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Rapid and Sustained Reversal of Ticagrelor–Intervention Trial - REVERSE-IT
Highlighted text has been updated as of March 29, 2025.
Contribution To Literature:
The REVERSE-IT trial showed that bentracimab (PB2452), a recombinant IgG1 monoclonal antibody that reverses the effect of ticagrelor, is safe and effective in promptly reversing the antiplatelet effect of ticagrelor among patients undergoing urgent surgery/procedure or with major bleeding.
Description:
The goal of the trial was to assess the safety and efficacy of bentracimab (PB2452) in reversing the antiplatelet effect of ticagrelor among patients needing urgent surgery or a procedure, or with major bleeding.
Study Design
Patients who either needed urgent surgery or a procedure (n = 142) or with major bleeding (n = 8) were enrolled in an open-label single-arm study.
- Total number of enrollees: 150
- Duration of follow-up: 48 hours
- Mean age: 65 years
- Percentage female: 23%
On day 1, patients received an intravenous (IV) infusion of an initial IV bolus of 6 g infused over 10 minutes for rapid reversal, followed immediately by a 6 g IV loading infusion over 4 hours and then a 6 g IV maintenance infusion over 12 hours (total 18 g). A higher dose of 36 g could be used in patients with potential drug interaction from recent concomitant use of moderate or strong CYP3A inhibitors with ticagrelor.
Inclusion criteria:
- Last ticagrelor dose within 3 days
- Age ≥18 years
- Patients needing urgent surgery or a procedure (when it is not medically advisable either to proceed urgently with impaired hemostasis or to delay the urgent procedure for 3 or more days as directed by ticagrelor labeling due to the high risk of bleeding) or with major bleeding
Exclusion criteria:
- Known sensitivity or contraindication to PB2452 or any of its excipients
- Patients in whom ticagrelor reversal is not considered urgent (e.g., patients with stable or nonacute conditions who have low hemoglobin due to chronic, low-grade gastrointestinal bleeding or who have stable, remote, or asymptomatic intracranial hemorrhage)
- Patients expected to be clinically unsalvageable, such as patients with intracranial hemorrhage with Glasgow Coma Scale ≤8, or an intracerebral hematoma volume >60 cc or patients with overwhelming sepsis
- Known use of clopidogrel, prasugrel, or ticlopidine within 5 days of study drug administration; known use of antiplatelet glycoprotein IIb/IIIa inhibitors, or cangrelor within 5 half-lives of expected study drug administration; or known use of warfarin, rivaroxaban, apixaban, or edoxaban within 5 half-lives or expected study drug administration
- Known recent use (<5 days) of vitamin K, prothrombin complex concentrate, recombinant factor VIIa, whole blood or plasma transfusions, idarucizumab, or andexanet alfa (coagulation factor Xa [recombinant], inactivated-zhzo)
Other salient features/characteristics:
- White race: 83%
- Estimated glomerular filtration rate <60: 21%
- Time from last ticagrelor dose 0-1 days: 71%, 2 days: 20%
Principal Findings:
This was a prespecified interim analysis for accelerated regulatory approval. The primary reversal endpoint, minimum % inhibition of VerifyNow PRU within 4 hours of bentracimab initiation, was successfully met (<-50%, p < 0.001). PRUs increased from a baseline of <100 to >200 within 5-10 minutes with a steady increase by 4 hours, and appeared to be sustained for 24 hours (p < 0.001 for all time points studied). This was confirmed using VASP platelet reactivity index (PRI) assay as well. Platelet inhibition results were consistent for patients needing urgent surgery/procedure or with major bleeding.
- Adjudicated achieved hemostasis (n = 113; surgical cohort): 100% (66.4% had GUSTO mild bleeding, 33.6% had GUSTO moderate bleeding, no severe bleeding)
- Total mortality: 2.8%
There was no evidence of platelet rebound activity, as measured by P-selectin and mean platelet volumes.
Outcomes from the final results in 212 eligible study patients showed a statistically significant improvement in the primary endpoint of the degree of restoration of normal platelet function after the start of bentracimab infusion compared with baseline. Effective hemostasis was achieved in 99% of the urgent surgery/procedure group and 85% of the major bleeding group. Results were similar for prespecified subgroups including age and sex. No thrombotic events or serious adverse events related to bentracimab occurred.
Interpretation:
The results of this phase III trial indicate that bentracimab (PB2452), a recombinant IgG1 monoclonal antibody antigen-binding fragment that binds with high affinity to ticagrelor and its active metabolite (AR-C124910XX), is safe and effective in reversing the antiplatelet effect of ticagrelor. Reversal was noted within 5 minutes, and the duration of reversal was infusion-time dependent. Effective hemostasis was achieved in most cases and no rebound increase in platelet activity was noted.
This drug is not expected to work against clopidogrel and prasugrel, which are irreversible P2Y12 receptor inhibitors.
References:
Presented by Dr. Deepak L. Bhatt at the American College of Cardiology Annual Scientific Session (ACC.25), Chicago, IL, March 29, 2025.
Presented by Dr. Deepak L. Bhatt at the American Heart Association Virtual Annual Scientific Sessions (AHA 2021), November 15, 2021.
Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Anticoagulation Management and ACS, Novel Agents, Interventions and ACS
Keywords: Acute Coronary Syndrome, Anticoagulants, Antibodies, Monoclonal, Broadly Neutralizing Antibodies, Cardiac Surgical Procedures, Cardiology Interventions, Clopidogrel, Drug Interactions, Hemorrhage, Hemostasis, Immunoglobulin G, Mean Platelet Volume, Platelet Aggregation Inhibitors, Prasugrel Hydrochloride, Ticagrelor, ACC25, ACC Annual Scientific Session
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