RE-VERSE AD

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Pollack CV, et al. "Idarucizumab for Dabigatran Reversal". The New England Journal of Medicine. 2015. 373(6):511-520.
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Clinical Question

Among patients receiving dabigatran who develop serious bleeding or need an urgent invasive procedure, does idarucizumab reverse the anticoagulant effects of dabigatran?

Bottom Line

Among patients receiving dabigatran who develop serious bleeding or need an urgent invasive procedure, idarucizumab reverses the anticoagulant effects of dabigatran within minutes of administration.

Major Points

Dabigatran is an orally administered direct thrombin inhibitor approved by the FDA for use in patients with non-valvular atrial fibrillation, DVT/PE, and for VTE prophylaxis after hip surgery, based in part upon data from RE-LY and RE-COVER studies. One major factor for both clinicians and patients when choosing between warfarin and newer direct oral anticoagulants (DOACs) has been the lack of a suitable reversal agent for the management of serious bleeding or urgent invasive procedures. Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity, and has been in development as a reversal agent for patients receiving dabigatran anticoagulation.

RE-VERSE AD is an ongoing prospective cohort study evaluating the efficacy of idarucizumab in reversing the anticoagulant effects of dabigatran in patients with serious bleeding and patients requiring an urgent invasive procedure. This manuscript reports results of an interim analysis of 90 patients on the study. Patients were predominantly elderly (median age 77 years) receiving anticoagulation mostly for atrial fibrillation (96% of patients enrolled). Approximately two-thirds of patients were receiving dabigatran at a dose of 110 mg twice daily, while most of the remainder received 150 mg twice daily. Among patients enrolled for serious bleeding, the site of bleeding was the GI tract or intracranial in 39% and 35%, respectively. The reasons for urgent invasive procedures varied widely, but included skeletal fractures in several patients (21%). Patients received two doses of idarucizumab 2.5 g IV, with both doses delivered within a span of 15 minutes. The total dose of 5 g was determined based on calculations of the required dose to neutralize 99% of the total body dabigatran in patients enrolled in the RE-LY study. The primary endpoint of this study was reversal of the anticoagulant effects of dabigatran based upon dilute thrombin or ecarin clotting times; secondary endpoints included clinical resolution of bleeding; and patients were followed for at least one month. Normalization of dilute thrombin time was achieved in 98% of patients with acute bleeding and 93% of patients requiring an invasive procedure. The time to cessation of bleeding was 11.4 hours. Thrombotic events occurred in 5 patients receiving idarucizumab, none of whom were receiving anticoagulation at the time their thrombosis was diagnosed.

As of February 2016, RE-VERSE AD continues to enroll patients.[1] In the meantime, analysis of three randomized, placebo-controlled trials in healthy volunteers demonstrated the utility of idarucizumab in dabigatran reversal.[2][3][4] As a result of these three studies, in October 2015, the FDA granted accelerated approval of idarucizumab for the treatment of dabigatran-associated life-threatening or uncontrolled bleeding, or for urgent reversal of anticoagulation before an invasive procedure. The agent is now available at some medical centers. Agents for reversing the anticoagulant effects of other DOACs are currently under clinical investigation and include andexanet alfa (for reversing the effects of factor Xa inhibitors)[5] and PER997 (a so-called universal reversal agent).

Guidelines

Updated Chest Guidelines for VTE management were published in January 2016,[6] but these do not incorporate DOAC reversal agents such as idarucizumab.

Design

  • Multicenter, prospective cohort study
  • N=90 of planned 300
    • Group A, major bleed (n=51)
    • Group B, urgent procedure (n=39)
  • Setting: 400 centers in 38 countries
  • Enrollment: 2014-2015 (planned through 2017)
  • Follow-up: At least 1 month or death
  • Primary outcome: Maximum reversal of anticoagulant effect of dabigatran based on central laboratory determination of dTT (direct thrombin time) or ECT (ecarin clotting time), at any time between the end of the first infusion to 4 hours after the last infusion.

Population

Inclusion Criteria

  • Group A (bleeding patients)
    • Overt major or life-threatening bleeding judged by the physician to require a reversal agent
      • Fatal bleeding
      • Symptomatic intracranial bleeding
      • Reduction in hemoglobin of at least 5 g/dL
      • Transfusion of at least 4 units of blood or packed cells
      • Bleeding associated with hypotension requiring use of intravenous inotropic agents
      • Bleeding necessitating surgical intervention
    • Currently taking dabigatran etexilate
    • Age ≥18 years
  • Group B (require emergency surgery or procedure for a condition other than bleeding)
    • Condition requiring emergency surgery or invasive procedure where adequate hemostasis is required. Emergency is defined as within the following 8 hours.
    • Current treatment with dabigatran
    • Age ≥18 years

Exclusion Criteria

  • Group A (bleeding Patients)
    • Patients with minor bleeds (epistaxis, hematuria) who can be managed with standard supportive care.
    • Patients with no clinical signs of bleeding
    • Contraindications to study medication including known hypersensitivity to the drug or its excipients.
  • Group B (require emergency surgery or procedure for a condition other than bleeding)
    • A surgery or procedure which is elective or where the risk of uncontrolled or unmanageable bleeding is low.
    • Contraindications to study medication including known hypersensitivity to the drug or its excipients (such as subjects with hereditary fructose intolerance who may react to sorbitol).

Baseline Characteristics

Group A
  • Demographics: Age 77 years, 47% female
    • Race or ethnic group: 10% Asian, 6% Hawaiian or Pacific Islander, 84% White
  • Median weight: 70.5 kg
  • Mean creatinine clearance: 59 ml/min
  • Dose of dabigatran: 27% at 150 mg twice daily, 67% at 110 mg twice daily, 2% at 75 mg twice daily 2%, 4% other
  • Indication for dabigatran: AF 92%, VTE 2%, other 6%
  • Median Time since last intake of dabigatran: 15.2 hr
  • Elevated dilute thrombin time at baseline: 78%
  • Elevated ecarin clotting time at baseline: 92%
  • Type of bleeding: Intracranial 35%, trauma-related 18%, GI 39%, other 22%
Group B
  • Demographics: Age 76 years, 54% female
    • Race or ethnic group: 3% Asian, 8% Hawaiian or Pacific Islander, 90% White
  • Median weight: 73 kg
  • Mean creatinine clearance: 65 ml/min
  • Dose of dabigatran: 38% at 150 mg twice daily, 62% at 110 mg twice daily, none at 75 mg twice daily
  • Indication for dabigatran: AF 100%, VTE 0%
  • Median time since last intake of dabigatran: 16.6 hr
  • Elevated dilute thrombin time at baseline: 72%
  • Elevated ecarin clotting time at baseline: 87%

Interventions

  • Two 50-ml boluses each containing 2.5 g of idarucizumab, spaced 15 minutes apart for a total of 5 g total of medication was given to all study participants

Outcomes

Primary Outcome

dTT (diluted thrombin time in seconds)
  • 22 patients had dilute thrombin times determined by central laboratory analysis to be within normal limits prior to treatment
  • In the remaining 68 of 90 who were included in the analysis, 40 patients in group A and 28 in group B, dilute thrombin time was normalized in 98% of the patients in group A and 93% in group B.
  • At 12 hours dTT below the upper limit of the normal range in 90% of the patients in group A who could be evaluated and in 81% of those in group B
  • Group A:
    • Mean dTT at baseline: 54.1 (n=51, SD=23.6)
    • Mean dTT between vials: 29.7 (n=51, SD=2.46)
    • Mean dTT 10-30 min after second vial: 29.8 (n=51, SD=2.42)
    • Mean dTT 4 h +/- 30 min after second vial: 29.6 (n=46, SD= 2.59)
  • Group B:
    • Mean dTT at baseline: 53.2 (n=39, SD=38.5)
    • Mean dTT between vials: 32.9 (n=39, SD=20.9)
    • Mean dTT 10-30 min after second vial: 31.3 (n=39, SD=12.4)
    • Mean dTT 4 h +/- 30 min after second vial: 35.8 (n=37. SD=25.5)
ECT (ecarin clotting time in seconds)
  • 9 patients (all of whom had normal dilute thrombin times) had ecarin clotting times determined to be within normal limits prior to treatment
  • In the remaining 81 of 90 who were included in the analysis, 47 in group A and 34 in group B, ecarin clotting time was normalized in 89% of patients in Group A and 88% of the patients in group B.
  • At 12 hours, the ecarin clotting time was below the upper limit of the normal range in 72% of the patients in group A who could be evaluated and 54% of those in group B
  • Group A:
    • Mean ECT at baseline: 113 (n=51, SD= 79.0)
    • Mean ECT between vials: 38.2 (n=51, SD=6.00)
    • Mean ECT 10-30 min after second vial: 39.3 (n=51, SD=6.72)
    • Mean ECT 4 h +/- 30 min after second vial: 37.7 (n=47, SD=4.06)
  • Group B:
    • Mean ECT at baseline: 111 (n=39, SD=97.1)
    • Mean ECT between vials: 45.3 (n=39, SD=44.0)
    • Mean ECT 10-30 min after second vial: 44.6 (n=39, SD=43.5)
    • Mean ECT 4 h +/- 30 min after second vial: 59.0 (n=37, SD=85.3)

Secondary Outcomes

Time to cessation of bleeding (for Group A only)
  • Could not be ascertained in 13 patients: 5 intracranial hemorrhage, 4 GI bleeding, 2 intramuscular bleeding, 1 pericardial bleeding, 1 retroperitoneal bleeding.
  • Median investigator-reported time to the cessation of bleeding for remaining patients was 11.4 hours
Occurrence of major bleeding (for group B only) intraoperatively and up to 24 hours post-surgery
  • Idarucizumab obviated the need for emergency dialysis in 1 patient in group B who had ingested a massive overdose of dabigatran
  • 2 of the remaining 38 patients remained too unstable for surgery despite the reversal of anticoagulation.
  • Of the 36 patients who received a procedure:
    • Normal intraoperative hemostasis was reported in 33 (92%) patients
    • Mildly abnormal hemostasis during the procedure was reported in 2 patients
    • Moderately abnormal hemostasis reported in 1 patient
Unbound unbound (free) dabigatran [ng/mL]
  • Group A:
    • Mean unbound dabigatran at baseline: 161 (n=48, SD=166)
    • Mean unbound dabigatran between vials: 1.11 (n=48, SD= 0.288)
    • Mean unbound dabigatran 10-30 min after second vial: 1.08 (n=48, SD=0.431)
    • Mean unbound dabigatran 4 h +/- 30 min after second vial: 1.01 (n=46, SD=0.0516)
  • Group B:
    • Mean unbound dabigatran at baseline: 218 (n=39, SD=503)
    • Mean unbound dabigatran between vials: 34.6 (n=39, SD=206)
    • Mean unbound dabigatran 10-30 min after second vial: 18.5 (n=39, SD=107)
    • Mean unbound dabigatran 4 h +/- 30 min after second vial: 63.9 (n=38, SD=277)

Subgroup Analysis

  • 22 patients with normal dTT had better renal function (median creatinine clearance 67 ml per minute vs 48 ml per minute in those with elevated dTT) and a longer time since the last dose of dabigatran (median, 30.3 hours vs. 12.8).

Adverse Events

Death
  • 18 deaths overall, with 9 in Group A, 9 in Group B
  • 10 deaths were due to vascular causes, including 5 fatal bleeding events.
  • 9 of 18 death were within 96 hours after treatment and appear to be related to the index event (2 septic shock, 3 intracranial hemorrhage, 1 multiorgan failure, 1 hemodynamic collapse, 1 respiratory failure, and 1 cardiac arrest)
Thrombotic events
  • Occurred in five patients overall (none were on any anti-thrombotic agents at the time of these events):
    • deep-vein thrombosis and pulmonary embolism occurred in one patient 2 days after treatment
    • deep-vein thrombosis, pulmonary embolism and left atrial thrombus occurred in one patient 9 days after treatment
    • deep-vein thrombosis alone occurred in one patient 7 days after treatment
    • non–ST-segment elevation myocardial infarction occurred in one patient 13 days after treatment
    • and ischemic stroke occurred in one patient 26 days after treatment.

Criticisms

  • Although the interim data is very promising, a more solid conclusion will be available upon the formal completion of the trial.
  • This study did not evaluate mortality (although this type of study inherently cannot).

Funding

  • Funded by Boehringer Ingelheim pharmaceutical company

Further Reading