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ATVB in Focus

Clinical Experience With the Novel Oral Anticoagulants


Series Editor: Jeffrey I. Weitz

Antidotes for Novel Oral Anticoagulants


Current Status and Future Potential
Mark Crowther, Mark A. Crowther
AbstractThe direct thrombin inhibitor dabigatran and the anti-Xa agents rivaroxaban, edoxaban, and apixaban are a new
generation of oral anticoagulants. Their advantage over the vitamin K antagonists is the lack of the need for monitoring
and dose adjustment. Their main disadvantage is currently the absence of a specific reversal agent. Dabigatrans, unlike
the anti-Xa agents, absorption can be reduced by activated charcoal if administered shortly after ingestion and it can be
removed from the blood with hemodialysis. Prothrombin complex concentrate, activated prothrombin complex concentrate,
and recombinant factor VIIa all show some activity in reversing the anticoagulant effect of these drugs but this is based
on ex vivo, animal, and volunteer studies. It is unclear, which, if any, of these drugs is the most suitable for emergency
reversal. Three novel molecules (idarucizumab, andexanet, and PER977) may provide the most effective and safest
way of reversal. These agents are currently in premarketing studies.(Arterioscler Thromb Vasc Biol. 2015;35:00-00.
DOI: 10.1161/ATVBAHA.114.303402.)
Key Words: anticoagulants apixaban factor VIIa hemorrhage prothrombin complex concentrate

he desired effect of an anticoagulant is to reduce the


chances of a pathological thrombosis; they achieve this
by altering the normal coagulation. Thus, it is unlikely that
there will ever be an anticoagulant where bleeding is not a side
effect, this is the most likely reason to reverse the effects of
anticoagulants, reversal may also be required to allow surgical
procedures and in cases of accidental or deliberate overdose.
The old anticoagulants (heparin and the vitamin K antagonists) have reversal agents but the advent of new anticoagulants currently leaves clinicians with the problem of lack of a
highly effective, universally available reversal strategies.

Possible Drug Reversal Mechanisms


Possible reversal strategies are dependent on the absorption,
metabolism, mechanism of action, and excretion of the drug.
Examples of drug reversal can be found in Table1.

Is Reversal Needed? An Approach


to the Bleeding Patient
Often when a patient on anticoagulants attends with bleeding
the emphasis is put on the management of the anticoagulant
rather than the bleeding. Minor bleeding, for example, epistaxis, may just require local measures rather than interruption or reversal of the anticoagulant. For major bleeding other
basic measures including resuscitation and optimization of

temperature and pH may be just as important as reversal of


the anticoagulant. Figure1 discusses some general measures
when presented with the bleeding patient.
Because of the short half-life of the new anticoagulants
waiting for the effect of the drug to wear off may be a suitable
strategy, weathering the storm. This watch and wait strategy
avoids the hazards of both the reversal agents and the risk of
thrombosis inherent in normalizing coagulation acutely in a
patient with an underlying predisposition to thrombosis and
is usually the preferred strategy in cases of minor bleeding.
A similar strategy for the management of emergency surgery
should be considered, that is, waiting for as long as possible after the last dose of the anticoagulant before operating,
because few emergency operations or procedures cannot be
delayed by several hours.

Reversal of the Vitamin K Antagonists


The vitamin K antagonists can be reversed although in practice clinicians rarely provide truly effective reversal as a result
of their choosing the incorrect type, dose, and route of administration of the reversal agents.
Vitamin K antagonists block vitamin K epoxide reductase
preventing the recycling of vitamin K which in turn is involved
in the -carboxylation of clotting factors II, VII, IX, and X and
the natural anticoagulant proteins C and S. -Carboxylation
of the clotting factors is required for their interaction with

Received on: September 3, 2014; final version accepted on: May 20, 2015.
From the Department of Haematology, Worcestershire Royal Hospital, Worcester, United Kingdom (M.C.); and Department of Haematology, St. Josephs
Hospital, McMaster University, Hamilton, Ontario, Canada (M.A.C.).
Correspondence to Mark Crowther, Department of Haematology, Worcestershire Royal Hospital, Worcester WR5 1DD, United Kingdom. E-mail
mark.crowther@nhs.net
2015 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org

DOI: 10.1161/ATVBAHA.114.303402

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2 Arterioscler Thromb Vasc Biol August 2015


VIIa rapidly normalizes the INR but it is unclear whether it
reduces bleeding in patients with hemorrhage . The administration of vitamin K overcomes the blockage caused by the
vitamin K antagonists and allows the production of normal
vitamin K clotting factors. Intravenous administration provides more rapid increase in coagulation factors than oral but
both methods usually provide normalization of coagulation
within 24 hours.

Nonstandard Abbreviations and Acronyms


aPCC
APTT
NOAC
PCC
PT
rFVIIa
TT

activated prothrombin complex concentrate


activated partial thromboplastin time
new oral anticoagulant
prothrombin complex concentrate
prothrombin time
recombinant factor VIIa
thrombin time

New Anticoagulants

phospholipids which is in turn required for their action as


enzymes. Immediate reversal of the anticoagulant effect is
achieved by the administration of the deficient clotting factors. Options include fresh frozen plasma or prothrombin
complex concentrate (PCC), these replace the deficient clotting factors normalizing coagulation in the time it takes to
infuse the product. PCC is a plasma-derived mixture of the
vitamin Kdependent clotting factors. PCC seems superior
to fresh frozen plasma because of speed of infusion, routine
viral inactivation, lack of need for crossmatching, the small
volume to be infused, and the effectiveness of reversal. Fresh
frozen plasma requires storage in a freezer and requires thawing before use; this is not the case for PCC. PCC may be either
3 factors (II, IX, and X) or 4 factors (II, VII, IX, and X), but
it is unclear what is the superior product. Recombinant factor
Table 1. Methods for Drug Reversal
Mechanism

Example

Reducing absorption

Drugs that have been


recently ingested can be
removed by administering
emetics or giving activated
charcoal that binds drugs
and prevents it from
being absorbed

Paracetamol overdose

Reducing metabolism

Reducing the metabolism


of prodrugs before their
conversion into the active form

Ethylene glycol
poisoning

Increasing
metabolism/excretion

Enhancing the normal


Alkalization of urine in
excretion of a drug or
aspirin poisoning
dialyzing the patient which
Dialysis in lithium
removes drugs will reduce the
poisoning
level of the drug in the body

Blockage of site of
action

Drugs may be blocked either by


the antidote binding to the drug
or the site of action

Digibind against
digoxin
Naloxone against
the -opioid receptor

Increasing the drugs


target or increasing
the substance that the
drugs action reduces

The effects of drugs that


Physostigmine to
reduce certain compounds
reduce the effect of
in the body may be reversed
atropine
by increasing the levels of
Glucose in insulin
these compounds, either by
overdose
the administration of these Prothrombin complex
compounds or reducing their concentrate in vitamin
metabolism/excretion
K antagonists

Bypassing the effect of


the drug

Drugs which block enzymic


Administration of
pathways effect can be
vitamin K for those on
reversed by administering the vitamin K antagonists
downstream products

Apart from low-molecular-weight heparin the old anticoagulants had the problems of variable pharmacokinetics and
multiple drug interactions requiring monitoring and dose
adjustments. With the better understanding of the molecular
structure of the clotting factors researchers were able to design
molecules which bound to specific clotting factors reducing
their effect. These molecules could then be chosen for dependable pharmacokinetics and minimal drugdrug interactions
allowing for standard dosing and oral administration. Licensed
drugs include the direct thrombin inhibitor dabigatran and the
anti-Xa agents apixaban and rivaroxaban. Edoxaban, an antiXa agent, is licensed in Japan and North America and is likely
to receive its license in Europe in the near future. These drugs
are summarized in Table2.
Unlike unfractionated heparin and the vitamin K antagonists, the new oral anticoagulant (NOAC) drugs have no obvious
mechanism of reversal, this is not dissimilar to low-molecularweight heparin whose effect can only be partially reversed by
protamine. Since their introduction, there are several problems
with researching reversal strategies, these include
1. Randomized controlled trials, although the gold standard, are difficult to perform in emergency situations.
The usual procedure of enrolment, consent, randomization, and drug administration is infeasible in many
acutely ill patients.
2. Nonrandomized studies, reversal strategies, can be
compared either between hospitals where they use different regimens or with historical controls (asking how
did patients fair when there was no reversal). These
have the problem of confounding factors, when compared with randomized trials, and where novel treatments are used ethically there still needs to be consent.
They tend to be easier to perform and can usually enrol
more patients and get results quicker. Patients can be
used as their own control looking at bleeding before
reversal and bleeding after, but blood loss in many situations is difficult to measure, for example, intracerebral
hemorrhage.
3. Human volunteers may agree to take the drug and have
reversal strategies tried, but the end point cannot be
bleeding or survival. Thus the end point, frequently ex
vivo measurement of residual anticoagulant effect, is a
surrogate end point. Clotting assays may demonstrate
correction of the anticoagulant effect of the drug, but as
discussed later, measured reversal of the drug may not
equate to reduction in bleeding.
4. Animal models can be designed so the drug is administered, bleeding is induced, and the reversal strategy
is tried. Unfortunately because of differences between

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Crowther and Crowther Antidotes for Novel Oral Anticoagulants 3

Figure 1. Approach to the bleeding patient. Figure derived from data from Makris et al.1

species, animal models may not be representative of


what happens in humans. For example, in many animal models, bleeding can only be induced through the
administration of doses of anticoagulant far larger than
those required to induce anticoagulation in humans, on a
per kilogram basis.
Therefore, the quality of the current evidence for reversal of the new anticoagulants is weak and comes from animal
models, healthy volunteer studies, and case series/case reports.
A summary of the reversal strategies can be found in Figure2.

Measurement of the Effect of the NOACs


Because the NOACs have, in most patients, dependable pharmacokinetics, routine measurement of effect is not required.
Measurement of effect is useful when there is
1. bleeding to determine whether reversal is required, and if
reversal is successful,
2. overdosage, and
3. Before surgery to determine when it is safe to operate or
to provide neuroaxial anesthesia.

Table 2. Pharmacokinetic Properties of the New


Anticoagulants Compared With Warfarin
Warfarin Dabigatran Apixaban

Rivaroxaban

Edoxaban

Bioavailability

100%

6.5%

50%

80%100%

60%

Maximum
concentration

4h

0.52 h

34 h

24 h

1.5 h

1214 h

12 h

59 h in young
1113 h in
elderly

Half-life

2060 h

1014 h

Renal clearance

0%

85%

27%

30%%

33%

Protein binding

99%

35%

87%

92%95%

40%59%

Data sourced from Summary of Product Characteristics.2

The NOACs can be measured using various methods including direct drug levels using chromatography, chromogenic
assays (that reflect the degree of inhibition of coagulation
enzymes by the agent), and their effects on the traditional
coagulation assays. Whether an individual laboratory can provide as assay in a timely manner will depend on several factors including staffing, skill mix, and resources. A summary
of the measurement of the new anticoagulants can be found
in Table3.
For many laboratories and clinicians this is a major problem as the only reliable coagulation test available 24 hours a
day is the prothrombin time (PT) and activated partial thromboplastin time (APTT), but the effect of the NOACs on the PT
and APTT varies significantly between the various reagents
used. For the management of bleeding or in preparation for
emergency surgery, every hospital/laboratory should have an
immediate method of determining whether the drug is present
in clinically significant quantities. Timing of dose is useful,
for the first 12 hours after ingestion (24 hours for rivaroxaban), as long as the drug is absorbed, it is likely to be present
in therapeutic levels and measurement of the level is unnecessary. After this time if the PT and APTT are normal, dabigatran, rivaroxaban, or edoxaban are unlikely to be present in
significant quantities; however, this approach may misidentify
some patients as being free of anticoagulant effect when, in
actuality, they are anticoagulated.
The UK NEQAS external quality assurance scheme performed a survey of its 700 participants on whom had an assay
available for measuring the NOACs, with 614 responding:
the percentage who had an assay was 7%, 12%, 20%, and
<1% for apixaban, dabigatran, rivaroxaban, and edoxaban,
respectively.10
With the NOACs becoming more widespread hopefully,
manufacturers of coagulation analyzers will produce tests that
can be performed on the majority of automated analyzers with
little training and in a timely manner.

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4 Arterioscler Thromb Vasc Biol August 2015

Figure 2. Possible reversal strategies for the new


oral anticoagulants. aPCC indicates activated
prothrombin complex concentrate; FXa, factor
Xa; PCC, prothrombin complex concentrate; and
rFVIIa, recombinant factor VIIa. *Idarucizumab and
Andexanet.

Dabigatran
The direct thrombin inhibitor dabigatran is rapidly but poorly
absorbed from the gut, its concentration peaks at between 30
minutes and 2 hours and half-life is 12 to 14 hours but extends
with renal impairment. Various reversal strategies have been
described:
1. Reduction of absorption: the lipophilic nature of
dabigatran should mean it will bind to the surface
of activated charcoal and reduce the amount of the
drug absorbed. Ex vivo experiments have confirmed
this process but it has yet to be demonstrated in humans.11 Dabigatran is rapidly absorbed therefore this
approach will only work within the first 2 to 3 hours
of administration.
2. Removal of the circulating drug: the majority of circulating dabigatran is free in the plasma with little being
protein bound, this along with its lipophilic properties
results in its removal by hemodialysis/hemofiltration,
ideally with a charcoal filter. This has been demonstrated
in the controlled setting of chronic hemodialysis patients
given single doses of dabigatran12 and in patients presenting with life-threatening hemorrhage.13 The main
problem with dialysis is obtaining prompt vascular access in a patient with a hemorrhagic diathesis, access
to the dialysis machine, the time taken to start dialysis,

and the requirement that the patient is hemodynamically


stable. It would be useful in overdosage.
3. Increased excretion: as the majority of the drug is excreted through the kidneys, ensuring good renal function
is important, this can be achieved by optimizing renal
blood flow with fluid administration and avoiding hypotension. Aggressive hemodynamic support, to mitigate
renal injury because of hypoperfusion, will reduce the
risk of delayed clearance of dabigatran.
4. Inactivating the drug: a specific antidote for dabigatran,
idarucizumab (aDabi-Fab), has been synthesized by
the manufacturers of dabigatran Boehringer Ingelheim.
This antibody fragment binds to the thrombin binding
site of the dabigatran hence inactivating the dabigatran
molecule.14 It is given intravenously as a one-off dose.
The idarucizumab molecule has a much greater affinity
for dabigatran than thrombin. In vitro studies suggests
that this molecule reverses the effect of dabigatran.14,15
Three studies in healthy volunteers have been reported
in abstract form at conferences. One hundred forty-five
men16 received 1, 2, or 4 g of idarucizumab after dabigatran for 4 days. Measurement of dabigatran levels and
coagulation assays were performed (dilute thrombin
time (TT), TT, APTT, ecarin clotting time, and activated
clotting time. Reversal for 30 minutes was seen with 1 g,
whereas complete reversal was achieved in 7 of the 9

Table 3. Measurement of the New Oral Anticoagulants


Drug/Assay
Dabigatran35

Apixaban6

Rivaroxaban3,7,8

Edoxaban9

PT

APTT

Chromogenic Assays

ECT*

dTT*

Insensitive

Demonstrates a
curvilinear response.
Peak level 1.41.8
normal, higher suggests
overanticoagulation

Specific commercial assays


available. Level <30 ng/mL
thought to be suitable for
operations

Calibrated ECT
demonstrates linear
response to concentrations
<300 ng/mL therefore can
be used to determine level

Calibrated dTT
demonstrates linear
response but sensitive

Causes prolongation but


great variability between
assays, should not be used

Causes prolongation but


great variability between
assays, should not be used

Specific commercial assays


available. Unclear what
level is suitable for surgery

No effect

No effect

Demonstrates a linear
relationship

Variable response therefore


should not be used

Specific commercial antiXa assays available. Level


<30 ng/mL thought to be
suitable for operations

No effect

No effect

Demonstrates linear
relationship but variability
between reagents

Demonstrates linear
relationship with little
variation between reagents

Unclear

Unclear

Unclear

APTT indicates activated partial thromboplastin time; dTT, dilute thromboplastin time; ECT, ecarin clotting time; and PT, prothrombin time.
*Only appropriately calibrated assays should be used.

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Crowther and Crowther Antidotes for Novel Oral Anticoagulants 5


who received 2 g and all the subjects who received 4 g
doses. The second study17 in healthy volunteers administered dabigatran for 4 days and then 1, 2, and 4 g of
idarucizumab or placebo. The effect of any reversal was
measured using fibrinopeptide A generation after small
skin cuts and ecarin clotting time, dilute TT, and dabigatran levels. Fibrinopeptide A generation returned to
24%, 45%, and 63% of normal after the addition of 1, 2,
and 4 g, respectively. The clotting tests returned to normal after 2 and 4 g administration. The third study18 investigated the effect of idarucizumab in older volunteers,
some with renal dysfunction. Four days of dabigatran
was given and then dose of 1, 2.5, 5, or 22.5 g (1-hour
apart) of idarucizumab. Coagulation was assessed using
the dilute TT, ecarin clotting time, and the APTT. The
1-g dose reversed the effect for 2 to 4 hours, whereas the
other doses led to complete reversal. The subjects were
rechallenged with dabigatran the following day without
problems and there were no side effects of readministering idarucizumab 2 months later.
Currently, there is a phase-III multinational study
(RE-VERSE AD) where patients taking dabigatran and presenting with bleeding or requiring emergency surgery are
given 5 g of idarucizumab and then information collected on
bleeding, coagulation assays (APTT, TT, dilute TT, and ecarin
clotting time), and dabigatran levels. The aim is to recruit 250
patients between May 2014 and March 2017.
As dabigatran is lipophilic intravenous lipid emulsion was
given to rats to determine whether this would sequester the
drug hence reducing its activity, this was not successful.19
1. Increasing the target: dabigatran binds to thrombin, in
theory administering thrombin would provide more
thrombin than dabigatran could inactivate normalizing
coagulation. At present there is no thrombin concentrate
(either recombinant or plasma derived) that could be
used. PCC and activated PCC (aPCC) are both plasmaderived products that contain prothrombin. PCC contains either 3 (factors II, IX, and X) or 4 (factors II, VII,
IX, and X) factors and is routinely used in the reversal of
the vitamin K antagonists. aPCC contains factors II, VII,
IX, and X, but compared with PCC some of the coagulation factors are activated during the purification process
making the aPCCs more thrombogenic than the PCCs.
aPCCs main role is in the treatment of hemophiliacs
with antibodies against factor VIII. Both PCC and aPCC
come as dry powder which can be rapidly reconstituted
and administered. Their main side effect is unwanted
thrombosis. They are costly and are human plasma derived, although virally inactivated. The evidence for their
use in dabigatran patients who are bleeding is contradictory and is summarized in Table4. Guidelines suggest
that their use is limited to life-threatening bleeding and
do not specify a preferred agent or dose.1,3 Case reports
have reported possible favorable outcomes.34,35
2. Enhancing coagulation: recombinant factor VIIa (rFVIIa) was originally developed, like aPCC, to treat bleeding in hemophiliacs with inhibitors having the advantage
that it is a recombinant product. Studies demonstrated its
benefit in massive hemorrhage36 and vitamin K antagonist reversal. Its use for the reversal of dabigatran has

been reported, and as with PCC and aPCC the evidence


is both indirect and contradictory. This is summarized
in Table4.

Rivaroxaban
Rivaroxaban is an oral anti-Xa agent which is rapidly and almost
completely absorbed from the gut. It is highly protein bound in
the plasma. Because of this removal strategies are limited
1. Reduced absorption: rivaroxaban does not bind to activated charcoal and because of its rapid absorption gastric
lavage is unlikely to be helpful unless used almost immediately after ingestion.
2. Removal of the circulating drug: because rivaroxaban is
highly protein bound it will not be dialyzable.
3. Increased excretion: with one third of the drug excreted through the kidneys unchanged ensuring good renal
function is important; this can be achieved by optimizing
renal blood flow with fluid administration and avoiding
hypotension.
4. Inactivating the drug: a recombinant protein (Andexanet
alfa [Annexa/PRT064445]) has been developed by Portola
Pharmaceuticals, which is similar in structure to factor Xa
but is not active. It lacks the -carboxyglutamic acid terminal preventing it from interacting with cell surface phospholipids, and a serine to alanine mutation at the active
site means it cannot convert prothrombin to thrombin. This
protein binds both the factor Xa inhibitors and heparin-activated antithrombin, with an affinity greater than natural
factor Xa, leading to inactivation of the anticoagulant. This
suggests that it can be used as reversal agent for the antiXa NOACs, heparin, and fondaparinux. It seems to have a
short half-life as after an hour infusion when andexanet is
stopped the anti-Xa activity of the anticoagulant returns;
therefore, in the treatment of bleeding, it may require a
continuous infusion until the drug is cleared from the circulation.37 Animal models37 demonstrate reduced bleeding
after the administration of andexant. Phase I/II human volunteer studies38 show correction of laboratory parameters
in humans. Phase III studies in healthy volunteers are ongoing. In the animal studies there may be interaction with
tissue factor pathway inhibitor decreasing levels, but despite this in the same animals there was no evidence of
increased thrombosis.37
A phase III study of andexanet in patients who have
received any therapeutic anti-Xa agent and are bleeding is in
set up and expected to start recruitment in 2015 with the aim
of recruiting 270 patients by 2022.
1. Increasing the target: there is no commercially available factor X concentrates. Similar to dabigatran, several
studies (summarized in Table4) have reported improvements in coagulation assays and thrombin generation in
vitro and in human studies with the addition of either
PCC or aPCC. There is no evidence from clinical studies
to support the use of these products. Guidelines suggest
that their use is limited to life-threatening bleeding and
do not specify a preferred agent or dose.1,3
2. Enhancing coagulation: the evidence for rFVIIa for the
reversal of rivaroxaban is similar to dabigatran in being
contradictory and limited. This is summarized in Table4.

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6 Arterioscler Thromb Vasc Biol August 2015


Table 4. Comparison of Reversal Strategies
Drug

Ex Vivo Model

Animal Model

Human Volunteers

PCC

No evidence

Reduced bleeding in rabbits with renal injury.20 In


high doses of dabigatran improvement in laboratory
parameters but no reduction in bleeding21

One study which infused PCC into


volunteers demonstrated no benefit,22
whereas 2 studies demonstrated
improvement in exogenous thrombin
potential when PCC was added in
vitro23,24

aPCC

Improvement in thrombin generation.

Reduced tail bleeding time but not blood loss21,25

Improvement in exogenous thrombin


potential and lag time23,26

rFVIIa

Failed to correct abnormal thrombin generation

Reduced tail bleeding time but not blood loss21,25

Improvement in exogenous thrombin


potential and lag time23,26

PCC

Improved thrombin generation27

Improved laboratory parameters but no effect on


blood loss28

No evidence

aPCC

Improved thrombin generation, clotting time, and clot


formation time27

No evidence

No evidence

rFVIIa

Improved thrombin generation, clotting time, clot


formation time, and platelet deposition27

Reduced bleeding time but no effect on blood loss in


rabbits28

No evidence

Dabigatran

Apixaban

Rivaroxaban
PCC

aPCC

rFVIIa

Demonstrated some improvement in PT, clotting time, Reduced PT and bleeding time in rats and baboons32
and thrombin potential but not as effective as aPCC or
rFVIIa.29 Different studies demonstrated no change30 or
only improvement in thrombin generation31

Improvement in laboratory parameters


including PT and thrombin potential22,23
Four factor concentrate reduces the PT
>3 factor but 3 factor improves thrombin
generation more33

Demonstrated the most effective reversal of PT,


Reduced PT and bleeding time in rats and baboons32 Improvement in laboratory parameters
clotting time, and thrombin potential compared with
including PT and thrombin potential22,24
aPCC and rFVIIa29
Some correction of thrombin
Generation29 and clotting time

Reduced PT and bleeding time in rats and baboons32 Improvement in laboratory parameters
including PT and thrombin potential22,24

Edoxaban
PCC

Demonstrated reduction in punch biopsy


bleeding time and thrombin generation,
with partial improvement in PT at 50 IU/
kg. Lesser effects with lower doses40

aPCC

Demonstrated improvement in PT, APTT, and anti-Xa


assay41

rFVIIa

Demonstrated improvement in PT, APTT, and anti-Xa


assay41

APTT indicates activated partial thromboplastin time; aPCC, activated prothrombin complex concentrate; PCC, prothrombin complex concentrate; PT, prothrombin
time; and rFVIIa, recombinant factor VIIa.

Apixaban
Apixaban is an oral anti-Xa agent. It is partially absorbed
from the gut, is protein bound, and only a small proportion of
its excretion (27%) is renal.
Although it is a similar class to rivaroxaban, there are a
few subtle differences to its reversal
1. Reduced absorption: it is unclear whether activated charcoal binds apixaban, but the slower uptake from the gut
may make charcoal or gastric lavage an option.
2. Removal of the circulating drug: the majority of apixaban is bound to protein but it is unclear whether dialysis
would be useful.
3. Increased excretion: with one third of the drug excreted through the kidneys it may be less important to ensure good renal function. Bioaccumulation should be

considered in patients with hepatic insufficiency who


present with bleeding.
4. Inactivating the drug: the recombinant protein
(Andexanet alfa) discussed above has the potential to
reverse apixaban. Phase III studies in healthy volunteers
have demonstrated reversal of the effects of apixaban39
by andexanet.
5. Increasing the target: there are less data on the use of
PCC and aPCC in apixaban when compared with that
in rivaroxaban and dabigatran. In vitro studies have
demonstrated improvements in coagulation parameters, but animal studies failed to demonstrate reduction in bleeding.
6. Enhancing coagulation: the evidence for rFVIIa for the
reversal of apixaban is similar to that for PCC. This is
summarized in Table4.

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Crowther and Crowther Antidotes for Novel Oral Anticoagulants 7

Edoxaban
Edoxaban is an oral anti-Xa agent. It is a similar class to rivaroxaban and apixaban, being a newer drug there are less data
on reversal strategies:
1. Reduced absorption: it is unclear whether activated charcoal binds edoxaban.
2. Removal of the circulating drug: it is unclear whether
edoxaban can be dialyzed.
3. Inactivating the drug: Andexanet alfa, discussed above,
has the potential to reverse apixaban but no studies have
reported.
4. Increasing the target: a small study has presented data on
the efficacy of PCC to mitigate bleeding in a punch biopsy
model of health patients receiving a single 60 mg dose of
edoxaban. This study demonstrated reduced shed blood
and overcorrection of the endogenous thrombin potential,
with less evident correction of the PT/INR, after 50 IU/
kg of a 4-factor PCC. Lower doses were ineffective for
correction of the outcomes measured.40 Ex vivo studies41
demonstrated reversal of edoxaban by aPCC.
5. Enhancing coagulation: the effects of edoxaban when
measured by PT, APTT, and anti-Xa levels were reversed
ex vivo by rFVIIa.41

PER977 (Arapazine/Ciraparantag)
An interesting development in the reversal of all the anticoagulants is PER977 from Perosphere. It is a small, synthetic,

water-soluble, catatonic molecule that binds to the drug inactivating it, originally developed as a reversal agent for heparin
and fondaparinux but also potentially seems to have activity
against the oral anti-Xa agents and dabigatran. It does not
seem to bind to plasma proteins or several common cardiovascular, antiepileptic, and anesthetic drugs.
Initial studies42 were in human plasma spiked with apixaban, rivaroxaban, or dabigatran or rats given overdosage of
anticoagulants and then subjected to tail bleeding. These demonstrated a reversal of the anti-Xa effect in the plasma or reduction in bleeding to baseline. Further animal studies43 again
demonstrated reduced bleeding and improvements in coagulation assays and thromboelastography with PER977, but no
changes to these measures were observed in rats not given anticoagulants, suggesting that the molecule is not procoagulant.
The first in vivo human study has been published44; this was
a placebo controlled study in healthy volunteers, which demonstrated that after a single dose of edoxaban the whole blood
clotting time improved with the addition of 25 mg of PER977,
with 100 and 300 mg almost completely reversed the effect.
Electron microscopy of fibrin fibers demonstrated larger fibers
with the higher doses. There was no evidence of coagulation
activation with no increase in D-dimers, prothrombin fragment
1.2, and tissue pathway inhibitor. Further similar studies with
unfractionated heparin and enoxaparin are taking place.
Two abstracts (produced by the manufactures of
Andexanet) have questioned whether PER977 truly reverses

Figure 3. Flowchart for the management of novel oral anticoagulant (NOAC) bleeding. aPCC indicates activated prothrombin complex
concentrate; APTT, activated partial thromboplastin time; PCC, prothrombin complex concentrate; PT, prothrombin time; and rFVIIa,
recombinant factor VIIa.

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8 Arterioscler Thromb Vasc Biol August 2015


the anticoagulant or is in fact a procoagulant molecule. A rabbit laceration model45 demonstrated reduced blood loss with
PER977, but no change in the rivaroxaban activity as measured by PT, APTT, and anti-Xa activity, and a trend toward
reduced blood loss in rabbits receiving PER977 but no anticoagulant. An in vitro study46 failed to demonstrate the reversal
of anti-Xa agents by PER977, but there was the suggestion
of procoagulant activity with increased thrombin generation
and platelet activation. Even if PER977 does not reverse the
anti-Xa agents but reduces bleeding, then it is still worthwhile
investigating further.

Discussion
The NOACs offer the ability to anticoagulate patients without the need for routine monitoring and dose adjustment,
hopefully enhancing quality of life. Within randomized controlled trials they seem to be as or more effective and possibly safer than their comparator agents,47 but it is unclear in
everyday clinical practice whether these benefits are present,
real-world registry data are awaited. Long-term side-effects,
if any, are still to be determined. The new anticoagulants still
cause bleeding and patients may require emergency surgery,
but unlike the vitamin K antagonists they replace there is no
specific reversal agent currently in widespread clinical use.
For the majority of episodes where reversal is required, the
short half-life of the drugs means the patient can be stabilized and supported until the effect of the drug effect is lost.
Routinely available coagulation tests, if elevated, suggest
that the patient has significant amounts of drug present. If
normal, they do not indicate the patient is free of clinically
important levels of drug. Education is important to ensure
patients and healthcare professionals do not continue to
administer the drug in the event of bleeding or symptoms
that require emergency surgery and that these new drugs
are readily recognized as anticoagulants by all healthcare
professionals.
Where bleeding is potentially life-threatening, then additional treatments may be considered, including PCC, aPCC,
and rFVIIa. Although none of these agents have been demonstrated to be effective in clinical trials involving patients with
hemorrhage, the evidence comes from volunteer studies, animal studies, and in vitro experiments. There is no consensus,
because of conflicting data, on which of these agents is superior and their optimum dose. PCC is likely to be cheaper and
because of its indication for warfarin, reversal is more readily
available than aPCC or rFVIIa. Because aPCC contains activated clotting factors, it could be theorized that it would be
more effective in stopping bleeding than PCC, but it is known
that it is more thrombogenic increasing the risk of unwanted
thrombosis.
The new anticoagulants were designed with the knowledge of the structure of their target molecule, the same principles have been applied to specific antidotes which mimic
either thrombin or factor Xa (idarucizumab and andexanet,
respectively) or bind to the drug inactivating it (PER977).
All the information on these new agents are from conference
abstracts which have not been thoroughly peer reviewed.
These antidotes are not functional as a clotting factor but

bind the drug with high affinity making it inactive. These


novel antidotes may provide the most effective method of
reversal; however, they are yet to be proven in clinical trials
with bleeding patients. Given they are inert they would probably be safer than recombinant thrombin or factor Xa, which
may lead to unwanted thrombosis; to date, none of the studies have demonstrated coagulation activation or unwanted
effects. PER977 seems to have the advantage of reversing all
the NOACs along with heparin but its exact mechanism is
still unclear.
When compared with the majority of drugs, these antidotes will be used relatively infrequently, the worry is that
the development costs, which will be passed on, will lead to
the drugs being prohibitively expensive, even when compared
with the cost of bleeds or alternative therapies.
In both bleeding and the work-up for emergency surgery,
time is critical. It is important that healthcare institutions have
readily accessible guidelines and procedures for managing
patients on the NOACs to ensure that they are assessed appropriately and if necessary specific management implemented.
A suggested algorithm is found in Figure3.

Disclosures
None.

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Antidotes for Novel Oral Anticoagulants: Current Status and Future Potential
Mark Crowther and Mark A. Crowther
Arterioscler Thromb Vasc Biol. published online June 18, 2015;
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