Idarucizumab Reverses the Anticoagulant Effect of Dabigatran Within Minutes in Patient Study

TORONTO,  Results from an interim analysis of the Phase III RE-VERSE AD™ patient study demonstrate that 5 g of idarucizumab* immediately reversed the anticoagulant effect of dabigatran (Pradaxa^® dabigatran etexilate mesylate) in patients requiring urgent anticoagulant reversal. No safety concerns relating to idarucizumab were identified. The results have been simultaneously published in the New England Journal of Medicine (NEJM) and presented today at the International Society of Thrombosis and Haemostasis 2015 Congress in Toronto, Canada. 

"The interim analysis from RE-VERSE AD is important for healthcare professionals as it provides the first insights into the effect of a specific reversal agent to a non-vitamin K antagonist oral anticoagulant during real-world emergency situations," said Dr. Charles Pollack, Professor of Emergency Medicine at the Perelman School of Medicine of the University of Pennsylvania School of Medicine inPhiladelphia, USA, and lead investigator of the patient study. "As observed in earlier research in volunteers, idarucizumab reversed the anticoagulant effect of dabigatran in patients completely within minutes, even in those rare critical care situations studied in RE-VERSE AD. These data demonstrate that use of idarucizumab can help physicians focus on other vital aspects of emergency management beyond anticoagulant reversal in dabigatran-treated patients."

RE-VERSE AD is designed to evaluate the types of patients and real-world situations healthcare professionals may see in the emergency setting. The broad inclusion criteria ensure that even the most severely ill or injured patients (e.g. patients with sepsis or a severe intracranial hemorrhage), who require urgent reversal of dabigatran, may be enrolled in the study. Patients were categorized into two groups – (A) patients with uncontrolled or life-threatening bleeding complications, e.g. intracranial hemorrhage or severe trauma after a car accident (Group A, n= 51), or (B) patients requiring emergency surgery or an invasive procedure, e.g. surgery for an open fracture after a fall (Group B, n=39). The primary endpoint of the study is the degree of reversal of the anticoagulant effect of dabigatran achieved by 5 g idarucizumab within 4 hours measured by diluted thrombin time (dTT) and ecarin clotting time (ECT).

The interim analysis from RE-VERSE AD included data from 90 patients in the emergency setting who were taking dabigatran and required reversal. Of the 81 patients that presented with elevated anticoagulation levels at baseline as measured with ECT, results showed:

• The study met its primary endpoint, achieving 100 percent maximum reversal as median value across all patients 
• Reversal was evident immediately after administration of the first vial of idarucizumab and was complete in all but 1 patient 
• After 4 and 12 hours, laboratory tests showed normal coagulation levels in almost 90 percent of patients 
• Normal blood clotting (haemostasis) during surgery was reported in 92 percent of the patients that required surgery or invasive procedures 
• There was no signal of a pro-coagulant effect following administration of idarucizumab 
• Thrombotic events occurred in five patients, none of whom was receiving antithrombotic therapy at the time of the event 
• There were 18 deaths overall.  Mortality within 96 hours of study enrollment appeared to be related to the original reason for emergency admission to the hospital, while all later events appeared to be related to co-morbidities 

"The real-world results from RE-VERSE AD are extremely encouraging and demonstrate how idarucizumab* can support patient management during emergency situations," said Professor Jorg Kreuzer, Vice President Medicine Therapeutic Area Cardiovascular, Boehringer Ingelheim. "The study is ongoing. We look forward to gaining further understanding of the potential of idarucizumab as yet another breakthrough in anticoagulant therapy for advancing care of patients who require urgent reversal of the anticoagulant effect of dabigatran."

About Idarucizumab
Idarucizumab is a humanized antibody fragment, or Fab, being investigated as a specific reversal agent for the anticoagulant effect of dabigatran in patients needing emergency surgery or urgent procedures or for life-threatening or uncontrolled bleeding events. The safety and efficacy of idarucizumab has not been established.

Boehringer Ingelheim scientists discovered and are developing idarucizumab. The research program was initiated in 2009, before PRADAXA was launched in the U.S. in 2010. The company has a rich history in supporting the development and manufacturing of biopharmaceutical products, and idarucizumab is an example of this dedication and experience.

The company completed three phase I trials of idarucizumab in human volunteers, and included these data in the idarucizumab Biologics License Application (BLA) submitted to the FDA. Interim data from RE-VERSE AD™ was also included in the idarucizumab BLA.

Boehringer Ingelheim is continuing to evaluate idarucizumab in RE-VERSE AD, a phase III global study that includes patients taking PRADAXA who have uncontrolled or life-threatening bleeding or require emergency procedures. The study is the first of its kind in patients, and has been underway since May 2014 enrolling patients in more than 35 countries.

About Pradaxa^® (dabigatran etexilate mesylate) Capsules

Indications and Usage
Pradaxa^® (dabigatran etexilate mesylate) capsules is indicated:

to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation;

for the treatment of deep venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days;

to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in patients who have been previously treated

Source:  Boehringer Ingelheim Pharmaceuticals, Inc.