LOS ANGELES—Idarucizumab normalized blood-clotting parameters within a few minutes in 18 patients with dabigatran-associated intracranial hemorrhage, according to interim results from a phase III trial presented at the International Stroke Conference 2016.
“When I put patients on [dabigatran], they always ask me what happens if they bleed or need surgery,” said lead investigator Richard A. Bernstein, MD, PhD, Professor of Neurology at Northwestern University and Director of the Stroke Program at Northwestern Memorial Hospital in Chicago. “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 Dr. Bernstein.
The FDA approved idarucizumab (Praxbind) in October 2015 to reverse the effects of the atrial fibrillation anticoagulant dabigatran (Pradaxa) during emergency situations. The labeling for idarucizumab doesn’t mention intracranial hemorrhage specifically. Boehringer Ingelheim of Ridgefield, Connecticut, makes both drugs and funded Dr. Bernstein’s research.
The 18 patients with intracranial hemorrhage were among 90 subjects enrolled in the ongoing Reversal Effects of Idarucizumab in Patients on Active Dabigatran (RE-VERSE AD) trial. The trial enrolled patients who had serious bleeding or needed emergency surgery. Eleven of the 18 patients with intracranial hemorrhage were men, and the average age was about 80. The patients had either subdural hematoma or bleeding into the brain itself.
Investigators followed label dosing: 5 g total given as two separate 2.5-g infusions. Blood samples were taken between doses 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.
“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, he said. “We hope to have a larger cohort of brain hemorrhage patients to answer these questions.”
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,” said Dr. Bernstein. Most thrombotic events in the trial have occurred many days after 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 [dabigatran] 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 that these events were drug related
—M. Alexander Otto