This document provides an overview of novel oral anticoagulant (NOAC) reversal agents praxabind and andexanet alfa. It summarizes results from the RE-VERSE AD trial evaluating praxabind's effectiveness in reversing dabigatran's anticoagulant effects in patients with serious bleeding or needing urgent procedures. It also summarizes results from the ANNEXA-A and ANNEXA-R trials evaluating andexanet alfa's effectiveness in reversing apixaban and rivaroxaban's effects in healthy volunteers. Both agents demonstrated immediate reversal of anticoagulation based on coagulation assays. However, their ability to predictably resolve bleeding in patients requires further study. Future research

1. Novel Oral Anticoagulant (OAC)
Reversal Agents
Alexander Mok
EPE-2 Pharmacy Student
June 2, 2016

2. Today’s Learning Objectives
• Briefly review the coagulation pathway and NOAC
pharmacology
• Describe the current limitations of NOAC uses
• Describe the pharmacology behind the NOAC reversal
agents (praxabind, andexanet alfa)
• Evaluating the literature on NOAC reversal agents by
using PICO to analyze the study objectives, population,
interventions, comparator, outcomes, and limitations
– RE-VERSE AD Trial (Praxabind)
– ANNEXA-A and ANNEXA-R trials (Andexanet)
• Discuss future directions for the reversal agents

3. Coagulation Pathway

4. NOACs vs Warfarin
Study Drug vs
Warfarin
Dabigatran
(RE-LY)
150mg BID
110mg BID*
Rivaroxban
(ROCKET-AF)
20mg QD
15mg QD*
Apixaban
(ARISTOTLE)
5mg BID
2.5mg BID*
Edoxaban (ENGAGE-
TIMI-AF 48)
60mg QD
30mg QD*
Stroke or
Systemic
Embolism
150mg: ↓
Non-inferior
↓
60mg: ↓
110mg: Non-inferior 30mg: Non-inferior
Major Bleeding
150mg: No
difference
No difference, but
demonstrated
superiority over
warfarin for fatal
and critical bleeds
↓
60mg: ↓
110mg: ↓ 30mg: ↓
GI Bleeding 150mg: ↑ ↑ No difference
60mg: ↑
30mg: ↓
ICH ↓
Mortality NS NS ↓ ↓

5. Limitations of NOACs
• Less clinical experience with NOACs1,2
– vs. 60 years of warfarin experience
• Measurement issues1,3
– Not widely available in clinical settings
• ECT, DTT  Dabigatran
• Anti-Factor Xa  Rivaroxaban or Apixaban
• No established reversal agents4,11
– Lack of guidance in emergency surgery or major
bleeding due to NOAC use

6. Andexanet Alfa
Idarucizumab
(Praxabind)
Reversal Agents on Coagulation
Pathway

7. Idarucizumab (Praxabind)1,5,9,10
• Monoclonal, humanized
antibody fragment
• Mimics thrombin (Factor II)
• Binds exclusively to
dabigatran (both free
dabigatran and
thrombin/Factor II-bound
dabigatran)
– Binding affinity for dabigatran
is 350X higher than
dabigatran’s affinity for
thrombin
• Complex is then eliminated by
kidneys

8. Andexanet Alfa1,6
• Recombinant modified human
Factor Xa decoy protein
• Catalytically inactive
• Binds to Factor Xa inhibitors in
their active site
• Enhances the activity of
endogenous factor Xa and
attenuates levels of
anticoagulant activity
• Half-life: ~1 hour

9. Current Status of Reversal Agents7
Praxabind

10. RE-VERSE AD1,5: Reversal Effects of
Idarucizumab on Active Dabigatran
• Study Objective:
– To determine the safety of idarucizumab
(praxabind) in those who have serious bleeding or
required an urgent procedure for those on
dabigatran

11. RE-VERSE AD
• Population:
90 patients (18 y.o. or older on
dabigatran) across 184 sites in 35
countries
Group A (n = 51): Those
with overt,
uncontrollable, or life-
threatening bleeding
(judged by the clinician)
Group B (n = 39): Those
who required surgery or
other invasive
procedures that could
not be delayed for at
least 8 hours and for
which normal hemostasis
was required

12. RE-VERSE AD
• Intervention:
– Total dose of praxabind 5g administered IV as two
bolus infusions (no more than 15 mins apart),
each bolus containing 2.5g praxabind
• Comparison:
– No control group as it was deemed unethical by
the authors to randomly assign patients to receive
placebo or no active treatment

13. RE-VERSE AD
• Outcomes:
– Efficacy Endpoints:
1° Outcomes (% Reversal of anticoagulant effect)
• Maximum reversal of anticoagulant effect of dabigatran based on
central laboratory determination of dTT (dilute thrombin time) or ECT
(ecarin clotting time), at any time between the end of the first infusion
to 4 hours after the last infusion
2° Outcomes (Clinical resolution of bleeding)
• Group A: Extent of bleeding and hemodynamic stability at 10 and 30
mins, 1, 2, 4, 12, and 24 hrs after 2nd infusion or when deemed
appropriate
• Group B: Hemostasis during the intervention was classified by the
physician as normal or abnormal (on a scale of mild, moderate or
severe) intra-operatively and 24 hrs post-surgery

14. RE-VERSE AD
• Outcomes:
– Safety Endpoints:
Adverse Events (Thrombotic Events or Death)
• Thrombotic events or deaths occurring from the time of idarucizumab
infusion to 90 days after, with deaths classified as vascular (including
bleeding) or nonvascular in origin

15. RE-VERSE AD
Baseline Characteristics
Parameter Group A (n = 51) Group B (n = 39)
Median Age 77.0 76.0
Sex 63% male 46% male
Median Weight (kg) 70.5 73.0
Mean CrCl (ml/min) 59 65
Dose of Dabigatran
• 150mg BID
• 110mg BID
• 75mg BID
• Other
• 27%
• 67%
• 2%
• 4%
• 38%
• 62%
• 0%
• 0%
Indication of Dabigatran (AFIB) 92% 100%
Median Time since last dabigatran dose
(hrs)
15.2 16.6
Elevated DTT at baseline (%) 78% 72%
Elevated ECT at baseline (%) 92% 87%
Type of Bleeding (%)
• ICH
• Trauma-related
• GI
• Other
• 35%
• 18%
• 39%
• 22%
N/A

16. RE-VERSE AD: 1° Outcome (% Reversal
of anticoagulant effect) in Group A
DTT in Group A ECT in Group A
2nd infusion 2nd infusion

17. RE-VERSE AD: 1° Outcome (% Reversal
of anticoagulant effect) in Group B
DTT in Group B ECT in Group B
2nd infusion 2nd infusion

18. • Data was normalized using this equation:
% Reversal =
– Median Maximum percentage reversal in patients
in group A and in those in group B was 100% for
both DTT and ECT, as seen after the first infusion
RE-VERSE AD: 1° Outcome (% Reversal
of anticoagulant effect)

19. • Out of the 90 patients analyzed:
– 31 patients (34%) had DTT or ECT values WNL at
baseline
– These patients were enrolled and given praxabind
because they fit the inclusion criteria, but were
excluded from efficacy analysis because baseline
clotting tests were within WNL
RE-VERSE AD: 1° Outcome (% Reversal
of anticoagulant effect)

20. RE-VERSE AD: 2° Outcome (Clinical
Resolution of Bleeding)
Patients that continued to Bleed
Type of Bleeding # of Patients (n =
13)
ICH 5
GI 4
Intramuscular 2
Pericardial 1
Retroperitoneal 1
Group A: Time to Cessation of Bleeding within 24
hours (n=51)
Remainder of Patients that
Stopped Bleeding (n = 38)
Median Time to Cessation for
Bleeding
11.4 hours

21. RE-VERSE AD: 2° Outcome (Clinical
Resolution of Bleeding)
Category of Hemostasis # of Patients (n = 39)
Normal 33 (92%)
Mildly Abnormal 2
Moderately Abnormal 1
Other 3
- 1 patient  idarucizumab obviated
need for emergency dialysis who
had ingested too much dabigatran
- 2 patients  despite full reversal,
patients were too unstable for
surgery
Group B: Occurrence of Major Bleeding
intraoperatively and up to 24hrs post-surgery

22. RE-VERSE AD: Adverse Events (Deaths
or Thrombotic Events)
Deaths Thrombotic Events
Total Number 18 in total 5 in total
Sub-categorized
into:
9 in Group A
9 in Group B
1 DVT + PE two days after Tx
1 DVT + PE + Left Atrial
Thrombus nine days after Tx
1 DVT seven days after Tx
1 NSTEMI thirteen days after
Tx
1 ischemic stroke twenty-six
days after Tx
10 deaths were due to
vascular causes, including 5
fatal bleeding events
9/18 deaths within 96 hrs
after treatment appear to be
related to the index event (2
septic shock, 3 ICH, 1
multiorgan failure, 1
hemodynamic collapse, 1
respiratory failure, 1 cardiac
arrest)

23. RE-VERSE AD
• Consider that:
– REVERSE-AD is still an ongoing trial
– Calculations are not all published
– Difficult study design

24. Limitations of RE-VERSE AD
• Lack of a control
• Inclusion criteria and bleeding outcomes are subjective,
due to judgements made by clinician
• Statistical analyses are descriptive
• Small sample size (n = 90, planned for 200-300; 34% were
removed from efficacy analysis)
• Mortality rate is 20% (n = 18/90) and 5.6% for thrombotic
events (n = 5/90)
• Correlation between prompt reversal and bleeding
cessation after 11.4 hours in Group A
• 56% of patients used blood products, which is only
reported in the supplemental appendix

25. Limitations of RE-VERSE AD
• Indications for patients in Group B undergoing surgery are
in the supplemental appendix
– Uncertain the type of surgeries were carried out, how
long they lasted
• 18% of the data on baseline renal function is
missing
• Many hospitals lack these tests for rapid assessment of
dabigatran levels

26. Summary of RE-VERSE AD
• 1st trial that looked at the reversal of dabigatran by
praxabind in those who were bleeding or undergoing
surgery
• Praxabind demonstrates immediate reversal of dabigatran’s
effects by time reductions of DTT and ECT
• However, reductions of DTT and ECT do not translate to
predictable times for clinical resolution of bleeding
• Remains to be seen if both the mortality and thrombotic
rates are attributable to praxabind or the patient’s index
event

27. ANNEXA-A and ANNEXA-R1,6
• Andexanet Alfa, a Novel Antidote to the
Anticoagulation Effects of FXa Inhibitors Apixaban
(ANNEXA-A) and Rivaroxaban (ANNEXA-R)
– 2 parallel trials
• Study Objective:
– To determine the efficacy and safety of andexanet alfa
for the reversal of anticoagulation with apixaban or
rivaroxaban in older healthy volunteers

28. ANNEXA-A and ANNEXA-R
• Population:
145 healthy volunteers years of age 50-75
ANNEXA-A (n = 65): given
apixaban
ANNEXA-R (n = 80): given
rivaroxaban

29. ANNEXA-A and ANNEXA-R
• Intervention and Comparison:
Step ANNEXA-A ANNEXA-R
Randomization
to andexanet or
placebo
allocation
3:1 2:1
Anticoagulant Apixaban 5mg BID for 3.5 days Rivaroxaban 20mg QD for 4 days
Intervention
Patients receive
either:
• Part 1
OR
• Both Parts 1
and 2
Part 1:
On day 4, 3 hours after last dose of
apixaban  andexanet 400mg IV bolus
(30mg/min)
Part 2:
Followed by continuous infusion of
4mg/min for 2 hours (480mg in total)
Part 1:
On day 4, 4 hours after last dose of
rivaroxaban  andexanet 800mg IV
bolus (30mg/min)
Part 2:
Followed by continuous infusion of
8mg/min for 2 hours (960mg in
total)
The dose for andenaxat is higher that in ANNEXA-A because of the higher initial maximum plasma
concentration and larger volume of distribution of rivaroxaban

30. ANNEXA-A and ANNEXA-R
• Outcomes:
– Efficacy Endpoints:
1° Outcome (% Reversal of anticoagulant effect)
• Percent change in anti-factor Xa activity from baseline
(before andexanet or placebo administration) to nadir
(after administration)

31. ANNEXA-A and ANNEXA-R
• Outcomes:
– Safety Endpoints:
Adverse Events
• Symptomatic thrombosis and bleeding
• Drug-related adverse events
• Safety outcomes were assessed on days 15, 36, and 43
after administration of the study drug

32. ANNEXA-A and ANNEXA-R
Baseline Characteristics
• Age, BMI, CrCl  generally similar
• Sex (39% were women from both trials)
• Race (varies; white is more predominant in all
arms of the trials)

33. ANNEXA-A: 1° Outcome (% Reversal of
anticoagulant effect)
Apixaban, Andexanet Bolus Apixaban, Andexanet Bolus + Infusion

34. ANNEXA-R: 1° Outcome (% Reversal of
anticoagulant effect)
Rivaroxaban, Andexanet Bolus Rivaroxaban, Andexanet Bolus + Infusion

35. ANNEXA-A & ANNEXA-R: 1° Outcome
(% Reversal of anticoagulant effect)

36. ANNEXA-A and ANNEXA-R
Adverse Events
• No serious or severe adverse events or thrombotic events reported

37. ANNEXA-A and ANNEXA-R
• Limitations:
– Different doses of andexanet are required depending
on the FXa inhibitor used
– Patients who require urgent reversal of factor Xa
inhibition activity due to bleeding or for emergency
surgery were excluded (ANNEXA-4 will address this)
– Unsure on the extent of duration of infusion to
achieve hemostasis
– Limited baseline demographics (doesn’t mimic real-
life situations)

38. Summary of ANNEXA-A and ANNEXA-R
• Trial looked at the efficacy and safety in reversal of apixaban or
rivaroxaban by andexanet alfa in healthy volunteers
• Andexanet demonstrates immediate reversal of apixaban’s or
rivaroxaban’s effects by time reductions of anti-factor Xa activity
over placebo
– Andexanet bolus + infusion allows for greater time reductions compared
to bolus alone
• However, this effect has not yet assessed if it can translate to
predictable times for clinical resolution of bleeding (will be
addressed by ANNEXA-4)
• Safety-wise there were no serious or severe adverse events or
thrombotic events reported

39. Future Directions for Reversal Agents1
• As indicated by RE-VERSE AD study, it is
challenging to design studies for these agents
in patients with critical bleeds
• Cost/Convenience of agents
• Mortality and morbidity have still yet to be
assessed in trials as primary outcomes
• Exact timing of usage for these drugs is not yet
established
• Rebound anticoagulation

40. References
1. Tummala, R., Kavtaradze, A., Gupta, A. and Ghosh, R.K., 2016. Specific antidotes against direct oral
anticoagulants: A comprehensive review of clinical trials data. International journal of cardiology, 214, pp.292-
298.
2. Weitz, J.I., Semchuk, W., Turpie, A.G., Fisher, W.D., Kong, C., Ciaccia, A. and Cairns, J.A., 2015. Trends in
Prescribing Oral Anticoagulants in Canada, 2008–2014. Clinical therapeutics, 37(11), pp.2506-2514.
3. Siegal, D.M. and Crowther, M.A., 2013. Acute management of bleeding in patients on novel oral
anticoagulants. European heart journal, 34(7), pp.489-498.
4. Tran, H.A., Chunilal, S.D., Harper, P.L., Tran, H., Wood, E.M. and Gallus, A.S., 2013. An update of consensus
guidelines for warfarin reversal. Med J Aust, 198(4), pp.198-199.
5. Pollack Jr, C.V., Reilly, P.A., Eikelboom, J., Glund, S., Verhamme, P., Bernstein, R.A., Dubiel, R., Huisman, M.V.,
Hylek, E.M., Kamphuisen, P.W. and Kreuzer, J., 2015. Idarucizumab for dabigatran reversal. New England Journal
of Medicine, 373(6), pp.511-520.
6. Siegal, D.M., Curnutte, J.T., Connolly, S.J., Lu, G., Conley, P.B., Wiens, B.L., Mathur, V.S., Castillo, J., Bronson, M.D.,
Leeds, J.M. and Mar, F.A., 2015. Andexanet alfa for the reversal of factor Xa inhibitor activity. New England
Journal of Medicine, 373(25), pp.2413-2424.
7. Leblanc, K. Stroke Prevention in Atrial Fibrillation: Adverse Bleeding. Presented on March 31 2016. University of
Toronto: PHM204 Cardiology Lecture.
8. Stöllberger, C., Pommer, P., Schneider, B. and Finsterer, J., 2016. Concerns about idarucizumab for dabigatran
reversal. Blood Coagulation & Fibrinolysis, 27(4), pp.473-474.
9. Dubé, P.A., Pharm, B. and Tox, C.C., 2014. Idarucizumab: a specific antidote for dabigatran. mars, 2015(6), p.1.
10. Glund, S., Stangier, J., Schmohl, M., Gansser, D., Norris, S., van Ryn, J., Lang, B., Ramael, S., Moschetti, V.,
Gruenenfelder, F. and Reilly, P., 2015. 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. The Lancet, 386(9994), pp.680-690.
11. 2015. Antidote Treatments for the Reversal of Direct Oral Anticoagulants. Canadian Agency for Drugs and
Technologies in Health, 138, Report.