Expert Review of Hematology

ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20

Reversal of dabigatran by idarucizumab: when and

how?

Thomas Vanassche, Peter Verhamme & Andreas Greinacher

To cite this article: Thomas Vanassche, Peter Verhamme & Andreas Greinacher (2016):
Reversal of dabigatran by idarucizumab: when and how?, Expert Review of Hematology, DOI:
10.1080/17474086.2016.1184569

To link to this article: http://dx.doi.org/10.1080/17474086.2016.1184569

Accepted author version posted online: 11

May 2016.

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 Publisher: Taylor & Francis

Journal: Expert Review of Hematology

DOI: 10.1080/17474086.2016.1184569
Drug Profile

Reversal of dabigatran by idarucizumab: when and how?

Thomas Vanassche1, Peter Verhamme1, and Andreas Greinacher2

1 Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven,

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Belgium

2 Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin

Greifswald, Greifswald, Germany

Corresponding author:

Andreas Greinacher
Institute for Immunology and Transfusion Medicine
University Medicine Greifswald
17475 Greifswald
Tel. +49-3834-86-5482
Fax. +49-3834-865489
Email: greinach@uni-greifswald.de

1
 Abstract

Introduction: Anticoagulants are highly effective in reducing the risk of

embolism in patients with atrial fibrillation and in the treatment of venous

thromboembolism. However, interfering with the coagulation system increases

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the risk of bleeding. Non-vitamin K oral anticoagulants (NOACs) are associated

with a reduced risk of major and life-threatening bleeding compared to

warfarin, but the absence of a specific reversal agent has caused concern

among clinicians.

Areas covered: This article describes the indications for and practical use of

idarucizumab, a specific reversal agent for the direct thrombin inhibitor

dabigatran.

Expert commentary: Each year, 3-5% of anticoagulated patients will experience

major bleeding and about 10% will require invasive interventions. While most

of these situations can be managed without the need for a reversal agent, the

ability to promptly switch off anticoagulant activity is likely beneficial in severe

bleeding situations and can help to avoid delays and improve safety in the

management of patients requiring urgent procedures. Idarucizumab rapidly

and completely reverses the anticoagulant effect of dabigatran in vitro, in

2
 healthy volunteers, and in patients presenting with severe bleeding or

requiring urgent procedures. Further clinical data will help to understand the

clinical impact of rapid reversal on the outcome of bleeding patients.

Keywords: Idarucizumab, NOACs , Dabigatran , reversal agent , anticoagulants

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3
 1. Introduction

Pharmacological inhibition of coagulation is very effective in the treatment and

prevention of venous thromboembolism (VTE) and in the prevention of

ischemic stroke in patients with atrial fibrillation (AF). However, by impeding

the balance of normal hemostasis, anticoagulants increase the risk for bleeding

resulting from tissue damage due to trauma or surgery. Furthermore, a

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reduced coagulation activity increases the likelihood that spontaneously

occurring microscopic bleeds lead to clinically overt bleeding.

Compared to vitamin K antagonists (VKA), non-VKA oral anticoagulants

(NOACs) have a more favorable benefit-risk profile. Both clinical trials and real-

life registries have shown that the unmonitored use of a fixed dose of a NOAC

provided similar levels of protection against thromboembolic complications as

monitored VKA therapy, but with a lower incidence of life-threathening

bleeding and especially of intracranial bleeding[1-3]. Nevertheless, major

bleedings still may occur. Additionally, patients treated with anticoagulants can

be confronted with urgent invasive procedures that require optimal

hemostasis. Over a 2 year follow-up, about 25% of patients receiving a NOAC

required invasive interventions[4,5].

Based on the long experience with prothrombin complex concentrates (PCCs),

many clinicians — especially in Europe — felt better armed to handle VKA-

4
 associated bleeding. The lack of experience with NOACs and the absence of

validated approaches to manage potentially life-threatening bleeding or urgent

surgery remained barriers for their use.

Since the introduction of the NOACs in clinical practice, experience with these

situations has greatly improved. For the majority of major bleeds (defined as a

drop in hemoglobin of > 2g/dL, need for red cell transfusion, or bleeding in a
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critical site) associated with NOACs, supportive measures have shown to be

sufficient. These are effective hemodynamic resuscitation with cristalloids and

colloids, packed cells transfusion, identification and control of the bleeding site

(e.g. endoscopy, arteriography)[6].

In contrast to VKAs, due to the short halflife of NOACs, simply withholding the

drug will suffise to allow normalization of coagulation activity in the vast

majority of patients within 24h. Nonetheless, some situations may require

more urgent correction When urgent correction of coagulation activity is

required, two strategies are available: first, the use of procoagulant therapies

such as (activated) factor concentrates, and second, the use of specific

anticoagulant reversal agents[6].

Prothromin complex concentrates (PCC) had been developed to replenish the

inactive clotting factors II, VII, IX, and X in patients treated with vitamin K

antagonists requiring urgent normalisation of coagulation. Activated PCC

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 (aPCC) is indicated to support haemostasis in patients with hemophilia who

developed inhibitors to factor VIII. In vitro, high doses of these coagulation

factor concentrates also corrected, to a variable degree, impaired hemostasis

in the presence of dabigatran, rivaroxaban, apixaban, and edoxaban in vitro[7].

There is limited evidence from preclinical studies and from pharmacokinetic

studies in healthy volunteers that high doses of PCC or aPCC can support
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coagulation in animals and patients treated with a NOAC, as recently

summarized[7]. In the absence of alternatives, despite limited and inconsistent

clinical evidence, and the concern of prothrombotic effects, current guidelines

support considering the use of these procoagulant agents in life-threathening

bleeding emergencies [8]. Even less guidance is available in those patients who

are not bleeding, but for whom urgent correction of hemostasis would allow a

timely intervention that can improve patient outcome.

This unsatisfactory situation is now changing. In the past years, specific reversal

agents for NOACs have been developed. Idarucizumab, the humanized Fab-

fragment of a monoclonal anti-dabigatran antibody, was recently approved by

the Food and Drug Administration (FDA) and the European Medicines Agency

(EMA) for the reversal of dabigatran[9,10]. This article summarizes the

indications for, and evidence of the reversal effect of idarucizumab, and offers

6
 a practical approach to manage situations where rapid correction of

coagulation activity in dabigatran-treated patients may be beneficial.

2. Dabigatran

2.1 What are key pharmacokinetic features of dabigatran?

Dabigatran is a small molecule direct thrombin inhibitor, which reversibly binds

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to the enzymatically active thrombin site and prevents the final step in the

coagulation cascade, the conversion of soluble fibrinogen in a network of fibrin.

It is administered as a prodrug, dabigatran etexilate, which is rapidly

enzymatically converted to dabigatran after gastro-intestinal

absorbtion[11,12]. Similarly to other NOACs, the peak anticoagulant effect is

achieved within 2 - 3 hours. Dabigatran depends mainly on renal elimination

for clearance, and is a substrate for the P-glycoprotein pump (PgP). Therefore,

concomitant intake of a strong PgP inhibitor can increase absorbtion and

plasma levels, and the relatively short half-life of about 12h can be increased in

patients with reduced renal function [8,11].

2.2 When is anticoagulation with dabigatran indicated?

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 Dabigatran is approved for the prevention of stroke and systemic embolism in

patients with non-valvular atrial fibrillation, for the treatment and prevention

of recurrence of VTE, and for the prevention of VTE following major orthopedic

surgery[13]. Ongoing studies evaluate the use of dabigatran in other

indications, such as in patients with embolic stroke of undetermined source

(ESUS)[14]. Due to risk for drug accumulation, dabigatran is not indicated in

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patients with severe renal dysfunction (creatinine clearance <30 mL/min).

Although these patients were not represented in the phase III trials, the FDA

approved a reduced dose of dabigatran 75mg BID for patients with a creatinine

clearance between 15 and 30ml/min[13].

The approved doses and criteria for dose reduction vary among indications and

are summarized in Table 1. The RE-COVER trials randomized 5,153 patients

with symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) to

150mg dabigatran twice daily or warfarin with a targeted INR of 2 to 3 after

initial treatment with low molecular weight heparin[15,16].

In the RE-LY study, 18,113 patients with non-valvular AF and at least one

additional stroke risk factor were randomized to either warfarin (target INR 2

to 3), dabigatran 110mg bid, or dabigatran 150mg bid[10].

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 3. Interruption of anticoagulant treatment

3.1 Which situations require interruption of treatment in anticoagulated

patients?

Any decision to anticoagulate a patient is the result of a careful consideration

of the risks and benefits of such treatment. However, the balance between risk

of thrombotic complications and the risk of bleeding varies over time. Even
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patients with a clear indication for anticoagulation, in whom the overall benefit

is expected to outweigh the risk of bleeding, can be exposed to situations

where the risk of bleeding is acutely elevated.

Obviously, this is the case when there is physical damage to the vasculature,

causing active bleeding. In the RE-LY study, rates of major bleeding were 3.32

and 2.71%/yr for dabigatran 150mg and 110mg, respectively[10],[18]. Recent

large real-world registries confirm the relative safety of dabigatran compared

to VKA, but with varying absolute rates of major bleeding, ranging from around

2% to 4.3%/yr[3,17]. Intracranial bleeding rate was 0.33%/yr (0.96%/yr for

warfarin), and gastrointestinal bleeding rate was 3.4%/yr (2.7%/yr for

warfarin)[3]. Despite this overall favorable safety profile, with dabigatran being

used in millions of patients worldwide, even low rates of bleeding will translate

into many bleeding episodes. These patients will be treated by a variety of

9
 physicians, such as emergency care physicians, anesthesiologists, gastro-

enterologists, intensive care physicians, etc.. Therefore, the availability of a

management plan for anticoagulant-related bleeding is an important factor in

improving patient care.

Beside acute bleeding, patients may encouter situations that require invasive
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diagnostic or therapeutic interventions. Often, these situations may overlap

when patients present with bleeding that requires an intervention to help

control the bleeding. Furthermore, accumulation of anticoagulants, either

through overdose or because of reduced elimination can put the patient at

increased bleeding risk, and can be a reason to interrupt treatment.

Each year, about one in ten patients treated with anticoagulants undergo

procedures that require to interrupt anticoagulant therapy. In the RE-LY trial,

over a two year follow-up, 25% of patients had at least a single planned or

urgent invasive procedure[4].

3.2 Which of those situations require reversal of the anticoagulant effect of

dabigatran?

3.2.1 Bleeding:

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 Patients who present with bleeding, regardless of whether they are treated

with anticoagulants, should be carefully assessed to determine the cause and

site of bleeding, the estimated volume of blood loss, and the repercussions on

hemodynamics and tissue oxygen delivery.

The general approach to the bleeding patient depends on the severity of the

bleeding episode. Spontaneously resolved minimal bleeding may not require

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interruption of anticoagulant therapy at all. Nevertheless, even minor bleeding,

especially when recurrent, should trigger an investigation for the underlying

cause. For minor bleeding, interruption of anticoagulant therapy often suffises

to allow hemostasis before blood loss reaches a clinically relevant volume[8].

Patients with major bleeding often require i.v. fluids to compensate loss of

intravascular volume, and red blood cells to ensure adequate blood oxygen

carrying capacity. Regardless of the volume of blood loss, bleeding in critical

sites (e.g. intracranial bleeding, intra-ocular bleeding, spinal bleeding,…)

require prompt aggressive treatment, because even small volumes of can cause

severe disability or organ damage[8,19]. In case of ongoing blood loss,

interventions are often required to achieve local control of bleeding, such as

compression and/or ligation of arterial punctures, endoscopic treatment of

upper gastrointestinal bleeding, or endovascular angiographic treatment.

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 These general measures are often sufficient to control bleeding, even in

anticoagulated patients.

3.2.2 Invasive procedures:

3.2.2.1 Elective procedures

Due to short halflife of dabigatran and other NOACs, simple interruption of

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the treatment ensures the restoration of normal coagulation activity within

12-24 hours in patients with normal renal function. Elective invasive

procedures should be timed taking into account renal clearance and the

bleeding risk of the procedure, i.e. 24 to 48 hours after the last intake for

standard risk procedures, and 72 to 96 hours after the last intake of

dabigatran for patients with impaired renal function or patients undergoing

procedures with a high bleeding risk[8].

3.2.2.2 Urgent procedures

However, in some situations, interventions cannot be delayed. Some life-

threathening conditions mandate the ability to promptly intervene, such as

drainage of pericardial tamponnade, urgent sugery for rupturing aortic

aneurysm, stabilization of severe fractures. In other situations, postponing

the procedure can increases the risk for complications. Early surgical

treatment for severe localized infections such as cholecystitis or acute

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 appendictis can often lead to quick recovery of the patient, whereas a delay

or perforce nonsurgical treatment can lead to spreading of the infection,

abcedation, and sepsis.

When surgery cannot be delayed, the risk of major bleeding is obviously

much higher than in elective conditions. An analysis from RE-LY showed that

the risk of peri-procedural major bleeding was 4 to 7 times higher when

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surgery was urgent rather than elective, increasing from 3.8% to 17.7% for

dabigatran 150mg bid[4].

The ability to reverse the anticoagulant effect in such patients would allow

the optimal treatment for their condition and mitigate this increased peri-

procedural risk.

Idarucizumab is an antidote for dabigatran which allows rapid reversal of its

anticoagulatory effects, when the general measures to prevent or manage

bleeding are not sufficient or would result in an inacceptable delay of

treatment.

4. Idarucizumab

4.1 What are the key pharmacokinetic and pharmacodynamic features of

idarucizumab?

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 Idarucizumab is the humanized Fab-fragment of a monoclonal antibody that

binds dabigatran with great affinity. Because the affinity of idarucizumab for

dabigatran is about 300-fold higher than that of dabigatran for thrombin,

idarucizumab will bind to and neutralize both free and thrombin-bound

dabigatran with binding kinetics very close to irreversible binding[20,21].

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Idarucizumab has an initial half-life of 45 minutes, which accounts for

approximately 90% of the drug, and a terminal half-life of approximately 6

hours. It is mainly renally cleared, together with the bound dabigatran. In

patients with severe renal impairment the half-life of idarucizumab is

prolonged[20-22]. Non-renal degradation may potentially prompt

reappearance of unbound dabigatran.

In patients with normal renal function, all idarucizumab will be excreted within

approximately 8-12 hours, which allows re-initiating dabigatran as soon as after

1 or 2 days, if necessary[22]. However, in most patients who experienced a

critical situation during treatment with dabigatran, low molecular weight

heparins will be typically used for several days until the patient is stabilized and

the underlying condition is controlled.

4.2 What are the potential side effects of idarucizumab?

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 Idarucizumab is specific for dabigatran, hence no effects other than binding

dabigatran and neutralizing its anticoagulant activity are currently described.

There are no other known interferences with the haemostatic system[9].

The administration of 5 gram of an antibody fragment raises questions on

potential side effects. However, the elemination of the Fc-fragment mitigates

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Fc-receptor mediated functions of the antibody.

Because idarucizumab is a humanized antibody fragment, the potential for

immunogenicity is low. However, about 10-20% of the general population have

preformed antibodies, which bind to the cleavage site of a Fab-fragment. The

clinical relevance of these anti-Fab antibodies seems to be low based on the

experience with another therapeutic Fab fragment, abciximab, which had been

used extensively in cardiac patients[23].

As with any protein based drug, anaphylactic or anaphylactoid reactions may

occur when preformed antibodies are present. To date, no such reactions have

been reported in the clinical studies.

Anti-drug antibodies may arise, which can be directed to either the constant or

variable region of idarucizumab. Antibodies directed to the variable region

would also be neutralizing antibodies.are directed against the variable region

could potentially neutralize idarucizumab by blocking the binding site for

15
 dabigatran[24]. As recently described by Glund and coworkers, there was no

difference in the reversal effect of a second administration of idarucizumab,

however, this was only studied in a relatively small group of healthy

volunteers[25]. More complex becomes the situation when antibodies are then

generated against such anti-idiotypic antibodies because they potentially may

have dabigatran-like features. Until now, no neutralizing anti-idarucizumab

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antibodies have been reported [21,22,26,27], but further analysis of the

ongoing RE-VERSE study will provide better insight on the frequency of

immunization.

4.3 How does Idarucizumab reverse dabigatran in vitro?

Dabigatran impacts on several coagulation assays, which can be used to

qualitatively (activated Partial Thrombin Time, thrombin time) or quantitatively

(diluted Thrombin Time, ecarin clotting time) assess the presence of

dabigatran[8]. In vitro addition of idarucizumab neutralizes all effects of

dabigatran on routine and specialized hemostasis assays[20,28]. This can be

very helpful to differentiate whether a prolonged aPTT is caused by remaining

dabigatran in the circulation, or by other factors, e.g. deterioation of

16
 hemostasis in severely ill patients (major blood loss, disseminated intravascular

coagulopathy).

Patients on dabigatran can test false-positive for the presence of a lupus

anticoagulans, and false-negative for aPC-resistance. Hence, ex vivo addition of

idarucizumab to samples of patients on dabigatran may allow to correctly

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diagnose thrombophilia or disorders of haemostasis[28].

4.4 Reversal of dabigatran in preclinical studies?

In animal studies, idarucizumab neutralized anticoagulation by dabigatran and

impacted on the outcome in several bleeding models. In a porcine polytrauma

model, idarucizumab reduced blood loss in dabigatran treated pigs and

improved outcome in a murine model of intracranial hemorrhage[29,30].

4.5 Reversal of dabigatran in healthy volunteers

As idarucizumab binds to the unbound dabigatran, there is a redistribution of

dabigatran from the extravascular compartment. Therefore, sufficient levels of

idarucizumab are required to neutralize the total body load of dabigatran. In

healthy male volunteers who were administered dabigatran 220 mg twice-

17
 daily, idarucizumab 2 gram and 4 gram prompted the immediate, complete,

and sustained reversal of dabigatran-anticoagulation[26]. Administration of 5

grams of idarucizumab provided similar results in phase I studies in elderly

healthy volunteers or volunteers with mild impaired renal function[31]. This

study identified the dose of 5 gram as the dose for further clinical

development, estimated that this dose would neutralize the total body load of
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dabigatran corresponding to the 99th percentile of dabigatran levels in the RE-

LY study.

4.6 Idarucizumab for dabigatran reversal in real-world emergency situations?

The REVERSE AD study evaluates the efficacy and safety of idarucizumab in a

prospective cohort study in patients with serious bleeding or patients who

required an urgent procedure and were prescribed dabigatran [32]. Patients

with serious bleeding or an urgent procedure are eligible if the physician judges

that reversal of dabigatran could potentially impact on the outcome of these

emergencies. There are no restrictions for eligibility. Laboratory confirmation

of the recent intake of dabigatran is not required. There are no restrictions

with respect to the use of other measures to support haemostasis[32].

18
 Idarucizumab is administered as a rapid infusion; the dose of 5 gram is

administered as 2 consecutive infusions of a 50ml vial containing 2.5 gram

idarucizumab. Blood is sampled to evaluate the reversal of dabigatran-

anticoagulation after the first and second bolus administration of 2.5 gram, and

thereafter after 1, 2 and 4 hours. Reversal up to 4 hours as assessed by the dTT

and ECT was defined as the primary outcome[27,32].

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This ongoing, prospective study will recruit up to 500 patients. An interim

analysis including the first 90 patients was recently published, including 51 who

received idarucizumab for serious bleeding and 39 who required an urgent

intervention[27].

Among patients with bleeding, intracranial hemorrhage, gastrointestinal

bleeding and trauma induced bleeding were the most frequent clinical

presentations of life-threathening bleeding. Abdominal and trauma surgery

were the most common indications for urgent surgery, though patients with

the whole spectrum of emergency procedures were represented. The median

time since last intake of dabigatran was approximately 15 hours[27].

19
 Main primary and secondary outcomes of the study are summarized in Table 4.

In 22 out of 90 patients, dTT at baseline was found to be within normal limits,

suggesting minimal residual dabigatran effect at the time of reversal. These

patients were excluded from the efficacy analysis. Across the remaining

patients, reversal of dabigatran was obtain in all but 1 patient, as assessed by

both dTT and ECT within the 4 hours after idaruciumab administration. The
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reversal of anticoagulation, assessed by the dTT below the upper limit of the

normal range, remained until 12 and 24 hours after administration of

idarucizumab in 90% of evaluable patients with bleeding and 81% of those who

underwent urgent procedures[27].

Investigator-reported time to haemostasis was obtained after a median period

of 12 hours in patients who presented with bleeding. In 33 out of 36 with an

invasive procedure, normal perioperative haemostasis was reported by the

surgeon (Table 4).

Importantly, thrombotic events occurred in 5 patients. Of five thrombotic

events, one occurred early (< 72 hours), and this was a deep vein thrombosis

with pulmonary embolism. The four other thrombotic events were 2 venous

thromboembolic events (7 and 9 days after reversal), one myocardial infarction

20
 13 days after reversal, and one stroke 26 days after reversal. None of these

patients received antithrombotic therapy at the time of the thrombotic event.

(Table 4). This illustrates that switching off anticoagulation will expose the

patient to the risks of thrombembolism. Inflammation, immobilisation and an

activated coagulation system in patients with bleeding or emergency

procedures may further increased the risk of thromboembolism. An evolving

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issue is therefore when to restart thromboprophylaxis after application of

idarucizumab.

The mortality in this study was high (18 out of 90 patients in the interim

analysis), reflecting the severity of the conditions of these emergency

situations[27].

5. Integrating idarucizumab in a bleeding management protocol

Due to the specific mechanism of action of idarucizumab, there is no indication

at all for its use in patients treated with other anticoagulants than dabigatran.

5.1 Management requires more than reversal of dabigatran by idarucizumab

The reversal of the anticoagulant effect of dabigatran should always be seen as

part of the general management of emergency situations (Figure 1).

21
 Idarucizumab only neutralizes the anticoagulant effect of dabigatran, restoring

normal hemostatic capacity provided no other disorder of hemostasis is

present. Importantly, platelet dysfunction due to concomittant use of

antiplatelet agents will not be affected by idarucizumab.

Even when hemostasis is normalized, this may not be sufficient to stop

bleeding in many cases. Supportive measures, aimed at restoring circulating

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volume and oxygen delivery capacity, local hemostatic procedures to ensure

physical control of the bleeding site are the first and most important steps in

managing these patients. Finally, in patients with concomitant platelet

dysfunction, transfusion of platelets can be required to support hemostasis.

5.2 When and how should idarucizumab be used?

In patients treated with dabigatran, reversal is only useful if there is significant

residual anticoagulant effect. Although specific and sensitive laboratory

assessment of dabigatran levels is possible using the dTT, this assay may not be

available in all hospitals. Furthermore, in many emergency situations, it is not

possible to wait for detailed laboratory tests. Therefore, dabigatran-specific

anticoagulant testing will often not be available to select candidates for

reversal.

22
 An estimate of the residual anticoagulant effect can be made taking into

account the time since last intake of dabigatran and the renal function. In

patients with normal creatinine clearance, the anticoagulant effect is expected

to be low 12h, and minimal 24h after the last dose. However, due to the mainly

renal excretion, halflife of dabigatran is significantly longer in patients with a

creatinine clearance below 30ml/min. Importantly, even in the absence of

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specific laboratory assays for dabigatran drug levels, routine clotting tests can

give a general estimate of its anticoagulant activity. Dabigatran prolongs the

aPTT. A normal aPTT suggests minimal residual anticoagulant activity of

dabigatran. Even though the aPTT may not be sensitive to exclude the presence

of low levels of dabigatran, such low levels of dabigatran are hardly an

indication for the use of idarucizumab.

If there is an indication for reversal (table 2), a 5g dose of idarucizumab can be

administered by rapid iv infusion or by bolus injection. Although at therapeutic

doses, there is a poor correlation with dabigatran levels[8], the aPTT prior to

and after reversal may hint the clinician towards the presence of dabigatran,

and the succesful reversal. Idarucizumab reverses the anticoagulatory effect of

dabigatran within minutes and a control blood sample can be drawn 5-10

minutes after the infusion of idarucizumab.

23
 The aPTT may be prolonged by other causes than dabigatran. This is especially

the case in severely bleeding patients[19], in disseminated coagulopathy, or in

the presence of a lupus anticoagulans. In these situations a prolonged aPTT is

usually not caused by a dabigatran overdose but by the underlying condition,

and other disorders of haemostasis (such as vitamin K deficiency, acquired

hemophilia, consumptive coagulopathy) should be taken into consideration,

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especially if the coagulation tests do not normalize after reversal of dabigatran.

As outlined above, in vitro addition of idarucizumab to the aPTT test might help

to differentiate between a residual dabigatran effect and other causes of a

prolonged aPTT. In the rare situation where very high concentrations of

dabigatran are measured or expected, reassessment of hemostasis may be

required to check completeness of reversal and to consider repeat dosing.

Successful reversal of dabigatran does not necessarily result in restoration of

normal hemostasis. Strict follow-up and continued treatment of the bleeding

patient is required until hemostasis is achieved. In patients exposed to different

anticoagulants, or, more frequently the case, to concomitant antiplatelet

therapy, specific reversal of dabigatran may improve, but not correct overall

hemostasis. Furthermore, correction of bleeding-induced coagulopathy by

24
 infusion of plasma or clotting factors can be required in massive

hemorrhage[19].

After management of the emergency situation, a renewed assessment of

bleeding and thrombotic risk is required.

5.3 The risk of thrombotic complications after application of idarucizumab

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With increasing clinical experience in using idarucizumab it becomes obvious

that the very high efficacy of idarucizumab in neutralizing dabigatran within

minutes bears the risk of thrombotic complications. In those patients with a

high thrombotic risk, timely restart of anticoagulants is an important

consideration.

In this regard it is an unresolved but interesting question, whether

idarucizumab should be used to neutralize dabigatran in patients with acute

stroke to allow thrombolysis. Based on theoretical considerations, the time

between application of idarucizumab and start of thrombolysis should be as

short as possible to reduce the risk of appositional thrombus growth. Patients

in this scenario have been included in the RE-VERSE trial, and further clinical

information on those patients is eagerly awaited.

25
 6. Other new reversal agents for NOACs

Ciraparantag (PER-977) is a small molecule that binds and neutralizes the effect

of several anticoagulants including NOACs.. The specificity of ciraparantag is

unknown[33,34]. In vitro it also showed reversal of dabigatran.

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Andexanet-alpha is a specific reversal agents for factor Xa inhibitors. It is a

modified inactive factor Xa that competes with factor Xa for the factor Xa

inhibitors[35] [36]. Andexanet-alpha does not reverse dabigatran.

7. Expert commentary:

For patients requiring anticoagulation, NOACs have a more favorable safety

profile as well as a more favorable pharmacokinetic profile for managing

emergency situations. Up to 25-30% of patients requiring anticoagulation for

AF are not sufficently anticoagulated. Having the possibility to precisely control

anticoagulant activity of dabigatran by idarucizumab may help to remove

barriers for anticoagulant therapy.

However, per year about 3-5 % of patients will experience major bleeding

when anticoagulated in therapeutic dose and about 10% will require invasive

interventions for comorbidities.

26
 Most of these situations can be managed without need for a reversal agent,

however, the ability to promptly switch off anticoagulant activity is likely to be

beneficial in severe bleeding situations, and certainly can allow to manage

patients requiring urgent procedures without delay.

In vitro and in vivo data show that idarucizumab allows prompt and sustained

correction of coagulation activity in dabigatran-treated patients. The results

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from the ongoing REVERSE-AD trial and the clinical use of this agent will help to

better understand the management of these situations. Although a specific

reversal agent may improve outcomes in emergency procedures, reversal of

dabigatran alone will often be not sufficient to stop bleeding or to control the

sequelae of massive blood loss. In addition, once dabigatran is neutralized by

idarucizumab appropriate measures must be taken to prevent new thrombotic

complications in high risk patients.

8. Five year view:

In the next five years, idarucizumab will become part of each hospital

emergency drug depot. In combination with the favorable pharmacokinetics of

NOACs, the additional possibility to immediately reverse the anticoagulatory

effects of dabigatran offers extremely precise control over the anticoagulant

effect. This can further improve the safety of anticoagulant treatment with

27
 dabigatran, and, importantly, can help to overcome barriers for the use of

anticoagulants. Indications for reversal are likely to evolve. Reversal of

anticoagulation offers additional therapeutic options in patients with life-

threathening bleeding, but also optimizes safety of urgent interventions.

Prompt reversal of anticoagulant activity will allow lysis treatment in acute

stroke patients, if the ongoing trials confirm safety of idarucizumab in this

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setting. In the laboratory, addition of idarucizumab to in vitro assays allows

detailed coagulation testing in patients treated with dabigatran.

9. Key issues:

• idarucizumab is only effective in reversing dabigatran

• idarucizumab is the humanized Fab-fragment of a monoclonal antibody

with high affinity for dabigatran

• its binding affinity is 300 times higher than that of something which

results in a nearly irreversible binding kinetic.

• Idarucizumab results in rapid clearance of all dabigatran from the

intravascular and extravascular space and is hereby reversing the

antithrombin effect of dabigatran within minutes.

• The therapeutic dose for reversal of dabigatran is 5 g intravenously.

28
 • The complex of idarucizumab and dabigatran is cleared via the kidneys,

in patients with renal impairment clearance is reduced but due to the

nearly your reversible binding of idarucizumab to dabigatran no rebound

effect is expected.

• Management of acute bleeding requires many more interventions than

just giving an antidote. Idarucizumab is therefore only one part of the

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management strategy in patients under anticoagulants presenting as

major bleeding.

• Idarucizumab can also be used in the laboratory to quench effects of

dabigatran on coagulation assays

• It is currently unresolved, whether it is safe to combine idarucizumab

and lysis treatment in patients with acute stroke who receive dabigatran.

Declaration of Interest

A Greinacher has recieved consultancy fees from Bayer, Boehringer, Astra-

Zeneca and GSK. He has recieved payment for lectures from Aspen, Boehringer,
NovoNordisk, Bayer Healthcare, BMS and GSK. Study support (third-party
funding) has been provided by Bayer, Boehringer and Aspen. T Vanassche
recieved speaker fees from Boehringer Ingelheim. P Verhamme received
honoraria for lectures and consultancy from Boehringer Ingelheim, Bayer,
Daiichi Sankyo, Pfizer and research support from Boehringer Ingelheim, Bayer,
Sanofi and LeoPharma. The authors have no other relevant affiliations or
financial involvement with any organization or entity with a financial interest in
or financial conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.

29
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33
 Reversal of dabigatran by idarucizumab: when and how?

Tables

Table 1 - Overview of studied and recommended doses of dabigatran in venous

thromboembolism (VTE) and atrial fibrillation.

Dose reduction Recommendations for Recommendations for dose

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Indication Studied dose

studied in clinical dose reduction (EMA) reduction (FDA)

110mg bid if

age ≥ 80year or

concomitant use of
Treatment of 150mg bid
verapamil
VTE (RE- (after 5-10 days
no dose reduction no dose reduction
COVER 1 and of parenteral
consider 110mg bid if age
2) anticoagulation)
75-80 year, moderate

renal insufficiency, or

increased risk of bleeding

110mg bid if
150mg bid no dose reduction
age ≥ 80year or

Stroke concomitant use of

75mg bid if creatinine
prevention in verapamil
clearance 15-30ml/min
non-valvular

AF consider 110mg bid if age

110mg bid no dose reduction (110mg not approved)
(RE-LY) 75-80 year, moderate

renal insufficiency, or

increased risk of bleeding

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 (110mg only approved as

reduced dose)

Table 2: Indications for specific reversal agents for dabigatran

Bleeding Intervention

No indication no residual dabigatran effect: no residual dabigatran effect:

- No recent treatment with - No recent treatment with dabigatran

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dabigatran or treatment or treatment with other

with other anticoagulant anticoagulant

- No recent intake - No recent intake

- Evidence of normal clotting - Evidence of normal clotting activity

activity

Minor bleeding Intervention can be delayed until clearance

of dabigatran

Spontaneous hemostasis or

bleeding responding well to

general measures

Possible Massive overdose or drug Intervention where delay could increase risk

indication accumulation in patients at of adverse outcome

imminent high risk of critical

bleeding

Need for intervention in patient with

compromised renal function

35
 Indication for emergency thrombolysis in

patients with ischemic stroke

Indication Life-threathening bleeding Life-threathening emergency requiring

immediate invasive intervention

Bleeding in critical organ Urgent surgery with high risk of bleeding

Major bleeding not responding to

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general measures

36
 Table 3: comparison of specific NOAC reversal agents

Idarucizumab Andexanet alpha Ciraparantag

mechanism Humanized monoclonal Modified Factor X Formation of hydrogen

Fab antibody fragment without active site or bonds to guanidine,

membrane-binding alpha amino groups,

domain amide nitrogen and

amide oxygen residues

Specific yes yes No (risk for off-target

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effects)

Spectrum dabigatran Direct Xa inhibitors Dabigatran

(rivaroxaban, apixaban, Edoxaban

edoxaban) Rivaroxaban

Indirect Xa inhibitors Apixaban

(LMWH, fondaparinux) LMWH

Unfractionated heparin

Relative affinity reversal 300:1 1:1 ?

agent and physiological

substrate

Prothrombotic effect - ? ?

halflife 6 hours 1 hour ?

Clinical development Preclinical, phase I, phase Preclinical, phase I, phase Preclinical, phase I

III III

available 2015 (expected 2018? ?

Phase III protocol Single dose, rapid iv Dose depends on Xa n/a

infusion or bolus inhibitor

Iv bolus + continued

infusion

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 Phase III patients Uncontrolled and life- Uncontrolled and life- n/a

threathening bleeding or threathening bleeding

need for urgent

procedure

Phase III – concomitant Any PCC use not allowed n/a

medication
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 Table 4: overview of primary and secondary outcomes of dabigatran reversal in the first 90
patients of the RE-VERSE AD trial.

Life-threatening bleeding Urgent procedure

N=51 N=39
Reversal
[unbound dabigatran] (ng/mL, upper limit of detection = 1ng/mL)
Prior to reversal (mean ± SD) 161±166* 218±503**
After 5g idarucizumab
(mean ± SD) 1.08±0.43* 18 ± 107**

Diluted Thrombin Time (s, upper limit of normal = 35s)

Prior to reversal (mean ± SD) 54.1±23 53.2±38
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After 5g idarucizumab
29.8±2.42 31.3±12.4
(mean ± SD)
% normalization after 5g
98% 93%
idarucizumab

Clinical Endpoints
Hemostasis
Assessable in 35 pts Surgery in 36 pts

33/36 normal
Mean time to cessation 2/36 mildly abnormal
11.4h*** 1/36 moderately abnormal
****

Mortality

overall 9/51 (17%) 9/39 (23%)

Cardiovascular 4/51 (7.8%) 6/39 (15.4%)
Cardiovascular, ≤48h 3/51 4/39
Cardiovascular, ≥48h 1/51 2/39
Thrombotic events
Overall 5/90
Day 0-3 1 (VTE)
Day 4-7 1 (VTE)
≥ 7 days 3 (VTE, NSTEMI, ischemic stroke)
* N=48
** N=39
*** as assessed by treathing physician
**** subjective evaluation of intra-operative hemostasis by surgeon
SD, standard deviation
Pts, patients
VTE, venous thromboembolism
NSTEMI, non-ST-elevation myocardial infarction
39