Key Points:
- A major limitation of antithrombotic therapy is the risk of bleeding if a patient requires urgent surgical or invasive procedures as well as the risk of spontaneous hemorrhage.
- Bentracimab is a first in class recombinant human immunoglobulin monoclonal antibody fragment that binds to ticagrelor and its active metabolite, rapidly neutralizing their antiplatelet effects.
- In this multi-center, phase 3 prospective, open-label, single-arm trial, bentracimab was shown to rapidly and effectively reverse ticagrelor in patients requiring urgent surgery or experiencing major bleeding, with high rates of hemostasis and favorable safety outcomes.
Multiple, high-quality randomized clinical trials have demonstrated that ticagrelor, an oral P2Y12 receptor antagonist, is effective in reducing ischemic events in patients with acute coronary syndromes, prior myocardial infarctions, high-risk coronary artery disease, transient ischemic attacks, and strokes. However, its major limitation is the risk of major bleeding during urgent surgical or invasive procedures and spontaneous hemorrhage. Platelet transfusions are ineffective at reversing ticagrelor. Therefore, a specific and fast-acting reversal agent is highly desirable. Bentracimab, a monoclonal antibody fragment, selectively binds ticagrelor and its active metabolite with high affinity. In a prior phase 1 clinical trial, bentracimab was shown to restore normal platelet activity in a group of healthy volunteers.
The REVERSE-IT trial was a phase 3, open-label, prospective, single-arm, multicenter study evaluating the safety and efficacy of bentracimab in patients who had received ticagrelor within the past 3 days and required urgent surgery or had major bleeding. A total of 226 patients were enrolled, including 141 with urgent surgical needs and 71 with major bleeding. The population was majority male (79.2%) and White (76.1%). The primary endpoint was the percentage inhibition of the P2Y12 Reaction Unit (PRU), as measured by the VerifyNow assay. Following bentracimab infusion, statistically significant (P < 0.001) reversal of ticagrelor’s antiplatelet effects occurred in all groups (enrolled, eligible, surgery, and bleeding) and across all pre-specified subgroups (sex, age, race, region, comorbidities, renal function, time since last ticagrelor dose). PRU returned to normal in over 80% of patients within 5–10 minutes and in over 90% within 30 minutes. Effective hemostasis, a secondary endpoint, was achieved in 100% of surgical patients, 83.1% of bleeding patients, and 94.3% of all patients (P < 0.0001). These results were consistent across prespecified subgroups.
There were 61 (31.9%) thrombotic events but none were considered bentracimab related. No allergic adverse events occurred and bentracimab was not discontinued in any of the patients.
Limitations of the trial include its single-arm design—there was no placebo comparator due to ethical concerns regarding withholding treatment in emergent settings given the results of the phase 1 trial. The study had a modest sample size and enrolled few Black patients (3.1%).
Presented as a Late Breaker at the 2025 American College of Cardiology conference, Dr. Deepak Bhatt concluded that “bentracimab, rapidly restored normal platelet function in ticagrelor-treated patients. [The availability of bentracimab] may make physicians more comfortable prescribing ticagrelor when it’s clinically indicated, which may help to solve the well-known problem of undertreatment with antiplatelet therapy.” Based on the results of these trials and prior work, the FDA has granted orphan drug designation for bentracimab.