Idarucizumab for Dabigatran Reversal

Pollack.NEJM.2015;373(6)511-520; DOI: 10.1056/NEJMoa1502000

Clinical Question

• In patients taking dabigatran, who present with serious bleeding or require urgent surgery/intervention is idarucizumab safe and efficacious for the reversal of anticoagulation?

Design

• Prospective cohort study
• Blinding of clinicians to coagulation tests determining primary outcome
• Non randomised
• Follow up for at least 1 month

Setting

• 184 sites in 35 countries
• June 2014 to February 2015

Population

• Inclusion:
  • Adult patients taking dabigatran
  • Group A: patients with overt, uncontrollable, or life-threatening bleeding that was judged to require a reversal agent (n=51)
  • Group B: patients who required surgery or other invasive procedures that could not be delayed for at least 8 hours and for which normal haemostasis was required (n=39)
• Exclusion: none stated
• 90 patients
• Baseline characteristics
  • Age 76.5 years (median)
  • Creatinine clearance 58ml/min (median)
  • Time since last dose of dabigatran 15.4 hours (median)
  • Site of bleeding (Group A)
    • Intracranial: 18 patients
    • Gastrointestinal: 20 patients
    • Trauma: 9 patients
    • Other: 11 patients

Intervention

• 5g IV idarucizmab
  • Given as two 50ml bolus infusions, no more than 15 minutes apart

Control

• No control group

Outcome

• Primary outcome:
  • Maximum % reversal assessed by dilute thrombin time: 100% (median), 95% C.I. 100-100%
    • Determined in 68 patients as 22 patients had baseline dilute thrombin times that were normal
  • Maximum% reversal assessed by escarin-clotting time: 100% (median), 95% C.I. 100-100%
    • Determined in 81 patients as 9 patients had baseline escarin-clotting times that were normal

• Secondary outcomes:
  • Clotting tests
    • Dilute thrombin time normalised in
      • 98% of patients in Group A
      • 93% of patients in Group B
    • Escarin-clotting time normalised in
      • 89% of patients in Group A
      • 88% of patients in Group B
    • Level of unbound dabigatran at presentation (median)
      • Group A: 84ng/mm (range 3-641)
      • Group B: 76ng/ml (range 4-2880)
    • Unbound dabigatran was <20ng/ml (level that produces little or no anticoagulant effect) in:
      • 89% of patients post 1st vial of idarucizumab
      • 93% of patients at 12 hours
      • 79% of patients at 24 hours

• Comparing patients with normal clotting results at presentation (n=22) vs. elevated clotting times at presentation (n=68)
  • Creatinine clearance: 48ml/min vs. 67ml/min
  • Median time since dabigatran dose: 12.8 hours vs. 30.3 hours
  • Mortality: 4.5% vs. 25%
  • Thrombotic events: 9.0% vs. 4.4%

• Clinical outcomes
  • Causes of death within 96 hours
    • Intracranial bleeding (n=3)
    • Septic shock (n=1)
    • Sepsis and GI bleeding (n=1)
    • Circulatory collapse (n=1)
    • Multiorgan failure (n=1)
    • Haemodynamic collapse (n=1)
    • Respiratory failure (n=1)
    • Cardiac arrest (n=1)
  • A further 8 patients died between 11 – 101 days post treatment of causes predominately secondary to co-existing conditions
  • Thrombotic events occured in 5 patients
    • 1 patient within 72 hours
    • 4 patients after 72 hours
  • For patients in group A, median reported time to cessation of bleeding 11.4 hours
  • For patients in group B, 36 of the 39 patients underwent urgent procedures, of whom normal operative haemostasis was reported in 92%

Authors’ Conclusions

• Idarucizumab completely reversed the effects of dabigatran in the majority of patients

Strengths

• Prospective
• Blinding of clinicians to coagulation tests that determined primary outcome
• Multi-centre
• The population studied was the group of patients that clinicians will want to be able to immediately reverse the effects of dabigatran

Weaknesses

• Significant conflict of interests with staff working for Boehringer Ingelheim Pharmaceuticals involved in the design, conduct and write-up of the trial
• No control group. BCSH guidelines recommend the use of prothrombin complex concentrates and other treatments for dabigatran reversal
• Causes for mortality not clear for some patients. i.e. some patient had cardiac arrest, was this due to a thrombosis, bleeding or anaphylaxis secondary to Idarucizumab?  (Idarucizumab is an antibody fragment. Other antibody fragments e.g. digibind can cause anaphylaxis.) One patient had a haemodynamic collapse whereas another patient had a circulatory collapse. What is the difference between these two, and what caused both of these ‘collapses’?
• Small number of patients