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Idarucizumab safely reverses anticoagulant effect of dabigatran
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Idarucizumab rapidly and effectively reversed anticoagulant effects of dabigatran in emergency situations for patients with uncontrolled bleeding or who required urgent procedures, according to a full cohort analysis of the RE-VERSE AD trial.
“The final results of RE-VERSE AD are extraordinarily consistent with both preclinical studies and the interim analysis, and show that idarucizumab rapidly, completely, durably and safely reverses the anticoagulant effect of dabigatran,” Charles V. Pollack, Jr., MA, MD, professor and senior advisor for interdisciplinary research and clinical trials in the department of emergency medicine at Sidney Kimmel Medical College of Thomas Jefferson University, told HemOnc Today.
The FDA approved idarucizumab (Praxbind, Boehringer Ingelheim) — a monoclonal antibody fragment administered via IV injection —in October 2015 to specifically reverse the anticoagulant of dabigatran etexilate (Pradaxa, Boehringer Ingelheim).
An interim analysis of RE-VERSE AD included data from 90 patients and showed idarucizumab instantly and completely reversed the anticoagulant effect of dabigatran among those who required urgent procedures or had serious hematologic complications.
The final analysis included data from 503 patients (median age, 78 years) administered 5 g idarucizumab. Group A patients (n = 301) had uncontrolled or life-threatening bleeding — 45.5% had gastrointestinal bleeding, 32.6% had intracranial hemorrhage and 25.9% had trauma-caused bleeding — and group B patients (n = 202) were scheduled to undergo urgent invasive procedure that required normal hemostasis.
At the time of the study, a majority of patients received dabigatran to prevent stroke (95%).
The maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours of idarucizumab administration served as the primary endpoint. Secondary endpoints included safety and restoration of hemostasis.
At study entry, 461 patients (group A, n = 276; group B, n = 185) had prolonged diluted thrombin or ecarin clotting times and were included in the primary efficacy analysis.
The median patient-reported time from the last dose of dabigatran to the first infusion of idarucizumab was 14.6 hours in group A and 18 hours in group B.
The median maximum percentage reversal of dabigatran within 4 hours — based on diluted thrombin or ecarin clotting times — was 100% (95% CI, 100-100).
Reversal occurred regardless of age, sex, renal function and baseline dabigatran concentration.
The median time to cessation of bleeding among patients was 2.5 hours in group A and 1.6 hours in group B.
Most group B patients (93.4%) experienced normal periprocedural hemostasis, with the remainder of patients assessed as abnormal (5.1%) and moderately abnormal (1.5%). “Idarucizumab is not a hemostatic agent; it is a true reversal agent,” Pollack said.
A single 5-g dose of idarucizumab appeared effective for 98% of patients. Nine patients received more than 5 g; three of these patients from group A experienced recurrent bleeding. Seven patients received a second dose of idarucizumab and one patient received two additional doses due to recurrent bleeding or undergoing a second invasive procedure. One patient received an additional dose in error.
Researchers reported no serious adverse events. Thrombotic events occurred in 4.8% of patients (group A, n = 14; group B, n = 10) within 30 and 6.8% of patients (group A, n = 19; group B, n = 15) within 90 days.
“There were no adverse safety signals seen in RE-VERSE AD, including among those patients who received more than one dose,” Pollack said.
The researchers suggest postmarketing surveillance to monitor the durability and effectiveness of idarucizumab, because other research suggested thrombolysis and thrombectomy may be performed safely after dabigatran reversal with idarucizumab. – by Melinda Stevens
For more information:
Charles V. Pollack, Jr., MA, MD , can be reached at Thomas Jefferson University, 1020 Walnut St., 6th Floor, Philadelphia, PA 19107; email: charles.pollack@jefferson.edu.
Disclosure: Pollack reports personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo and Pfizer. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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