From bloodjournal.hematologylibrary.org by guest on November 6, 2011. For personal use only.

2010 115: 15-20

Prepublished online October 30, 2009;
doi:10.1182/blood-2009-09-241851

The new oral anticoagulants

David Garcia, Edward Libby and Mark A. Crowther

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Review article

The new oral anticoagulants

David Garcia,1 Edward Libby,1 and Mark A. Crowther2
1University of New Mexico, Albuquerque; and 2McMaster University, Hamilton, ON

Although their first application in clinical
practice occurred in the 1940s, vitamin K
antagonists remain the only form of oral
anticoagulant medication approved for long-
term use. Although the available vitamin K
antagonists are highly effective for the pre-
vention and/or treatment of most throm-
botic disease, the significant interpatient
and intrapatient variability in dose-response,
the narrow therapeutic index, and the numer-
ous drug and dietary interactions associ-
ated with these agents have led clinicians,
patients, and investigators to search for
alternative agents. Three new orally adminis-
tered anticoagulants (apixaban, dabigatran,
and rivaroxaban) are in the late stages of
development and several others are just
entering (or moving through) earlier phases
of investigation. These novel anticoagulant
medications are being studied for the pre-
vention and treatment of venous thrombo-
embolism, the treatment of acute coronary
syndromes and the prevention of stroke in
patients with atrial fibrillation. This review
summarizes published clinical trial data per-
tinent to apixaban, dabigatran, and rivaroxa-
ban. (Blood. 2010;115:15-20)

Introduction
During the past 20 years, the approval of anticoagulants such as
low-molecular-weight heparins (LMWHs), indirect factor Xa inhibitors
(eg, fondaparinux), and direct thrombin inhibitors (eg, argatroban, bivaliru-
din, lepirudin, and desirudin) has signaled a growing interest in antithrom-
botic compounds that have relatively discrete targets within the coagula-
tion pathway.Although these medications offer several potential advantages
over unfractionated heparin, they all require parenteral administration and
are substantially more expensive than oral vitamin K antagonists (VKAs).
Thus VKAs, despite disadvantages such as variability in dose response, a
narrow therapeutic index, and numerous drug and dietary interactions, are
the only option for most patients requiring chronic anticoagulation.
An anticoagulant that shares some of the positive attributes (eg, wide
therapeutic index, less complex pharamacodynamics) of the newer
parenteral agents, but can be administered orally, may represent a
significant improvement over warfarin and other currently available
VKAs. Although several compounds are being considered, the 3 oral
agents that are most advanced in clinical development programs achieve
their anticoagulant effect by stoichiometrically inhibiting a single
activated clotting factor, either thrombin (factor IIa) or factor Xa. This
approach of directly antagonizing a single target in the clotting pathway
is quite different from the mechanism of action for VKAs, whereby the
hepatic synthesis of multiple clotting proteins is altered.
This review describes the pharmacology and clinical trial
experience (both completed and planned) of apixaban, dabigatran
etexilate, and rivaroxaban. A partial list of other compounds
currently in various stages of development (along with their
target/mechanism) can be found in Table 1.
Pharmacology
Apixaban
Apixaban is a direct inhibitor of factor Xa (both within and outside
the prothrombinase complex). When taken by mouth, apixaban has
more than 50% bioavailability and reaches peak plasma concentra-
tion in 3 to 4 hours. The terminal half-life is 10 to 14 hours after
repeated doses. Apixaban is metabolized in part by CYP3A4; it is
partly eliminated by the kidneys (25%) and, to some extent, also
processed via CYP-independent mechanisms in the liver.1,2 Apixa-
ban does not induce or inhibit CYP enzymes and is expected to
have a low likelihood of drug-drug interactions. It remains to be
determined whether combined hepatic and renal elimination means
that apixaban can be safely used in patients with mild (or moderate)
hepatic or renal impairment.
Dabigatran etexilate
Dabigatran directly inhibits both free and clot-bound thrombin.
Dabigatran etexilate (a pro-drug) is rapidly converted (after oral
administration and hepatic processing) to dabigatran, with peak
plasma dabigatran concentrations recorded approximately 1.5 hours
after oral ingestion. Once at steady state, dabigatran has a half-life
of 14 to 17 hours. With oral treatment, bioavailability is 7.2%, and
dabigatran is predominantly excreted in the feces.3,4 Although part
of the bioconversion from pro-drug to active metabolite occurs in
the liver, the cytochrome p450 system is not involved. Potentially
important drug interactions with quinine/quinidine and verapamil
have been described. Elimination of dabigatran after hepatic
activation occurs predominantly (up to 80%) in the kidneys; thus,
patients with significant renal impairment have been excluded from
most clinical trials involving dabigatran. Approved labels in
Canada and elsewhere recommend an arbitrary dose reduction in
the setting of moderate renal dysfunction, and recommend against
use with severe renal dysfunction.
Rivaroxaban
Rivaroxaban, a direct factor Xa inhibitor, achieves maximum
plasma levels approximately 3 hours after oral ingestion. Once at
steady state, the terminal half-life is 4 to 9 hours (up to 12 hours in

Submitted September 10, 2009; accepted October 6, 2009. Prepublished © 2010 by The American Society of Hematology
online as Blood First Edition paper, October 30, 2009; DOI 10.1182/blood-
2009-09-241851.

BLOOD, 7 JANUARY 2010 䡠 VOLUME 115, NUMBER 1 15

 From bloodjournal.hematologylibrary.org by guest on November 6, 2011. For personal use only.
16 GARCIA et al BLOOD, 7 JANUARY 2010 䡠 VOLUME 115, NUMBER 1

Table 1. Partial list of anticoagulants in development 24 hours after surgery; all patients underwent venography approxi-
Agent Company Status, phase mately 2 weeks later. The proportion of patients who reached the
Direct thrombin inhibitors primary endpoint (VTE, both symptomatic and venographically
Dabigatran etexilate Boehringer Ingelheim 3 detected, or death from any cause) was similar for the apixaban
AZD0837 Astra Zeneca 2 (8.99%) and enoxaparin (8.85%) arms; however, the predetermined
MCC 977 Mitsubishi Pharma 2 noninferiority endpoint was not met.7 It is unclear whether the
Direct factor Xa inhibitors failure to prove noninferiority can be explained by inaccurately low
Rivaroxaban Bayer, Ortho-McNeill 3 prestudy estimates of event rates, the dose/timing of apixaban, or
Apixaban Bristol-Myers Squibb, 3
some other cause. In any case, the comparable event rates (neither
Pfizer
regimen was found superior to the other), along with less clinically
Betrixaban Portola 2
YM150 Astellas 2
relevant bleeding in the apixaban arm, strongly suggest that
Edoxaban (DU-176b) Daichi Sankyo 3 apixaban is an effective anticoagulant. Results from ADVANCE-2,
TAK-442 Takeda 2 a randomized double-blind multicenter trial comparing apixaban
Otamixaban* Sanofi-Aventis 2 2.5 mg orally twice a day with enoxaparin 40 mg subcutaneously
Indirect factor Xa inhibitor once daily for preventing VTE after total knee replacement were
Idraparinux* Sanofi-Aventis 3 presented at the congress of the International Society of Thrombo-
Idrabiotaparinux* Sanofi-Aventis 3 sis and Hemostasis in July 2009. The primary efficacy outcome (all
Novel VKA VTE) occurred in 147 of 976 evaluable patients (15.1%) in the
ATI-5923 Aryx Therapeutics 2b
apixaban group and 243 of 997 evaluable patients (24.4%) in the
*Parenteral agent. enoxaparin group (relative risk ⫽ 0.62; 95% confidence interval,
0.51-0.74, 1-sided P ⬍ .001). A nonsignificant trend toward less
clinically relevant bleeding also favored apixaban (53 patients,
patients ⬎ 75 years old). Very few significant drug-drug interac- 3.5% vs 72 patients, 4.8%; P ⫽ .09).
tions are anticipated, and food does not affect absorption from the A phase 3 study (AMPLIFY) of patients with acute VTE (deep
gastrointestinal tract; the oral bioavailability is more than 80%.5
vein thrombosis [DVT] and/or pulmonary embolism [PE]) will
Like apixaban, rivaroxaban inhibits both the “free” and prothombinase-
compare apixaban (10 mg twice daily for 7 days, followed by
complex-bound forms of activated factor X. Sixty-six percent of
apixaban 5 mg, twice daily for 6 months) to a standard strategy
orally ingested rivaroxaban is excreted by the kidneys6; and in
using enoxaparin followed by VKA. A phase 3 “extension” study
jurisdictions where it is available, rivaroxaban is currently contrain-
will enroll patients for whom there is clinical uncertainty about
dicated in patients with a creatinine clearance less than 30 mL/min.
whether to continue oral anticoagulation after 6 months of routine
Caution is advised if rivaroxaban is used in patients with less
treatment with a VKA. Participants will be randomly assigned to
severe renal insufficiency. No specific dose reduction algorithm is
receive 1 of 3 possible interventions for 12 months: placebo,
available.
apixaban 2.5 mg twice daily, or apixaban 5 mg twice daily. In both
trials, the primary outcome measure will be a composite of
symptomatic, objectively confirmed recurrent VTE or death during
Clinical trial data the treatment period.
The APPRAISE trial was a phase 2 dose-finding study in which
For each of the 3 agents, Tables 2 through 4 provide an overview of
1700 patients were randomized to receive placebo or 1 of
the phase 3 clinical trials that are ongoing or completed.
4 apixaban doses for the 6 months after standard acute therapy for
Apixaban acute coronary syndrome.18 For patients receiving the 2 highest
doses of apixaban, the trial was terminated prematurely because of
Phase 2 data for apixaban in the prevention and treatment of venous excess bleeding. In this population of patients receiving one or
thromboembolism (VTE) suggested that this compound may be a more concomitant antiplatelet agents, the 2 lower-dose apixaban
safe and effective anticoagulant over a wide range of doses.16,17 The arms had higher rates of the primary endpoint (major bleeding plus
first phase 3 orthopedic prophylaxis trial (ADVANCE-1) random- clinically relevant nonmajor bleeding) than did the placebo group.
ized 3195 patients, in double-blind fashion, to either apixaban The trial was not powered to detect a statistically significant
(2.5 mg orally twice a day) or enoxaparin (30 mg subcutaneously difference in the rates in the composite efficacy endpoint of
every 12 hours). In both arms, treatments were begun 12 to cardiovascular death, nonfatal heart attack, severe recurrent ischemia,

Table 2. Overview of completed/ongoing phase 3 clinical trials involving apixaban

No. of patients Results
Comparator (approximate) expected/published Acronym

AF VKA 15 000 2011 ARISTOTLE

VTE, primary prophylaxis
Orthopedic LMWH 6 200 2009,7 2010 ADVANCE-1,2
Orthopedic LMWH 5 400 2010 ADVANCE-3
Medical LMWH 6 500 Early 2010 ADOPT
VTE acute treatment LMWH ⫹ VKA 2 900 2012 AMPLIFY
VTE secondary prevention Placebo (before randomization, all patients have 2 400 2012 AMPLIFY extension study
received 6-12 months of anticoagulation)
Post–acute coronary syndrome Placebo (all patients will receive standard 11 000 2012 APPRAISE-2
treatment, such as aspirin, ␤-blocker)
 From bloodjournal.hematologylibrary.org by guest on November 6, 2011. For personal use only.
BLOOD, 7 JANUARY 2010 䡠 VOLUME 115, NUMBER 1 THE NEW ORAL ANTICOAGULANTS 17

Table 3. Overview of completed/ongoing phase 3 clinical trials involving dabigatran

No. (approximate)
Comparator of patients Results expected/published Acronym

AF VKA 18 000 200911 RELY

VTE primary prophylaxis, LMWH 7 500 2007-20098-10 RE-NOVATE, RE-MOBILIZE, RE-MODEL
orthopedic
VTE acute treatment VKA (patients will have LMWH therapy 2 600 2011, 2012 RECOVER
during the first week of therapy with
dabigatran or VKA)
VTE secondary Placebo (before randomization, all 4 500 2011 REMEDY, RECOVER II
prevention patients have received 6-18 months
of anticoagulation)

and nonhemorrhagic stroke but showed trends favoring apixaban
over placebo for these endpoints. A phase 3 trial (APPRAISE-2)
comparing apixaban 5 mg twice daily versus placebo in this
clinical setting is under way.
Finally, apixaban is being studied as a stroke prevention
strategy for patients with atrial fibrillation (AF). When completed,
the ARISTOTLE trial will randomize approximately 18 000 pa-
tients with chronic nonvalvular AF to apixaban 5 mg orally twice
daily or warfarin, target international normalized ratio (INR) 2.0 to
3.0. This event-driven, double-blind, parallel arm study is designed
to show that apixaban is noninferior to well-managed warfarin in
the prevention of stroke or systemic embolism. In a different
randomized, double-blind study (AVERROES), apixaban (5 mg
orally twice daily) is being compared with aspirin (81-324 mg
daily) among AF patients who have failed or are unsuitable for
VKA treatment. This trial will include 5000 to 6000 patients;
follow-up will be up to 36 months.
Dabigatran etexilate
After completing phase 2 dose-finding studies,19,20 the manufac-
turer of dabigatran designed 3 large phase 3 studies examining the
utility of dabigatran for the prevention of VTE after orthopedic
surgery. The RE-NOVATE trial randomized patients to either
dabigatran 220 mg daily or 150 mg daily or enoxaparin 40 mg
subcutaneously daily, with the first dose administered preopera-
tively.8 The primary endpoint was a composite of total VTE and
death from all causes. Both doses of dabigatran were noninferior to
enoxaparin; major bleeding was similar between dabigatran 220 mg,
2.0% (P ⫽ .44); dabigatran 150 mg, 1.3% (P ⫽ .6); and enoxapa-
rin, 1.6%. Patients undergoing total knee replacement were studied
in the RE-MODEL study.9 The primary outcome, the composite of
total VTE and mortality, occurred in 36.4% of patients in the
dabigatran 220 mg group and 40.5% of patients in the dabigatran
150 mg group and 37.7% of patients in the enoxaparin 40 mg
group. Both trials demonstrated noninferiority for dabigatran
compared with enoxaparin. The RE-MOBILIZE study compared
dabigatran with enoxaparin administered at a dose of 30 mg twice
daily, started postoperatively. The primary outcome of total VTE
and death occurred in 31.1% of patients in the dabigatran 220 mg
group, 33.7% of patients in the dabigatran 150 mg group, and
25.3% of those in the enoxaparin group. Dabigatran, as adminis-
tered in the RE-MOBILIZE study, was thus inferior to enoxaparin
administered at standard North American doses after knee replace-
ment surgery.10 Large phase 3 studies of dabigatran versus warfarin
for the secondary prevention of acute VTE are ongoing: patients in
both arms will receive short-term “overlap” treatment with LMWH.
More than 18 000 patients with nonvalvular AF were enrolled in
RELY, an open-label study of stroke prevention where 2 doses of
dabigatran (110 mg or 150 mg twice daily) were compared with
warfarin (target INR ⫽ 2-3); median follow-up was 2 years.
Designed as a noninferiority trial with a primary outcome of stroke
or systemic embolism, RELY demonstrated that dabigatran 110 mg
twice daily not only provided antithrombotic protection similar to
well-managed warfarin but also was associated with a lower annual
rate of major bleeding (3.36% vs 2.71%, P ⫽ .003). The twice
daily 150-mg dose of dabigatran resulted in a lower rate of
stroke/systemic embolism, 1.11% vs 1.69%; (relative risk ⫽ 0.66;
95% confidence interval, 0.53-0.82; P ⬍ .001 for superiority), and
was associated with a similar risk of major bleeding (Figure 1).
Dyspepsia was reported by approximately 12% of patients taking
both doses of dabigatran, compared with only 5.8% of patients
taking warfarin. Because of concerns that arose with another direct
thrombin inhibitor, ximelagatran, transaminase levels were moni-
tored closely in this trial, and no evidence of hepatoxicity was
reported.11

Table 4. Overview of completed/ongoing phase 3 clinical trials involving rivaroxaban

No. (approximate)
Comparator of patients Results expected/published Acronym

AF VKA 14 000 2010 ROCKET-AF

VTE primary prophylaxis
Orthopedic LMWH 8 500 2008, 200912-15 RECORD 1-4
Medical LMWH 8 000 2011 MAGELLAN
VTE acute treatment LMWH ⫹ VKA 6 200 2010 EINSTEIN DVT and EINSTEIN PE
VTE secondary prevention Placebo (before randomization, all 1 300 2010 EINSTEIN extension study
patients received 6-12 months
of anticoagulation)
Post–acute coronary syndrome Placebo (all patients will receive 16 000 Unknown ATLAS ACS TIMI 51
standard treatment, such as
aspirin, ␤-blocker)
 From bloodjournal.hematologylibrary.org by guest on November 6, 2011. For personal use only.
18 GARCIA et al
Figure 1. Dabigatran versus warfarin in patients with nonvalvular AF: cumula-
tive hazard rates for the primary outcome of stroke or systemic embolism,
according to treatment group. Reprinted from Connolly et al11 with permission.
Rivaroxaban
Based on the results of 4 phase 3 clinical trials, rivaroxaban is now
approved both in Canada and Europe for the prevention of VTE
after major orthopedic surgery. In May 2009, the US Food and
Drug Administration decided not to approve rivaroxaban for
similar indications in the United States, citing a concern that
rivaroxaban “could lead to bleeding events in significantly more
patients” than enoxaparin on the Food and Drug Administration
website. The agency has requested more safety data, and the
possibility of approval at a later date remains open. In each of the
4 “REgulation of Coagulation in ORthopaedic surgery to prevent
Deep-vein thrombosis and pulmonary embolism” (RECORD)
studies, rivaroxaban 10 mg by mouth once daily proved superior to
the comparator in the prevention of VTE.12-15 Taken together, the
results from these clinical studies suggest that a 10-mg oral dose of
rivaroxaban can, compared with standard doses of enoxaparin,
reduce the risk of VTE after total hip or knee arthroplasty (Table 5).
Overall rates of major hemorrhage were low, but the pooled results
from more than 12 000 patients included in these 4 trials show a
trend toward increased major bleeding (0.39% vs 0.21%, P ⫽ .08)
with rivaroxaban. When the trial definition of major bleeding is
combined with surgical site bleeding, the rates for rivaroxaban and
enoxaparin are 1.80% and 1.37%, respectively (P ⫽ .06; Table 6).
After a phase 2 trial of rivaroxaban for the treatment of acute
VTE,21 2 phase 3 studies are currently underway: one for patients
Table 5. Total VTE
RECORD 1 (hip) RECORD 2 (hip)
Rivaroxaban
n 1595 864
Endpoint 18 (1.1%) 17 (2.0%)
Enoxaparin
n 1558 869
Endpoint 58 (3.7%) 81 (9.3%)
Total VTE ⫽ occurrence of: any DVT (symptomatic or asymptomatic), nonfatal PE, or death of any cause in RECORD studies of rivaroxaban after major orthopedic
surgery.12-15 All differences favor rivaroxaban, and all reach statistical significance (P ⬍ .05).
Table 6. Pooled rates of bleeding from the 4 RECORD trials
Rivaroxaban, no. per 1000 patients
Major bleeding 3.9
Major bleeding ⫹ surgical site bleeding 18.0
Adapted from the FDA Advisory Committee Briefing Document (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascu-
larandRenalDrugsAdvisoryCommittee/UCM181524.pdf; accessed October 5, 2009).
BLOOD, 7 JANUARY 2010 䡠 VOLUME 115, NUMBER 1
with DVT with or without PE and one for patients with PE with or
without DVT. Both trials have a randomized, open-label design in
which rivaroxaban 15 mg is given twice a day orally for the first
3 weeks; the rivaroxaban dose is then reduced to 20 mg once daily
for the remainder of the study. The comparator in both trials is
enoxaparin plus VKA. The average duration of therapy is expected
to be 6 months. A secondary prophylaxis study is also underway; in
this trial, patients who have received at least 6 to 12 months of
anticoagulation (and for whom there is clinical equipoise about
whether to continue anticoagulation) will be randomized to rivar-
oxaban 20 mg daily or placebo.
In patients with AF, rivaroxaban 10 mg once daily is being compared
with warfarin therapy in a phase 3 trial where the composite of stroke
and systemic embolism and the combination of major plus clinically
relevant nonmajor bleeding are the primary endpoints. This large,
randomized, double-blind multicenter study is now closed to recruit-
ment, and results are expected in 2010 or early 2011. Participants are
expected to be on study medication for an average of 2 years.
Rivaroxaban is also being studied in a phase 3 trial of patients with
recent acute coronary syndrome. In this randomized, double-blind
16 000-patient trial, 2 doses of rivaroxaban (2.5 mg twice daily and
5 mg twice daily) will be compared with placebo as an adjunct to the
current standard of care. The primary outcome measure is the reduction
in the risk of the composite endpoint of cardiovascular death, myocar-
dial infarction, or stroke. A dose-finding phase 2 study (ATLAS, TIMI
46) demonstrated benefit with respect to the primary (composite
endpoint) but also showed increased bleeding with higher rivaroxaban
doses.22 The decision to administer rivaroxaban twice daily in the phase
3 acute coronary syndrome study emerged from observations in ATLAS
that, for this population (many of whom are also taking one or more
antiplatelet agents), the risk-benefit ratio may be better when the
total amount of drug is split into 2 doses rather than adminis-
tered as a single tablet.
Practical considerations
All 3 drugs discussed in this review are eliminated, to some extent,
by the kidneys; thus, whether (or at what dose) patients with
moderate to severe renal insufficiency can use these agents may not
be determined for some time. Although each of these agents affects
conventional clotting assays to some degree (Table 7),23,24 further
research will be needed to determine how clinicians can best assess
RECORD 3 (knee) RECORD 4 (knee)
824 965
79 (9.6%) 67 (6.9%)
878 959
166 (18.9%) 97 (10.1%)
Enoxaparin, no. per 1000 patients P
2.1 .08
13.7 .06
 From bloodjournal.hematologylibrary.org by guest on November 6, 2011. For personal use only.
BLOOD, 7 JANUARY 2010 䡠 VOLUME 115, NUMBER 1 THE NEW ORAL ANTICOAGULANTS 19

Table 7. Effect of novel anticoagulants on traditional laboratory assessments of coagulation in humans

ECT Xa inhibition TCT PT aPTT

Dabigatran 200 mg TID 5.2* No effect 27* Not reported 2.3*

Rivaroxaban 30 mg BID No effect 68% No effect 2.6* 1.8*
Apixaban 25 mg BID No effect Not reported Not reported Not reported 1.2*

Modified from Eriksson et al.24

ECT indicates ecarin clotting time; TCT, thrombin clotting time; PT, prothrombin time; aPTT, activated partial thromboplastin time; TID, three times daily; and BID, twice
daily.
*Estimated fold increase from baseline at peak levels.

Table 8. Summary of the pharmacology and clinical status of apixaban, rivaroxaban, and dabigatran
Apixaban Rivaroxaban Dabigatran

Brand name — Xarelto Pradaxa

Target Factor Xa Factor Xa Factor IIa
tmax, h 1-31 2-45 1.25-34
Half-life, h 8-151 9-135 12-144
Renal excretion ⬃ 25%1 66%25 80%4
Food effect Not reported Delays absorption26 Delays absorption27
Effect of age Not reported Variable28 None29
Effect of body weight Not reported None30 None31
Clinical status — Approved in Canada and Europe for VTE prevention after Approved in Canada and Europe for VTE prevention after
orthopedic surgery orthopedic surgery

— indicates not applicable; and tmax, time to maximum plasma concentration.

plasma anticoagulant activity for each agent (when such an
assessment is necessary). No evidence-based reversal strategy is
available for a bleeding patient taking one of these novel anticoagu-
lants. Although the need for such an intervention is expected to
arise infrequently because all 3 drugs have relatively short half-
lives (Table 8), the lack of an antidote or evidence-based bleeding
management plan may be a disadvantage in the eyes of many
clinicians. Principles for the management of anticoagulant-related
bleeding (with a specific focus on new agents) have been outlined
elsewhere32; at least one in vitro study has identified a possible
strategy worthy of further investigation.33
It is possible that one or more of these agents will have a wider
therapeutic index than warfarin, thus reducing the risk of hemor-
rhage while preserving the beneficial antithrombotic effects. How-
ever, at least some of the large studies in orthopedic surgery suggest
that there will continue to be a tradeoff (fewer thromboembolic
events will be balanced by extra bleeding and vice versa). These
novel anticoagulants will certainly be more expensive than
warfarin (but will probably be less expensive than LMWH).
Definitive cost-effectiveness analyses will have to account for the
cost of regular INR measurement; the potential to eliminate such
testing will certainly offset at least some of the additional
acquisition cost of these novel agents. Whether their increased cost
relative to VKAs can, in light of these concerns, be justified by
increased patient convenience and a small reduction in the risk of
stroke with dabigatran therapy in patients with AF remains to be
seen. On the other hand, the greatest potential for net benefit from
these novel agents may rest with patients who currently do not have
access to the sort of frequent INR monitoring and dose adjustment
that maximize the safety of VKAs. In addition, the pharmacologic
characteristics of these drugs will probably eliminate the need for
perioperative anticoagulation (“bridge therapy”) with parenteral
agents. Finally, in some settings (such as for extended prophylaxis
after major orthopedic surgery), these agents may replace LMWHs
where their oral administration and price may provide a compelling
case for their use.
In conclusion, clinical trial data published thus far suggest that
oral agents may soon be widely available as alternatives to VKAs
(and currently available parenteral therapies) for patients at risk of
thromboembolism. It remains to be seen which of the 3 agents
discussed here (and others in earlier phases of development) will be
used for the various disease states in which they are being studied.
The overall utility of any novel anticoagulant will depend on
many factors, including efficacy compared with current
agents, cost, risk-benefit profile, reversibility, and patient
convenience/satisfaction.
Authorship
Contribution: D.G., E.L., and M.A.C. contributed to the literature
search; D.G. created the first draft of the manuscript; and D.G.,
E.L., and M.A.C. participated in revising and preparing the final
draft of the manuscript.
Conflict-of-interest disclosure: Within the past 2 years, D.G. has
received research funding from and/or acted as a consultant for
CSL Behring, Roche Diagnostics, Aryx Therapeutics, Boehringer
Ingelheim, and Bristol-Myers Squibb. Within the past 2 years,
M.A.C. has received honoraria from Sanofi-Aventis, Leo Laborato-
ries, Pfizer, Bayer, Boehringer Ingelheim, and Artisan Pharma. E.L.
declares no competing financial interests.
Correspondence: David Garcia, University of New Mexico,
MSC08-4630, 900 Camino de Salud NE, Albuquerque, NM
87131-0001; e-mail: davgarcia@salud.unm.edu.

References
1. Raghavan N, Frost CE, Yu Z, et al. Apixaban me-
tabolism and pharmacokinetics after oral admin-
istration to humans. Drug Metab Dispos. 2009;
37(1):74-81.
2. Pinto DJ, Orwat MJ, Koch S, et al. Discovery of 562247), a highly potent, selective, efficacious,
1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin- and orally bioavailable inhibitor of blood coagula-
1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- tion factor Xa. J Med Chem. 2007;50(22):5339-
c]pyridine-3-carboxamide (apixaban, BMS- 5356.
 From bloodjournal.hematologylibrary.org by guest on November 6, 2011. For personal use only.
20 GARCIA et al
3. Blech S, Ebner T, Ludwig-Schwellinger E,
Stangier J, Roth W. The metabolism and disposi-
tion of the oral direct thrombin inhibitor, dabiga-
tran, in humans. Drug Metab Dispos. 2008;36(2):
386-399.
4. Stangier J, Rathgen K, Stahle H, Gansser D,
Roth W. The pharmacokinetics, pharmacodynam-
ics and tolerability of dabigatran etexilate, a new
oral direct thrombin inhibitor, in healthy male sub-
jects. Br J Clin Pharmacol. 2007;64(3):292-303.
5. Kubitza D, Becka M, Wensing G, Voith B,
Zuehlsdorf M. Safety, pharmacodynamics, 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(12):873-880.
6. Lang D, Freudenberger C, Weinz C. In vitro me-
tabolism of rivaroxaban, an oral, direct factor Xa
inhibitor, in liver microsomes and hepatocytes of
rats, dogs, and humans. Drug Metab Dispos.
2009;37(5):1046-1055.
7. Lassen MR, Raskob GE, Gallus A, Pineo G,
Chen D, Portman RJ. Apixaban or enoxaparin for
thromboprophylaxis after knee replacement.
N Engl J Med. 2009;361(6):594-604.
8. Eriksson BI, Dahl OE, Rosencher N, et al. Dabig-
atran etexilate versus enoxaparin for prevention
of venous thromboembolism after total hip re-
placement: a randomised, double-blind, non-infe-
riority trial. Lancet. 2007;370(9591):949-956.
9. Eriksson BI, Dahl OE, Rosencher N, et al. Oral
dabigatran etexilate vs subcutaneous enoxaparin
for the prevention of venous thromboembolism
after total knee replacement: the RE-MODEL ran-
domized trial. J Thromb Haemost. 2007;5(11):
2178-2185.
10. Ginsberg JS, Davidson BL, Comp PC, et al. Oral
thrombin inhibitor dabigatran etexilate vs North
American enoxaparin regimen for prevention of
venous thromboembolism after knee arthroplasty
surgery. J Arthroplasty. 2009;24(1):1-9.
11. Connolly SJ, Ezekowitz MD, Yusuf S, et al.
Dabigatran versus warfarin in patients with atrial
fibrillation. N Engl J Med. 2009;361(12):1139-
1151.
12. Eriksson BI, Borris LC, Friedman RJ, et al. Rivar-
oxaban versus enoxaparin for thromboprophy-
laxis after hip arthroplasty. N Engl J Med. 2008;
358(26):2765-2775.
13. Kakkar AK, Brenner B, Dahl OE, et al. Extended
duration rivaroxaban versus short-term enoxapa-
rin for the prevention of venous thromboembolism
after total hip arthroplasty: a double-blind, ran-
BLOOD, 7 JANUARY 2010 䡠 VOLUME 115, NUMBER 1
domised controlled trial. Lancet. 2008;372(9632):
31-39.
14. Turpie AG, Lassen MR, Davidson BL, et al. Rivar-
oxaban versus enoxaparin for thromboprophy-
laxis after total knee arthroplasty (RECORD4): a
randomised trial. Lancet. 2009;373(9676):1673-
1680.
15. Lassen MR, Ageno W, Borris LC, et al. Rivaroxa-
ban versus enoxaparin for thromboprophylaxis
after total knee arthroplasty. N Engl J Med. 2008;
358(26):2776-2786.
16. Buller H, Deitchman D, Prins M, Segers A. Effi-
cacy and safety of the oral direct factor Xa inhibi-
tor apixaban for symptomatic deep vein throm-
bosis: the Botticelli DVT dose-ranging study.
J Thromb Haemost. 2008;6(8):1313-1318.
17. Lassen MR, Davidson BL, Gallus A, Pineo G,
Ansell J, Deitchman D. The efficacy and safety of
apixaban, an oral, direct factor Xa inhibitor, as
thromboprophylaxis in patients following total
knee replacement. J Thromb Haemost. 2007;
5(12):2368-2375.
18. Alexander JH, Becker RC, Bhatt DL, et al. Apixa-
ban, an oral, direct, selective factor Xa inhibitor, in
combination with antiplatelet therapy after acute
coronary syndrome: results of the Apixaban for
Prevention of Acute Ischemic and Safety Events
(APPRAISE) trial. Circulation. 2009;119(22):
2877-2885.
19. Eriksson BI, Dahl OE, Ahnfelt L, et al. Dose esca-
lating safety study of a new oral direct thrombin
inhibitor, dabigatran etexilate, in patients under-
going total hip replacement: BISTRO I. J Thromb
Haemost. 2004;2(9):1573-1580.
20. Eriksson BI, Dahl OE, Buller HR, et al. A new oral
direct thrombin inhibitor, dabigatran etexilate,
compared with enoxaparin for prevention of
thromboembolic events following total hip or knee
replacement: the BISTRO II randomized trial.
J Thromb Haemost. 2005;3(1):103-111.
21. Buller HR, Lensing AW, Prins MH, et al. A dose-
ranging study evaluating once-daily oral adminis-
tration of the factor Xa inhibitor rivaroxaban in the
treatment of patients with acute symptomatic
deep vein thrombosis: the Einstein-DVT Dose-
Ranging Study. Blood. 2008;112(6):2242-2247.
22. Mega JL, Braunwald E, Mohanavelu S, et al. Ri-
varoxaban versus placebo in patients with acute
coronary syndromes (ATLAS ACS-TIMI 46): a
randomised, double-blind, phase II trial. Lancet.
2009;374(9683):29-38.
23. Mueck W, Becka M, Kubitza D, Voith B,
Zuehlsdorf M. Population model of the pharmaco-
kinetics and pharmacodynamics of rivaroxa-
ban—an oral, direct factor Xa inhibitor—in
healthy subjects. Int J Clin Pharmacol Ther. 2007;
45(6):335-344.
24. Eriksson BI, Quinlan DJ, Weitz JI. Comparative
pharmacodynamics and pharmacokinetics of oral
direct thrombin and factor xa inhibitors in devel-
opment. Clin Pharmacokinet. 2009;48(1):1-22.
25. 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(5):1056-
1064.
26. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Ef-
fect of food, an antacid, and the H2 antagonist
ranitidine on the absorption of BAY 59-7939 (ri-
varoxaban), an oral, direct factor Xa inhibitor, in
healthy subjects. J Clin Pharmacol. 2006;46(5):
549-558.
27. Stangier J, Eriksson BI, Dahl OE, et al. Pharma-
cokinetic profile of the oral direct thrombin inhibi-
tor dabigatran etexilate in healthy volunteers and
patients undergoing total hip replacement. J Clin
Pharmacol. 2005;45(5):555-563.
28. Mueck W, Eriksson BI, Bauer KA, et al. Popula-
tion pharmacokinetics and pharmacodynamics of
rivaroxaban—an oral, direct factor Xa inhibi-
tor—in patients undergoing major orthopaedic
surgery. Clin Pharmacokinet. 2008;47(3):203-
216.
29. Stangier J, Stahle H, Rathgen K, Fuhr R. Phar-
macokinetics and pharmacodynamics of the di-
rect oral thrombin inhibitor dabigatran in healthy
elderly subjects. Clin Pharmacokinet. 2008;47(1):
47-59.
30. 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(2):218-226.
31. Stangier J. Clinical pharmacokinetics and phar-
macodynamics of the oral direct thrombin inhibi-
tor dabigatran etexilate. Clin Pharmacokinet.
2008;47(5):285-295.
32. Crowther MA, Warkentin TE. Bleeding risk and
the management of bleeding complications in pa-
tients undergoing anticoagulant therapy: focus on
new anticoagulant agents. Blood. 2008;111(10):
4871-4879.
33. Lu G, DeGuzman FR, Lakhotia S, Hollenbach SJ,
Phillips DR, Sinha U. Recombinant antidote for
reversal of anticoagulation by factor Xa inhibitors
[abstract]. Blood. 2008;112(11):Abstract 983.