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Idarucizumab Reverses Anticoagulant Effect of Dabigatran Within Minutes in Late-Stage Trial

Drug binds only to dabigatran molecules

Results from an interim analysis of the ongoing phase III RE-VERSE AD study have demonstrated that the investigational agent idarucizumab (Boehringer Ingelheim) immediately reversed the anticoagulant effect of dabigatran (Pradaxa, Boehringer Ingelheim) in patients requiring urgent anticoagulant reversal. The findings were published in the New England Journal of Medicine.

RE-VERSE AD was designed to evaluate the types of patients and real-world situations health care professionals may see in emergency settings. Broad inclusion criteria ensured that even the most severely ill or injured patients, such as those with sepsis or a severe intracranial hemorrhage, who require urgent reversal of dabigatran, may be enrolled in the study.

 The patients were divided into two groups: those with uncontrolled or life-threatening bleeding complications, such as intracranial hemorrhage or severe trauma after a car accident (n = 51), and those requiring emergency surgery or an invasive procedure, such as surgery for an open fracture after a fall (n = 39). The patients received 5 g of intravenous idarucizumab administered as two 50-mL bolus infusions, each containing 2.5 g of idarucizumab, no more than 15 minutes apart. Blood was collected and assessed for the treatment’s anticoagulant effect at baseline; after administration of the first vial of idarucizumab; and then between 10 and 30 minutes and 1, 2, 4, 12, and 24 hours after administration of the second vial.

The trial’s primary endpoint was the degree of reversal of the anticoagulant effect of dabigatran achieved by 5 g of idarucizumab within 4 hours, as measured by the diluted thrombin time (dTT) and the ecarin clotting time (ECT).

The interim analysis included data from 90 patients in emergency settings who were being treated with dabigatran and required reversal. Of the 81 patients that presented with elevated anticoagulation levels at baseline, as measured with ECT, the results showed the following:

  • The study met its primary endpoint, achieving 100% maximum reversal as a median value across all patients.
  • Reversal was evident immediately after administration of the first vial of idarucizumab and was complete in all but one patient.
  • After 4 and 12 hours, laboratory tests showed normal coagulation levels in almost 90% of the patients.
  • Hemostasis during surgery was reported in 92% of the patients that required surgery or invasive procedures.
  • There was no signal of a pro-coagulant effect after the administration of idarucizumab.
  • Thrombotic events occurred in five patients; none of these patients was receiving antithrombotic therapy at the time of the event.
  • Eighteen deaths occurred. Mortality within 96 hours of study enrolment appeared to be related to the original reason for emergency admission to the hospital, whereas all later events appeared to be related to comorbidities.

Idarucizumab is a humanized antibody fragment designed as a specific reversal agent to dabigatran. Idarucizumab binds only to dabigatran molecules, thereby neutralizing their anticoagulant effect without interfering with the coagulation cascade.

Boehringer Ingelheim began research on idarucizumab in 2009. In February and March 2015, the drug was submitted to the FDA under an accelerated approval pathway. The agency granted idarucizumab both “orphan drug” and “breakthrough therapy” designations.

The FDA submission included results from studies in healthy volunteers as well as in elderly and renally impaired individuals. These data showed that a 5-minute infusion of idarucizumab (greater than 2 g) led to immediate, complete, and sustained reversal of dabigatran, with no clinically relevant adverse effects or pro-coagulant effects. The FDA submission also included first data from the RE-VERSE AD study.

Source: Boehringer Ingelheim; June 22, 2015.

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