Anticoagulation Therapy Your key questions for 2018 clinical - - PowerPoint PPT Presentation

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Latest Frontiers in Anticoagulation Therapy

Your key questions for 2018 clinical practice addressed

Course Director

• Prof. Saskia Middeldorp

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Practical guidance on NOACs and safety: How to deal with challenging situations in AF

John Eikelboom McMaster University

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Bleeding management principles

• Hold drug(s)
• Local measures to control bleeding
• Resuscitation (i.v. access, fluid administration, blood

product transfusion)

• General hemostatic measures
• Percutaneous and/or surgical intervention to stop bleeding

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NOAC specific approaches

NOACs have a relatively short half life

• Determine the presence, concentration and expected

duration of the drug

• Limit drug absorption
• Remove, bypass or reverse the drug

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Indications for specific reversal

• Life-threatening (e.g., intracranial)
• Critical organ (e.g., pericardial, retroperitoneal)
• Ongoing (despite measures to control bleeding)
• Expected long delay in spontaneous restoration of normal

hemostasis (over-anticoagulation, renal failure)

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NOAC reversal agents

Idarucizumab Andexanet alfa Structure Humanized Fab fragment Human rXa variant Target Dabigatran FXa inhibitors Binding Non-competitive High affinity Competitive Phase 2 results Rapid complete sustained reversal Rapid complete reversal during infusion Phase 3 trial Completed Ongoing

Lauw M, et al. Can J Cardiol 2014; 30: 381-4.

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REVERSE AD design

Group A: Uncontrolled bleeding Group B: Emergency surgery

• r procedure

N = 503

Hospital arrival

Dabigatran etexilate treated patients:

Patients treated based only

• n clinical presentation

0–15 min 5 g idarucizumab

(2 x 2.5 g IV)

Between vials Baseline

Secondary endpoints:

90 day follow-up 12 h 24 h 30 d

Determined locally Hemostasis within 24 hours (non-ICH) Hemostasis during procedure /surgery Primary endpoint: Blood sample time points

2 h 4 h 1 h

~20 min

Maximum reversal within 4 hrs with dTT and ECT measures

• Thrombotic

events

• Restart of

anticoagulation

• Mortality
• aPTT / TT
• Drug levels
• Immunogenicity

173 sites in 39 countries

Pollack C, et al. Thromb Haemost 2015;114:198–205; Pollack C, et al. New Engl J Med 2017; 377: 431-441.

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Idarucizumab: dabigatran reversal

Pollack C, et al. New Engl J Med 2017; 377: 431-441.

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REVERSE AD: Haemostasis and thromboembolism

• Haemostasis
• Group A: cessation of bleeding
• GI bleeding: median time to bleeding cessation 3.5 hours
• Non GI, non ICH bleeding: median time to bleeding cessation 4.5 hours
• Group B: peri-procedural haemostasis
• 93% normal, 5% mildly abnormal, 2% moderately abnormal
• Thromboembolism
• Overall rate 4.4% at 30 days; 6.3% at 90 days

Pollack C, et al. New Engl J Med 2017; 377: 431-441.

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ANNEXA-4 design

Connolly SJ, et al. N Engl J Med 2016; 375: 1131-41.

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Andexanet alfa: rivaroxaban and apixaban reversal

Connolly SJ, et al. N Engl J Med 2016; 375: 1131-41.

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Haemostasis and thromboembolism

• Haemostasis
• Excellent or good in 79% (95% CI: 64-89%)
• Thromboembolism
• Overall rate 12% at 30 days

Connolly SJ, et al. N Engl J Med 2016; 375: 1131-41. Connolly SJ, et al. N Engl J Med 2016; 375: 2499-2500.

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Challenges and unresolved issues

• Evaluation to date has been restricted to bleeding patients
• Requires continuous infusion
• Incomplete reversal in 50%
• Transient reversal (only during infusion)
• Increased rate of thromboembolic events (>10% at 30

days)

• Delayed approval

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2016 ESC guidelines for the management of AF

Kirchhof P, et al. Eur Heart J 2016; 37: 2893-2962.