The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran

Abstract

Idarucizumab is a monoclonal antibody fragment designed for reversing the anticoagulant effects of dabigatran. Administration is recommended as two intravenous boluses of 2.5 g within 15 min of each other or as a single 5 g bolus. However, in certain situations a second dose of the drug could be necessary. We report the case of a 77-year-old man, treated with dabigatran for paroxysmal atrial fibrillation. He presented at our department with acute renal failure, concomitant massive dabigatran accumulation and subsequent acute gastrointestinal bleeding. Fifty minutes after the administration of idarucizumab, the dabigatran plasma concentration decreased from a peak of 1630 ng ml to a level below the detection limit of 30 ng ml and bleeding stopped. Eight hours after administration, the dabigatran plasma level started to increase up to 1560 ng ml (96% of the maximum value obtained), accompanied by a further drop in hemoglobin. Concomitant hemodialysis and hemofiltration led to a continuous decrease in dabigatran plasma levels. However, sepsis and multiorgan failure ensued, which led to death. With this case report we raise the question of whether massive dabigatran accumulation requires repeated doses of idarucizumab, or alternatively, if the combination of antidote with hemodialysis/renal replacement therapy is advisable in order to remove circulating levels of dabigatran.

Lessons learnt from local real‐life experience with idarucizumab for the reversal of dabigatran

“…Although TT/APTT is often used as a surrogate marker of dabigatran anticoagulant effect, we were unable to assess the association between renal impairment and definite dabigatran rebound due to an insufficient number of patients with dabigatran level measurements, despite the test’s availability at our central laboratory. Nevertheless, our results support the observation that patients with chronic or acute kidney injury are at an increased risk of experiencing a dabigatran rebound . The dabigatran rebound is thought to occur as a result of redistribution of unbound dabigatran from the extravascular to the intravascular compartment .…”

“…Nevertheless, our results support the observation that patients with chronic or acute kidney injury are at an increased risk of experiencing a dabigatran rebound. 10,11 The dabigatran rebound is thought to occur as a result of redistribution of unbound dabigatran from the extravascular to the intravascular compartment. 9 It is plausible that patients with renal failure and, consequently, higher plasma dabigatran levels have increased extravascular concentrations of dabigatran that is redistributed back into the intravascular compartment over time.…”

Pharmacological reversal of the direct oral anticoagulants—A comprehensive review of the literature

“…Some patients experienced a rise in unbound dabigatran levels around 24 hours following the dose of idarucizumab which may be related to redistribution of dabigatran from the extravascular compartment. There have been a few isolated reports of incomplete dabigatran reversal using the standard 5 g idarucizumab dosing in the setting of severe renal failure . There may be a role for repeated doses idarucizumab in these situations, as well as hemodialysis for dabigatran reversal …”

The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran: comment

“…I read with interest the case report by Simon et al . published in a recent issue of this journal, and I wish to make some comments.…”

“…The patient reported by Simon et al . was taking dabigatran, and received idarucizumab for immediate reversal of anticoagulation. Measurement of the dabigatran concentration showed that the antidote administration was successful, but, after a few hours, there was a rebound in the plasma level of dabigatran that was greater than expected based on previous reports .…”