Innovations and Expert Guidance in Antiplatelet Reversal and Bleeding Management

[00:34:18]

Antiplatelet Therapy for Acute Stroke Management: Current Strategies and Unmet Needs

I will be speaking first on the spectrum of antiplatelet therapy for acute stroke management. And then Doctor Bhatt will be speaking on reversal approaches for antiplatelet management.

[00:34:43]

Most Common Oral Anticoagulants and Antiplatelet Agents

And the story of antiplatelet therapy for acute ischemic stroke has become very complicated and nuanced, which is great. When I started out, all we had was aspirin and all we argued about was the dose of aspirin. Now we have many combinations of agents, and a solid evidence base for their knowledgeable use. And here you see some of the different antithrombotic agents; we have both anticoagulants best for stasis, clotting, slow flow, activation of coagulation proteins. And then antiplatelet agents, best for rapidly flowing—just laminar flow streams over irregular surfaces, as in atherosclerosis. The classic red clot anticoagulation, white clot antiplatelet therapy distinction.

[00:35:40]

Antiplatelet Agents: Mechanism of Action

And when we look closely at antiplatelet agents, here are the mechanisms of action of those we have available. Our classic is aspirin acting on the COX inhibitors. Then there are the thienopyridines acting in the P2Y target. Then there's the phosphodiesterase inhibitors, and finally the G2P3 agents.

[00:36:11]

Ticagrelor: Reversible Mechanism of Action

And ticagrelor has some distinctive aspects. First it is a reversible mechanism of action, other of the phosphate – of the thienopyridines are irreversible antagonists, but ticagrelor is a reversible antagonist. It is absorbed rapidly through the GI tract. It is not a prodrug, it is directly active, but it does have this dynamic interaction with the target.

[00:36:46]

Oral P2Y12 Inhibitors: FDA-Approved Indications

And if we look at the approved indications for the oral thienopyridines, you can see here the widest range is for clopidogrel and ticagrelor in the stroke space, both for indicated for prevention of first stroke. And if you've had a coronary event and then secondary prevention of stroke, prasugrel, a bit more bleeding concerns, so less of a breadth of indication.

[00:37:25]

Properties of P2Y12 Inhibitors

Here in text form, the distinctive aspects of the different P2Y12 inhibitors. And you can see that clopidogrel and prasugrel are irreversible. Ticagrelor and the intravenous agent, cangrelor, are reversible. You can see the half-lives of these agents, the onset of action is pretty quick for prasugrel, ticagrelor and cangrelor, a little longer for clopidogrel to have its onset of action. The offset of action is longest for clopidogrel and prasugrel, moderate for ticagrelor, and of course, much quicker for cangrelor.

[00:38:18]

Antiplatelet Regimen Head-to-Head Clinical Trials to Prevent Stroke Early After Acute TIA/Stroke

If you look at the clinical trial evidence base, we have for using these agents in acute stroke and TIA, and of course, we primarily use these agents in the first 21 to 30 days after a TIA or minor stroke. Those were the original trials, although there was a trial soon to come out that shows that these could potentially be used in moderate strokes as well. But the double antiplatelet therapy approaches are beneficial in the in the first 3 to 4 weeks after onset of an event, non-cardioembolic event, when the risk of recurrence is highest, and the benefit of preventing recurrence of ischemic stroke outweighs the risk of hemorrhage. As time goes on, the risk of recurrence of ischemic stroke goes down, while the risk of hemorrhage continues at a steady rate, and those cross, and therefore we do not continue these therapies, usually, except in special circumstances beyond the first 3 to 4 weeks. And we have actually now a total of 7 randomized trials that have compared, DAPT, double antiplatelet therapy to SAPT, single antiplatelet therapy, including CHANCE, POINT, INSPIRES and FASTER for clopidogrel and aspirin, vs aspirin alone. THALES for ticagrelor aspirin vs aspirin alone. CHANCE-2 and PRINCE for comparing a DAPT regimen vs another DAPT regimen, in patients with genetic resistance to clopidogrel. And ADS, which looked at aspirin plus cilostazol vs aspirin alone.

[00:40:20]

Phase III DAPT Studies: Stroke recurrence

And if we look at the phase III trials of these agents, you can see here the clopidogrel studies clustered at the top, the ticagrelor study at the bottom, there's a hint that there might be a little bit more of an effect with clopidogrel on average, although there's no statistically significant heterogeneity in the degree of benefit of these agents.

[00:40:54]

Phase III DAPT Studies: Intracranial hemorrhage

And here's the hemorrhagic risk with these agents. And here there is a little more hemorrhagic risk with ticagrelor than with aspirin. Let me note these event rates are much lower. If you look at the event rates for THALES for the DAPT regimen, it's 20 events out of 5523 patients. If we go back, and you look at the ischemic stroke rates, it's 284 out of 505,000 plus patients. So the relative risk is there, but the absolute risk is much smaller, and so this clear overall benefit.

[00:41:40]

CHANCE-2: Cumulative Incidence of Stroke in CYP2C19 Loss of Function Carriers

And a very important subgroup of patients are those who have genetic resistance to clopidogrel. And if you look at the bottom here, you can see that patients with the genetic change in the CYP2C19 converting enzyme to make the prodrug of clopidogrel become active are not infrequent. There are – if you have 2 copies of the abnormal gene, you're a poor metabolizer. If you have 1 copy, you're an intermediate metabolizer. Poor metabolizers get very little benefit and intermediate metabolizers certainly less than full benefit of taking clopidogrel. Very common among Asian patients; 15% of Asian patients, 4% of Black patients, 2% of White patients and their risk of stroke on clopidogrel, compared to patients who do not have the genetic resistance is increased by 68%. in the trials that have been done in this patient population, specifically, you can see that clopidogrel plus aspirin vs ticagrelor plus aspirin, there's a substantial benefit, as you would expect, from ticagrelor plus aspirin, when the patients with clopidogrel plus aspirin are nearly on really aspirin alone.

[00:43:34]

CHANCE-2: Secondary Endpoints and Safety

And here are the secondary efficacy endpoints from CHANCE-2, and across the board a very substantial additional benefit. So I think what we're seeing in clinical practice is we have been regularly starting patients on aspirin and clopidogrel, and then we have had failures, and we've started testing for resistance. Now there's a fast turnaround genetic test that you can get the results back in several hours, so instead of sending the patient out on clopidogrel plus aspirin and not being sure until you can do it, they've been on the drug for a while and you can do a functional resistance test, if they're adequately protected or not. You can do the genetic testing upfront and know when you're sending them out that they don't have resistance, and clopidogrel and aspirin is the best, or is a very good therapy for them, or that they do have resistance, and that's not the best therapy for them, ticagrelor plus aspirin will be.

[00:44:40]

Monotherapy Options with Clopidogrel: CAPRIE

Let's turn briefly to talking about monotherapy comparisons rather than DAPT comparisons.  There's not been a study of the thienopyridines alone vs aspirin alone in the acute period only, but we do have data from the CAPRIE trial, which looked at these agents over a long term. And you can see that there was very little difference, a non-significant but favorable effect of clopidogrel alone over aspirin, for stroke, but very little difference in the upfront first month of the start of therapy. So I think no major advantage early.

[00:45:26]

Monotherapy Options with Ticagrelor: SOCRATES

Here's the findings with ticagrelor as a sole agent in the first early period vs aspirin alone during the first 90 days. And here you can see there was a benefit of ticagrelor alone over aspirin alone. So historical evidence now that we have moved to DAPT therapy, but that ticagrelor alone is a superior agent.

[00:46:03]

Monotherapy Options with Cilostazol: CSPS 2

There are also data on the phosphodiesterase inhibitors from the CSPS 2 trial, showing that cilostazol alone is better than aspirin alone, in the acute period.

[00:46:16]

Antiplatelet Interruption Recommendations for Surgery

Now, one issue that comes up often in managing these patients is when they're going to surgery or dental procedures or having colonoscopies, and we have to think about whether the antiplatelet agents can be continued or need to be stopped. And if they need to be stopped, when should they be stopped? And here's the recent recommendation that for most procedures, aspirin can be continued unless the interventionalist is insistent that aspirin be stopped for prasugrel and clopidogrel, best to stop the agents long before the intervention, 7 to 10 days for prasugrel, 5 to 10 for clopidogrel. For ticagrelor, a little bit of a faster offset, so best to do it 5 to 10 days, but you can probably get away with 3 to 5 days. And of course, cangrelor, which is a very fast offset, you can stop shortly before the procedure.

[00:47:29]

Factors associated with increased bleeding after PCI

As these agents are being used increasingly, although the DAPT therapies are associated with only small increases in intracerebral hemorrhage, they are being used so often that intracerebral hemorrhages are becoming more frequent, and the challenge of managing intracerebral hemorrhages in patients who have been on active antiplatelet therapy is becoming a common clinical challenge. And here are the patients who are particularly at increased risk; patients who have older age, who have liver or renal disease or active cancer, who have already problems with their hemostatic system, anemia, low platelet count, prior stroke, and prior bleeding history, co-use of NSAIDs or steroids. So these are the patients you have to be very careful with.

[00:48:41]

ICH vs Ischemic Stroke: It’s a balancing act

And it's a balance between looking for the sweet spot patients, where their risk of hemorrhage is relatively low and their risk of ischemic stroke relatively high, where we want to go to double antiplatelet therapy. And I'll point out at the bottom of the box here for the ischemic stroke patients whom we manage, in addition to the risk factors I showed before, things to particularly think about from neuroimaging are large ischemic strokes more likely to bleed than smaller ischemic strokes? Patients with extensive leukoaraiosis, and patients with multiple microbleeds at increased risk for intracerebral hemorrhage.

[00:49:26]

Intracranial Hemorrhage and DAPT

So to take a closer look at the occurrence of intracranial hemorrhage in patients on DAPT, overall DAPT is associated with a 40% increased risk of intracerebral hemorrhage compared to aspirin alone, and 30% of patients who present with intracerebral hemorrhage are on antiplatelet therapy at the time of presentation. Nearly one third of patients have the challenge of managing intracerebral hemorrhage in a patient who has antiplatelet agents on board. And comparative studies of patients on antiplatelet therapy at the time of the hemorrhage vs patients not on antiplatelet therapy, show that they present with larger hemorrhagic volumes at baseline, there's greater frequency of hemorrhage growth from baseline to a few hours afterward, and there's greater amount of hematoma expansion. So we know the story from anticoagulants, where there's even more marked adverse course in patients who are active therapy, but the same is true with antiplatelet therapy; these agents do have a more challenging course than patients not on antithrombotics.

[00:50:45]

Antiplatelet Therapy Reversal Agents: Current Approaches and Latest Clinical Data

So the issue of managing intracerebral hemorrhage is becoming more and more a challenge in neurologists’ lives. And now I get to turn the program over to my colleague, Deepak Bhatt, who will go over how you all can meet this challenge. So, Deepak, are you with us?

Dr. Deepak Bhatt: Oh, yes. No, I've been with you right from the beginning. Hopefully you can hear and see me.

Jeffrey Saver: Yes, we can see you and hear you.

Dr. Deepak Bhatt: Oh, fantastic. And hopefully it's coming through clearly. I wish I could be with all of you in person; I love the ISC meeting, I've been many times, but I had patients scheduled in the cath. lab and there's just no way I could change the schedule, but great to be with you all virtually.

If I could have the first of my slides, please. I don't have the ability to advance them, so I'll just have to give a verbal cue in terms of next slide.

[00:51:36]

Current strategies to reverse antiplatelet agents

So here are some current strategies to reverse antiplatelet agents. Desmopressin which increases the release of large factor VIII and von Willebrand factor. The dosing you can see there 0.4 mcg/kg IV x1. And then platelet transfusions which have variable efficacy based on P2Y12 inhibitor characteristics. Now as far as Desmopressin goes, we'll look at some of the data for that. I must say, I think it's more popular in neurological circles than it is in cardiac circles; we tend not to really use that. Platelet transfusions, you know, it sort of depends on the situation. As you heard from Doctor Saver, for irreversible antiplatelet agents such as aspirin or clopidogrel or prasugrel, aspirin binds to the platelet for its 7- to 10-day lifespan. So whatever aspirin is there, whatever platelets it binds to, it's staying there until those platelets are removed from the circulation. Of course, people are producing new platelets every day if they're healthy, but the ones that have been inactivated, a transfusion can help reverse the effect of aspirin related platelet inhibition. And then this is why the biology matters, the reverse – the irreversible ADP P2Y12 receptor antagonists are clopidogrel and prasugrel. And there each of those drugs, or more precisely, their active metabolites, bind to the ADP receptor irreversibly. So just like aspirin, they're there for some period of time, the exact time might matter in specific situations, but it's typically several days. It's more variable with the clopidogrel, I'll say around 5 days, and a little bit longer with prasugrel, more consistently around 7 days. So there's the possibility again, for platelet transfusions to help somewhat. With ticagrelor, on the other hand, that is a reversible ADP receptor antagonist, and therefore if you've just gotten ticagrelor, well it is binding, and it's a directly binding agent, though there's also an active metabolite; it binds directly and it does its thing in terms of inhibiting the platelet, and giving platelet transfusions doesn't really help in that circumstance, especially when the ticagrelor has been given recently. So those are the key points, but I'm going to go through some of the data and some of the mechanisms in a little greater detail, because those are some important learning points. Next slide.

[00:53:57]

Desmopressin in ICH

So here are some data on desmopressin, specifically in intracranial hemorrhage. Relatively small study, just a little over 50 patients with spontaneous ICH, taking antiplatelets and given desmopressin vs placebo. And you can see the results here in terms of day 90 modified Rankin score and the shift analysis. So, you know, there does seem to be some effect here, one could say, with respect to shifts in the Rankin score. But, you know, I've got to say, at least in my own clinical experience, this hasn't necessarily been the most useful agent, but in our discussion it will be interesting to hear Dr Saver's opinion; I think he's a bit more of a believer than I am. You do need to be aware that there can be hyponatremia that occurs with desmopressin, just based on its mechanism of action? Next slide.

[00:54:56]

Efficacy of Desmopressin in Patients on Antiplatelet Agents Prior to Surgery

And here is just a summary of efficacy of desmopressin in patients on antiplatelet agents prior to surgery. Again, you know, it's, I think, not the most compelling sort of story for this, relatively modest number of patients here to say anything. And if you look at the rightmost column, that's the GRADE quality assessment's way of saying, are the studies any good or not? You know, most of these are graded as low and very low. One is graded as moderate, in terms of the benefit. But you know, directionally there are some signals in some of these studies, such as looking at re-operation for bleeding, you know, that perhaps there is some modest effect of desmopressin. Next slide.

[00:55:50]

The PATCH Trial: Platelet Transfusions Demonstrate Limited Efficacy in Urgent Settings

Well, then there's platelet transfusions in the PATCH trial. And this was patients with nontraumatic intracranial hemorrhage on antiplatelet agents not requiring any surgical intervention. And you know, you can see the data here as well, in terms of things like being alive at 3 months, no significant difference there. Directionally, the rate is a little bit lower with platelet transfusions. But, you know, small numbers of patients here really, if you look at the modified Rankin score, at 3 months there, there is a slight bit of a difference, and you know, there the P value, I guess I'll say is nominally statistically significant. So maybe some, you know, sort of weak evidence, if one really is looking for signals. But on the other hand, you know, the median intracranial hemorrhage growth at 24 hours, not really different between the two. So really, the way I look at this is not any clearly meaningful benefit from platelet transfusions in this particular setting. Next slide.

[00:56:56]

The PATCH Trial: Baseline Antiplatelet Use

A caveat though in interpreting this is just to look at what the baseline antiplatelet inhibitor use is. It's mostly aspirin that these patients are getting; some aspirin and dipyridamole. So, you know, what does that mean in terms of implications for platelet transfusions and dual antiplatelet therapy? You know, it's harder to say from this study. Can't really answer that question from this trial, because, of course, if you've got 2 modes of platelet inhibition, maybe transfusions, in the case of the irreversible agents, you know, at least theoretically, one might expect should provide some benefit. Next.

[00:57:32]

Effects of Platelet Transfusions to Reverse Antiplatelet Activity in Patients with Bleeding During Surgery

But the actual data don't clearly support that platelet transfusions are, in fact, so useful. But certainly when one is talking about ticagrelor, that's the yellow lines here at the bottom, hopefully you can see it clearly, you know, there are really no good evidence that transfusions are reversing ticagrelor's effect. On the other hand, maybe with clopidogrel 600mg loading dose is shown in the top orange one, you know, maybe there is in fact some recovery of platelet function there that's meaningful. Likewise, with prasugrel it's sort of in between, in green. So, I guess the way I would summarize the data is, you know, based on the biology, based on what data that exist, is that for the irreversible agents, at least biologically, you are reversing some of the antiplatelet effect with a platelet transfusion. With the reversible agent, ticagrelor, not so much. Next slide.

[00:58:29]

Utility of Platelet Transfusions as a Reversal Strategy

And here's just another summary of basically what I said, but some guidance from 1 source. I mean, there are lots of different opinions on this, but for aspirin, platelet transfusions are recommended to neutralize the antiplatelet effect for clopidogrel as well, it is recommended, prasugrel also. But the efficacy with clopidogrel and prasugrel, in particular, can be reduced if it's less than 6 hours after the last intake of those agents. With ticagrelor, less than 24 hours, there is no evidence that platelet transfusions are going to work. This particular author suggests recombinant factor 7A, and when the intake is greater than 24 hours, then the platelet transfusion is recommended here for partial neutralization. I'm not really sure on biologic basis that's necessarily so true because again, you know, I guess on one level there are fresh platelets there and maybe less ticagrelor—and less ticagrelor active metabolites circulating around. Maybe there's a little bit more use of the platelet transfusions if the ticagrelor has been given, you know, a few days before, but even that's quite debatable. But certainly if it's intake within the past 24 hours, based on the biology, very unlikely that a platelet transfusion is going to do much. Next slide.

[00:59:57]

Bentracimab

All right. Well that brings us to bentracimab. What this is, is a recombinant human IgG1 monoclonal antibody fragment. It binds to free ticagrelor, and then that complex is eliminated from the bloodstream, allowing ADP to then bind to the ADP P2Y12 receptor and activate it. So bentracimab then has the potential to reverse the antiplatelet effect of the reversible agent, ticagrelor, won't apply to aspirin and won't apply to clopidogrel or prasugrel, but it would apply to ticagrelor. Next slide.

[01:00:34]

Reversal of Ticagrelor by Bentracimab

And these are some of the data. These are data with respect to bentracimab. Some data presented a few years back as a late breaker at the American College of Cardiology. This is a phase I study, so that means healthy human volunteers published in New England Journal, where we looked at the effects of ticagrelor. Again, these are healthy human volunteers who have been given ticagrelor and then given bentracimab. And as you can see from the curves, hopefully, bentracimab is up top in the green. The placebo is in orange. So the bentracimab essentially is almost immediately restoring the function of the platelets vs placebo. And within just 5 minutes, in fact, it's a statistically significant reversal of the antiplatelet effect of ticagrelor, and the duration lasted for about 20 to 24 hours after a 16-hour infusion. So bentracimab, of course, is an infusion, and while it's being given, and a little bit thereafter, there is an effect on reversing the ticagrelor that's sustained and profound. Next slide.

[01:01:48]

Platelet function after ticagrelor reversal: LTA

So some more data from that same study. It's basically the same concept, so I'm going to go through these slides pretty quickly, but this is just looking at different assays of platelet function. This is, what some would say, is the gold standard, light transmission aggregometry LTA, you know, it's cumbersome, hard to do, can't do it at the bedside. Many hospitals can't do it, but it's basically the same message as the last slide. Now within 5 minutes or so, you're getting pretty substantial restoration of platelet aggregation, a greater than 80% of the baseline platelet function, so should be enough, one would think, for hemostasis. Next slide.

[01:02:28]

Platelet function after ticagrelor reversal: VerifyNow P2Y12 PRU

And yes, as I mentioned, it's immediate and sustained. And this is another assay, same message, looking at the P2Y12 PRU or platelet reactivity units, using the FDA approved VerifyNow test. For some of you that are doing point of care testing, this is a point of care test. Doctor Saver mentioned genetic testing that can be done for things like CYP2C19 polymorphisms for clopidogrel, VerifyNow can be done just to look at the antiplatelet effect here of P2Y12 inhibitors. And bottom line using this assay, same message, pretty quick and substantial restoration of close to normal platelet function. Next slide.

[01:03:09]

Platelet function after ticagrelor reversal: VASP PRI

And here we are looking at, what some would say is the best test, in terms of looking at platelet reactivity and functionality. That's the VASP test, and here you can see again, virtually immediate really profound reversal of ticagrelor's effect, essentially restoring the patients to baseline by this particular assay. Again some people think it's the gold standard. Next.

[01:03:36]

Platelet aggregation with low-dose and high-dose ADP

And a concern that some people raise when they think is, oh, you know platelets or platelet inhibitors, like ticagrelor, you're reversing them is there going to be some rebound prothrombotic effect? This has also, you know, been a theoretical concern raised, for example, with the factor 10a inhibitor reversal agents. But there's no evidence of that, and these are the data with bentracimab, and they're a little tricky to interpret, but we're looking at platelet aggregation using light transmittance, aggregometry, looking at different agonists of platelet activation such as ADP at different doses, 5 and 20 micromolar. And the bottom line is, when we look at bentracimab, those are the different colors, orange, green, blue, yellow, vs placebo in purple, basically once the infusion stopped you see that they all converge. So there's no evidence that there is rebound activity or hyper reactivity of the platelets once you stop the bentracimab. So no theoretical reason or no reason then, there should be a rebound or prothrombotic effects of bentracimab. Of course, if a patient really needs ticagrelor and you stop the ticagrelor because they're having a massive bleed, or they need urgent or emergent surgery, or whatever, they're not getting the benefit that the ticagrelor was providing. So that part of things does go away, so there might, in fact, be more thrombotic events in sick, bleeding patients. In fact, there usually are, and sometimes that leads to confusion, where people think, oh, the reversal agent is causing the thrombotic event. But at least with bentracimab, no evidence of rebound. And you can resume the ticagrelor when you feel you should or when it's safe to, from the patient's bleeding perspective. Next slide.

[01:05:35]

Platelet aggregation with AA and TRAP

And basically same message here, looking at different agonists of platelet aggregation in arachidonic acid, and the most potent agonist TRAP or thrombin receptor activating peptide. And again you can see in the hours when the infusion is stopped, towards the tail end of these curves, that the purple placebo line and all the other doses of bentracimab are converging. So once more, with very potent agonist different agonists, no evidence of platelet rebound. Next.

[01:06:09]

Summary of Phase I Trial

So the summary of the phase I trial, again, 64 healthy volunteers randomized to bentracimab or placebo, so a randomized trial, after getting 48 hours of ticagrelor, which of course suppressed the platelet aggregation by about 80%, or so. We see that bentracimab, compared with the placebo administered as an IV bolus, followed by an infusion, significantly restored platelet function, as measured by multiple different assays. The onset of reversal occurred within about 5 minutes and was sustained for over 20 hours. Multiple different platelet endpoints, multiple different subgroups all highly statistically significant with no evidence of rebound. So randomized study, healthy human volunteers, high degree of confidence that it reverses ticagrelor quickly and successfully but doesn't cause rebound. Next slide.

[01:07:06]

REVERSE-IT: Phase III Interim Analysis Performed

And that's healthy human volunteers. Now I'm going to move on to actual patients. There's no real reason to think that it would work differently based on its mechanism of action in patients vs healthy human volunteers, but always theoretically think, oh, you know, actual patients, comorbidities, might there be some sort of funny interaction or loss of efficacy? And so this is the phase III trial, the REVERSE-IT trial. It's the interim analysis that I'm showing here. This was done with the FDA's explicit approval, where they wanted us to go ahead and look at interim data, which we did. That has been published in New England Journal of Medicine evidence, I think this was at AHA. I presented this as a late breaker a couple of years ago. And so these are actual patients, this is not a randomized trial, this is a multicenter, open label, prospective single arm study. So these are patients who have an uncontrolled major or life-threatening bleeding episode or who require urgent surgery or invasive procedures, who have received ticagrelor within the prior 3 days. So they're on ticagrelor, they're either bleeding or need surgery. Next.

[01:08:19]

REVERSE-IT: Platelet Function Tests

And these are the folks after consent and so forth, that we went ahead and gave bentracimab to. And the bottom line here is that it worked as well in actual patients as it did in the healthy human volunteers. And you can see the inhibition of PRU, measure of platelet reactivity and platelet function and inhibition, pre dose and then 4 hours post dose with the bentracimab essentially restoring normal platelet function. The time course of that is shown on the right-hand panel, again within about 5 minutes or so, you're getting significant substantial reversal of the antiplatelet effect of ticagrelor. Next.

[01:09:00]

REVERSE-IT: Adjudicated Surgical Hemostasis

What about hemostasis? Well, this trial I should say, first of all, is mostly surgical patients and that mostly bypass surgery patients, though there were other surgical patients, and there were some bleeding patients in this first interim analysis here. And the bottom line is, in the opinion of the investigators, it did pretty well. And in the opinion of the independent adjudicators, and this was an experienced group that was adjudicating this, a group that's adjudicated for multiple different trials, the independent adjudicators said that hemostasis was achieved 100% of the time. They felt that there was no GUSTO severe bleeding. There was some GUSTO moderate bleeding, which, as you may know, is mostly transfusions, and GUSTO mild bleeding, which is pretty mild stuff. Interestingly, the investigators also thought there was great hemostasis, but they were stricter than the independent adjudicators, I suppose. But still, they thought there was a good hemostasis achieved in 95% of the patients with just severe bleeding occurring post bentracimab in only 5 patients. So overall, with the caveat that it's not randomized, looks pretty good, including by independent adjudicators. In terms of blood product transfusions, you can see here that of the population, 7% got blood transfusions for a bleeding event, and about 13% or so, got platelet transfusions. So, overall looked like, in a largely surgical population, you know, really acceptable rates of bleeding after ticagrelor, better than historical controls, better than other trials of ticagrelor where patients underwent surgery. Restarting of the P2Y12 inhibitor also did occur in the majority of patients. Three quarters of them got restarted on their P2Y12 inhibitor, and the median time of starting was 2 days. So as I mentioned, it's safe to restart ticagrelor after bentracimab, from a bentracimab perspective, assuming that it's okay to do it from the patient's clinical and bleeding perspective. Next slide.

[01:11:21]

REVERSE-IT: Adjudicated Thrombotic Events

And what about thrombotic events? The overall rate was low, and in the impression of the independent adjudicators, none of the thrombotic events that we're seeing here were believed to be related to the bentracimab. So overall, again within the context of a nonrandomized trial, no evidence of an association with thrombotic events. And from the biology, as I mentioned, were not really expected. Next slide.

[01:11:50]

REVERSE-IT: Interim Analysis Summary

So in summary then, for this interim analysis, bentracimab is a specific reversal agent for ticagrelor, provided immediate and sustained reversal of ticagrelor antiplatelet effects in ticagrelor treated patients undergoing invasive procedures or with major bleeding. Though it was mostly invasive surgical type bleeding. The rates of effective hemostasis were adjudicated as good or excellent in over 90% of the cases, with no drug related serious adverse events or allergic or infusion related reactions. So we did look for that as well and didn't find any allergic reactions. And the benefits, though I didn't show the data, were consistent; all pre-specified groups by demographic, age, sex, race, etc, including those undergoing surgery or with major bleeding, even though we didn't have a lot of patients with major bleeding, in fact, the results were consistent in the surgical and major bleeding subgroups. Next.

[01:12:48]

Coming Soon!

So those are the interim data. But the final data are in the process of being analyzed right now. We're hard at work, and if the analysis gets done in time by our statistician, I'm hoping to present the main results of the phase III REVERSE-IT trial, so the final results of what I just was showing you the interim analysis for, at the American College of Cardiology. It's on as a late breaking clinical trial for Saturday, March 29th for any of you that might be there. So, you know, hopefully that will provide the full picture of the additional surgical patients we had and a lot more bleeding patients. Next.

[01:13:26]

What would you do? Patient Cases

Alright. So hopefully that was a useful review of some of the latest data with respect to bentracimab. Now we're going to move on to some patient cases. And I think Doctor Saver, you're leading the charge, if I remember right.

Jeffrey Saver: Yes. Thank you Deepak, and thanks for that wonderful overview. And now we'll do some interactive patient cases, beginning with Christina, a 68-year-old woman with a history of cirrhosis, secondary to MASH, admitted to the ED after a sudden severe headache, nausea and confusion, and found on CT to have a large intracerebral hemorrhage. She's taking aspirin as secondary prevention from a prior TIA. Her platelet count is low at 32,000. The INR is 1.2 and the hemoglobin 11.5.

[01:14:25]

Poll 2

What's the most appropriate step in managing this patient's intracerebral hemorrhage? Desmopressin to improve platelet function, fresh frozen plasma to correct the clotting abnormalities, platelet transfusion to raise platelets above 50,000 or continue monitoring without intervention as the patient's not on any anticoagulant agents? So please go ahead and we have – this has been designed to be interactive, so you have a chance to discuss this with your neighbors. So we're going to give you some time to turn to your neighbor and come up with the answer.

[01:15:17]

Discuss with the person next to you

Okay. So let's go ahead and take a look at the entered answers. And the substantial majority of patients said, administer platelet transfusion to raise platelets above 50,000, and that is circled in green, indicating that the best answer – not – other things can be done, but the first priority would be to get the platelets back into a numerically optimal range, and the – and the new platelets should work a little better than the old platelets.

[01:16:27]

Poll 3

Okay. Next, what if the same platelet count in this patient was 123,000? So no thrombocytopenia, but still with the intracerebral hemorrhage and still having taken aspirin. Now what would be the best thing to do? The same 4 choices as before. Please make your vote. And while you're voting, please also discuss with the person next to you.

[01:16:56]

Discuss with the person next to you

Okay, so two thirds of the people said administer desmopressin to improve platelet function. And that circled in green as perhaps the best answer in this setting. Next.

[01:17:57]

Poll 4

Again, the same patient, but the patient is on ticagrelor instead of clopidogrel. And how would you manage it now? Platelet counts 123,000, fresh acute intracerebral hemorrhage, the patient is on ticagrelor. Would you administer tranexamic acid to improve platelet function? FFP? Administer platelet transfusion or, if available, administer bentracimab to reverse ticagrelor? Please make your vote. And talk to the person next to you.

[01:19:12]

Okay. And here we have 96% with the answer that's circled in green; administer bentracimab to reverse the effects of ticagrelor. So it shows when we have a specific reversal agent that it's very helpful. We know exactly what to do because we have an antidote to what's going on, and that is the favored answer.

[01:19:40]

Algorithm for the reversal of antithrombotic therapy

There is a recent algorithm for the use of reversible therapy that is very detailed and granular from the Italian Association of Cardiologists and Emergency Medicine that covers both anticoagulant agents and anti-platelet agents. And you can see here the pathway, and this is a nice, easy to digest one to have in your pocket. And it is forward looking, so it does include bentracimab for ticagrelor, in anticipation of it becoming available. Currently bentracimab is not marketed in the US, but it is progressing at FDA. And there's every expectation that within the next 12 months it will become available to us. Currently, it's not in any US guidelines, they've been waiting for the phase III data, and the timing of guideline updates, and I presume that after Deepak presents his data in March, that there will be sufficient evidence to drive guideline change.

[01:21:07]

Posttest 1

Okay, now we're going back to the questions we asked at the beginning and see if we've made any progress. Which of the following P2Y12 inhibitors act as a reversible inhibitor of platelet receptors? Clopidogrel only, clopidogrel and prasugrel, prasugrel only, or ticagrelor only. Please make your vote.

[01:21:53]

Okay. And you can see a dramatic increase in the people giving the correct answer, ticagrelor only going from 46% to 81%. And I want to congratulate the designers of these slides. Having the pre-test and post-test bars immediately on there is very effective to know how we're doing, and I've never seen it accomplished before, so that is great. And because the other agents are irreversible inhibitors, giving this agent will not help because they're already locked in to the target. But the reversible inhibitor, ticagrelor comes on and off, so it will be effective.

[01:22:51]

Posttest 2

Okay. Number 2, an individual with a history of coronary artery disease presents to the ED with sudden headache, confusion and weakness. And CT shows an intracerebral hemorrhage requiring neurosurgery. The patient's been taking aspirin and clopidogrel for the past 6 months following a PCI. Which of the following interventions is most appropriate? Andexanet alfa, bentracimab, desmopressin or platelet transfusion? Please place your votes.

[01:23:53]

Okay. And here we did pretty well pre and we've done a little worse post. So the platelet transfusion is the best way to rapidly as possible effect aspirin and clopidogrel. Even though the PATCH trial has limited applicability to this setting because DAPT therapy was present in only 5% of the patients, the desmopressin is likely to have a mild effect, and it's – the degree of evidence for its effect is insubstantial. Andexanet alfa is intended for anticoagulants, and bentracimab is only going to work for ticagrelor, so the best option here is platelet transfusion.

[01:24:51]

Posttest 3

And lastly, I think a 72-year-old person on ticagrelor presents with a spontaneous intracerebral hemorrhage, according to the neurologist, considers bentracimab for antiplatelet reversal. According to the latest evidence, if approved and available, when should bentracimab be administered after confirming the patient's renal function is greater than 60 mls per minute, after platelet transfusion has been attempted, immediately upon diagnosis of ICH, or only if the patient has been taking ticagrelor for more than 7 days? Please place your votes.

[01:25:52]

Okay. Here again we see a substantial improvement, which is great. Immediately upon the diagnosis of the intracerebral hemorrhage, already a majority of people were there before. Now we're up to 96% because the bentracimab provides immediate and effective reversal in patients heading – with a recent hemorrhage and at high risk for progression. We want to stop the restore hemostatic effect as soon as we can. Platelet transfusions are not effective for ticagrelor, of limited effectiveness, and there's not a renal concern with ticagrelor use.

[01:26:42]

Question and answer session

Alright. So we've made progress in education. Now we'll turn to your questions for us. And if you do have questions, both those with us virtually and people here in the room, please enter them into the pads and they will be magically transported to my pad, and I will be able to say them out loud for you. We already have some questions that have come in. And one question, Deepak, I think this will be a good one for you. If a patient had a coronary stent in the last 30 days and then receives bentracimab, what is the rate of stent thrombosis?

Dr. Deepak Bhatt: That's a great question. I can't directly answer it; we don't have any data for that. But I – based on its mechanism of action, and some of the data that I just shared, in terms of the biology, we wouldn't expect bentracimab to cause any sort of prothrombotic or rebound in platelet activity. But the benefit of whatever ticagrelor the patient was getting will be gone for the period of time that ticagrelor is held until it's resumed. So, in a patient with a recent stent, if one needed to reverse the ticagrelor effect because of, say, an intracranial hemorrhage or they needed, you know, emergency surgery for an aortic dissection or something like that, I think, assuming it were available, it'd be fine to give the bentracimab, and then just resume the ticagrelor and/or aspirin, as quickly as possible. But, you know, we don't have data specifically on what the stent thrombosis rates would be in that context. I mean, in general, you know, patients that are bleeding do tend to have higher rates of thrombotic and ischemic events, and those pathways are somewhat interrelated and complex. Some of the pathways just have to do with the fact that if somebody is bleeding, typically the antithrombotic agents, in this case antiplatelet agents are held. Maybe in the case of the patient you mentioned with a recent stent, you know, that maybe the aspirin and ticagrelor are held. So of course that patient is going to be at higher risk of stent thrombosis and other thrombotic events because they're no longer getting the protection of those 2 agents. And a lot of times when patients bleed, other things get held; sometimes a beta blocker gets held because there's a fear it's, you know, masking some sort of compensatory tachycardia or might contribute to hypertension, in the case of a really big bleed. Interestingly, registries show that statins are often held when patients are bleeding, maybe because they're NPO, if it's, say, a gastrointestinal bleed, or there might be a need for an emergency surgery to control the bleeding. But for whatever reason, even statins get held, and even more interestingly, registries have showed a lot of times those medicines that are held, like the beta blocker or the statin, aren't resumed at discharge, even when the bleeding is stopped. So there are a lot of things that happen that can lead to pro-thrombotic states and ischemic events, in patients that are bleeding, as well as the teleological factors. That is, when the body is bleeding, it's sending out signals saying, 'Hey, stop bleeding', and therefore it does move the body into a more pro-thrombotic setting. That's good, if you were just, you know, bit by a bear or running from a tiger or something, but it's not good if you have plaque in your heart or brain arteries, and in that context, a pro-thrombotic effect, in that patient who's bleeding, can backfire and provoke ischemic events. So one does always have to be mindful for that potential. But as far as we can tell, bentracimab doesn't contribute in any way to any pro-thrombotic effect.

Jeffrey Saver: Great. Thank you. And Another question is, in patients with intracerebral hemorrhage who are not heading for surgery on Plavix, is there any role for platelet transfusion since these patients were not well studied in PATCH? And I think that depends, in part, on case specific aspects, that if the patient has a spot sign, has the radiologic signs of heterogeneity of the ICH, that indicate they are at high risk for immediate progression, if you're very early after the start of symptoms, then I do think platelet transfusion may be worthwhile. On the other hand, if the platelet is arriving – if patient is arriving at your institution well after onset, has had a stable course without expansion, then I don't think a platelet transfusion would need to be used.

Another question, and this one I'm going to give to you, Deepak, is about the infusion of bentracimab; is the infusion continuous for 16 hours? And if so, do you think it will be shortened in the future?

Dr Deepak Bhatt: Sure. Well, you know, that's ultimately going to depend not just on the data, but, you know, discussions with the FDA and the ultimate labeling. So, you know, this is an investigational agent, but once it is hopefully approved in the – in the future, you know, once we're done sorting through all the data, and everything, you know, the package insert will say exactly how to use it. But in terms of just the biology, as long as you're infusing it, you're able to reverse ticagrelor's effect. And I imagine, you know, as we have studied it so far, durations of, sort of, you know, relatively short infusions like 16 or 20 hours or so, probably would be what's sufficient to get the patient through a surgical procedure, certainly, or an invasive procedure. And depending on the exact bleeding event, you know, may be sufficient as well. So it may depend a bit on the clinical situation. That is, you know, if you've just had your surgical procedure successfully, you know, the surgical site is sutured up and there's no bleeding, you know, then it might be fine to stop at that point, the infusion. In other folks where maybe they've had an intracranial hemorrhage and there's concern of, despite bentracimab, the volume of hemorrhage seems to be growing on serial imaging, that you know, maybe there's still some utility in continuing it to make sure ticagrelor effect is completely reversed. So I think it would be dependent on the on the situation to an extent. But yes, in general, an infusion in that range of hours would probably be what's needed. But, you know, my final answer would be to do what's in the ultimate label for the drug.

Jeffrey Saver: Great. Thank you. And this next question, I'll take a first swing at it, and then Deepak, ask you to comment as well. What are practical considerations for implementing bentracimab into clinical practice, to jump the evidence to practice gap? And I think one challenge we face with this agent, as we have with other reversal agents, is that we're dealing with low frequency, high impact events. And so people don't have, in their mind, continuously reactivated hippocampal memory stores that this agent is available and how to use it, and it's something that works best if you use it right away. So we want the penny to drop immediately, not after delay. This is one setting in which the electronic medical record can help a great deal with alerts or other things coming up, if the patient is on ticagrelor. It's also useful to have a monthly refresher of all the low frequency, high impact events that you'll be seeing in the emergency department, so there's continuous reactivation. Deepak.

Dr Deepak Bhatt: I mean; I think that's a really a great answer. My sense is, again, this is, you know, contingent on the drug getting approved, the label being consistent with, I say, but I would think that the drug would need to be available, you know, in every emergency room, and probably have to stock a couple of doses in case, you know, somebody drops the first one or something. So even a small rural ER, I think, would have to carry it. Same with ICUs, neuro ICUs, neurosurgical ICUs, trauma ICUs, cardiac ICUs, basically any ICU would need to also, you know, have doses available in the hospital pharmacy. So I think everyone is going to have to be familiar with it, you know, that's why, you know, programs like this, I think, are really useful. Even if the physician doesn't remember every detail, just remembering, oh, this patient is on ticagrelor, that's a reversible agent, therefore this bentracimab thing could be useful. You know, as long as they remember that, then that's, you know, good enough. But, in terms of just the practicalities, I think, you know, if someone came with an intracranial hemorrhage, that's a pretty infrequent event, especially if it's a, sort of, low volume emergency room. You know, it's just a matter of having it in stock and remembering to do it. But, you know, frequency of use may not be so infrequent, I mean, intracranial hemorrhage, of course, in general, other than at, you know, larger centers, is a rather infrequent event. But if the drug is also approved for just surgical procedures, that's much more common. That is, patients that are sitting in the hospital that have had ticagrelor and they're waiting, say, for cardiac or other surgery. You know, right now they're sitting in the hospital waiting for 3 to 5 days, depending on where you are in the world and which guideline and which countries label you look at, you know, it varies exactly what the guidance is. Many would say you have to wait 5 days after ticagrelor to be able to operate safely. The biology dictates it's probably, you know, between 3 to 5 days, possibly could get away with 3. But nonetheless, you're stuck in the hospital; patient's unhappy, you know, the family is unhappy, they're just waiting for surgery. They're potentially prone to ischemic events because they're just sitting there in the hospital. They're not getting their ticagrelor, so their ischemic risk is getting elevated, and you know, nothing's happening in the hospital, you’re waiting for the ticagrelor to wash out. So potentially, if in that circumstance, I'm not saying even a bleeding patient, but a patient where, you know, they need surgery, maybe for a tight left main, they've gotten ticagrelor, you don't want to wait several days before taking the OR, you could reverse them. If the drug, in fact, is utilized in that way, then it will be very common to use it in hospitals, and there'll be a great deal of familiarity with it. Obviously, some of that will depend on not just the data, which, as I said, already looks quite good for surgical patients, but it will depend on, you know, what the labeling says its use is. And it’ll also obviously depend on the cost, you know, if it's going to be used in elective surgery, the cost would have to be felt to, you know, sort of, outweigh what the incremental cost is of a, you know, length of stay increase from just having the patient parked in the hospital waiting for the ticagrelor to wash out.

Jeffrey Saver: And we did have a question about, what is going to be the cost of bentracimab? And I think, Deepak, I don't know if you have any insider knowledge, but usually the physicians are not part of that economic decision making by companies. So I don't know where the planned price point is. Do you know Deepak?

Dr Deepak Bhatt: No, I don't, because, Jeff, you're quite right, physicians are rarely consulted because physicians always say the same thing to make drugs inexpensive. And that's not an answer that's ever warmly received. So I don't know what the price would be, but in general, even companies won't know until the label of a drug is set. That is, that often does impact, in part, what the price is going to be. You know, for example, drugs that have very restrictive labels, where there's going to be very infrequent use, are typically going to be priced very high, otherwise, it's not worth making them. That's just sort of basic economics. And if it's drugs that are going to be used very, very frequently, that usually does allow the cost to be at least a little bit lower because, you know, you make up in volume what you lose in the actual price. So it'll, in part, at least, depend on how broad the label is. I mean, personally, I hope the label is broad enough to allow patients who could benefit, to benefit. So those, you know, of course, with obvious bad bleeding like an intracranial hemorrhage, but – but also those that require urgent surgery, emergent surgery, potentially even those that require elective surgery where it's just not a great idea to keep them in the hospital off ticagrelor for several days. But, yes, so, you know, the pricing will depend on all of that. And then ultimately, you know, the use in some of those more elective situations, likely, as I alluded to, would depend on the price. I mean, my hope is it doesn't come out sort of like a factor 10A inhibitor type pricing, because at least in the hospitals I've been, since those agents have been introduced, it's been tough to actually use them, where you often need hematology approval and a sick patient that's detuning. You know, practically speaking, it can sometimes be tough. And I think that's actually led to a fair amount of underuse of the anti-10A inhibitors, in patients who maybe could have benefited, where you always want to just give them the benefit of the doubt, even if the data aren't necessarily clear. So hopefully that won't be the case. But yes, the short answer is, I don't know.

Jeffrey Saver: Great. Thank you. And we have a question about any plans for a bridging trial for cangrelor, for patients with a recent stroke or coronary event who need cardiac or non-cardiac procedures in an urgent manner, but not am emergent manner, to bridge the time period, if you were stopping ticagrelor or clopidogrel, 5 to 10 days beforehand to use as a bridging agent? And I'll say a couple of words and then ask you, Deepak, to weigh in. The – you know, as Deepak said, we – with ticagrelor, we have the prospect of being able to give bentracimab and immediately reverse and not have to worry about how to handle a bridging period by eliminating the existence of a bridging period, if the price point allows that. If not, then I think using cangrelor IV is an option, maybe a good option for patients who are hospitalized, but often we'll have patients who are outpatients, and it's challenging to bring them in for the IV infusion. Another option there is short acting dipyridamole given 3 times a day and stopped 36 hours before any procedure. And the short acting dipyridamole has a very fast onset and offset and can provide an oral bridging option. Deepak.

Dr Deepak Bhatt: So let me – yes, great – great points about cangrelor, I'm not sure what I can add to that. And the dipyridamole bridging, I don't have any personal experience doing, so I can't comment on that. But you know, with respect to cangrelor, I was a co-PI, along with Bob Harrington, of the phase III trial that led to its approval, CHAMPION PHOENIX. That was a trial, a bit over 10,000 patients undergoing PCI for a variety of indications, you know, published in NHM, led to the FDA approval of the drug that showed efficacy, so significant reductions in, you know, stent thrombosis and other ischemic events. So in the context of [inaudible 01.43.20], it’s an approved drug, it's really useful in the cath lab, especially in higher risk patients, patients coming in with a STEMI, for example, large thrombus burden, that's a higher dose than what is possibly, or possible to use for bridging, for the bridging indication, well I shouldn't say indication, for the bridging use, it's a lower dose. Now, the FDA approved cangrelor, based on CHAMPION PHOENIX. There was a smaller study called BRIDGE with just a couple of hundred patients, that I thought the data looked pretty good from that. I wasn't involved with it, but it looked good. It was more of a pharmacokinetic, pharmacodynamic type study, just looking at platelet inhibition and things like that, but it showed that at the lower infusion dose of cangrelor for bridging, that it provides an antiplatelet effect similar to clopidogrel, 75mg a day. So if someone comes in on clopidogrel, you can stop the clopidogrel, you know, start the infusion. Of course it's an infusion, so they're in the hospital while they're getting the cangrelor, and you know, some potential cost implications to that. But for a really high risk patient where you don't want to stop the oral antiplatelet therapy, but you have to, as a prelude to surgical procedure, cangrelor, certainly I've used many times as a bridging strategy. But it is not FDA approved; the FDA looked at the data and said, you know, 'Thanks, but no thanks.' They didn't find the data compelling enough, I guess, to give it an indication, but as I said, I personally used it many times in a bridging indication. The – and the bleeding is similar to what you would get with – if your patient was taking 75mg of clopidogrel a day, in terms of spontaneous bleeding risk, but in terms of surgical bleeding risk, you stop the cangrelor. It's basically out of the system in an hour or so with essentially full restoration of platelet function, even if there's hepatic or kidney dysfunction, the cangrelor still is out of the of the system. So very clinically useful, I think. Doctor Saver may have alluded to the price issue, I mean, it does get expensive if you have someone on cangrelor for a long time, you know, in the cath lab, it's about $700 a vial. But if you're doing a 24-hour infusion for several days, it really can add up. I remember when I was in the Mass General Brigham system, we looked at our cangrelor use, and we were using a fair amount for bridging, say, somebody where, you know, they got a left main stent, but, you know, for shock, but now they need an LVAD or a transplant. You know, that sort of patient could go any day to the OR, so you know, there's an advantage, theoretically, of not having them on aspirin and clopidogrel or whatever, ADP receptor antagonists, have them on cangrelor. But, you know, you could be waiting a month or more for a transplant, and you know, the cangrelor does add up in terms of price. But putting that point aside, yes, it is a safe and, I believe, effective way of substituting an oral antiplatelet agent. But the randomized data supporting that is a modest 200 patient bridge trial, and it is an off label use of cangrelor.

Jeffrey Saver: Great. Thank you. And now I'm going to put you on the spot. Deepak, we have a question of, patient who is on antiplatelet therapy for a cardiac indication, who develops a DVT and needs to be started on anticoagulation. Do you stop the antiplatelet agent, or do you continue both? And I will say, as a neurologist, we know that combined antiplatelet and anticoagulant therapy doubles the risk of hemorrhage over single anticoagulant therapy. So any indication for continuing has to be strong enough to outweigh that increased risk of hemorrhage. And so, Deepak, which indications do you think do outweigh and which indications can you stop the antiplatelet agent?

Dr Deepak Bhatt: It's a terrific question. The registry data almost all show when you stack antithrombotics, you know, bleeding risk goes up, as is intuitive. I mean, more bleeding, more, you know, antithrombotic agents, of course, there'd be more bleeding. There may or may not be more, you know, ischemic or thrombotic protection. It depends on the exact clinical scenario. So I guess I'd first say, you know, does the patient really need anticoagulation if they've got a DVT or PE or atrial fibrillation, the answer is yes. So you know, barring a contraindication they should be on, you know, full dose therapeutic anticoagulation dosage adjustment, if needed, based on the specific agent and, you know, age, kidney function, weight, whatever else might factor into the specific agents dosing instructions. So that part, I think the data really support. Now what do you do with the antiplatelets? Well, I'd say look closely about whether they're needed. So if it's a patient that's on aspirin for primary prevention, now they've got AFib or PE or DVT or something, they definitely need anticoagulation. I wouldn't continue the antiplatelet because the data for aspirin primary prevention is rather weak to begin with. And now if I'm adding an anticoagulant it's just gone from weak to really bad idea, so you know there, just stop the antiplatelet. If, you know, it's somebody that just got a left main stent last week, you know, there I would be uncomfortable stopping the dual antiplatelet therapy. And the strategy that I use that, you know, many consensus documents would support, and we don't have direct randomized trial data to answer the question of, you know, you need to start a new agent for a new disease state that's come up, like a DVT or AFib. But what data exists, that have examined patients who've come in, say, with atrial fibrillation and need a stent, it supports the strategy in general of double antithrombotic therapy. That is a full dose of an anticoagulant, again if it needs to be adjusted for the DOAC, you know, based on age or anything like that, you know, make the adjustment, but otherwise it should be full dose. And by that I mean, if they really should be, say, on apixaban 5 BID, you shouldn't just be doing 2.5 BID because you're just worried because you're worried. I mean, if the, you know, sort of, label would say you should use 2.5 based on, you know, things I mentioned, then do it. So, assuming that they're on an appropriate full dose of anticoagulant, I then just have one antiplatelet on board, most often clopidogrel, just because it has a low bleeding risk, and has been studied the most when combined with anticoagulants. But if, you know, the patient were really low bleeding risk, high ischemic risk may be combined ticagrelor with just the anticoagulant. I try to avoid triple antithrombotic therapy that is aspirin, P2Y12 receptor and anticoagulant, that's definitely a recipe for bleeding, if you do it for more than, say, a week or so. There might be some circumstances where you might do it for a week, but certainly not beyond a week.

Jeffrey Saver: Great. And I'll add, if the patient is on the antiplatelet because they had a prior cerebral ischemic event, then one good option is to use cilostazol, which has less bleeding effect than other antiplatelet agents. But cilostazol does not work as well for coronary indications as the other antiplatelet agents, so it's a cerebral only consideration. The question here, is there a role for a P2Y12 functional goal when you're using bentracimab to monitor with functional testing?

Dr Deepak Bhatt: Sure, I mean, we did a bunch of fancy platelet function tests, you know, for the sake of science and the trial. In clinical practice, I don't think you have to do that, but I guess ultimately, I'd say is, if the FDA approved label, assuming the drug gets approved, said that you have to use that sort of device, then you'd be stuck using it. But I personally don't think that that's necessary. I would just, you know, give the agent, and you can sort of assume that it's doing its thing because, you know, we checked in a number of different patient, patient subgroups, that, you know, it shouldn't be the case of there being non-responders. I mean, it's basically, you know, monoclonal antibody fragment binding to a drug and, you know, getting removed from the circulation. So I don't think there's a need to sort of check. Likewise, you know, ticagrelor isn't – I mean, there's always some variability to every drug and every antiplatelet as well, but you know, ticagrelor is not like clopidogrel, where there's a fair amount of variability in response to clopidogrel, but ticagrelor tends to provide a more consistent level of antiplatelet effect. There's a little bit of variability, but with the bentracimab, I wouldn't, myself, feel obligated to check, say, a VerifyNow P2Y12 assay.

Jeffrey Saver: Okay, great. Well, I think we will bring the event to a close, and I think we have some closing slides. Is that right, to put up? Or –

[01:52:31]

Go Online for More CCO Coverage of Antiplatelet Reversal and Bleeding Management!

Yes, so there's online resources for you, for more coverage of antiplatelet reversal and bleeding management, downloadable slides of all the data presented today, an online webcast of this presentation, if you want to refresh your memory or tell your friends and colleagues that it's worth taking a look at. And clinical thought commentaries featuring expert informed strategies in bleeding management at clinical options.com.

[01:53:10]

Thank you for attending

Whoops. So thank you very much for attending. To claim CME or other credit go to Clinicaloptions.com/AntiplateletReversalEval, to access the online evaluation form, and you can view and print your certificate upon completion of the online evaluation. And with that we'll again thank you for getting up so early in the morning and hearing about the bentracimab and general reversal story. And we look forward to having this addition to our armamentarium, hopefully within the next year, and look forward to another day and a half of excitement at the meetings. Thanks very much.

[END OF TRANSCRIPT]