©ORUEN LTDCNS 2019: 5:(1). JULY 2019 34

Introduction: Keeping pace with advances in anticoagulationMore than 30 million people globally are estimated to have

atrial fibrillation.1 The presentation of data with dabigatran

in 2009 in the Evaluation of Long Term Anticoagulant

Therapy (RE-LY) study introduced the modern era of stroke

prevention in patients with AF using direct oral anticoagulant

agents. Approval of dabigatran was achieved in 2010 in

the US and in 2011 in Europe, and since then other novel

oral anticoagulant agents (NOACs) have been approved,

including rivaroxaban, apixaban, and edoxaban.2-5 The 2015

approval of idarucizumab for dabigatran specific reversal

is another landmark development in the NOAC field, as is

the recent approval for andexanet–alpha as a reversal agent

for factor Xa-inhibitors. NOACs address many of the limita-

tions associated with using vitamin K antagonists, including

the narrow therapeutic window and the need for frequent

monitoring with warfarin; warfarin’s slow onset and offset

of action, its variability in dose response; and the increased

risk of intracranial hemorrhage (ICH) with warfarin.4-9

However, clinical practice challenges persist. Registries and

observational data consistently show that NOAC therapy is

underused in eligible patients and in some countries aspirin

is still used in patients who are eligible for OAC therapy.

In addition, reduced NOAC doses are sometimes used in

clinical practice in patient populations that were not tested

in clinical trials.10-13 In addition, in emergency situations

when anticoagulation needs to be removed quickly, it

Received – 16 July 2019; Accepted – 19 July 2019

Abstract The global burden of atrial fibrillation remains high. The approval of several novel oral anticoagulant agents (NOACs) as well as of idarucizumab for dabigatran reversal and andexanet-alpha for factor Xa-inhibitors represent landmark developments in the NOAC field. Although NOACs have also shown a positive net clinical benefit, even in patients with one additional stroke risk factor, clinical practice challenges persist. NOAC therapy is often underused in eligible patients despite clear recommendations in international guidelines. Moreover, it remains challenging to implement appropriate strategies for reversing NOACs in emergency settings. A symposium, How NOAC Selection and Reversal Can Help Protect Our Patients: Your Questions Answered, was held during the 5th European Stroke Organization Conference in May 2019 in Milan, Italy. This symposium reviewed advances in anticoagulation, including: NOAC selection; dosing strategies; evidence concerning anticoagulation reversal strategies; and strategies for using reversal agents before surgery, in patients with intracerebral hemorrhage, and in patients presenting with ischemic stroke prior to thrombolysis.

KEYWORDS: ATRIAL FIBRILLATION; ICH; NOACS; DABIGATRAN; REVERSAL AGENTS; IDARUCIZUMAB

How NOAC Selection and Reversal Can Help Protect Our Patients: Your Questions Answered

Corresponding author: James Coe – editor@oruen.com

Acknowledgements: Manuscript preparation provided by Thistle Editorial, LLC

Disclaimer: The views and opinions expressed in this article are not necessarily endorsed by Oruen Ltd or Thistle Editorial LLC.

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HOW NOAC SELECTION AND REVERSAL CAN HELP PROTECT OUR PATIENTS: YOUR QUESTIONS ANSWERED

patient populations. This dosing distinction is important.

The 150 mg—and most effective dabigatran dose—the

only NOAC associated with significant reduction in both

all stroke and ischemic stroke. This dose is also associated

with reduction in cardiovascular mortality, comparable major

bleeding, and a dramatic reduction in ICH. As the worst

complication of anticoagulation, this dramatic reduction

in ICH makes NOACs especially appealing to neurolo-

gists. The 110 mg BID dabigatran dose is associated

with ischaemic outcomes that are similar to warfarin, but

significant reductions in both major bleeding and also in

ICH. A post-hoc outcomes analysis of RE-LY according to

the European Union (EU) label, which allows for age-based

dose reduction to 110mg bid, showed reduced major

bleeding, life threatening bleeding, ICH, and mortality but

still significant stroke prevention vs warfarin.17

Both dabigatran doses also have efficacy in the secondary

prevention setting with patients who have had a transient

ischemic attack (TIA) or stroke.18 Bleeding rates in patients

with prior TIA or ischemic stroke also remains a concern.

This patient population is typically older, frail, at risk for

falls, and polypharmacy is a problem; therefore, the safety

of a drug regimen in stroke patients is important. Compared

with warfarin, dabigatran at either dose of 150mg or 110mg,

apixaban, and edoxaban all show significantly improved

safety profiles and a non-significant trend was seen with

rivaroxaban. In general, NOACs have demonstrated greater

safety than warfarin in patients with a previous stroke and

TIA.

remains challenging to implement appropriate strategies for

reversing NOACs.14

A symposium, How NOAC Selection and Reversal Can Help

Protect Our Patients: Your Questions Answered, was held

during the 5th European Stroke Organization Conference in

May 2019 in Milan, Italy. This symposium reviewed advances

in anticoagulation, including: NOAC selection; dosing

strategies; evidence concerning anticoagulation reversal

strategies; in patients with intracerebral hemorrhage, and in

patients presenting with ischemic stroke who may require

thrombolysis.

The evidence for dabigatranNOAC Safety and Efficacy Profiles in Patients with AF

A wealth of results from both randomized controlled trials

(RCTs) and real-world analyses consistently demonstrate

the safety and efficacy profiles of dabigatran in patients

with AF and show improved outcomes for patients with AF

compared with INR-adjusted warfarin. In the pivotal clinical

trials of NOACs, all showed favorable profiles as compared

to warfarin. Notably, all of the NOACs are associated with a

dramatic reduction in ICH (Figure 1).

The RE-LY trial is the only trial to evaluate two independent

fully randomized doses that were subsequently both

approved.2 The ARISTOTLE and ROCKET AF trials for

apixaban and rivaroxaban,15,16 respectively, included a dose

reduction as an addition to the standard dose in pre-defined

Figure 1. Outcomes associated with NOACs

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NOACs in Embolic Stroke of Undetermined Source

In addition to the pivotal clinical trials in AF, other clinical

studies have tested NOACs in the neurology setting.

The recently published RE-SPECT ESUS trial compared

dabigatran to aspirin in patients with recent embolic stroke

of undetermined source.19 RE-SPECT ESUS provides the only

comparison for dabigatran with aspirin in stroke patients

that do not have AF. When dosed in keeping with the EU

label, dabigatran had a similar safety profile as aspirin in this

population of stroke patients (Figure 2).

No significant difference was evident in the risk of major

bleeding with dabigatran versus aspirin. Aspirin is generally

considered a benign drug. Although the RE-SPECT ESUS

trial was not comprised of an AF population, the similarity

in major bleeding risk between dabigatran and aspirin

provides reassurance for neurologists as they discuss AF with

their patients.

In contrast to RE-SPECT ESUS, the RE-SPECT CVT trial

involved a very different patient population.20 RE-SPECT

CVT included younger people with sinus thrombosis (a form

of venous thromboembolism) treated with anticoagulation

approximately for six months. Though this trial only enrolled

120 patients, 60 in each group, this is the largest randomized

trial performed so far in this indication. The risk of major

bleeding between dabigatran and warfarin was similar,

though the number of outcome events was small. The risk

of clinically relevant but non-major bleeding was negligible

and the risk for any bleeding was the same in both groups.

The risk of worsening ICH was very low in both groups.

Real world studies provide additional data about how NOACs

are being used in everyday clinical practice. These studies

take their information from sources such as health insurance

databases and are not as robust as clinical trials; however,

such studies have the advantage of being able to include

large number of patients and also potentially those not

included in clinical trial populations. Such studies, provide

considerable evidence for the safety profile of dabigatran

in a wide range of practice settings and consistently

demonstrate that dabigatran has a similar or better safety

profile compared with VKAs in terms of major bleeding; less

major bleeding and ICH compared with rivaroxaban; and

Figure 2. RE-SPECT ESUS Safety Profile19

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Vitamin K

l  Specific for VKAs

l  Slow acting (4 to 6 hrs even if administered IV)

l  Clinically significant variability between patients

l  Not a true reversal agent as it does not counter the effects of warfarin, but merely allows production of depleted coagulation factors

(a)PCC, rFVIIa (or FFP)

l  Act by repletion of coagulation factors in the blood

l  Not approved for NOAC reversal

l  Limited clinical data

l  Prothrombotic risk

l  FFP: can be used for fluid repletion but concerns about large volumes required for coagulation factor supplementation

Figure 3. Previous options for OAC reversal8,30

Although vitamin K is available for vitamin K antagonists, it

is slow acting. This agent requires at least 4 to 6 hours, even

if administered intravenously (IV), with total effects occurring

in approximately 24 hours. Vitamin K is associated with

clinically significant variability between patients. Vitamin K

is not considered a true reversal agent as it does not directly

interact with warfarin but counters its effects by allowing

the resumption of the production of vitamin K-dependent

coagulation factors. Activated prothrombin complex

concentrate (aPCC), prothrombin complex concentrate

(PCC), recombinant Factor VII (rFVIIa), and to some extent

frozen fresh plasma (FFP), act by repletion of coagulation

factors in the blood, thereby replacing the depleted vitamin

K-dependent coagulation factors.30 However, these products

are not approved for NOAC reversal, are associated with

prothrombotic risk, and are supported by limited clinical

data. FFP can be used for fluid repletion but concerns have

emerged about the large volumes required for coagulation

factor supplementation.

similar ICH to apixaban.21-26 Analysis of data from the large,

global GLORIA registry of AF patients treated with antico-

agulation also supports the long-term safety of dabigatran

in routine clinical practice.27

While NOACs have been shown to reduce the risk of stroke

in patients with AF, use of these agents does not eliminate

the risk. Thus some AF patients treated with NOACs still

experience stroke due to non-thrombotic related causes,

such as carotid disease, intracranial disease, or small vessel

disease or to uncontrolled hypertension or frequently also

to non-compliance. NOAC failure in many patients is often

associated with suboptimal anticoagulation. Retrospective

analysis of data from the Get with the Guidelines Stroke

Program in the United States (US) found that a majority of

AF patients who have a stroke are not being treated with

any medications, are being treated with aspirin, are not

therapeutic on warfarin, or are underdosed on their novel

anticoagulant.28 The gravitation of clinicians towards lower

NOAC doses may reflect an inherent fear of bleeding;

however, underdosing can harm patients by leading to an

increased risk of stroke. For instance, analysis of Danish

registry data found that compared with warfarin, lower doses

of apixaban and rivaroxaban were associated with similar

rates of ischemic stroke/SE, hemorrhagic stroke, and any

bleeding, but higher risk of death. In contrast, compared

with warfarin, lower-dose dabigatran (110 mg BID), which

was tested as a standalone arm in the randomized RE-LY

trial, was associated with similar rates of ischemic stroke/SE

and death and lower rates of hemorrhagic stroke and any

bleeding.29

EVIDENCE FOR NOAC REVERSAL STRATEGIESCharacteristics of Historically Available Reversal Options

Patients being treated with anticoagulants may experiencing

bleeding for a variety of reasons, such as fractures, trauma,

acute renal failure, that requires an emergency intervention.8

In high-risk AF patients, other reasons for bleeding include

thrombolysis for acute ischemic stroke, intracranial hemorr-

haging, urgent cardiac surgery, and complications of percuta-

neous coronary intervention (PCI) or AF ablation. Historically,

few options have been available for reversal of oral anti co-

agulants (Figure 3).

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patients, with immediate, complete, and sustained reversal

of effect of anticoagulation reversal (Figure 4).

The median time to bleeding cessation among Group A

patients who could be assessed was 2.5 hours. The median

time from first vial to procedure initiation was 1.6 hours in

Group B and hemostasis was normal in >90% of patients

during their surgery or procedure. At 90 days, 6.3% and

7.4% of Group A and Group B patients, respectively, had a

thrombotic event. Idarucizumab has no contraindications, is

easy to use via infusion or IV injection, and is widely available

in more than 8,500 hospitals worldwide. Anticoagulation with

dabigatran can be restarted within 24 hours and heparin can

be initiated at any time. Post-marketing surveillance data

(RE-VECTO) show that idarucizumab performs well in clinical

practice, is consistent with use in the clinical trial, and no

new safety signals were observed.33

Andexanet Alfa

Andexanet alfa is a recombinant Factor Xa modified to lack

catalytic activity, but still capable of binding to factor Xa

inhibitors. It acts as a reversal agent for all direct specific

factor Xa inhibitors, fondaparinux, low molecular weight

heparin, and unfractionated heparin.34 Andexanet alfa

binds reversibly to factor Xa and thus is most effective when

given as an infusion.35,36 Andexanet alfa requires reconsti-

tution prior to IV administration by bolus and continuous

2-hour infusion. This agent has

a short half-life and transient

procoagulant signals have been

observed. The 2019 ANNEXA-4

trial evaluated reversal of factor

Xa inhibitors, including rivaro-

xaban and apixaban, in patients

with acute major bleeding

within 18 hours after ingesting

their last dose.36 All patients

(n=352) received an andexanet

bolus followed by a 2-hour

infusion and were evaluated

for changes in measures of

anti-factor Xa activity as well

as clinical hemostatic efficacy.

Following bolus admini-

stration, median anti-factor Xa

activity decreased by 92% from

Idarucizumab: A New Era in Reversal

In 2015, idarucizumab was approved for rapid reversal

when the anticoagulant effects of dabigatran is required

for emergency surgery, urgent intervention, or in life-thre-

atening or uncontrolled bleeding.31 Idarucizumab is a

humanized antigen-binding fragment, that binds both free

dabigatran and dabigatran bound to thrombin. There are no

known off-target effects and idarucizumab does not reverse

heparins or any other anticoagulants. Its binding affinity for

dabigatran is approximately 350 times higher than that of

dabigatran for thrombin. Idarucizumab is administered IV

with immediate onset of action. It has a short half-life and is

not associated with intrinsic procoagulant or anticoagulant

activity.

The RE-VERSE AD trial enrolled patients requiring urgent

surgery and patients with life-threatening bleeding (n=503).32

This multicenter, prospective, open-label, single-arm Phase

III study included patients with life threatening bleeding

(Group A) and patients who required emergency surgery

or procedures (Group B). Patients received idarucizumab

at hospital arrival. The primary endpoint was complete

dabigatran reversal within 4 hours of idarucizumab admini-

stration. The secondary endpoints at follow-up were

hemostasis within 24 hours (Group A), and hemostasis during

procedure (Group B), and thrombotic events, and mortality

in 90 days in all patients. Results showed efficacy for all

Figure 4. RE-VERSE AD efficacy of idarucizumab in patients with life-threatening bleeding (Group A) and requiring surgery (Group B)32

Group A Group B

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normalizing levels of anticoagulant activity, controlling

blood pressure, and all this treatment should be initiated

rapidly. Strategies for achieving these goals do not differ

among different NOACs or OACs. ICH is a rare compli-

cation associated with NOACs, with clinical trials for NOACs

showing an improvement over warfarin, but still an annual

residual risk of approximately 0.5% for ICH and approxi-

mately 3% per year for major bleeding.2,4,5,15

A subanalysis of 98 ICH patients treated with dabigatran in

the RE-VERSE AD study, which represented 32.6% of the full

trial cohort, suggests a rapid-acting benefit for idarucizumab

in the management of such patients.32 Complete reversal

of the diluted thrombin time and ecarin clotting time was

observed in 100% and >90% of evaluable patients, respec-

tively after the administration of idarucizumab. The diluted

thrombin time was reversed to normal levels, and none

of these patients required two doses of idarucizumab.39

Mortality was 16.4%, which is lower than mortality observed

in the RE-LY study.40

Results from a retrospective national case series study

provide additional clinical insight in the use of idarucizumab

in patients treated with dabigatran who present with ICH

(Figure).41

Forty patients presented with signs of stroke at 59 stroke

centers in Germany; 27 patients presented with ICH, 11

baseline in both groups. Twelve hours after infusion, clinical

haemostasis was adjudicated as excellent or good in 82% pf

patients. At 30 days, thrombotic events had occurred in 10%

of patients (Figure 5).36

Andexanet alfa is currently approved in Europe and the US

for the reversal of rivaroxaban and apixaban in patients with

life-threatening or uncontrolled bleeding;37 however, this

agent is associated with some challenges in clinical practice

including its limited availability, the lack of approved anti-FXa

assays, and the lengthy time required for preparation and

administration.38

In summary, it is important to consider the characteristics of

NOAC reversal agents when selecting initial OAC therapy.

Idarucizumab provides immediate, sustained, and predic-

table reversal of dabigatran’s anticoagulant effect, it is easy

to use, widely available, and has no contraindications, no

procoagulant effect. Andexanet alfa provides reversal of

apixaban and rivaroxaban but it is not approved for use in

patients requiring surgery or procedures.

MANAGING DABIGATRAN AND IDARUCIZUMAB IN NEUROLOGICAL EMERGENCIESBleeding Reversal in ICH

Treatment goals for patients who present with OAC-

associated ICH include preventing hematoma growth,

Figure 5. Reversal of Rivaroxaban or Apixaban in Patients with Bleeding

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no contraindications. Andexanet alfa provides reversal of

apixaban and rivaroxaban, although it is not approved for

use in patients requiring surgery or procedures. Finally, an

ICH subanalysis of RE-VERSE AD showed that idarucizumab

provides immediate reversal of dabigatran anticoagulation

for patients with ICH, which was supported by a growing

body of clinical practice data. In patients with acute

ischemic stroke, idarucizumab can be administered prior

to IV thrombolysis in dabigatran-treated patients. The wide

availability of this rapid-acting specific reversal agent for

dabigatran adds further support to the safety and efficacy

profile of dabigatran.

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