Study Demonstrates Effectiveness, Safety, of Reversal Agent for Novel Oral Anticoagulants

By Debra Gordon and Mellanie True Hills

The blood thinners used in people with atrial fibrillation (AF) work well to prevent blood clots and stroke. But all carry some risk of major bleeding. So doctors need some way to quickly stop this anticoagulation process if bleeding occurs.

Such a “reversal” agent has been available for warfarin for decades. However, until recently, there was none available for the novel oral anticoagulants (NOACs) dabigatran (Pradaxa®), rivaroxaban (Xarelto®), apixaban (Eliquis®), and edoxaban (Savaysa), also called Factor Xa (pronounced “10a”) inhibitors. A reversal agent is important because bleeding from these medications leads to more than 100,000 hospitalizations a year in the US, 15 to 20 percent of which are fatal.

A reversal agent for dabigatran, idarucizumab (Praxbind®), was approved in 2015.Now one might soon be available for the other 3 NOACs.

In March, researchers at the 2018 American College of Cardiology conference announced positive results from a large trial of the reversal agent andexanet (AndexXa®), that showed it, too, could successfully and safely stop the anticoagulant actions of the other NOACs.

In the ANNEXA-4 trial (Andexanet For Reversal of Anticoagulation in Factor Xa – Associated Acute Major Bleeding), researchers assessed how well andexanet worked in 227 individuals with AF and/or venous thromboembolic (VTE) disease (in which blood clots form in the legs that could travel to the lungs) who were experiencing bleeding. They also looked at whether the drug was safe in another 137 people. About 60 percent of the volunteers in each group had bleeding in their brain and a third had bleeding in their stomach.

All received a two-hour infusion of andexanet, which safely stopped the bleeding in 83% of participants in the efficacy group. Neither group showed any serious side effects. The results are similar to those seen with already approved reversal agents for dabigatran and warfarin.

“The NOACs were a major step forward in the prevention of VTE and AF-related strokes,” said lead investigator Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, during a press conference, “but the obstacle has always been the question of being able to reverse the effects in the setting of major bleeding.”

Now, he said, there are tools available to quickly reverse the actions of the NOACs so the patient’s own clotting mechanism can kick in enabling them to recover from major bleeding.”

He also highlighted another important finding from the trial. Six participants in the group that was assessed for the safety of the drug experienced a thrombotic event (stroke, VTE, blood clot to the lungs, or heart attack) within 3 days of the anticoagulation reversal and 24 within a month. Overall, 27 died, 11 related to cardiovascular events. This highlights the high risk of stroke and other serious events in people with AF if they do not receive blood thinners, he noted.

“One of the most important concepts to come out of this is the issue of thrombosis (clots) in patients who had their anticoagulant discontinued and reversed,” he said. Thus, it is important that once anticoagulation is reversed, doctors try to restart it as soon as it is safe.

The trial is still continuing, with more long-term results expected later.