Idarucizumab reverses the anticoagulant effect of dabigatran

July 14, 2017 – In patients receiving dabigatran (anticoagulant treatment), Idarucizumab had a safe and effective reversal of the anticoagulant effects dabigatran, based on a multicenter, prospective cohort study.

Dr. Charles V Pollack Jr., MD with the Thomas Jefferson University, Philadelphia and other investigators on the RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) study reported their findings in the July 14 online issue of the New England Journal of Medicine.

Idarucizumab is a monoclonal antibody fragment that has a higher affinity for binding to dabigatran compared to thrombin. This property allows a neutralization of the anticoagulant effects of dabigatran, through binding to free dabigatran and thrombin displacement from thrombin-bound dabigatran. Thus, idarucizumab can induce a turnaround in the anti-clotting effects of dabigatran in patients with severe bleeding or need for urgent surgery.

The study was conducted to assess the degree of reversal of idarucizumab on the anticoagulant effects of dabigatran in patients with uncontrollable bleeding and those about to undergo surgery or other invasive procedures.

A total of 503 patients from 39 countries were divided into two groups (301:202), one with uncontrollable bleeding in need of a quick anticoagulant reversal and the other of patients about to undergo surgery or other invasive procedure. Both received 5 g of intravenous Idarucizumab in two 50-ml bolus infusions. In cases of repeat bleeds or sustained bleeding, an additional 5 g dose of idarucizumab was allowed.

Primary outcomes of focus included clotting times and pharmacokinetic/pharmacodynamic assessments for idarucizumab at separate time points from the completion of the first infusion (baseline, 10-30 minutes, 1, 2, 4,12, 24-hour intervals). Secondary endpoints included clinical outcomes, based on the clinician’s assessment and differed for both groups. For group A, this included bleeding severity and hemodynamic stability, based on a standardized scale. For group B, this included periprocedural hemostasis as defined by the clinician.

A complete reversal of anticoagulation was observed within 4 hours (100% (95% confidence interval, 100 to 100), based on the diluted thrombin time and ecarin clotting time, for 91.7% of patients in both groups (276 in group A and 185 in group B). Assessments of the drug concentration correlated with results from the clotting tests. On administration of idarucizumab, improved hemostasis occurred with a decrease in the unbound concentration of dabigatran, from 110 ng/ml (group A) and 73.8 ng/ml (group B) to 20 ng/ml. This decrease was maintained for about 24 hours in a majority of patients in both groups.

In 9 patients in group A (in need of rapid anticoagulant reversal), the idarucizumab-induced reduction in the concentration of unbound dabigatran was short-lived (12 hours). In cases where the recurrent bleeding was reported, an additional dose(s) of idarucizumab given. Time to bleeding cessation occurred within 24 hours in 67.7% of group A patients, with a median time to hemostasis of 2.5 hours (95% CI, 2.2 to 3.9). Periprocedural hemostasis was assessed as normal in 93.4% of patients in group B.

Thrombotic events (4.8%; 14 in group A and 10 in group B), potential hypersensitivity events (rash, vomiting, and loss of consciousness in 2 patients; both groups), and other serious adverse events were recorded. Among the serious side-effects, delirium (2.3%, group A), cardiac arrest (3.5%, group B) and septic shock (3.0%, group B) were the most prevalent. In both groups, patient deaths were also recorded as 30-day mortality rates (13.5%, 12.6%) and 90-day mortality rates (18.8%, 18.9%).

Dr. Pollack and his colleagues conclude that “idarucizumab is effective for dabigatran reversal among patients who have uncontrolled bleeding or will be undergoing urgent surgery.” They also note that the incidence of thrombotic events in treated patients was lower in idarucizumab-treated patients compared to those treated with an alternative (prothrombin complex concentrate). However, the lack of a control group in this study limits the quality of the evidence provided. Thus, a need for close monitoring of the effectiveness of the drug for anticoagulation reversal would assist safety assessments.

Boehringer Ingelheim Pharmaceuticals supported this study. The authors report financial relationships or are employees of a host of pharmaceutical companies including Boehringer Ingelheim Pharmaceuticals. A full list of disclosures is provided in the journal article. RE-VERSE AD ClinicalTrials.gov number, NCT02104947.

N Engl J Med. Published on July 14, 2017.