Final phase III study results confirm benefit of NOAC reversal agent in emergency situations
Final results from RE-VERSE AD were presented as a late-breaker at the ISTH 2017 Congress in Berlin, Germany. The data show that idarucizumab was able to immediately and completely reverse the anticoagulant effect of dabigatran etexilate in patients in emergency situations. The effects were consistent both in patients requiring an urgent surgery or intervention, and in patients presenting with uncontrollable or life-threatening bleeding. The reversal of the anticoagulant effect of dabigatran allowed physicians to quickly initiate necessary emergency interventions.
Idarucizumab is a humanised antibody fragment, or Fab, designed as a specific reversal agent to dabigatran. Idarucizumab binds specifically to dabigatran molecules only, neutralizing their anticoagulant effect without interfering with the coagulation cascade. RE-VERSE AD is a phase III global study of patients taking dabigatran who require urgent procedures or have uncontrolled bleeding. The study began in May 2014, and is the largest study to investigate a reversal agent for a non-vitamin K antagonist oral anticoagulant (NOAC) in real-world emergency settings. It enrolled a total of 503 patients at 173 sites in 39 countries.
The primary endpoint of RE-VERSE AD was reversal of the anticoagulant effect of dabigatran within four hours as measured by diluted thrombin time (dTT) and ecarin clotting time (ECT), and was observed in 100% of patients (95%CI, 100-100). Reversal became evident immediately after administration of idarucizumab and was maintained for 24 hours in most patients. Reversal was independent of age, sex, kidney function or dabigatran concentration at baseline. A single 5 g dose of idarucizumab was sufficient in 98% of patients.
The clinical outcomes captured as secondary endpoints provide insights into the clinical relevance of anticoagulation reversal: in patients enrolled with acute bleeding (Group A), who could be assessed for time to cessation of bleeding, it took a median of 2.5 hours until the bleeding had stopped; in patients enrolled with a need for urgent surgery or intervention (Group B), the required procedures could be initiated after a median of 1.6 hours. In 93.4% of patients requiring procedures, hemostasis during the procedure was described as normal.
No serious adverse safety signals related to idarucizumab were observed in the study. Patients in this study were elderly, had numerous comorbidities and presented with serious index events such as intracranial hemorrhage, multiple trauma or sepsis. Mortality rates at 90 days were 18.8% (Group A) and 18.9% (Group B). At 90 days, thrombotic events had occurred in 6.3% of Group A patients and 7.4% of Group B patients, which is consistent with rates reported after major surgical procedures or hospitalization for uncontrolled bleeding in patients who had taken a vitamin K antagonist.
Idarucizumab is the first and only approved specific reversal agent for a NOAC currently available. Idarucizumab will further be studied in the RE-VECTO program, which evaluates usage patterns in a clinical practice setting. Expected completion of the RE-VECTO program is the end of 2018.