Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center and professor of medicine at Harvard Medical School, explains the interim findings of the REVERSE-IT trial that were presented at the 2021 AHA Scientific Sessions.
Can you summarize the interim results of REVERSE-IT that were presented today at AHA Scientific Sessions 2021?
What REVERSE-IT studied was a drug called bentracimab, an investigational agent that is a ticagrelor reversal drug. Ticagrelor is an antiplatelet agent that is a reversible antiplatelet agent. It's not reversible meaning it's reversible right away—that's what many people sort of understand the word to mean—but it means reversible really in terms of how the drug binds to the ADP P2Y12 receptor. That is reversible binding. Because of that property—which is different from irreversible antiplatelet agents such as clopidogrel or prasugrel, for that matter, aspirin—that reversible nature of ticagrelor has allowed the development of bentracimab, which is an intravenous monoclonal antibody. It's a recombinant human monoclonal antibody fragment to be precise, and it binds to ticagrelor with very high affinity and specificity, thereby reversing its action. And we know it reverses its action because that was studied in a phase 1 trial.
Actually, I presented those data as a late breaker in 2019 at the American College of Cardiology. That work was published in New England Journal of Medicine, where we took healthy human volunteers—a phase 1 study—randomized them to bentracimab or placebo, and found immediate and sustained reversal of ticagrelor with a bolus and infusion of bentracimab. That was the prior data.
What I presented here from REVERSE-IT is the phase 3 trial, so [these are] not healthy human volunteers, but rather actual patients, specifically patients that needed urgent or emergent surgery or patients with major bleeding. Those were the patients we studied. This was a prespecified interim analysis, prespecified in accordance and in consultation with the FDA—who had granted bentracimab breakthrough therapy designation—and in consultation with the [European Medicines Agency]—who had granted the drug PRIME or priority medicines designation. And, again, this was all done in consultation with them. Otherwise, we wouldn't have necessarily just presented a prespecified analysis. Typically in trials here, it was specifically with their permission and in consultation with them in the ideas to support a BLA, or biologics license application submission, for an accelerated conditional approval.
So that's why we were presenting these interim data, but the findings actually were quite striking with very significant reversal of ticagrelor’s effect by 2 different platelet function tests: the verifying PRU test [P2Y12 reaction units] and the VASP PRI—or platelet reactivity index—both showed highly significant reversal of ticagrelor early by 5 minutes, which was the first time we studied and worked and throughout the full 24 hours of measurement. Furthermore, that reversal was significant across multiple prespecified subgroups, so it looked like it was doing what was supposed to do, even in patients.
Ticagrelor uptake has increased, but an NCDR study found there is a distinct regional effect, with greater use in parts of the country that have fewer STEMI events. As mentioned during the Q&A today, is uptake limited because a reversal agent has not been available?
I thought that was a great point by the discussant. I do think having a reversal agent available will make doctors more comfortable using ticagrelor preferentially to using prasugrel or clopidogrel. Obviously, in the US, there are price issues as well: it’s even a differentiating feature versus aspirin, which is also an irreversible agent. If there's a patient who you're worried about bleeding, maybe they're at high bleeding risk, the possibility of a reversal agent—for to be approved—might make it more appealing to use ticagrelor, even in the patient who's not necessarily at priori at high bleeding risk.
If you're trying to figure out whether [you’re] going to use clopidogrel or prasugrel or ticagrelor, and you know there's a reversal agent, again, it might push towards that use. In particular, I would say once ticagrelor is generic, but even now, when it is still branded, because there are indications that ticagrelor has that are not shared by clopidogrel and prasugrel and the data for even the shared indications like acute coronary syndromes are pretty good with ticagrelor from the PLATO trial. But then there's also PEGASUS, THEMIS and THEMIS PCI, and THALES, so a variety of other indications based on randomized clinical trials for ticagrelor. I'm not 100% sure why the use of ticagrelor isn't more than it is. I think probably the major reason is cost. But I think that having a reversal agent will certainly address the concerns of physicians who are worried about using it because of the fact that does tend to cause more bleeding, say, than clopidogrel, but not more than prasugrel.
You discussed the potential reluctance of investigators to randomize very sick patients to a placebo arm in a conventional randomized controlled trial. Is the approach you took likely to become more common, given the availability of RWD as a control?
It's a good question but I think, again, for this sort of patient, it's tough to do a randomized clinical trial. All the NOAC [novel oral anticoagulant] reversal trials basically did what we did: they didn't randomize those patients because they realized it's going to be tough to get investigators to randomize. I know there are always investigators that say, “Oh, I would have been willing to randomize,” but they don't have the investigational agent in hand.
So it's not a theoretical question of “would you participate in a randomized trial with us?” Rather, you’re site investigator, you got a patient with an intracranial hemorrhage, you've got a ticagrelor reversal agent in hand. Would you really feel comfortable randomizing? At least our investigators seem to not feel comfortable with that thought, and the regulatory agencies—the FDA and the EMA—they got it. They realized that a randomized trial actually wouldn't be feasible here.
So it really didn't have to do with COVID. Even pre-COVID, with the NOAC reversal agents, this wasn't an option. One thing I may not have made so clear in my presentation and probably should have—and the discussant may not have picked up on it—is, the phase 1 data that had been published in the Journal of Medicine, that was randomized. So there, we did have a randomized assessment of bentracimab versus placebo, double blind, all the bells and whistles there. And we showed significant reversal of ticagrelor’s effect. At this point, we were pretty sure when we were doing it—and for that matter, the phase 2A and 2B were also randomized—at this point, we already had really good safety data, we had great data for platelet reversal.
So yeah, in theory, we could have done a randomized phase 3 in REVERSE-IT, but we already had so much data showing it works. In that context, it would have been hard at an investigators meeting, to say, “look, we've got all this great data, it shows it works, but we're going to make you randomize it.” Again, theoretically, I think there's some points there. But practically speaking, this is exactly why the NOAC reversal trials did it the way we are. But I must say this didn't have anything to do with COVID, that wasn't the reason that we didn't randomize. COVID did make enrolling patients a little bit more difficult, as it did with every trial. I think we did learn some lessons about doing a trial in COVID here and trying to find ways of keeping sites engaged and trying to help them when COVID might be surging in their region, trying to give them some tips to keep the trial going. That did pose some challenges for sure, but I think we did learn some lessons that can be applied even in a—hopefully we'll get there—postpandemic world.