LOS ANGELES – It only took a few minutes for idarucizumab to normalize blood-clotting parameters in 18 patients with dabigatran-associated intracranial hemorrhages, according to interim results from an ongoing phase III trial presented at the International Stroke Conference.
“When I put patients on [dabigatran], they always ask me what happens if they bleed or need surgery. … Until now, I haven’t been able to tell them with any confidence that I have a way of reversing it. Now I think I can. ... It makes a big difference” in their comfort, said lead investigator Dr. Richard Bernstein, a Northwestern University neurology professor and director of the stroke program at Northwestern Memorial Hospital, in Chicago.
Dr. Richard Bernstein
“We would love to know if hematoma expansion was limited [and outcomes improved] by giving this reversal agent,” but the study so far is too small. “We hope to have a larger cohort of brain hemorrhage patients to answer these questions,” he said.
Approved in October 2015, idarucizumab (Praxbind) was fast tracked by the Food and Drug Administration to reverse the blockbuster atrial fibrillation anticoagulant dabigatran (Pradaxa); the labeling for idarucizumab doesn’t mention intracranial hemorrhage patients specifically. Boehringer Ingelheim makes both drugs, and funded Dr. Bernstein’s work.
Eleven of the 18 patients were men, and the average age in the study was about 80 years. The patients had either subdural hematomas or bleeding into the brain itself. They were culled from the 90 subjects analyzed so far in the idarucizumab trial, dubbed RE-VERSE AD (Reversal Effects of Idarucizumab in Patients on Active Dabigatran).
The team followed label dosing: 5 g total given as two separate 2.5-g infusions. Blood samples were taken in between to check how well idarucizumab worked. The whole process took no more than 15 minutes.
The first 2.5 g completely reversed dabigatran in all 18 patients, based on their dilute thrombin or ecarin clotting times. Patients “remained reversed out to 12 hours, and all but one out to 24 hours,” Dr. Bernstein said at the conference, sponsored by the American Heart Association.
Idarucizumab is a monoclonal antibody fragment that binds dabigatran more powerfully than dabigatran binds thrombin. In vitro studies have found no prothrombotic effects. “It has no endogenous target, so the drug has no effect on any other clotting factors that we can tell. We did have, I think, five thrombotic events in our cohort, most of them many days after the dabigatran was reversed. It may have just been a reversion to [patient] clotting risks,” he said.
When – or if – to restart dabigatran “is a clinical question.” If bleeding is controlled or patients are stable after surgery, you can go back on the next day,” he said.
Idarucizumab’s labeling notes that 5% or more of patients developed hypokalemia, delirium, constipation, pyrexia, and pneumonia. It wasn’t clear these events were drug related. Patients had dabigatran reversed either for serious bleeding or emergency surgery.
Dr. Bernstein is a speaker and adviser for Boehringer Ingelheim, and reported honoraria from the company.