Idarucizumab for reversal of direct thrombin inhibitor dabigatran

Idarucizumab for reversal of direct thrombin inhibitor dabigatran

Idarucizumab is a monoclonal antibody fragment used to reverse the anticoagulant effect of direct thrombin inhibitor dabigatran. RE-VERSE AD (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab) clinical trial evaluated the safety and efficacy of 5 g idarucizumab given intravenously [1]. An article on interim analysis of 90 patients was published first. In that report, 51 patients in group A of the study had serious bleeding while 39 patients in group B required an urgent procedure. Primary end point of the study was the maximum percentage reversal of the anticoagulant effect of dabigatran within four hours of administration of Idarucizumab. This was determined using dilute thrombin time or ecarin clotting time. Important secondary end point was restoration of hemostasis. Authors of the interim report concluded that Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. One thrombotic event occurred within 3 days in a patient in whom anticoagulant had not been restarted. Major limitation of the study was lack of a control group. But it was deemed unethical to have a control group in the patients evaluated who were having either a life threatening bleeding or need for urgent surgery.

Idarucizumab has an affinity for dabigatran that is about 350 times stronger than its affinity for thrombin. Idarucizumab does not bind known thrombin substrates and has no activity in coagulation tests or platelet aggregation [2]. Idarucizumab binds free as well as thrombin bound dabigatran and neutralizes its activity.

Full cohort analysis of the RE-VERSE AD trial had 503 patients; 301 in group A and 202 in group B [3]. 45.5% of the patients in group A had gastrointestinal bleeding at presentation while 32.6% had intracranial hemorrhage. Among those patients who could be assessed, the median time to cessation of bleeding was 2.5 hours. In group B the median time to the initiation of the intended procedure was 1.6 hours. Periprocedural hemostasis was normal in 93.4% of the patients. 90 day thrombotic event rate was 6.3% in group A and 7.4% in group B. Mortality rate was 18.8% and 18.9% respectively in the two groups. No serious safety adverse signals were documented in the study.

Recurrent elevation of clotting time, mainly between 12-24 hours after treatment was noted in 114 patients. This was probably due to redistribution of unbound dabigatran from the extravascular compartment to the intravascular compartment. But this elevation was associated with bleeding in only 10 patients. Authors suggested that among patients with a recurrent elevation in clotting time, only those with new-onset or recurrent bleeding should be considered for a second dose of idarucizumab.

Enrolled patients were elderly, had numerous comorbidities and presented with serious index events such as intracranial hemorrhage, multiple trauma, sepsis, acute abdomen or open fracture. These could account for the significant mortality noted in both groups. Authors attribute the thrombotic events to the low rate of reinitiation of anticoagulation, particularly in group A. Idarucizumab has a half-life of 45 minutes and all thrombotic events in the study within 72 hours occurred in patients in whom anticoagulation had not been restarted. Thrombotic events which occurred later are likely to be due to the underlying prothrombotic state rather than the effect of dabigatran reversal.

A substudy of RE-VERSE AD trial reported more details of the 137 patients who presented with gastrointestinal bleeding [4]. 84% of these were major or life threatening. 35% of them had upper GI bleed while 31.4% had lower GI bleed. 33.6% had either both or unknown origin bleeds. Bleeding stopped within 24 hours in 68.7% of the evaluable patients after a median duration of 2.4 hours.

References

1. Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015 Aug 6;373(6):511-20. 
2. Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, Nar H, Litzenburger T. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013 May 2;121(18):3554-62. 
3. Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med. 2017 Aug 3;377(5):431-441.
4. Van der Wall SJ, Lopes RD, Aisenberg J, Reilly P, van Ryn J, Glund S, Elsaesser A, Klok FA, Pollack CV Jr, Huisman MV. Idarucizumab for Dabigatran Reversal in the Management of Patients With Gastrointestinal Bleeding. Circulation. 2019 Feb 5;139(6):748-756.