Latest Frontiers in Anticoagulation Therapy Your key questions for 2018 clinical practice addressed Supported by an unrestricted educational grant from Course Director Prof. Saskia Middeldorp
Practical guidance on NOACs and safety: How to deal with challenging situations in AF John Eikelboom McMaster University www. phri .ca
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 www. phri .ca
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 www. phri .ca
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) www. phri .ca
NOAC reversal agents Idarucizumab Andexanet alfa Humanized Human Structure Fab fragment rXa variant Target Dabigatran FXa inhibitors Non-competitive Binding Competitive High affinity Rapid complete Rapid complete Phase 2 results sustained reversal reversal during infusion Phase 3 trial Completed Ongoing www. phri .ca Lauw M, et al. Can J Cardiol 2014; 30: 381-4.
REVERSE AD design Dabigatran etexilate treated patients: Primary endpoint: Secondary endpoints: Group A: • Thrombotic Hemostasis within Uncontrolled events 24 hours (non-ICH) Maximum bleeding reversal • Restart of 5 g idarucizumab Determined within 4 hrs N = 503 anticoagulation locally (2 x 2.5 g IV) with dTT • Mortality and ECT Group B: Hemostasis during measures Emergency surgery • aPTT / TT procedure /surgery or procedure • Drug levels 0 – 15 min • Immunogenicity Hospital 90 day 12 h 24 h 30 d Baseline Between ~20 min 1 h 2 h 4 h arrival follow-up vials Blood sample time points Patients treated based only 173 sites in on clinical presentation 39 countries www. phri .ca Pollack C, et al. Thromb Haemost 2015;114:198 – 205; Pollack C, et al. New Engl J Med 2017; 377: 431-441.
Idarucizumab: dabigatran reversal www. phri .ca Pollack C, et al. New Engl J Med 2017; 377: 431-441.
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 www. phri .ca Pollack C, et al. New Engl J Med 2017; 377: 431-441.
ANNEXA-4 design www. phri .ca Connolly SJ, et al. N Engl J Med 2016; 375: 1131-41.
Andexanet alfa: rivaroxaban and apixaban reversal www. phri .ca Connolly SJ, et al. N Engl J Med 2016; 375: 1131-41.
Haemostasis and thromboembolism • Haemostasis • Excellent or good in 79% (95% CI: 64-89%) • Thromboembolism • Overall rate 12% at 30 days www. phri .ca Connolly SJ, et al. N Engl J Med 2016; 375: 1131-41. Connolly SJ, et al. N Engl J Med 2016; 375: 2499-2500.
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 www. phri .ca
2016 ESC guidelines for the management of AF www. phri .ca Kirchhof P, et al. Eur Heart J 2016; 37: 2893-2962. October 4, 2017
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