1. Bleeding complications and management in patients treated with NOACs
Nico De Crem
ASO Interne Geneeskunde

2. Overview Introduction Safety-efficacy profile: NOACs versus VKAs
Management of bleeding
Reversal agents

3. NOACs versus VKAs Several indications
DVT prophylaxis after knee of hip replacement surgery
Treatment VTE (DVT or PE)
Non-valvular AF
Treatment of VTE of non-valvular AF
UH or LMWH, followed by VKAs
NOACs or DOACs
Factor IIa inhibitor
Dabigatran (Pradaxa®)
Factor Xa inhibitor
Rivaroxaban (Xarelto®)
Apixaban (Eliquis®)
Edoxaban (Lixiana®)

4. NOACs versus VKAs Advantages
Laboratory monitoring and subsequent dose adjustment are not necessary
More predictable pharmacokinetics
Less food and drug interactions
Fixed dose regimens
Depending on renal function, age,…
Rapid onset of anticoagulant effect

5. In clinical trials, NOACs have demonstrated favourable safety and efficacy profiles vs warfarin
STROKE/SE
MAJOR BLEEDING
ICH
In stroke prevention for NVAF*1
In treatment of acute DVT/PE†2
RECURRENT SYMPTOMATIC
VTE
similar
MAJOR BLEEDING
RRR 19%
ARR 0.7%
RRR 40%
ARR 0.7%
RRR 14%
ARR 0.9%
In prevention of recurrence of DVT/PE up to 36 months (active comparator data available only for dabigatran)3
RECURRENT OR FATAL VTE
similar
MAJOR BLEEDING
RRR 52%
ARR 0.8%
RRR 48%
ARR 0.9%
* †Meta-analysis of data from RE-COVER™, RE-COVER™ II, EINSTEIN-DVT, EINSTEIN-PE, AMPLIFY, and HOKUSAI 1. Ruff CT et al. Lancet 2014;383:955–62; 2. Hirschl M, Kundi M. Vasa 2014;43:353–64; 3. Schulman S et al. N Engl J Med 2013;368:709–18

6. INCIDENCE RATE PER 100 PERSON-YEARS
Low rate of major bleeding events in RE-LY® confirmed by real-world evidence: FDA Medicare analysis
EVENT RATE (% PER YEAR) 5 4 3 2 1
HR: 0.76
P=0.04
RR: 0.41
P<0.001
RR: 0.94
P=0.41
RR: 1.48
P=0.001
RR: 1.27
P=0.12
RR: 0.88
P=0.05
RE-LY®2–5
Warfarin
D150 BID
RCT
ISCHAEMIC
STROKE
MAJOR
BLEEDING GI
BLEEDING
ICH MI
MORTALITY
INCIDENCE RATE PER 100 PERSON-YEARS 1 2 3 4 5
MEDICARE*1
Warfarin
D150 & D75 BID combined
Real-world data
HR: 0.80
P=0.02
HR: 0.34
P<0.001
HR: 0.97
P=0.50
HR: 1.28
P<0.001
HR: 0.92
P=0.29
HR: 0.86
P=0.006
In the USA, the licensed doses for Pradaxa® are: 150 mg BID and 75 mg BID for the prevention of stroke and systemic embolism in adult patients with NVAF. RE-LY® was a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) study
*Primary findings for dabigatran are based on analysis of both 75mg &150mg together without stratification by dose. 1. Graham et al. Circulation 2014; 2. Connolly et al. NEJM 2009; 3. Connolly et al. NEJM 2010; 4. Pradaxa®: EU SPC, 2015; 5. Connolly S et al. NEJM 2014

7. Management of bleeding
NOACs provide effective treatment for stroke prevention in AF and for prevention and treatment of VTE vs warfarin
Associated with less serious bleeding than warfarin based on clinical testing and has since been confirmed by independent real world data
Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

8. Management of bleeding and emergencies
However… Fear of bleeding and the lack of a reversal agent are barriers for appropriate use of NOACs

9. Management of bleeding and emergencies
However… Fear of bleeding and the lack of a reversal agent are barriers for appropriate use of NOACs
A specific reversal agent could improve patient management during these emergency situations
Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

11. NOAC reversal agents in development
Idarucizumab1
Target: dabigatran
Submitted to EMA/FDA/ Health Canada
Feb/Mar 2015
Phase III Patients requiring urgent surgery/with major bleeding; started May 20142,3
Phase III Patients with major bleeding; started Jan 20154
Phase II
Ongoing5
Phase I
Andexanet alfa (PRT064445)1
Target: FXa inhibitors
Ciraparantag
(PER977)1
Target: universal
1. Adapted from Greinacher A et al. Thromb Haemost 2015;113:931–42; 2. Clinicaltrials.gov: NCT ; 3. Pollack CV et al. Thromb Haemost. 2015;114:198–205; 4. ClinicalTrials.gov Identifier: NCT ; 5. ClinicalTrials.gov Identifier: NCT

12. Idarucizumab: specific reversal agent for dabigatran
Humanized Fab fragment
Binding affinity ~350× higher than dabigatran to thrombin
No procoagulant or anticoagulant effects expected
Dabigatran
IV administration, onset of action within 1 min
Short half-life
Idarucizumab
Adapted from: Schiele F et al. Blood 2013;121:3554–62; Stangier J et al. ISTH 2015; OR320

13. RE-VERSE AD™: multicentre, ongoing, open-label, single-arm Phase III study
Group A:
Uncontrolled bleeding + dabigatran-treated
Group B: Emergency surgery or procedure* + dabigatran-treated
5 g idarucizumab (two separate infusions of 2.5 g)
N=300
0–15 minutes
90 days follow-up
0–24 hours
Blood
samples
Pre-1st vial
Pre-2nd vial
10–30 min
1 h
2 h
4 h
12 h
24 h
7 d
30 d
90 d
Hospital arrival
Primary endpoint:
dabigatran reversal within 4 hours (dTT or ECT)
Idarucizumab is currently in development and is not approved for use in the EU.
*Other than bleeding. dTT, diluted thrombin time; ECT, ecarin clotting time
Pollack CV et al. Thromb Haemost 2015;114:198–205

14. NEJM, 6 aug 2015

15. Conclusions 1
In clinical trials, NOACs have demonstrated favourable safety and efficacy profiles vs warfarin1–3 2
Guidance is available to aid decision-making for patients on NOACs who are bleeding, or undergoing emergency procedures4–6 3
NOAC reversal agents are in development and may improve treatment options for patients undergoing emergency procedures, or with life-threatening bleeding7–9
NOAC reversal agents are investigational compounds under development and have not been approved for use in the EU.
1. Ruff CT et al. Lancet 2013;383:955-62; 2. Hirschl M, Kundi M. Vasa 2014;43:353–64; 3. Schulman S et al. N Engl J Med 2013;368:709–18; 4. Pradaxa SPC; Current version available online at: 5. Huisman M et al. Thromb Haemost 2012;107:838–47; 6. Heidbuchel H et al. Europace 2013;15:625–51; 7. Pollack CV et al. N Engl J Med 2015:373:511–20; 8. ClinicalTrials.gov Identifier: NCT ; 9. ClinicalTrials.gov Identifier: NCT