Ep. 174: Breakthrough Stroke: Diagnostic and Therapeutic Dilemmas

00:00:00: Welcome to EA Uncast, your weekly source for education, research and updates from the European Academy of Neurology.

00:00:15: Hello, everyone.

00:00:16: My name is Theodoros Mavridis.

00:00:18: I'm a consultant neurologist and stroke specialist in Tala University Hospital in Dublin, Ireland.

00:00:25: And I'm honored today that I have with me Professor David Saevke, who is a professor of clinical neurology at the University of Bern and the head of the Stroke Unit at the Department of Neurology of the Insel Spittat University Hospital in Bern, Switzerland.

00:00:41: and today we're gonna go through a very very interesting subject which is breakthrough stroke and diagnostic and therapeutic dilemmas.

00:00:50: so with no more waiting I would like to ask the first question how would you define what is a breakthrough

00:01:01: stroke?

00:01:02: Thank you, Todoros, for this nice invitation and introduction.

00:01:05: And of course, I think that that's a very interesting topic.

00:01:09: So a breakthrough stroke, in general, you would define this as an ischemic stroke happening in a patient who is already taking an antithromotic therapy, either antiplated therapy or anti-corculation.

00:01:24: the stroke breaks through the protection the patient was supposed to take to protect the patient from the stroke.

00:01:31: In general, there are two types that we would differentiate between two types, those who breaks the strokes on antiplated therapies.

00:01:37: And on the other hand, and those which are, from my perspective, even more interesting and more worrisome are those patients who have a bracer stroke despite being an oral anticoagulation therapy.

00:01:51: Great.

00:01:52: Thank you for this initial experience on that.

00:01:55: I would like to ask you further and how would you distinguish a real breakthrough stroke in terms of if a patient, for example, is on anti-gogulation and the patient has a breakthrough stroke, what would you investigate further?

00:02:10: Is it a true breakthrough stroke?

00:02:12: Is it a treatment failure?

00:02:14: What would be the mechanisms and what does the evidence say about

00:02:18: it?

00:02:19: Yeah, that's a very frequent scenario that we see in our stroke units.

00:02:23: We are talking about patients who are already known to have age revelation, who have already been started on oral anticoagulation by their treating physicians, but they still suffer a stroke.

00:02:33: And that's actually a quite important number of patients.

00:02:36: We count about.

00:02:38: half of all age-repellation-related strokes in Switzerland, which sums up to an overall of about ten percent of all strokes in Switzerland, and these are comparable numbers in other European countries, for example, like Norway.

00:02:52: And what we have to do in those patients is we have to use our brains to think what could be the cause of the stroke, because just the patient has age-repellation doesn't mean that the stroke is actually cardiombolic.

00:03:04: So we need to investigate those patients as we would do for any other stroke patients, meaning we would take a personal history to see whether the patient was actually taking the anticoagulation, which he was supposed to take, whether the patient was actually stopped for a few days on anticoagulation because he was undergoing any intervention which requires stopping anticoagulation.

00:03:27: So then we actually have a cause of the stroke.

00:03:30: There are also some patients who just don't take their medication.

00:03:34: So malcompliance or lack of compliance is an issue.

00:03:38: But at the end, this turns out to be a minority of all patients.

00:03:42: Historically, we thought that we have many of them having strokes because they just stopped articulation.

00:03:46: But overall, it's about ten to twenty percent of all strokes that we see.

00:03:51: In those remaining patients, we actually need to go deeper into actual causes.

00:03:56: So we need to investigate the blood vessels and we need to also investigate other potential causes, meaning we have to see whether, for example, the patient has concomitant large artery artery cirrhosis with a high grade cirrhosis, which may cause a stroke or small vessel disease, which causes stroke or other causes of stroke.

00:04:16: So just because the patient has age regulation, mustn't be in the stroke is cardiombolic.

00:04:23: And at the end, we will find probably patients having other competing non-cardiabolic cause of stroke which in turn means that the vast majority still has a pure breakthrough stroke of a cardiometric origin.

00:04:41: Thank you for this insight.

00:04:43: It's true that it's better to investigate further when we have a breakthrough stroke to see again the compliance and of course if there's a competing etiology.

00:04:56: Let's start with the compliance, then we'll go into competing etiologies and then we'll finally go to the true breakthrough strokes.

00:05:03: In terms of compliance and let's go for the patients who are, for example, with atrial fibrillation and they need anticoagulation.

00:05:13: Nowadays, we mostly use a direct or anticoagulation instead of varfarin or aceno-kumarol, but Still, how would you assess compliance on those patients?

00:05:27: Do you fear that some of the patients are not taking proper medication?

00:05:32: And I'm not talking about the patients who tell you that they stop the medication for a surgical procedure, but you're not quite sure if they're taking the medication properly, even though prescribed properly.

00:05:45: Yes, that's a good question.

00:05:47: So, ten, fifteen years ago, assessing compliance of a patient on antichrination was much easier because we had only vitamin K antinists.

00:05:55: We could measure the INR and then determine whether the INR was on a therapeutic level or not.

00:06:00: But this is unfortunately much more complicated, as you said, nowadays.

00:06:04: So these diet-oriented corgans are actually very beneficial drugs.

00:06:08: But the limitation is that many centers are not able to or do not have the possibility to measure actually drug-specific integration activity for those agents, which is possible, which is available, so you can measure anti-TNA or calibrated anti-TNA activity for the TNA inhibitors or a specific aspirin trotting time for WCATRON, for example, in your central lab and you get values back.

00:06:34: But also interpreting these values is much more complicated because the drug levels highly fluctuating over time, decreasing over time with renal clearance, meaning that you have to interpret the level that your measure with respect to the dosage of the drug the patient was taking, the time point of last intake, and the time point of blood sampling, which makes it a very, very complicated process.

00:06:59: So in our daily practice, what we are doing in my hospital, we are measuring drug-specific anticoagulation activity for DOAX in the emergency department.

00:07:09: Rather than looking at the exact level, we are looking at it in a qualitative way, meaning that if there was some activity present we assume that the patient was at least taking the drug.

00:07:24: If there was no activity at all measurable then actually we have a good argument that the patient was very likely to be non-compliant with the drug.

00:07:31: The absolute levels are very very difficult to interpret and I think adjusting anticulation based on these measurements is also quite complicated so I would refrain from it.

00:07:44: Yes this is very very useful in terms of clinical practice.

00:07:48: so we basically What we do in clinical practice, we basically take the world of the patient.

00:07:54: If the patient is taking the medication, then the patient is taking the medication basically.

00:07:59: But yeah, there are other ways to figure out if it was done properly.

00:08:04: So, the next question is about competing etiologies, which is the most common one, and how would you address that specific etiology?

00:08:13: Because we know, for example, in other trials with patients with AFib and heart, for example, as the nose carotid artery, there was no... much difference in terms of if we put antiplatelet on top of anti-calculation compared to anti-calculation in a recent trial that was published.

00:08:34: But I want to hear your expert thoughts on that.

00:08:38: Yeah, so you already pointed out the most frequent competing non-cardiabolic etiology in patients at fibrillation having a racist stroke is actually large artery artery sclerosis.

00:08:50: And in those patients usually you will find moderate to high-grade stenosis, ipsilateral to the stroke.

00:08:57: And if this picture turns out so you actually investigate the patient you see a high-grade stenosis and you also see a neuroimaging that the in fact pattern in the brain on MRI or CT.

00:09:09: corresponds to a unilateral stroke within the territory of the supplying artery.

00:09:14: Then you can be quite confident that this is actually a archus carotid stroke and not an affibrated stroke.

00:09:21: And what we do in our clinical practice is actually we are quiet, pro-aggressive.

00:09:26: in suggesting reverse scolization therapies to those patients, meaning to stand or to perform carotid antarterectomy for a high or medium-grade stenosis, if suitable, on top of oral antiviral therapy.

00:09:43: to be continued afterwards.

00:09:45: It is a bit more complicated for patients with an intracranial stenosis, where stenting is usually only a second line choice, or for low-grade arteriosclerosis patients who don't qualify actually for a reversalization because the degree of stenosis is not high enough.

00:10:03: And then these patients actually don't have real evidence what to do.

00:10:07: And as you mentioned, adding antiplatelet therapy on top of anticulation, those patients also seeming a good idea turned out to be quite not protective for further strokes, at least in observational data and mostly associated with a higher bleeding risk rather than protecting those patients from stroke.

00:10:28: So in generally, I would advise not to add antiplatelets to those patients.

00:10:34: Great.

00:10:36: Let's go into the my favorite and most interesting part the true breakthrough strokes on those patients.

00:10:44: for this specific subgroup of anti-coagulated patients who we have done all the investigation.

00:10:51: you didn't find any other competing cause.

00:10:54: the patient was taking proper medication they had a really good level of inhibition and they still have a breakthrough stroke.

00:11:03: how.

00:11:04: Would you treat those patients?

00:11:06: What more investigation would you do?

00:11:09: And what about trials?

00:11:13: That's actually the most frequent subgroup of patients.

00:11:16: At the end, the majority of patients actually fall into this category they just mentioned.

00:11:21: So they have a real cardiabolic brachial stroke and it's also a bit disappointing for those patients because actually they did everything right.

00:11:28: They took their drug, they took the right drug and they still had a stroke.

00:11:31: So first it's quite disappointing for patients.

00:11:35: What we do in those patients, actually we start with investigating also the left atrial and the left atrial pernage to see, to investigate the structure and whether there are still remaining traumas, which actually we did some studies with colleagues together and in a quarter of those patients you will actually find remaining traumas in the left atrium and left atrial pernage, which seems like a smoking gun for you, seeing that one part of the traumas already cause a stroke, but there's still some remaining traumas in the heart and we actually need to protect those patients from further strokes.

00:12:08: These are the patients at the highest risk of having early recurrent strokes with an annual risk of about seven percent in the first year, which is really high for stroke population.

00:12:18: Historically, we actually changed anti-glation frequently because there are different types of TNA inhibitors, trombone inhibitors.

00:12:27: So we switched from one agent to the other, taking one daily to taking twice daily or the other way around.

00:12:33: because we were we are actually human beings would like to do something and I told your patients are probably disappointed because something happened although they took their drug.

00:12:42: so we are going to change the drug to have done something which helps the patient which helps our self our psychology.

00:12:50: but at the end we at least from observational studies we found that it doesn't really matter for the patient.

00:12:56: the risk of recurrence is the same whether you change the anti-currant or not.

00:13:00: so you can just continue with the same drug as before as long as it is correctly dosed and taken in the way it should be taken.

00:13:10: So we have to actually investigate new ways to protect those patients from reconstructive because, as I said, the risk is high.

00:13:19: There are currently several trials ongoing which investigate this topic and from different perspectives.

00:13:27: So one potential option would be early rhythm control.

00:13:31: So we know that for patients with age population, who at the time they are actually in atrial fibrillation, what we would call the burden of atrial fibrillation, is also important for the stroke list.

00:13:42: And the more the patients are actually in a sinus rhythm and the less frequent they are in AFIP, the lower the risk of stroke is for those patients.

00:13:50: The only downside is that it actually hasn't never been tested in patients with acute stroke theory.

00:13:55: We don't know whether it's safe to do it in patients with acute stroke.

00:14:00: Fortunately, there is now an ongoing trial, which is going to start soon.

00:14:03: It's called e-stroke.

00:14:05: It's an academic trial, mainly coordinated from Hamburg in Germany, which is going to investigate early rhythm control in patients with age violation strokes and not limited to breakthrough stroke patients.

00:14:17: But I think these data are very likely to be also beneficial for patients' breakthrough stroke.

00:14:23: So that's the part of rhythm control.

00:14:26: Another option would be to actually target the culprit.

00:14:29: And as I told you, the left age appendage is actually a structure adjacent to left atrium, which harbors the majority of all cardiac thrombi in patients' age fibrillation.

00:14:41: And we know from patients who cannot take oral anticoagulation that closing the left age appendage is beneficial to protect them from stroke.

00:14:50: There are two ways to do it.

00:14:52: There are surgical ways.

00:14:53: You just... operate and close the left age appendage.

00:14:59: But they are also, and it's the most frequent way to do it, it's a percutaneous left age appendage closure.

00:15:05: But this hasn't been tested so far in combination with oral anticoagulation.

00:15:09: We know it from patients who cannot take anticoagulants, so we take it as a substitute for anticoagulation therapy.

00:15:15: But what about combining it with oral anticoagulation therapy?

00:15:19: Together with colleagues we did some observational studies hypothesis generating to see whether combining or anti-gagalation with left adiabatic closure in patients.

00:15:29: with Brexit stroke is beneficial and preliminary data suggests that it might be of benefit.

00:15:36: And now we are going to test it in a randomized controlled trial because we have to prove it.

00:15:39: This trial is called ELAPS.

00:15:41: It's also an academic trial, funded by the Swiss National Science Foundation.

00:15:45: And we started recruiting about one year ago in several countries in Europe and outside of Europe to enroll actually patients with a breakthrough stroke to receive left adipose closure on top of oral intercalation or oral intercalation alone.

00:16:00: And we will see whether this treatment turns out to be beneficial.

00:16:05: And the third option actually is to protect the brain directly, because the majority of age-revibulation-related strokes are actually larger trombi.

00:16:14: going up the carotid arteries in the anterior circulation.

00:16:17: So it might be a good idea to protect the anterior circulation and shield the anterior circulation from these large clots.

00:16:25: And there is now a new trial going to start quite soon, which will investigate bilateral carotid filter devices on top of oral anticoagulation in patients with age, relation, and stroke, to see whether these filters actually are also beneficial to protect the anterior circulation, which is the carpet in here.

00:16:43: from further strokes.

00:16:44: and it's also going to be tested in a randomized controlled trial which I think is very beneficial because at the end we will have really good data from randomized controlled trial to make treatment decisions.

00:16:57: This is a very interesting things that we heard and I think that of course as a take-home message I will go a bit further.

00:17:06: on your talk that you said that we shouldn't be changing oral anticoagulation from one to the other.

00:17:13: it may be more harmful to change and there are data that support

00:17:17: that.

00:17:17: and of course we need to explore other alternatives.

00:17:21: and of course all those things are very very interesting and we're waiting for the results of the randomized trials the prospective the observational trials are really promising but we need the results from the randomized trials.

00:17:38: And this is very, very important.

00:17:40: Now I will go to something different.

00:17:44: I will jump from the anticoagulation breakthrough strokes to the antiplatelet breakthrough strokes.

00:17:49: So we see patients who get recurrent strokes instead of putting antiplatelet therapy.

00:17:57: We know that the number needed to treat is not... Really impressive, even though aspirin is the main choice of clopidogrel and nothing seems to beat it so far.

00:18:08: We have the new drugs that are coming from the randomized trials, specifically the anti-eleven drugs.

00:18:18: And I want your thoughts on breakthrough strokes in patients who are under antiplatelet therapy.

00:18:26: Yeah, that's also actually... quite even larger patient population.

00:18:31: so we recently did an analysis from our National Swiss Drug Registry.

00:18:36: which actually covers all strokes happening in Switzerland.

00:18:40: And actually, more than thirty percent of all stroke patients were already on aspirin at the time point of stroke.

00:18:46: For any reason, might be that they have had previous stroke, might have coronary artery disease or peripheral artery disease or other conditions that require antiplated therapy.

00:18:56: But a significant number of all stroke patients is already on antiplated therapy.

00:19:00: And as you said, our current paradigm is we may probably put them on a dual antiplatelet therapy for short term but or for short or long they will finish up being again on antiplatelet therapy single antiplatelet therapy and it's also very uh.

00:19:15: it's not very satisfying.

00:19:17: we also know from literature that those patients tend to have also higher risk um higher risk of stroke.

00:19:23: so usually what we should do in those patients is of course looking for other etiologies that warrant therapy change.

00:19:30: probably look for H-velation, which then requires anti-coglation, or look for a high-grade stenosis, which requires trumpet arteriactomy or stenting.

00:19:40: But at the end, the majority of those patients will not have these conditions, and we are forced to still continue with anti-platelet therapy.

00:19:49: You're elucidated to several currently ongoing trials, which are investigating a very interesting approach, meaning that to combine antiplated therapy with another very specific agent to inhibit Factor XI, which is a very specific factor in the coagulation cascade.

00:20:10: So we're not very sure what they should call this anti-coagulants or just Factor XI inhibitors.

00:20:16: I think Factor XI inhibitors may be the best way to describe it because it's very precise.

00:20:21: And we know that they are... seem to be very safe, so they seem not to increase the risk of bleeding, but they might add an additional protection for stroke to those patients.

00:20:33: And there are two trials, one is called Oceanic, the other one is called Dibrexia, which are currently ongoing and some of them will likely have results within the next few months, which are very exciting because they might fundamentally change our way to treat those patients.

00:20:49: If proven positive, then we will have a new tool in our toolbox to treat those patients and I think those patients who already had a stroke despite being on depleted therapy would be the first for me to put on this new drugs because I think then we have really something to offer to those patients.

00:21:07: but at the moment we unfortunately have to speculate about the results because the trials haven't been finished so we don't actually know whether or not they are beneficial.

00:21:18: I would like to thank you for all your interesting thoughts and all your expertise that you provided to us about this very intriguing topic, which is breakthrough strokes.

00:21:30: And we're hoping that we'll see more in the near future from the randomized control trials, and we'll have more things to discuss in the next time.

00:21:40: Thank you, Professor Saifge.

00:21:42: Thank you very much for this interesting talk.

00:21:45: Thank you very much, Dr.

00:21:46: Mavridis, and thank you very much EAN for this opportunity.

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