Issues in Emerging Health Technologies
Issue 138  June 2015
Antidote Treatments for the Reversal of Direct
Oral Anticoagulants
Summary
 There are three intravenous antidotes currently
under development for the reversal of direct oral
anticoagulants.
 Idarucizumab is a humanized, monoclonal,
antibody fragment that reverses the direct
thrombin inhibitor dabigatran. Andexanet alfa is
a modified recombinant factor Xa molecule that
reverses oral direct (e.g., apixaban, edoxaban,
rivaroxaban) and injectable indirect (e.g.,
enoxaparin, fondaparinux) factor Xa inhibitors.
Aripazine is a small, synthetic molecule with
potentially universal anticoagulant reversal
activity.
 Clinical evidence to support the use of individual
antidotes is currently limited to phase 1 and
phase 2 trials in healthy volunteers. All three
antidotes were well tolerated during these studies
and no pro-coagulant activity was observed.
Phase 3 trials are underway for idarucizumab
and andexanet alfa.
 Preliminary data shows promising results but
assessment of long-term safety and efficacy
requires more research. Additional research is
also needed to determine impact on clinical
practice. Clear guidance should be available at
the time these reversal drugs are commercialized
to promote their appropriate use.
The Technology
In the past decade, the use of direct oral anticoagulants
(DOACs; apixaban, dabigatran, edoxaban, rivaroxaban)
has been approved for a number of conditions such as
the prevention of stroke in patients with non-valvular
atrial fibrillation (AF); the prevention of venous
thromboembolism (VTE) after hip or knee replacement
surgery; and the treatment of VTE, as well as the
prevention of VTE recurrence. [Note: apixaban,
dabigatran, and rivaroxaban are currently available in
Canada.]1-3 Unlike warfarin and other vitamin K
antagonists, there are no specific antidotes available to
reverse the anticoagulant effect of DOACs. Although
the latter have short half-lives, which suggests reversal
drugs may not be needed in non-urgent situations, the
lack of such antidotes is a concern in emergency
situations such as life-threatening major bleeding or
non-elective major surgery.4 Currently, there are three
specific reversal drugs for DOACs under clinical
development (see Table 1).
Idarucizumab (aDabi-Fab/BI 655075/Boehringer
Ingelheim, Germany) is a humanized, monoclonal,
antibody fragment that specifically binds with high
affinity to dabigatran, an oral direct thrombin inhibitor
(DTI), also developed by Boehringer Ingelheim. It acts
by competitively displacing dabigatran from thrombin
to reverse anticoagulation and restore fibrin formation.5
Dabigatran has an affinity for idarucizumab that is 350
times greater than its affinity for thrombin.8 The dose
currently studied in the phase 3 trial is 5 g.9 Based on
pre-marketing information obtained from the
manufacturer, idarucizumab will be available as a
single package consisting of two 50 mL vials (2 x
2.5 g); no reconstitution will be required. The complete
dose of 5 g will be administered intravenously as two
consecutive infusions over 5 to 10 minutes each, or as
bolus injections (Ernie Hampel, Executive Director,
Market Access and Healthcare Affairs, Boehringer
Ingelheim Canada Ltd., Burlington, ON: personal
communication, 2015 Mar 9).
Andexanet alfa (PRT064445 or PRT4445*/Portola
Pharmaceuticals Inc., US) is a modified recombinant
factor Xa (FXa) molecule intended for intravenous (IV)
administration. It was developed as an antidote to
reverse anticoagulant activity of oral direct (e.g.,
apixaban, edoxaban, and rivaroxaban) and injectable
indirect (e.g., enoxaparin and fondaparinux) FXa
inhibitors. Andexanet alfa acts as a decoy to target and
sequester with high specificity both oral and injectable
FXa inhibitors in the blood.10 It lacks a membranebinding gamma-carboxyglutamic acid domain,
rendering it catalytically inactive, but it retains a high
binding affinity to FXa inhibitors.6 Two doses are
currently being studied in phase 3 trials: 400 mg IV
bolus followed by continuous infusion at 4 mg per
minute for 120 minutes (reversal of apixaban)11,12 and
800 mg IV bolus followed by continuous infusion at
8 mg per minute for 120 minutes (reversal of
rivaroxaban).11,13
Aripazine (PER977/ciraparantag/Perosphere Inc., US)
is a small, synthetic molecule designed with broad
reversal activity and administered as a single IV bolus
1
dose. It binds to oral FXa inhibitors and DTIs, as well
as to injectable unfractionated heparin (UFH) and lowmolecular-weight heparin (LMWH) via non-covalent
bonding and charge-charge interactions to neutralize
anticoagulation and bleeding.7,14 As the clinical
development program for aripazine is currently at the
phase 2 stage, it is not possible to comment on the dose
that will be studied in the phase 3 trial and which is
therefore more likely to be approved for clinical use.
TABLE 1: ANTIDOTES UNDER DEVELOPMENT FOR DIRECT ORAL ANTICOAGULANTS
Antidote
Target
Idarucizumab
(BI 655075)
Oral DTI
Andexanet alfa
(PRT064445 or
PRT4445*)
Aripazine
(PER977)
Oral FXa inhibitors;
injectable LMWH
and fondaparinux
Oral FXa inhibitors
and DTI;
injectable UFH,
LMWH, and
fondaparinux
5-7
Structure
Route
Storage
Humanized
monoclonal antibody
fragment
Modified
recombinant FXa
protein
Synthetic small
molecule
IV
Refrigerated
IV
Refrigerated
IV
Room temperature
DTI = direct thrombin inhibitor; FXa = factor Xa; IV = intravenous; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.
Regulatory Status
Currently, idarucizumab, andexanet alfa, and aripazine
are not approved for use in Canada, the US, the United
Kingdom, or European Union (EU) countries.15-17
Andexanet alfa and idarucizumab were granted
breakthrough therapy designation by the US Food and
Drug Administration (FDA) in November 2013 and
June 2014, respectively.18-20 On February 26, 2015, the
FDA also granted orphan drug designation to andexanet
alfa for reversing the anticoagulant effect of direct or
indirect FXa inhibitors in patients experiencing a
serious, uncontrolled bleeding event or who require
urgent or emergency surgery.10 On March 3, 2015,
Boehringer Ingelheim, the manufacturer of
idarucizumab, announced that submission for approval
was filed in the US, the EU, and Canada for use in
patients requiring an antidote to dabigatran.21 On April
24, 2015, the FDA granted priority review/accelerated
approval status to idarucizumab.22 Of note, final results
from phase 3 clinical studies for both idarucizumab and
andexanet alfa are pending.9,18,23 Aripazine was granted
fast-track status in the US on April 15, 2015; phase 3
trials are planned.14
Patient Group
Pending confirmation of their efficacy and safety, these
antidote treatments will fulfill an unmet need in
patients using a DOAC and who need immediate
reversal of the anticoagulant effect. At this time, it is
anticipated that the targeted population for these drugs
will be patients in emergency situations such as those
with major bleeding or who require non-elective major
surgery.4,9,24 Although the definition for major bleeding
may vary across clinical trials, the International Society
on Thrombosis and Haemostasis (ISTH) developed a
classification commonly used in research and that
provides a good description of these serious adverse
events (AEs). Overall, major bleeds are those that result
in death, are life-threatening, cause chronic sequelae, or
consume major health care resources. Types of major
bleeding events defined by ISTH’s classification
include fatal bleedings and bleedings occurring in
critical anatomical sites such as the brain, spine, eyes,
abdominal cavity, joints, or pericardium, or in muscle if
compartment syndrome is present. Other types of major
bleeding events under ISTH’s definition include a fall
in hemoglobin levels of at least 2 g/dL or the need for
transfusing at least two red cell packs.25 Of interest,
other potential conditions where reversal of DOACs
may be considered have been identified in a recent
review. These include clinical conditions at high risk of
bleeding such as major head injury in patients treated
with DOACs, DOAC overdose in patients with
coagulation or platelet disorders or in patients also
taking antithrombotic drugs at the same time.26 Of note,
these conditions are not specifically included in
currently ongoing phase 3 clinical trials.
2
Current Practice
In patients experiencing a DOAC-induced major
bleeding event, current consensus-based guidelines
recommend withdrawing the anticoagulant and
administering oral charcoal (if within two hours of
DOAC ingestion). The use of prothrombin complex
concentrate (PCC, Octaplex) at a dose of 25 U/kg
(which may be repeated once or twice), activated
prothrombin complex concentrate (aPCC, FEIBA) at a
dose of 50 IE/kg (max 200 IE/kg/day) or recombinant
factor VIIa (rFVIIa, NiaStase) may be considered.26-30
Overall, there appears to be relatively limited available
data supporting the efficacy of these non-specific drugs
in the reversal of DOAC-induced bleeding events.29,31
Also, given that thrombosis is a potential AE from
anticoagulant reversal therapy, these pro-coagulant
drugs must be administered with caution.
Hemodialysis may also be considered to reverse the
anticoagulant effect but only in the case of dabigatranassociated bleeding.26-30 Despite edoxaban being
relatively low-protein-bound and slightly cleared by
hemodialysis (6% to 20%), a small open-label
pharmacokinetic study of 10 patients with end-stage
renal disease indicates that hemodialysis is not effective
at removing edoxaban from the bloodstream.30,32,33
The Evidence
Current evidence for the reversal of a DOAC
anticoagulant effect with antidote treatments is mostly
limited to in vitro studies, animal models, and trials
with healthy volunteers.
Idarucizumab
In an early phase trial, Van Ryn et al. evaluated the
reversal of dabigatran’s anticoagulant effect with
idarucizumab in 35 healthy volunteers.5 They each
received 1 g, 2 g, or 4 g of idarucizumab or placebo.
The treatment was administered as a five-minute IV
infusion after four days of dabigatran 220 mg twice
daily orally. Blood was collected from an incision
wound to explore restoration of wound site fibrin
formation by measuring fibrinopeptide A (FPA). There
was a significant, dose-dependent return of fibrin
formation with increasing doses of idarucizumab;
reversal allowed participants to reach 24%, 45%, and
63% of control FPA values 30 minutes after 1 g, 2 g,
and 4 g of idarucizumab was administered, respectively
(P < 0.05).5 A global phase 3 case series study known
as RE-VERSE AD is currently enrolling patients
treated with dabigatran who have uncontrolled bleeding
or require emergency surgery or procedures (see Table
2). A dose of 5 g idarucizumab will be administered
intravenously to reverse the effect of dabigatran. The
trial will measure plasma-diluted thrombin time and
ecarin clotting time as primary outcome measures.
Time to cessation of bleeding will be a secondary
outcome. Results from the trial are anticipated in July
2017.9
Andexanet alfa
Two phase 2 trials evaluated the safety and efficacy of
andexanet alfa in healthy volunteers receiving apixaban
or rivaroxaban, which are two DOACs available in
Canada. Patients in one study by Crowther et al.34
received apixaban 5 mg twice daily orally for six days
before 420 mg of andexanet alfa was administered as an
IV bolus dose. This treatment was followed by a
continuous IV infusion of andexanet alfa for either 45
minutes or two hours, at a rate of 4 mg per minute. At
two minutes following the IV bolus dose, plasma
concentrations of unbound apixaban had decreased and
the mean anti-FXa activity was reduced by more than
90%, with the level of reversal sustained throughout the
infusion periods for both regimens (P < 0.0001).
Thrombin generation remained within the normal range
for two hours following cessation of infusion.34 In the
other placebo-controlled study, healthy patients were
given rivaroxaban 20 mg per day orally for six days and
were then randomly assigned to four different dosing
cohorts of andexanet alfa (210 mg IV bolus, 420 mg IV
bolus, 600 mg IV bolus, or 720 mg IV bolus followed
by a one-hour IV infusion administered at a rate of
4 mg per minute). Results showed a dose-dependent
reduction in anti-FXa activity by 20%, 53%, 70%, and
81%, respectively; anti-FXa activity returned to levels
seen with placebo approximately two hours after
treatment cessation. Similarly, the plasma concentration
of unbound rivaroxaban decreased by 32%, 51%, 75%,
and 70%, respectively, relative to pre-andexanet alfa
values.35,36 Findings from the two first-dose cohorts of
another small phase 2 trial were recently reported in
abstract form; in this study patients received edoxaban,
a DOAC not currently available in Canada. This study
evaluated andexanet alfa for the reversal of the
anticoagulant effect of edoxaban, administered at a
dose of 60 mg daily for six days prior to andexanet alfa.
Both dose cohorts (andexanet alfa 600 mg bolus [n = 9]
and 800 mg bolus followed by 8 mg per minute
infusion for one hour [n = 9]) resulted in an immediate
decrease in anti-FXa activity of 52% and 73%,
respectively, compared with the pre-andexanet alfa
administration level. This decrease remained constant
during the infusion and returned to placebo levels
approximately two hours following cessation of
3
andexanet alfa. The antidote was well tolerated and
there were no serious or severe AEs and no thrombotic
events.37
is ongoing and will investigate IV bolus followed by a
two-hour continuous infusion to demonstrate sustained
reversal.11,40
Part 1 of two phase 3 clinical trials — ANNEXA-A and
ANNEXA-R — was recently completed. They
evaluated reversal of apixaban and rivaroxaban with
andexanet alfa in older healthy volunteers (ages 50 to
75 years);12,20,24 final results of these trials are pending
(see Table 2). Primary outcomes were measured by
anti-FXa activity. Secondary outcomes include
unbound FXa inhibitor plasma levels and thrombin
generation.38,39 Of note, preliminary results from part 1
of the ANNEXA-R trial — which compared the
administration of an 800 mg IV bolus of andexanet alfa
to placebo in 39 patients pre-treated with rivaroxaban
20 mg for four days — were presented at the 2015
American College of Cardiology (ACC) Scientific
Sessions on March 16, 2015.40 Andexanet alfa
produced a statistically significant and rapid reduction
in anti-FXa activity from baseline (primary outcome);
mean per cent change anti-FXa from baseline to nadir
was 92% (P < 0.0001 versus placebo). Normalization
of coagulation parameters was achieved within two
minutes of completing the IV bolus infusion; the effect
lasted one to two hours with the IV bolus dose.11 Part 2
Aripazine
In a double-blind, placebo-controlled, phase 1/2 trial
involving 80 healthy volunteers, single IV doses
(administered over the course of two to five minutes) of
aripazine (5 mg to 300 mg) or placebo were
administered three hours after a 60 mg dose of
edoxaban was given orally.7,16,41 The degree of reversal
in anticoagulation was measured by whole-blood
clotting time. At doses of 100 mg to 300 mg, aripazine
reduced whole-blood clotting time to within 10% above
baseline value in 10 minutes; this effect was sustained
for 24 hours. In comparison, the time to reach that level
in patients receiving placebo was approximately 12 to
15 hours. Aripazine restored normal clot formation and
fibrin integrity within the clot, as shown by scanning
electron micrographs. There was also no evidence of
pro-coagulant activity.7,16,41 A phase 2 clinical trial that
evaluates re-anticoagulation in patients with edoxaban
following reversal of anticoagulant effect by aripazine
is near completion. This study aims to identify a dose
regimen for aripazine that reverses the effects of
edoxaban for up to 21 hours (see Table 2).42
TABLE 2: ONGOING PHASE 2 AND 3 CLINICAL TRIALS WITH ANTIDOTES FOR DIRECT ORAL ANTICOAGULANTS
9,12,24,38,39,42
Key Study
Descriptors
Title
Study Design and
Intervention
Primary Outcomes
Idarucizumab
A phase 3 case series
clinical study of the reversal
of the anticoagulant effects
of dabigatran by IV
administration of 5 g
idarucizumab in patients
treated with dabigatran
etexilate who have
uncontrolled bleeding, or
require emergency surgery
or procedures.
(RE-VERSE AD; A Study of
the RE-VERSal Effects of
Idarucizumab on Active
Dabigatran)
Phase 3, single-group, openlabel, case series study
Maximum reversal of anticoagulant
effect of dabigatran based on central
laboratory determination of dTT or
ECT, at any time point from the end of
the first infusion up to 4 hours after the
last infusion
A study in older patients to
evaluate the safety and
ability of andexanet alfa to
reverse the anticoagulation
effect of apixaban.
(ANNEXA-A; Andexanet
alfa: A Novel Antidote to the
Anticoagulant Effects of FXa
Inhibitors — Apixaban)
Phase 3, randomized,
double-blind, placebocontrolled study
NCT02104947
N = 300
Andexanet alfa
NCT02207725
N = 64
Idarucizumab 5 g IV
Reversal of apixaban anticoagulation
effect as measured by anti-factor Xa
activity
Andexanet alfa 400 mg IV
bolus followed by continuous
infusion at 4 mg/minute for
120 minutes
4
Key Study
Descriptors
Andexanet alfa
NCT02220725
N = 79
Aripazine
NCT02207257
N = 50
Title
A study in older patients to
evaluate the safety and
ability of andexanet alfa to
reverse the anticoagulation
effect of rivaroxaban.
(ANNEXA-R; Andexanet
alfa: A Novel Antidote to the
Anticoagulant Effects of FXa
Inhibitors — Rivaroxaban)
A phase 2, randomized,
sequential group evaluation
of ascending reversal doses
of PER977 administered to
patients with steady state
edoxaban dosing and reanticoagulation with
edoxaban following PER977
reversal.
Study Design and
Intervention
Phase 3, randomized,
double-blind, placebocontrolled study
Primary Outcomes
Reversal of rivaroxaban
anticoagulation effect as measured by
anti-factor Xa activity
Andexanet alfa 800 mg IV
bolus followed by continuous
infusion at 8 mg/minute for
120 minutes
Phase 2, randomized,
sequential group, single-blind
study
Whole-blood clotting time as a
measure of edoxaban anticoagulation
reversal by aripazine
Aripazine 25 mg, 50 mg,
100 mg, 300 mg, and
600 mg IV
dTT = diluted thrombin time; ECT = ecarin clotting time; FXa = factor Xa; g = gram; IV = intravenous; mg = milligram; mg/minute = milligram per
minute; N = estimated enrolment.
Harms
Idarucizumab was well tolerated during a phase 1 trial
with 145 healthy volunteers receiving dabigatran. Only
minor drug-related AEs were reported including
headache, migraine, warmth, and flushing.43 Similarly,
in patients who received andexanet alfa and
rivaroxaban in a phase 2 randomized controlled trial
(n = 18), the investigational antidote was well tolerated
with no serious or severe AEs observed. Reported AEs
included mild infusion-related reactions (n = 3; 33%),
post-procedural hematoma (n = 2; 22%), headache
(n = 2; 22%), and postural dizziness (n = 2; 22%).35
Preliminary findings from part 1 of the phase 3
ANNEXA-R trial included no serious or severe AEs
with andexanet alfa in any patient, including thrombotic
events. No antibodies to FX or FXa were reported.11
Lastly, in a phase 1/2 clinical trial of 80 healthy
volunteers, the use of aripazine in reversing edoxabaninduced anticoagulation was well tolerated, with no
evidence of clinically significant or dose-limiting AEs.
Reported AEs with aripazine were transient, mild,
perioral, and facial flushing; dysgeusia; and moderate
headache. One patient developed moderate muscle
cramping with elevation in creatinine phosphokinase
levels; these AEs were considered to be unrelated to
aripazine.7
All three antidotes have yet to exhibit thrombotic
and/or pro-coagulant properties in clinical studies. This
is critical considering that numerous patients requiring
these antidotes will be using DOACs for stroke
prevention or VTE treatment. Rebound anticoagulation
may also be a concern, especially for antidotes with a
short half-life and a single IV bolus administration.
Although no antibodies toward the antidotes have been
detected in the studies conducted, another safety
concern relates to immunogenicity, given that
idarucizumab is a monoclonal antibody and andexanet
alfa is an endogenous FXa variant. More research is
needed to elucidate their long-term safety.
Administration and Cost
The manufacturers’ prices for idarucizumab, andexanet
alfa, and aripazine are currently unavailable, as these
drugs have not yet been approved for sale in Canada.
Given that these antidotes are biologics in nature, with
the exception of aripazine, they are expected to be
relatively costly. As the antidotes will most likely be
administered intravenously in a hospital setting,
additional costs could potentially be encountered for
their administration and subsequent monitoring of
coagulation status.
Concurrent Developments
There are ongoing studies evaluating the use of
andexanet alfa and aripazine to reverse supratherapeutic
anticoagulation states induced by non-oral
anticoagulants including UFH and LMWH. Current
recommendations to reverse UFH involve administering
protamine sulfate but no drug is effective for the
5
complete reversal of LMWH. Protamine sulfate can
only partially reverse 60% to 75% of enoxaparin.28
Early results from phase 2 trials demonstrate that
andexanet alfa is able to safely and rapidly reverse the
anticoagulant effects of enoxaparin in healthy
volunteers by reducing anti-FXa activity and restoring
thrombin generation.44,45 Given andexanet alfa’s design
and mechanism of action, reversal of pentasaccharide
antithrombin III-dependent inhibitors such as
fondaparinux is possible, as well.11 More research is
required to determine the safety and efficacy of
andexanet alfa when used in that context.
Aripazine is designed with broad reversal activity.
Based on dynamic light-scattering data, it is a
potentially universal antidote for parenteral heparin
anticoagulants including UFH, LMWH, fondaparinux,
as well as all DOACs.46 Results are pending from a
phase 1/2 clinical trial completed in healthy volunteers
evaluating the safety and pharmacodynamic effects of
aripazine following a single dose of enoxaparin.47
Another trial evaluating aripazine following
administration of UFH is anticipated to be completed in
March 2016.48
Rate of Technology Diffusion
Considering the anticipated growth in the use of
DOACs, the advent of these antidotes is of profound
interest. Thus far, virtually all phase 2 or phase 3
studies are limited by small sample size, with healthy
volunteers enrolled as patients in several of these
studies and for short study duration. Portola
Pharmaceuticals Inc. recently announced the initiation
of an open-label, single-group, phase 4 (ANNEXA-4)
clinical trial evaluating andexanet alfa’s ability to
decrease anti-FXa activity and restore hemostasis. It
will be conducted in over 50 sites located in North
America and Europe. Participants will be patients
receiving apixaban, rivaroxaban, or enoxaparin, who
present with a major bleeding event.11,17,49 There are
also plans to add edoxaban to the study by mid-2015.11
In the future, additional data will be necessary to
compare the pharmacoeconomics and cost-effectiveness
of the antidotes for DOACs, especially for those with
potential overlapping indications. For example, both
andexanet alfa and aripazine can reverse the effects of
apixaban, but andexanet alfa may require a continuous
IV infusion whereas aripazine is administered as a
single IV bolus.7,34 The broad activity of both andexanet
alfa and aripazine also creates a potential for off-label
use in the reversal of non-oral anticoagulants including
UFH, LMWH, and fondaparinux, unless manufacturers
intend to also pursue regulatory approval for the
reversal of these drugs. Off-label use for reversal of
DOACs may also be possible as the studied populations
are narrowly defined. Once these antidotes become
available, it is possible that they will contribute to a
larger adoption of DOACs, though clinical experience
with the latter remains limited and their comparative
cost-effectiveness versus vitamin K antagonists is
unclear.
Implementation Issues
Availability and timely administration may be a barrier
to the optimal usage of these antidotes. Given that
idarucizumab and andexanet alfa are injectable
biologics that require refrigeration, they will likely be
used exclusively in hospital settings because of storage
and distribution issues.50 Unlike the biologics, aripazine
is a small molecule that is stable at room temperature
with the current formulation; this feature may result in
the potential for out-of-hospital use.51
It is anticipated that these antidotes will be more costly
than the antidote traditionally used for warfarininduced bleeding, i.e., vitamin K. However, compared
with the cost of current non-specific reversal drugs for
DOACs (i.e., PCC, aPCC, and rFVIIa), the use of these
antidotes may be more favourable from a budget
impact perspective.
Despite the promising results from existing clinical
data, currently available evidence to establish the safety
and efficacy of these antidotes remains limited. For
example, whether the measurements of various
surrogate markers (i.e., PT, aPTT, ecarin clotting time,
diluted thrombin time, or anti-FXa) can be extrapolated
to mortality or morbidity benefits remains to be
demonstrated.4 Also, all ongoing phase 2 (aripazine)
and phase 3 trials (andexanet alfa and idarucizumab)
enrolled a small number of patients. In the case of
idarucizumab, the phase 3 trial is the study with the
largest sample size (N = 300) and is recruiting patients
who have either bleeding or require emergency surgery.
However, it is an open-label case series — a design in
which findings are typically not as robust as those from
randomized controlled trials. In the case of andexanet
alfa, data on patients who are bleeding will have to
await the release of the findings from the ANNEXA-4
study.
It is essential that clear guidance be provided to
practitioners at the time these reversal drugs are
commercialized in Canada to promote their optimal
use. Areas of uncertainty for which guidance will be
6
needed for antidotes for DOACs include but are not
limited to:

Indications: type of bleeding, type of emergency
procedures, overdose without bleeding.

Dosing: standard dose for all patients, or
situational dosing (e.g., based on type of
procedure); duration of effect; risk of rebound
anticoagulation; IV bolus versus continuous
infusion.

Appropriate use: optimal use (based on clinical
and economic factors), off-label use, use of
laboratory tests.
Given that the use of these reversal drugs is directly
linked to the use of DOACs, clear guidance on the use
of the latter may also reduce the need to reverse their
anticoagulant effect. Development of such guidance is
of interest to a number of organizations including
Canadian health technology assessment agencies that
recently produced guidance for some of the approved
indications of DOACs.52,53 Also, ongoing clinical
trials and future research on reversal drugs will help
determine which patients are the most appropriate
candidates to benefit from these antidotes and how to
use these antidotes optimally.
References
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http://www.bmscanada.ca/static/products/en/pm_pd
f/ELIQUIS_EN_PM.pdf
4. Mo Y, Yam FK. Recent advances in the
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5. Van Ryn J, Schmoll M, Pillu H, Gheyle L, Brys J,
Moschetti V, et al. Effect of dabigatran on the
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10
Cite as: Chu S, Boucher M, Spry C. Antidote treatments for the reversal of direct oral anticoagulants [Issues in emerging
health technologies, Issue 138]. Ottawa: CADTH; 2015.
CADTH would like to acknowledge the contribution of William Geerts, MD, FRCPC, Thromboembolism Consultant,
University of Toronto, and Marc Carrier, MD, MSc, FRCPC, Associate Professor, Senior Scientist, University of Ottawa
and Ottawa Hospital Research Institute for their review of the draft version of this bulletin.
******************
Issues in Emerging Health Technologies is a series of concise bulletins describing drug and non-drug technologies that are
not yet used (or widely diffused) in Canada. The contents are based on information from early experience with the
technology; however, further evidence may become available in the future. These summaries are not intended to replace
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ISSN: 1488-6324 (online)
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