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

Reversal Agents voor NOACs: Hebben we een antidote nodig?

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• Prof. ¡Dr. ¡Peter ¡Verhamme ¡

Bloedings-­‑ ¡en ¡Vaatziekten ¡ UZ ¡Gasthuisberg ¡– ¡KU ¡Leuven ¡

Research Support; Honoraria for lectures and advisory boards

• Boehringer Ingelheim
• Bayer
• Daiichi Sankyo
• Pfizer
• Bristol Myers Squib
• Sanofi
• Portola
• Leo Pharma

Disclosures

• 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)

Why do we need a reversal agent for new oral anticoagulants (NOACs) ?

NOACs vs. Warfarin: Lower Risk of Stroke

Outcome Relative risk (95% CI)

Relative risk (95% CI) NOAC events Warfarin events

Ischaemic stroke

0.92 (0.83-1.02) p=0.10 665/29,292 724/29,221

Haemorrhagic stroke

0.49 (0.38-0.64) p<0.0001 130/29,292 263/29,221

All-cause mortality

0.90 (0.85-0.95) p=0.0003 2022/29,292 2245/29,221

0.5 1.0 Favours NOAC Favours warfarin 1.5

Ruff et al. Lancet 2014;383:955-962

• 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) ?

Meta-analysis: ARISTOTLE, ENGAGE-AF, RE-LY and ROCKET AF

Rela%ve ¡risk ¡difference ¡(%) ¡(95% ¡CI) ¡ Intracranial ¡bleeding ¡ Other ¡major ¡bleeding ¡ GastrointesEnal ¡bleeding ¡

NOACs vs Warfarin: Less Serious bleeding

Vanassche et al, Thrombosis and Haemostasis, 2014

Favours novel OAC Favours warfarin

–100 –50 50 100

84,540 patients and 4781 bleeding events

Efficacy and Safety of Dabigatran

• 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

RE-LY

Warfarin D150 BID MORTALITY ISCHAEMIC STROKE ICH MAJOR BLEEDING GI BLEEDING

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: 0.88 P=0.05

EVENT RATE (% PER YEAR)

5 4 3 2 1

Efficacy and Safety of Dabigatran

• 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

RE-LY

Warfarin D150 BID

FDA Analysis

Warfarin D150 & D75 BID combined MORTALITY ISCHAEMIC STROKE ICH MAJOR BLEEDING GI BLEEDING

HR: 0.76 P=0.04 HR: 0.80 P=0.02 RR: 0.41 P<0.001 HR: 0.34 P<0.001 RR: 0.94 P=0.41 HR: 0.97 P=0.50 RR: 1.48 P=0.001 HR: 1.28 P<0.001 RR: 0.88 P=0.05 HR: 0.86 P=0.006

Real-world data

EVENT RATE (% PER YEAR)

5 4 3 2 1

INCIDENCE RATE PER 100 PERSON-YEARS

1 2 3 4 5

• 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)

Why do we need a reversal agent for new oral anticoagulants (NOACs) ?

• 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)

Emergencies: can we switch off anticoagulation?

Life-threatening bleeding: 4-factor concentrate supports hemostasis

Eerenberg, ¡CirculaEon ¡2011 ¡

50 ¡U ¡PCC ¡reversed ¡PT ¡and ¡ETP ¡ ¡

Rivaroxaban + placebo Rivaroxaban + 4FC

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

• Glund et al. Lancet 2015

Praxbind: Immediate and complete reversal

• f dabigatran in healthy volunteers

15 End of idarucizumab injection (5-min infusion)

Dabigatran + placebo

dTT (s)

70 65 60 55 50 45 40 35 30

Dabigatran Idarucizumab Time after end of infusion (hrs)

Minutes

72 –2

120 90 60 30

36 24 12 6 4 8 10 48 60

Dabigatran etexilate plus: Placebo (n=9)

Internal use only – strictly confidential

4 g idarucizumab (day 4) Normal upper reference limit (n=86) Mean baseline (n=86)

Dabigatran + antidote

• Glund et al. Lancet 2015

Immediate and complete reversal of dabigatran in healthy volunteers

16 End of idarucizumab injection (5-min infusion)

Dabigatran + placebo

dTT (s)

70 65 60 55 50 45 40 35 30

Dabigatran Idarucizumab Time after end of infusion (hrs)

Minutes

72 –2

120 90 60 30

36 24 12 6 4 8 10 48 60

Dabigatran etexilate plus: Placebo (n=9)

Internal use only – strictly confidential

4 g idarucizumab (day 4) Normal upper reference limit (n=86) Mean baseline (n=86)

Dabigatran + antidote

Andexanet: Reversal of Anti-FXa Activity

Siegal, ¡NEJM ¡2015 ¡

• 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 Why do we need a reversal strategy for new oral anticoagulants (NOACs) ?

• NOACs are effective to prevent stroke
• NOACs cause less serious bleeding

than warfarin

• Emergencies: need a strategy to switch
• ff anticoagulation & support hemostasis

Conclusion: Why we need reversal agents for new oral anticoagulants (NOACs)