REVERSE-IT: Bentracimab provides immediate, sustained reversal of ticagrelor effects
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An IV monoclonal antibody accomplished quick and sustained reversal of the antiplatelet effects of ticagrelor, according to the REVERSE-IT trial presented at the American Heart Association Scientific Sessions.
The antiplatelet effects of ticagrelor (Brilinta, AstraZeneca), a P2Y12 inhibitor, cannot be reversed by platelet transfusion, so a reversal agent is an unmet need, Cardiology Today Intervention Section Editor Deepak L. Bhatt, MD, MPH, executive director of interventional cardiology programs at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, told Healio.
“The difference between ticagrelor and clopidogrel or prasugrel is that ticagrelor is a so-called reversible antiplatelet agent,” he said in an interview. “The way ticagrelor binds has allowed development of a monoclonal antibody called bentracimab (PhaseBio), which binds to ticagrelor or its active metabolite and is removed from the circulation.”
The REVERSE-IT trial included 150 patients taking ticagrelor (mean age, 65 years; 77% men) who had uncontrolled or major life-threatening bleeding (n = 8) or were undergoing an urgent surgical or invasive procedure (n = 142). The primary reversal endpoint was minimum percent inhibition of P2Y12 reaction units within 4 hours as assessed by a platelet function assay (PRUTest, VerifyNow). The primary hemostasis endpoint was achievement of effective hemostasis within 24 hours.
“This is a prespecified interim analysis in accordance with discussions with the FDA in order to provide an early look at a therapy that could be potentially lifesaving in certain circumstances,” Bhatt told Healio.
At 4 hours, the percent inhibition of platelet function as assessed by the platelet reactivity index was lower than before dosage of bentracimab (P < .0001), as well as at all time intervals up to 24 hours (P < .0001 for all time points), according to the researchers.
“There is a significant reversal of the antiplatelet effects from ticagrelor by bentracimab,” Bhatt told Healio. “The benefits on platelet function kick in very quickly, by 5 to 10 minutes, and are sustained. The primary platelet endpoint was very easily met.”
In the surgical cohort, among 113 with adjudicated hemostasis, 66.4% achieved the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) mild criteria and 33.6% achieved the GUSTO moderate criteria at 24 hours. Among 135 surgical patients with investigator-reported hemostasis, 77.5% were normal or had mildly abnormal bleeding, 17.6% had moderately abnormal bleeding and 4.93% had severely abnormal or unknown bleeding at 24 hours, according to the researchers. In addition, 39.04% had blood transfusions, 13.4% had platelet transfusions and 2.8% died.
Among the surgical cohort, 74% restarted P2Y12 inhibition at a median of 2 days.
In the bleeding cohort, among those with adjudicated hemostasis, 66.7% achieved excellent hemostasis, 11.1% achieved good hemostasis, 11.1% achieved poor hemostasis and 11.1% had hemostasis that was unable to be determined. In addition, 62.5% had a blood transfusion, 25% had a platelet transfusion and none died. P2Y12 inhibition was restarted in 62.5% of patients at a median of 5 days.
The reversal and hemostasis results were consistent by patient population (surgical vs. bleeding), sex, age, race, region, renal function, MI, diabetes, hypertension, CYP3A inhibitor and time from last ticagrelor.
There was no platelet rebound activity as measured by P-selectin and by mean platelet volume at 72 hours.
Eight patients had thrombotic events, none of which were related to bentracimab.
“A theoretical concern is that we’re reversing the effect of ticagrelor — is there a risk of overshooting the mark and causing a prothrombotic state?” Bhatt told Healio. “The monoclonal antibody is getting rid of the ticagrelor, so it should return a person to whatever their thrombotic risk is without ticagrelor, not more than that. There was no hint of any sort of thrombotic rebound. For adjudicated thrombotic events, in this high-risk population, there were a lot of thrombotic and ischemic events occurring, but the adjudicators thought that none of them were due to bentracimab.”
Bhatt said the study is in press at NEJM Evidence, a digital journal launching in January.
“This looks like a promising option for ticagrelor reversal,” Bhatt told Healio. “We will be discussing the data with the FDA once the data are in the public domain.”
Perspective
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B. Hadley Wilson, MD, FACC
This was an exciting trial. This drug has features that are going to be helpful to treat patients who are having bleeding or require emergency surgery after starting dual antiplatelet therapy with ticagrelor.
The need for a ticagrelor reversal agent is uncommon but not rare. It occurs in every practice at some time or another, maybe even several times per year. When it does, these are urgent cases where the patient has a bleeding problem or needs surgery, so it would be great to have an agent like this that could provide a possible solution.
Also important was that there was a low rate of side effects and no drug- or infusion-related adverse reactions.
There were some concerns that the study was not large, but this is a difficult area to recruit for. It is also difficult to conduct a randomized trial in this population and may not be ethical to do so. The investigators should be commended for having as many patients in this trial as they did, and for having two different patient groups for whom they could show that this is an effective agent.
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Bhatt DL, et al. LBS.07. New Drugs and New Drug Indications in Cardiovascular Disease. Presented at: American Heart Association Scientific Sessions; Nov. 13-15, 2021 (virtual meeting).
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