Idarucizumab for Dabigatran Reversal

Reversal Effects of Idarucizumab

on Active Dabigatran (RE-VERSE AD).

NEJM
August 6, 2015
Comparison of NEW ORAL ANTICOAGULANTS
with WARFARIN

Features Warfarin New Agents

Onset Slow Rapid
Dosing Variable Fixed
Indications Same Same
Food effect Yes No
Drug interactions Yes Yes
Monitoring Yes No
Half-life Long Short
Antidote Yes No
 Oral Anticoagulant Target Sites

Factor IX Factor VII

Factor X FVIIa
FIXa VKA drugs
Anti-FXa drugs •Warfarin
•Apixaban
•Betrixaban
•Edoxaban
•Rivaroxaban Factor Xa
•LY 517717 Antithrombin
•TAK 442

Anti-FIIa drugs
Factor II Factor IIa •Dabigatran
(Prothrombin) (Thrombin) •Ximelagatran
•AZD 0837

Fibrinogen Fibrin
Dabigatran Etexilate
• Specific, competitive, reversible univalent thrombin
inhibitor
• Pro-drug converted to active form
• Rapid onset within 2 hours
• Low protein binding
• Half life 12-17 hours
• Renal clearance as glucuronic acid conjugate: 85%
RE-LY: Study Outcomes
Efficacy
• dabigatran non-inferior to warfarin on the primary endpoint
• reduction of the incidence of stroke including
hemorrhagic and systemic embolism; p<0.001
• Dabigatran 150 mg BID was superior to warfarin on the
primary endpoint by 34%
• RR 0.66, 95% CI, 0.53-0.82; p<0.001
Safety
• No significant difference in the rate of major bleeding for
dabigatran 150 mg BID compared to warfarin
The New Oral Anticoagulants:
Similar Yet Different

• Thrombin Inhibitors:
1. Dabigatran: pro-drug, renal clearance - twice daily

• FXa Inhibitors:
1. Rivaroxaban: renal clearance - once daily
2. Apixaban: hepatic clearance - twice daily
3. Edoxaban: hepatic clearance - once daily
 The New Oral Anticoagulants:
Similar Yet Different
Dabigatran
Features Rivaroxaban Apixaban
Etexilate
Target Xa Xa IIa
Molecular Weight 436 460 628
Prodrug No No Yes
Bioavailability (%) 80 50 6
Time to peak (h) 3 3 2
Half-life (h) 9 9-14 12-17
Renal excretion (%) 65 25 80
Idarucizumab
• Idarucizumab, a monoclonal antibody fragment,
binds dabigatran with an affinity that is
350 times as high as that observed with thrombin.

• Consequently, idarucizumab binds free

and thrombin-bound dabigatran and neutralizes
its activity.
Aims & Objectives

• Prospective cohort study

• To examine the efficacy and safety of idarucizumab

for the reversal of the anticoagulant effects of
dabigatran in patients who presented with serious bleeding
or who required urgent surgery or intervention
Study
• Inclusion
 adults more than 18 years of age who were taking dabigatran.

Group
Group
B
A
required surgery or
overt, uncontrollable, other invasive
or life-threatening procedures that could
not be delayed for at
bleeding that least 8 hours and for
required a reversal which normal
agent. hemostasis was
required
Method
• Patients received 5 g of intravenous idarucizumab, as two bolus
infusions, each containing 2.5 g of idarucizumab, 15 minutes apart.
• Blood samples for were obtained
1. at baseline
2. Immediately after the first infusion
3. After second infusion
4. between 10 and 30 minutes
5. and at 1, 2, 4, 12, and 24 hours after.
 1- Reversal of Anticoagulation
(DTT , ECT)

2 - Dabigatran and Idarucizumab Concentrations

1st 2nd
Infusion Infusion 1 HR 2 HR 4 HR 12 HR 24 HR
Method
• The plasma concentrations of dabigatran were determined by means
HPLC method.
• the plasma concentrations of idarucizumab by means of enzyme
immunoassay.
1- Reversal of Anticoagulation
(DTT , ECT)

2 - Dabigatran and Idarucizumab Concentrations

Primary End Point
• The primary end point was the maximum percentage reversal of the
anticoagulant effect of dabigatran, as determined at any point from the
end of the first idarucizumab infusion to 4 hours after the second infusion

• Secondary end points included the proportion of patients who had

complete normalization of the dilute thrombin time or ecarin clotting time
in the first 4 hours and the reduction in the concentration of unbound
dabigatran.
• the percentage reversal assessed on the basis of the measurement of the
dilute thrombin time or ecarin clotting time at a central laboratory
percentage reversal

(predose test result– minimum post dose test result)

(predose test result– upper limit of the normal range)

• Calculated values of 100% or higher were interpreted as complete

reversal
. Dabigatran prolongs the thrombin time (TT), ECT
• Routine coagulation assays such as the prothrombin time, activated
partial thromboplastin time, and thrombin time do not reliably
determine levels of dabigatran anticoagulation.
• Diluted thrombin time (dTT), provides a quantitative measurement of
dabigatran plasma concentrations
• There is a clear correlation between plasma dabigatran concentration
and degree of anticoagulant effect. Dabigatran prolongs the thrombin
time (TT), ECT.
• The ECT can provide a direct measure of the activity of direct
thrombin inhibitors.
• In general, it can be assumed that these measures of anti-coagulant
activity may reflect dabigatran levels and can provide guidance for the
assessment of bleeding risk

• The dilute thrombin time and ecarin clotting time were chosen
because they are highly correlated with the concentrations of
unbound dabigatran
ECT
• Ecarin clotting time (ECT) is used to monitor anticoagulation .
• Ecarin, the primary reagent in this assay, is derived from the venom of
the saw-scaled viper, Echis carinatus.
• This assay shows no interference from prothrombin or fibrinogen in
the sample and is suitable for the measurement of all direct thrombin
inhibitors
Patient characteristics
• Group A (N = 51)
• Group B (N = 39)
• Total (N = 90)

• The median age was 77 years

• median creatinine clearance was 55 mL/min.
Clinical Characteristics
Results
• The median maximum percentage reversal in the patients in group A
and in those in group was 100% as assessed by both the dilute
thrombin time and ecarin clotting time, and reversal was evident on
the sample taken after the first infusion itself.

• Even At 12 hours and 24 hours, the dilute thrombin time was below
the upper limit of the normal range in 90% of the patients in group A
who could be evaluated and in 81% of those in group B
Time Course of the Dilute Thrombin Time before and after
the Administration of Idarucizumab.
Time Course of the Ecarin Clotting Time before and after
the Administration of Idarucizumab.
The median plasma concentration of unbound dabigatran at
baseline was 84 ng per milliliter in group A and 76 ng per
milliliter in group B

In samples obtained after the first vial of idarucizumab was

administered, the concentration of unbound dabigatran was less
than 20 ng per milliliter — a level that produces little or no
anticoagulant effect
Time Courses of Plasma Concentrations of Unbound
Dabigatran before and after the Administration of
Idarucizumab.
Time Courses of Plasma Concentrations of Idarucizumab
before and after the Administration.
Results
• Idarucizumab rapidly and completely reversed the anticoagulant
effect of dabigatran in 88 to 98% of the patients who had had
elevated clotting times at baseline

• Among the 36 patients who underwent a procedure, normal

hemostasis was reported in 92% and mild to- moderate impairment in
the remaining 8%.
• Only 1 of the 90 patients (1%) had a thrombotic event within 72 hours
after idarucizumab administration,
Discussion
• The RE-VERSE AD study was undertaken to examine the efficacy and
safety of idarucizumab in dabigatran-treated patients who had
serious bleeding or required urgent procedures.
• idarucizumab will offer a novel treatment option for patients on
dabigatran therapy experiencing life-threatening or uncontrolled
haemorrhage, or in need of emergency surgery/procedures, who
currently have no specific targeted treatment options available.

• Most hospitals lack tests for the rapid assessment of dabigatran

levels.
strengths of study
• the broad inclusion criteria, simple study design,
• and confirmation that normalization of the results of the coagulation
tests reflected dabigatran reversal by determination of the
concentrations of unbound drug.
Limitation
• The major limitation is the lack of a control group.
• Phase IV trials yet to be done
• Post Approval Studies with Wider Population Groups Not done
FDA approves Praxbind
the first reversal agent for the anticoagulant
Pradaxa

based on REVERSE AD TRIAL

October 16, 2015

Idaracuzimab
• humanized monoclonal antibody fragment (Fab) indicated in patients
treated with dabigatran when reversal of the anticoagulant effects of
dabigatran is needed.

• Mechanism of Action
• binds to dabigatran with higher affinity than the binding affinity of
dabigatran to thrombin, neutralizing their anticoagulant effect.
• recommended dose is 5 g, as two separate vials each containing
2.5 g.
 Idaracuzimab
• No dose adjustment is required in renal impaired patients.

• Onset Of Action – IMMEDIATE

• Duration Of Action– 24 hrs.

Future
• A reversal agent (Andexanet) is in development for Xarelto
(Rivaroxaban)