Effectiveness of Idarucizumab Reversal Effect
It is, of course, a great advantage if doctors have a specific substance available that counteracts the effect of oral anticoagulants in urgent need. Idarucizumab is a humanized monoclonal antibody that binds dabigatran with high affinity. The drug was approved for clinical use based on an interim analysis of the results of 90 patients enrolled in the RE-VERSE AD study. What conclusions were drawn based on the results of the entire study population?
Methodology and Study Progress
The RE-VERSE AD (Reversal Effects of Idarucizumab on Active Dabigatran) multicenter prospective open study aimed to determine whether idarucizumab stops the anticoagulation effect of dabigatran in patients experiencing uncontrolled or life-threatening bleeding (Group A) or requiring urgent surgery that cannot be postponed for more than 8 hours and requires normal hemostasis (Group B).
Participants were given idarucizumab in the form of two 50ml bolus infusions, each containing 2.5 g of the drug. The reversal effect was assessed by measuring the diluted thrombin time and ecarin time.
The primary goal was to evaluate the maximum reversal effect against dabigatran within 4 hours of administering idarucizumab. Secondary goals included other clinical parameters such as peri-procedural hemostasis and the safety of the application. Adverse events occurring within 5 days of administering idarucizumab were considered related to its administration. Bleeding intensity (in Group A) and any suspicion of thrombotic events or deaths that occurred within 90 days of administration were assessed by an independent committee.
Patient Population Observed
The study included 503 adult patients taking dabigatran, of which 301 were in Group A and 202 in Group B. Their median age was 78 years. Over 95% of participants took dabigatran to prevent stroke in atrial fibrillation.
At the start of the study, 461 patients (91.7%) had prolonged diluted thrombin time or ecarin time. The average time from the last reported dose of dabigatran to the first infusion of idarucizumab was 14.6 hours in Group A and 18.0 hours in Group B. Group A had 137 (45.5%) patients with gastrointestinal bleeding, 98 (32.6%) with intracranial bleeding, and 78 (25.9%) with bleeding due to trauma. In Group B, an average of 1.6 hours elapsed from the first infusion to the procedure.
Findings
The median maximum reversal effect of idarucizumab within 4 hours of administration reached 100% (95% confidence interval [CI] 100–100). The reversal effect was rapid and did not depend on age, renal function, or baseline dabigatran concentration. Data from 134 patients in Group A showed an average time to stop bleeding of 2.5 hours (95% CI 2.2–3.9). In Group B, peri-procedural hemostasis was assessed as normal in 93.4% of patients, slightly abnormal in 5.1%, and moderately abnormal in 1.5%. No highly abnormal hemostasis was recorded. The reversal effect maintained for up to 24 hours in most patients.
The 30-day mortality in Groups A and B was 13.5% and 12.6%, respectively, and the 90-day mortality was 18.8% and 18.9%, respectively. Thrombotic events occurred within the first 90 days in 6.3% of Group A patients and 7.4% of Group B patients. No severe adverse events directly related to the administration of idarucizumab were recorded.
Summary and Conclusion
The final results of the RE-VERSE AD study indicated that in patients with severe bleeding or requiring urgent surgery, idarucizumab administered at a dose of 5 g quickly, completely, and adequately reversed the anticoagulant effects of dabigatran.
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Source: Pollack C. V. jr., Reilly P. A., van Ryn J. et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med 2017; 377: 431–441, doi: 10.1056/NEJMoa1707278.
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