Dabigatran Reversal With Idarucizumab in Patients Requiring Urgent Surgery

A Subanalysis of the RE-VERSE AD Study

Jerrold H. Levy, MD; Joanne van Ryn, PhD; Frank W. Sellke, MD; Paul A. Reilly, PhD; Amelie Elsaesser, PhD; Stephan Glund, PhD; Jörg Kreuzer, MD; Jeffrey I. Weitz, MD; Charles V. Pollack Jr., MD, MA

Disclosures

Annals of Surgery. 2021;274(3):e204-e211. 

In This Article

Methods

Study Design

Our investigation was a multicenter, prospective, single-cohort study. The study design has been previously reported,[7] and the study protocol is available at http://www.nejm.org/doi/full/10.1056/NEJMoa1707278?query=featured_home (accessed September 30, 2019). Surgical patients (group B) are those treated with dabigatran etexilate with a condition requiring surgery or other invasive procedures that could not be delayed for 8 hours or more and for which normal hemostasis was required. The inclusion criteria were broad in order to reflect the real-world population in which the use of idarucizumab might be considered and allowed for the enrollment of severely ill patients. Patients received 5 g of intravenous idarucizumab administered as two 50 mL (2.5 g) bolus infusions, no more than 15 minutes apart. All patients or their authorized representatives provided written informed consent. The 5 g dose was calculated to reverse the total body load of dabigatran that was associated with the 99th percentile of the dabigatran levels measured in the Randomized Evaluation of Long-Term Anticoagulation Therapy trial.[8]

Assessments and Study End Points

The primary efficacy endpoint was the maximum percentage reversal of the diluted thrombin time (dTT) or ecarin clotting time (ECT) determined at any point from the end of the first idarucizumab infusion until 4 hours after the second infusion.[6,7] Blood was obtained at baseline, after the first vial of idarucizumab, and then between 10 and 30 minutes and at 1, 2, 4, 12, and 24 hours after the second vial. Clotting assays, including dTT, ECT, thrombin time, activated partial thromboplastin time (aPTT), and unbound dabigatran levels, which were all measured in a central laboratory. Measurement of unbound dabigatran and aPTT have been previously described.[9] The treating physicians were unaware of these results at baseline and throughout the course of care. In parallel, the aPTT was also assessed locally at baseline and at various time points post idarucizumab. A second dose of idarucizumab was permitted if there was recurrent or continued bleeding or surgery was required and there was concurrent objective evidence of a dabigatran anticoagulant effect.

Clinical endpoints included the time from reversal to surgery or intervention and the extent of hemostasis during the surgery or procedure as assessed by the surgeon or treating physician. Hemostasis was classified as normal or as mildly abnormal (eg, slight oozing), moderately abnormal (eg, controllable bleeding), or severely abnormal (eg, severe refractory hemorrhage). Any postprocedural bleeding within 24 hours was classified according to ISTH criteria as minor, major, life-threatening, or fatal.[10] Rates of thromboembolic events and mortality within 30 days of idarucizumab administration were evaluated. Suspected thrombotic events were adjudicated by an independent committee. Mortality was determined at 5, 30, and 90 days.

Statistical Analysis

No hypothesis testing was done for this study, and all analyses were descriptive in nature. Only patients with an elevated dTT or ECT above the upper limit of normal at study entry were included in the primary endpoint analysis. All patients given idarucizumab were included in the analysis of safety endpoints. The time to surgery or procedure was defined as the time from the beginning of the administration of the first idarucizumab vial to initiation of the intervention. Hemostasis was measured during the intervention and for up to 24 hours postintervention. Continuous data are represented as the median and IQR, unless otherwise stated; categorical data are shown as absolute and relative frequencies.

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