Is Idarucizumab the First “Antidote” to a Direct Oral Anticoagulant?

Idarucizumab “rapidly and completely” reversed the blood-thinning effects of the direct oral anticoagulant dabigatran in patients who had uncontrolled bleeding or were about to undergo an emergency procedure, according to results from the RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) trial published in the New England Journal of Medicine.

In the multicenter, prospective, single-cohort trial, Charles V. Pollack Jr., MD, from Thomas Jefferson University in Philadelphia, Pennsylvania, and co-authors enrolled 503 adult patients (median age = 78 years; range = 21-96 years) who were receiving dabigatran between June 2014 and July 2016: 301 had uncontrollable or life-threatening bleeding that required rapid anticoagulant reversal (group A), and 202 were about to undergo surgery or an invasive procedure that required normal hemostasis (group B).

The study inclusion criteria were kept intentionally broad to reflect real-world clinical practice, the authors noted, adding that the protocol “was designed to mimic routine emergency care,” and patients received idarucizumab without coagulation studies and regardless of clinical presentation.

In group A, most bleeding events were gastrointestinal (n=137; 45.5%) or intracranial (n=98; 32.6%). In group B, the most common reasons for an urgent procedure were abdominal condition or infection (n=49; 24.3%), fracture or septic arthritis (n=41; 20.3%), and cardiovascular condition (n=37; 18.3%). Most patients (n=478; 95%) were receiving dabigatran for atrial fibrillation.

Idarucizumab 5 g was administered intravenously as two 50 mL bolus infusions, each containing 2.5 g of idarucizumab and given no more than 15 minutes apart. The median patient-reported time from last dabigatran dose to idarucizumab infusion was 15.6 hours (range = 1.5-105.8 hours).

A total of 461 patients (97.1%; 276 in group A and 185 in group B) had coagulation measurements (diluted thrombin time or ecarin clotting time) available at baseline and were included in the primary efficacy analysis. Within four hours of idarucizumab administration, the median maximum percentage reversal of dabigatran (primary endpoint) was 100 percent (95% CI 100-100) in 98 percent of patients. “Reversal was rapid and occurred independently of age, sex, renal function, and dabigatran concentration at baseline,” the authors reported.

Before idarucizumab was administered, the median baseline concentration of unbound dabigatran was 110 ng/mL in group A and 73.6 ng/mL in group B; after idarucizumab, the concentration dropped to ≤20 ng/mL in all but three patients. These concentrations remained at ≤20 ng/mL for 24 hours in the majority of patients but increased in 23 percent of patients (n=114/497), mostly after 12 hours. Sixty-seven patients had elevated levels only at the 24-hour measurement.

Elevated dabigatran concentration levels that persisted for more than 24 hours were associated with recurrent or continuous bleeding in 10 patients in group A (none in group B), three of whom received an additional dose of idarucizumab. After 24 hours, their median idarucizumab concentration decreased to <1 percent of the peak median, “a finding consistent with the short half-life of idarucizumab,” the authors noted.

Nine patients (1.8%) in the entire cohort received >5 g of idarucizumab, including three in group A who had recurrent bleeding.

Ninety-eight patients in group A were not evaluable for cessation of bleeding; among the other 203 patients, 134 (67.7%) had confirmed bleeding cessation within 24 hours, and the median time to hemostasis after idarucizumab was 2.5 hours (95% CI 2.2-3.9).

In group B, 197 patients underwent their planned procedure a median of 1.6 hours after idarucizumab administration (range not provided), and 184 of those patients (93.4%) had normal hemostasis after surgery. The remaining patients had mildly abnormal (5.1%) or moderately abnormal (1.5%) hemostasis.

The 30-day mortality rate was 13.5 percent in group A and 12.6 percent in group B, and the 90-day mortality rates were 18.8 percent and 18.9 percent, respectively. Nineteen patients in group A (6.3%) and 16 in group B (7.9%) died within five days of idarucizumab treatment.

Idarucizumab did not appear to have a “procoagulant” effect, with thrombotic events occurring in 24 patients (4.8%) within 30 days of treatment (14 in group A and 10 in group B). Three days after idarucizumab infusion, 22.9 percent of patients in group A and 66.8 percent of patients in group B restarted anticoagulation or antiplatelet therapy.

Within five days of idarucizumab administration, 117 patients (23.3%) experienced serious adverse events (AEs). In group A, the most common AE was delirium (2.3%), and in group B the most common AEs were cardiac arrest (3.5%) and septic shock (3.0%). The other most frequently reported AEs were worsening of the index event or a coexisting condition.

Overall, the researchers did not observe any “serious adverse safety signals” with idarucizumab. “The safety of idarucizumab observed in this study supports its urgent use, even if patients later prove to have had little or no circulating dabigatran.”

The study is limited by its lack of a control group, and some patients had normal clotting times at study entry. Because experience with direct oral anticoagulants is limited, there also are no standardized measures for determining effective and ineffective anticoagulation reversal.

Dr. Pollack and contributing authors report financial support from Boehringer Ingelheim, which supported the study and is the manufacturer of idarucizumab.


Reference

Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal — full cohort analysis. N Engl J Med. 2017;377:431-41.

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