A drug developed as an antidote to the antiplatelet agent ticagrelor safely and effectively reversed ticagrelor's antiplatelet effects in patients undergoing urgent surgery or experiencing major bleeding, according to a study presented at the American College of Cardiology's Annual Scientific Session (ACC.25).
The antidote, bentracimab, rapidly restored normal platelet function in ticagrelor-treated patients. This was true for both surgical patients and those with major bleeding. Most patients in both groups also achieved normal hemostasis—that is, normal blood clotting and repair of damaged blood vessels —after bentracimab treatment."
Deepak L. Bhatt, MD, MPH, MBA, director of the Mount Sinai Fuster Heart Hospital, the Dr. Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai in New York and the study's principal investigator
The availability of a safe and effective antidote "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," Bhatt said.
Known as dual antiplatelet therapy, ticagrelor is used in combination with aspirin to prevent repeat heart attacks and blood clots in people who have had a stent placed in a coronary artery. It works by blocking a protein that stimulates platelets (blood components that help with normal clotting) to form a clot in response to bleeding.
Like all drugs that interfere with blood clotting, ticagrelor increases patients' risk of having a bleeding episode, especially during urgent surgery or another type of invasive procedure, Bhatt said. Bentracimab was developed specifically to reverse ticagrelor's antiplatelet effects and restore platelets' normal ability to form blood clots and stop bleeding.
"A patient on ticagrelor who needs emergency heart surgery is at high risk for developing serious bleeding during the surgery," he said. "If you delay the surgery, there's a risk the patient could have a heart attack. Or say a patient on ticagrelor develops bleeding in the brain. Ordinarily, we might give platelet transfusions to control the bleeding, but because of ticagrelor's mechanism of action, platelet transfusions don't work in patients who are taking it. Bentracimab was developed as an antidote to ticagrelor precisely for use in situations like this."
In 2019, Bhatt and his colleagues published the results of a randomized Phase 1 study in which, compared with a placebo, bentracimab safely reversed the antiplatelet effects of ticagrelor in 64 healthy volunteers. The single-arm, Phase 3 REVERSE-IT trial was designed to assess the effects of bentracimab in patients who needed urgent surgery or were experiencing major bleeding.
Between 2020 and 2024, 226 patients were enrolled in the trial in the United States, Canada, Europe and China. Eligible patients must have received ticagrelor within the previous three days and either needed surgery or another invasive procedure that could not be delayed (the surgery group) or were experiencing major bleeding (the bleeding group).
The patients' average age was 65 years, 79.2% were men, and 76.1% were White. Most (75.7%) had high blood pressure, 74.3% had had a prior heart attack, 41.6% had diabetes and most were overweight (average body mass index 28.6). Most patients in the surgery group (78.7%) were undergoing cardiac bypass surgery. All patients received bentracimab by slow infusion over about 16 hours.
The primary efficacy endpoint was the average minimum percentage of ticagrelor's activity that was blocked within four hours of starting the bentracimab infusion. The key secondary endpoint was the number of patients who achieved normal blood clotting and repair of damaged blood vessels during their hospital stay after treatment with bentracimab. Patients were followed until the end of the study for adverse events such as allergic reactions, bleeding and blood clots.
In a prespecified interim analysis published in 2022 in NEJM Evidence, bentracimab restored platelet function in patients on ticagrelor who were undergoing urgent or emergent surgery, though that analysis had relatively few patients with major bleeding. The current study reports the trial's final results, including patients with serious bleeding complications. Outcomes were analyzed for the 212 eligible patients and adverse events for the entire enrolled population of 226 patients.
The primary endpoint, the degree of restoration of normal platelet function after the start of bentracimab infusion compared with baseline, was statistically significant. Results were similar for patients in both the surgery and bleeding groups, as well as in all prespecified subgroups of patients including age and sex.
In total, 94.3% of patients—100% in the surgical group and 83.1% in the bleeding group—achieved normal blood clotting and repair of damaged blood vessels after bentracimab treatment. Again, results were similar in both the surgery and bleeding groups and subgroups.
About 18% of patients in the surgery group experienced serious adverse events deemed related to treatment, compared with about 12% in the bleeding group. No patients had serious allergic reactions to bentracimab treatment, and no patients withdrew from the trial because of treatment-related adverse drug reactions, Bhatt said.
The study has limitations, including a limited number of Black patients and the lack of a control group. The investigators believed it would be unethical to randomly assign some patients to receive a placebo when they were experiencing or at high risk for potentially life-threatening bleeding. In the randomized Phase 1 trial, healthy volunteers who received bentracimab rapidly recovered normal platelet function compared with those who received the placebo. As an additional safeguard against potential bias in a single-arm study, Bhatt said, the Phase 3 trial was designed to include a panel of physicians who decided which patients were truly eligible to enroll in the trial and made all determinations of patient outcomes and adverse events independent of the study investigators.
The study was funded by PhaseBio Pharmaceuticals, Inc., and SFJ Pharma, Inc. Bhatt is a paid consultant to SFJ Pharma.
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