Dabigatran Reversal Agent’s Safety, Efficacy Affirmed With Updated Study Results

NEW ORLEANS, LA—Administration of idarucizumab induces rapid and complete reversal of the anticoagulant effects of dabigatran, both in patients presenting with uncontrolled bleeding and in those requiring emergency surgery or other interventions, according to updated results from the RE-VERSE AD study.

The effect of the agent, a humanized monoclonal antibody fragment that selectively binds to dabigatran (Pradaxa; Boehringer Ingelheim), was seen within minutes of initial administration and was sustained for at least 4 hours, Charles Pollack Jr., MD (Thomas Jefferson University, Philadelphia, PA), said during his presentation at the American Heart Association (AHA) Scientific Sessions 2016 here.

Although low levels of dabigatran reappeared within 24 hours in some patients, there were no clinical consequences, he reported. No safety concerns were identified.

Commenting on the study for TCTMD, former AHA president Gordon Tomaselli, MD (Johns Hopkins Medicine, Baltimore, MD), said the results—consistent with a preliminary report—were reassuring. “I think idarucizumab really does pretty safely, pretty effectively, pretty quickly reverse anticoagulation.”

Moreover, said Tomaselli, who was one of the moderators of the session at which Pollack presented the findings, “I think it may engender greater use of dabigatran over other NOACs [non-vitamin K antagonist oral anticoagulants] until the others have a reversal agent that’s available.”

The lack of effective ways to neutralize the anticoagulant effects of the NOACs “most definitely” has discouraged some physicians and patients from using the agents, Tomaselli added. Now, with the approval of idarucizumab (Praxbind; Boehringer Ingelheim) more than a year ago and the ongoing development of reversal agents for the other NOACs, that hesitancy will go away, he said.

Pollack agreed in a question-and-answer period after his talk, saying that the comfort of having a reversal agent may help accelerate the shift from warfarin to the NOACs, particularly in older patients with multiple comorbidities.

Rapid, Sustained Reversal

Results from the first 90 patients enrolled in RE-VERSE AD were reported in June 2015. Pollack presented data from the 494 patients who had completed 3 months of follow-up and he said final results from the 503 total patients included in the study will be released early next year.

The study, which lacks a control group because a “scientifically or ethically supported” gold standard with which to compare idarucizumab doesn’t exist, Pollack said, includes two types of patients: those who present with uncontrolled bleeding and those who require emergency surgery or other interventions that cannot be delayed for at least 8 hours.

In the bleeding group, the vast majority of patients (92%) had ISTH major or life-threatening bleeding. There was a wide range of indications for surgery in the other group, but the most common were acute abdominal, bone fracture, and infection.

Regardless of indication, idarucizumab is administered at a fixed dose of 5 grams, delivered in two separate vials of 2.5 grams in rapid succession. Overall, seven patients (1.4%) required a second dose of idarucizumab due to recurrent or postoperative bleeding.

As seen in the initial study findings, administration of the agent achieved rapid reversal of dabigatran’s anticoagulant effects. Median maximum reversal according to diluted thrombin time was 100% within 4 hours. That measure normalized within this time period in about 99% of patients. The results were similar for other measures of coagulation.

Hemostasis was subjectively assessed by site investigators. For the patients with extracranial bleeding, the median time to bleeding cessation was 3.5 to 4.5 hours. In the procedure group, 97.4% of patients ultimately underwent surgery at a median of 1.6 hours after administration of the first vial of idarucizumab. Local investigators classified the adequacy of hemostasis during surgery as normal in 93%.

In terms of clinical outcomes, thrombotic events were observed in 6.3% of patients within 90 days, including 15 cases of venous thromboembolism, eight ischemic strokes, seven MIs, and one systemic embolism. About two-thirds of patients who had an event were not taking any antithrombotic therapy before it occurred.

Physicians focused on reinitiating antithrombotic therapy whenever possible, and by 90 days, 72% of patients who presented with bleeding and 90% who required a procedure were taking some type of anticoagulation. The median time to restarting therapy was 5.3 days after a bleed and 1.2 days after a procedure.

By 90 days, about 19% of patients had died, mostly from underlying illness, Pollack reported.

‘An Important Advance’

Serving as a discussant following Pollack’s presentation, Christian Ruff, MD (Brigham and Women’s Hospital, Boston, MA), touted the study’s broad entry criteria and heterogeneity of the patient population as strengths that make the results generalizable to real-world practice.

However, the open-label design—though justified due to the lack of an established gold standard—influences interpretation of some of the results, he said.

What is conclusive, Ruff said, is that idarucizumab effectively achieves complete and sustained reversal of dabigatran. “And it’s certainly safe, which is very reassuring,” he said. “There [don’t] seem to be any prothrombotic, immunologic, or off-target concerns identified. So this is really an important advance.”

Less definitive is the determination of hemostasis by site investigators, although the findings are encouraging and consistent with what would be expected from complete reversal, he said.

Overall, RE-VERSE AD “really places [idarucizumab] first in line in the management of patients taking dabigatran who present with life-threatening emergencies,” Ruff said, adding that the simplicity of administration is “very attractive.”

He pointed out that serious bleeding with the NOACs is rare. “So one of the biggest impacts of specific reversal agents may be reassurance,” Ruff stated, alluding to the hesitancy of some physicians and patients to use NOACs. “We can finally tap into those unprotected patients, the 30%, 40% that were not even prescribed anticoagulation because we think that they’re too frail.”