Antidote to ticagrelor reverses bleeding, restores platelet function
Key takeaways:
- Bentracimab restored platelet function in patients on ticagrelor with major bleeding or undergoing urgent surgery.
- Bentracimab is an intravenous monoclonal antibody.
CHICAGO — Bentracimab, a recombinant human immunoglobulin G1 monoclonal antibody fragment, restored platelet function in patients on ticagrelor undergoing urgent surgery or with major bleeding, according to data from the REVERSE-IT trial.
The phase 3 trial was presented at the American College of Cardiology Scientific Session. 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 and a Healio | Cardiology Today Editorial Board member, and colleagues enrolled 226 patients using the P2Y12 inhibitor ticagrelor (Brilinta, AstraZeneca) for at least 3 days and who presented with major bleeding or required an urgent surgical procedure.
“Ticagrelor is unlike clopidogrel, prasugrel and aspirin, which are irreversible antiplatelet agents,” Bhatt told Healio. “Ticagrelor is an inhibitor of the [adenosine diphosphate] P2Y12 receptor, but it is reversible because of how it binds to the [adenosine diphosphate] P2Y12 receptor. This has allowed the development of an intravenous monoclonal antibody known as bentracimab. It’s a recombinant human monoclonal antibody fragment that binds to ticagrelor and its active metabolite. By doing that, it restores platelet function.”
There is no established way to reverse the effects of ticagrelor, Bhatt told Healio. “Platelet transfusions are not particularly effective because of ticagrelor’s reversible nature,” Bhatt said. “The ticagrelor can still bind to those new platelets.”
In the REVERSE-IT trial, all patients received bentracimab (SFJ Pharma); the trial was a single-arm study with no placebo group, Bhatt told Healio.
The primary outcome was percent reduction of P2Y12 reaction units (PRU). The key secondary outcome was effective hemostasis as independently adjudicated by a clinical events committee.
The minimum percent reduction of PRU within the first 4 hours post-dose was much lower than at baseline (P < .0001), signaling that bentracimab restored platelet function, Bhatt said.
The results were consistent across subgroups, Bhatt said during a press conference.
“In these patients, there is rapid and significant restoration of normal platelet function,” Bhatt told Healio. “By about 5 minutes, there was significant reversal of the antiplatelet effect of ticagrelor. That was sustained for the duration of the infusion.”
Effective hemostasis was defined as normal, mild or moderate by Global Use of Strategies to Open Occluded Arteries (GUSTO) criteria for the surgery group and as excellent or good by Connolly criteria for the major bleeding group. The clinical events committee determined that effective hemostasis was met in 94.3% of the overall cohort (95% CI, 87.6%-100%; P < .0001), 100% of the surgery cohort (95% CI, 91.7%-100%; P < .0001) and 83.1% of the major bleeding cohort (95% CI, 71.5%-94.7%), Bhatt said during the press conference.
The effective hemostasis results were consistent across subgroups other than those for which there was a very small sample size, according to the researchers.
Five patients (2.2%) — three from the surgery group and two from the major bleeding group — had drug-related adverse events, but there were no serious drug-related adverse events, Bhatt said.
The FDA granted orphan drug status to bentracimab in March. It is not approved for commercial use in the United States and is going through the regulatory process, Bhatt said.
“This looks to be a very promising option for ticagrelor reversal, but we have to see what the FDA’s assessment is,” Bhatt told Healio. “The data, in terms of the platelet function and bleeding, look very favorable. Speaking with the investigators in this trial, the surgeons say they don’t see the bleeding they normally see when they operate on patients on ticagrelor. If this drug were to be approved, I think it would be a really useful option in the ICU setting, the emergency room setting and any other setting where bad bleeding complications can occur.”
For more information:
Deepak L. Bhatt, MD, MPH, MBA, can be reached at deepak.bhatt@mountsinai.org.
Perspective
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I think this was a great study. It addresses a very important issue: exposure to P2Y12 inhibitor agents in patients with acute MI or who undergo PCI and then have the need for subsequent surgical procedures. We know there is a strong link between increased risk for surgical bleeding and exposure to ticagrelor. This often results in delays for surgery, which can be inefficient for the patient and the entire system. In patients who need urgent surgery, risk for bleeding is much higher. Often this forces decisions about avoiding surgery when surgery is what is best for the patient.
A ticagrelor reversal agent has been elusive. This study finally shows there is a safe and effective agent to reduce the effect of ticagrelor. It addresses a major concern that we have as practicing interventional cardiologists.
This study suggests bentracimab is safe because there were no drug reactions, and hemostasis was successful in the vast majority of cases. The drug was successful during administration and acts virtually immediately, which is great. However, it also wears off quickly, so needs to be administered for the duration of surgery, and maybe after. It binds to ticagrelor and reverses its effect while it’s being administered, but when it stops, it is not effective.
However, when you think about patients who come in with acute MI, are administered ticagrelor and then need to go to urgent bypass surgery, there is no need to delay the surgery anymore. You can administer this agent, take the patient to surgery safely and speed the time to their definitive operation. Hopefully this can be a game changer in that regard.
Program Director, Interventional Cardiology Fellowship
Robert and Suzanne Tomsich Department of Cardiovascular Medicine
Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute
Cleveland Clinic
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Bhatt DL, et al. Late-breaking clinical trials II. Presented at: American College of Cardiology Scientific Session; March 29-31, 2025; Chicago (hybrid meeting).