praxbind : pradaxa reversal agent · 5 g idarucizumab (two separate infusions of 2.5 g) hospital...

PRAXBIND®: PRADAXA®

REVERSAL AGENT

Sarai Hamodat

Emergency Department Clinical Pharmacist

QEII Center

DISCLOSURE

Nothing to disclose

OUTLINE:

Dabigatran

Reversal agents

Praxbind

What it is?

How does it work?

RE-VERSE study

Things to consider

Is it available?

Praxbind and the future of stroke patients

PRADAXA: DABIGATRAN

Direct thrombin inhibitor

Indications:

Reduce risk of stroke in AFIB

Treat / prevent DVT & PE

Risk of serious bleeds

Renal clearance

3- and 4-factor PCC, FFP, rFVIIa

Replacing coagulation factors in the blood

Reversal

Repletion

None available

• Vitamin K often misleadingly named an ‘antidote’ for VKAs

• Restores physiological clotting factor synthesis, via a slow, complex process with clinically significant variability between patients1

• INR corrects more quickly than coagulopathy

Reversing the action of the anticoagulant

Hanley et al. J Clin Pathol 2004 57:1132–39

Molecule Idarucizumab

Developed by Boehringer Ingelheim

Molecule type Humanized Antibody Fab

Target(s) Dabigatran

Binding qualities (affinity) Noncompetitive

(350x for dabigatran)

Route of administration Intravenous (5 min infusion/bolus)

PK/PD Terminal t½

Elimination:

4.5-9h

Renal

Effect: Start:

Sustained:

<5min

12-14h

Safety In volunteers:

Clinical settings:

Up to 8g

5g (Phase 3)

Off Target Effects None known

PRAXBIND: IDARUCIZUMAB

IDARUCIZUMAB MODE OF ACTION

Eikelboom et al., Circulation. 2015 Dec 22;132(25):2412-22

RE-VERSE AD: Reversal Effects of Idarucizumab on Active Dabigatran

Primary endpoint

Reversal of dabigatran activity

Secondary efficacy endpoints

Multiple safety endpoints

Group A:

Uncontrolled

bleeding +

dabigatran-treated

Group B:

Emergency surgery

or procedure* +

dabigatran-treated

N= 200 – 300(Post approvalCommitment:Extension to

N ~ 500)

0–15 minutes 90 days follow-up

0–24 hours

5 g idarucizumab

(two separate

infusions of 2.5 g)

Hospital arrival

Pre-2nd dose 2 h 4 h 12 h 24 h 30 d 90 dPre-1st dose 1 h

Blood samples~20 min

*Requires invasive procedure that cannot be delayed by 8 hours or more

Multicentre, open-label, single-arm Phase III

trial

5 g

idarucizumab(2x separate

infusions of 2.5 g)

Calculated to reverse

up to the 99th

percentile of

dabigatran levels as

measured in RE-LY

Pollack CV Jr, et al. N Engl J Med. 2015;373(6):511-20

CrCl: creatinine clearance; dTT: diluted thrombin time; ECT: ecarin clotting time.

Group A

(n=51)

Group B

(n=39)

Total

(N=90)

Male, n (%) 32 (63) 18 (46) 50 (56)

Age (yrs), median (min, max) 77.0 (48, 93) 76.0 (56, 93) 76.5 (48, 93)

CrCl (Cockcroft-Gault), n (%)

Median (min, max) 54 (16, 187) 60 (11, 171) 58 (11, 187)

<30 mL/min 5 (10) 7 (18) 12 (13)

≥30‒<50 mL/min 14 (27) 6 (15) 20 (22)

≥50‒<80 mL/min 16 (31) 11 (28) 27 (30)

≥80 mL/min 6(12) 9 (23) 15 (17)

Missing 10 (20) 6 (15) 16 (18)

Elevated dTT at baseline, n (%) 40 (78) 28 (72) 68 (76)

Elevated ECT at baseline, n (%) 47 (92) 34 (87) 81 (90)


*Two patients in Group A had ‘other’ daily dose; †In Group A, one patient was taking dabigatran for venous thromboembolism; three for

‘other’ indications.

BID: twice daily dosing.

Group A

(n=51)

Group B

(n=39)

Total

(N=90)

Daily dose of dabigatran*, n (%)

75 mg BID 1 (2) 0 (0) 1 (1)

110 mg BID 34 (67) 24 (62) 58 (64)

150 mg BID 14 (27) 15 (38) 29 (32)

Time since last dabigatran intake, n (%)

Median (hrs) 15.2 16.6 15.4

<12 hrs 17 (33) 15 (38) 32 (36)

12‒<24 hrs 21 (41) 10 (26) 31 (34)

24‒<48 hrs 12 (24) 10 (26) 22 (24)

>48 hrs 1 (2) 4 (10) 5 (6)

Dabigatran indicated for atrial

fibrillation†, n (%)

47 (92) 39 (100) 86 (96)

Baseline plasma unbound dabigatran

levels, ng/mL, median (min, max)84.4 (3.3, 641) 76.4 (4.4, 2880) –


Group A

(n=51)

Type of bleeding,‡ n (%)

Intracranial 18 (35)

Trauma 9 (18)

Gastrointestinal 20 (39)

Other* 11 (22)

Group B

(n=39)

Reason for surgery,† n (%)

Aortic dissection 1 (3)

Pericardial tamponade 1 (3)

Peritonitis 1 (3)

Acute mesenteric ischaemia with

sepsis2 (5)

Bone fractures 8 (21)

Acute cholecystitis 5 (13)

Acute renal insufficiency, catheter

placement4 (10)

Acute appendicitis 3 (8)

Joint/wound infection 3 (8)

Abscess (suprapubic, scrotal) 2 (5)*’Other’ bleeding types: urogenital, epistaxis, liver, aortic aneurism and aortic dissection. ‡Patients may have had more than one type of bleeding

†Other reasons for surgery (one patient each) were: acute deterioration of aortic valve; small bowel obstruction; pneumothorax; probable perforation of

the viscera; incarcerated umbilical hernia; lumbar puncture; left leg gangrene; unstable angina, ureteral obstruction, and hydronephrosis.

Pollack CV Jr, et al. N Engl J Med. 2015;373(6):511-20.

RE-VERSE AD™: Interim Results

Bleeding Type and Reasons for Surgery


Idarucizumab is under clinical development for the reversal of dabigatran induced anticoagulation. The efficacy and safety of this agent has not been

established and it is not available for sale in Canada.

13



Primary Endpoint: Reversal of Dabigatran Anticoagulation

with Idarucizumab based on dTT

Idarucizumab

2x 2.5 g

Dilu

ted

th

rom

bin

tim

e dT

T (

s)

130

110

70

60

50

40

30

20

120

100

90

80

1h 2h 4h 12h 24hBaseline Between

vials

10–30

min

Time post idarucizumab

Idarucizumab

2x 2.5 g

Dilu

ted

th

rom

bin

tim

e d

TT

(s)

130

110

70

60

50

40

30

20

120

100

90

80

1h 2h 4h 12h 24hBaseline Between

vials

10–30

min

Time post idarucizumab

Groupe A: Uncontrolled Bleeding Groupe B: Urgent Surgery

=> Similar results observed with Ecarin Clotting Time (ECT)

Group A

51 Patients

Surgery

performed in 36

patients **

Assessable in 38

patients

Median local investigator-

determined time to bleeding

cessation 11.4 hours*

Group B

39 Patients

Intraoperative hemostasis:

• 33 normal

• 2 mildly abnormal

• 1 moderately abnormal

Additional information on clinical outcomes will be provided by the full study data set following recruitment of the planned 500 patients

* Assessment of bleeding cessation may be difficult in internal bleeding into confined space such as intramuscular or intracranial bleeding

** Median time between first administration of idarucizumab and surgery was 1.7 (range –1.2–26.4) hours.


Secondary Endpoint Clinical Outcomes




Concomitant Blood Products Used with Idarucizumab

SAFETY

Safety Outcomes

Death 18/90 (20%)

Serious Adverse Event 21/90 (23.3%)

MI 1/90 (1%)

Stroke 1/90 (1%)

DVT/PE 3/90 (3.3%)

Age / Gender

Thromboembolic events

Time after Idarucizumab

application (days)

Reason for anticoagulation

Treatment group

Index event

75/M Deep vein thrombosis and pulmonary embolism

2 Atrial fibrillation A Gastrointestinal bleed

82/F Bilateral deep vein thrombosis 7 Atrial fibrillation B Acute cholecystitis

85/M Atrial thrombus, deep vein thrombosis and pulmonary embolism

9 Atrial fibrillation A Intracranial hemorrhage

86/F Myocardial infarction, non-ST 13 Atrial fibrillation A Intracranial hemorrhage

72/F Ischemic stroke 24 Atrial fibrillation B Infected left knee joint

None of these patients were receiving antithrombotic therapy at the time of the thromboembolic event



Thrombotic Events

THINGS TO CONSIDER:

PRECAUTION:

• Thromboembolic risk

• Re-elevation of coagulation parameters

• Hypersensitivity

• Fructose intolerance

Does not directly induce hemostasis

Can restart Dabigatran 24 hours after

administration of Praxbind

Cost ~ 3500$ per 5g dose

IS IT AVAILABLE ?

Approved in USA October 16,2015

Approved in Canada May 2016

Not available in NS yet..

Approved by Drug & Therapeutics Committee

Approved by the Central Zone Medical Advisory

Committee

Awaiting approval by the Provincial Committee

WILL IT CHANGE PRACTICE?

ANY QUESTIONS?

praxbind : pradaxa reversal agent · 5 g idarucizumab (two separate infusions of 2.5 g) hospital...

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