Rapid Reversal of Dabigatran Anticoagulation With Idarucizumab

Daniel M Keller, PhD

July 13, 2017

BERLIN — Using the monoclonal antibody reversal agent idarucizumab (Praxbind, Boehringer Ingelheim), researchers have shown rapid, complete, and sustained reversal of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) anticoagulation in a cohort of elderly, multimorbid patients with life-threatening emergencies[1].

Patients in this study, RE-VERSE AD, required reversal of anticoagulation because of uncontrolled bleeding or because they needed emergency surgery or an invasive procedure.

"Among bleeding patients who were reversed, the median time to investigator-reported hemostasis was 2.5 hours," said lead researcher Dr Charles Pollack (Thomas Jefferson University in Philadelphia, PA).

For patients undergoing invasive procedures, "nearly all of these 202 patients actually underwent the procedure for which they were reversed, [and] then at the time of their procedure 93.4% were reported to have hemostasis as if they had not been anticoagulated," he said. All of the remaining 6.6% had only mildly to moderately abnormal hemostasis. The median time from reversal to procedure was 1.6 hours.

Laboratory studies were consistent with the observed cessation of bleeding. "The [diluted thrombin time] dTT normalized at nearly 99% of all bleeding and preprocedure patients by 4 hours," Dr Pollack said.

The results were reported here at the International Society on Thrombosis and Haemostasis 2017 Congress and published online July 11, 2017 in the New England Journal of Medicine.

Idarucizumab is a humanized antibody-binding fragment (Fab) that essentially irreversibly binds free and thrombin-bound dabigatran with high affinity. It is specific for dabigatran and does not reverse the effects of heparin or other anticoagulants. After intravenous administration, it has a rapid onset of action and is short-lived in the circulation, with a half-life of about 45 minutes.

RE-VERSE AD was an international, multicenter, open-label, single-arm, phase 3 study. The researchers enrolled 503 patients, 301 in group A, patients presenting with uncontrolled bleeding, and 202 in group B, those requiring urgent surgery or interventions, from 173 sites.

However, patients with intracranial bleeding (32.6% of patients with bleeds) were not evaluable because the study did not mandate interval brain imaging.

Patients were treated based only on their clinical presentation and without coagulation studies. They received a total of 5 g of idarucizumab, administered as two 2.5-g infusions 15 minutes apart. This fixed dose is based on anticipated dabigatran loads.

The primary end point was the maximum reversal of anticoagulation within 4 hours, as assessed by dTT and ecarin clotting-time measures. Blood samples were drawn frequently over the 4 hours as well as at 12 hours and 24 hours, 30 days, and 90 days.

Patients in both groups were mostly elderly, with mean ages of 77 to 79 years (range 21–96 years). About a third of the patients had congestive heart failure, diabetes, coronary artery disease, and/or prior stroke or transient ischemic attack. About 95% were taking dabigatran for atrial fibrillation.

Of the bleeds, 88% were considered major and life-threatening, with 45.5% of those being gastrointestinal. The rest were in a variety of other internal sites. The three most prevalent indications (62%) among the surgical/invasive-procedure patients were acute abdomen, bone fracture, and cardiovascular.

At 72 hours after idarucizumab infusion, 22.9% of the previously bleeding and 66.8% of the procedural patients had restarted anticoagulation or antiplatelet therapy. By 90 days, antithrombotic therapy had been restarted in 72.8% and 90.1% of the patients, respectively.

In either group, thrombotic events occurred in 5% or fewer of the patients at 30 days. At 90 days, the rate was less than 7.5% for either group.

Mortality at 30 days was 13.5% for the patients with bleeds and 12.6% for the invasive-procedure patients. At 90 days, mortality was 18.8% and 18.9%, respectively, most of which Pollack attributed to the underlying conditions on admission.

He said this open-label cohort study "provides a broad and heterogeneous emergency-patient population, including patients requiring urgent surgery and interventions." He noted that no safety concerns or antibody formation against idarucizumab have been seen so far.

Dr Wolfram Ruf (Center for Thrombosis and Hemostasis at Johannes Gutenberg University, Mainz, Germany) commented to theheart.org | Medscape Cardiology that the seemingly large dose of 5 g of idarucizumab is necessary "if you have to neutralize the drug and suck it up more or less." As seen in the RE-VERSE AD results, he said, "I think you can safely do interventions and so on, which is very good for a patient who comes in with comorbidities to be treated."

Dr Sam Schulman (McMaster University, Hamilton, ON) and cochair of the late-breaking abstract session in which the RE-VERSE AD study was presented, said that even though there is now a reversal agent for the anticoagulant effect of dabigatran, he does not think it would change prescribing patterns to favor this drug over other novel oral anticoagulants (NOACs), although he said some patients "clearly are worried about taking anticoagulants at all or switching from warfarin to a new anticoagulant because they know that we have [prothrombin complex concentrate] PCC for warfarin, and they have heard . . . that new anticoagulants have no antidote."

He added that some prescribers have been hesitant to use NOACs, but he referred to Pollack's presentation, in which he noted that overall, the NOACs are safer than warfarin, with a 50% reduction in the risk of intracranial bleeding.

Schulman said there is a need for standardization of measures of anticoagulant reversal and an ISTH subcommittee is looking into "how to define effective vs noneffective reversal."

Criteria are needed for intracranial bleeding, gastrointestinal bleeding, and bleeding at other sites so that all reversal studies will use standardized measures "so that we can compare outcomes between the studies."

The study was supported by Boehringer Ingelheim.Pollack is a consultant to and has research support from Boehringer Ingelheim, Janssen Pharma, Daiichi-Sankyo, and Portola. He also has research support from CSL Behring and is a consultant to Bristol Myers-Squibb/Pfizer. Disclosures for the coauthors are listed on the journal website. Ruf had no relevant financial relationships. Schulman is on the advisory board and study committees for Boehringer Ingelheim.

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