Content uploaded by Michael Palladino
Author content
All content in this area was uploaded by Michael Palladino
Content may be subject to copyright.
New oral anticoagulants
Taki Galanis •Lynda Thomson •Michael Palladino •
Geno J. Merli
Published online: 16 February 2011
ÓSpringer Science+Business Media, LLC 2011
Abstract The new oral anticoagulants may prove to be
one of the most significant innovations in clinical practice
in the past 60 years. Apixaban and rivaroxaban are specific
inhibitors of Factor Xa while dabigatran inhibits Factor IIa.
The predictable pharmacological profile of these new
agents will allow physicians to use these drugs without the
need for routine coagulation monitoring which is the
mainstay of warfarin therapy. In addition, these new agents
have not been shown to have any food interactions and
limited drug–drug interactions due to their minimal
metabolism through the CYP450 system. This unique
pharmacokinetic profile may usher in for clinicians a new
era of managing thromboembolic disorders. In this paper,
the pharmacology of these new oral anticoagulants are
reviewed along with the major clinical trials in venous
thromboembolism prevention in total hip and knee
replacement orthopedic surgery, the treatment of venous
thromboembolic disorders and stroke prevention in atrial
fibrillation.
Keywords Apixaban Rivaroxaban Dabigatran Atrial
fibrillation Venous thrombosis Orthopedic surgery
Introduction
Over the past 60 years clinicians have used vitamin K
antagonists, primarily warfarin, as the sole oral anticoag-
ulants for managing a variety of thrombotic disorders.
Warfarin has a variable dose response, a narrow therapeutic
index, and numerous drug and dietary interactions and
requires frequent monitoring. Intravenous and subcutaneous
agents were introduced over the past 30 years, which have
included unfractionated heparin, low-molecular-weight
heparin, direct thrombin inhibitors and most recently a
pentasaccharide. Unfractionated heparin, low-molecular-
weight heparin and the pentasaccharide indirectly inhibit
Factor Xa by binding to and activating anti-thrombin III.
The direct thrombin inhibitors bind reversibly or irrevers-
ibly to the active site on Factor IIa.
Recently three new oral anticoagulants have been
developed and evaluated in the prevention and treatment of
thromboembolic diseases as well as the prevention of stroke
in patients with atrial fibrillation. These agents directly act
on Factor IIa or Factor Xa, do not require monitoring, have
a broad therapeutic window, have low patient variability
and display minimal drug or dietary interactions. The pur-
pose of this paper is to review the pharmacology and clin-
ical trial experience with the three new oral anticoagulants
apixaban, dabigatran and rivaroxaban.
Pharmacology
Apixaban
Apixaban is a selective, reversible, direct inhibitor of
Factor Xa. Its time to maximum plasma concentration is
30 min to 2 h. The half-life of this drug is 8–15 h [1]. This
agent is metabolized by CYP3A4 in the CYP450 system
and the route of elimination is 30% renal and 70% fecal
[1]. Apixaban showed moderate selectivity for clot-bound
over free factor Xa and also inhibits thrombin generation
[2,3]. In addition apixaban is a substrate for the transport
T. Galanis (&)L. Thomson M. Palladino G. J. Merli
Jefferson Medical College, Thomas Jefferson University
Hospitals, Jefferson Vascular Center, Suite 6270, Gibbon
Building, 111 South 11th Street, Philadelphia, PA 19107, USA
e-mail: Taki.Galanis@jefferson.edu
123
J Thromb Thrombolysis (2011) 31:310–320
DOI 10.1007/s11239-011-0559-8
protein p-glycoprotein (p-GP) which functions as an efflux
pump to prevent the absorption or increase the renal
secretion of certain drugs known as p-GP substrates [2,3].
In healthy volunteers, aPTT and modified PT were dose
dependently prolonged and correlated with the determined
plasma concentrations of apixaban [4]. Apixaban has a
minimal impact on the prothrombin time (INR) and aPTT
at therapeutic concentrations, but Factor Xa inhibition
appears sensitive to detect its presence. There are no spe-
cific reversing agents for this medication.
Rivaroxaban
Rivaroxaban is a selective, reversible direct inhibitor of
Factor Xa. The time to maximum plasma concentration is
30 min to 3 h. Rivaroxaban’s half-life has been reported to
be 3–9 h [5,6]. Three aspects of the pharmacodynamics of
rivaroxaban are its concentration dependent inhibition of
Factor Xa with high potency and selectivity, its inhibition
of thrombin generated from prothrombin and a dose
dependent inhibition of tissue factor [8]. This agent is
metabolized by CYP3A4 in the CYP450 system and the
route of elimination is 70% renal and 30% fecal [7]. Riv-
aroxaban does interact with the CYP450 system with
specific interactions with CYP3A4 and CYP2J2 [9]. In
addition this agent, like the others, is a substrate for
transport p-GP and therefore affected by drugs that interact
with p-GP. There have not been any relevant effects of
extreme body weight, age or gender on the pharmacolog-
ical profile of this drug. Rivaroxaban prolongs the pro-
thrombin time (INR) with the sensitivity dependent on the
reagent being used. Factor Xa inhibition may be a more
appropriate surrogate marker for evaluating the plasma
concentration of rivaroxaban. There are no specific
reversing agents for this medication.
Dabigatran
Dabigatran etexilate is the prodrug of dabigatran that
selectively and reversibly inhibits both free and clot-bound
thrombin by binding to the active site of the thrombin
molecule. The time to maximum plasma concentration is
1.25–1.5 h with maximum effect in 2 h [10]. Its half-life is
about 12 h. In human studies, over 90–95% of systemically
available dabigatran was eliminated unchanged via renal
excretion with the remaining 5–10% excreted in bile [11].
A unique aspect of this drug is that it is neither metabolized
by nor induced or inhibited by the cytochrome P450 drug
metabolizing enzymes. Because this drug exhibits low
plasma protein binding (35%), it is a dialyzable agent with
few displacement interactions to affect its pharmacody-
namics [12]. In cases of overdose or severe bleeding, where
more rapid reversal of the anticoagulant effects is required,
hemodialysis could be effective in accelerating plasma
clearance of dabigatran, especially in patients with renal
impairment [12]. Both the Thrombin Clotting Time (TT)
and Ecarin Clotting Time (ECT) are highly sensitive tests
for quantitating the anticoagulant effects of dabigatran
[13]. The prothrombin time (INR) is prolonged by dabig-
atran, but it is not sensitive enough to detect clinically
relevant changes in drug concentration and the aPTT is
prolonged but not in a dose dependent manner. Thus, the
aPTT may serve as a qualitative test because it is less
sensitive at supratherapeutic concentrations of dabigatran.
There are no specific reversing agents for dabigatran.
Food interactions
Apixaban has not been reported to have any food interac-
tions. Rivaroxaban was evaluated in 10 young, healthy
volunteers in a fed state [14]. The variability for pharma-
cokinetic parameters was lower in the fed state but the
presence of food delayed the time to maximum concen-
tration (t
max
) and increased the maximum plasma concen-
tration (C
max
) and area under the drug plasma
concentration–time curve (AUC). The type of food such as
a high caloric breakfast or a high carbohydrate meal did not
affect the response. Dabigatran was assessed in 39 healthy
subjects receiving a high fat, high caloric breakfast [15].
The study demonstrated a delay in the t
max
of dabigatran
but no difference in the C
max
and AUC compared with the
fasted state. Another finding in this study was that a
reduction in inter-individual variability for C
max
and AUC
was noted with the high fat meal.
Drug interactions
Apixaban and rivaroxaban are metabolized by the CYP450
enzyme system. Dabigatran, however, is not a substrate,
inhibitor, or inducer of CYP450 enzymes and undergoes
conjugation to active acyl glucuronides to a limited extent.
All of these medications serve as substrates for the P-gly-
coprotein transport system. At this time, interactions with
certain drugs that impact the above systems must be con-
sidered when using these new agents.
Atorvastatin is a substrate of CYP3A4 and P-glycopro-
tein. In one study comparing dabigatran concomitantly
administered with atorvastatin in 22 healthy volunteers, the
AUC for dabigatran was reduced 18% with a concurrent
increase in atorvastatin plasma concentration [16]. The
affect on the activated partial thromboplastin time and
ecarin clotting time were unaltered. The paper concluded
that the above findings were not clinically relevant. In a
study of rivaroxaban and atorvastatin in 38 healthy male
subjects, there was no difference in plasma concentration
profiles or steady state of atorvastatin when these drugs
New oral anticoagulants 311
123
were concomitantly administered and factor Xa inhibition
was unaffected [17]. The RECORD trials in joint
replacement surgery showed that 23% of the patients
treated with rivaroxaban and a statin had major or non-
major clinically relevant bleeding in comparison to 18% in
those receiving enoxaparin and a statin [18].
Digoxin is a P-glycoprotein substrate and its use was
studied in 23 healthy volunteers receiving dabigatran [19].
The steady state C
max
increased 7% and AUC 3% but the
plasma concentration of digoxin was not effected and the
activated thromboplastin time and ecarin clotting time were
unchanged. Amiodarone is a P-glycoprotein inhibitor and
when administered with dabigatran, the C
max
of dabigatran
increased 60% and AUC 50% [20]. In Europe and Canada
but not the U.S., the product monograph advises that,
because of the long half-life of amiodarone, a reduction
in the dose of dabigatran be recommended when it is
co-administered with this drug. Further studies with ami-
odarone and bunetarone will better define the use of
dabigatran in atrial fibrillation.
Ranitadine is a weak CYP450 inhibitor. No clinically
relevant effect was documented when ranitidine was used
with dabigatran. On the other hand, proton pump inhibitors
decreased the AUC of dabigatran in two clinical trials of
healthy young and older adult males [11,15]. Pantoprazole
and other proton pump inhibitors were co-administered in
dabigatran clinical trials and no clinically relevant effects
on efficacy and bleeding risks were noted [20]. A study by
Kubitza et al. showed no significant differences in the
plasma concentrations, prothrombin time prolongation or
inhibition of Factor Xa activity in patients receiving riva-
roxaban and either ranitidine or antacids [14].
All of the above interactions must be viewed with
caution as we learn more about these new oral anticoagu-
lants as their use becomes more wide spread in clinical
practice. At the present time, the use of quinidine, which is
a potent P-glycoprotein inducer, is contra-indicated with
dabigatran in certain countries but not the U.S. Rivarox-
aban is contraindicated in patients receiving systemic HIV-
protease inhibitors or azole antimycotics, as they are strong
inhibitors of both CYP3A4 and P-glycoprotein [21]. These
drugs increase the C
max
and AUC of rivaroxaban and
therefore potentiate the risk of bleeding (Table 1).
Clinical trials—venous thromboembolism (VTE)
prophylaxis for joint replacement surgery
Apixaban
On the basis of the results of a phase II study in patients
undergoing knee arthroplasty, the phase III Apixaban for the
Prevention of Thrombosis-Related Events (ADVANCE)
program compared a 2.5-mg twice-daily dose of apixaban
(started in the morning of the day after surgery) with en-
oxaparin in patients undergoing knee arthroplasty [22,23]
(Tables 2and 3). For both trials, the primary efficacy out-
come (total event rate) was a composite of asymptomatic
and symptomatic deep-vein thrombosis, nonfatal pulmonary
embolism, and death from any cause during treatment. In
ADVANCE 1, which involved 3195 patients, a 10–14 day
course of apixaban was compared to a similar duration of
enoxaparin (30 mg twice daily). Apixaban had efficacy
similar to enoxaparin with total event rates of 9.0 and 8.8%,
respectively [22]. Major bleeding rates were 0.7% with
apixaban and 1.4% with enoxaparin (P=0.05). Despite
similar efficacy, apixaban did not meet the pre-specified
non-inferiority goal because the event rates were lower than
expected. The ADVANCE 2 trial, which included 3057
patients, compared the same apixaban regimen with an
equal duration of treatment with enoxaparin at a dose of
40 mg once daily [23]. In this trial, apixaban significantly
reduced total event rates compared with enoxaparin (15.1
and 24.4%, respectively; P\0.0001) and was associated
Table 1 Comparison of new oral anti-thrombotic agents
Characteristic Dabigatran Rivaroxaban Apixaban
1. Target IIa Xa Xa
2. Bioavailability 7% 60–80% 80%
3. Half-Life 12–17 h 7–11 h 12 h
4. Clearance 80% renal 60% renal
33% biliary
25% renal
75% biliary
5. Metabolism Conjugation to active glucuronides CYP3A4
CYP2J2
CYP3A4
6. p-GP interaction Yes Yes Minimal
p-GP transport glycoproteins which prevent the absorption or increase secretion of certain drugs known as p-GP substrates. Dabigatran and
Rivaroxaban are p-GP substrates. Amiodarone, verapamil, clarithromycin inhibit p-GP therefore increase the anticoagulant effect of Dabigatran
and Rivaroxaban
312 T. Galanis et al.
123
with a trend for less major bleeding (0.6 and 0.9% respec-
tively; P=0.3) (Table 4).
Rivaroxaban
The phase II Oral Direct Factor Xa Inhibitor (ODIXa) VTE
prevention studies established the dose for rivaroxaban that
was used in the phase III RECORD trial program [24–26].
This program evaluated the efficacy and safety of riva-
roxaban compared with enoxaparin in over 12,000 patients
undergoing hip or knee arthroplasty. Tables 5and 6outline
the design of the above trials as well as the primary out-
comes. The dose of rivaroxaban in all four RECORD trials
was 10 mg once daily started 6–8 h after wound closure.
The European-approved dose of enoxaparin (40 mg once
daily with the first dose given in the evening before sur-
gery) was used as the comparator in the first three
RECORD trials, whereas the North American–approved
dose of enoxaparin (30 mg twice daily starting 12–24 h
after surgery) was the comparator in the RECORD 4 trial
[27–30]. The primary efficacy outcome (total event rate) in
all of the trials was the composite of deep-vein thrombosis
(either symptomatic or detected by bilateral venography if
the patient was asymptomatic), nonfatal pulmonary
embolism, or death from any cause.
In the RECORD 1 trial, which included 4541 patients
undergoing hip arthroplasty, a 31- to 39 day course of
rivaroxaban significantly reduced the total event rate
compared with an equal duration of treatment with
enoxaparin (1.1 and 3.7%, respectively; P\0.001) [27]. In
the RECORD 2 trial involving 2,509 patients undergoing
total hip arthroplasty, a 31–39 day course of rivaroxaban
significantly reduced the total event rate compared with a
10–14 day course of enoxaparin followed by 21–25 days of
placebo (2.0 and 9.3%, respectively; P\0.0001) [29]. The
RECORD 3 trial included 2531 patients undergoing knee
arthroplasty. A 10–14 day course of treatment with riva-
roxaban significantly reduced the total event rate compared
with an equal duration of treatment with enoxaparin (9.6
and 18.9%, respectively, P\0.001) [28]. Finally, in the
RECORD 4 trial involving 3148 patients undergoing
knee arthroplasty, a 10–14 day course of treatment with
rivaroxaban significantly reduced the total event rate
compared with an equal duration of enoxaparin at the
higher 30 mg twice-daily dose (6.9 and 10.1%, respec-
tively; P\0.012) [30]. In both the RECORD 2 and 3
trials, rivaroxaban significantly reduced the incidence of
symptomatic VTE compared with enoxaparin [28,29].
Rivaroxaban did not increase major bleeding in any of
the trials, but a pooled analysis of the four RECORD
Table 2 Apixaban: total knee arthoplasty (TKA) study designs
Key points ADVANCE 1 [22](n=3195) ADVANCE 2 [23](n=3057)
1. Surgery TKA TKA
2. Apixaban 2.5 mg BID 2.5 mg BID
3. First dose apixaban 12–24 h postop 12–24 h postop
4. Comparator Enoxaparin 30 mg BID started 12–24 h postop Enoxaparin 40 mg Qday started 12 h preop
6. Duration of prophylaxis 10–14 days 10–14 days
7. DVT endpoint Venogram Venogram
8. Primary outcome Total VTE
a
?all cause mortality Total VTE
a
?all cause mortality
9. Analysis Apixaban inferior to enoxaparin Apixaban not inferior to enoxaparin
a
Total VTE =symptomatic and asymptomatic DVT plus non-fatal PE
Table 3 Apixaban: total knee arthoplasty (TKA) study outcomes
Study Primary outcome Major bleeding
Apixaban (%) Enoxaparin (%) Apixaban (%) Enoxaparin (%)
ADVANCE 1 [22] 9 8.8 0.7 1.4
ADVANCE 2 [23] 15 24 0.6 0.9
ADVANCE 1 and 2 =TKA
Primary outcome Symptomatic and asymptomatic DVT, non-fatal PE, and all cause death
Major bleeding Acute clinically overt bleeding accompanied by one or more of the following: a decrease in blood hemoglobin concentration of
2 g/dl or more during 24 h; transfusion of two or more units of packed red blood cells; critical site bleeding (including intracranial, intraspinal,
intraocular, pericardial, or retroperitoneal bleeding); bleeding into the operated joint needing reoperation or intervention; intramuscular bleeding
with compartment syndrome; or fatal bleeding
New oral anticoagulants 313
123
trials revealed a small but significant increase in major
plus clinically relevant non-major bleeding with riva-
roxaban. On the basis of these results, rivaroxaban is
approved in Europe and Canada for the prevention of
VTE in patients undergoing elective hip or knee
arthroplasty.
Table 4 Rivaroxaban: total knee arthroplasty (TKA) and total hip arthoplasty (THA) study designs
Key points RECORD1 [27](n=4541) RECORD2 [29](n=2509) RECORD3 [28](n=2531) RECORD4 [30](n=3148)
1. Surgery THA THA TKA TKA
2. Rivaroxaban 10 mg Qday 10 mg Qday 10 mg Qday 10 mg Qday
3. First dose of
rivaroxaban
6–8 h postop 6–8 h postop 6–8 h postop 6–8 h postop
4. Comparator Enoxaparin 40 mg Qday
started 12 h preop
Enoxaparin 40 mg Qday
started 12 h preop
Enoxaparin 40 mg Qday
started 12 h preop
Enoxparin 30 mg BID started
12–24 h postop
6. Duration of
prophylaxis
a
34 days 34 days R
b
12 days E
c
12 days 11 days
7. DVT endpoint Venogram Venogram Venogram Venogram
8. Primary
outcome
Total VTE
d
?all cause
mortality
Total VTE ?all cause
mortality
Total VTE ?all cause
mortality
Total VTE ?all cause
mortality
9. Analysis Rivaroxaban superior Rivaroxaban superior Rivaroxaban superior Rivaroxaban superior
a
Mean duration of treatment
b
Rivaroxaban
c
Enoxaparin
d
Total VTE =asymptomatic and symptomatic DVT plus non-fatal PE
Table 5 Rivaroxaban: total knee arthroplasty (TKA) and total hip arthoplasty (THA) study outcomes
Study Primary outcome Major bleeding
Rivaroxaban (%) Enoxaparin (%) Rivaroxaban (%) Enoxaparin (%)
RECORD 1 [27]: THA 1.1 3.7 0.3 0.1
RECORD 2 [29]: THA 2 9.3 \0.1 \0.1
RECORD 3 [28]: TKA 9.6 18.9 0.6 0.5
RECORD 4 [30]: TKA 6.9 10.1 0.7 0.3
Primary endpoint of study DVT, Non-Fatal PE, Death
Major bleeding Bleeding that was fatal, occurred in a critical organ (retroperitoneal, intracranial, intraocular, and intraspinal), or required
reoperation or extrasurgical site bleeding that was clinically overt and was associated with a fall in the hemoglobin level of at least 2 g/dl or that
required transfusion of 2 or more units of whole blood or packed cells
Table 6 Dabigatran: total knee arthoplasty (TKA) and total hip arthoplasty (THA) study designs
Key points RE-MOBILIZE [33](n=2615) RE-MODEL [31](n=2101) RE-NOVATE [32](n=3494)
1. Surgery TKA TKA THA
2. Dabigatran 150 or 220 mg once daily 150 or 220 mg once daily 150 or 220 mg once daily
3. First dose dabigatran 6–12 h postop (1/2 dose on day 1) 1–4 h postop (1/2 dose on day 1) 1–4 h postop (1/2 dose on day 1)
4. Comparator Enoxaparin 30 mg BID started 12–24 h
postop
Enoxaparin 40 mg Qday started 12 h
preop
Enoxaparin 40 mg Qday started 12 h
preop
6. Duration of
prophylaxis
12–15 days 6–10 days 28–35 days
7. DVT endpoint Venogram Venogram Venogram
8. Primary outcome Total VTE ?all cause mortality Total VTE ?all cause mortality Total VTE ?all cause mortality
9. Analysis Dabigatran inferior to enoxaparin Dabigatran non-inferior to
enoxaparin
Dabigatran non-inferior to
enoxaparin
Total VTE events =symptomatic or venographically-detected deep vein thrombosis and/or symptomatic pulmonary embolism
314 T. Galanis et al.
123
Dabigatran
Based on results from phase II studies, two doses of
dabigatran were investigated in the phase III trials for
thromboprophylaxis after hip or knee arthroplasty: 220 or
150 mg (both given once daily) which was initiated at
half the usual dose on the first day. The European-
approved dose of enoxaparin (40 mg once daily with the
first dose given in the evening before surgery) was used
as the comparator in the RE-MODEL study after total
knee replacement and RE-NOVATE study after total hip
replacement [31,32]. The North American-approved
dose of enoxaparin (30 mg twice daily starting 12–24 h
after surgery) was the comparator in the RE-MOBILIZE
study after total knee replacement [33]. In all three trials,
the primary efficacy end point (total event rate) was a
composite of venographically detected or symptomatic
DVT, nonfatal PE, and all-cause mortality (Tables 6
and 7).
In the RE-MODEL trial involving 2076 patients
undergoing knee arthroplasty, 6–10 days of either dose of
dabigatran etexilate had efficacy similar to that of enox-
aparin (dabigatran 220 mg, 36.4%; dabigatran 150 mg,
40.5%; enoxaparin, 37.7%) [31]. The incidence of major
bleeding did not differ significantly among the three
groups (1.5, 1.3, and 1.3%, respectively) [31]. In the
RE-NOVATE trial involving 3,494 patients undergoing hip
arthroplasty, treatment with either dose of dabigatran
etexilate for 28–35 days had efficacy similar to that of
enoxaparin (dabigatran 220 mg, 6.0%; dabigatran 150 mg,
8.6%; enoxaparin, 6.7%). The incidence of major bleeding
did not differ significantly among the three groups (2.0,
1.3, and 1.6%, respectively) [32]. In the RE-MOBILIZE
study of 2,615 patients undergoing knee arthroplasty,
treatment with either dose of dabigatran etexilate for
12–15 days was statistically inferior to a similar duration
of treatment with enoxaparin (dabigatran 220 mg, 31%;
dabigatran 150 mg, 34%; enoxaparin, 25%). The incidence
of major bleeding did not differ significantly among the
three groups (0.6, 0.6, and 1.4%, respectively) [33].
Dabigatran etexilate is approved in Europe and Canada
for VTE prevention after elective hip or knee arthroplasty.
The 220-mg dose of dabigatran etexilate is recommended
for the majority of patients, whereas the 150-mg dose is
reserved for patients also taking amiodarone and for those
at higher risk for bleeding, such as patients older than
75 years or with a creatinine clearance \50 ml/min.
Clinical trials—treatment of venous thromboembolism
Apixaban
In a dose-ranging study, 520 consecutive patients with
symptomatic lower extremity DVT (either proximal or
extensive distal DVT) were randomized to receive low-
molecular-weight heparin followed by a vitamin K antag-
onist (VKA) or to apixaban 5 mg twice daily, 10 mg twice
daily or 20 mg once daily for 84–91 days [34]. The pri-
mary efficacy outcome was the composite of symptomatic
recurrent venous thromboembolism and asymptomatic
deterioration of bilateral compression ultrasound or perfu-
sion lung scan findings. The safety outcome was the
composite of major and clinically relevant, non-major
bleeding. The primary outcome occurred in 17 of the 358
apixaban-treated patients (4.7%) and in five of the 118
VKA-treated patients (4.2%). There were no differences
noted among the apixaban groups in terms of efficacy with
no evidence of a dose response relationship. The principal
safety outcome occurred in 28 of the 385 (7.3%) apixaban-
treated patients and in 10 of the 126 (7.9%) VKA-treated
patients. As with the efficacy outcome, no differences were
noted among the apixaban groups for the safety analysis
and there was no evidence of a dose response relationship
(Table 8).
Rivaroxaban
Rivaroxaban was evaluated in a randomized study for the
treatment of acute symptomatic deep vein thrombosis [35].
Table 7 Dabigatran: total knee arthoplasty (TKA) and total hip arthoplasty (THA) study outcomes
Study Primary outcome Major bleeding
Dabig-220 mg (%) Dabig-150 (%) Enox (%) Dabig-220 (%) Dabig-150 (%) Enox (%)
RE-NOVATE [32] 6.0 8.6 6.7 2 1.3 1.6
RE-MODEL [31] 36.4 40.5 37.7 1.5 1.3 1.3
RE-MOBILIZE [33] 31.1 33.7 25.3 0.6 0.6 1.4
Primary outcome asymptomatic and symptomatic DVT, non-fatal PE, all cause death
Major bleeding Fatal bleeding, clinically overt bleeding in excess of expected and associated with a fall of 2 g/dl, or leading to transfusion of [2
units packed red cells or whole blood; symptomatic retroperitoneal, intracranial, intraocular, or intraspinal bleeding; bleeding requiring treatment
cessation and/or operation
New oral anticoagulants 315
123
The study was an open label, randomized, event driven,
non-inferiority study that compared oral rivaroxaban alone
(15 mg, BID for 3 weeks followed by 20 mg, Qday) with
subcutaneous enoxaparin followed by a vitamin K antag-
onist for 3, 6, or 12 months in patients with acute symp-
tomatic deep vein thrombosis. A parallel study was
completed in a double blind, randomized, event driven
superiority study that compared rivaroxaban alone (20 mg,
Qday) with placebo for an additional 6 or 12 months of
treatment for venous thromboembolism (Tables 9and 10).
Three thousand four hundred and forty nine patients were
randomized to rivaroxaban (n=1,731) and enoxaparin
plus vitamin K antagonist (n=1,718). Rivaroxaban had
non-inferior efficacy with respect to the primary outcome.
Thirty-six events (2.1%) occurred in the rivaroxaban cohort
while 51 events (3.0%) were documented in the enoxaparin
plus vitamin K antagonists group (hazard ratio, 0.68; 95%
CI, 0.44–1.04; p\0.001). Major bleeding and clinically
relevant non-major bleeding occurred in 8.1% of the
patients in each group. In the continued treatment study
602 patients received rivaroxaban and 594 placebo. Riva-
roxaban had superior efficacy with 8 events (1.3%) versus
42 recurrences (7.1%) in the placebo group (hazard ratio,
0.18; 95% CI, 0.09–0.39; P, 0.001). Four patients in the
rivaroxaban group had major bleeding (0.7%) while none
of the patients in the placebo group experienced major
bleeding.
Dabigatran
Dabigatran was studied in a randomized, double blind,
non-inferiority trial in patients with acute venous throm-
boembolism (Re-COVER) [36]. Patients diagnosed with
Table 8 Botticelli study [34]: treatment of venous thromboembolism
with apixaban
Outcomes Apixaban Apixaban Apixaban LMWH/VKA
5 mg,
BID
10 mg,
BID
20 mg,
Qday
N=130 N=134 N=128 N=128
Primary outcome 6% 5.6% 2.6% 4.2%
Major bleeding 0.008% 0% 0.016% 0%
Primary outcomes Symptomatic recurrent venous thromboembolism
and asymptomatic deterioration of bilateral compression ultrasound or
perfusion lung scan findings
Major bleeding Clinically overt bleeding that was fatal, was into a
critical organ (intracranial, retroperitoneal, pericardial), or led to a fall
in hemoglobin [2 g/dl, or transfusion of 2 or more units of blood
Table 9 Treatment of acute venous thromboembolism with rivaroxaban [35]
Outcomes Rivaroxaban (n=1731) LMWH?VKA (n=1718) Pvalue
Recurrent VTE 2.1% (36) 3.0% (51) \0.001
Major bleeding, clinically relevant non-major bleeding 8.1% (139) 8.1% (138) 0.77
Rivaroxaban =15 mg, BID for 3 weeks than 20 mg, Qday
Primary outcome Incidence of the composite of symptomatic venous thromboembolic events and asymptomatic deterioration in thromboembolic
burden as assessed by comparison of venous ultrasound and perfusion lung scanning
Major bleeding was defined as major if it was clinically overt and associated with a fall in the hemoglobin level of 2 g/dl or more, or if it led to
transfusion of two or more units of red cells, or if it was retroperitoneal, intracranial, occurred in a critical site, or contributed to death
Clinically relevant non-major bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical
intervention, unscheduled contact with a physician, interruption or discontinuation of study treatment, or associated with any other discomfort
such as pain or impairment of activities of daily life
Table 10 Continued treatment of acute venous thromboembolism with rivaroxaban [35]
Outcomes Rivaroxaban (n=602) LMWH?VKA (n=594) Pvalue
Recurrent VTE 1.3% (8) 7.1% (42) \0.001
Major bleeding, clinically relevant non-major bleeding 6.0% (36) 1.2% (7) \0.001
Rivaroxaban =15 mg, BID for 3 weeks than 20 mg, Qday
Primary outcome Incidence of the composite of symptomatic venous thromboembolic events and asymptomatic deterioration in thromboembolic
burden as assessed by comparison of venous ultrasound and perfusion lung scanning
Major bleeding was defined as major if it was clinically overt and associated with a fall in the hemoglobin level of 2 g/dl or more, or if it led to
transfusion of two or more units of red cells, or if it was retroperitoneal, intracranial, occurred in a critical site, or contributed to death
Clinically relevant non-major bleeding was defined as overt bleeding not meeting the criteria for major bleeding but associated with medical
intervention, unscheduled contact with a physician, interruption or discontinuation of study treatment, or associated with any other discomfort
such as pain or impairment of activities of daily life
316 T. Galanis et al.
123
either a proximal lower extremity DVT or a pulmonary
embolism were anticoagulated initially with unfractionated
heparin or low-molecular-weight heparin followed by the
administration of either oral dabigatran 150 mg twice daily
or warfarin adjusted to achieve an INR of 2–3. The primary
outcome was the 6 month incidence of recurrent symp-
tomatic, objectively confirmed venous thromboembolism
and related deaths. Safety endpoints included major and
minor bleeding as well as liver function abnormalities.
Recurrent venous thromboembolism occurred in 2.4% of
patients (30/1274 pts) receiving dabigatran versus 2.1% of
patients (27/1265 pts) treated with warfarin. The difference
in risk was 0.4 points (95% CI -0.8 to 1.5, P\0.001) for the
pre-specified inferiority margin. Major bleeding episodes
occurred in 1.6% of patients in the dabigatran group and
1.9% of those treated with warfarin (Table 11).
Clinical trials—stroke prevention in atrial fibrillation
Apixaban
The Apixaban VERsus acetylsalicylic acid to prevent
stROkES (AVERROES) trial, a multinational, double-
blind, controlled trial to evaluate the use of apixaban
2.5 mg twice daily as a replacement for ASA in 5600
patients with AF who have failed or are unsuitable for
vitamin K and antagonist (VKA) therapy, had a primary
outcome of stroke or systemic embolism and a primary
safety outcome of major bleeding [37]. It was reported at
the 2010 ESC meeting that AVERROES was halted early
due to preliminary findings of the clear benefit of apixaban
over ASA, with a relative risk reduction of [50%. Fur-
thermore, there was no increase in major bleeding or evi-
dence of liver toxicity. The annual rate of the primary
outcome (stroke or systemic embolism) on aspirin was
4.0% compared to and 1.7% with apixaban (P=.000004).
The rate of major hemorrhage was 1.2%/year on aspirin
and 1.5%/year on apixaban (P=.33) [38].
ARISTOTLE, a large trial of apixaban versus warfarin
for the reduction of stroke and other thromboembolic
events in AF, is currently underway. It has randomized
more than 18,000 patients to examine whether apixaban is
noninferior to warfarin, whether apixaban has benefits in
warfarin-naı
¨ve populations, its effects on thromboembolic
events and death, and its effects on bleeding [39].
Rivaroxaban
Results from the Rivaroxaban Once-daily oral direct Factor
Xa inhibition Compared with vitamin Kantagonism for the
prevention of stroke and Embolism Trial in Atrial Fibril-
lation (ROCKET-AF) trial were recently reported [40].
This study was a double-blind, placebo-controlled, non-
inferiority study of more than 14,000 high-risk AF patients.
Participants were randomly assigned to dose-adjusted
warfarin (INR target range of 2.0–3.0) or rivaroxaban
20 mg once daily (qd). Rivaroxaban patients with moderate
renal impairment (creatinine clearance [CrCl] between 30
and 49 ml/min) received a reduced 15-mg qd dose. The
design of this trial was notable in that sham INR results
were provided for the rivaroxaban group to maintain the
double-blind design, and monitoring (by an unblinded
physician) occurred as often as was clinically indicated
[40]. Patients were monitored for 24 months for the pri-
mary composite outcome of stroke or systemic embolism;
secondary endpoints included all-cause death, vascular
death, and MI. The primary safety endpoint was the rate of
major and nonmajor bleeding events. In the per-protocol
population, rivaroxaban was noninferior to warfarin for the
primary efficacy outcome (1.71 versus 2.16 events per 100
patient-years, P\.001). While rivaroxaban was also
found to be superior to warfarin in this population
(P=.015), rivaroxaban failed to reach superiority to
Table 11 Re-COVER study: treatment of venous thromboembolism with dabigatran [36]
Outcomes Dabigatran (n=1,274) Warfarin (n=1,265) Hazard ratio
Primary Outcome 30 (2.4%) 27 (2.1%) 1.10 (0.65-1.84)
Major Bleeding 20 (1.6%) 24 (1.9%) 0.82 (0.45-1.48)
AST [39ULN 38/1220 (3.1%) 25/1199 (2.1%) P=0.14
ALT [39ULN 42/1220 (3.4%) 46/1199 (3.8%) P=0.68
AST aspartate transaminase, ALT alanine transaminase, ULN upper limit of normal
The primary outcome =6 month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths
Primary outcome Symptoms suggestive of recurrent venous thromboembolism were evaluated with the use of the same diagnostic methods that
had been used for the initial diagnosis
Major bleeding Clinically overt and if it was associated with a fall in the hemoglobin level of at least 2 g/dl, resulted in the need for transfusion
of 2 or more units of red cells or whole blood, involved critical site, or was fatal
New oral anticoagulants 317
123
warfarin in the full intent-to-treat population (P=.117).
Rates of the primary safety endpoint, a composite of major
and clinically-relevant nonmajor bleeding events, were
similar between treatment groups; rates of intracranial
hemorrhage and hemorrhagic stroke were significantly
lower in the rivaroxaban group (P=.019 and P=.024,
respectively). In addition, while rates of critical organ
bleeding (P=.007) and bleeding that caused death
(P=.003) were lower in the rivaroxaban group, rates of
both transfusion requirements and hemoglobin drops of
more than 2 g/dl were higher in the rivaroxaban group
(P=.019 and P=.044, respectively) [40]. Overall, this
study suggests that rivaroxaban may provide similar safety
and efficacy generally comparable with warfarin in a high-
risk patient population.
The median percentage of the study period during which
the INR was in the therapeutic range (TTR) was 57.8 in
patients treated with warfarin. As the TTR increased, the
event rate for the composite outcome of stroke and non-
CNS embolism decreased in patients treated with warfarin;
however, the hazard ratio of rivaroxaban versus warfarin
for the composite outcome remained in favor of rivarox-
aban because the event rate also decreased in patients
taking this drug in the highest TTR quartile. The afore-
mentioned data is based on preliminary results which were
recently presented during a scientific session. A more
thorough analysis of the data will have to take place once
the results of ROCKET-AF are formally published.
Dabigatran
The RE-LY study (Randomized Evaluation of Long-Term
Anticoagulation Therapy) evaluated the efficacy and safety
of two doses of dabigatran relative to warfarin in patients
with atrial fibrillation and at least one additional risk factor
for stroke [41]. Dabigatran 150 mg or 110 mg (both given
twice daily) was compared to warfarin. The doses of
dabigatran were administered in a blinded manner while
warfarin was used in an open-labeled fashion. The primary
study outcome was stroke or systemic embolism while the
primary safety outcome was major hemorrhage. A total of
18,113 patients with a mean CHADS
2
score of 2.1 were
enrolled in the study and followed for a median duration of
2 years. The primary efficacy outcome occurred at a rate of
1.11, 1.53, and 1.69%/year for the patients treated with
dabigatran 150 mg, dabigatran 110 mg, and warfarin
respectively. Both doses of dabigatran were non-inferior to
warfarin while the higher dose of the direct thrombin
inhibitor proved to be superior for the primary outcome.
For the primary safety outcome, major bleeding occurred at
a rate of 3.11, 2.71, and 3.36%/year for the patients treated
with dabigatran 150 mg, dabigatran 110 mg, and warfarin
respectively. The differences in both the efficacy and safety
outcomes were statistically significant. The only adverse
event that was significantly more common in the dabiga-
tran-treated patients was dyspepsia. Table 12 summarizes
the results of the RE-LY study.
In RE-LY, the mean percentage of the study period
during which the INR was within the therapeutic range in
patients taking warfarin was 64% [41]. Wallentin et al. [42]
performed an investigation to assess the primary and sec-
ondary outcomes of the RE-LY trial in relation to each
center’s mean time in the therapeutic range (cTTR) for INR
control in the warfarin population. Four quartiles of cTTR
were established with the highest quartile indicating
more time in the therapeutic range. The results of the
investigation support the original findings of superiority
of the 150 mg dose of dabigatran and non-inferiority of the
110 mg dose compared to warfarin irrespective of the
quality of INR control for the composite outcome of stroke
and systemic embolism. However, there was a trend for
fewer non-hemorrhagic strokes in patients treated with
warfarin compared to dabigatran 150 mg as the quality of
INR control improved. Also, there were lower rates of
major bleeding and major gastrointestinal bleeding in the
highest cTTR quartile of the warfarin population versus the
150 mg dabigatran dose. Lastly, there was a trend for lower
mortality in the highest cTTR quartile of the warfarin
Table 12 RE-LY trial: dabigatran vs. warfarin in patients with atrial fibrillation [41]
Dabigatran 150 mg BID Dabigatran 110 mg BID Warfarin
Stroke/systemic embolism 1.11%/year 1.53%/year 1.69%/year
RR vs. warfarin =0.66 [0.53–0.82] RR vs. warfarin =0.91 [0.74–1.11]
Major bleeding 3.11%/year 2.71%/year 3.36%/year
RR vs. warfarin =0.93 [0.81–1.07] RR vs. warfarin =0.80 [0.69–0.93]
Intracranial hemorrhage 0.30%/year 0.23%/year 0.74%/year
RR vs. warfarin =0.40 [0.27–0.60] RR vs. warfarin =0.31 [0.20–0.47]
Primary outcome Stroke or Systemic Embolization
Major bleeding Reduction in the hemoglobin level of at least 2 g/dl, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical
organ
318 T. Galanis et al.
123
population compared to either dose of dabigatran. The
results of this investigation indicate that the risk/benefit
profile may be less favorable for dabigatran compared to
warfarin as the quality of INR control improves.
Conclusion and clinical considerations
The new oral anticoagulants have the potential to play a
significant role in a wide range of clinical settings. Up to
now, vitamin K antagonists have been the only oral agents
available for the treatment and prevention of VTE in var-
ious clinical scenarios as well as preventing stroke in the
atrial fibrillation population. The pharmacological studies
of the direct factor Xa inhibitors (apixaban and rivarox-
aban) and the direct thrombin inhibitor (dabigatran) have
demonstrated the predictable pharmacological profile of
these agents. In addition, phase III clinical studies have
indicated that these agents are at least as effective and safe
as warfarin for a variety of patient populations.
The predictable pharmacological profile of these new
drugs will allow the physician to potentially use these
agents without the requirement for routine coagulation
monitoring. All three agents were developed and studied
with the intent not to require monitoring due to their
predictable pharmacologic effects. These medications,
however, prolong certain coagulation tests in a concentra-
tion-dependent manner but therapeutic ranges have not
been delineated. Yet clinicians will likely attempt to use
the standard clotting tests such as the prothrombin time
(INR) and activated partial thromboplastin time (aPTT) to
assess compliance with therapy and overdoses as well as to
assist them in evaluating therapeutic failures or drug
interactions. As stated above, there are known drug inter-
actions with some of these new agents. In addition, the
aforementioned studies excluded patients with renal or
hepatic impairment. The lack of standardized coagulation
monitoring will pose a challenge to the care of patients
with these conditions. Evaluating bleeding complications
may also be problematic with a lack of standardized test-
ing. As stated above, no specific antidotes exist to reverse
the anticoagulation effects of these new drugs. Also, the
use of available products such as fresh frozen plasma and
prothrombin concentrates have not been systematically
evaluated for the treatment of bleeding complications
associated with these new agents. All of these issues will be
encountered as these new oral agents will likely become
available in the near future. Because of this, the imple-
mentation of these antithrombotic agents will require a
multi-modal team approach and diligent post-approval
monitoring for effectiveness and safety.
References
1. Raghavan N, Frost CE, Yu Z et al (2009) Apixaban metabolism
and pharmacokinetics after oral administration to humans. Drug
Metab Dispos 37:74–81
2. Jiang X, Crain EJ, Luettgen JM et al (2009) Apixaban, an oral
direct factor Xa inhibitor, inhibitis human clot-bound factor Xa
activity in vitro. Thromb Haemost 101:780–782
3. Luettgen JM, Wang Z, Seiffer DA, et al (2007) Inhibition of
measured thrombin generation in human plasma by Apixaban: a
predictive mathematical model based on experimentally deter-
mined rate constants. J Thromb Haemost 5(Suppl 2):p-T-633
4. Frost C, Yu Z, Moore K, et al (2007) Apixaban, an oral direct
factor Xa inhibitor: multiple-dose safety, pharmacokinetics and
pharmacodynamics in healthy subjects. J Thromb Haemost 5:
P-M-664
5. Kubitza D, Becka M, Wensing G et al (2005) Safety, pharma-
codynamics, and pharmacokinetics of BAY 59-7939: an oral,
direct Factor Xa inhibitor after multiple dosing in healthy male
subjects. Eur J Clin Pharmacol 61:873–880
6. Kubitza D, Becka M, Voith B et al (2005) Safety, pharmacody-
namics, and pharmacokinetics of single doses of BAY 59-7939,
an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 78:
412–421
7. Weinz C, Schwartz T, Kubitza D et al (2009) Metabolism and
excretion of rivaroxaban, an oral, direct Factor Xa inhibitor, in
rats, dogs, and humans. Drug Metab Dispos 37:1056–1064
8. Perzborn E, Strassburger J, Wilmen A et al (2005) In vitro and in
vivo studies of the novel antithrombotic agent BAY 59-7939, an
oral, direct Factor Xa inhibitor. J Thromb Haemost 3:514–521
9. Ufer M (2010) Comparative efficacy and safety of the novel oral
anticoagulants dabigatran, rivaroxaban and apixaban in preclini-
cal and clinical development. Thromb Haemost 103:572–585
10. Stangier J, Rathgen K, Stahle H et al (2007) The pharmacoki-
netics, pharmacodynamics and tolerability of dabigatran etexi-
late, a new oral direct thrombin inhibitor, in healthy male
subjects. Br J Clin Pharmacol 64:292–303
11. Stangier J, Rathgen K, Stahle H et al (2008) Pharmacokinetics and
pharmacodynamics of the direct oral thrombin inhibitor dabigatran
in healthy elderly subjects. Clin Pharmacokinet 47:47–59
12. European Medicines Agency (EMA). Product information. Avail-
able at: http://www.ema.europa.eu/docs/en_GB/document_library/
EPAR_Product_Information/human/000829/WC500041059.pdf.
Accessed Jan 2011
13. Van Ryn J, Stangier J, Naertter S, et al (2010) Dabigatran etex-
ilate – a novel, reversible, oral direct thrombin inhibitor: inter-
pretation of coagulation assays and reversal of anticoagulant
activity. Thrombo Haemost 103:1116–1127
14. Kubitza D, Becka M, Zuehlsdorf M et al (2006) Effects 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 46:549–558
15. Stangier J, Eriksson BI, Dahl OE et al (2005) Pharmacokinetic
profile of the oral direct thrombin inhibitor dabigatran etexilate in
healthy subjects and patients undergoing total hip replacement.
J Clin Pharmacol 45:555–563
16. Stangier J, Rathgen K, Stahle H et al (2009) Coadministration of
dabigatran etexilate and atorvastatin: assessment of potential
impact on pharmacokinetics and pharmacodynamics. Am J Car-
diovasc Drugs 9:59–68
17. Kubitza D, mueck W, Becka M (2008) No interaction between
rivaroxaban—a novel, oral, direct Factor Xa- and atorvastatin. In:
Poster P062 presented at the 20th international congress on
thrombosis (ICT), Athens, Greece 25–28 June 2008
New oral anticoagulants 319
123
18. Walenga JM, Adiguzel C (2010) Drug and dietary interactions of
the new oral anticoagulants. Int J Clin Pract 64:956–967
19. Stangier J, Stahle H, Rathgen K, et al (2007) No interaction of the
oral direct thrombin inhibitor dabigatran etexilate and digoxin
(abstract). J Thromb Haemost 5(52):abstract P-W 672
20. Pradaxa (dabigatran etexilate). Summary of product characteris-
tics, last updated 3/2009. Boehringer Ingelheim International
GmbH. http://www.pradaxa.com/Include/media/pdf/Pradaxa_SPC_
EMEA.pdf. Accessed Jan 2011
21. Xarelto (rivaroxaban). Summary of product characteristics, last
update 9/2008. Bayer Schering Pharma. http://www.xarelto.com/
htm/downloads/Xeralto_summary_of_Product_Characteristics_
May 2009.pdf. Accessed Jan 2011
22. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ
(2009) Apixaban or enoxaparin for thromboprophylaxis after
knee replacement. N Eng J Med 361:594–604
23. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P
(2010) ADVANCE-2 Investigators. Apixaban versus enoxaparin
for thromboprophylaxis after knee replacement (ADVANCE-2):
a randomised double-blind trial. Lancet 375:807–815
24. Turpie AG, Fisher WD, Bauer KA, Kwong LM, Irwin MW,
Kalebo P, Misselwitz F, Gent M (2005) BAY 59-7939: an oral,
direct factor Xa inhibitor for the prevention of venous thrombo-
embolism in patients after total knee replacement: a phase II
dose-ranging study. J Thromb Haemost 3:2479–2486
25. Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar
AK, Muehlhofer E, Dierig C, Misselwitz F, Kalebo P (2006) A
once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY
59-7939), for thromboprophylaxis after total hip replacement.
Circulation 114:2374–2381
26. Eriksson BI, Borris L, Dahl OE, Haas S, Huisman MV, Kakkar
AK, Misselwitz F, Kalebo P (2006) Oral, direct factor Xa inhi-
bition with BAY 59-7939 for the prevention of venous throm-
boembolism after total hip replacement. J Thromb Haemost 4:
121–128
27. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV,
Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz
F, Geerts W (2008) Rivaroxaban versus enoxaparin for throm-
boprophylaxis after hip arthroplasty. N Engl J Med 358:
2765–2775
28. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N,
Bandel TJ, Misselwitz F, Turpie AG (2008) Rivaroxaban versus
enoxaparin for thromboprophylaxis after total knee arthroplasty.
N Engl J Med 358:2776–2786
29. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz
J, Soglian AG, Pap AF, Misselwitz F, Haas S (2008) Extended
duration rivaroxaban versus short-term enoxaparin for the pre-
vention of venous thromboembolism after total hip arthroplasty: a
double-blind, randomised controlled trial. Lancet 372:31–39
30. 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 (2009) Rivaroxaban versus
enoxaparin for thromboprophylaxis after total knee arthroplasty
(RECORD4): a randomised trial. Lancet 373:1673–1680
31. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN,
Frostick SP, Kalebo P, Christiansen AV, Hantel S, Hettiarachchi
R, Schnee J, Buller HR (2007) Oral dabigatran etexilate vs.
subcutaneous enoxaparin for the prevention of venous thrombo-
embolism after total knee replacement: the RE-MODEL ran-
domized trial. J Thromb Haemost 5:2178–2185
32. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN,
Frostick SP, Prins MH, Hettiarachchi R, Hantel S, Schnee J,
Buller HR (2007) Dabigatran etexilate versus enoxaparin for
prevention of venous thromboembolism after total hip replace-
ment: a randomised, double-blind, non-inferiority trial. Lancet
370:949–956
33. Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ,
Huo MH, Lieberman JR, Muntz JE, Raskob GE, Clements ML,
Hantel S, Schnee JM, Caprini JA (2009) Oral thrombin inhibitor
dabigatran etexilate vs North American enoxaparin regimen for
prevention of venous thromboembolism after knee arthroplasty
surgery. J Arthroplasty 24:1–9
34. Botticelli Investigators, Buller H, Deitchman D, Prins M, Segers
A (2008) Efficacy and safety of the oral direct factor Xa inhibitor
apixaban for symptomatic deep vein thrombosis The Botticelli
DVT dose-ranging study. J Thromb Haemost 6:1313–1318
35. The Einstein Investigators et al (2010) Oral rivaroxaban for symp-
tomatic venous thromboembolism. N Eng J Med 363:2499–2510
36. Schulman S, Kearon C, Kakkar AK et al (2009) Dabigatran
versus warfarin in the treatment of acute venous thromboembo-
lism. N Engl J Med 361:2342–2352
37. Eikelboom JW, O’Donnell M, Yusuf S, et al (2010) Rationale
and design of AVERROES: apixaban versus acetylsalicylic acid
to prevent stroke in atrial fibrillation patients who have failed or
are unsuitable for vitamin K antagonist treatment. Am Heart J
159(3):348–353 e1
38. AVERROES: Apixaban versus acetylsalicylic acid (ASA) to
prevent strokes. Presented at the meeting of the Euroean Society
of Cardiologists. Available at: http://www.escardio.org/congresses/
esc-2010/congress-reports/Pages/708-3-AVERROES.aspx. Accessed
Dec 2010
39. Lopes RD, Alexander JH, Al-Khatib SM et al (2010) Apixaban
for reduction in stroke and other ThromboemboLic events in
atrial fibrillation (ARISTOTLE) trial: design and rationale. Am
Heart J 159(3):331–339
40. Mahaffey KW FK, on belhalf of the ROCKET-AF investigators
(2010) Stroke prevention using the oral direct factor Xa inhibitor
rivaroxaban compared with warfarin in patients with nonvalvular
atrial fibrillation (ROCKET AF). AHA Scientific Sessions 2010.
2010;Presentation 21839
41. Connolly SJ, Esekowitz MD, Yusuf S et al (2009) Dabigatran
versus warfarin in patients with atrial fibrillation. N Engl J Med
361:1139–1151
42. Wallentin L, Yusuf S, Ezekowitz MD et al (2010) Efficacy and
safety of dabigatran compared to warfarin at different levels of
international normalised ratio control for stroke prevention in
atrial fibrillation: an analysis of the RE-LY trial. Lancet 376:
975–983
320 T. Galanis et al.
123
