Reversal Agents voor NOACs: Hebben we een antidote nodig? Prof. - PowerPoint PPT Presentation

Reversal Agents voor NOACs: Hebben we een antidote nodig? ¡ Prof. ¡Dr. ¡Peter ¡Verhamme ¡ Bloedings-­‑ ¡en ¡Vaatziekten ¡ UZ ¡Gasthuisberg ¡– ¡KU ¡Leuven ¡

Disclosures Research Support; • Boehringer Ingelheim Honoraria for lectures • Bayer and advisory boards • Daiichi Sankyo • Pfizer • Bristol Myers Squib • Sanofi • Portola • Leo Pharma

Why do we need a reversal agent for new oral anticoagulants (NOACs) ? • NOACs are effective to prevent stroke • NOACs cause less serious bleeding than warfarin Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

Why do we need a reversal agent for new oral anticoagulants (NOACs) ? • NOACs are effective to prevent stroke • NOACs cause less serious bleeding than warfarin Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

NOACs vs. Warfarin: Lower Risk of Stroke Relative risk Warfarin Outcome Relative risk (95% CI) (95% CI) NOAC events events 0.92 (0.83-1.02) Ischaemic stroke 665/29,292 724/29,221 p=0.10 Haemorrhagic 0.49 (0.38-0.64) 130/29,292 263/29,221 p<0.0001 stroke 0.90 (0.85-0.95) All-cause mortality 2022/29,292 2245/29,221 p=0.0003 0.5 1.0 1.5 Favours NOAC Favours warfarin Ruff et al. Lancet 2014;383:955-962

Why do we need a reversal agent for new oral anticoagulants (NOACs) ? • NOACs are effective to prevent stroke • NOACs cause less serious bleeding than warfarin Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

NOACs vs Warfarin: Less Serious bleeding Meta-analysis: ARISTOTLE, ENGAGE-AF, RE-LY and ROCKET AF Rela%ve ¡risk ¡difference ¡(%) ¡(95% ¡CI) ¡ Intracranial ¡bleeding ¡ Other ¡major ¡bleeding ¡ GastrointesEnal ¡bleeding ¡ –100 –50 0 50 100 Favours novel OAC Favours warfarin 84,540 patients and 4781 bleeding events Vanassche et al, Thrombosis and Haemostasis, 2014

Efficacy and Safety of Dabigatran HR: 0.76 RR: 0.41 RR: 0.94 RR: 1.48 RR: 0.88 EVENT RATE (% PER YEAR ) RE-LY 5 P=0.04 P<0.001 P=0.41 P=0.001 P=0.05 4 Warfarin D150 BID 3 2 1 0 ISCHAEMIC MAJOR GI ICH MORTALITY STROKE BLEEDING BLEEDING 1. Graham et al. Circulation 2014; 2. Connolly et al. NEJM 2009; 3 . Connolly et al. NEJM 2010; 4 . Connolly S et al. NEJM 2014

Efficacy and Safety of Dabigatran HR: 0.76 RR: 0.41 RR: 0.94 RR: 1.48 RR: 0.88 EVENT RATE (% PER YEAR ) RE-LY 5 P=0.04 P<0.001 P=0.41 P=0.001 P=0.05 4 Warfarin D150 BID 3 2 1 0 ISCHAEMIC MAJOR GI ICH MORTALITY STROKE BLEEDING BLEEDING 0 FDA Analysis INCIDENCE RATE PER 100 PERSON-YEARS 1 Warfarin 2 D150 & D75 BID 3 combined 4 Real-world data 5 HR: 0.80 HR: 0.34 HR: 0.97 HR: 1.28 HR: 0.86 P=0.02 P<0.001 P=0.50 P<0.001 P=0.006 1. Graham et al. Circulation 2014; 2. Connolly et al. NEJM 2009; 3 . Connolly et al. NEJM 2010; 4 . Connolly S et al. NEJM 2014

Why do we need a reversal agent for new oral anticoagulants (NOACs) ? • NOACs are effective to prevent stroke • NOACs cause less serious bleeding than warfarin Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

Why do we need a reversal agent for new oral anticoagulants (NOACs) ? • NOACs are effective to prevent stroke • NOACs cause less serious bleeding than warfarin • Emergencies : can we switch off anticoagulation? Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

Emergencies : can we switch off anticoagulation? • Non-specific strategies to support haemostasis (4FC) • Specific reversal agents Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

Life-threatening bleeding: 4-factor concentrate supports hemostasis Rivaroxaban + placebo Rivaroxaban + 4FC 50 ¡U ¡PCC ¡reversed ¡PT ¡and ¡ETP ¡ ¡ Eerenberg, ¡CirculaEon ¡2011 ¡

XANTUS: Bleeding Events during 1 year of rivaroxaban Rivaroxaban (N=6784) Incidence rate, %/year (95% CI)* Major bleeding 2.1 (1.8–2.5) Fatal 0.2 (0.1–0.3) Critical organ bleeding 0.7 (0.5–0.9) Intracranial haemorrhage 0.4 (0.3–0.6) Mucosal bleeding # 1.0 (0.7–1.3) Gastrointestinal 0.9 (0.6–1.1) Non-major bleeding events 15.4 (14.4–16.5) *Events per 100 patient-years; # numbers are for major mucosal and gastrointestinal bleeding events; ‡ representing major bleeding Patients could experience multiple bleeding events in different categories Camm AJ et al , Eur Heart J 2015 ; doi:10.1093/eurheartj/ehv466

Praxbind: Immediate and complete reversal of dabigatran in healthy volunteers End of idarucizumab injection (5-min infusion) 70 Dabigatran etexilate plus: Placebo (n=9) 65 4 g idarucizumab (day 4) Dabigatran + placebo 60 Normal upper reference limit (n=86) Mean baseline (n=86) 55 dTT (s) 50 45 Dabigatran + antidote 40 35 30 –2 0 4 6 8 10 12 24 36 48 60 72 30 60 90 120 Time after end of infusion (hrs) Minutes Dabigatran Idarucizumab 15 Internal use only – strictly confidential • Glund et al. Lancet 2015

Immediate and complete reversal of dabigatran in healthy volunteers End of idarucizumab injection (5-min infusion) 70 Dabigatran etexilate plus: Placebo (n=9) 65 4 g idarucizumab (day 4) Dabigatran + placebo 60 Normal upper reference limit (n=86) Mean baseline (n=86) 55 dTT (s) 50 45 Dabigatran + antidote 40 35 30 –2 0 4 6 8 10 12 24 36 48 60 72 30 60 90 120 Time after end of infusion (hrs) Minutes Dabigatran Idarucizumab 16 Internal use only – strictly confidential • Glund et al. Lancet 2015

Andexanet: Reversal of Anti-FXa Activity Siegal, ¡NEJM ¡2015 ¡

Why do we need a reversal strategy for new oral anticoagulants (NOACs) ? • A 75-year old women with intracranial bleeding after fall from stairs • A 83-year old woman with open tibia fracture • A 71-year old woman with uncontrollable gastro-intestinal bleeding

Conclusion: Why we need reversal agents for new oral anticoagulants (NOACs) • NOACs are effective to prevent stroke • NOACs cause less serious bleeding than warfarin • Emergencies: need a strategy to switch off anticoagulation & support hemostasis