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 Standard therapeutic approach to many cardiovascular
 As an example, in patients with atrial fibrillation (AF),
anticoagulation is known to reduce the reported 2% to
18% annual risk of embolic stroke for patients with a
CHADS score of 1 to 6 by two-thirds [
 Until recently, warfarin has been the only available oral
anticoagulant exhibiting a positive benefit-risk profile
when the extent of anticoagulation is carefully
monitored and managed with dose adjustments.
 The global introduction of several novel oral
anticoagulants (NOACs) has recently transformed the
clinical practice of oral anticoagulation.
 Orally given Direct Thrombin Inhibitor

 Approved for
 Preventions of stroke for patients with Non valvular AF- 2012
 VTE prophylaxis post orthopedic surgeries- 2008

 Mean Half Life: 12-17hrs

 Eliminated renally

 Monitoring (Difficult) however APTT and TT

 C/I: If Creat Clearance <30mls/kg

 Less and less drug interaction than the conventional rat poison

 No agent for reverse the anticoagulant effect, yet so far

The problem
Do not know how to measure?
Cannot give in renal failure
Do not know how to reverse?
And if some one bleeds, did not know how to treat?

Despite all European Society approved the drug in

2008 for VTE prophylaxis post knee and hip
And in 2010 extended its application to stroke
prevention following non valvular AF
Dabigatran & Bleeding
 Risk of bleeding with dabigatran in atrial fibrillation
 JAMA Intern Med. 2015 Jan;175(1):18-24.
 Dabigatran was associated with a higher incidence of major
bleeding (regardless of the anatomical site),
 A higher risk of gastrointestinal bleeding, but a lower risk of
intracranial hemorrhage.

 Comparative risk of gastrointestinal bleeding with

dabigatran, rivaroxaban, and warfarin: population based
cohort study.
 BMJ. 2015 Apr 24;350:h1857
 The risk of gastrointestinal bleeding related to novel oral
anticoagulants was similar to that for warfarin.
 Caution should be used when prescribing novel oral
anticoagulants to older people, particularly those over 75 years
of age
Key question to answer was how to reverse the effect
of dabigatran?
Several studies have proven some efficacy
*Use of Activated charcoal
Arterioscler Thromb Vasc Biol. 2015;35:1736-45

*Use of PCC
Thromb Res. 2015;135:544-7.

*Use of hemofiltration
Clin J Am Soc Nephrol. 2013;8:1533-9.
Dabigatran and Bleeding

•Withhold dabigatran •Mechanical •Consider use of one of

Minor Bleeding

Major Bleeding
Moderate Bleeding
•discontinue treatment compression a) Prothrombinex-VF
as appropriate. •Surgical intervention 25-50 IU/kg b)
•Apply local measures or wound packing FEIBA 50 IU/kg
and treat any •Administer fluid c) Tranexamic acid
aggravating factors replacement to 15-30 mg/kg IV+/-
maintain good urine infusion for mucosal
output as dabigatran bleeds
is renally excreted. •Consider dialysis for
•Consider platelets if dabigatran,
levels less than 70-80 •Neither pro-
x 109/L or patient on haemostatic agents or
anti-platelet agent. dialysis improve
•Oral activated outcome in pts taking
charcoal if ingested in dabigatran with a
last two hours. normal APTT or level
of < 50 ng/mL.
•Consult Haemotology

New oral anticoagulants: a practical guide on prescription, laboratory testing and

periprocedural/bleeding management, Internal Medicine Journal 44 (2014)
Key question was, is
their a specific
Answer was yes
A humanized monoclonal antibody fragment with >350 times
the affinity for dabigatran compared to thrombin, as a specific
antidote for dabigatran-associated coagulopathy.

Phase 1 trails:
Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, and
efficacy of idarucizumab for the reversal of the anticoagulant
effect of dabigatran in healthy male volunteers: a randomised,
placebo-controlled, double-blind phase 1 trial. Lancet.

Glund S, Moschetti V, Norris S, et al. A randomised study in

healthy volunteers to investigate the safety, tolerability and
pharmacokinetics of idarucizumab, a specific antidote to
dabigatran. Thromb Haemost. 2015;113:943-51.

Glund S, Stangier J, Schmohl M, et al. Idarucizumab, a specific

antidote for dabigatran: immediate, complete and sustained
reversal of dabigatran induced anticoagulation in elderly and
renally impaired subjects. Blood. 2014;124
After phase 1 trails
FDA approved the
use of drug as
reversal agent.
TGA also followed
that in Oct 2015!!!!
Clinical Question
 The REVERSE AD study was undertaken to
examine the efficacy and safety of idarucizumab in
dabigatran-treated patients who had serious bleeding
or required urgent procedures.

 Reverse-AD (Reversal of Active Dabigatran with


 So what is this Idarucizumab?

Study Design
 RE-VERSE AD: Multicentre Prospective Cohort
 Study evaluating the efficacy of idarucizumab in
reversing the anticoagulant effects of dabigatran in
patients with serious bleeding and patients requiring an
urgent invasive procedure
 Interim analysis – ( interestingly following just phase1
release, agent has been approved for use by TGA and
 400 centers and 38 countries
 Steering committee composed of members from
academia and sponsored by Boehringer Ingelheim
Patient Selection
Adults 18yrs
and above,
Group A
• Overt life threatening bleed

Group B
• Requiring Surgery or invasive
Study Treatment
Patient received 5gm of study drug IV,
administered as 2 x 50ml boluses over 5-10mins
infusion 10mins apart

Blood samples were obtained at baseline, after
the first infusion of idarucizumab, and then
between 10 and 30 minutes and at 1, 2, 4, 12,
and 24 hours after the second infusion

2 tests conducted which included the Dilute TT

and Escarin clotting time

Monitored dabigantran level as well

End Point
Primary End-Point
• Max percentage reversal of anticoagulant effect as
determined at any point from first infusion to 4hrs after

Secondary End-Point
• Proportion of patient who had complete
normalization of dilute thrombin time or escarin time
in first 4hrs and the reduction of dabigatran level
• Clinical Outcome: Extent of bleeding, hemodynamic
instability, Severity of bleeding, ICH patient, Death
defined as vascular or non vascular
18 death overall with 9 in each group
5 fatal bleeding
2 septic shock
3 intracranial bleeding

Thrombotic events – 5 Pts

PE – 1 Pts
DVT – 1Pt

21 Adverse event



Dashed line is the upper

limit of normal range of test
 This interim analysis included 90 patients who received darucizumab (51patients
in group A and 39 in group B). Among 68 patients with an elevated dilute
thrombin time and 81 with an elevated ecarin clotting time at baseline, the median
maximum percentage reversal was 100%.

 Idarucizumab normalized the test results in 88 to 98% of the patients, an effect

that was evident within minutes.

 Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24

hours in 79% of the patients.

 Among 35 patients in group A who could be assessed, hemostasis, as determined

by local investigators, was restored at a median of 11.4 hours.

 Among 36 patients in group B who underwent a procedure, normal intraoperative

hemostasis was reported in 33, and mildly or moderately abnormal hemostasis
was reported in 2 patients and 1 patient, respectively.

 One thrombotic event occurred within 72 hours after idarucizumab

administration in a patient in whom anticoagulants had not been reinitiated.
 It works

 Ok

 TGA has approved it

 Cost is 3800
Strength of the study
 Broad inclusion criteria

 By studying these two populations and including

elderly patients, the authors mimicked the most
common use cases as closely as possible

 Additionally, 65% of the patients had mild to severe

renal function impairment, defined by a creatinine
clearance <80 mL/min; yet, the trial achieved
impressive, sustained anticoagulant reversal
 First, the time between receiving the final dabigatran dose and initiation of
idarucizumab infusion was longer than the two-hour interval studied in the
Phase 1 trials.

 Of the 90 patients, 64% had taken their last dose of dabigatran more than
12 hours prior to idarucizumab infusion. Of these, 30% had taken it greater
than 24 hours prior. Since the half-life of dabigatran is 12 to 17 hours, this
raises the question of whether patients were truly anticoagulated at the time
of idarucizumab infusion.

 The results of RE-VERSE AD indicate that prior to infusion, 68 patients

had elevated dTT, and 81 patients had elevated ECT, indicating
anticoagulation; only these patients were included in the efficacy analysis.

 However, yet another question arises: do these lab parameters accurately

measure dabigatran anticoagulant activity? Strong, conclusive data in this
area are currently lacking, as discussed previously.

 This is only an interim analysis and will have to wait for complete report