Final Phase III results support safety of idarucizumab as reversal agent for dabigatran etexilate mesylate

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Manufacturing at Boehringer Ingelheim

Final results from RE-VERSE AD study show that idarucizumab, marketed in the US as Praxbind (Boehringer Ingelheim), was able to immediately reverse the anticoagulant effect of dabigatran etexilate mesylate (Pradaxa, Boehringer Ingelheim) 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 etexilate mesylate allowed physicians to quickly initiate necessary emergency interventions. The findings were presented at the International Society on Thrombosis and Haemostasis 26th Biennial Congress (ISTH; 8–13 July, Berlin, Germany) and simultaneously published in the New England Journal of Medicine.

The primary endpoint of RE-VERSE AD was reversal of the anticoagulant effect of dabigatran etexilate mesylate 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 5g 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, haemostasis during the procedure was described as normal.

“Emergencies or accidents can happen to anyone. Patients with atrial fibrillation on an anticoagulant may feel anxious about how they might be managed in an emergency,” says Charles Pollack, lead investigator of RE-VERSE AD, professor of Emergency Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, USA. “RE-VERSE AD has shown that idarucizumab reverses the anticoagulant effect of dabigatran within minutes, so that treating physicians can fully focus on dealing with the emergency at hand.”

There were no adverse safety signals related to idarucizumab observed in the study. Patients in this study were elderly, had numerous comorbidities and presented with serious index events such as intracranial haemorrhage, 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 hospitalisation for uncontrolled bleeding.

Idarucizumab is the first and only approved specific reversal agent for a novel oral anticoagulant currently available. It is approved as a specific reversal agent for dabigatran etexilate mesylate by the US Food and Drug Administration (FDA) under accelerated approval. Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study.

Boehringer Ingelheim continues to study idarucizumab in the RE-VECTO programme, which evaluates usage patterns in a clinical practice setting. Expected completion for RE-VECTO is at the end of 2018.

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