Transcript Latest data on management of bleeding in patients taking DOACs

Latest data on the Management of Bleeding in
Patients taking the Direct Oral Anticoagulants
Tim Nokes
Haematologist
Derriford Hospital
Plymouth
Conflicts of interest
 Bayer
 Boerhinger-Ingelheim
 BMI-Pfizer
 Daicho-Sanyo
 Advisory boards, Attendance at meetings,
Presentations
Overview
 What is the risk for bleeding from trials ?
 Non-specific reversal of bleeding
 Specific reversal agents for DOACs
Benefit v Risk of Anticoagulation
Risk
More bleeding
Benefit
Less VTE /
CVA
Warfarin and its challenging therapeutic window
Therapeutic
range
20
Stroke
Odds ratio
15
Intracranial bleed
10
5
1
0
1
2
3
4
5
6
International normalized ratio (INR)
7
8
Comparisons to ideal anticoagulant
Type of
Drug
Oral
No
interaction
Predictable
No
monitoring
Fixed
dose
Wide
Reversible
therapeutic
window
Ideal
✔
✔
✔
✔
✔
✔
VKA
✔
LMWH
✔
✔
✔
✔
✔
Anti Xa
ODI
✔
✔
✔
✔
✔
✔
Anti
thrombi
n
ODI
✔
✔
✔
✔
✔
✔
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
110: RR 0.90 NS
HR 0.88 NS
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)
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):1018-23
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
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
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
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
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)
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
Studies evaluating bleeding management agents
with direct oral anticoagulants
Dabigatran
Rivaroxaban
Apixaban
In vitro
Rat in vivo
Dog in vivo
Human in vivo
No data
No data
Haemoperfusion with
activated charcoal
In vivo
No data
No data
Fresh frozen plasma
Mice in vivo
No data
No data
Rodent in vivo
Ex vivo; rat, rabbit
and baboon in vivo
In vitro
Non-activated three-factor PCC
No data
No data
No data
Non-activated four-factor PCC
Ex vivo, rodent and
human in vivo
Ex vivo; rat, rabbit,
baboon and human in
vivo
In vitro
Ex vivo and
rodent in vivo
Ex vivo and
rabbit in vivo
In vitro
Oral activated charcoal
Haemodialysis
Recombinant Factor VIIa
Activated PCC
Kaatz et al, J Thromb Thrombolysis 2013
Derriford NOAC Poster
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
Idarucizumab: mode of action
Dabigatran inhibiting
thrombin
Dabigatran bound
to plasma proteins
Thrombin
Dabigatran molecule
Antidote
(idarucizumab)
Unbound
dabigatran
Idarucizumab alters the
equilibrium – dabigatran
dissociates from thrombin
Idarucizumab rapidly binds to
dabigatran in the plasma
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.
Idarucizumab showed immediate, complete and
sustained reversal of dabigatran anticoagulation
70
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)
65
dTT (sec)
60
55
DE + placebo
50
45
40
35
30
-2 0 2 4 6 8 10 12
Dabigatran
DE = dabigatran etexilate
24 36 48 60 72
Time after end of infusion (hr)
Antidote
Similar effects were seen for 5g + 2.5g dose(data not shown)
Normal upper reference limit’ refers to (mean+2SD) of 86 pre-dose measurements from a total of 51 subject
Glund S et al. Lancet. Jun 16, 2015. Epub ahead of print. Glund S et al. Presented at AHA, Dallas, TX, USA, 16-20
November 2013, Abstract 17765; Disclaimer: idarucizumab is not currently licensed for use
UK/CVS-151023
Date of prep: July 2015
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.
Idarucizumab for Dabigatran
Reversal. Pollack CV et al. NEJM. 2015 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 periprocedure in 33pts (92%)
Initial results group A: Primary endpoint
Reversal of dabigatran induced anticoagulation with idarucizumab
130
Diluted thrombin time
325
120
300
110
275
250
100
225
Idarucizumab
2x 2.5 g
ECT (s)
dTT (s)
90
Ecarin clotting time
80
70
200
Idarucizumab
2x 2.5 g
175
150
60
125
50
100
Assay
upper limit
of normal
40
30
20
75
50
25
Baseline Between 10–30
vials
min
1h
2h
4h
Time post idarucizumab
Pollack C et al. NEJM 2015;377:511-520
12h
24h
Baseline Between 10–30
vials
min
1h
2h
4h
12h
24h
Time post idarucizumab
UK/CVS-151023
Date of prep: July 2015
Initial results group B: Primary endpoint
Reversal of dabigatran induced anticoagulation with idarucizumab
130
Diluted thrombin time
325
120
300
110
275
250
100
225
Idarucizumab
2x 2.5 g
ECT (s)
dTT (s)
90
Ecarin clotting time
80
70
200
Idarucizumab
2x 2.5 g
175
150
60
125
50
100
Assay
upper limit
of normal
40
30
20
75
50
25
Baseline Between 10–30
vials
min
1h
2h
4h
Time post idarucizumab
Pollack C et al. NEJM 2015;377:511-520
12h
24h
Baseline Between 10–30
vials
min
1h
2h
4h
12h
24h
Time post idarucizumab
UK/CVS-151023
Date of prep: July 2015
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
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.
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.
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
Crowther M et al. oral presentation at AHA November 2014; Chicago, Illinois , USA.
 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
Andexanet Alfa for the Reversal of Factor Xa
Inhibitor Activity
Deborah M. Siegal,.N Engl J Med 2015; 373:2413-2424 December 17,
2015DOI: 10.1056/NEJMoa1510991
 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.
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
1. Press release Perosphere: http://decreased after the test persons received
aripazinewww.perosphere.com/content/news/httpwww.perosphere.comcontentnewsreleases042513.htm
2. Clinicaltrials.gov NCT 01826266; http://clinicaltrials.gov/ct2/show/NCT01826266?term=per977&rank=1
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 14. 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
& 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.
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