RESEARCH HIGHLIGHTS Nature Reviews Cardiology advance online publication 7 July 2015; doi:10.1038/nrcardio.2015.93
ANTICOAGULATION THERAPY
Preliminary results for the dabigatran-reversal agent idarucizumab
Brain light/Alamy
Although non-vitamin-K antagonist oral anticoagulants are associated with a lower risk of serious bleeding than vitamin K antagonists, management of bleeding in patients administered these drugs is still challenging. Various groups are, therefore, developing agents aimed at effectively reversing the effects of these anticoagulants. Results from a proof-of-concept phase I trial and the interim findings of a prospective phase III cohort study to assess the safety and efficacy of idarucizumab—a humanized monoclonal antibody fragment developed as a specific antidote to dabigatran—have now been reported. In total, 47 healthy men (18–45 years) were enrolled into the phase I proof-ofconcept study. All participants received 220 mg dabigatran etexilate twice daily for 3 days and then a final 220 mg dose on day 4. When the peak dabigatran concentration was expected, ~2 h after the
final dabigatran etexilate dose, participants received a 5 min intravenous infusion of placebo or 1 g, 2 g, 4 g, or 5 g idarucizumab. Individuals who received the largest dose of idarucizumab received an additional 5 min intravenous infusion of 2.5 g 1 h later. All doses of idarucizumab were associated with immediate and complete reversal of dabigatran anticoagulation, which was sustained for all but the 1 g dose. The investigators noted no clinically relevant difference in the incidence or intensity of adverse events for the treatment groups. All adverse events were of mild intensity, and no adverse event led to discontinuation of therapy. The idarucizumab dose did not affect the frequency of adverse events. The dabigatran antidote is currently also being tested in older volunteers with characteristics that are more similar to those of the patients for whom the drug is targeted, as well as in the phase III RE-VERSE AD study in patients who need immediate reversal of dabigatran anticoagulation, owing to serious bleeding or the need for an emergency procedure. The interim analysis for RE-VERSE AD has been published and involved data for 51 patients who had serious bleeding (group A) and 39 patients who urgently required an invasive procedure (group B). Almost all patients (96%) had atrial fibrillation and were taking dabigatran etexilate for stroke prevention. All received 5 g idarucizumab intravenously and were followed up until death or for ≥1 month.
NATURE REVIEWS | CARDIOLOGY
The median maximum percentage reversal of the anticoagulant effect of dabigatran (the primary end point) was 100% in both groups. Depending on the measure assessed, dabigatran anticoagulation was deemed to be completely reversed in 88–98% of participants. Among the 35 group A patients for whom the measure could be assessed, the median investigatorreported time to bleeding cessation was 11.4 h. In group B, normal intraprocedural haemostasis was noted for 92% of patients; the remaining patients had mild or moderately abnormal haemostasis. All 18 deaths during the study (nine per group) were deemed to be related to the index event or a coexisting condition. The investigators concluded that no safety concerns existed in the patients assessed. The RE-VERSE AD investigators acknowledge that the major limitation of their study is the lack of a control group. They point out, however, that “a cohort design was selected because it was deemed unethical to randomly assign patients to receive placebo or no active treatment”. Bryony M. Mearns
Original article Glund, S. 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 doi:10.1016/S0140-6736(15)60732-2 | Pollack, C. V. Jr et al. Idarucizumab for dabigatran reversal. N. Engl. J. Med. doi:10.1056/NEJMoa1502000
ADVANCE ONLINE PUBLICATION © 2015 Macmillan Publishers Limited. All rights reserved
ANTICOAGULATION THERAPY
Preliminary results for the dabigatran-reversal agent idarucizumab
Brain light/Alamy
Although non-vitamin-K antagonist oral anticoagulants are associated with a lower risk of serious bleeding than vitamin K antagonists, management of bleeding in patients administered these drugs is still challenging. Various groups are, therefore, developing agents aimed at effectively reversing the effects of these anticoagulants. Results from a proof-of-concept phase I trial and the interim findings of a prospective phase III cohort study to assess the safety and efficacy of idarucizumab—a humanized monoclonal antibody fragment developed as a specific antidote to dabigatran—have now been reported. In total, 47 healthy men (18–45 years) were enrolled into the phase I proof-ofconcept study. All participants received 220 mg dabigatran etexilate twice daily for 3 days and then a final 220 mg dose on day 4. When the peak dabigatran concentration was expected, ~2 h after the
final dabigatran etexilate dose, participants received a 5 min intravenous infusion of placebo or 1 g, 2 g, 4 g, or 5 g idarucizumab. Individuals who received the largest dose of idarucizumab received an additional 5 min intravenous infusion of 2.5 g 1 h later. All doses of idarucizumab were associated with immediate and complete reversal of dabigatran anticoagulation, which was sustained for all but the 1 g dose. The investigators noted no clinically relevant difference in the incidence or intensity of adverse events for the treatment groups. All adverse events were of mild intensity, and no adverse event led to discontinuation of therapy. The idarucizumab dose did not affect the frequency of adverse events. The dabigatran antidote is currently also being tested in older volunteers with characteristics that are more similar to those of the patients for whom the drug is targeted, as well as in the phase III RE-VERSE AD study in patients who need immediate reversal of dabigatran anticoagulation, owing to serious bleeding or the need for an emergency procedure. The interim analysis for RE-VERSE AD has been published and involved data for 51 patients who had serious bleeding (group A) and 39 patients who urgently required an invasive procedure (group B). Almost all patients (96%) had atrial fibrillation and were taking dabigatran etexilate for stroke prevention. All received 5 g idarucizumab intravenously and were followed up until death or for ≥1 month.
NATURE REVIEWS | CARDIOLOGY
The median maximum percentage reversal of the anticoagulant effect of dabigatran (the primary end point) was 100% in both groups. Depending on the measure assessed, dabigatran anticoagulation was deemed to be completely reversed in 88–98% of participants. Among the 35 group A patients for whom the measure could be assessed, the median investigatorreported time to bleeding cessation was 11.4 h. In group B, normal intraprocedural haemostasis was noted for 92% of patients; the remaining patients had mild or moderately abnormal haemostasis. All 18 deaths during the study (nine per group) were deemed to be related to the index event or a coexisting condition. The investigators concluded that no safety concerns existed in the patients assessed. The RE-VERSE AD investigators acknowledge that the major limitation of their study is the lack of a control group. They point out, however, that “a cohort design was selected because it was deemed unethical to randomly assign patients to receive placebo or no active treatment”. Bryony M. Mearns
Original article Glund, S. 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 doi:10.1016/S0140-6736(15)60732-2 | Pollack, C. V. Jr et al. Idarucizumab for dabigatran reversal. N. Engl. J. Med. doi:10.1056/NEJMoa1502000
ADVANCE ONLINE PUBLICATION © 2015 Macmillan Publishers Limited. All rights reserved
