Idarucizumab for Dabigatran Reversal | Journal Scan

Study Questions:

What is the safety, tolerability, and efficacy of increasing doses of idarucizumab, a monoclonal antibody fragment that binds dabigatran, for the reversal of dabigatran’s anticoagulant effect?

Methods:

In a two-part phase 1 study (rising-dose and dose-finding proof-of-concept investigation), healthy male volunteers were randomized 3:1 to receive idarucizumab or placebo. All participants received oral dabigatran 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab was administered 2 hours after the final dabigatran dose. Idarucizumab was given at a dose of 1 g, 2 g, or 4 g infusion over 5 minutes, or as a 5 g infusion followed 1 hour later by a 2.5 g infusion each over 5 minutes. The primary endpoint was drug-related adverse events. Reversal of the diluted thrombin time, ecarin clotting time, activated partial thromboplastin time, and thrombin time were secondary endpoints measured as an area under the effect curve between 2 and 12 hours post dabigatran administration (AUEC2-12).

Results:

Between February and November 2013, 47 healthy male volunteers completed this study. Twelve volunteers were assigned to each dosing group (11 in the 4 g idarucizumab group), with six volunteers receiving idarucizumab and three receiving placebo. All drug-related adverse events were considered mild intensity in seven patients, including infusion site erythema, hot flushes, epistaxis, and infusion site hematoma. Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation, as measured by the various coagulation tests in a dose-dependent manner. The mean ratio of a day 4 to 3 AUEC2-12 was 1.01 for the placebo group, while mean AUEC2-12 reduction was 74% reduction for the 1 g dose, 94% for the 2 g dose, 98% for the 4 g dose, and 99% for the 5 g plus 2.5 g dose.

Conclusions:

The authors concluded that this phase 1 study demonstrates immediate and complete reversal of dabigatran-induced anticoagulation among healthy men. The authors also concluded that use of idarucizumab was well tolerated without any significant safety concerns.

Perspective:

This study provides important information about the key limitation for many practitioners and patients considering use of the new direct oral anticoagulants, such as dabigatran. While idarucizumab, a monoclonal antibody fragment that binds dabigatran, was highly effective in reducing the anticoagulant effect of dabigatran in healthy male volunteers, it remains to be seen how well it will reverse anticoagulant activity among actively bleeding patients or patients with multiple comorbidities. However, the biggest limitation may be the declining market share for dabigatran, as compared to rivaroxaban and apixaban. With other reversal agents in development for the factor Xa inhibitors, the impact of idarucizumab on dabigatran’s use remains to be seen.

Clinical Topics: Anticoagulation Management, Novel Agents

Keywords: Anticoagulants, Benzimidazoles, Double-Blind Method, Endopeptidases, Erythema, Factor Xa Inhibitors, Hematoma, Maximum Tolerated Dose, Immunoglobulin Fragments, Morpholines, Partial Thromboplastin Time, Pyrazoles, Pyridones, Safety, Treatment Outcome, Thiophenes, Thrombin Time


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