Article:
Pollack CV et al. Idarucizumab for Dabigatran Reversal. NEJM. 2015;373: 511-20. PubMedID: 26095746
Background
Novel oral anticoagulant agents such as dabigatran (direct thrombin inhibitor) and rivaroxaban (factor Xa inhibitor) are being used more often for long-term anticoagulation. Major benefits include rapid onset of action, shorter half-lives, and predictable pharmacokinetics, eliminating the requirement for routine coagulation monitoring. Major disadvantages include serious bleeding and the lack of specific reversal agents. Currently, guidelines recommend prothrombin complex concentrate (PCC) for the management of serious bleeding in these patients, but there is no high-quality evidence for its efficacy. Idarucizumab is a monoclonal antibody designed as a reversal agent for dabigatran. It has the ability to neutralize both free and thrombin-bound dabigatran.
Clinical Question
Is idarucizumab a safe and effective agent to reverse dabigatran?
Population
All adult patients ( ‰¥18 yrs old) on dabigatran who developed uncontrollable, life-threatening bleeding requiring reversal (group A) or who were undergoing an emergent or necessary invasive procedure within 8 hours that required normal hemostasis (group B).
Intervention
5 grams of intravenous idarucizumab, administered as two 2.5 g boluses
Control: None
Outcome (Primary): Maximum percentage reversal of anticoagulant effect within 4 hours of administering the second dose of idarucizumab. This percentage was based on measurement of dilute thrombin time (dTT) or ecarin clotting time (ECT) and comparison of pre-dose and post-dose test results.
Outcome (Secondary): Reversal of aPTT, reversal of thrombin time (TT), duration of reversal, occurrence of major bleeding in group B up to 24 hrs post-surgery, time to cessation of bleeding in group A, minimum unbound (free) dabigatran, and reversal of anticoagulation as measured by dTT or ECT after the first infusion and before the start of the second infusion. Clinical outcomes were also monitored, including the occurrence of thrombotic events and occurrence of additional adverse events such as GI hemorrhage, post-operative wound infections, and pulmonary edema.
Design: Ongoing multicenter, prospective cohort study, beginning May 2014
Excluded: Patients with no bleeding or insignificant bleeding (eg minor epistaxis), patients with contraindications to the study medication (such as a known hypersensitivity reaction), or surgeries/procedures that were elective or had a low risk of uncontrolled bleeding.
Clinical Bottom Line
Primary Results (preliminary; study is ongoing)
- 90 patients recruited in more than 184 centers in 35 countries over a 9-month period.
- More than 90% of patients were receiving dabigatran for stroke prevention in the context of atrial fibrillation.
- Median time since last dose of dabigatran was 15.4 hours.
Critical Findings
- Median maximum percentage reversal in both groups was 100%.
- 31 patients with normal dTT and ECT were excluded from efficacy analysis. Of the remaining patients:
- In group A, the dTT was normalized in 98% patients, and the ECT was normalized in 89% of patients.
- In group B, the dTT was normalized in 93% of patients, and the ECT was normalized in 88% of patients.
Secondary Outcomes
- Median time to cessation of bleeding was 11.4 hours in group A.
- 92% of patients in group B achieved normal intra-operative hemostasis, with 8% of patients having mild-to-moderate impairment of hemostasis.
- 18 deaths overall, including 5 fatal bleeding events.
- 5 thrombotic events.
Strengths
- International, multi-center, ongoing trial
- Broad inclusion criteria to mirror clinical practice
- Providers were blinded to the results of clotting tests
Limitations
- Preliminary results of an ongoing trial
- Small patient population (n=90), therefore underpowered
- Excluded patients with normal clotting times
- No control group for comparison
Other Issues
This study was funded by Boehringer Ingelheim, creator of both Pradaxa (dabigatran) and Praxbind (idarucizumab).
Authors' Conclusions
“Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes.”
Our Conclusions
This study showed that idarucizumab can decrease levels of dabigatran and normalize abnormal clotting tests. However, this study is based only on preliminary results of the first 90 patients enrolled. Whether these laboratory findings correlate with clinically improved outcomes needs to be further analyzed as more patients are enrolled.
Potential to Impact Current Practice
FDA approved idarucizumab for reversal of dabigatran in October 2015.