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The desired effect of an anticoagulant is to reduce thechances of a pathological thrombosis; they achieve thisby 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 antago-

nists) have reversal agents but the advent of new anticoagu-

lants currently leaves clinicians with the problem of lack of a

highly effective, universally available reversal strategies.

Possible Drug Reversal MechanismsPossible reversal strategies are dependent on the absorption,

metabolism, mechanism of action, and excretion of the drug.

Examples of drug reversal can be found in Table 1.

Is Reversal Needed? An Approach

to the Bleeding PatientOften 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, epi-

staxis, may just require local measures rather than interrup-

tion 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. Figure 1 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 ofthrombosis 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 possi-

ble 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 AntagonistsThe vitamin K antagonists can be reversed although in prac-

tice clinicians rarely provide truly effective reversal as a result

of their choosing the incorrect type, dose, and route of admin-istration 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

2015 American Heart Association, Inc.Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.303402

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 safestway 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

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. [email protected]

Antidotes for Novel Oral Anticoagulants

Current Status and Future Potential

Mark Crowther, Mark A. Crowther

Series Editor: Jeffrey I. Weitz

ATVB in Focus

Clinical Experience With the Novel Oral Anticoagulants

at Charit - Universitaetsmedizin Berlin on July 8, 2015http://atvb.ahajournals.org/Downloaded from


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2 Arterioscler Thromb Vasc Biol August 2015

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 fac-

tors. Options include fresh frozen plasma or prothrombin

complex concentrate (PCC), these replace the deficient clot-

ting 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, routineviral 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 thaw-

ing 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

VIIa rapidly normalizes the INR but it is unclear whether it

reduces bleeding in patients with hemorrhage . The admin-

istration of vitamin K overcomes the blockage caused by the

vitamin K antagonists and allows the production of normal

vitamin K clotting factors. Intravenous administration pro-

vides more rapid increase in coagulation factors than oral but

both methods usually provide normalization of coagulation

within 24 hours.

New AnticoagulantsApart from low-molecular-weight heparin the old antico-

agulants 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 depend-

able pharmacokinetics and minimal drugdrug interactions

allowing for standard dosing and oral administration. Licensed

drugs include the direct thrombin inhibitor dabigatran and theanti-Xa agents apixaban and rivaroxaban. Edoxaban, an anti-

Xa 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 Table 2.

Unlike unfractionated heparin and the vitamin K antago-

nists, the new oral anticoagulant (NOAC) drugs have no obvious

mechanism of reversal, this is not dissimilar to low-molecular-

weight 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 stan-

dard, are difficult to perform in emergency situations.The usual procedure of enrolment, consent, random-

ization, and drug administration is infeasible in many

acutely ill patients.

2. Nonrandomized studies, reversal strategies, can be

compared either between hospitals where they use dif-

ferent regimens or with historical controls (asking how

did patients fair when there was no reversal). These

have the problem of confounding factors, when com-

pared with randomized trials, and where novel treat-

ments 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 beforereversal and bleeding after, but blood loss in many situ-

ations 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 admin-

istered, bleeding is induced, and the reversal strategyis tried. Unfortunately because of differences between

Nonstandard Abbreviations and Acronyms

aPCC activated prothrombin complex concentrate

APTT activated partial thromboplastin time

NOAC new oral anticoagulant

PCC prothrombin complex concentrate

PT prothrombin timerFVIIa recombinant factor VIIa

TT thrombin time

Table 1. Methods for Drug Reversal

Mechanism Example

Reducing absorption Drugs that have been

recently ingested can be

removed by administeringemetics 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

excretion of a drug or

dialyzing the patient which

removes drugs will reduce the

level of the drug in the body

Alkalization of urine in

aspirin poisoning

Dialysis in lithium

poisoning

Blockage of site of

action

Drugs may be blocked either by

the antidote binding to the drugor the site of action

Digibind against

digoxinNaloxone against

the -opioid receptor

Increasing the drugs

target or increasing

the substance that the

drugs action reduces

The effects of drugs that

reduce certain compounds

in the body may be reversed

by increasing the levels of

these compounds, either by

the administration of these

compounds or reducing their

metabolism/excretion

Physostigmine to

reduce the effect of

atropine

Glucose in insulin

overdose

Prothrombin complex

concentrate in vitamin

K antagonists

Bypassing the effect of

the drug

Drugs which block enzymic

pathways effect can be

reversed by administering the

downstream products

Administration of

vitamin K for those on

vitamin K antagonists



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Crowther and Crowther Antidotes for Novel Oral Anticoagulants 3

species, animal models may not be representative of

what happens in humans. For example, in many ani-

mal 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 rever-

sal 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 Figure 2.

Measurement of the Effect of the NOACsBecause the NOACs have, in most patients, dependable phar-

macokinetics, 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.

The NOACs can be measured using various methods includ-

ing 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 pro-

vide as assay in a timely manner will depend on several fac-

tors including staffing, skill mix, and resources. A summary

of the measurement of the new anticoagulants can be found

in Table 3.

For many laboratories and clinicians this is a major prob-lem as the only reliable coagulation test available 24 hours a

day is the prothrombin time (PT) and activated partial throm-

boplastin 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 rivaroxa-

ban), as long as the drug is absorbed, it is likely to be present

in therapeutic levels and measurement of the level is unneces-

sary. After this time if the PT and APTT are normal, dabiga-

tran, rivaroxaban, or edoxaban are unlikely to be present insignificant 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 per-

formed 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


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DabigatranThe 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 hu-

mans.11Dabigatran 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 circu-

lating 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 dabigatran12and in patients pre-

senting with life-threatening hemorrhage.13 The main

problem with dialysis is obtaining prompt vascular ac-

cess 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 ex-

creted through the kidneys, ensuring good renal function

is important, this can be achieved by optimizing renal

blood flow with fluid administration and avoiding hypo-tension. 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 dabi-

gatran 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 PT APTT Chromogenic Assays ECT* dTT*

Dabigatran35 Insensitive Demonstrates a

curvilinear response.

Peak level 1.41.8normal, higher suggests

overanticoagulation

Specific commercial assays

available. Level


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who received 2 g and all the subjects who received 4 g

doses. The second study17 in healthy volunteers admin-

istered 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 dabi-

gatran 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 nor-

mal after 2 and 4 g administration. The third study18in-

vestigated 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 readminister-

ing idarucizumab 2 months later.

Currently, there is a phase-III multinational study(RE-VERSE AD) where patients taking dabigatran and pre-

senting 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 normalizingcoagulation. At present there is no thrombin concentrate

(either recombinant or plasma derived) that could be

used. PCC and activated PCC (aPCC) are both plasma-

derived products that contain prothrombin. PCC con-

tains 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 coagula-

tion 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 reconstitutedand administered. Their main side effect is unwanted

thrombosis. They are costly and are human plasma de-

rived, although virally inactivated. The evidence for their

use in dabigatran patients who are bleeding is contradic-

tory and is summarized in Table 4. Guidelines suggest

that their use is limited to life-threatening bleeding and

do not specify a preferred agent or dose.1,3Case reports

have reported possible favorable outcomes.34,35

2. Enhancing coagulation: recombinant factor VIIa (rFVI-

Ia) was originally developed, like aPCC, to treat bleed-

ing in hemophiliacs with inhibitors having the advantage

that it is a recombinant product. Studies demonstrated its

benefit in massive hemorrhage

36

and vitamin K antago-nist 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 Table 4.

RivaroxabanRivaroxaban 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 acti-

vated charcoal and because of its rapid absorption gastric

lavage is unlikely to be helpful unless used almost im-

mediately 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 excret-

ed 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 (Andexanetalfa [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 termi-

nal preventing it from interacting with cell surface phos-

pholipids, 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-ac-

tivated 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 anti-

Xa 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 cir-

culation.37Animal models37demonstrate reduced bleeding

after the administration of andexant. Phase I/II human vol-

unteer studies38show correction of laboratory parameters

in humans. Phase III studies in healthy volunteers are on-

going. In the animal studies there may be interaction with

tissue factor pathway inhibitor decreasing levels, but de-

spite 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 aimof recruiting 270 patients by 2022.

1. Increasing the target: there is no commercially avail-

able factor X concentrates. Similar to dabigatran, several

studies (summarized in Table 4) have reported improve-

ments 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 beingcontradictory and limited. This is summarized in Table 4.



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Apixaban

Apixaban is an oral anti-Xa agent. It is partially absorbedfrom 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 char-

coal 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 apixa-

ban is bound to protein but it is unclear whether dialysis

would be useful.

3. Increased excretion: with one third of the drug excret-

ed through the kidneys it may be less important to en-sure 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 param-

eters, but animal studies failed to demonstrate reduc-

tion in bleeding.

6. Enhancing coagulation: the evidence for rFVIIa for the

reversal of apixaban is similar to that for PCC. This issummarized in Table 4.

Table 4. Comparison of Reversal Strategies

Drug Ex Vivo Model Animal Model Human Volunteers

Dabigatran

PCC No evidence Reduced bleeding in rabbits with renal injury.20In

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 thrombinpotential 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 Fai led to correct abnormal thrombin generation Reduced tai l bleeding t ime but not blood loss21,25 Improvement in exogenous thrombin

potential and lag time23,26

Apixaban

PCC Improved thrombin generation27 Improved laboratory parameters but no effect on

blood loss28No evidence

aPCC Improved thrombin generation, clotting time, and clot

formation time27No evidence No evidence

rFVIIa Improved thrombin generation, clotting t ime, clot

formation time, and platelet deposition27

Reduced bleeding time but no effect on blood loss in

rabbits28

No evidence

Rivaroxaban

PCC Demonstrated some improvement in PT, clotting time,

and thrombin potential but not as effective as aPCC or

rFVIIa.29Different studies demonstrated no change30or

only improvement in thrombin generation31

Reduced PT and bleeding time in rats and baboons32 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

aPCC Demonstrated the most effective reversal of PT,

clotting time, and thrombin potential compared with

aPCC and rFVIIa29



rFVIIa Some correction of thrombin

Generation29and clotting time



Edoxaban

PCC Demonstrated reduction in punch biopsybleeding 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.



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EdoxabanEdoxaban is an oral anti-Xa agent. It is a similar class to riva-

roxaban and apixaban, being a newer drug there are less data

on reversal strategies:

1. Reduced absorption: it is unclear whether activated char-

coal binds edoxaban.

2. Removal of the circulating drug: it is unclear whetheredoxaban 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.40Ex 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 antico-

agulants is PER977 from Perosphere. It is a small, synthetic,

water-soluble, catatonic molecule that binds to the drug inac-

tivating 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 cardiovas-

cular, antiepileptic, and anesthetic drugs.

Initial studies42were in human plasma spiked with apixa-

ban, rivaroxaban, or dabigatran or rats given overdosage of

anticoagulants and then subjected to tail bleeding. These dem-

onstrated a reversal of the anti-Xa effect in the plasma or reduc-

tion in bleeding to baseline. Further animal studies43 again

demonstrated reduced bleeding and improvements in coagu-

lation assays and thromboelastography with PER977, but no

changes to these measures were observed in rats not given anti-

coagulants, 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 dem-

onstrated 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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the anticoagulant or is in fact a procoagulant molecule. A rab-

bit laceration model45demonstrated reduced blood loss with

PER977, but no change in the rivaroxaban activity as mea-

sured by PT, APTT, and anti-Xa activity, and a trend toward

reduced blood loss in rabbits receiving PER977 but no antico-

agulant. An in vitro study46failed 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.

DiscussionThe NOACs offer the ability to anticoagulate patients with-

out the need for routine monitoring and dose adjustment,

hopefully enhancing quality of life. Within randomized con-

trolled trials they seem to be as or more effective and pos-

sibly safer than their comparator agents,47but 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 stabi-

lized 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 toadminister 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 addi-

tional treatments may be considered, including PCC, aPCC,

and rFVIIa. Although none of these agents have been demon-

strated to be effective in clinical trials involving patients with

hemorrhage, the evidence comes from volunteer studies, ani-

mal studies, and in vitro experiments. There is no consensus,

because of conflicting data, on which of these agents is supe-

rior and their optimum dose. PCC is likely to be cheaper and

because of its indication for warfarin, reversal is more readilyavailable than aPCC or rFVIIa. Because aPCC contains acti-

vated 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 knowl-

edge of the structure of their target molecule, the same prin-

ciples 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 prob-

ably be safer than recombinant thrombin or factor Xa, which

may lead to unwanted thrombosis; to date, none of the stud-

ies 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 anti-

dotes 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 appro-

priately and if necessary specific management implemented.A suggested algorithm is found in Figure 3.

DisclosuresNone.

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Mark Crowther and Mark A. Crowther

Antidotes for Novel Oral Anticoagulants: Current Status and Future Potential

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