However, administration of the
factor Xa inhibitors, darexaban at ascending doses and
apixaban at standard doses, was associated with an el-
evated risk for bleeding without a reduction in compos-
ite ischemic end points when added on top of standard
antiplatelet therapy in patients with ACS.74,75
The initial clinical evidence to support the benefit of
a very low factor Xa inhibitor dose on top of antiplate-
let therapy came from the ATLAS ACS studies (Anti-Xa
Therapy to Lower Cardiovascular Events in Addition to
ASA With or Without Thienopyridine Therapy in Sub-
jects with Acute Coronary Syndrome) (Table 2).9,76–80 In
the phase 2 ATLAS ACS-TIMI 46 trial (Rivaroxaban in
Combination With Aspirin Alone and With Aspirin and
a Thienopyridine in Patients With Acute Coronary Syn-
dromes), patients with stabilized ACS (n=3491) were
treated with escalating doses of rivaroxaban (5–20
mg/d) to select the most favorable dose in combination
with ASA or ASA plus a thienopyridine. Clinically sig-
nificant bleeding increased in a dose-dependent man-
ner (P<0.0001).76 Among patients treated with ASA
alone and ASA plus a thienopyridine, the lowest doses
of rivaroxaban (2.5 mg and 5 mg twice daily) were as-
sociated with a trend toward a reduced risk of death,
MI, or stroke (hazard ratio [HR], 0.54; P=0.08 and HR,
Circulation. 2019;139:2170–2185. DOI: 10.1161/CIRCULATIONAHA.118.033580
Antiplatelet and Oral Anticoagulant Therapy
0.55; P=0.09, respectively) in comparison with placebo.
Among patients treated with the lowest doses of riva-
STATE OF THE ART
roxaban, the increase in the risk of thrombolysis in MI
major bleeding was more pronounced with ASA plus
clopidogrel than with ASA monotherapy.76
d-Dimer levels may reflect both increased thrombotic
activity as well as inflammation. d-Dimer was reported
to be a predictor of cardiovascular events in patients
with PAD, and in patients with acute MI in comparison
with unstable angina.81,82 In a hypothesis-generating
substudy of the ATLAS ACS-TIMI 46 trial, d-dimer levels
were measured in 53% of patients enrolled. Elevated
baseline d-dimer level was associated with an increased
risk of the composite outcome occurrence within 6
months of the index event, and the administration of
rivaroxaban was persistently associated with lower d-
dimer levels in comparison with placebo over 6 months,
suggesting the attenuation of in vivo thrombus forma-
tion and inflammation.83
Based on the outcomes observed in the ATLAS ACS-
TIMI 46 trial, rivaroxaban administered at the low dose of
5.0 mg twice daily, and a very low dose of 2.5 mg twice
daily, was therefore chosen and compared with place-
bo in the phase 3 ATLAS ACS 2-TIMI 51 trial (Anti-Xa
Therapy to Lower Cardiovascular Events in Addition to
Standard Therapy in Subjects With Acute Coronary Syn-
drome ACS 2–Thrombolysis In Myocardial Infarction) of
patients (n=15 526) with recently stabilized ACS treated
with standard antiplatelet therapy.76,77 Major exclusion
criteria included history of intracranial hemorrhage or
history of either ischemic stroke or transient ischemic
attack among patients receiving ASA plus thienopyri-
dine. All patients were treated with low-dose ASA, and
patients were stratified by the administration of a thi-
enopyridine (clopidogrel or ticlopidine). Overall, rivar-
oxaban therapy was associated with a lower rate of the
primary composite end point of cardiovascular death,
MI, or stroke versus placebo (HR, 0.84; P=0.008), and
the primary efficacy end point was lower in both the
2.5 mg twice-daily dose (9.1% versus 10.7%; P=0.02)
and the 5 mg twice-daily dose groups (8.8% versus
10.7%; P=0.03). A decreased incidence of cardiovascu-
lar death (2.7% versus 4.1%; P=0.002), death from any
cause (2.9% versus 4.5%; P=0.002), and also fewer fa-
tal bleeding events were observed in the 2.5 mg twice-
daily group in comparison with the 5 mg twice-daily
dose (0.1% versus 0.4%; P=0.04). However, increased
rates of non–coronary artery bypass grafting (CABG)
major bleeding (2.1% versus 0.6%; P<0.001) and in-
tracranial hemorrhage (0.6% versus 0.2%; P=0.009)
were also associated with rivaroxaban without a sig-
nificant increase in fatal bleeding (0.3% versus 0.2%;
P=0.66) or other adverse events. Both doses of rivar-
oxaban were associated with a significant reduction in
stent thrombosis. The latter observation may indicate
that stent thrombosis events are not exclusively modu-
April 30, 2019 2177
 Gurbel et al Antiplatelet and Oral Anticoagulant Therapy

lated by platelet P2Y12 and COX-1 pathways and that COMPASS TRIAL DESIGN
thrombin, with its influence on platelet activation, fibrin
STATE OF THE ART

COMPASS was the first randomized clinical trial of a

formation, and stabilization of the platelet-fibrin clot,
non–vitamin K antagonist direct oral anticoagulant in
plays an important role in selected patients. To further
patients with chronic CAD, PAD, or chronic CAD plus
support this observation, apixaban was associated with
PAD (n=27 395). It was planned as an event-driven trial
numerically fewer stent thromboses in the prematurely
designed to continue until at least 2200 patients ex-
terminated APPRAISE-2 trial (Apixaban for Prevention
perienced a primary end point. Chronic CAD was de-
of Acute Ischemic Events 2), and vorapaxar was also
fined as MI within 20 years or multivessel CAD with
demonstrated to reduce stent thrombosis in patients
symptoms or history of stable or unstable angina, or
with ACS.67,75
multivessel percutaneous coronary intervention (PCI)
It is important to note that ATLAS was the first study
or CABG. PAD was defined as percutaneous or surgi-
to demonstrate that the addition of a very low dose
cal revascularization or amputation for arterial insuffi-
of rivaroxaban on top of antiplatelet therapy was as-
ciency, or claudication with either ankle-brachial index
sociated with a reduction in cardiovascular death in
<0.90, stenosis >50%, or carotid revascularization or
stabilized patients with a recent ACS event.77 Thus, in
stenosis >50%. Approximately 18% of the population
patients with stabilized ACS with low risk for bleeding,
had polyvascular disease (CAD+PAD); 73% had CAD
the ATLAS ACS 2 study results suggest that simultane-
alone and 9% had PAD alone. Patients were eligible
ous inhibition of platelet function with ASA and a thi-
for randomization if they completed a 30-day run-in
enopyridine and thrombin generation with a very low
period with rivaroxaban-matched placebo plus ASA
dose of rivaroxaban is effective in reducing cardiovas-
and did not have adverse events, or if they were 4 to
cular events at the cost of significant excess in nonfatal
14 days after CABG surgery. Eligible patients were ran-
bleeding, including intracranial hemorrhage. Patients
domly assigned to 2.5 mg twice-daily rivaroxaban plus
who were taking both ASA and a thienopyridine with
ASA, 5 mg twice-daily rivaroxaban alone, or 100 mg
a previous ischemic stroke or transient ischemic attack
once-daily ASA for a median of 1.95 years.9 Similar
were excluded in ATLAS ACS 2. The latter patients may
to ATLAS, the COMPASS trial excluded patients with
not derive a greater net benefit from more potent an-
stroke within 1 month and also patients with any his-
tithrombotic therapy as previously observed.6,67,84 For
tory of hemorrhagic or lacunar stroke. The primary ef-
example, in the TRITON-TIMI 38 trial (Trial to Assess
ficacy outcome was the composite of cardiovascular
Improvement in Therapeutic Outcomes by Optimiz-
Downloaded from http://ahajournals.org by on June 29, 2023

death, stroke, or MI. The main safety outcome was a

ing Platelet Inhibition with Prasugrel–Thrombolysis in
Myocardial Infarction), patients who had a previous
stroke or transient ischemic attack had net harm from
the more potent antithrombotic regimen of prasugrel
plus ASA versus clopidogrel plus ASA (HR, 1.54; 95%
CI, 1.02–2.32; P=0.04).6 The findings of ATLAS ACS 2
stand in contrast with those of the APPRAISE trial that
implemented full-dose apixaban on top of standard an-
tiplatelet therapy.75,77
The safety of replacing ASA with very-low-dose riva-
roxaban on top of clopidogrel or ticagrelor was studied
in patients with stabilized ACS in the GEMINI-ACS-1
trial (A Study to Compare the Safety of Rivaroxaban
Versus Acetylsalicylic Acid in Addition to Either Clopi-
dogrel or Ticagrelor Therapy in Participants With Acute
Coronary Syndrome) (n=3037).80 Non-CABG–related
thrombolysis in MI clinically significant bleeding was
similar between groups. Although undersized to de-
finitively assess the relation of therapeutic strategy to
ischemic events, there was no efficacy signal for rivar-
oxaban in the overall population or within subgroups.
In a post hoc analysis, the ASA arm had a numerically
lower occurrence of the ischemic composite end point
in the first 30 days, suggesting the strong influence
of platelet function on thrombosis in this acute time
period and the importance of inhibiting both COX-1
and P2Y12.80,85
modification of the International Society on Thrombo-
sis and Haemostasis criteria for major bleeding that
included fatal bleeding, symptomatic bleeding into a
critical organ, bleeding into a surgical site requiring
reoperation, and bleeding that led to hospitalization.
Patients were well managed with respect to secondary
prevention strategies (eg, 90% received lipid-lowering
therapies, 71% received angiotensin-converting en-
zyme inhibitors or angiotensin receptor blockers, and
70% received β-blockers).9
COMPASS RESULTS
Overall Population
Because of efficacy observed in the very-low-dose riva-
roxaban plus ASA arm at the first interim analysis, the
Data Safety Committee recommended stopping the trial
early with a mean follow-up of 23 months after 1323
primary outcome events among 27 395 patients. Very-
low-dose rivaroxaban plus ASA was associated with a
24% reduction in MACE in comparison with ASA alone
(4.1% versus 5.4%; HR, 0.76; P<0.001), whereas riva-
roxaban 5 mg twice daily alone did not reduce MACE
more than ASA alone (4.9% versus 5.4%; HR, 0.90;
P=0.12). In comparison with ASA monotherapy, very-
low-dose rivaroxaban plus ASA was associated with

2178 April 30, 2019 Circulation. 2019;139:2170–2185. DOI: 10.1161/CIRCULATIONAHA.118.033580

 Gurbel et al Antiplatelet and Oral Anticoagulant Therapy

STATE OF THE ART

HR= 0.76
6 ASA + 2.5mg Rivaroxaban ASA Alone
p<0.001
5.4

4.1
4 HR= 0.58 HR= 0.78 HR= 0.86 HR= 1.70
p<0.001 p=0.02 p=0.14 p<0.001
Events (%)

3.1
3

2.2
1.9 2.2 1.9
2 1.7
1.6

1 0.9

0
MACE Stroke Cardiovascular Myocardial Major
Death Infarction Bleeding
B
7 HR= 0.74
p<0.0001
6
6

5 Figure 3. Clinical outcomes in the COMPASS

trial.
4 HR= 0.50 HR= 0.75 HR= 0.86 HR= 1.66 A, Overall COMPASS cohort. B, COMPASS
Events (%)

4 p<0.0001 p=0.010 p=0.15 p<0.0001 stable coronary artery disease cohort. C,

3 COMPASS peripheral artery disease cohort. ASA
3 indicates acetylsalicylic acid; COMPASS, Cardio-
vascular Outcomes for People Using Anticoagu-
2 2 2 2 2 2 lation Strategies; HR, hazard ratio; and MACE,
2
major adverse cardiovascular events.
Downloaded from http://ahajournals.org by on June 29, 2023

1
1

0
MACE Stroke Cardiovascular Myocardial Major
Death Infarction Bleeding
C HR= 0.72
8
p=0.0047
7
7

6
5
5
Events (%)

HR= 0.54 HR= 0.54 HR= 0.56 HR= 1.61

4 p=0.0054 p=0.0037 p=0.042 p=0.0089

3
3
2 2 2
2
1 1 1 1
1

0
MACE Major Adverse Major Adverse Acute Limb Major
Limb Events Limb Events + Ischemia Bleeding
Major Amputation

lower incidences of ischemic stroke (0.7% versus 1.4%;
HR, 0.51; P<0.001), overall stroke (0.9% versus 1.6%;
HR, 0.58; P<0.00), all-cause death (3.4% versus 4.1%;
HR, 0.82; P=0.01), and cardiovascular death (1.7% ver-
sus 2.2%; HR, 0.78; P=0.02). Analysis of the individual
components of MACE indicated that the risk reduction
with very-low-dose rivaroxaban plus ASA was largely
driven by a significant reduction in the risk of overall
stroke and cardiovascular death, whereas the rates of MI
were similar among the 3 treatment arms (Figure 3A).9

Circulation. 2019;139:2170–2185. DOI: 10.1161/CIRCULATIONAHA.118.033580 April 30, 2019 2179

 Gurbel et al
Overall, major bleeding was higher with very-low-
dose rivaroxaban plus ASA versus ASA alone (3.1% ver-
STATE OF THE ART
sus 1.9%; HR, 1.70; P<0.001) and was mainly driven
by more gastrointestinal bleeding events (1.5% versus
0.7%; HR, 2.15; P<0.001); the 1.3% absolute reduction
in MACE by combination therapy was equally offset by
a 1.2% absolute increase in major bleeding. Rates of
fatal bleeding and intracranial hemorrhage were simi-
lar between the combination and ASA treatment arms.
Treatment with 5.0 mg twice-daily rivaroxaban versus
ASA alone was associated with a higher rate of major
bleeding (2.8% versus 1.9%; HR, 1.5; P<0.001), intra-
cranial bleeding (0.5% versus 0.3%; HR, 1.8; P=0.02),
fatal bleeding or symptomatic intracranial hemorrhage
(0.5% versus 0.3%; HR, 1.59; P=0.05), and fatal bleed-
ing or symptomatic bleeding into a critical organ (1.0%
versus 0.6%; HR, 1.58; P=0.006).
Very-low-dose rivaroxaban plus ASA resulted in a
20% relative reduction in the risk of the composite net
clinical benefit outcome, which was defined as a com-
posite of cardiovascular death, stroke, MI, fatal bleed-
ing, or symptomatic bleeding into a critical organ versus
ASA alone (4.7% versus 5.9%; HR, 0.80; P<0.001).9
This definition of net clinical outcome did not account
for other major bleeding that was approximately twice
as high in the combination therapy arm as in the ASA
arm (2.3% versus 1.2%; HR, 1.88; P<0.001).
Downloaded from http://ahajournals.org by on June 29, 2023
Stable CAD Group
Among 24 842 patients with stable CAD, 69% had a
history of MI, with 55% occurring ≥2 years previously
with a mean of 7.1 years. Most patients had undergone
revascularization (CABG 32%; PCI 60%). Very-low-dose
rivaroxaban plus ASA reduced MACE by 26% (4.0% ver-
sus 6.0%; HR, 0.74; P<0.0001), an effect that was driven
by significant reductions in stroke and death without an
influence on MI. Low-dose rivaroxaban alone versus ASA
alone was associated with a nonsignificant reduction in
MACE (5.0% versus 6.0%; HR, 0.89, P=0.094). Similar
to the overall trial population, the 66% increase in the
major bleeding associated with very-low-dose rivaroxa-
ban plus ASA versus ASA alone (3.0% versus 2.0%; HR,
1.66; P<0.0001) was mainly driven by gastrointestinal
bleeding (2.0% versus 1.0%; HR, 2.13; P<0.0001) (Fig-
ure 3B). The net clinical outcome (defined as cardiovas-
cular death, stroke, MI, fatal bleeding, or symptomatic
bleeding into a critical organ) occurred in 5% of patients
receiving very-low-dose rivaroxaban plus ASA versus
6.0% with ASA alone (HR, 0.78; P=0.0003).78
In an exploratory analysis, the reduction in MACE
with very-low-dose rivaroxaban plus ASA versus ASA
alone was consistent in patients with and without
prior MI (HR, 0.74; 95% CI, 0.63–0.88; and HR, 0.76;
95%% CI, 0.58–0.98; P for interaction=0.91) and
patients with a prior MI <2 years (HR, 0.70; 95% CI,
2180 April 30, 2019
Antiplatelet and Oral Anticoagulant Therapy
0.48–1.01), 2 to 5 years (HR, 0.81; 95% CI, 0.59–1.10),
and >5 years (HR, 0.72; 95% CI, 0.57–0.91) before en-
rollment. Results were also independent of history of
PCI, although in the subgroup of patients with a his-
tory of CABG, combination therapy was not beneficial
(HR, 0.99; 95% CI, 0.77–1.28; versus HR, 0.66; 95%
CI, 0.56–0.78 in the subgroup without prior CABG; P
for interaction=0.01). Patients with stable clinical symp-
toms, ie, in the absence of MI events, PCI, or CABG ≥2
years before enrollment, had a benefit with low-dose
rivaroxaban plus ASA similar to those who had MI, PCI,
or CABG <2 years before enrollment.78
PAD Group
The COMPASS study included 7470 patients with
chronic PAD. In addition, ≈65% of these patients had
a history of CAD and ≈7% had a history of stroke. In
the PAD subgroup, very-low-dose rivaroxaban plus ASA
reduced MACE by 28% versus ASA alone (5.0% versus
7.0%; HR, 0.72; P=0.0047), major adverse limb events
(MALE) by 46% (1% versus 2%; HR, 0.54; P=0.0054),
and MALE plus major amputation by 46% (1.0% ver-
sus 2.0%; HR, 0.54; P=0.0037). With respect to safety
outcomes, very-low-dose rivaroxaban plus ASA versus
ASA alone was associated with a 61% increase in ma-
jor bleeding (3.0% versus 2.0%; HR, 1.61; P=0.0089)
that was again mainly driven by a significant increase in
gastrointestinal bleeding (2.0% versus 1.0%; HR, 2.28;
P=0.0027). The composite net clinical benefit outcome
(defined per protocol as MACE, MALE including major
amputation, fatal bleeding, and bleeding into a critical
organ) occurred in 7% of patients treated with very-
low-dose rivaroxaban plus ASA and 9% of patients
treated with ASA alone (HR, 0.72; 95% CI, 0.59–0.87;
P=0.0008), a prevention of 27 MACE or MALE events
including major amputations for every 1000 patients
treated over a 21-month period at the expense of 1
fatal and 1 critical organ bleeding event (Figure 3C).79
INTERPRETATION OF THE COMPASS
TRIAL
The COMPASS study demonstrated favorable anti-
thrombotic effects from the combination of low-dose
ASA and very-low-dose rivaroxaban. In contrast, rivar-
oxaban alone at 5 mg twice daily had similar effects on
the primary outcome as ASA but with more bleeding.
Absolute reduction in MACE occurrence was numeri-
cally greatest in those with polyvascular disease: abso-
lute risk reduction, 2.7% versus 1.0% versus 0.4%, and
relative risk reduction, 33% versus 23% versus 11%
for the CAD+PAD, CAD alone, and PAD alone groups,
respectively.9,78,86 The relative reduction in MACE and
MALE events was also numerically greatest in patients
Circulation. 2019;139:2170–2185. DOI: 10.1161/CIRCULATIONAHA.118.033580
 Gurbel et al
with CAD+PAD versus PAD alone: 35% versus 18%.79
These data should be considered hypothesis-generating
in support of a stronger benefit in patients with polyvas-
cular disease. Similar benefits were observed in patients
with polyvascular disease from ticagrelor plus ASA ther-
apy in a subanalysis of the PEGASUS-TIMI 54 trial (Pre-
vention of Cardiovascular Events in Patients with Prior
Heart Attack Using Ticagrelor Compared to Placebo on
a Background of Aspirin–Thrombolysis in Myocardial
Infarction 54); ticagrelor plus ASA significantly reduced
MACE and MALE in comparison with ASA monothera-
py.87 At this time, the optimal antithrombotic treatment
strategy for patients with PAD remains unresolved.
The COMPASS findings are particularly noteworthy
because they apply to a population already receiving a
high level of adjunctive secondary prevention strategies.
An approximate halving of the rate of ischemic stroke
by dual pathway inhibition versus ASA monotherapy
was the major event driving the significant reduction
in MACE (see below). It is interesting to note that a
definite effect on reduction in MI was not observed by
combination therapy, suggesting potential differences
in the pathways modulating these clinical events. The
benefit of combination therapy was present irrespective
of prior MI, the time of enrollment in relation to prior
MI occurrence, and the performance of PCI. Although
underpowered to make a firm conclusion, patients who
underwent CABG did not appear to benefit from dual
pathway inhibition. It is notable that the efficacy ad-
Downloaded from http://ahajournals.org by on June 29, 2023
vantage comes at a cost of increased major bleeding,
but not fatal bleeding or intracranial hemorrhage, and
bleeding is mostly in the gastrointestinal tract. It should
be noted that patients with a high risk for bleeding and
stroke within 1 month or any history of hemorrhagic
or lacunar stroke were excluded from the COMPASS
trial. Therefore, the optimal patients for dual pathway
inhibition are likely those with chronic disease who are
at highest risk for recurrent ischemic events. Such pa-
tients would include those with polyvascular disease or
symptomatic PAD, and patients with CAD who had ad-
ditional risk factors. At the same time, patients at high
risk for bleeding such as the elderly, and patients with
prior bleeding, advanced kidney disease, anemia, and
low body weight may not be suitable candidates.
It is important to note that the clinical benefit of
adding very-low-dose rivaroxaban to ASA was present
irrespective of the length of the history of CAD in the
COMPASS trial. This is in contrast to results from the
PEGASUS-TIMI 54 trial, where ischemic event reduction
with ticagrelor plus low-dose ASA was not observed in
patients who had been stable for ≥1 years on single
antiplatelet therapy.87
The antithrombotic benefit of combination therapy
on ischemic stroke reduction may, in part, be explained
by the benefit of an anticoagulant to reduce cardio-
embolic stroke in comparison with antiplatelet therapy
Circulation. 2019;139:2170–2185. DOI: 10.1161/CIRCULATIONAHA.118.033580
Antiplatelet and Oral Anticoagulant Therapy
alone and is supported by a comparison of the rivar-
oxaban alone arm versus ASA, where there were fewer
STATE OF THE ART
ischemic strokes with rivaroxaban (HR, 0.69; P=0.006)
but at the cost of more hemorrhagic strokes (HR, 2.7;
P=0.005). Low-dose ASA may attenuate platelet acti-
vation and resultant formation of the prothrombinase
complex. Very-low-dose rivaroxaban may synergize the
attenuation of initial thrombin generation as described
earlier.
Thus, after vessel wall injury, the simultaneous in-
hibition of platelet activation by low-dose aspirin that
attenuates prothrombinase complex formation and
low-dose rivaroxaban that inhibits factor Xa within the
complex may effectively blunt the initial amplification
of thrombin generation required for thrombus forma-
tion while at the same time preserve endogenous he-
mostasis pathways. Finally, noncanonical effects of fac-
tor Xa inhibition on inflammation, vascular remodeling,
atherosclerotic plaque progression, and tissue fibrosis
and ASA may also modulate the occurrence of ischemic
stroke (see above). At this time, the type of stroke (ie,
lacunar, large vessel, cardioembolic) has not yet been
reported by the COMPASS investigators. The stroke
findings of COMPASS contrast with the effects of DAPT
versus ASA,8,9,88 clopidogrel monotherapy versus ASA
plus clopidogrel,64 or potent DAPT versus weak DAPT
strategies6,7 on ischemic stroke, where no differences
were observed.
In the recently published COMMANDER-HF trial (A
Study to Assess the Effectiveness and Safety of Riva-
roxaban in Reducing the Risk of Death, Myocardial
Infarction, or Stroke in Participants with Heart Failure
and Coronary Artery Disease Following an Episode of
Decompensated Heart Failure) of patients with recent
worsening of chronic heart failure, reduced ejection
fraction, and coronary artery disease, a strategy of very-
low-dose rivaroxaban on top of standard therapy (93%
ASA and 35% ASA+thienopyridine) was not associated
with a reduction in MACE (death from any cause, MI,
or stroke) in comparison with placebo, but, similar to
the results of COMPASS, was associated with a lower
stroke rate.9,89 Most outcomes in COMMANDER-HF
were death events, and, in this heart failure population,
the mechanism for death may not be strongly influ-
enced by thrombin generation and platelet activation.
In summary, the results of COMPASS support the
concept of the enhancement of antithrombotic effects
by combining blockade of COX-1 and a very low dose
of a factor Xa inhibitor in patients with stable ath-
erosclerotic vascular disease, in particular, those with
polyvascular disease. Very-low-dose rivaroxaban still
provides substantial inhibition of ex vivo thrombin gen-
eration.90 This potentiation may be based on the com-
bined antithrombotic action of the drugs: inhibition of
platelet function and coagulation. However, other po-
tential effects of factor Xa blockade and COX-1 block-
April 30, 2019 2181
 Gurbel et al
ade mediated through noncanonical pathways should
be considered, and are discussed below.
STATE OF THE ART
The European Medicines Agency has approved (1)
rivaroxaban 2.5 mg twice daily with ASA alone or with
DAPT for the secondary prevention of atherothrombotic
events in adult patients after an ACS event with elevat-
ed cardiac biomarkers and (2) rivaroxaban 2.5 mg twice
daily with ASA for the prevention of atherothrombotic
events in adult patients with CAD or symptomatic PAD
at high risk of ischemic events.91 In addition, rivaroxa-
ban 2.5 mg twice daily in combination with low-dose
ASA was approved to reduce the risk of MACE in pa-
tients with CAD/PAD by the US Food and Drug Admin-
istration in 2018.86
CONCLUSIONS
A basic pathophysiological construct is that thrombus
formation at the site of atherosclerotic plaque rupture is
mediated by the function of platelets and coagulation.
The totality of clinical evidence is directly in line with the
basic data and demonstrates that, in the setting of early
administration for secondary prevention, the blockade
of 2 key pathways that amplify platelet activation, COX-
1 and the P2Y12 receptor, provides enhanced inhibition
of coronary arterial thrombosis and reduced MACE. The
benefit of a very-low-dose factor Xa inhibitor in this
time period, as in ATLAS, was observed when added to
Downloaded from http://ahajournals.org by on June 29, 2023
clopidogrel, a weak P2Y12 inhibitor, and ASA. This ad-
ditional benefit likely reflects the combined attenuation
of platelet activation and thrombin generation, 2 major
modulators of atherothrombosis. In contrast, when full-
dose apixaban was added on top of DAPT in ACS, there
was no significant reduction in MACE, whereas there
was a significant increase in major bleeding. Therefore,
the selection of the appropriate anticoagulant and the
appropriate dose requires careful balancing of benefits
and risks.
The success of combined antiplatelet and antico-
agulant therapy is critically dependent on the safety
profile of the anticoagulant. For example, therapeutic
doses of warfarin reduced recurrent ischemic events
after MI, but this effect was offset by an increase in se-
rious bleeding. In the chronic disease phase, the COM-
PASS trial revealed a reduction in MACE with a com-
bination of very-low-dose rivaroxaban plus ASA, dual
pathway inhibition, in patients with CAD and PAD that
was largely driven by a reduction in ischemic stroke fol-
lowed by cardiovascular death. The enhanced clinical
effect of the latter strategy, which includes a reduction
in MALE in the PAD population, may be explained by
direct potentiation of antithrombotic effects. In addi-
tion, noncanonical effects modulating inflammation
and reparative processes may play a role. Increased
bleeding may also be explained by potentiation of an-
tithrombotic effects.
2182 April 30, 2019
Antiplatelet and Oral Anticoagulant Therapy
Challenges in the uptake of dual pathway inhibition
as administered in COMPASS into clinical practice will
focus on the careful selection of patients and imple-
mentation of a multidisciplinary approach involving
stratification of competing risks of thrombosis and
bleeding. Those most likely to benefit would include
patients at high risk for recurrent ischemia with the
following characteristics: polyvascular disease, symp-
tomatic PAD, and additional risk factors. The ongoing
VOYAGER study (Efficacy and Safety of Rivaroxaban in
Reducing the Risk of Major Thrombotic Vascular Events
in Subjects With Symptomatic Peripheral Artery Disease
Undergoing Peripheral Revascularization Procedures of
the Lower Extremities) will provide further information
in the PAD population.92 Finally, a remaining challenge
is when to transition patients with high-risk ACS from
DAPT to dual pathway inhibition. Because guidelines
recommend DAPT for at least 1 year in patients with
ACS, this may be an appropriate time to make the
switch, but trials are needed to examine this possibil-
ity. Still unknown is whether biomarkers of platelet-
fibrin clot generation properties can help to identify
patients at high thrombotic risk who would derive the
greatest net clinical benefit from dual pathway inhibi-
tion or whether new anticoagulant strategies such as
those targeting factor XI will provide a safer platform
on which to add antiplatelet therapy.93
ARTICLE INFORMATION
Correspondence
Paul A. Gurbel, MD, FAHA, Director, Interventional Cardiology and Cardiovas-
cular Medicine Research, Inova Center for Thrombosis Research and Drug De-
velopment, Inova Heart and Vascular Institute, 3300 Gallows Rd, Falls Church,
VA 22042. Email Paul.Gurbel@inova.org
Affiliations
Inova Center for Thrombosis Research and Drug Development, Inova Heart and
Vascular Institute, Falls Church, VA (P.A.G.). Sinai Center for Thrombosis Re-
search, Sinai Hospital of Baltimore, MD (U.S.T.). British Heart Foundation Centre
for Cardiovascular Sciences, University of Edinburgh, United Kingdom (K.A.A.F.).
Laboratory for Clinical Thrombosis and Hemostasis, Departments of Internal
Medicine and Biochemistry, Cardiovascular Research Institute Maastricht, Maas-
tricht University Medical Center, Netherlands (H.t.C.). Thrombosis and Athero-
sclerosis Research Institute and McMaster University, Hamilton, Canada (J.I.W.).
Acknowledgments
We are grateful to Mr Patrick Lane for Figures 1 and 2.
Disclosures
Dr Gurbel reports receiving grants from the National Institutes of Health, Bayer,
Medicure, Instrumentation Labs, Haemonetics, Amgen, Idorsia, Ionis, Haemon-
etics, Janssen, and Merck; receiving honoraria and payment for lectures, con-
sultations including service on speakers’ bureaus from Bayer, Janssen, Merck,
UptoDate, and Medicure; and holding patents in the area of personalized an-
tiplatelet therapy and interventional cardiology. Dr Fox received grants from
Bayer, Janssen, and AstraZeneca and is a consultant for Bayer, Janssen, Astra-
Zeneca, Sanofi/Regeneron, and Verseon. Dr Tantry reports receiving honoraria
from AstraZeneca, UptoDate, and Medicure. Dr Ten Cate received research sup-
port from Bayer, Pfizer, and Leo Farma; performed consultancy for Stago; and
was on the advisory board for Bayer and Pfizer. Dr Ten Cate received noncom-
Circulation. 2019;139:2170–2185. DOI: 10.1161/CIRCULATIONAHA.118.033580
 Gurbel et al
mercial support from the Dutch Heart Foundation (RACE-5 and CONTRAST). Dr
Ten Cate is the chair of the board of the Dutch Federation of Anticoagulation
Clinics. Dr Weitz is a consultant for and has received honoraria from Bayer,
Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis, Janssen,
Merck, Novartis, Pfizer, and Portola.
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