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Rivaroxaban – an oral, direct Factor Xa inhibitor – lessons
from a broad clinical study programme
Sylvia Haas
Institut fu
¨r Experimentelle Onkologie und Therapieforschung, Technische Universita
¨tMu
¨nchen, Mu
¨nchen, Germany
Anticoagulants are recommended for a broad spectrum
of indications, including the prevention and treatment of
venous thromboembolism (VTE; comprising deep vein
thrombosis [DVT] and pulmonary embolism [PE]) (1, 2),
the prevention of stroke in patients with atrial fibrillation
(AF) (3) and secondary prevention in patients with acute
coronary syndrome (ACS) (4).
Without prophylaxis, DVT occurs in 10–40% of gen-
eral surgical or medical patients (1). Patients undergoing
major orthopedic surgery are at a higher risk; without
prophylaxis, 40–60% of these patients develop DVT (1).
Guidelines for VTE prevention recommend the routine
use of thromboprophylaxis with low molecular weight
heparins (LMWHs), fondaparinux or vitamin K antago-
nists (VKAs) for patients undergoing major orthopedic
surgery; however, the oral VKAs are rarely used for this
indication in Europe (1, 5). ACCP guidelines currently
recommend that thromboprophylaxis be continued for at
least 10 d, and up to 35 d after total knee replacement
(TKR) and total hip replacement (THR) (1). LMWHs
and fondaparinux are effective; however, their long-term
use is limited by their parenteral route of administration.
Atrial fibrillation is the most common significant car-
diac arrhythmia; it predisposes patients to the develop-
ment of atrial thrombi and is associated with a four to
fivefold increase in the risk of stroke as a result of car-
dioembolism (6–9). Anticoagulants are recommended in
patients with these conditions and, due to the nature of
these conditions, long-term therapy is required (9). ACS
comprises three cardiac diseases: unstable angina, non-
ST-elevated myocardial infarction, and ST-elevated myo-
cardial infarction. The underlying cause of ACS is pla-
que rupture followed by thrombosis in the coronary
arteries and, because many patients remain at high risk
of recurrent events, they therefore require secondary pre-
ventative therapy (10). Therefore, an oral anticoagulant
Abstract
Anticoagulants are recommended for the prevention and treatment of venous thromboembolism (VTE),
prevention of stroke in patients with atrial fibrillation (AF) and secondary prevention in patients with acute
coronary syndrome (ACS). There is a clinical need for novel anticoagulants offering improvements over cur-
rent standard of care, such as fixed oral dosing and no need for routine monitoring. Rivaroxaban, an oral,
once-daily, direct Factor Xa inhibitor, has recently completed the RECORD phase III programme for the
prevention of VTE in patients undergoing total hip or knee replacement (THR or TKR), an indication for
which it is approved in Europe and Canada. It is being investigated in large-scale phase III studies for VTE
treatment and prevention of stroke in patients with AF, and phase III studies will soon commence for sec-
ondary prevention in patients with ACS. Phase I studies demonstrated that no routine anticoagulation mon-
itoring was required, while phase II studies suggested that fixed daily doses had a wide therapeutic
window. The four RECORD studies consistently showed that rivaroxaban was significantly more effective
than enoxaparin in the prevention of VTE after THR and TKR, with a similar safety profile. This review
describes the development of this novel anticoagulant, from bench to bedside.
Key words anticoagulation; atrial fibrillation; Factor Xa inhibitor; rivaroxaban; venous thromboembolism
Correspondence Sylvia Haas, Institut fu
¨r Experimentelle Onkologie und Therapieforschung, Technische Universita
¨tMu
¨nchen,
Normannenstr. 34a, 81925 Munich, Germany. Tel: +49 89 917191; Fax: +49 89 917177; e-mail: sylvia.haas@lrz.tum.de
Accepted for publication 19 January 2009 doi:10.1111/j.1600-0609.2009.01230.x
Re-use of this article is permitted in accordance with the
Creative Commons Deed, Attribution 2.5, which does
not permit commercial exploitation.
REVIEW ARTICLE
European Journal of Haematology ISSN 0902-4441
ª2009 The Author
Journal compilation 82 (339–349) ª2009 Blackwell Munksgaard 339
would be advantageous in these indications. VKAs are the
only licensed oral anticoagulants and, although they are
effective, they have unpredictable pharmacokinetics (PK)
and pharmacodynamics (PD), which are affected by drug
and food interactions. As a result, VKAs require frequent
monitoring and dose adjustment to ensure that their anti-
coagulant effects remain within the therapeutic range.
Advances in the understanding of the coagulation
pathway have enabled the development of novel antico-
agulants targeting specific enzymes within the coagula-
tion cascade, including Factor Xa (FXa) and Factor IIa.
FXa has been identified as a particularly attractive target
for effective anticoagulation: by catalyzing the conver-
sion of prothrombin to thrombin through the prothrom-
binase complex, one molecule of FXa results in the
generation of more than 1000 thrombin molecules (11).
Therefore, inhibition of FXa activity may block the
amplification of thrombin generation, limiting thrombin-
mediated activation of coagulation and platelets, without
affecting existing thrombin levels.
Several FXa inhibitors, such as rivaroxaban, apixaban,
betrixaban and edoxaban, are currently at advanced
stages of development. Rivaroxaban (Bayer Healthcare
AG, Wuppertal, Germany) is a novel, oral, direct FXa
inhibitor in advanced development for the prevention
and treatment of thromboembolic disorders. Rivarox-
aban once-daily (od) has recently received approval in
the European Union and in Canada for the prevention
of VTE in patients undergoing elective total hip or knee
replacement (THR or TKR) surgery. This article will
review the results of the clinical studies performed to
date and summarize the lessons obtained from this broad
development programme.
Clinical pharmacology
Rivaroxaban exhibits predictable, dose-proportional PK,
with high oral bioavailability and a rapid onset of action
(maximum plasma concentrations are reached after 1.5–
2.0 h) (12). Elimination of rivaroxaban from plasma
occurs with terminal half-lives of 5–9 h in young individ-
uals, and with terminal half-lives of 12–13 h in subjects
aged >75 yrs (13–15). Pharmacodynamic activity corre-
lates closely with plasma concentrations (12).
Rivaroxaban is distributed heterogeneously to tissues
and organs, and exhibits only moderate tissue affinity;
importantly, it does not substantially penetrate the
blood–brain barrier (16). The drug has a dual mode of
elimination: two-thirds are metabolized by the liver
(mostly via CYP3A4 and CYP2J2), with no major or
active circulating metabolites identified, and one-third is
excreted unchanged by the kidneys (17–19).
Results of phase I studies showed that body weight,
age, and gender did not have a clinically relevant effect on
the PK and PD of rivaroxaban (14, 15, 20); therefore, it is
likely that fixed doses of rivaroxaban can be administered
to patients, irrespective of their weight, age, or gender.
This was supported by the phase II studies investigating
rivaroxaban for the prevention and treatment of VTE and
the PK and PD analyses of these studies (21–28). Further-
more, phase III studies are investigating fixed doses of riv-
aroxaban. Rivaroxaban demonstrated a low propensity
for drug–drug interactions; results of interaction studies
have shown no clinically relevant interaction between riv-
aroxaban and potential concomitant medications in
patients receiving anticoagulants for the prevention or
treatment of thromboembolic disorders, i.e. naproxen
(29), acetylsalicylic acid (30), clopidogrel (31), or digoxin
(32). Furthermore, there are no reported food–drug inter-
actions and dietary restrictions are not necessary in
patients receiving rivaroxaban (33). Because rivaroxaban
has predictable PK and PD and a low propensity for drug
interactions, it is unlikely to require monitoring.
As a result of inhibiting FXa, rivaroxaban inhibits
thrombin generation (34), thereby preventing clot forma-
tion (35). This mechanism of action results in the dose-
dependent prolongation of global clotting tests, such as
prothrombin time (PT), activated partial thromboplastin
time, and HepTest, with rivaroxaban (12, 13). Further-
more, there was a linear correlation between rivaroxaban
plasma concentration and PT measured using Neopla-
stin
(13, 36), suggesting that PT may be used to assess
rivaroxaban exposure, if this was necessary.
While there is no specific antidote to reverse the effects
of rivaroxaban, in vitro and in vivo studies suggest that
recombinant Factor VIIa (rFVIIa; NovoSeven
) and
activated prothrombin complex concentrate (FEIBA
)
may reverse the effects of high-dose rivaroxaban (37–39).
If strategies such as delaying the next dose of rivarox-
aban or discontinuation, mechanical compression, surgi-
cal intervention, fluid replacement and haemodynamic
support, blood product, or component transfusion fail to
control bleeding, administration of rFVIIa or FEIBA
may be considered. However, it is important to note that
there is currently no experience with the use of these
agents in patients receiving rivaroxaban, and re-dosing
of these procoagulants should be considered depending
on improvement of the patient’s bleeding status.
Prevention of VTE in patients undergoing elec-
tive THR and TKR surgery
Phase II studies
The efficacy and safety of rivaroxaban for the prevention
of VTE in patients undergoing elective THR and TKR
surgery were evaluated in four phase II studies involving
2907 patients (23–25, 28). Both od and twice-daily (bid)
Clinical progress of rivaroxaban Haas
340
ª2009 The Author
Journal compilation 82 (339–349) ª2009 Blackwell Munksgaard
dosing regimens were investigated in these studies. A
similar study design was utilized for each study, includ-
ing the same assessment parameters and endpoints,
enabling comparison of the findings across the different
studies. All events were assessed centrally by the same
blinded adjudication committees. All venograms were
evaluated by the Gothenburg Center, Sweden.
Mandatory, standardized, bilateral venography was car-
ried out 5–9 d after surgery in the open-label study and in
the studies investigating bid administration of rivaroxaban,
or 6–10 d after surgery in the od study, or earlier if symp-
tomatic. The primary efficacy endpoint in each study was
the composite of any DVT (proximal or distal), non-fatal,
objectively confirmed PE, and all-cause mortality. The sec-
ondary efficacy endpoints included major VTE (composite
of proximal DVT, non-fatal, symptomatic, objectively con-
firmed PE, and VTE-related death). The primary safety
endpoint was major bleeding, defined as fatal bleeding,
bleeding into a critical organ (retroperitoneal, intracranial,
intraocular, or intraspinal), bleeding leading to re-opera-
tion, bleeding warranting treatment cessation, clinically
overt bleeding leading to a ‡2g⁄dL drop in hemoglobin,
or bleeding leading to a transfusion of ‡2 units of blood.
Open-label study – THR
This proof-of-principle, open-label, dose-escalation study
was designed to investigate the efficacy and safety of riv-
aroxaban, relative to enoxaparin, for VTE prevention in
patients undergoing THR (25). A total of 641 patients
were randomized to receive oral rivaroxaban (2.5–30 mg
bid, or 30 mg od) or subcutaneous enoxaparin (40 mg
od); rivaroxaban was initiated 6–8 h after surgery and
then every 12 h (bid regimens) or 24 h (od regimen).
Enoxaparin was first administered the evening before
surgery and od thereafter, according to standard Euro-
pean practice. Administration of study drug was contin-
ued for 5–9 d after surgery.
The primary efficacy endpoint occurred with similar
frequency for rivaroxaban and enoxaparin. There was a
flat dose–response relationship between rivaroxaban and
the primary endpoint. For the secondary efficacy end-
point (major VTE), the dose–response relationship with
rivaroxaban was significant (P= 0.0108), with increas-
ing doses resulting in a reduced incidence of major VTE.
With respect to safety, major bleeding increased dose
dependently with rivaroxaban and the dose–response
relationship was significant (P= 0.0008).
The results from this study demonstrated proof of
principle for rivaroxaban for the prevention of VTE in
patients undergoing elective THR and TKR surgery,
supporting its continued assessment in double-blind stud-
ies. These findings also provided the first evidence of the
feasibility of od dosing with rivaroxaban.
Twice-daily dosing studies – THR or TKR
Following the proof-of-principle study, two separate
double-blind, double-dummy, dose-ranging studies were
conducted to assess the efficacy and safety of bid admin-
istration of a 12-fold range of rivaroxaban doses (2.5, 5,
10, 20, or 30 mg bid) relative to enoxaparin (24, 28). A
total of 722 patients undergoing THR were randomized
into one study in Europe (24), and 621 patients undergo-
ing TKR were randomized into a separate study in
North America (28). Rivaroxaban was initiated 6–8 h
after surgery and continued for 5–9 d. Enoxaparin was
administered according to European or North American
prescribing information: in the European hip study,
patients received enoxaparin 40 mg od, with the first
dose given the evening before surgery; in the North
American knee study, enoxaparin 30 mg bid was admin-
istered every 12 h, with the first dose given the morning
after surgery.
There was a flat dose–response relationship for riva-
roxaban with respect to the primary efficacy endpoint in
the hip (P= 0.93) and knee studies (P= 0.29). In the
hip study, the incidence of the primary endpoint ranged
between 6.9% and 18.2% for rivaroxaban, which was
similar to that observed with enoxaparin (17%). The
incidence of the primary efficacy endpoint was also simi-
lar between rivaroxaban and enoxaparin in the knee
study (23.3–40.4% for rivaroxaban and 44.3% for enox-
aparin). Differences in the incidence of the primary end-
point between the hip and knee studies are in line with
previous studies showing a higher rate of venographically
detected DVT in TKR compared with THR (40). The
incidence of major VTE was similar for all rivaroxaban
doses and enoxaparin in both studies. For the primary
efficacy endpoint, a flat dose–response relationship was
observed between rivaroxaban and major VTE. The
safety profile of rivaroxaban was consistent across the
two studies. For rivaroxaban total daily doses 5–20 mg,
the incidence of major bleeding events was similar to
enoxaparin. As expected, a dose–response relationship
was observed for major bleeding events (P= 0.045 and
P= 0.0007 in the hip and knee studies, respectively).
The findings from these two studies suggested that riv-
aroxaban has a wide therapeutic window, which may
indicate a favorable risk–benefit profile. Balancing effi-
cacy and bleeding risk, it was concluded from these stud-
ies that the optimal dose range was a total daily dose of
5–20 mg.
Pooled analysis
The two double-blind studies were designed to allow the
results to be pooled and analyzed based on a larger pop-
ulation size, and to determine if any differences in the
Haas Clinical progress of rivaroxaban
ª2009 The Author
Journal compilation 82 (339–349) ª2009 Blackwell Munksgaard 341
results existed between the efficacy and safety of rivarox-
aban in patients undergoing elective THR or TKR. The
results of this study demonstrated that there were no sig-
nificant differences between the dose–response relation-
ships with rivaroxaban after THR or TKR: there was no
significant dose trend for the primary efficacy endpoint
(P= 0.39), whereas there was a significant dose trend
for the primary safety endpoint (P< 0.001) (41). This
study also confirmed that, based on both efficacy and
safety, a total daily dose of 5–20 mg was the optimal
dose range.
Once-daily dosing study – THR
Earlier studies showed that rivaroxaban inhibited FXa
activity for around 12 h after administration (13);
therefore, bid administration was investigated initially.
However, it was subsequently found that thrombin gen-
eration remained inhibited for 24 h after rivaroxaban
administration, suggesting that od administration would
be possible (34). This was supported by the efficacy
and safety of the 30 mg od dose in the open-label
study. Therefore, this study was conducted to determine
the efficacy and safety of od dosing of rivaroxaban
across an eightfold dose range (5–40 mg) (23). Rivarox-
aban was administered 6–8 h after surgery and then
every 24 h. Enoxaparin was first administered the even-
ing before surgery, and od thereafter. Administration
was continued for 5–9 d after surgery for rivaroxaban
and enoxaparin.
The incidence of the primary efficacy endpoint was
similar between rivaroxaban (across the eightfold dose
range) and enoxaparin. Although there was a tendency
towards a lower incidence of the primary efficacy end-
point with increasing doses of rivaroxaban, the trend
was not significant (P= 0.0852). These results were sim-
ilar to those obtained in the bid studies (24), indicating
similar efficacy with od dosing of rivaroxaban. The
observed incidence of major VTE was lower in all riva-
roxaban dose groups compared with enoxaparin, except
for the rivaroxaban 5 mg dose group. A dose–response
relationship was observed between rivaroxaban and
major VTE (P= 0.0072). For the primary safety end-
point, the two lower doses of rivaroxaban (5 and 10 mg)
showed a similarly low rate of major bleeding compared
with enoxaparin (2.3% and 0.7%, respectively, relative
to 1.9%). There was a significant trend in the dose–
response relationship between rivaroxaban and major
bleeding (P= 0.039). Safety endpoints were similar to
those observed in the bid studies (24).
When both efficacy and safety were considered, it was
concluded that the optimum dose of rivaroxaban for
VTE prevention was 10 mg od, a dose within the range
identified in the bid studies (Fig. 1) (23).
Adverse events and laboratory parameters
In all of the studies, the incidence of serious treatment-
emergent adverse events considered to be drug-related
was similar for rivaroxaban and enoxaparin, and no dose
arm was stopped because of safety concerns. There was
no evidence of compromised liver function attributable
to rivaroxaban in these studies, and the results of the
liver function tests were similar to those obtained with
enoxaparin. The incidence of liver enzyme elevations was
not dose-related for rivaroxaban, and any elevations
observed were transient (23–25, 28).
PK and PD analyses
Rivaroxaban demonstrated predictable PK and PD in
patients undergoing major orthopedic surgery (27). Age,
body weight, and renal function had a moderate effect
on rivaroxaban exposure; however, the effect was not
considered clinically relevant (27). Furthermore, a sub-
group analysis of the two bid studies and the dose-esca-
lation study showed that the dose–response relationships
with rivaroxaban for efficacy and safety were not
affected by age, gender or weight (42).
As a result, phase III studies investigating rivaroxaban
for the prevention of VTE in patients undergoing major
orthopedic surgery have enrolled patients with no upper
age limit and those with mild or moderate hepatic
impairment. Furthermore, fixed doses of rivaroxaban are
being investigated, irrespective of body weight, age or
gender.
The phase III RECORD program
Based on the results from the phase II studies, rivarox-
aban 10 mg od was selected to be investigated in the
Enoxaparin 40 20 10
5
0 30
0
10
20
40
30
0
10
20
Incidence – safety (%)
DVT, PE, and all-cause mortality
Major, postoperative bleeding
30
Incidence – efficacy (%)
Total daily dose (mg) of rivaroxaban
Figure 1 Dose–response relationships between rivaroxaban and the
primary efficacy endpoint and the primary safety endpoint in the od
study investigating rivaroxaban for the prevention of VTE after major
orthopedic surgery (23).
Clinical progress of rivaroxaban Haas
342
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Journal compilation 82 (339–349) ª2009 Blackwell Munksgaard
phase III RECORD programme, comprising four large
studies in more than 12 500 patients undergoing elective
THR or TKR.
In all of the studies, the primary efficacy endpoint was
the composite of DVT, non-fatal PE and all-cause mor-
tality, and the main secondary efficacy endpoint was
major VTE (the composite of proximal DVT, non-fatal
PE, and all-cause mortality). The primary safety end-
point was major bleeding (Table 1).
Current guidelines recommend extended prophylaxis
for patients undergoing THR; however, these recommen-
dations have not been implemented into clinical practice
in many countries. Therefore, RECORD2 investigated
the efficacy and safety of extended thromboprophylaxis
with rivaroxaban (5 wks) compared with short-term en-
oxaparin (10–14 d) in patients undergoing THR (43).
The results of this study demonstrated that extended pro-
phylaxis with rivaroxaban 10 mg od was superior to
short-term prophylaxis with enoxaparin 40 mg od for the
prevention of VTE, including symptomatic events, after
THR (Table 1) (43). Despite rivaroxaban being given for
3 wks longer than enoxaparin, the incidence of major
bleeding at 5 wks was 0.1% in both groups. This study
confirmed the benefits of extended prophylaxis over
short-term prophylaxis and the safety of its use.
The RECORD1 and 3 studies were designed to com-
pare rivaroxaban 10 mg od (starting 6–8 h after surgery)
with enoxaparin 40 mg od (starting the evening before
surgery) given for 31–39 d (extended prophylaxis) after
THR (RECORD1) (44) and 10–14 d (short-term prophy-
laxis) after TKR (RECORD3) (45). In both studies, riva-
roxaban was significantly more effective than enoxaparin
for the prevention of VTE (Table 1) (44, 45). RECORD3
also showed a significant reduction in symptomatic VTE,
and whereas RECORD1 showed a general trend for
reduction in symptomatic VTE, this was not significant.
RECORD4 compared the efficacy and safety of oral
rivaroxaban 10 mg od with the North American regimen
of enoxaparin 30 mg bid, given subcutaneously (10–14 d)
in patients undergoing TKR (46). Rivaroxaban was sig-
nificantly superior to enoxaparin for the primary efficacy
endpoint, with no significant difference in the rates of
major bleeding between the two groups (Table 1).
There was no evidence of compromised liver function
attributable to rivaroxaban in all four studies. The inci-
dence rates of predefined abnormal liver function tests
(alanine aminotransferase [ALT] levels elevated to three
times the upper limit of normal [ULN] and bilirubin
greater than twice the ULN) were similar in the rivarox-
aban and enoxaparin groups (43–46).
Rivaroxaban head-to-head comparison with enoxapa-
rin in these four studies showed the efficacy and safety
of rivaroxaban in the prevention of VTE in patients
undergoing major orthopedic surgery. The superiority of
Table 1 Incidence of venous thromboembolism and bleeding events across the four RECORD studies (43–46)
Endpoint
RECORD1 (THR) RECORD2 (THR) RECORD3 (TKR) RECORD4 (TKR)
Enoxaparin,
40 mg od
Rivaroxaban,
10 mg od
Enoxaparin,
40 mg od
Rivaroxaban,
10 mg od
Enoxaparin,
40 mg od
Rivaroxaban,
10 mg od
Enoxaparin,
30 mg bid
Rivaroxaban,
10 mg od
5 wks 10–14 d 5 wks 10–14 d 10–14 d
Efficacy endpoints
Total VTE (primary endpoint)
%(n) 3.7 (58⁄1558) 1.1 (18 ⁄1595) 9.3 (81⁄869) 2.0 17⁄864) 18.9 (166⁄878) 9.6 (79 ⁄824) 10.1 (97 ⁄959) 6.9 (67 ⁄965)
P-value <0.001 <0.0001 <0.001 0.012
Major VTE
%(n) 2.0 (33⁄1678) 0.2 (4⁄1686) 5.1 (49 ⁄962) 0.6 (6⁄961) 2.6 (24⁄925) 1.0 (9 ⁄908) 2.0 (22⁄1112) 1.2 (13 ⁄1122)
P-value <0.001 <0.0001 0.01 0.124
Symptomatic VTE
%(n) 0.5 (11⁄2206) 0.3 (6⁄2193) 1.2 (15 ⁄1207) 0.2 (3⁄1212) 2.0 (24 ⁄1217) 0.7 (8 ⁄1201) 1.2 (18 ⁄1508) 0.7 (11 ⁄1526)
P-value 0.22 0.0040 0.005 0.187
Bleeding endpoints, % (n)
Major bleeding 0.1 (2⁄2224) 0.3 (6 ⁄2209) <0.1 (1 ⁄1229) <0.1 (1 ⁄1228) 0.5 (6 ⁄1239) 0.6 (7 ⁄1220) 0.3 (4 ⁄1508) 0.7 (10 ⁄1526)
Clinically relevant non-major bleeding 2.4 (54 ⁄2224) 2.9 (65 ⁄2209) 2.7 (33 ⁄1229) 3.3 (40 ⁄1228) 2.3 (28 ⁄1239) 2.7 (33 ⁄1220) NA
1
NA
1
All P-values for efficacy calculated from absolute risk reduction.
1
Correction added 16 March 2009 after online publication. Previous values have been replaced by ’NA’
od, once daily; RRR, relative risk reduction; THR, total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism; NA, Not Applicable.
Haas Clinical progress of rivaroxaban
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Journal compilation 82 (339–349) ª2009 Blackwell Munksgaard 343
rivaroxaban for the primary efficacy endpoint was dem-
onstrated in all four studies. Rivaroxaban also showed a
good safety profile, with low incidence of major bleeding
similar to that observed with enoxaparin, and no evi-
dence of drug-induced liver injury.
Prevention of VTE in medically ill patients
A phase III study has also been initiated to investigate
the efficacy and safety of prophylaxis with rivaroxaban
10 mg od (for up to 5 wks), compared with short-term
enoxaparin, in hospitalized, medically ill patients (http://
www.clinicaltrials.gov; NCT00571649).
Treatment of VTE
Phase II studies
The efficacy and safety of rivaroxaban for the treatment
of VTE were assessed in two phase IIb studies: ODIXa-
DVT (21) and EINSTEIN-DVT (22) (Table 2). In both
studies, patients with acute, symptomatic, objectively
confirmed, proximal DVT without symptomatic PE
received double-blind rivaroxaban or open-label standard
therapy (LMWH ⁄heparin and a VKA) for 3 months.
ODIXa-DVT
In the ODIXa-DVT study, rivaroxaban 10, 20 or 30 mg
bid, or 40 mg od doses were assessed relative to stan-
dard therapy (i.e. enoxaparin 1 mg ⁄kg bid followed by
a VKA) (21). The primary efficacy endpoint was
reduced thrombus burden on day 21 (assessed by quan-
titative compression ultrasonography; ‡4-point improve-
ment in thrombus score) without recurrent VTE or
VTE-related death. The primary efficacy endpoint was
achieved in 43.8–59.2% of patients receiving rivarox-
aban and in 45.9% of patients receiving standard ther-
apy. The incidence of the primary safety endpoint
(major bleeding) was 1.7–3.3% in the rivaroxaban
groups; there were no events in the standard therapy
group. It was concluded that, over a wide range of
doses, the oral, direct FXa inhibitor demonstrated good
efficacy and safety for the treatment of acute symptom-
atic DVT. This was the first phase II trial to use quanti-
tative compression ultrasonography to demonstrate
reduced thrombosis burden after initial course of ther-
apy with a new anticoagulant.
EINSTEIN-DVT
In the EINSTEIN-DVT study, rivaroxaban 20, 30 or
40 mg od were assessed relative to standard therapy (22).
The primary efficacy endpoint was the composite of
symptomatic, recurrent VTE and deterioration of throm-
botic burden, as assessed by compression ultrasound and
perfusion lung scan, at 3 months.
The primary efficacy endpoint occurred in 5.4–6.6% of
patients receiving rivaroxaban vs. 9.9% in the standard
therapy group. The primary safety endpoint (any clini-
cally relevant bleeding) occurred in 2.9–7.5% of patients
receiving rivaroxaban vs. 8.8% in the standard therapy
group. Major bleeding occurred in 0–1.5% of patients
receiving rivaroxaban vs. 1.5% of patients receiving
standard therapy.
Overall, the results of this study demonstrated that
rivaroxaban 20–40 mg od had good efficacy and safety for
the treatment of acute symptomatic DVT. This study, in
which deterioration of thrombus burden was a component
Table 2 Efficacy and safety results of the ODIXa-DVT and EINSTEIN-DVT studies (21, 22)
ODIXa-DVT study
Rivaroxaban
Enoxaparin + VKA
(n= 109)
10 mg bid
(n= 100)
20 mg bid
(n= 98)
30 mg bid
(n= 109)
40 mg od
(n= 112)
Improvement in thrombus burden
without recurrent VTE at 3 wks, %
53.0 59.2 56.9 43.8 45.9
Recurrent DVT, PE, and VTE-related
death at 3 months, n(%)
2 (1.9) 2 (2.0) 2 (1.8) 3 (2.6) 1 (0.9)
Major bleeding, n(%) 2 (1.7) 2 (1.7) 4 (3.3) 2 (1.7) 0 (0.0)
EINSTEIN-DVT study
Rivaroxaban
LMWH ⁄heparin + VKA
(n= 101)
20 mg od
(n= 115)
30 mg od
(n= 112)
40 mg od
(n= 121)
Recurrent VTE and thrombus
deterioration at 3 months, n(%)
7 (6.1) 6 (5.4) 8 (6.6) 10 (9.9)
Major bleeding, n(%) 1 (0.7) 2 (1.5) 0 (0.0) 2 (1.5)
bid, twice daily; DVT, deep vein thrombosis; LMWH, low molecular weight heparin; od, once daily; PE, pulmonary embolism; VKA, vitamin K
antagonist; VTE, venous thromboembolism.
Clinical progress of rivaroxaban Haas
344
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Journal compilation 82 (339–349) ª2009 Blackwell Munksgaard
of the primary endpoint assessment at 3 months, comple-
ments the findings of the ODIXa-DVT trial.
Adverse events
In both studies, there was no evidence of compromised
liver function attributable to rivaroxaban during the
3 months of treatment. Increases in liver enzyme levels
were not dose dependent for rivaroxaban, and any
increases were transient. In the ODIXa-DVT study, riva-
roxaban was stopped prematurely in three patients (21).
Two patients had early (on the day, or on the day after,
initiation of treatment) elevations of ALT and aspartate
aminotransferase levels, which returned to levels below
the ULN after treatment was stopped. In the third
patient, rivaroxaban was stopped after 23 d, when hepa-
titis B with seroconversion was diagnosed; the patient
died of acute liver failure, mostly due to fatal hepatitis B
infection, 48 d after starting treatment (21).
PK and PD analyses
Predictable PK and PD were demonstrated in patients
receiving rivaroxaban for the treatment of DVT (27).
Furthermore, the PK and PD were similar with od and
bid dosing, suggesting that od dosing would not increase
either the risk of bleeding or thrombus growth, com-
pared with bid dosing. Demographic factors such as age,
renal function and body weight had only moderate
effects on the PK and PD, suggesting that fixed doses of
rivaroxaban can be administered to patients. This was
consistent with findings in both healthy subjects and
patients undergoing major orthopedic surgery.
Phase III dose and regimen selection
In the ODIXa-DVT study, improvement in complete
compression ultrasound without recurrent VTE was
achieved in 43.8% of patients receiving rivaroxaban
40 mg od and 53.0–59.2% of those receiving the drug
bid. These results suggested that the bid regimen could
be more effective for thrombus regression at 3 wks (21).
At 3 months, the od and bid regimens performed simi-
larly. Therefore, an initial intensified bid regimen (riva-
roxaban 15 mg bid for 3 wks) followed by convenient,
long-term 20 mg od was selected for investigation in
phase III studies.
The phase III EINSTEIN studies
The efficacy and safety of rivaroxaban for the treatment
of VTE are being further assessed in three phase III
studies involving approximately 7500 patients – EIN-
STEIN-DVT, EINSTEIN-PE and EINSTEIN-EXTEN-
SION (http://www.clinicaltrials.gov; NCT00440193,
NCT00439777, and NCT00439725).
EINSTEIN-DVT and EINSTEIN-PE are multicenter,
randomized, open-label studies. Patients with confirmed
symptomatic DVT (for the DVT study) or PE (for the
PE study) are randomized to receive either standard ther-
apy (enoxaparin, followed by a VKA) or rivaroxaban.
Rivaroxaban is being administered at 15 mg bid for the
first 3 wks of treatment, after which patients will receive
a dose of 20 mg od for a predefined treatment period of
3, 6 or 12 months.
The EINSTEIN-EXTENSION study is recruiting
patients who have been treated for 6 or 12 months with
rivaroxaban or a VKA. These patients will be random-
ized to receive double-blind rivaroxaban 20 mg od or
placebo for a further 6 or 12 months.
Prevention of stroke in patients with AF
The phase II studies investigating the efficacy and safety
of rivaroxaban for the treatment of VTE were also used
to select 20 mg od for investigation in phase III studies
for the prevention of stroke in AF (Table 3).
Rivaroxaban 20 mg od is being compared with warfa-
rin for the prevention of stroke in approximately 14 000
patients with AF in the Rivaroxaban Once daily oral
direct FXa inhibition Compared with vitamin K antago-
nism for prevention of stroke and Embolism Trial in
Atrial Fibrillation (ROCKET AF) study. Patients with
moderate renal impairment (creatinine clearance 30–
49 mL ⁄min) will receive a fixed dose of 15 mg od (http://
www.clinicaltrials.gov; NCT00403767).
A separate study, the J-ROCKET AF study, is also
being conducted in Japan, with rivaroxaban 15 mg od
(10 mg od for patients with moderate renal impairment)
being compared with warfarin (http://www.clinicaltri-
als.gov; NCT00494871).
Secondary prevention in patients with ACS
A phase IIb study investigating the use of rivaroxaban in
patients with ACS has recently been completed. The
Anti-Xa Therapy to Lower cardiovascular events in
Addition to aspirin with ⁄without thienopyridine therapy
in Subjects with Acute Coronary Syndrome [ATLAS
ACS (TIMI 46)] study assessed safety and efficacy in
approximately 3500 patients with recent, non-ST-elevated
myocardial infarction, ST-elevated myocardial infarction,
or unstable angina. All patients received standard anti-
platelet therapy of low-dose ASA, and a thienopyridine
(such as clopidogrel) at the physician’s discretion.
Patients were then randomized to additionally receive
either rivaroxaban or a placebo for six months. Escalat-
Haas Clinical progress of rivaroxaban
ª2009 The Author
Journal compilation 82 (339–349) ª2009 Blackwell Munksgaard 345
ing total daily doses of rivaroxaban, ranging from 5 mg
up to 20 mg (eight dosing regimens in total), were
administered od or bid. Safety was evaluated by measur-
ing clinically significant bleeding, defined as a composite
of TIMI major bleeding, TIMI minor bleeding and any
reported bleeding event requiring medical attention. As
expected, patients in the rivaroxaban regimens had
higher rates of bleeding vs. placebo when administered in
combination with antiplatelet therapy. However, no
study arm was halted due to increased bleeding. No evi-
dence of drug-induced liver injury was seen. Although
the study was not powered to demonstrate significance in
the composite efficacy endpoint of death, myocardial
infarction, stroke or severe recurrent ischemia requiring
revascularization, a definite trend towards reduction in
cardiovascular events was also observed (47). Two doses
of rivaroxaban, 2.5 and 5 mg bid, have been identified
that will be investigated in a phase III study, ATLAS 2
TIMI 51. This study is expected to enroll up to 16 000
patients, commencing in December 2008 (Table 3).
Discussion
Rivaroxaban is a novel, oral, direct FXa inhibitor in
advanced clinical development for the prevention and
treatment of thromboembolic disorders. The drug has
undergone extensive evaluation in phase II studies for
the prevention and treatment of VTE. These studies sug-
gested that rivaroxaban had a wide therapeutic window,
with similar efficacy and safety to standard therapy.
Rivaroxaban is currently being investigated in large-
scale phase III studies in two indications, treatment of
VTE and prevention of stroke in patients with AF, with
phase III studies to be started soon for another indication,
secondary prevention in patients with ACS. Results from
all four phase III studies investigating rivaroxaban once
daily for prevention of VTE after elective THR and TKR
surgery are now available. In RECORD1 and
RECORD3, the drug was significantly more effective than
enoxaparin for the prevention of VTE in patients under-
going THR and TKR, respectively. In RECORD2,
extended prophylaxis with rivaroxaban demonstrated
superior efficacy to short-term prophylaxis with enoxapa-
rin in patients undergoing THR. In RECORD4, rivarox-
aban was superior to the North American regimen of
enoxaparin for the primary efficacy endpoint. Impor-
tantly, safety was not compromised: rivaroxaban was not
associated with a statistically significant increased risk of
major bleeding in all four phase III studies. The
RECORD trial programme confirms that direct FXa inhi-
bition can significantly reduce the burden of VTE in high-
risk orthopedic patients, and oral administration has the
potential to increase the uptake of postdischarge prophy-
laxis in patients undergoing THR, thereby facilitating the
implementation of guidelines in clinical practice.
Although rFVIIa or FEIBA may reverse the effects of
high-dose rivaroxaban in case of over-anticoagulation or
in patients needing emergency surgery (37–39), there is
currently no experience with the use of these agents in
patients receiving rivaroxaban, which could constitute a
drawback to the use of this drug.
The terminal half-life of rivaroxaban is prolonged in
subjects over 75-yr old compared with younger subjects.
However, analyses of the pharmacokinetics of rivarox-
aban in patients participating in phase II studies demon-
strated that age influenced the pharmacokinetics of the
drug, but that the effects were minor and within expecta-
tions (26, 27).
Although two-thirds of rivaroxaban are metabolized
via the cytochrome P (CYP)450 (mostly CYP3A4 and
CYP2J2), (19) the risk of observing clinically relevant
drug–drug interactions with rivaroxaban through inhibi-
Table 3 The clinical development programme for rivaroxaban
Trial Indication Trial design Notes
Phase III RECORD VTE prevention in patients
undergoing major orthopedic
surgery
>11 000 patients
Hip replacement or knee
replacement
vs. standard therapy
(enoxaparin)
Approved in EU and Canada; US
NDA filed in July 2008
Phase III MAGELLAN VTE prevention in the
medically ill
vs. standard therapy
(enoxaparin)
Phase III ROCKET AF Prevention of stroke in
patients with atrial fibrillation
14 000 patients
Non-inferiority vs. standard
therapy (warfarin)
Regulatory filing expected in 2010
Phase III EINSTEIN VTE treatment 7500 patients
vs. standard therapy
Regulatory filing expected in 2010
Phase III ATLAS 2 TIMI 51 Secondary prevention of fatal
and non-fatal cardiovascular
events in patients with acute
coronary syndrome (ACS)
16 000 patients
In addition to standard therapy
Regulatory filing expected in 2012
Clinical progress of rivaroxaban Haas
346
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Journal compilation 82 (339–349) ª2009 Blackwell Munksgaard
tion or induction of CYP1A2, CYP3A4 and other CYP
isoforms is considered to be low,(Unpublished results)
and only strong CYP3A4 inhibitors, given at doses
resulting in high maximum plasma concentrations, have
an effect on the metabolism of rivaroxaban and might
lead to a decrease in renal clearance (19).
Other oral anticoagulants, both direct thrombin inhibi-
tors (DTIs) and direct FXa inhibitors, are currently at
advanced stages of development. Of these new agents,
the direct thrombin inhibitors dabigatran and AZD0837,
and the direct FXa inhibitors YM150, betrixaban, edoxa-
ban and apixaban are the most promising. Dabigatran
has also been approved in the EU and Canada for the
prevention of VTE in adult patients who have undergone
elective THR or TKR. Dabigatran is also undergoing
phase III studies for the treatment of VTE, and for
stroke prevention in AF. Among the FXa inhibitors,
apixaban is currently undergoing phase III studies for
the prevention and treatment of VTE, as well as for
stroke prevention in patients with AF.
As well as demonstrating efficacy and safety in the
prevention of VTE after elective hip and knee replace-
ment surgery, the drug is administered orally, once daily,
and does not require routine anticoagulation monitoring
because of its predictable PK ⁄PD profile. As a result, riv-
aroxaban has the potential to be an attractive alternative
to current anticoagulants, providing effective and well-
tolerated anticoagulation in a convenient manner, from
hospital to home.
Acknowledgements
The author would like to acknowledge Caroline Mas-
terman and Carole Mongin-Bulewski, who provided edito-
rial assistance with funding from Bayer HealthCare AG.
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