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

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

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®)

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

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

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

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)

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

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)

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: NCT02104947; 3. Pollack CV et al. Thromb Haemost. 2015;114:198–205; 4. ClinicalTrials.gov Identifier: NCT02329327; 5. ClinicalTrials.gov Identifier: NCT02207257

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

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

NEJM, 6 aug 2015

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: http://www.medicines.org.uk/emc/; 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: NCT02329327; 9. ClinicalTrials.gov Identifier: NCT02207257