Rivaroxaban: A New Oral Factor Xa Inhibitor

Elisabeth Perzborn, Susanne Roehrig, Alexander Straub, Dagmar Kubitza, Wolfgang Mueck
and Volker Laux

Arterioscler Thromb Vasc Biol. 2010;30:376-381; originally published online February 5, 2010;
doi: 10.1161/ATVBAHA.110.202978
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 DVT: A New Era in Anticoagulant Therapy
Rivaroxaban: A New Oral Factor Xa Inhibitor
Elisabeth Perzborn, Susanne Roehrig, Alexander Straub, Dagmar Kubitza,
Wolfgang Mueck, Volker Laux

Abstract—Rivaroxaban is a direct inhibitor of factor Xa, a coagulation factor at a critical juncture in the blood coagulation
pathway leading to thrombin generation and clot formation. It is selective for human factor Xa, for which it has
⬎10 000-fold greater selectivity than for other biologically relevant serine proteases (half-maximal inhibitory
concentration [IC50], ⬎20 ␮mol/L). Rivaroxaban inhibits factor Xa in a concentration-dependent manner (inhibitory
constant [Ki], 0.4 nmol/L) and binds rapidly (kinetic association rate constant [kon], 1.7⫻107 mol/L⫺1 s⫺1) and
reversibly (kinetic dissociation rate constant [koff], 5⫻10⫺3 s⫺1). By inhibiting prothrombinase complex-bound (IC50,
2.1 nmol/L) and clot-associated factor Xa (IC50, 75 nmol/L), rivaroxaban reduces the thrombin burst during the propagation
phase. In animal models of venous and arterial thrombosis, rivaroxaban showed dose-dependent antithrombotic activity. In
healthy individuals, rivaroxaban was found to have predictable pharmacokinetics and pharmacodynamics across a 5- to 80-mg
total daily dose range, inhibiting factor Xa activity and prolonging plasma clotting time. In phase III clinical trials, rivaroxaban
regimens reduced rates of venous thromboembolism in patients after total hip or knee arthroplasty compared with enoxaparin
regimens, without significant differences in rates of major bleeding, showing that rivaroxaban has a favorable benefit-to-risk
profile. (Arterioscler Thromb Vasc Biol. 2010;30:376-381.)
Key Words: anticoagulants 䡲 blood coagulation 䡲 factor Xa 䡲 rivaroxaban 䡲 venous thromboembolism

F actor Xa is a coagulation factor that acts at the convergence

point of the intrinsic and extrinsic pathways in the blood
coagulation system.1 It catalyzes the cleavage of prothrombin
and, therefore, is critical for thrombin generation (Figure 1).1,2
Indirect factor Xa inhibitors, such as fondaparinux and
biotinylated idraparinux, exert their thrombotic effect by binding
to antithrombin; therefore, their efficacy depends on the circu-
lating level of antithrombin. They are parenteral agents and
cannot be administered orally.3 Rivaroxaban is the first direct
factor Xa inhibitor to be licensed (in the European Union4 and
several other countries) for the prevention of venous thrombo-
embolism (VTE) in adult patients after elective hip or knee
arthroplasty. Studies of rivaroxaban in the treatment of VTE,
prevention of cardiovascular events in patients with acute coro-
nary syndrome, prevention of stroke in those with atrial fibril-
lation, and prevention of VTE in hospitalized medically ill
patients are ongoing (Supplementary Table I, available at http://
atvb.ahajournals.org). Other direct factor Xa inhibitors are also
in advanced development; apixaban and edoxaban (DU-176b)
are undergoing phase III study, whereas betrixaban and YM150
have passed clinical phase II testing. This review discusses the
properties of rivaroxaban and findings from clinical trials.
See accompanying article on page 369
Pharmacological Properties
Compound Characteristics
Rivaroxaban (chemical name 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-
oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]thiophene-
2-carboxamide) is a small-molecule factor Xa inhibitor (molec-
ular weight, 436 g/mol). Rivaroxaban is only slightly soluble in
organic solvents and is practically insoluble in water.5 Plasma
protein binding varies between species (rats, 98.7%; rabbits,
76.6%5; and humans, 92%–95%),4 and serum albumin is the
main circulating binding component.4,5
Mode of Binding
As a prerequisite for potent activity, factor Xa inhibitors of the
first generation, such as DX-9065a, needed a basic arginine-
mimic P1 group for direct electrostatic interaction with Asp189
in the S1 pocket of factor Xa. However, those basic groups are also
generally critical for oral bioavailability. The X-ray crystal structure
of rivaroxaban in complex with human factor Xa6 revealed a
different binding mode for the S1 pocket, which no longer
requires the P1 group to be basic. Instead, the key interaction in
the S1 pocket involves the chlorine substituent of the chlorothio-
phene moiety, which interacts with the aromatic ring of Tyr228 at
the bottom of the S1 pocket (Figure 2). This novel chlorine–Tyr228
interaction enabled the combination of high potency and sufficient
oral bioavailability for the nonbasic compound rivaroxaban.
Preclinical In Vitro and In Vivo
Pharmacological Profile
In Vitro Studies
Factor Xa Inhibition
Rivaroxaban inhibits factor Xa in a concentration-dependent
manner (inhibitory constant [Ki], 0.4 nmol/L), and it is a

Received January 6, 2010; revision accepted January 15, 2010.

From Bayer Schering Pharma AG, Wuppertal, Germany.
Correspondence to Elisabeth Perzborn, PhD, Cardiovascular Pharmacology, Pharma R&D Discovery Research, Bayer Schering Pharma AG, Aprather
Weg 18a, D-42096 Wuppertal, Germany. E-mail elisabeth.perzborn@bayerhealthcare.com
© 2010 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.110.202978

376
Downloaded from http://atvb.ahajournals.org/ by guest on November 21, 2012
 Perzborn et al
Intrinsic pathway Extrinsic pathway
Factor XIa
Factor IXa Factor VIIa
Tenase Factor VIIIa Tissue factor
complex Phospholipids Phospholipids
Ca2+
Free Factor Xa
Rivaroxaban
Phospholipids
Prothrombinase
Factor Va–Factor Xa
complex
Ca2+
Prothrombin Thrombin
Fibrinogen Fibrin
Figure 1. Role of factor Xa in the coagulation cascade. Tissue
factor/factor VIIa activates factor X and factor IX. Factor IXa also
activates factor X. Factor Xa binds factor Va on membrane sur-
faces. The prothrombinase and tenase trigger the amplified for-
mation of thrombin.2,53 Rivaroxaban inhibits factor Xa, free or
within the prothrombinase.
competitive inhibitor of the amidolytic activity of factor Xa.7 It
has a rapid onset of action (kinetic association rate constant
[kon], 1.7⫻107 mol/L⫺1 s⫺1) and is reversible (kinetic dissoci-
ation rate constant [koff], 5⫻10⫺3 s⫺1).8 Rivaroxaban inhibits
prothrombinase-bound (half-maximal inhibitory concentration
[IC50], 2.1 nmol/L)7 and clot-associated factor Xa (IC50, 75
nmol/L).9
Rivaroxaban was found to be selective for human factor Xa,
for which it has ⬎10 000-fold greater selectivity than for other
biologically relevant serine proteases (IC50, ⬎20 ␮mol/L).7 The
inhibition of factor Xa is species-dependent, as was shown for a
number of factor Xa inhibitors.10 –12 Rivaroxaban showed a
similar affinity to purified human and rabbit factor Xa (IC50,
0.7 nmol/L and 0.8 nmol/L, respectively) but showed lower
affinity to rat factor Xa (IC50, 3.4 nmol/L).
In commercially available chromogenic assays designed
for measuring heparins in human plasma, rivaroxaban
concentration-dependently inhibited factor Xa activity, with IC50
values between 21 and 80 ng/mL, depending on the anti-factor
Xa assay.13
Inhibition of Thrombin Generation
In vitro studies in platelet-poor and platelet-rich plasma
demonstrated that rivaroxaban prolonged the initiation phase
of thrombin generation and reduced the thrombin burst
produced in the propagation phase.14,15 In human plasma
obtained from healthy volunteers receiving rivaroxaban, ri-
varoxaban inhibited thrombin generation at clinically relevant
plasma concentrations and, thus, the propagation processes of
coagulation through the inhibition of factor Xa generated via
the intrinsic and extrinsic coagulation pathways.
Plasma Clotting Times
Rivaroxaban demonstrated effective anticoagulant effects in
human plasma; it prolongs prothrombin time (PT) and acti-
vated partial thromboplastin time in a concentration-
dependent manner, with greater sensitivity for PT.7 However,
the prolongation of clotting time varies depending on the PT
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Rivaroxaban: A New Oral Factor Xa Inhibitor 377
Ca2+
Figure 2. The entire X-ray crystal structure of factor Xa (FXa)
with a focus on the active site showing the key interaction
between rivaroxaban and Tyr228 in the S1 pocket.
or activated partial thromboplastin time reagent used because
the reactivity of rivaroxaban in the clotting assays is
influenced by the composition of the reagents.16,17 This
variation cannot be reduced by conversion of PT values
given in seconds to international normalized ratio values17;
therefore, PT and activated partial thromboplastin time are
not useful for measuring the pharmacodynamic effects of
rivaroxaban.
Thrombin–Thrombomodulin-Activated Protein C System
The coagulation pathway comprises negative and positive feed-
back reactions to regulate hemostasis, and anticoagulants at
therapeutic doses ideally should not interfere with the negative
feedback mechanisms important in downregulating coagulation.
One of the negative feedback reactions is the thrombin–
thrombomodulin-activated protein C system, which limits fur-
ther thrombin generation by inhibiting factor Va and factor
VIIIa. In in vitro investigations of human plasma from healthy
individuals or protein C-deficient plasma, factor Xa inhibitors,
such as rivaroxaban, inhibited thrombin generation in a
concentration-dependent manner after stimulation by tissue fac-
tor and in the presence or absence of thrombomodulin.18 This
suggests that rivaroxaban does not measurably interfere with the
thrombin–thrombomodulin-activated protein C system.18 Inter-
estingly, direct thrombin inhibitors, such as melagatran and
dabigatran, also showed a concentration-dependent inhibition
of thrombin generation over the whole range in the absence
of thrombomodulin or in protein C-deficient plasma but in-
creased thrombin generation at low concentrations in the pres-
ence of thrombomodulin.18,19 This suggests that low concentra-
tions of a direct thrombin inhibitor may partly suppress the negative
feedback by activated protein C. However, whether this effect will
influence clinical efficacy or safety remains to be investigated.
Platelet Aggregation
Rivaroxaban does not affect platelet aggregation induced by
collagen, adenosine diphosphate, the selective agonist of pros-
taglandin H2/thromboxane A2 receptor U46619, or throm-
bin.20,21 However, rivaroxaban effectively and concentration-
dependently inhibited tissue factor-induced platelet
378 Arterioscler Thromb Vasc Biol March 2010
aggregation by the inhibition of thrombin generation (IC50,
0.06 ␮mol/L) in defibrinated plasma.22 In addition to the
anticoagulant effects of a factor Xa inhibitor, this indirect
effect on platelet aggregation may be particularly beneficial
for the prevention or treatment of arterial thrombosis.
In Vivo Studies
Venous Thrombosis Models
Rivaroxaban reduced thrombus formation7,23 in venous
thrombosis models (fibrin-rich and platelet-poor) in which a
combination of stasis and an injection of tissue factor was
used to induce thrombus formation. In rabbits, rivaroxaban
was administered orally, leading to a half-maximal effective
dose (ED50) of 1.3 mg/kg23; in rats, rivaroxaban was admin-
istered intravenously, leading to ED50 of 0.1 mg/kg.7,24 These
findings suggested rivaroxaban might reduce thrombus forma-
tion in humans. In a rabbit thrombosis model, rivaroxaban also
inhibited thrombus growth of preformed clots in the jugular vein
(assessed by measuring the accretion of radiolabeled fibrino-
gen),23 which supported further research in VTE treatment.
Arterial Thrombosis Models
Rivaroxaban showed effective dose-dependent antithrombotic
activity in arterial (fibrin-poor and platelet-rich) thrombosis
models, such as the arteriovenous shunt model in rats and rabbits
(ED50, 5.0 mg/kg after oral rivaroxaban in rats; ED50, 0.6 mg/kg
after oral administration in rabbits7), and the ferric chloride
model in rats and mice (ED50, 2.4 mg/kg after intravenous
rivaroxaban in rats; ED50, 1.0 mg/kg after intravenous rivaroxa-
ban in mice24). These results are consistent with a role of the
coagulation system in arterial thrombus formation.
Bleeding Models
The antihemostatic effect of rivaroxaban was evaluated in
well-characterized bleeding time models in rats (tail transec-
tion bleeding time model) and rabbits (ear-bleeding time
model). Bleeding times were not significantly affected at
antithrombotic doses below the ED50 required for antithrom-
botic efficacy in the bleeding time models. At higher doses in
the rat tail-bleeding time model, bleeding times were dose-
dependently prolonged.7 Together with the antithrombotic
findings, these findings demonstrate that rivaroxaban might
have a favorable efficacy-to-bleeding ratio.
Clinical Pharmacology
Rivaroxaban has a favorable safety and tolerability profile in
healthy individuals.25,26
Pharmacodynamic and Pharmacokinetic Profiles
Rivaroxaban was found to have predictable pharmacokinetics
and pharmacodynamics across a wide range of doses in
healthy individuals (5– 80 mg total daily doses)25,26 and
patients undergoing total hip or total knee arthroplasty (5– 60
mg total daily doses).27
The inhibition of factor Xa activity and the prolongation of
PT correlated strongly with the plasma concentrations of
rivaroxaban in healthy individuals28 and patients undergoing
total hip arthroplasty or total knee arthroplasty,27 corroborat-
ing the predictability of the pharmacodynamics and pharma-
cokinetics of rivaroxaban.
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Studies in healthy individuals showed that rivaroxaban is
rapidly absorbed, with maximum concentrations appearing 2
to 4 hours after tablet intake.4,25,26 Oral bioavailability for the
10-mg dose (which has health regulatory authority approval
for thromboprophylaxis after elective hip or knee arthroplasty
in adult patients) is high (80%–100%).4 The mean terminal
half-life of rivaroxaban is 7 to 11 hours.4
The elimination of rivaroxaban from plasma was rapid,
with no major or pharmacologically active circulating metab-
olites detected in plasma.29 Excretion occurred via renal and
fecal/biliary routes. Approximately two-thirds of the admin-
istered dose is metabolized to inactive metabolites, with half
then being eliminated renally and the other half eliminated by
the fecal route. The remaining one-third of the administered
dose undergoes direct renal excretion as unchanged active
substance in the urine.29
Rivaroxaban is metabolized by a number of independent
metabolic pathways involving different classes of enzymes;
thus, rivaroxaban should be less prone to drug– drug interac-
tions. The main oxidative metabolic pathway is hydroxylation
at the morpholinone moiety and, to a lesser extent, at the
oxazolidinone moiety, catalyzed by CYP3A4/3A5 and
CYP2J2.30 In addition, hydrolytic pathways were identified,
occurring at the morpholinone ring and the chlorothiophene
amide moiety.
Effect of Rivaroxaban in Different Populations
Phase I and II clinical studies have investigated the effect of
several factors on rivaroxaban pharmacokinetics and pharma-
codynamics. The area under the plasma concentration curve
was higher in healthy men and women older than age 75 years
compared with younger men and women, but maximum
plasma concentration was unaffected.31,32 Gender did not
affect the area under the plasma concentration curve or
maximum plasma concentration of rivaroxaban.31,32 Area
under the plasma concentration curve was not affected by
extreme body weight (ⱕ50 kg or ⬎120 kg), and although
maximum plasma concentration was increased by 24% in
those weighing ⱕ50 kg, this increase was not considered to
be clinically relevant.32 In patients with mild (creatinine
clearance, 50 –79 mL/min), moderate (creatinine clearance,
30 – 49 mL/min), or severe (creatinine clearance ⬍30 mL/
min) impairment of renal function, area under the plasma
concentration curve was 44%, 52%, and 64% higher, respec-
tively, compared with control subjects, whereas maximum
plasma concentration was relatively unaffected.33 In patients
with mild (Child–Pugh A) hepatic functional impairment,
there were no clinically relevant differences in pharmacoki-
netics and pharmacodynamics of rivaroxaban.34 Together,
these findings suggest that rivaroxaban can be administered
to individuals with varying physical characteristics (age,
gender, body weight, mild or moderate impairment of renal
function, and mild hepatic functional impairment) at a fixed
dose, with no requirement for dose adjustment or routine
coagulation monitoring.4
Interaction With Food and Drugs
Phase I interaction studies have demonstrated no food interac-
tions and no significant and few clinically relevant drug inter-
 Perzborn et al
actions with rivaroxaban, with the exception of azole antimy-
cotics or human immunodeficiency virus protease inhibitors.
These strong inhibitors of CYP3A4 and P-glycoprotein lead to
reduced clearance of rivaroxaban; therefore, rivaroxaban is not
recommended in patients receiving these drugs. Strong CYP3A4
inducers may lead to reduced rivaroxaban plasma concentrations
and should be coadministered with caution.4
No clinically significant interactions were observed when
rivaroxaban was coadministered with the statin atorvastatin (a
substrate of CYP3A4 and P-glycoprotein),35 the cardiac
glycoside digoxin (a substrate of P-glycoprotein),36 or the
benzodiazepine derivative midazolam (a substrate of
CYP3A4).4 The histamine H2-receptor antagonist ranitidine
(a CYP3A4 inhibitor) and the antacid aluminum–magnesium
hydroxide have no significant effect on the pharmacokinetics
and pharmacodynamics of rivaroxaban.37
Coadministration of antiplatelet agents, such as the non-
steroidal antiinflammatory drugs acetylsalicylic acid38 and
naproxen,39 had no significant effect on the pharmacokinetics
and pharmacodynamics of rivaroxaban. The antiplatelet agent
clopidogrel did not show a pharmacokinetic interaction with
rivaroxaban.40
Clinical Trials in the Prevention of
Venous Thromboembolism
Phase II Trials
The Oral Direct Factor Xa (ODIXa) program of four phase II
dose-finding studies of rivaroxaban for the prevention of VTE in
patients undergoing total hip or knee arthroplasty suggested that
rivaroxaban 10 mg once daily (compared with approved enox-
aparin doses) would provide the best balance between efficacy
and safety.41– 44
Phase III Trials
In the orthopaedic setting, the phase III Regulation of
Coagulation in Orthopaedic surgery to prevent deep vein
thrombosis and pulmonary embolism (RECORD) program
included ⬎12 700 patients undergoing total hip arthroplasty
or total knee arthroplasty.45– 48 Patients were randomized to
oral rivaroxaban 10 mg once daily administered 6 to 8 hours
after wound closure or after adequate hemostasis had been
achieved, or subcutaneous enoxaparin 40 mg once daily
starting 12 hours before surgery (enoxaparin dose approved
in the European Union, North America, and other countries)
in RECORD1, 2, and 3 or 30 mg twice daily administered 12
to 24 hours after wound closure (dose approved and more
often used in North America) in RECORD4. In RECORD1
and 2, patients undergoing total hip arthroplasty were admin-
istered rivaroxaban for 35⫾4 days. Enoxaparin was admin-
istered for 35⫾4 days in RECORD1 or 12⫾2 days followed
by placebo for up to 35⫾4 days in RECORD2. In RECORD3
and 4, patients undergoing total knee arthroplasty received
prophylaxis for 12⫾2 days. All patients were followed-up for
30 to 35 days after the last dose of study medication.
The rivaroxaban regimens were significantly more effec-
tive than both enoxaparin regimens at reducing the composite
of symptomatic and asymptomatic (detected by systematic
bilateral venography) deep vein thrombosis, nonfatal pulmo-
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Rivaroxaban: A New Oral Factor Xa Inhibitor 379
nary embolism, and all-cause mortality.45– 48 Rates of major
bleeding did not differ significantly between rivaroxaban and
enoxaparin regimens.45– 48 Also, the proportion of patients
with elevated liver enzymes (alanine aminotransferase level
⬎3-times the upper limit of the normal range) was low in the
rivaroxaban and enoxaparin groups.45– 48
In a pooled analysis of the RECORD1– 4 data, the composite
of symptomatic VTE and death was reduced for the rivaroxaban
regimens compared with the enoxaparin regimens at day 12⫾2
(0.47% vs 0.97%; P⫽0.001) and in the planned treatment period
(rivaroxaban or enoxaparin for 12⫾2 days [RECORD3 and 4] or
35⫾4 days [RECORD1 and 2], including the enoxaparin pla-
cebo phase in RECORD2; 0.57% vs 1.32%; P⬍0.001). There
were no statistical differences in the rates of major bleeding at
any of the time points analyzed. The composite of major and
clinically relevant nonmajor bleeding for the rivaroxaban and
enoxaparin regimens were 2.85% vs 2.45% (P⫽0.186) at day
12⫾2 and 3.19% vs 2.55% (P⫽0.039) in the planned treatment
period.49
Clinical Trials in the Treatment of
Venous Thromboembolism
The phase III EINSTEIN EXT study (NCT00439725) showed
that in patients who had completed 6 or 12 months of previous
therapy for acute VTE, there was a risk reduction of 82% for
rivaroxaban vs placebo for recurrent symptomatic VTE.50 Re-
search is ongoing in the EINSTEIN DVT (NCT00440193) and
EINSTEIN PE (NCT00439777) studies (Supplementary Table I).
Other Studies
Rivaroxaban is also being studied for the prevention of cardio-
vascular events in patients with acute coronary syndrome
(ATLAS ACS TIMI 51; NCT00809965), stroke prevention in
patients with atrial fibrillation (ROCKET AF51; NCT00403767),
and thromboprophylaxis in hospitalized medically ill patients
(MAGELLAN; NCT00571649; Supplementary Table I).
Conclusion
Rivaroxaban was selected as a drug candidate based on its
hypothetical therapeutic potential as a direct inhibitor of factor
Xa, in vitro potency, demonstrated selectivity against factor Xa,7
anticoagulant activity in clotting assays in human plasma,7 and
consistent in vivo antithrombotic activity in venous and arterial
thrombosis models.7,23,24 Because of its favorable safety and
tolerability profile in healthy individuals and a positive benefit-
to-risk ratio for the prevention of VTE in patients after total hip
arthroplasty or total knee arthroplasty,41– 44 the 10-mg once-daily
dose has been granted health regulatory authority approval for
the prevention of VTE after elective hip or knee arthroplasty in
adult patients.4 The oral bioavailability of rivaroxaban is an
advantage over parenteral anticoagulant agents and could pro-
vide better convenience in outpatient settings.
The pharmacodynamic and pharmacokinetic profiles, which
were found to be predictable,25–27 together with the low interac-
tion potential with food or other drugs,4,35– 40 the wide therapeu-
tic window,7 and the absence of a requirement for routine
coagulation monitoring,4 enhance the likelihood that oral factor
Xa inhibitors such as rivaroxaban may become an alternative to
vitamin K antagonists in patients at risk for thromboembolism.
380 Arterioscler Thromb Vasc Biol March 2010
Use of factor Xa inhibitors might also obviate the drawbacks of
vitamin K antagonists, which include unpredictable pharmaco-
dynamics and pharmacokinetics, multiple food– drug and drug–
drug interactions, considerable interindividual variability in dose
response, and requirement for regular coagulation monitoring.52
At present, there is a substantial clinical need for an oral
anticoagulant to replace vitamin K antagonists for long-term
prevention or treatment of patients with venous and arterial
thromboembolic events. There is currently a variety of new,
promising, oral anticoagulants at various stages of clinical
evaluation, with the most advanced being the direct factor Xa
inhibitor rivaroxaban and the direct thrombin inhibitor dabigat-
ran (reviewed in this series).
One major focus in the development of drugs targeting 1
coagulation factor was factor Xa. Emerging data for rivar-
oxaban and other potent factor Xa inhibitors, such as apixa-
ban, betrixaban, edoxaban, and YM150, suggest that factor
Xa is a highly promising target for new antithrombotic agents
for short-term and long-term usage.
Orthopaedic surgery has proved to be a reliable clinical model
for assessing the efficacy and safety profile of a new oral
anticoagulant. Rivaroxaban has shown superiority over standard
therapy with enoxaparin without significantly increasing the
major bleeding rate;45– 48 thus, it might be effective and safe in
other indications such as the prevention and treatment of VTE,
the prevention of stroke in patients with atrial fibrillation, and the
recurrence of cardiovascular events in patients with acute coro-
nary syndrome. Thus, new oral factor Xa inhibitors such as
rivaroxaban herald a new era of anticoagulation.
Acknowledgments
The authors acknowledge Li Wan, who provided medical writing
services with funding from Bayer Schering Pharma AG and Johnson
& Johnson Pharmaceutical Research & Development, LLC.
Disclosures
The authors are employees of Bayer Schering Pharma AG.
References
1. Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb
Haemost. 2007;5(Suppl 1):60 – 64.
2. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med.
2008;359:938 –949.
3. Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American
College of Chest Physicians Evidence-Based Clinical Practice
Guidelines, 8th Edition. Chest. 2008;133:234S–256S.
4. Xarelto. Summary of Product Characteristics. Available at: http://
www.xarelto.com/html/downloads/Xarelto_Summary_of_Product_
Characteristics_ May2009.pdf. 2009. Accessed January 14, 2010.
5. European Medicines Agency (EMEA). CHMP Assessment Report for
Xarelto. Available at: http://www.emea.europa.eu/humandocs/PDFs/EPAR/
xarelto/H-944-en6.pdf. 2008. Accessed January 14, 2010.
6. Roehrig S, Straub A, Pohlmann J, Lampe T, Pernerstorfer J, Schlemmer
KH, Reinemer P, Perzborn E. Discovery of the novel antithrombotic
agent 5-chloro-N-([(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-
oxazolidin-5-yl]methyl)thiophene-2-carboxamide (BAY 59-7939): an
oral, direct Factor Xa inhibitor. J Med Chem. 2005;48:5900 –5908.
7. Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S,
Schlemmer KH, Straub A. In vitro and in vivo studies of the novel
antithrombotic agent BAY 59-7939 —an oral, direct Factor Xa inhibitor.
J Thromb Haemost. 2005;3:514 –521.
8. Tersteegen A, Schmidt S, Burkhardt N. Rivaroxaban—an oral, direct
Factor Xa inhibitor— binds rapidly to Factor Xa. J Thromb Haemost.
2007;5(Suppl 2):Abstract P-W-651.
Downloaded from http://atvb.ahajournals.org/ by guest on November 21, 2012
9. Depasse F, Busson J, Mnich J, Le Flem L, Gerotziafas GT, Samama MM.
Effect of BAY 59-7939 —a novel, oral, direct Factor Xa inhibitor— on
clot-bound Factor Xa activity in vitro. J Thromb Haemost. 2005;3:
Abstract P1104.
10. Abendschein DR, Baum PK, Martin DJ, Vergona R, Post J, Rumennik G,
Sullivan ME, Eisenberg PR, Light DR. Effects of ZK-807834, a novel
inhibitor of factor Xa, on arterial and venous thrombosis in rabbits.
J Cardiovasc Pharmacol. 2000;35:796 – 805.
11. Hara T, Yokoyama A, Morishima Y, Kunitada S. Species differences in
anticoagulant and anti-Xa activity of DX-9065a, a highly selective factor
Xa inhibitor. Thromb Res. 1995;80:99 –104.
12. Wong PC, Pinto DJ, Knabb RM. Nonpeptide factor Xa inhibitors:
DPC423, a highly potent and orally bioavailable pyrazole antithrombotic
agent. Cardiovasc Drug Rev. 2002;20:137–152.
13. Perzborn E, Harwardt M, Samama M. Assessment of Factor Xa chromo-
genic assays for measuring the pharmacodynamics of rivaroxaban—an
oral, direct Factor Xa inhibitor. Haemostaseologie. 2010;in press:Abstract
A-218 – 0051-00067.
14. Gerotziafas GT, Elalamy I, Depasse F, Perzborn E, Samama MM. In vitro
inhibition of thrombin generation, after tissue factor pathway activation,
by the oral, direct Factor Xa inhibitor rivaroxaban. J Thromb Haemost.
2007;5:886 – 888.
15. Perzborn E, Harwardt M, Huetter J. Inhibition of thrombin generation by
rivaroxaban (BAY 59-7939)—an oral, direct Factor Xa inhibitor-in
human plasma. Hamostaseologie. 2007;27:A47.
16. Samama MM, Martinoli J, Leflem L, Guinet C, Plu-Bureau G, Depasse
F, Perzborn E. Assessment of laboratory assays to measure rivaroxa-
ban—an oral, direct Factor Xa inhibitor. Thromb Haemost. Published
online before print February 2, 2010. DOI: 10.1160/th09-03-0176.
17. Smith SA, Morrissey JH. Thromboplastin composition affects the sensi-
tivity of prothrombin time (PT) clotting tests to direct Factor Xa inhibi-
tors. Blood. 2007;110:Abstract 928.
18. Perzborn E, Harwardt M. Direct Thrombin Inhibitors, but Not Factor Xa
Inhibitors, Enhance Thrombin Formation in Human Plasma by Interfering
with the Thrombin–Thrombomodulin–Protein C System. Blood. (ASH
Annual Meeting Abstracts). 2008;112:Abstract 528.
19. Furugohri T, Shiozaki Y, Muramatsu S, Honda Y, Matsumoto C, Isobe K,
Sugiyama N. Different antithrombotic properties of factor Xa inhibitor
and thrombin inhibitor in rat thrombosis models. Eur J Pharmacol.
2005;514:35– 42.
20. Perzborn E, Strassburger J, Wilmen A, Lampe T, Pernerstorfer P,
Pohlmann J, Roehrig S, Schlemmer KH, Straub A. Biochemical and
pharmacologic properties of BAY 59-7939, an oral, direct Factor Xa
inhibitor. Pathophysiol Haemost Thromb. 2004;33(Suppl 2):Abstract
PO079.
21. Hoppensteadt D, Neville B, Schultz C, Cunanan J, Duff R, Perzborn E,
Misselwitz F, Fareed J. Interaction of BAY 59-7939 —a novel, oral,
direct Factor Xa inhibitor—with antiplatelet agents: monitoring and ther-
apeutic applications. J Thromb Haemost. 2005;3 Suppl 1:Abstract P1717.
22. Perzborn E, Lange U. Rivaroxaban—an oral, direct Factor Xa inhibitor—
inhibits tissue factor-mediated platelet aggregation. J Thromb Haemost.
2007;5(Suppl 2):Abstract P-W-642.
23. Biemond BJ, Perzborn E, Friederich PW, Levi M, Buetehorn U, Buller
HR. Prevention and treatment of experimental thrombosis in rabbits with
rivaroxaban (BAY 59-7939)—an oral, direct Factor Xa inhibitor. Thromb
Haemost. 2007;97:471– 477.
24. Perzborn E, Arndt B, Fischer E, Harwardt M, Lange U, Trabandt A. Anti-
thrombotic effects of rivaroxaban—an oral, direct Factor Xa inhibitor—in
animal models of arterial and venous thrombosis: comparison with enox-
aparin, an antithrombin-dependent anticoagulant. Eur Heart J. 2006;
27(Suppl):762 Abstract P4571.
25. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharma-
codynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral,
direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78:412–421.
26. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, phar-
macodynamics, and pharmacokinetics of BAY 59-7939 —an oral, direct
Factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur
J Clin Pharmacol. 2005;61:873– 880.
27. Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, Gent
M, Haas S, Huisman MV, Kakkar AK, Kalebo P, Kwong LM, Misselwitz
F, Turpie AG. Population pharmacokinetics and pharmacodynamics of
rivaroxaban—an oral, direct factor xa inhibitor—in patients undergoing
major orthopaedic surgery. Clin Pharmacokinet. 2008;47:203–216.
28. Mueck W, Becka M, Kubitza D, Voith B, Zuehlsdorf M. Population
model of the pharmacokinetics and pharmacodynamics of rivaroxa-
 Perzborn et al
ban—an oral, direct Factor Xa inhibitor—in healthy subjects. Int J Clin
Pharmacol Ther. 2007;45:335–344.
29. Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D. Metabolism and
excretion of rivaroxaban, an oral, direct Factor Xa inhibitor, in rats, dogs
and humans. Drug Metab Dispos. 2009;37:1056 –1064.
30. Lang D, Freudenberger C, Weinz C. In vitro metabolism of rivaroxa-
ban—an oral, direct Factor Xa inhibitor—in liver microsomes and hepa-
tocytes of rat, dog and man. Drug Metab Dispos. 2009;37:1046 –1055.
31. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. The effect of extreme age,
and gender, on the pharmacology and tolerability of rivaroxaban—an
oral, direct Factor Xa inhibitor. Blood. 2006;108:Abstract 905.
32. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited
influence on the safety, tolerability, pharmacokinetics, or pharmacody-
namics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin
Pharmacol. 2007;47:218 –226.
33. Halabi A, Maatouk H, Klause N, Lufft V, Kubitza D, Zuehlsdorf M, Becka
M, Mueck W, Schaefers R, Wand D, Philipp T, Bruck H. Effect of renal
impairment on the pharmacology of rivaroxaban (BAY 59-7939)—an oral,
direct Factor Xa inhibitor. Blood. 2006;108:Abstract 913.
34. Halabi A, Kubitza D, Zuehlsdorf M, Becka M, Mueck W, Maatouk H.
Effect of hepatic impairment on the pharmacokinetics, pharmacody-
namics and tolerability of rivaroxaban—an oral, direct Factor Xa inhib-
itor. J Thromb Haemost. 2007;5(Suppl 2):Abstract P-M-635.
35. Kubitza D, Mueck W, Becka M. No interaction between rivaroxaban—a
novel, oral, direct factor Xa inhibitor—and atorvastatin. Pathophysiol
Haemost Thromb. 2008;36:A40.
36. Kubitza D, Becka M, Zuehlsdorf M. No interaction between the novel,
oral direct Factor Xa inhibitor BAY 59-7939 and digoxin. J Clin
Pharmacol. 2006;46:702 Abstract 11.
37. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an antacid,
and the H2 antagonist ranitidine on the absorption of BAY 59-7939
(rivaroxaban), an oral, direct Factor Xa inhibitor, in healthy subjects.
J Clin Pharmacol. 2006;46:549 –558.
38. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, tolerability,
pharmacodynamics, and pharmacokinetics of rivaroxaban—an oral,
direct Factor Xa inhibitor—are not affected by aspirin. J Clin Pharmacol.
2006;46:981–990.
39. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Rivaroxaban (BAY
59-7939)—an oral, direct Factor Xa inhibitor— has no clinically relevant
interaction with naproxen. Br J Clin Pharmacol. 2007;63:469 – 476.
40. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Co-administration of
rivaroxaban—a novel, oral, direct Factor Xa inhibitor—and clopidogrel
in healthy subjects. Eur.Heart J. 2007;28(Suppl 1):189 Abstract P1272.
41. Turpie AG, Fisher WD, Bauer KA, Kwong LM, Irwin MW, Kalebo P,
Misselwitz F, Gent M. BAY 59-7939: an oral, direct factor Xa inhibitor
for the prevention of venous thromboembolism in patients after total knee
replacement. A phase II dose-ranging study. J Thromb Haemost. 2005;
3:2479 –2486.
42. Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK,
Muehlhofer E, Dierig C, Misselwitz F, Kalebo P; ODIXa-HIP Study
Investigators. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban
Downloaded from http://atvb.ahajournals.org/ by guest on November 21, 2012
Rivaroxaban: A New Oral Factor Xa Inhibitor 381
(BAY 59-7939), for thromboprophylaxis after total hip replacement.
Circulation. 2006;114:2374 –2381.
43. Eriksson BI, Borris L, Dahl OE, Haas S, Huisman MV, Kakkar AK, Mis-
selwitz F, Kälebo P; ODIXa-HIP Study Investigators. Oral, direct Factor Xa
inhibition with BAY 59-7939 for the prevention of venous thromboembolism
after total hip replacement. J Thromb Haemost. 2006;4:121–128.
44. Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK,
Misselwitz F, Muehlhofer E, Kalebo P. Dose-escalation study of rivar-
oxaban (BAY 59-7939)—an oral, direct Factor Xa inhibitor—for the
prevention of venous thromboembolism in patients undergoing total hip
replacement. Thromb Res. 2007;120:685– 693.
45. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK,
Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W;
RECORD1 Study Group. Rivaroxaban versus enoxaparin for thrombo-
prophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765–2775.
46. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J,
Soglian AG, Pap AF, Misselwitz F, Haas S. Extended duration rivar-
oxaban versus short-term enoxaparin for the prevention of venous throm-
boembolism after total hip arthroplasty: a double-blind, randomised con-
trolled trial. Lancet. 2008;372:31–39.
47. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel
TJ, Misselwitz F, Turpie AG. Rivaroxaban versus enoxaparin for throm-
boprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:
2776 –2786.
48. Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM,
Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz
F, Fisher WD. Rivaroxaban versus enoxaparin for thromboprophylaxis
after total knee arthroplasty (RECORD4): a randomised trial. Lancet.
2009;373:1673–1680.
49. Turpie AGG, Lassen MR, Kakkar AK, Eriksson BI, Misselwitz F, Bandel TJ,
Homering M, Westermeier T, Gent M. A pooled analysis of four pivotal
studies of rivaroxaban for the prevention of venous thromboembolism after
orthopaedic surgery: effect on symptomatic venous thromboembolism and
death, and bleeding. Haematologica. 2009;94(Suppl 2):Abstract 0439.
50. Buller HR. Once-daily oral rivaroxaban versus placebo in the long-term
prevention of recurrent symptomatic venous thromboembolism. The
Einstein-Extension Study. Late breaking abstract presented at 51st
American Society of Haematology annual meeting and exposition, New
Orleans, LA, December 5– 8, 2009. Abstract. http://ash.confex.com/ash/
2009/webprogram/Paper25669.html. Accessed January 14, 2010.
51. Patel M, Becker R, Breithardt G, Hacke W, Halperin J, Hankey G,
Mahaffey K, Singer D, Califf R, Fox K. Rationale and design of the
ROCKET AF study: comparison of rivaroxaban with warfarin for the
prevention of stroke and systemic embolism in patients with atrial fibril-
lation. Eur Heart J. 2009;30(Suppl):705.
52. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G; American
College of Chest Physicians. Pharmacology and management of the vitamin
K antagonists: American College of Chest Physicians evidence-based clinical
practice guidelines (8th Edition). Chest. 2008;133:160S–198S.
53. Leadley RJ Jr. Coagulation factor Xa inhibition: biological background
and rationale. Curr Top Med Chem. 2001;1:151–159.
 Supplemental Material

Table I. Ongoing Rivaroxaban Phase III Trials

Indication Patient Regimens Treatment Period Estimated

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Characteristics Enrolment (n)

ROCKET AF Stroke prevention in Non-valvular AF Rivaroxaban 20 mg Event-driven, 14,266

(NCT00403767) patients with AF od (15 mg od in therefore no

patients with minimum; maximum

moderate renal of 4 years1

impairment (CrCl 30–

49 mL/min) versus

warfarin

EINSTEIN DVT VTE treatment Acute symptomatic Rivaroxaban 15 mg 3, 6, or 12 months 3,465

(NCT00440193)
 DVT without bid for first 3 weeks,

symptomatic PE then 20 mg od versus

enoxaparin 1.0 mg/kg

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bid for at least 5

days, followed by

warfarin

EINSTEIN PE VTE treatment Acute symptomatic Rivaroxaban 15 mg 3, 6, or 12 months 3,300

(NCT00439777) PE with or without bid for first 3 weeks,

symptomatic DVT then 20 mg od versus

enoxaparin 1.0 mg/kg

bid for at least 5 days

followed by VKA

EINSTEIN EXT VTE treatment Patients with Rivaroxaban 20 mg 6 or 12 months 1,197

(NCT00439725) confirmed
 symptomatic DVT or od versus placebo

PE who completed 6

or 12 months of
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treatment with

rivaroxaban or a VKA

MAGELLAN VTE prevention Hospitalized Rivaroxaban 10 mg Up to 35 days 8,000

(NCT00571649) medically ill patients od for 35±4 days

versus subcutaneous

enoxaparin 40 mg od

for 10±4 days)

ATLAS ACS TIMI 51 Prevention of Patients with recent Rivaroxaban 2.5 mg At least 6 months 16,000
(NCT00809965) cardiovascular ACS receiving bid or 5 mg bid or

events in patients standard antiplatelet placebo bid

therapy of low-dose
 with ACS acetylsalicylic acid

with or without a

thienopyridine
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ACS, acute coronary syndrome; AF, atrial fibrillation; bid, twice daily; CrCl, creatinine clearance; DVT, deep vein thrombosis; od,

once daily; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Supplemental Material Reference

1. Patel M., Becker R, Breithardt G, Hacke W, Halperin J, Hankey G, Mahaffey K, Singer D, Califf R, Fox K. Rationale and design

of the ROCKET AF study: comparison of rivaroxaban with warfarin for the prevention of stroke and systemic embolism in patients

with atrial fibrillation. Eur Heart J. 2009;30 (suppl):Abstract 705.