Platelet Biology and Function

So let's just start with a little review here of platelet biology and function. I realize this is likely familiar to most of you in the room and online. But broadly speaking, there are anticoagulants, listed here are things like dabigatran, apixaban, rivaroxaban, betrixaban, edoxaban and there are reversal agents that are available and approved when patients are bleeding. And those agents are on board.

And then there are antiplatelet agents. Aspirin of course, is very familiar to everyone. And then the ADP receptor antagonist or the P2Y12 receptor antagonists that are clopidogrel, prasugrel and ticagrelor.

In general, for atherosclerotic diseases, patients that have received stents, patients that have received bypass grafts, antiplatelet therapies typically use whereas anticoagulants typically in the setting of things like atrial fibrillation, pulmonary embolism, DVT, etc..

[00:07:37]

Ticagrelor: Reversible Mechanism of Action

So now let's speak a bit about ticagrelor, one of the antiplatelet agents. But unlike the other antiplatelet agents or at least the other oral antiplatelet agents, it has a reversible mechanism of action. A lot of times doctors are confused by and they say, “Well, it's not reversible because if you take ticagrelor today, even tomorrow, the patient has bleeding risk that's elevated. If it were reversible, it should be out of their system”.

Well, the reversible doesn't really mean reversible in the way that we think about something where you take a medicine and then you stop and then the effect is gone. Here reversible really means how the platelet is behaving. That is when ticagrelor binds to the P2 well—P2Y12 receptor. It binds reversibly. So it can bind. It can dissociate. That's unlike the active metabolites of clopidogrel or prasugrel. Those are prodrugs. They have active metabolites that are formed.

And those active metabolites when they bind to that P2Y—P2Y12 receptor, they're there for the lifespan of the platelet. Seven days, 7 to 10 days or so as platelet turnover is occurring. So this is a bit different.

Does that matter in terms of efficacy? Well, I'll show you some efficacy data. Does it matter in terms of safety? Well, that's going to be the topic of—of much of this morning. So it is a direct-acting, reversible ADP receptor antagonist. And direct-acting means that it doesn't have to be metabolized in the liver. There is a pathway by which it is. And there's another active metabolite, but it doesn't actually need hepatic metabolism to be able to bind to the receptor. So a bit different as well from clopidogrel and prasugrel, which are prodrugs.

[00:09:14]

Antiplatelet Drugs in Cardiac Surgery

So there are a number of antiplatelet drugs, of course, that can be used in the patient that might be undergoing cardiac surgery. Aspirin, of course, everybody in general is on. The thienopyridines. Ticlopidine really isn't used anymore. It's of historical significance. A few neuro patients that might still be on it here and there around the world, but in general its use has been abandoned due to side effects.

But clopidogrel and prasugrel are the 2 thienopyridines in very common use. Both are generically available. Clopidogrel in particular is used quite a bit. Prasugrel less so.

Ticagrelor, another ADP receptor antagonist, P2Y12 receptor antagonists, like clopidogrel and prasugrel. But as I mentioned, it's a different class and it is a reversible agent. Also different from these oral drugs up here, it's given twice a day. So it's a little bit different.

Then there are intravenous glycoprotein 2B3 inhibitors, abciximab, eptifibatide, tirofiban. You can't get abciximab anymore. So 2 is of historical interest. But these are potent intravenous agents that are used in acute coronary syndrome patients, much less so these days than in years past, sometimes in stented patients as well when there are complications.

Then it's here on the list of antiplatelets. It's debatable just how potent antiplatelet agents these are, but cilostazol, which is a PDE inhibitor, and dipyridamole that works through a number of mechanisms, including PDE inhibition, but those are relatively weak in terms of antiplatelet effect.

And then finally in the P2Y12 ADP receptor class is cangrelor, which is a reversible antiplatelet agent, short acting. And you may see it on the cardiac surgical ward. Sometimes patients that come in on clopidogrel are bridged in an off-label way with cangrelor up until the time of surgery. Essentially, it's got a short half-life so that it's out of the system completely in terms of effect in about an hour, even if there's hepatic or—or kidney dysfunction present.

[00:11:20]

DAPT in ACS

So what's the role of DAPT in acute coronary syndromes? It's pretty foundational. Everybody gets aspirin with acute coronary syndromes. And these days everybody also gets an oral P2Y12 inhibitor. And the choices are clopidogrel, prasugrel or ticagrelor.

Clopidogrel in particular gets a lot of use when cost is an issue because it's generic and it's been around the longest and it's the least potent, and for that reason has the least amount of amount of bleeding, but their data, and I'll review it in a bit, that show that prasugrel and ticagrelor in the context of ACS are superior agents, and ticagrelor in particular, is demonstrated in a randomized trial to have lower mortality in ACS patients than clopidogrel.

So it would be the preferred agent in many cardiologists minds, though, cost is an issue. It's currently branded medicine, but it'll be going generic in the next couple of years worldwide. It's already generic in some parts of the world, but in the US. And once that happens, I think we'll see use even higher than it is now. And then I mentioned the intravenous cangrelor.

[00:12:26]

DAPT

So there have been a bunch of trials of dual antiplatelet therapy. I'm not going to review all of them. It's probably not critical from a surgical perspective that you know all the details of these trials. But again, ticlopidine of historical interest, clopidogrel has been around the longest and prasugrel and ticagrelor more recently. But all these agents have multiple randomized clinical trials supporting their use on a background of aspirin largely. There are some more recent trials with ticagrelor monotherapy and some older and even some recent—more recent trials with clopidogrel monotherapy.

But for the most part, these trials were done here with aspirin as a background. And these other ADP receptor antagonists added on board the concept of dual antiplatelet therapy. But lots of trials, well done trials have influenced the guideline, have influenced FDA labeling for these agents.

[00:13:22]

Oral P2Y12 Inhibitors: FDA-Approved Indications

The most recent bolus of information, though, actually has come for ticagrelor from THEMIS and THEMIS-PCI and the THALES trial, that led—all published in New England Journal, Lancet, so forth led to guideline changes, led to labeling updates for ticagrelor. But all this came out during the pandemic, so I don't think a lot of cardiologists actually know about this, or neurologists. And I also don't think a lot of cardiac surgeons did.

But in terms of indications, clopidogrel, ticagrelor, prasugrel and ACS, everyone knows their utility when PCI is performed.

For medical therapy, both clopidogrel and ticagrelor, but not prasugrel, has a role. The trial of prasugrel and the medical therapy of ACS didn't meet its primary end point. That's why that's not there.

For prior MI, clopidogrel and ticagrelor have data. But then for coronary artery disease without a prior ischemic event, ticagrelor is FDA approved for use. So, for example, a patient with diabetes and bad coronary artery disease, you can use ticagrelor there, whereas clopidogrel and prasugrel aren't specifically labeled for that. And as well as stroke, both clopidogrel and ticagrelor have an indication.

So these last 2 check marks here really all happened during the pandemic. So I think between the impending generic availability of ticagrelor and the fact that it has data that's pretty vast across different indications, you'll see a lot more patients coming to the OR on ticagrelor.

[00:14:56]

Properties of P2Y12 Inhibitors

So the P2Y12 inhibitors are a bit different. I mentioned some of this, but I'll just quickly review it again that clopidogrel and prasugrel are irreversible in terms of how they bind to the life span of the platelet, whereas ticagrelor is reversible. But that doesn't mean its biological effects out of your system right away. That's not true. Takes a few days still for the antiplatelet effect to wear off. Again, that refers to receptor binding kinetics, that it's reversible. And cangrelor is reversible and is short-acting but is intravenous.

The prodrugs are clopidogrel and prasugrel, whereas ticagrelor and cangrelor aren't prodrugs. As I mentioned before, the ticagrelor can bind directly to the ADP receptor antagonist. And as I reviewed before, clopidogrel, prasugrel, ticagrelor, oral. Cangrelor, intravenous.

The offset of action is important from a surgical perspective, so I'll focus on that a little bit. Clopidogrel is a very variable drug. I don't know how much in the surgical literature you've heard about clopidogrel variability, but there are different things that can influence clopidogrel, and its—its mode of action, biological activity, whether a person smokes, potentially their weight, some genotypes potentials for drug interactions, each of which is probably a pretty minor contribution to variability. But in some it—it leads to the fact that clopidogrel can be pretty variable.

So its effect, you know, it can be out of one patient's system, even though the slice is 5 to 10 days. Even in 3 days, when other patients, it can linger for 10 days in terms of its biological activity. So it's a little bit hard to know exactly when it's fully out of the system.

Prasugrel is a bit more consistent. Typically folks would say about, you know, 7 to 10 days, Usually 7 days is the number of people anchor on. There are usually 5 days is the number of people anchor on for clopidogrel in terms of offset of action.

For ticagrelor, you know it's 3 to 5 days. A lot of depending on where in the world you are, which guideline or labeling you look at, will say 5 days before operating. But, you know, probably could get away with 3 days based on the biology of ticagrelor. That is after 3 days, for the most part, its effect is out of the system.

And cangrelor, as I mentioned, an hour after stopping the infusion, its effect on platelets is—is almost entirely gone.

[00:17:16]

AHA/ACC/SCAI Guideline Recommendations for DAPT in ACS

These are the guidelines, the most recent guidelines from American Heart Association, American College of Cardiology with respect to dual antiplatelet therapy and ACS. And here in a patient undergoing PCI for ACS, at least 12 months of aspirin plus clopidogrel or prasugrel, ticagrelor are still recommended. And that's important because the proportion of these patients are going to go on to needing bypass surgery down the road or some other form of cardiac or noncardiac surgery. So there's still going to be a lot of DAPT use out there.

There's been an emerging set of data based on randomized clinical trials show that in patients who are at high bleeding risk, it might be a good idea—or I shouldn't say might, it is a good idea to discontinue aspirin in the first 3—1 to 3 months and then continue the P2Y12 inhibitor. So that is dual antiplatelet therapy for at least a month. And then in a patient who's super high bleeding risk actually to stop the aspirin but continue the P2Y12 inhibitor.

So that is a bit of a more recent development. And the amount of data for that and meta analyses supporting that continue to grow. And it's even in the guidelines now to an extent as a IIa recommendation at least. Though, in patients who aren't at high bleeding risk in general, the duration of DAPT in ACS is still considered to be 12 months as an anchor, but I wouldn't be surprised even in that context, if it starts to get ratcheted down, even in normal bleeding risk patients such that aspirin has stopped earlier and the P2Y12 inhibitors continue.

Therefore, you're going to see a lot more ticagrelor monotherapy in the future than you may have up till now, based on some of the trials that have supported the strategy I just mentioned.

[00:19:07]

Clinical Trials of P2Y12 Inhibitors in CABG

So there are a number of clinical trials of P2Y12 inhibitors, specifically in CABG, where these large randomized pivotal trials had subgroups of patients undergoing CABG. These weren't dedicated CABG trials per se.

But CURE had a subgroup of patients undergoing CABG with dual antiplatelet therapy having been given initially for the ACS. The TRITON trial had a similar sort of subgroup. Here, this was prasugrel versus clopidogrel on a background of aspirin, unlike CURE, which was clopidogrel plus aspirin versus aspirin plus placebo. So CURE was the trial that put clopidogrel on the map for ACS.

But then TRITON was a trial that put prasugrel on the map, beating clopidogrel for efficacy, but having more—having more bleeding, including in patients with prior stroke and TIA, more intracranial hemorrhage. So more bleeding potential for intracranial hemorrhage in folks with cerebrovascular disease, where there's a black box warning, but better efficacy in terms of ischemic events.

PLATO was ticagrelor versus clopidogrel, again on a background of aspirin, where ticagrelor or beat clopidogrel, including significantly lower rates of cardiovascular mortality and even all-cause mortality was significantly lower. So that's why, if cost weren't an issue, most cardiologists would favor ticagrelor over clopidogrel.

And then there's cangrelor For a potential bridging therapy based on the BRIDGE trial, which was a pharmacokinetic/pharmacodynamic study showing that cangrelor produced similar efficacy to clopidogrel without any obvious increase in bleeding. But cangrelor for this purpose is an off-label use. The FDA elected not to grant cangrelor an indication for that.

It is approved for PCI based on the CHAMPION PHOENIX trial.

[00:21:01]

DAPT in Patients Undergoing CABG: US vs European Guideline Recommendations

So these are some DAPT guidelines in patients undergoing CABG, trying to summarize the US versus European guidelines. There are a lot of guidelines out there, some variability across the pond and just from year to year.

But this summarizes more or less what the guidelines say in patients with coronary artery bypass who have had an acute coronary syndrome, who are at high bleeding risk. You know, there the duration of DAPT is recommended to be in the US as a IIb recommendation 6 months in Europe. Also IIb—6 months is a IIa in acute coronary syndromes. Not at high bleeding risk in the US, there it's 12 months based on the trials that I just showed you.

And in Europe it's also 12 months. And they even say with—as IIb recommendation can keep going longer up to 30-plus months. And that's based on a number of trials that do show a benefit of long-term DAPT if a patient isn't at high bleeding risk.

And then there are patients that have undergone CABG for stable coronary artery disease. And there the US has a IIb recommendation, does allow up to 12 months of DAPT, whereas in Europe there's no particular indication for DAPT unless there's concomitant or prior indications, in which case then you might use DAPT or other antithrombotic regimens also the European guidelines allow.

So lots of different guidelines. But in general, you know, sort of an anchoring in the ACS patient of around, you know, 6 to 12 months depending on bleeding risk.

[00:22:35]

CABG: Antiplatelet Interruption Recommendations

Well, what about antiplatelet interruption recommendations in CABG patient? Again, there are lots of different guidance, guidelines, expert consensus, statements and so forth. But in general it's recommended that aspirin be continued these days, right through the time of bypass surgery, that is, before, during, and after.

Cangrelor can be used again in an off-label way for bridging in the time before bypass surgery and potentially afterward, you know, until the oral P2Y12 inhibitors resumed, if it's deemed that it should be resumed or started.

So strategies that have been employed are stopping prasugrel 7 days before, stopping clopidogrel 5 days before, and stopping ticagrelor 5 days before. The bulk of randomized evidence in the majority of guidelines would say to do that.

As I mentioned, you can push the envelope a little bit with ticagrelor and say 3 days, but that's not concordant with the majority of guidelines and labeling, but it is probably consistent with the pharmacokinetics and pharmacodynamics. But at any way, whenever you stop, you could then potentially bridge with cangrelor.

You know, I—I actually led the CHAMPION PHOENIX trial that led to the approval of cangrelor. Wasn't involved with the BRIDGE trial, which was the basis for this bridging strategy. But as I said, is not an FDA approved approach. It has merit in some really high-risk patients. But you can see here it would mean bringing the patient in and hospitalizing them for at least 3 to 5 to 7 days. So that's not always so desirable or practical. So some issues there. And it would be an expensive strategy to—to do that. But it is an option with some degree of evidence from the BRIDGE trial.

[00:24:19]

Efficacy and Safety Profile of P2Y12 Inhibitors in ACS

Here is a summary of the overall efficacy and safety profile of P2Y12 inhibitors in ACS. So prasugrel versus clopidogrel reduction in ischemic events had significant CV mortalities, heading in the right direction, not quite significant.

Ticagrelor versus clopidogrel, significant reduction in ischemic events, including CV and not shown here also including all-cause mortality.

And prasugrel versus ticagrelor, in terms of efficacy, pretty much the same. Bleeding is pretty much the same. But for bleeding, though prasugrel versus clopidogrel and ticagrelor versus clopidogrel, in each case, there is a price to pay for the better efficacy. There's more bleeding, so do need to be aware of that.

[00:24:58]

Intracranial Hemorrhage and DAPT

What about intracranial hemorrhage and DAPT? Does occur every now and then in patients undergoing CABG on the pump, getting a bunch of heparin, DAPTs on board, it's a setup potentially for intracranial hemorrhage.

Well, in general, this is, I think, an underappreciated fact. But DAPT is associated with a 40% increased risk of intracranial hemorrhage compared with aspirin alone. Now, the risk with aspirin is really low. So that DAPT risk is still relatively low, but it is significantly higher than just with aspirin alone.

I think doctors think about warfarin in these days, NOACs or DOACs. Those anticoagulants cause intracranial hemorrhage. That's true, but so does dual antiplatelet therapy. And the rates are not that dissimilar.

About 30% of patients that come in with an intracranial hemorrhage are on antiplatelet agents upon presentation. So that association isn't, I think so well appreciated either, because once more I think doctors think anticoagulants, oh yeah, that's what was causing intracranial hemorrhage. But antiplatelets are contributory in about a third of cases.

And patients with an intracranial hemorrhage while receiving antiplatelet therapy tend to have larger hemorrhagic volume, more hemorrhagic growth than hematoma expansion.

And this summary slide, this is something along with some cardiac surgeons we pulled together a few years ago, looking at the totality of data that was out there at the time, and the risk of intracranial hemorrhage with aspirin versus aspirin plus clopidogrel. So about a 1.4 or 40% excess risk here.

And if you talked about ticagrelor, prasugrel, it gets a little bit trickier. With prasugrel for sure, we know it's higher because in its pivotal trial there was actually an increase, a significant increase in intracranial hemorrhage in the subgroup of patients from TRITON, who had a previous TIA or stroke.

In PLATO, which is a trial of ticagrelor, there was a signal as well in the overall trial, p value wasn't significant, but there was a numerical trend towards more intracranial hemorrhage. So have to remember of this potential.

[00:27:03]

Current Strategies to Reverse Antiplatelet Agents

Current strategies to reverse antiplatelet agents are shown here. Desmopressin is listed, as you know, that increases the release of large Factor VIII and von Willebrand Factor. I personally don't think the data are so great, but for the sake of completeness, it's listed here.

And then there are platelet transfusions. Those have variable efficacy based on P2Y12 inhibitor characteristics. I'll show some of the data. But in general, for irreversible agents like aspirin, clopidogrel, prasugrel, there are some utility. For reversible agents like ticagrelor, not so much, especially if it's been given recently.

[00:27:44]

Efficacy of Desmopressin in Patients on Antiplatelet Agents Prior to Surgery

So this table summarizes the efficacy of desmopressin in patients on antiplatelet agents prior to surgery. I'm not going to go through each of these different studies, but it's—in general, if you look at the grade quality of assessment, you know, it's low, moderate, very low, low. So it's not really the strongest data.

I know some cardiac surgeons—some non-cardiac surgeons do it. Some neurologists are particularly fond of this agent. But I don't really find the data that compelling.

[00:28:16]

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

This is a PATCH trial looking at platelet transfusions, which in this particular trial had actually rather limited efficacy in—in—in urgent settings in terms of things like intracranial hemorrhage growth. So it's intuitive to think that platelet transfusions would be useful. But even with the irreversible agents, it's not clear that they are so great. But with the reversible one, ticagrelor really very, very limited benefit of any.

[00:28:48]

Effects of Platelet Transfusions to Reverse Antiplatelet Activity in Patients With Bleeding During CABG

This particular study looks at the effects of platelet transfusions to reverse antiplatelet activity, specifically in CABG patients. And what is shown in this color-coded format is clopidogrel, 600 milligram loading dose of clopidogrel, 900 milligram loading dose. Nobody actually uses the 900 that was studied for a period of time, but the 600 is the most common loading dose.

Prasugrel at a 60 milligram loading dose, or ticagrelor at a 180 milligram loading dose. And you can see in terms of the restoration of platelet function after platelet transfusion, some, you know, effect on clopidogrel, less so with prasugrel and really very little with ticagrelor. And especially if the ticagrelor is given, you know, within 24 hours, you wouldn't really expect platelet transfusions to do anything based on its receptor binding kinetics.

[00:29:38]

Utility of Platelet Transfusions as a Reversal Strategy

So here's another slide, just summarizing platelet transfusions as a reversal strategy. So for aspirin and a lot of patients on the clopidogrel, prasugrel, ticagrelor are on aspirin. So they're even in the ticagrelor plus aspirin treated patients may be utility to reverse the aspirin effect of a platelet transfusion.

But it's just important to realize with clopidogrel that's a prodrug. So the drug—the prodrug is given and it's out of there pretty soon. But then an active metabolite lingers for a few hours. And you may need to redose or, you know, re-transfuse a similar sort of phenomenon with prasugrel, which is a prodrug.

And with ticagrelor, when it's a transfusion within 24 hours, there's really no good evidence that it would reverse ticagrelor effects in an emergent setting. You can give the platelets for the aspirin if they are also on aspirin, but otherwise it wouldn't really be expected to do much. You can think about things like recombinant Factor VIIA.

And if the intake has been greater than 24 hours, then platelet transfusions might provide a little bit of a reversal of ticagrelor.

[00:30:48]

Bentracimab

So what can we do? Well, in terms of actual reversal agents, for those of you that were here at the beginning, I mentioned reversal agents for the anticoagulants. Now one has been developed for an antiplatelet specifically to reverse ticagrelor. So this wouldn't work for clopidogrel, prasugrel, but this would be for ticagrelor. It's called bentracimab.

As I mentioned before, this is an investigational agent. It's currently under FDA review. It's a recombinant human IgG1 monoclonal antibody fragment. It binds to free ticagrelor. And then that complex is eliminated from the bloodstream and it allows ADP to then activate platelets.

[00:31:27]

Reversal of Ticagrelor by Bentracimab

It has been studied. These are some data. About 6 years ago, I think I presented as a late breaker at the American College of Cardiology, published in New England Journal, a phase I trial that means healthy human volunteers randomized to various regimens and doses of bentracimab up top in blue versus a placebo in red in patients—or again, in healthy volunteers that had received ticagrelor.

And what is seen is an immediate and then a sustained reversal with a bolus and infusion of bentracimab. There was a significant reversal seen just within 5 minutes after the start of the infusion. It's a bolus and infusion. And the duration of the reversal lasted about 20 to 24 hours after the 16-hour infusion that was used here. So those are the basic findings.

[00:32:17]

Platelet Function After Ticagrelor Reversal: LTA

I'm going to quickly just go through some of the platelet function studies. It's probably more important that you remember and understand the message and the specific assays. But just in case we have anyone in the audience or online that's a platelet aficionado. This was looking at light transmission aggregometry, so one particular way of looking at platelet response to ADP.

And what was seen was that there was normal platelet function post reversal of over 80%. So the 80% mark is here. And within 5 minutes, it's already there and it's sustained. So similar to the message of what I said on the last slide but now with a specific assay. And this occurred within 5 minutes and was sustained for 20 hours, as I mentioned.

[00:33:01]

Platelet Function After Ticagrelor Reversal: VerifyNow P2Y12 PRU

Now this is using a different assay. This is an FDA-approved assay for looking at a P2Y12 inhibitor activity. Platelet reactivity units is what PRU stands for. Again, it's not critical that you remember that nomenclature. But once more with this different assay, again, very early and sustained reversal with using this FDA approved assay.

It's a point of care assay, unlike the prior slide, where you have to have a fancy lab to do it. Here, a number of hospitals, ICUs, cath labs have this assay available. And it was really the same pattern as shown on the previous slide.

[00:33:40]

Platelet Function After Ticagrelor Reversal: VASP PRI

And here now is looking at an even fancier way of assessing platelet function, the VASP test. Some people think it's the best way. But you can see here normal platelet function again occurs very early after the bolus and same pattern of reversal as the other assays. Maybe if anything a bit more profound with the better assay. So multiple assays, same message really.

[00:34:04]

Platelet Aggregation With Low-Dose and High-Dose ADP

Now a concern that physicians sometimes have is that if you reverse something, will there be rebound? And probably for certain antithrombotics that does occur, I think with heparin the literature—it's older literature is probably pretty good that, some patients, when you stop heparin, there's actually a rebound in thrombin activity. So that means you're sort of worse off than where you started. That's rebound.

If you're—where you would have started if you weren't on the medicine, that's not a rebound. That's a removal of a protective biological effect. Sometimes doctors mix that up. What we see here is no evidence of rebound using ADP as the agonist. And again, I won't go through all the data. I think the message is more important.

But if you look after—towards the tail end of these curves, there's no evidence of platelet hyperreactivity or rebound. And I think this is pretty reassuring. And this was assayed between 5 minutes and 48 hours. So really no evidence of—of—of rebound.

[00:35:10]

Platelet Aggregation With AA and TRAP

That was using ADP as an agonist. This is using arachidonic acid or TRAP, which is believed to be the most potent agonist in this circumstance. But even with those different provocateurs, there's no evidence of a platelet rebound effect. So very reassuring that if this agent, bentracimab, were approved and available, and if you were to use it in reverse ticagrelor’s effect for the purposes of preventing bleeding, say, during CABG or some other active bleeding issue that comes up spontaneously, that's great, but you wouldn't really have to worry, “Oh, might there be a rebound?”

Now, if you don't resume the antiplatelet agent, ticagrelor on this question, there will be an absence of its protective effect. So if the patient just got a left main stent yesterday and you're stopping the ticagrelor today, they might have a thrombotic event. But it wouldn't be because of the bentracimab. It would be because of the lack of appropriate antiplatelet coverage. So it gets a little bit tricky sometimes when looking at different data sets. But the biology here is very clear that it doesn't cause rebound.

[00:36:11]

Summary of Phase I Trial

So here's just a quick summary of that phase I trial. 64 volunteers were randomized, 48 received bentracimab, 16 received placebo. And after 48 hours of ticagrelor that preceded that bentracimab platelet aggregation, was suppressed by 80%. And then bentracimab is given compared with placebo, with a bolus and infusion of bentracimab, significantly restored platelet function, as I showed with multiple assays, highly significant across all the different time points with no evidence of rebound.

[00:36:44]

REVERSE-IT: Phase III Interim Analysis Performed

So that's the phase I healthy human volunteer. And I'm going to share with you some interim data from the REVERSE-IT trial. This is the phase III pivotal trial that was designed for approval of bentracimab.

So what REVERSE-IT is, is a multi-center, open-label, prospective single-arm study. So unlike what I just presented—this isn't randomized. But unlike what I just presented, this is actual patients, not healthy human volunteers. And it consists of patients with uncontrolled major bleeding, life-threatening bleeding, or require urgent surgery or invasive procedures, including CABG, among all this.

And the patients would have had to have used ticagrelor within the prior 3 days. And this is a planned interim analysis. So this was an interim analysis done with the FDA's permission, blessing pre-specified to do it. And in fact, I presented as a late-breaker at the American Heart Association a couple of years ago, and it was published in New England Journal of Medicine Evidence, NEJM’s companion journal.

[00:37:40]

REVERSE-IT: Platelet Function Tests

And what was seen here in actual patients, basically was what we saw in healthy human volunteers. So the theoretical concern was, oh, maybe the drug won't work as well in actual sick patients with comorbidities and other meds and all sorts of things going on versus healthy human volunteers. But in fact, it worked just as well as you would have expected from the biology.

And then, you know, using various assays, such as the VerifyNow PRI assay that I described a little bit earlier. You can see that there is significant reversal of ticagrelor again, in terms of these platelet reactivity units at multiple different time points post treatment, including 5 to 10 minutes afterwards. So basically it behaved just like we would have wanted and expected, but then confirmed.

[00:38:26]    

REVERSE-IT: Adjudicated Surgical Hemostasis

So that is the platelets. Same story in terms of quick potent reversal of ticagrelor’s effect. What about hemostasis? So it's not a randomized trial. It's single arm. We didn't feel that it was going to be possible to do a randomized trial because, you know, in addition to patients with surgical bleeding considerations, we're also enrolling folks with intracranial hemorrhage and all sorts of bad bleeding. And we just couldn't find investigators who would be willing to randomize when they knew there was potentially an agent that could reverse the effect of ticagrelor.

But at any rate, single-arm. What we did do was independently adjudicate hemostasis. So it wasn't just the surgeon that said, oh, yeah, great hemostasis, because if surgeons are like interventionalists, you know, I never see bleeding in my patients. I know other people have bleeding complications, but I never see them.

So you know, there's always a risk when the investigators reporting events that, yeah, perfect hemostasis. But that's why it’s independently adjudicated by a group that does that sort of thing in Boston. And what it turned out was the adjudicated rate of achieved hemostasis in this initial cohort of about 100 patients or so was 100%. So they thought it was really great hemostasis.

And the investigators in fact, were a little bit tougher. It turned out that there was a 95% rate that said, okay, hemostasis has been achieved. Now, it doesn't mean that there was no bleeding. If you look at the GUSTO scale of bleeding, if you’re—any of you recall that from the lytic era, that was a definition. GUSTO mild bleeding is pretty mild bleeding, but there are about two thirds of the patients had that. In GUSTO moderate, which includes things like transfusions, was about a third of patients. But GUSTO severe, which is really bad things like bleeding needing pressor support, or intracranial hemorrhage, or really life-threatening bleeding that was adjudicated to be 0% in the surgical patients.

And these were largely CABG patients. There were some other surgeries, but it was mostly CABG.

And similarly with the investigators, for the most part, they said there was normal or mild bleeding or moderate bleeding. They did—again, they were a little tougher than the independent adjudicators. They said about 4% or 5% had severe bleeding despite use of the agent.

As far as blood product transfusions, the majority of patients were getting some sort of blood product, about 39% getting blood—whole blood or packed RBCs and platelet transfusions and about 13% or so.

Another I think factoid that's important from the trial is what about restarting the P2Y12 inhibitor? Well, in an average of about 2 days or so, there were three quarters of the patients restart on the P2Y12 inhibitor.

Overall mortality seemed low at 2.8%. So this showed that hemostasis appeared to be good. It showed that you could start a P2Y12 inhibitor afterwards if that was clinically indicated, and didn't appear to be anything bad happening.

[00:41:30]

REVERSE-IT: Adjudicated Thrombotic Events

But to be more precise about that, in addition to hemostasis, thrombotic events were independently adjudicated. Once more, this independent committee of folks from the various teaching hospitals in Boston were taking a look and determined that of the thrombotic events that occurred in this trial, and they're all listed here. These are all patients with CABG, with things like MIs and TIAs and graft occlusions and—and peripheral embolic complications and so forth.

With all of these, the time from bentracimab and surgery is listed here. Whether P2Y12 inhibitor was restarted before the event is listed here. But the most important part of the adjudication. And the take home point from this slide is the independent adjudicators didn't think any of these thrombotic events were related to the bolus or infusion per se.

So seem to be safe in addition to effective.

[00:42:25]

REVERSE-IT: Interim Analysis Summary

Here's a quick summary of the interim analysis of REVERSE-IT. Bentracimab once more. That's a specific reversible agent for ticagrelor, provided immediate and sustained reversal of ticagrelor’s antiplatelet effect in ticagrelor-treated patients undergoing invasive procedures with major bleeding. Again, of this cohort, at the interim analysis, the bulk of them had had CABG.

The rates of effective hemostasis were adjudicated as good or excellent in over 90% of the cases as I just showed, with no drug-related serious adverse events or allergic or infusion-related reactions. As I mentioned, it's a monoclonal antibody, so that—it's theoretically a concern. Might there be some sort of allergic reaction? We didn't see any within the context, at least of the sample size.

And the benefits were consistent in a number of number of pre-specified subgroup, in fact significant in a variety of different pre-specified subgroups, including those undergoing surgery or with major bleeding. The 2 main groups that were interested in—in evaluating this agent.

[00:43:22]

Coming Soon!

And I'm happy to say for the first time from the podium that the main results, the final results of the phase III REVERSE-IT trial will be presented at the upcoming American College of Cardiology meeting at a late-breaking clinical session. For any of you that might be there, it will be Saturday at 15:15.

So by then, we'll have the final results and they'll be available for public consumption. So that's a really exciting development. And our hope with that data set is not only to provide some more perspective on surgical patients, but also those that specifically have major bleeding complications, not just in the context of surgery, but just spontaneously, including things like intracranial hemorrhage and so forth. So stay tuned for that late-breaker.

[00:44:09]

Patient Cases

All right. Let's return to the patient cases and then wrap things up here.

[00:44:15]

Patient Case: Rick, 58-Yr-Old Man With Severe Chest and Back Pain

So this is a patient, a 58-year-old with severe chest and back pain. Past medical history is an MI 4 weeks prior with a drug-eluting stent to the LAD, which was 100% occluded. So this is someone with both an MI, now a relatively recent drug-eluting stent.

Medications include aspirin, statin, ACE inhibitor, beta blocker, and prasugrel. So in terms of bleeding potential, it's aspirin and prasugrel.

The patient presents to the emergency room with sudden onset severe chest and back pain, tearing in nature, radiates to his mid-back. Looks sounds like is a aortic dissection type A, which a CT angio confirmed.

So a month ago MI stent and now type A aortic dissection. Actually got to wonder if there was any sort of iatrogenic tear maybe at the time the procedure, or maybe it's just bad luck. But at any rate, patients here are. Now, what do you do with them?

[00:45:10]

Poll 1

All right. Would you go ahead, given the patient's recent MI and DAPT:

1. Administer a platelet transfusion and proceed to surgery;
2. If available, administer bentracimab to reverse prasugrel;
3. Would you administer a tranexamic acid to reduce the bleeding risk; or
4. Would you delay surgery for 7 days until the prasugrel is eliminated from the system.

So go ahead and vote.

[00:45:51]

Poll 1: Answer

All right. Well, the majority of folks got what I think is the right answer to—to administer a platelet transfusion for this irreversible antiplatelet agent, prasugrel, also the aspirin and proceed with surgery.

Bentracimab is specific to ticagrelor reversible. So if it were approved and available and this had been ticagrelor in here instead. Sure, that would have been the right answer. But with prasugrel, it wouldn't have any effect.

And, you know, delaying the surgery for 7 days with a type A aortic dissection, you all know the data better than I do. Every hour of delay, the mortality is going up. So that wouldn't be the right answer.

[00:46:32]

Poll 2

All right. What about desmopressin in this scenario?

1. It may be used as an adjunct due to the established safety despite weak evidence demonstrating efficacy;
2. It may be used as an adjunct due to strong evidence demonstrating efficacy;
3. It should be used in all patients on antiplatelet therapy requiring emergent surgery;
4. It should not be used in any patients on antiplatelet therapy requiring emergent surgery.

So go ahead and vote on that one.

[00:47:09]

Poll 2: Answer

All right. So the majority of people picked A, which I think is probably the right answer too, like I said, I'm not personally a big believer in desmopressin, but does seem pretty safe. So as I said, in particular, in some communities like the stroke world neurologists, they do tend to like it.

[00:47:25]

Patient Case: Rick, 58-Yr-Old Man With Severe Chest and Back Pain

All right. So let's come back to our gentleman with the MI and DES 4 weeks ago. What would we do differently if he was receiving ticagrelor? So if everyone was actually awake I just actually gave the answer.

[00:47:43]

Assessment 1

But—so which of the following P2Y12 inhibitors acts as a reversible inhibitor of platelet receptors? So that gets to the biology that helps answer that question. So reversible is:

1. Clopidogrel;
2. Clopidogrel and prasugrel;
3. Prasugrel only; or
4. Ticagrelor only.

All right, so we've got the pre and post. And I was going to say but then I didn't want to jinx myself. I mean if people didn't get this right, it would really mean that I put everyone to sleep both here and at home.

Yes. Ticagrelor is a reversible agent. That is correct.

[00:48:24]

Assessment 1: Rationale

All right. You know, this is just the explanation. But I've already told you a bunch of times that ticagrelor is the only reversible one of the oral agents.

[00:48:33]

Assessment 2

All right. So in this same patient—oh, this is going back to the other patient, the 68-year-old that came in with an ACS to the ED. This is a one from the beginning that needed urgent CABG because he acutely clinically decompensated. What's the most appropriate option to manage bleeding risk in this patient?

1. Administer a platelet transfusion. Again, he's on ticagrelor;
2. Would you delay surgery to allow ticagrelor to naturally clear. So that's going to be at least 3 to 5 days, depending on which source you believe, but at least 3;
3. Would you prioritize bleeding control and proceed with surgery; or
4. Would you proceed with surgery as ticagrelor does not significantly increase bleeding risk.

So which one is the correct answer here?

Yeah. So the majority of people got the correct answer. Some still said to delay surgery again. I guess it depends on clinical judgement, but the question just say that he needed urgent CABG to begin with. And he’s had an acute clinical decompensation. So the intent there is he needs to go to the OR, can't wait.

[00:49:43]

Assessment 2: Rationale

So C was the correct answer, for the reasons I just mentioned. So I won't go through that again.

[00:49:50]

Assessment 3

So the primary finding of the interim results from the REVERSE-IT trial showed that bentracimab:

1. Induced rapid and sustained reversal of ticagrelor’s antiplatelet effects;
2. Only partially reversed ticagrelor’s effects with limited clinical applicability;
3. Was associated with significant adverse events, which may limit its use;
4. Was less effective in patients with major bleeding compared with those with minor bleeding.

So go ahead and pick the right answer.

Yes. So that is the correct answer. Everybody got that. That's terrific. So in the REVERSE-IT trial, the interim results did show rapid and sustained reversal of ticagrelor as antiplatelet effects.

[00:50:38]

Key Take-home Points 

So some take-home points just to emphasize things to remember, both for the audience here and online. The use of P2Y12 inhibitors is expanding giving demonstrate—given the demonstrated clinical efficacy in ACS and stroke prevention and other conditions as well, as I alluded to, especially ticagrelor’s recent label updates.

Current options for options for reducing bleeding risk in patients on antiplatelet therapy include urgent or emergent surgery, including platelet transfusions.

Desmopressin one can throw in there just for the sake of balance and completion, but I'm not really sure that that really is doing that much, but one could consider it. Ticagrelor is a reversible P2Y12 inhibitor, which limits the efficacy of platelet transfusions to reverse its effect versus, say, clopidogrel or prasugrel.

And finally, bentracimab is an investigational monoclonal antibody fragment. It's demonstrated rapid and sustained reversal of ticagrelor’s antiplatelet effect. And it might address a very critical gap in patients who require antiplatelet reversal while taking cag—while taking ticagrelor. That actually includes a lot of potential patients. But I would say at the STS here, in particular, the consideration in patients that might require urgent or emergent CABG.

Well, thank you very much for your attention both to this online and in-person audience. I know it's early in the morning. I appreciate your attention. If there are there are any questions which have already come in, I will quickly take them in the few minutes we have left here.

Q&A

Dr Bhatt: So what is the DAPT recommendation for patients who have AFib and then undergo CABG? And then if AFib stops after CABG or ablation? That's a really great question.

In general, even without putting CABG into the mix, DAPT isn't part of AFib management. It's been studied in a randomized trial some years ago. And in fact, warfarin, in the context of a randomized clinical trial with great INR control, beat aspirin and clopidogrel in the setting of AFib. Beat it for efficacy, also beat it for bleeding, which many people didn't realize that part, which is why I made the comment earlier on that DAPT’s bleeding potential isn't that different from an anticoagulant, even though we all think, oh, anticoagulant, lots of bleeding. And that's even more true in the NOAC or DOAC era, because the NOACs/DOACs have significantly less intracranial hemorrhage bleeding risk than warfarin is shown in randomized trials.

So in the AFib patient, in general, if they've got AFib, they should just be on an anticoagulant at the appropriate dose with the NOACs or DOACs. There can be renal or weight adjustment depending on the DOACs. You want to follow the label and use the right dose. But in that context, really they shouldn't be on an antiplatelet agent.

What if they have CAD? They should still just be on an anticoagulant. The trials that have looked at it largely from East Asia have not shown an incremental benefit of an antiplatelet plus an anticoagulant in that AFib patient who also has stable coronary artery disease, you just increase the bleeding. So you would just use an anticoagulant.

Now, if they just got a stent last week and they had AFib, it gets more complex. And that would be another symposium in its own right. But in general there you would want to discharge the patient after that stent procedure with AFib on a good dose of an anticoagulant and a single antiplatelet, typically the ADP receptor antagonist. So a common regimen might be apixaban and clopidogrel, for example.

Now, what if the AFib stops after CABG or ablation? It sort of depends if it was there before and then it stops. The stroke risk persists for at least a few months because the left atrium is often still stunned. So you know, the EP folks, for example, when they ablate, will continue the anticoagulation for a period of time, sometimes indefinitely, or until they're sure that the patient isn't having bouts of AFib as an outpatient. So in general, you would still want to continue.

Another question. Is there any practical protocols for managing emergent CABG with DAPT and decreasing post-op bleeding?

So I was going to be careful as a cardiologist giving cardiac surgeons advice about post-op bleeding. I mean, you know, if I say something like good hemostasis or good surgical technique, people might start throwing bagels or things at me.

So obviously, you know, you want to be particularly careful when a patient is on DAPT or any antithrombotic and doing surgery. But, you know, the practical sort of things are what I really mentioned. You know, one consideration is timing of surgery, can it wait or can it not wait? And if it's, you know, in the context of a high risk ACS, oftentimes it can't wait. If it's more stable ACS, sometimes you can wait. But you know, in the US nobody really discharges patients that have come in with ACS and brings them back for CABG and other parts of the world, that sometimes happens.

But in the US it's rather rare. If someone comes in with a troponin positive ACS, the decision is CABG. They typically stay there for the duration. And that patient, you know, may have been on antiplatelet therapy a priori or they may have been started in the emergency department. In either case, as a surgeon, you're stuck with somebody on DAPT. So it can be an issue. And it's a matter of again, waiting—you know, just weighing those things, the potential ischemic risk of just letting them sit in the hospital off their antiplatelet therapy, the costs, length of stay, all those issues that come up.

Considerations of cangrelor bridging, but with respect to the ADP receptor antagonist and replacing that. So that all has to be factored in. Of course, if bentracimab were approved and available, that would simplify things for those patients that come in on ticagrelor.

And I actually think there are a few things that are going to push ticagrelor’s use in the future. Once it goes generic, I think it's going to be used up. It's already used a lot in ACS. But I think it's going to be used a lot more. And I think assuming that the reversal agent gets approved, when there's a reversal agent, I think it will become the preferred ADP receptor antagonist with clopidogrel, as I mentioned. There are already issues with its variability.

With prasugrel, there's good data, but it never really caught on because of that black box warning on—in the label about intracranial hemorrhage in patients with prior cerebrovascular disease. Now, of course, if you're in the office, you can usually figure out if someone has prior cerebrovascular disease. In the emergency department, it's not always that easy to figure out. I mean, if they have an obvious stroke and deficit, then, you know, don't use prasugrel.

But what if they had a TIA? That can sometimes be hard to elicit. That history in the emergency department, as you're rushing to take care of a sick ACS patient. Patients don't always know what a TIA is. Some people think dizziness is a TIA. So that can get really tricky. So prasugrel never really caught on to the extent I thought it might have, despite efficacy data showing superiority in ACS patients undergoing PCI and the lack of additional indications for prasugrel. Also heard it a bit. Clopidogrel has a bunch of indications, ticagrelor as well.

So my guess is that ticagrelor use will—will really increase. And if that happens and if bentracimab is available, then from a cardiac surgery perspective, I'd say that should be a part of the regimen.

Now here's a question. What would you do for intracranial hemorrhage of bentracimab is not readily available. So if it were available and approved, then I would use it. If the patient had received ticagrelor, if it weren't approved or available, then if someone has intracranial hemorrhage, I mean, you would consult your friendly local neurologist and neurosurgeon and see what to do.

It certainly would hold any DAPT or anticoagulation for a period of at least a week, even if someone had AFib, you know, you would hold their anticoagulant, typically for at least a week. And then when to resume? It is a matter of debate. There's some data depends on the size of the intracranial hemorrhage, depends on the degree of disability that has occurred from that intracranial hemorrhage.

There's some guidance out there. But I mean, you really have your neurosurgeon neurologist help with that. You know, it's not clear that platelet transfusions really help in that situation. But if it were aspirin or prasugrel or clopidogrel on board, I would give platelet transfusions. And if it were a DOAC, I would give one of the specific reversal agents despite the fact that they're pricey in many hospitals, you need hematology approval to do it.

In that circumstance, I would do it, despite the recent data suggesting that maybe, you know, the reversal agents in the context of DOACs may not improve heart outcomes, but it's hard with the intracranial hemorrhage patient. You know, there are tough patients to study because you're giving them a therapy to salvage them. Well, if someone's already herniating, probably nothing's going to make a difference, but you'd still want to give them a shot.

So it can be very difficult getting the right intracranial hemorrhage patients to show a benefit on clinical outcomes of a—of a particular therapy. But maybe it hasn't hit the surgical literature. But there's been some recent controversy in the DOAC reversal. But—but myself, if someone's on a DOAC, I would give the reversal agent if they came in with an intracranial hemorrhage.

What is the role of triple antiplatelet therapy with addition of low-dose rivaroxaban, a DAPT and PCR CABG? That's a great question. Strictly speaking, it wouldn't be triple antiplatelet therapy. It'd be triple antithrombotic. Because rivaroxaban is not an antiplatelet. It's an anticoagulant, a DOAC or a NOAC. It is FDA approved for a variety of things at a higher dose for AFib DVT. But what is being referred to here, I think with the low dose rivaroxaban is the 2.5 twice a day, which is FDA-approved for coronary artery disease or peripheral artery disease, or both.

And in that circumstance, the COMPASS trial showed a benefit of that regimen, largely with aspirin. There were some patients also on clopidogrel, but mostly it was on background of aspirin. With respect to DAPT plus low-dose rivaroxaban, I mean, in general, that's not something that we recommend because the bleeding risk does go up with that. That was studied in a trial ATLAS-2 published in New England Journal, but that never led to an FDA approval in the ACS context. It was a subsequent trial with that dose in stable CAD or PAD that led to FDA approval.

And again, in that trial, it was aspirin plus rivaroxaban versus aspirin plus placebo. There was a third arm with a different dose of rivaroxaban that wasn't approved. So I wouldn't use that triple therapy regimen is the bottom line in general.

I think in that patient who was post PCI or CABG, DAPT would be the way to go. Now if they have had a remote PCR CABG, then one could consider the COMPASS regimen of aspirin, plus the 2.5 BID of rivaroxaban, that would be based on the COMPASS trial and quite reasonable.

And the final question here and we're out of time, so it works out well, is thoughts on thrombotic effects not being related to bentracimab despite occurring with 1 day of infusion?

Yeah, it's tricky, especially, you know, with the lack of randomization. I told you why randomization is challenging in these sort of trials. A lot of times the investigators—at least our investigators said if there's an agent available, you know, we want to just give it. We don't want to have a placebo. Maybe not everyone would have felt that way, but that's how we got a non-randomized study.

So yeah, it's a little bit tough to say you give bentracimab. A day later there's a thrombotic event. How do you know it's not related? That's why we had experienced adjudicators independently do it. So short of randomization that's the only way to tell. And there's always going to be an increase in thrombotic events in these patients, regardless of whether you give bentracimab or DOAC reversal or anything, because you are removing—in many cases, you're not giving that antithrombotic agent.

So whatever protective effect it had, it's not going to be there. So there will be an increase in thrombotic events absent any reversal agent, just because you're not getting the protection from the antithrombotic event. There are a couple of other reasons too. When patients bleed, lots of other bad things happen. Teleologically if you think back to evolution, you know, if we were bit by a saber tooth tiger, well, bleeding is occurring, but the body is saying clot.

So whenever there's bleeding, there actually are signals in the body saying clot. So that's why a lot of times you see bleeding patients. If you review the literature absent any reversal agent, there's a higher rate of thrombotic events. That's why we’ve seen in—in—in registry studies years ago of aspirin, where when aspirin was stopped, there was an increase in—in thrombotic events and it wasn't a platelet rebound or anything like that. It's just that, well, aspirin was preventing ischemic and thrombotic events. It stopped. The patient is maybe undergoing surgery, which is a very thrombotic milieu.

Well, yeah, there are going to be ischemic and thrombotic events occurring. It's not a platelet rebound. It's not aspirin rebound. It's just that the aspirin isn't on board to—to do what it's supposed to do. So—so I think, you know, it gets tricky sometimes when those thrombotic events are occurring. But in this case at least to reverse it, we had an independent, very experienced group, you know, folks that have done tons of other studies of bleeding and hemostatic agents that independently adjudicated those events as not being related to the drug.