1. Tim Nokes Haematologist Derriford Hospital Plymouth
Latest data on the Management of Bleeding in Patients taking the Direct Oral Anticoagulants
Tim Nokes
Haematologist
Derriford Hospital
Plymouth

2. Conflicts of interest Bayer Boerhinger-Ingelheim BMI-Pfizer
Daicho-Sanyo
Advisory boards, Attendance at meetings, Presentations

3. Overview What is the risk for bleeding from trials ?
Non-specific reversal of bleeding
Specific reversal agents for DOACs

4. Benefit v Risk of Anticoagulation
More bleeding
Benefit
Less VTE / CVA

5. Warfarin and its challenging therapeutic window
Therapeutic range 20
Stroke 15
Intracranial bleed 10
Odds ratio 5 1 1 2 3 4 5 6 7 8
International normalized ratio (INR) 5 5 5

6. Comparisons to ideal anticoagulant
Type of Drug
Oral
No interaction
Predictable
No monitoring
Fixed dose
Wide therapeutic window
Reversible
Ideal ✔
VKA
LMWH
Anti Xa
ODI
Anti thrombin
Once daily – perhaps!

7. SPAF trial outcomes for DOACs
Primary outcome = CVA or arterial embolism
ROCKET-AF
RE-LY
ARISTOTLE
Primary outcome
HR 0.79 NS
150: RR 0.65 p=0.03
110: RR 0.90 NS
HR 0.79 p=0.01
Haemorrhagic CVA
HR 0.67 p=0.02
150: RR 0.31 p<0.001
110: RR 0.26 p<0.001
HR 0.51 p<0.001
Major bleeding
HR 1.04 NS
150: RR 0.93 NS
110: RR 0.80 p=0.003
HR 0.69 p<0.001
GI bleeding
HR 1.07 NS
150: RR 1.48 p=0.001
110: RR 1.08 NS
HR 0.89 NS MI
HR 0.81 NS
150: RR 0.85 p=0.04
HR 0.88 NS

8. Rivaroxaban, Apixaban & Edoxaban for SPAF
Rocket-AF: annual major bleeding risk = 3.6% (warfarin = 3.4%) (Patel 2011)
Aristotle: annual major bleeding risk = 2.1% (warfarin = 3.1%) (Granger 2011)
Engage AFTIMI 48: Edoxaban superior over Warfarin for major bleeding
Dabigatran for SPAF
Annual risk for major bleeds = 2.71% (110mg) & 3.11% (150mg), (warfarin = 3.36%) (Connolly et al 2009)

9. Intracranial Haemorrhage
Significantly reduced against warfarin in all trials for all DOACs
Real life data:
About 50% reduction in relative risk of ICH
34% reduction in Haemorrhagic extension (17% v 26%)
60% reduction in Mortality (16% v 35%)
Saji et al. Circ J 2015 (5):

10. VTE trials with DOACs
Rivaroxaban: Pooled data – significantly less major bleeds
Apixaban: Significantly less major & CRNM bleeds
Edoxaban: Significantly less bleeding
Dabigatran: Noninferiority for major bleeding – trend to less

11. Care in interpreting bleeding in trials of anticoagulants
Trials are not real-life patients!
Selected group and therefore bleeding likely to be higher in real world use.
Extremes of body weight not included
Renal impairment not accounted for
Multiple comorbidities rare in trial patients

12. Guideline on the management of bleeding in patients on antithrombotic agents British Committee for Standards in Haematology. 2012, 160: 35–46
General non-pharmacological measures.
Stop the antithrombotic drug
Document the timing and amount of the last drug dose and presence of pre-existing renal or hepatic impairment
Estimate the half-life and length of functional defect of the drug
Assess the source of bleeding

13. Guideline on the management of bleeding in patients on antithrombotic agents British Committee for Standards in Haematology. 2012, 160: 35–46
FBC, PT, APTT, thrombin time, fibrinogen, creatinine
If available, request a specific laboratory test to measure the antithrombotic effect of the drug
Correct haemodynamic compromise with intravenous fluids and red cell transfusion
Apply mechanical pressure, if possible
Use endoscopic, radiological or surgical measures

14. Specific measures for bleeding
Activated charcoal binds both Dabigatran & Rivaroxaban in water suspension – therefore give if within 2 hours of ingestion (van Ryn, 2010)
Only Dabigatran can be dialysed or haemofiltered (van Ryn, 2010)
Tranexamic acid (0.5-1 g 3 times daily IV) should be given if not contraindicated (BCSH, 2012)

15. Life threatening Bleeding: BCSH
PCC, APCC or rVIIa considered for life- threatening bleeding associated with Dabigatran, Rivaroxaban or Apixaban.
After carefully balancing the risks and benefits associated with these products.
Risks for thrombosis & DIC with all these drugs and mentioned in SPCs
Trial of rVIIa off-license in bleeding patients showed increase in arterial events

16. Studies evaluating bleeding management agents with direct oral anticoagulants
Dabigatran
Rivaroxaban
Apixaban
Oral activated charcoal
In vitro
Rat in vivo
Dog in vivo
Haemodialysis
Human in vivo
No data
Haemoperfusion with activated charcoal
In vivo
Fresh frozen plasma
Mice in vivo
Recombinant Factor VIIa
Rodent in vivo
Ex vivo; rat, rabbit and baboon in vivo
Non-activated three-factor PCC
Non-activated four-factor PCC
Ex vivo, rodent and human in vivo
Ex vivo; rat, rabbit, baboon and human in vivo
Activated PCC
Ex vivo and rodent in vivo
Ex vivo and rabbit in vivo
Abbreviation
PCC, prothrombin complex concentrate.
Reference
Kaatz et al. J Thromb Thrombolysis 2013;DOI /s y
Kaatz et al, J Thromb Thrombolysis 2013

17. Derriford NOAC Poster

19. Idarucizumab: Praxabind
Idarucizumab (BI655075), a humanized mouse monoclonal antibody fragment directed against Dabigatran.
>300-fold higher than the affinity of Dabigatran for Thrombin.
In sufficiently high doses, Idarucizumab binds both free & thrombin-bound Dabigatran
Rapid reversal of anticoagulant effect in preclinical studies & reduced bleeding in animals, with no thrombogenicity

20. Idarucizumab: mode of action
Antidote
(idarucizumab)
Thrombin
Dabigatran molecule
Dabigatran inhibiting thrombin
Dabigatran bound to plasma proteins
Unbound
dabigatran
Idarucizumab alters the equilibrium – dabigatran dissociates from thrombin
Idarucizumab rapidly binds to dabigatran in the plasma

21. Idarucizimab
Preclinical studies indicate idarucizumab binds specifically to and inhibits dabigatran.
Data from Phase 1 healthy volunteers demonstrating that idarucizumab provided immediate, complete and sustained reversal of the anticoagulant effect of dabigatran.

22. Time after end of infusion (hr)
Idarucizumab showed immediate, complete and sustained reversal of dabigatran anticoagulation 70 65 60 55 50 45 40 35 30
DE + placebo (n=9)
DE + 1 g idarucizumab (day 4) (n=9)
DE + 2 g idarucizumab (day 4) (n=9)
DE + 4 g idarucizumab (day 4) (n=8)
Normal upper reference limit (n=86)
Mean baseline (n=86)
dTT (sec)
DE + placebo
1. Complete reversal of anticoagulation activity (as measured by dTT) was seen immediately after antidote administration
2. Antidote 2 g and 4 g doses restored clotting activity to within the range seen before dabigatran dosing for the complete time frame (24 hrs)
3. The 1 g dose demonstrates that the effect of idarucizumab is dose-dependent. As expected, when only half of the equimolar dose is applied some return of anticoagulation is seen -2 2 4 6 8 10 12 24 36 48 60 72
Dabigatran
Antidote
Time after end of infusion (hr)
DE = dabigatran etexilate
Similar effects were seen for 5g + 2.5g dose(data not shown)
Glund S et al. Lancet. Jun 16, Epub ahead of print. Glund S et al. Presented at AHA, Dallas, TX, USA, November 2013, Abstract 17765;
Normal upper reference limit’ refers to (mean+2SD) of 86 pre-dose measurements from a total of 51 subject
UK/CVS
Date of prep: July 2015
Disclaimer: idarucizumab is not currently licensed for use

23. REVERSE-AD
Phase 3 global prospective cohort study investigating idarucizumab in clinical settings.
Patients treated with Dabigatran who experience an uncontrolled or life-threatening bleeding event or in need of emergency intervention.

24. Idarucizumab for Dabigatran Reversal. Pollack CV et al. NEJM
Idarucizumab for Dabigatran Reversal. Pollack CV et al. NEJM Aug 6; 373(6):511-20
Interim analysis from Reverse-AD trial
90 patients - Group A = 51 with serious bleeding & group B = 39 requiring urgent procedures
68 patients with increased dilute Thrombin Time, 81 with elevated Ecrine clotting time, idarucizumab normalised test levels in 88-98% patients
35 group A patients: Haemostasis restored at 11.4 hr
36 group B patients: Median of 1.7 hours between reversal & starting procedure. Haemostasis peri- procedure in 33pts (92%)

25. Initial results group A: Primary endpoint
Reversal of dabigatran induced anticoagulation with idarucizumab
Diluted thrombin time
Ecarin clotting time
130
325
120
300
110
275
250
100
Idarucizumab
2x 2.5 g
225 90
Idarucizumab
2x 2.5 g
200
dTT (s) 80
ECT (s)
175 70
150 60
125 50
100
Assay upper limit of normal 40 75 30 50 20 25
Baseline
Between vials
10–30 min 1h 2h 4h
12h
24h
Baseline
Between vials
10–30 min 1h 2h 4h
12h
24h
Time post idarucizumab
Time post idarucizumab
Pollack C et al. NEJM 2015;377:
UK/CVS
Date of prep: July 2015

26. Initial results group B: Primary endpoint
Reversal of dabigatran induced anticoagulation with idarucizumab
Ecarin clotting time
Assay upper limit of normal
Diluted thrombin time
Idarucizumab
2x 2.5 g
dTT (s)
130
110 70 60 50 40 30 20
120
100 90 80 1h 2h 4h
12h
24h
Baseline
Between vials
10–30 min
Time post idarucizumab
ECT (s)
325
275
175
150
125 75 25
300
250
225
200
Pollack C et al. NEJM 2015;377:
UK/CVS
Date of prep: July 2015

27. Thrombotic Events
Thrombotic events reported in five patients over a period of 90 days of follow up
1 early event (DVT + PE) 2 days after idarucizumab administration
4 events 7–26 days after idarucizumab administration
DVT: 7 days
DVT + PE + left atrial thrombus: 9 days
MI: 13 days
Ischaemic stroke: 26 days
None of these 5 patients were receiving any antithrombotic therapy when the events occurred

28. Idarucizumab – FDA approval
October 16, 2015, the U. S. Food and Drug Administration granted accelerated approval to idarucizumab (Praxbind  Injection, Boehringer Ingelheim Pharmaceuticals, Inc.) for the treatment of patients treated with dabigatran (Pradaxa) when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. 

29. Andexanet alfa by Portola
Andexanet alfa is a modified human Factor Xa molecule that acts as a decoy to target and sequester (therefore reverse) with high specificity both oral and injectable Factor Xa inhibitors in the blood.
Portola currently evaluating andexanet alfa (AnXa, PRT064445) in Phase 3 trial ANNEXA™
Efficacy initially evaluated using anti-Factor Xa levels as the primary endpoint.

30. Andexanet (ANXa): designed to reverse activity of fXa inhibitors
Recombinant engineered version of human factor Xa produced in CHO cells
Acts as a FXa decoy and retains high affinity for all FXa inhibitors
Change of Serine to Alanine to eliminate catalytic activity and prevent prothrombin cleavage
GLA domain removed to prevent anticoagulant effect
No known interaction with other coagulation factors except Tissue Factor Pathway Inhibitor (TFPI)
No significant antibody signal found in development programme to date
Abbreviations
AT, antithrombin; GLA, gamma-carboxyglutamic acid-rich; LMWH, low molecular weight heparin.
Reference
Lu et al. Nat Med 2013;19:446–453
Crowther M et al. oral presentation at AHA November 2014; Chicago, Illinois , USA.

31. Part 1: 39 subjects age 50 to 75 randomized to receive either AnXa or placebo in a 2:1 ratio. All subjects received rivaroxaban 20 mg for 4 days. AnXa at a dose of 800 mg IV bolus or placebo was administered on Day 4
andexanet alfa significantly and immediately reversed the anticoagulation activity of rivaroxaban and well tolerated

32. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity
Deborah M. Siegal,.N Engl J Med 2015; 373: December 17, 2015DOI: /NEJMoa
Part 2 of ANNEXA-R & A studies: 40 healthy volunteers given Rivaroxaban 20 mg or Apixaban 5 mg bd, for four days then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes or to placebo.
Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects.

33. Aripazine (PER977) - universal antidote
Small synthetic water soluble molecule, rich in D-Arginine, developed by Perosphere1
Targets: DOACs, fondaparinux, LMWH and UFH
Under clinical development as a sterile, intravenous injection
In vitro in animal models and ex vivo in human blood: PER977 successfully reverses anticoagulant activity for various anticoagulants1
Reference
Press release Perosphere:
Clinicaltrials.gov NCT ;
Press release Perosphere: after the test persons received aripazinewww.perosphere.com/content/news/httpwww.perosphere.comcontentnewsreleases htm
Clinicaltrials.gov NCT ;

34. Aripazine PER977 (Ciraparantag)universal antidote
Phase 1 clinical trial showed the ability of PER977 to reverse the anticoagulant activity of Edoxaban
Phase 2 single-blind, sequential,PER977 reversal dose study in 80 healthy volunteers, randomized in a 4:1 ratio to receive either PER977 or placebo. All subjects received a single dose of edoxaban 60 mg on Days Aripazine administered 3 hours following edoxaban reduced whole blood clotting time to within 10% above baseline within 10 mins. In all subjects
Perosphere in clinical collaboration with Daiichi Sankyo to investigate PER977 in Phase 3 trials with Edoxaban

35. & finally!
A specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development.
This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair.

36. Summary
Serious bleeding is a challenge with DOACs but probably safer than VKA (ICH)
Local and simple measures may be important
Tranexamic acid an important adjuvent
Evidence for some effectiveness of PCC, aPCC and rVIIa in reversing anticoagulant effect but not always clinical bleeding
Reversal agents now available & effective in reversing laboratory tests
Idarucizumab: interim-result from phase 3 trial demonstrates clinical effectiveness & FDA approved
Other reversal agents for anti-Xa drugs are in trials currently