Editor's Note: Commentary based on Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-520.

Background

Dabigatran is a direct thrombin inhibitor utilized for stroke prevention in patients with non-valvular atrial fibrillation (AF), and for venous thromboembolism prevention and treatment. Despite the increasing use of direct oral anticoagulants, there currently are no available drug-specific reversal agents. Idarucizumab is a monoclonal antibody fragment binding dabigatran with neutralizing effect on anticoagulation.^1-2

Methods

In an ongoing multicenter prospective cohort study, Pollack et al. investigate the safety and efficacy of the intravenous administration of 5g idarucizumab in reversing the anticoagulant effect of dabigatran in patients presenting with serious bleeding (group A), or needing urgent invasive procedures (group B).³ The maximum percentage reversal of the anticoagulant effect of dabigatran (determined by measuring dilute thrombin time (dTT) or ecarin clotting time (ECT); percentage reversal = [(predose test result - minimum postdose test result)/(predose test result-upper limit of the normal range) x 100]) within four hours of idarucizumab administration was used as the primary endpoint. Clinical outcomes, including hemostasis, thrombosis, and other adverse effects, were used as secondary outcomes. The authors report the results from the interim analysis involving the first 90 patients enrolled (51 in group A, and 39 in group B).

Results

Among the 90 patients, 68 had elevated dTT and 81 had elevated ECT upon presentation. Of these patients, 96% were on dabigatran for stroke prevention for AF. The median age was 76.5 years. The median creatinine clearance was 58 mL/min, with the wide range of 11-187 mL/min. The median time since dabigatran intake was 15.4 hours, with the majority presenting within 48 hours. Idarucizumab effectively corrected the elevated dTT and ECT in 88-98% of participants within minutes, with the median maximum percentage reversal of 100% (95% confidence interval [CI], 100 to 100). This correlated with concurrent reduction in the serum concentrations of unbound dabigatran. The median time to adequate hemostasis among 35 patients presenting with serious bleeding was 11.4 hours. In others, it was not possible to accurately determine the time to hemostasis. 92% of patients undergoing urgent procedures (group B) were found to have normal intraoperative hemostasis. Among 18 total deaths, ten were deemed vascular-related, including five with fatal bleeding. Out of five total thrombotic events, one occurred two days after the treatment, and all others following 7-26 days.

Conclusion

Idarucizumab effectively reversed the elevated coagulation studies in the majority of the participants on dabigatran presenting with serious bleeding, or in need of urgent procedures within minutes.

Commentary/Perspective

Despite growing evidence supporting the use of direct oral anticoagulants^4-6 and their increasing use, the absence of a specific reversal agent remains a concern. Those in development include andexanet alfa,⁷ PER977,⁸ and idarucizumab.^1-2

In this interim analysis of the ongoing prospective cohort study of idarucizumab, Pollack et al. report the pharmacodynamic and clinical observations that appear to be promising: idarucizumab rapidly corrected the prolonged dTT and ECT in the majority of participants. What is further encouraging is restoration of hemostasis seen in the majority of patients without a large number of immediate thrombotic complications.

A major limitation of this study was the absence of a control group. It is therefore difficult to fully assess the extent of the contribution by idarucizumab to achievement of hemostasis or to subsequent adverse events. In the absence of alternative established reversal agents, it was not feasible to design a safe study including a control group.

In individuals with normal renal function, the half-life of dabigatran is 12-17 hours; however, the half-life is substantially longer in patients with moderate-severe renal dysfunction, since dabigatran is cleared 80% via the kidneys. An important question to address is which individuals on dabigatran will most likely benefit from idarucizumab, and when to reverse in relation to the dabigatran pharmacokinetic profile, given the variable half-life of dabigatran dependent upon renal function.

It is worth noting the vast heterogeneity seen in the key determinants of dabigatran pharmacokinetics and pharmacodynamics in this study. This included a wide range of dabigatran dosage, serum dabigatran levels at the time of presentation, creatinine clearance and the presence of other medications that may potentially interact with, or augment its anticoagulant effect. Importantly, a broad range was noted in the duration of time since last dabigatran dosing with the median of 15.4 hours, with the range between less than 12 hours to greater than 48 hours. In the absence of impaired renal function, idarucizumab is less likely to be beneficial in the individuals presenting after multiple half-lives have elapsed. It will therefore be informative to perform a subgroup analysis based on this particular parameter to identify the optimal time window for reversal for those with normal renal function. For those with impaired renal function or other confounding factors, concurrent measurements of serum coagulation studies and dabigatran levels and their clinical correlation will be helpful. Remaining questions also include further assessment of the short- and long-term thrombotic risks, as well as the pharmacokinetics and pharmacodynamics of reintroducing anticoagulants.

In summary, these findings represent an important basis from which to evaluate further the safety and efficacy of idarucizumab, and other agents, in development in reversing the direct oral anticoagulants in individuals presenting with serious bleeding, or those requiring urgent reversal for procedures.

References

1. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121:3554-62
2. Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet. 2015;Jun 16:[Epub ahead of print].
3. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-20
4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51
5. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15
6. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2014;369:2093-104
7. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013;19:446-51
8. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014;371:2141-2

Keywords: Administration, Intravenous, Anticoagulants, Antithrombins, Atrial Fibrillation, Benzimidazoles, Blood Coagulation, Cohort Studies, Confidence Intervals, Control Groups, Creatinine, Half-Life, Immunoglobulin Fragments, Prospective Studies, Reference Values, Stroke, Thrombin Time, Venous Thromboembolism, beta-Alanine

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