Results of the RE-VERSE AD Study Confirm Idarucizumab Efficacy, Safety, at Follow-Up

The study now includes 494 patients, and will be complete when 503 are enrolled. Of the participants, 60% required anticoagulant reversal to undergo surgery.

The thrombin inhibitor dabigatran is a commonly used direct-acting anticoagulant, and is the only agent available with a specific reversal agent for reversal of anticoagulants effects—idarucizumab. This humanized antibody is directed against dabigatran.

Interim results of the RE-VERSE AD study were first published in a 2015 edition of the New England Journal of Medicine. These early interim results in 90 patients assessed the capacity for idarucizumab to reverse the effects of dabigatran in 51 patients with a serious bleeding episode (group A), and in 39 patients requiring an urgent medical procedure (group B).1

All patients received 5 grams of idarucizumab through a bolus intravenous injection. The primary end point of this study was maximum reversal of the anticoagulant effect of dabigatran within 4 hours of idarucizumab administration.

Interim results indicated full reversal of the anticoagulant effect of dabigatran (Pradaxa) within 4 hours of administration of idarucizumab for all 90 participants. Moreover, test results were normalized in 88% to 98% of patients within minutes of administration.

Follow-up results of the RE-VERSE AD study presented at the 2016 American Heart Association Scientific Sessions in New Orleans, Louisiana, further confirm the efficacy and safety of idarucizumab (Praxbind) in patients who require dabigatran reversal.2

This follow-up analysis includes 494 patients, 60% (n = 285) of whom required anticoagulant reversal for serious bleeding episodes (group A), and the remaining 40% (n = 196) of whom required reversal to undergo an urgent medical procedure (group B). As the RE-VERSE AD study was designed to include approximately 500 patients, these result mark near-completion of the study, which will be published when 503 patients are accrued.

Of patients enrolled, 62% were taking 110 mg of dabigatran twice daily, 30% received dabigatran 150 mg twice daily, and the remaining 5% received dabigatran 75 mg twice daily. The median age was 78 years, the median creatinine clearance was approximately 53%. At presentation, the median time since last dose of treatment was 15.3 hours, ranging from 1.5 to 106 hours. At baseline, dilute thrombin time (dTT) was elevated in 77% of patients, and ecarin clotting time (ECT) was elevated in 90% of patients.

In group A patients (ie, patients with severe bleeding episodes), of 298 patients, the site of bleeding was categorized by site, with some patients bleeding in more than one site. Of all bleeds, 97 were intracranial, 135 were gastrointestinal, and 87 were of other types, including pericardial, intramuscular, retroperitoneal, intra-articular and others.

In group B patients (ie, patients with indications for surgery), common indications for surgery included acute abdomen (n = 45), bone fracture (n = 30), infection (n = 20), and acute renal failure due to obstruction (n = 11).

In patients receiving idarucizumab, dTT was rapidly reversed within 10 to 30 minutes of administration, and remained below the upper limit of normal for both dTT and ECT through 4 hours. Readings of ECT were reduced, with the median ECT level below the lower limit of normal through 12 hours. On the primary end point, the median maximum reversal within 4 hours was 100% for both dTT and ECT (95% CI, 100%-100%).

In terms of normalization of coagulation tests, dTT was normalized within 4 hours in 98.7% of patients (235/238) in group A (acutely bleeding patients), and 98.6% (131/143) in group B patients (patients urgently requiring surgical intervention). Normalization of ECT within 4 hours occurred in 81.5% of group A patients (220/270), and 83.5% of group B patients (147/176) of group B.

On the secondary end point of confirmation of hemostasis, of 298 patients in group A, 201 patients with non-intracranial hemorrhage, time to bleeding cessation as determined by an investigator occurred within a median of 3.5 hours in 97 patients with gastrointestinal bleeding, and within a median of 4.5 hours in 61 patients with non-gastrointestinal, non-intracranial bleeds.

A total of 35 thrombotic events occurred in 31 out of 494 patients (6.3% of patients). At day 30 after administration, 4.4% of patients (4.4% in group A and 4.6% in group B) experienced adjudicated thrombotic events. At day 90, 6.3% of patients (6.0% in group A and 6.6% in group B) experienced this outcome. Antithrombotic therapy was reinitiated in approximately two-thirds of patients who experienced thrombotic events.

With respect to mortality in these elderly, multi-comorbid patients, day-30 mortality rates were 12.3% in group A patients and 12.4% in group B patients. By day 90, these rates increased to 18.7% in group A patients and 18.5% of group B patients.

In patients receiving more than 1 dose of idarucizumab, re-bleeding or re-elevation of clotting tests 12 to 24 hours after receipt of a second dose occurred in 1.4% of patients (n = 7), 5 of which were group A patients, and 2 of which were group B patients. “For the vast majority of patients, a single 5-gram dose is effective,” noted Pollack.

In his conclusion, Pollack stated, “In a cohort of multi-morbid elderly patients taking dabigatran presenting with life-treating emergencies, 5 grams of idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulation.” Pollack continued, “Idarucizumab appears to be extraordinarily effective and safe.”

References

1. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373(6):511-520.

2. Pollack CV. Idarucizumab for Dabigatran Reversal: Updated Results of the RE-VERSE AD Study. Presented at 2016 American Heart Association Scientific Sessions 2016; New Orleans, Louisiana.