Study affirms bentracimab potential for ticagrelor reversal in patients requiring surgery or with bleeding

The first-in-class monoclonal antibody bentracimab effectively and safely reverses the antiplatelet effects of ticagrelor in patients with an indication for urgent or emergent surgery or with major bleeding in the single-arm phase III REVERSE-IT trial.

“Bentracimab rapidly and significantly restored platelet function in ticagrelor-treated patients,” said principal investigator Dr Deepak Bhatt from the Mount Sinai Fuster Heart Hospital, New York, New York, US, at ACC.25. “This was true for both surgical patients and those with major bleeding. Most patients in both groups also achieved normal haemostasis (ie, normal blood clotting and repair of damaged blood vessels) after bentracimab treatment.”

A total of 226 patients (average age 65 years, 79.2 percent men) were enrolled and received bentracimab by slow infusion over about 16 hours. Eligible patients (n=212) must have received ticagrelor within the previous 3 days and require either urgent surgical procedures (surgery arm; n=141) or present with major bleeding (bleeding arm; n=71). The primary endpoint was restoration of normal platelet function as measured by the minimum percent inhibition of P2Y₁₂ Reaction Unit (PRU). [Bhatt, et al, ACC.25]

The reversal of the antiplatelet effects of ticagrelor within 4 hours after starting bentracimab vs pre-dose was deemed statistically significant (p<0.0001).

“We used 50 percent as the expected rate. Compared with that, there was a significant increase in the adjudicated effective haemostasis rate – 94 percent in the overall trial, 100 percent in the surgical group, and 83.1 percent in the major bleeding group,” said Bhatt. The p-values across all arms were p<0.0001. The results were similar across all prespecified subgroups.

Five drug-related adverse events (AEs) were reported. None were serious, and none led to early termination of treatment or to study withdrawal. According to Bhatt, the safety profile looked good, with no serious allergic, thrombotic, or other events, confirming the safety profile observed in the phase I study wherein bentracimab safely reversed the antiplatelet effects of ticagrelor in 64 healthy volunteers. [N Engl J Med 2019;380:1825-1833]

Increased bleeding risk

“[However,] while an effective antiplatelet, [ticagrelor] does come with the risk of bleeding, and unlike other anticoagulants … there is no good option to reverse its antiplatelet effect,” said Professor Toby Trujillo from the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, US, during a press conference discussion of REVERSE-IT.

“A patient on ticagrelor who needs emergency heart surgery is at high risk for developing serious bleeding during the surgery. If you delay the surgery, there is a risk the patient could have a heart attack,” said Bhatt.

“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 do not work in patients taking it,” he continued. Trujillo echoed Bhatt’s sentiments, adding that other haemostatic approaches are not well-supported in literature. Also, there is no FDA-approved reversal agent for ticagrelor.

“Therefore, a rapid-acting reversal agent would be useful … Bentracimab was developed as an antidote to ticagrelor precisely for use in situations like this,” said Bhatt.

Generic version may increase ticagrelor use

In the prespecified interim analysis of REVERSE-IT, bentracimab restored platelet function in ticagrelor recipients undergoing urgent or emergent surgery. However, this analysis had few patients with major bleeding. [NEJM Evid 2022;doi:10.1056/EVIDoa2100047]

The current analysis includes patients with serious bleeding complications. However, Bhatt and colleagues noted that the lack of a placebo arm may have limited the findings, but they pointed out that they felt uncomfortable randomizing patients who needed emergent surgery or those with life-threatening bleeding, considering what was already known about the drug.

To protect against potential bias, the phase III study was designed to include a panel of physicians who decided which patients were truly eligible to enrol and made all determinations of patient outcomes and AEs independent of the investigators.

“It is important to note that ticagrelor is already used clinically to a relatively good degree, and that will likely continue to increase due to its availability as a generic drug in the coming years,” said Trujillo.

Therefore, the availability of a safe and effective antidote “may make physicians more comfortable prescribing ticagrelor when it is clinically indicated, which may help to solve the well-known problem of undertreatment with antiplatelet therapy,” said Bhatt.

“The ability to reverse the antiplatelet effect in a clinical situation, which you deem is going to help improve the patient’s clinical outcome –  either major bleeding or in urgent surgery – will be a welcome addition to our ability to manage these particular patients,” Trujillo shared.

A practice-changing agent

“Based on the REVERSE-IT findings, bentracimab appears to be a very promising option for ticagrelor reversal,” concluded Bhatt.

Regulatory assessment for bentracimab is ongoing. The FDA has recently granted orphan drug designation for bentracimab.

“We are curious to see how it makes its way to regulatory approval … It has an interesting dosing strategy needed to achieve reversal over the 24 hours after you start it … Institutions and healthcare systems will need to figure out how it can be appropriately used,” Trujillo said. “Again, [bentracimab] will be a welcome and practice-changing agent once it becomes available.”