Aristeidis Katsanos

Hello everyone and welcome to the third and final session on secondary stroke prevention. In the two previous webinars, we focused on modifiable risk factors and current interventions to reduce the risk of stroke recurrence. Today, our panel of experts will discuss some secondary prevention strategies tested in ongoing or recently completed clinical trials. Contrary to our previous webinars, I would like to begin by emphasizing that by the time of the publication of this webinar, some of the interventions discussed have not been officially approved for stroke prevention.

I’m delighted to be joined in this discussion by Drs. Valeria Casso, Mike Sarma, Ashkan Shoamanesh, and Peter Kelly. Could I ask each one of you to introduce briefly yourselves and describe your main research areas of interest.

Valeria Caso

Hello, my name is Valeria Caso. As you heard already, I’m a stroke neurologist and my main research focus is on stroke in women. And this is why, because it’s more in a broader approach, because I want to understand why there are some categories, and here we’re talking about 50% of all the population, have less access to stroke treatment. And looking at women, you can understand even more why there is a gap in implementation.

Aristeidis Katsanos

Thanks so much, Valeria. Mike, can you please introduce yourself?

Mike Sharma

Hello, everyone. I’m Mike Sharma. I’m a stroke neurologist and clinical trialist at McMaster University in Hamilton, Canada. My main research focus has been on stroke prevention, principally through the use of novel antithrombotic therapies.

Aristeidis Katsanos

Thank you, Mike. Staying in McMaster. So, Ashkan, can you please introduce yourself?

Ashkan Shoamanesh

Hello, everyone. My name is Ashkan Shoamanesh. I’m a stroke neurologist at McMaster and clinical trialist as well at the affiliated Population Health Research Institute. My clinical program really focuses on the interface of hemorrhagic stroke, thrombosis, antithrombotic and thrombolytic therapies, trying to improve advances in care without compromising bleeding.

Aristeidis Katsanos

Thank you so much Ashkan. Going back to the other side of the Atlantic. Peter?

Peter Kelly

Hello, everyone. My name is Peter Kelly. I’m a vascular neurologist and clinical scientist based at University College Dublin. My main research interest is in risk stratification and therapeutics for secondary stroke prevention, with a particular focus on atherosclerosis. And within atherosclerosis in recent years, we’ve been really focusing on the role of inflammation as a potentially modifiable vascular risk factor.

Aristeidis Katsanos

Thank you all for being here and sharing your expertise. Valeria, the word is back to you. And I would like to start by asking you to summarize the unmet needs for patients experiencing cardioembolic stroke.

Valeria Caso

Thank you very much for this question because I did a lot of research on this. We see often patients, we see patients who are on anticoagulation and despite this have a recurrent ischemic stroke. And we know from different sources, there’s the data from Zyfke et al, there’s an 8% annual risk of having a stroke recurrence. We did our study, the RENO-EXTEND study, which were high-risk patients with a previous stroke, and we detected a 13.8% of risk recurrence in patients who are already on DOAC. Probably there are many factors altogether that we have to understand, maybe due to the cardiac conformation, the heart conformation. Sometimes their patients do not take the anticoagulation. They are concomitant other risk factors. For example, 30% of those patients do not have cardioembolic stroke. So probably there’s a combination of factors where we have to look at the heart and all the global risk profile of these patients.

Aristeidis Katsanos

Thank you so much, Valeria, for this nice and comprehensive overview. And not only patients with cardioembolic stroke, but also patients with non-cardioembolic strokes, they have a high risk of recurrence despite available treatment options. Is this correct, Mike?

Mike Sharma

Yeah, absolutely. So, you know, we made a lot of advances in cardioembolic stroke, principally through the development of DOACs, which are overall safer agents, much easier to use. And they result in a reduction over placebo in patients with atrial fibrillation of over 60% in the risk of recurrent stroke. The same, however, doesn’t apply to non-cardioembolic ischemic stroke. Now, it’s important to note that non-cardioembolic strokes are the majority, somewhere around 75% to 80% of the strokes that we see, and yet for the past 50 years, with the exception of short-term dual antiplatelet therapy, our main option has been aspirin. Aspirin initially and aspirin that continues indefinitely. Aspirin is effective, but only modestly so with relative risk reductions for stroke somewhere around 20%. So, you know, we’ve lived with this situation now for about 50 years, and really we need better options. Valeria has laid out very nicely the high recurrence risk, and that recurrence risk is highest early on, then second highest in the first year, and it comes down, but it never returns to baseline. So patients who have an event are always at an increased risk for recurrence.

Aristeidis Katsanos

Thank you so much, Mike, for the detailed overview and highlighting the significant risk of stroke recurrence in this patient population. Not only do we have cardioembolic and non-cardioembolic stroke, but there is also a population which is called strokes of a determined source, commonly known as ESUS. Peter, what is our current understanding of this patient population based on the recent data that we have?

Peter Kelly

Yeah, so thanks very much, Aris. So the ESUS concept was first introduced back in 2014 by Professor Hart and colleagues, and it was really a positive construct to try to address this very large proportion of patients, right about a quarter of all patients with ischemic stroke for whom no high-risk source was identified. And previously in classification schemes like the TOAST scheme, these had been referred to as cryptogenic stroke. But cryptogenic stroke is a kind of a, it’s almost a negative or a neutral term. Whereas the ESUS term was, the ESUS concept was that these strokes were caused by embolism. And patients meeting the criteria of non-lacunar stroke without a high-risk cardioembolic source or without extracranial or intracranial atherosclerosis of 50% or greater would be defined as ESUS. The hypothesis then was that given that these were caused by emboli, that antithrombotic agents and in particular direct oral anticoagulants might be effective in secondary stroke prevention in this category of patients. So this hypothesis was tested first in the NAVIGATE ESUS trial, then in the RE-SPECT ESUS trial, and both trials were neutral. Together, they randomized about 13,000 patients. And in the NAVIGATE ESUS trial, which compared rivaroxaban at a dose of 15 milligrams daily to aspirin 100 milligrams daily, there was an excess of bleeding seen in the rivaroxaban arm. So that really slowed, I think, the enthusiasm for testing directorial anticoagulants in this population. So I think the take-homes as things currently stand, at least in my opinion, are firstly that the concept as proposed by Bob Hart and colleagues way back over 10 years ago now remains valid. There is a very large amount of excellent observational data to support the construct that was put forward in the original article. But I think direct oral anticoagulants for unselected patients with ESUS is probably not the way to go. And we need to do a better job, perhaps, of selecting outpatients with ESUS for whom antithrombotic therapies other than aspirin may be effective. So recently, there’s been a lot of focus on the concept of atrial cardiopathy, which has been independently associated with embolic stroke in patients with ESUS. And we’re beginning to see some initial trials testing markers of atrial cardiopathy without atrial fibrillation and testing direct oral anticoagulants in those populations.

Aristeidis Katsanos

Thank you so much, Peter. When we think of secondary stroke prevention, we actually tend to think only of ischemic stroke overlooking hemorrhagic stroke. Ashkan, what are the unmet needs in this patient population?

Ashkan Shoamanesh

Thanks for, I think, a question that we should be asking ourselves more and more as we think about medicine stroke as a whole. On the one hand, beyond blood pressure lowering therapy or chronic treatment of hypertension, we’ve made very little advances in terms of the prevention of recurrent ICH, and those are ICH survivors. But we should also acknowledge that what we’ve learned mainly over the past decade, although, of course, there was early literature suggesting this as well, is that ICH does not beget only further hemorrhage, but also begets further thrombotic events. And that patients with ICH have a high rate of thrombotic events, such as ischemic stroke, in addition to the risk of recurrent intracerebral hemorrhage. And literature-based estimates put that anywhere about 1% to 10% risk of recurrent ICH, as well as 1% to 10% risk of ischemic stroke. And there was a nice meta-analysis published in the International Journal of Stroke earlier this year, demonstrating that across roughly 200,000 patient aggregate data, that the rate of major adverse cardiovascular events, putting all ischemic and hemorrhagic events together, was about kind of 5% to 15% annualized rate. When looking at recurrent ICH and ischemic stroke in isolation, they were actually very equivalent, about 2% annualized rate. So very similar trade-off. Now, there is some individualization there. For instance, in patients with AFib, the risk of ischemic stroke predominates over ICH. In patients with lober ICH, particularly the cerebral amyloid angiopathy, the converse is true. The rates of ICH predominate over ischemic events. And this is all about all intracranial hemorrhage survivors. But it does really highlight a major unmet need, particularly when thinking, for instance, regarding some of the strategies we currently use to mitigate thrombotic events, such as antithrombotic therapies, lipid lowering therapies, that can have offsetting harm by increasing the hemorrhagic stroke side of that equation, and how best to balance the overall holistic net benefit with these strategies.

Valeria Caso

Regarding the point that Ashkan made, I think we… What we did in all this last 20 years in also improving all the stroke prevention strategy, the stroke prevention, the stroke treatment, that we split too much, as you said, the identities, the two identities, hemorrhagic and ischemic stroke. We are talking about vessels. And vessel can, in the same time leading atherosclerosis can lead to rupture. It can lead to thrombosis. So we have to think globally to protect the vessels. And this is something that we have to learn, especially we have to be probably more bright also to using antiplatelets after bleeding. I’m not talking about anticoagulants because Ashkan put us in a deep crisis after the publication of the trial. But at least to have this whole vascular protection, especially after intracerebral hemorrhage, this will reduce clearly recurrence.

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Aristeidis Katsanos

Thank you so much, Valeria, for this excellent comment. And you mentioned about antithrombotics and anticoagulants and the net benefit, right? So as already put forward by Ashkan. So I would like to ask you that there are so many unmet needs, right? And we’re always looking for safer antithrombotics so that they can reduce the risk of ischemia, vascular events, without increasing the risk of bleeding. So factor XI inhibition was tested for stroke prevention in patients with atrial fibrillation about the population actually that, you know, that we’d like to hear your thoughts on. And can you explain a little bit on the rationale and the findings of the trials completely in patients with AFib?

Valeria Caso

 Yes, thank you for this question. We know that in Ashkenazi Jews, there is where the factor XI deficiency is widespread. There is a lower risk of having thrombotic complication without a higher risk of bleeding. So factor XI in the chain of the coagulation, it’s involved in the intrinsic pathway. So, it amplifies. So, the anti-XI stopped the amplification of the thrombotic event without interrupting what is the hemostasis. So, factor XI is what we always say, uncoupling thrombosis from hemostasis. And this is something that, especially as neurologists, where we often have to handle a condition like the brain that is more prone to bleed compared to the heart, is what we call the holy grail.

Aristeidis Katsanos

Thank you so much, Valeria. So, factor XI inhibition has also been tested after a non-cardioembolic stroke with the first trial showing both the results. Mike, are factor XI hipers ready for clinical use in that setting? And I mean, a non-cardioembolic stroke, secondary stroke prevention in those patients?

Mike Sharma

Well, Aristeidis, the clinical trial results are quite compelling and making the case for clinical use of these agents. Just, you know, an introduction to how the trial was designed. It really went on the dual pathway approach, which is a combination of antiplatelets and agents that affect fiber in that position in doses which do not cause an unnecessary risk of hemorrhage. So these two agents, asundexian, for which we have Phase III trial results, and milvexian, where the Phase III trial is ongoing, had doses developed in stroke patients. Now, that seems straightforward and obvious until we realized that all of the antithrombotics you and I use had doses developed in a DVT model. It’s not surprising then that they don’t always work for stroke patients and aren’t always safe in our patients. So these two trials, PACIFIC and AXIOMATIC, were the first Phase II trials done in stroke patients to find a dose of an agent that was safe in stroke patients. With asundexian, we arrived at a dose of 50 milligrams once a day. And with that, we designed the OCEANIC-STROKE trial to examine the efficacy and safety of this agent and stroke patients. We enrolled over 12,000 patients who had either acute non-cardioembolic ischemic stroke within the last 72 hours, and those stroke patients could have an NIHSS of up to 15 or high-risk TIA, which was defined as an ABCD2 score of 6 or 7. Those patients were followed until we had enough events to design on the efficacy. The efficacy outcome was ischemic stroke, and asundexian reduced the occurrence of ischemic stroke by 26%, a hazard ratio of 0.74. Now, very nicely, and in keeping with the theoretical basis, what we had seen with factor XI deficiency genetically, there wasn’t an increase in ISTH major bleeding. And we saw similarly sort of intracranial bleeding, intracerebral bleeding, and even minor bleeding. Minor bleeding being very important to patients as a result of anxiety and very often causes them to stop their medication. Now, you know, so I think those results are really quite compelling, especially when you consider that asundexian was used on top of antiplatelet therapy. So the treating physicians decided on dual antiplatelet therapy or single antiplatelet therapy at the outset and follow clinical criteria for the duration of the dual antiplatelet therapy. In spite of that, no increase in bleeding, no matter how we defined it. So I think that makes quite a compelling clinical case for its use in patients. It’s one thing where we’re going to have to change our thinking to date. Even for dual antiplatelet therapy, the approach has been to eliminate those patients who have a hazard of bleeding and to treat patients who don’t have a hazard. And with these agents, I think we’ll have to think quite differently. LIBREXIA-STROKE, which is a phase three trial with milvexian, is ongoing. We do not, as of today’s date, know when that trial will end, though we hope it’s soon. And we hope those results are positive as well.

Ashkan Shoamanesh

In terms of the direct clinical applicability to the bedside and whether we’re ready for it, one major advancement that had occurred just in the past 24 hours is that the first regulatory approval of asundexian has come through in China. The NMPA has approved asundexian for this indication. This is the first time a factor XI inhibitor has received approval for any indication on the basis of the OCEANIC-STROKE results, and we anticipate that additional regulators around the world will follow.

Aristeidis Katsanos

Thanks, Ashkan. That’s very useful information. And I would like also to pick up your brain because Valeria presented the results of clinical trials published so far in atrial fibrillation testing factor XI inhibitors, and they were neutral to date versus the positive results, overwhelmingly positive results presented to date in factor XI after a non-cardioembolic stroke by Mike. So what do you make of it? So that’s the first part of my question. And the second part is whether you think there are any other avenues except for antithrombotics to mitigate the stroke risk in patients with atrial fibrillation.

Ashkan Shoamanesh

Thanks, Aristeidis. So you can imagine we were conducting OCEANIC-STROKE and we hadn’t completed the trial with the OCEANIC-AF results had read out. And we, Mike and I, thought about this carefully and really we never broke a sweat, to be entirely honest, because of several factors. The first was that in Phase II, there was always indication of an effect on the outcome of the ischemic stroke in the non-cardioembolic ischemic stroke trials. Whereas we never saw that in AFib, in that even if you think about the monoclonal antibody studies that compared against rivaroxaban, this was an abelacimab, two doses of abelacimab versus rivaroxaban. Numerically, although the trial was small, it wasn’t meant to look at efficacy. Numerically, the rates of ischemic stroke weight against the factor XI inhibitor. And this was also true in the PACIFIC-AF trial that preceded OCEANIC-AF. And whereas in contrast in Phase II, we had actually very dear signals of efficacy that were consistent between the PACIFIC-STROKE and AXIOMATIC-SSP studies. So then the question is, well, why? There’s two possible, I think, leading explanations. The first is that obviously there’s a different underlying substrate. In secondary stroke prevention, we’re going in patients with non-cardioembolic ischemic stroke, whereas in patients with AF, we’re thinking about cardioembolic stroke and whether there may be any differences in there. However, that argument would go against the Medallion randomization data that has consistently demonstrated a strong relationship between polygenic risk scores that drive higher rates of factor XI and risk of cardioembolic stroke. So I personally gravitate more to the second explanation, and that’s really the comparative. In OCEANIC-STROKE, our comparator was a non-active comparator. We compared asundexian to placebo on top of background antiplatelet therapy, and actually also capitalized on this dual pathway inhibition that Mike spoke about earlier. Whereas in OCEANIC-AF, asundexian was compared to a very effective and safe DOAC, and that was apixaban. So there, there wasn’t efficacy or even non-inferiority for the outcome of ischemic stroke with asundexian versus apixaban. However, on the safety side, it’s worth noting that there was an 80% reduction in hemorrhagic stroke with asundexian versus apixaban. Apixaban, as you know, was previously compared to aspirin in patients with ischemic stroke, such as the ARCADIA trial, in patients with AF, such AVERROES or ARTESIA. And in those settings, the rates of intracranial hemorrhage were actually numerically less with apixaban versus aspirin. And yet in OCEANIC-AF, we see an 80% reduction in intracranial hemorrhage with the asundexian dose being treated used in SSP against apixaban, which indirect comparisons, prone to faults, but indirect comparison suggests that asundexian at this dose may be even safe for the aspirin. So where I think there’s a lot of promise for factor XI inhibitors in AFib on the basis of the Mendelian randomization data is in comparison to a non-active comparator. And there is a trial of abelacimab ongoing right now called the LILAC trial, which is testing abelacimab versus an inactive comparator in patients who are unsuitable for anticoagulation. And I would bet quite highly that that would be a positive trial, but of course, time will tell.

Now, what are our current other kind of strategies that we can incorporate? Well, there’s a lot of interest in combining mechanical therapies with anticoagulation as an alternative strategy, particularly in patients who have had breakthrough strokes despite anticoagulation. This really stems from observations of a trial that was led at our PHRI, our colleagues Richard Whitlock and Stuart Connolly, called the LAAOS III trial. In this trial, patients undergoing open-heart surgery, either for valvular disease or coronary artery disease, who had a for randomized to have surgical ligation or excision of their left atrial appendage versus not. The majority of this population, over 80%, remained on anticoagulation on both arms. And it was observed that the left atrial appendage surgical excision or ligation group had about a 30% reduction in stroke above and beyond kind of the background anticoagulation. So this has really led interest in whether mechanical treatments added to anticoagulation can provide further stroke prevention. Of course, the majority of AF patients do not undergo open heart surgery. So the generalizability of that trial is fairly limited. But percutaneous left facial appendage occlusion is more widely available. And there are trials such as ELAPSE, as well as LAAOS-4, where in the latter, kind of 30% of the baseline participants thus far have a history of stroke. And in ELAPSE, all patients require part of history of stroke, trying to address this question. I would, however, caution our colleagues not to just jump to the conclusion that the results of LAAOS III are necessarily generalized to percutaneous LAAO. It’s tempting, but the reality is in LAOS, there’s a couple of nuances to appreciate. One is that in LAAOS III, there was no prothrombotic device being exposed to your circulation. You did not have an appendage occluder and expose this to the blood flow in the heart. This was a surgical excision ligation treatment. In addition, in LAAOS III, everyone is undergoing surgery. The perioperative risk was balanced between the two treatment arms, right? Because everyone was undergoing open heart surgery. Whereas when you’re testing the paradigm of percutaneous LAAO versus not, all the period procedural risks will be in the intervention arm. And that’s a very different paradigm than what the LAAOS III trial tested.

Another mechanical treatment that we’re very excited about is the Vine carotid filter system, which is a novel filter system that gets implanted in the common carotid arteries through a percutaneous procedure involving a very fine 22-gauge needle. And this filter is designed to prevent a large emboli, those 1.4 millimeters or greater in size, from reaching the anterior circulation. And because it’s not aiming to filter all clot sizes, it has a very unique kind of pigtail or helix design that allows it to provide filtration along the length of the filter without disrupting laminar flow or exposing the circulation to a prothrombotic surface. In Phase II single arm studies, we’ve seen some promising results that suggest an 80% reduction in large vessel occlusion strokes relative to similar natural history controls, as well as 30% reduction in all ischemic stroke. On the basis of those results and the reassuring periprocedural complication rates that we observed in those studies. We’re now conducting a large global trial called the INTERCEPT study. This is a superiority study comparing the Vine carotid filter system to standard of care anticoagulation. The filter will be used on top of anticoagulation for the prevention of LVO as well as ischemic stroke. And this trial is called the INTERCEPT study.

Valeria Caso

Just a question, Ashkan, regarding factor XI and AF, do you think it’s only due to the fact that there was a non-active comparator? So what we expect that in patients unsuitable, it will be positive. But thinking about the thrombosis, so all the LAA, the thrombosis, the embolization, do you think that the factor XI is really strong enough to protect our patients. Because we are very active, we have very good comparators. We have DOACs, which are, we can say, at an excellent level. So a new drug compared to DOAC would be very difficult to have a successful drug in this case.

Ashkan Shoamanesh

I think you’re right, Valeria. So I guess your question is about the underlying substrate and also the potency of the comparators. Regarding the underlying substrate, there are some hypotheses that perhaps the degrees of tissue factor may be higher in the left atrial appendage. And certainly, we know that factor XI inhibition will provide greater benefit in mitigating thrombosis in relatively lower tissue factor states. Having said that, I go back to the Mendelian randomization and data demonstrating this very strong correlation between factor XI levels and cardioembolic stroke. So some other potential questions that I think we’ll learn more about what the completion of the LIBREXIA-AF trial is whether dosing played a role. And the LIBREXIA-AF dose of the factor XIa inhibitor is going to be about four times as potent as the one tested in OCEANIC-AF. And then I think really combination treatments warrant consideration as well. For instance, I think the dual pathway inhibition combining factor XI inhibitors with antiplatelet therapy likely lead to an additive or synergistic effect that can also play a role in anticoagulants. And their safety really create a compelling case that maybe we can even combine them with other direct anticoagulants like factor Xa or direct thrombin inhibitors. And that remains to be seen as to whether the… I think it just takes… It’s going to take time to get the right recipe to practice that. But I think it is going to happen over time.

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Aristeidis Katsanos

Thanks so much. That’s excellent discussion. And thanks for sharing your thoughts. I’d like to say a little bit more on alternative pathways, I mean, beyond antithrombotics. And I would like to come back to you, Peter, and ask you about inflammation. Do you think it’s a tangible target for secondary stroke prevention? What are your thoughts?

Peter Kelly

Absolutely, Aris. I strongly, strongly am of the view that it’s a very compelling treatment target for secondary stroke prevention. So over the last 30 to 40 years, there has been a very large literature developed, both experimental and clinical, implicating inflammation in the initiation and the development and the destabilization of atherosclerotic plaque. Specifically in stroke, we see multiple lines of evidence triangulating through, all pointing towards the same direction. So we have experimental studies that I mentioned in athero. We’ve got genetic epidemiological studies and Mendelian randomization studies of polymorphisms and various pro and anti-inflammatory genes, blood biomarker studies, clinical pathological correlation studies with resected carotid plaque. And we even have some imaging studies using validated non-invasive markers of inflammation such as FTG PET uptake in the carotid. And we have the example set in the cardiology field where two compounds to date, canakinumab, an interleukin-1 antagonist and colchicine, a microtubule inhibitor, have both been independently associated with a reduction of major adverse cardiovascular events in patients who survived a coronary event. So we really have a compelling rationale, both from observational data and clinical trials in non-stroke populations, pointing us in this direction in the setting of stroke.

So we’ve had, to date, we’ve had two clinical trials completed in stroke populations. We’ve had the CHANCE-3 trial. CHANCE-3 used colchicine, generally given within 24 hours of stroke or high-risk TIA onset. And the target for CHANCE-3 was early stroke recurrence. And CHANCE-3 was a neutral trial conducted exclusively in patients in China. And personally, my view is that it was unlikely, in my opinion, that CHANCE-3 would have been positive from the beginning because the hypothesis being tested there was that acute anti-inflammatory therapy would somehow prevent very, very early recurrent ischemic events. And we know from many studies that these are primarily related via recurrent thromboembolism rather than inflammation. The other strategy is for late secondary stroke prevention and late MACE prevention. And we tested this in the CONVINCE trial. So in CONVINCE, we used 0.5 milligrams of colchicine in patients with non-cardioembolic stroke, randomized between 72 hours and 28 days, and compared with standard of care alone. There was no placebo in CONVINCE. Unfortunately, CONVINCE ran up against the COVID-19 pandemic. And although we met the pre-specified sample size in the trial, we had about a 10% limitation on the duration of follow-up that was pre-planned for the preset sample size. So there were 338 outcomes in CONVINCE and we needed about 360. The direction of effect of colchicine in CONVINCE favoured, sorry, the direction of effect for the primary outcome on ITT analysis favoured colchicine and the result was significant on treatment analysis and on a range of secondary exploratory and subgroup analyses. There are multiple signals suggesting efficacy of colchicine in high-risk individuals in CONVINCE.

So the current situation is that there are a number of trials ongoing and planned. Probably the largest of these is the CHANCE-3 EX trial, which is ongoing in China and which has randomized about 7,000 patients of all ischemic stroke subtypes, not restricted to patients with atherosclerosis alone. CHANCE-3 EX will read out, I would expect, in late 2027, early 2028. There are two smaller trials going on. There’s the RISC trial and the CASPER trial in France and in Australia. I think these will provide valuable information, but they are significantly smaller than other trials. And we are currently planning the CONVINCE-2 trial, which will be placebo controlled, will have a run-in period to minimise discontinuation due to intolerability and will focus on patients with atherosclerosis at baseline. So hopefully we will have an answer to the colchicine question and stroke quite soon. In the meantime, meta-analyses suggest about a 25% relative risk reduction for the outcome of stroke when stroke patients are combined with coronary patients. So a lot of exciting signals pointed towards colchicine at this point in time.

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Aristeidis Katsanos

Thank you so much, Peter. Not only there are many exciting interventions in the pipeline tested in clinical trials, but let’s move from the actual testing of the interventions in clinical trials to the implementation in clinical practice. What are the opportunities and challenges you see, Valeria?

Valeria Caso

Yeah, this is, I said from the beginning that for me, the implementation side is what I’m mostly interested in because we can do our best research, we can do our best trials. But if we do not bring the evidence to the patients or from our academic institution to the real world, then we are not where we want to be. So first of all, what I learned that we did is consensus together with the patient organization to create an alliance together with the patient organization to say there’s an unmet need. Because often what, you know, when we talk about stroke, we are very focused on the acute phase and we did all what we could do on the acute phase. We did, we measure, we have parameters, we have key performance indicator for the acute phase. When you’re coming to the secondary prevention, we do not have the same structured way of dealing with stroke disease on the long run. And this is something that needs to change because we know that secondary prevention by our colleagues from cardiology is taken very seriously. They have controls three months, six months, one year, two years. It’s clear our community is smaller. We need probably to delegate other specialists or involve them, what we call it is multi-special team because, you know, when you have a stroke patient on the long run, you have to take care of his or her cognition. All the neurological and neurological complications, it means everything has to be structured. But for this, you need the patients on your side. They have to come out. They have to ask for it together because as doctor, every doctor thinks that his or her pathology is the most important. But it’s not if you go into the stakeholder, you have to say this is an opportunity to have healthier people and patients. We prevent. We have to show the economic model, health economic models that preventing strokes, it brings money, there’s a return of investment. So I think there’s a lot of work to do. And this cannot only be done by us, but also together with the patients.

Aristeidis Katsanos

Thank you so much, Valeria. So sometimes clinicians, healthcare providers, they come up with some reasonable questions. So they say that, you know, there are very strict inclusion and exclusion criteria in the clinical trials and the intervention hasn’t been tested for a couple of years, right? So does it make sense to use this intervention for my patient, the patient that I have in front of me, which may not be very similar to what was tested in the clinical trial, and use this intervention lifelong, for example, not only for two or three years that was tested in clinical trials. So, Mike, what are your thoughts? How would you respond to those questions?

Mike Sharma

Yeah, so, you know, I think that some of them are legitimate concerns, but we really do have to think carefully. Trial entry criteria are not criteria which are useful in judging who the results apply to. Trial entry criteria are rather like a letter to Santa Claus. It’s a wish list. Table one, which is the baseline data that is what’s actually under the tree Christmas morning. That’s what you actually have in the trial. So if you want to decide who these results apply to, look at table one, not the trial entry criteria, and they’ll let you know the range of people that were there. The second important principle for people to remember is that the best estimate for any subgroup is the overall estimate in the trial. If you think there is a reason why treatment of factor safety might be different, that forms a hypothesis which may be tested later on. Now, you know, I frequently hear this, well, it’s only been a couple of years. The truth is we don’t have 10-year, 20-year trials in any therapeutic category. Patients are on statins for decades. The trials lasted a few years. And there are good reasons for this. So in a trial like OCEANIC, once you have a result, once you have evidence that one arm is better than the other, it is unethical to keep randomizing patients to what you now know is an ineffective arm. And at some point, that trial has to end. The important question of rare adverse effects that you see only when you’ve treated a million patients, you won’t see in a trial. That you’ll see really in follow-up after the medication has been approved, as it’s in use. So surveillance systems then become very important. The other thing is some knowledge of relatively rare occurrences. One of these is the use of thrombolysis and the presence of factor XIa inhibition, specifically with asundexian. And I think that takes a special dedicated data collection after the medication has been approved. We might have our theories on how this works, but important to find out by observing what happened to patients who are thrombolysed while they’re taking factor XIa inhibition. You know, one other thing I will suggest to you is what you get from a trial which eliminates biases and unknown confounders is better than what you’ll get from even very good observational data. Just as an example, the Mendelian randomization study suggested that factor XI inhibition would not be effective in small vessel occlusion, and yet it is. So in our OCEANIC trial results, we see good efficacy across the range of major TOAST subtypes. We randomize people up to 72 hours, and the question arises, can you treat or initiate treatment after this? Looking at the cumulative incidence curves, that separation just continues, suggesting that the effect isn’t lost, unlike the dual antiplatelet trials, and can be used afterwards. Now, in terms of long-term efficacy, it would be peculiar to think of an antithrombotic that suddenly loses efficacy, and I think that’s unlikely on a biological basis. The absolute benefit may change with time, and that much is true, and that we would have to watch for. So, you know, I think a large, well-done clinical trial provides a good basis for making clinical decisions. A lot of the long-term questions, questions about rare events, really have to do with, or really we have to discover by doing follow-up over the long term while the medication is in use.

Aristeidis Katsanos

Thank you so much, Mike. That’s very insightful. So it is not the case, actually, that many of the interventions we use, although we’re testing in clinical trials, they have a benefit and not a harm. When you have that, as in OCEANIC-STROKE, we can deliver a very clear and powerful message. The reality is that most of the interventions we use in our everyday clinical practice and also the interventions we test in clinical trials, what you do see is a beneficial effect that comes with some concerns, with some safety risks or some downsides. The question is how easy it is to deliver that message and how you can actually inform a clinical practice and pass those messages of the clinical trials to the physicians that they’re practicing. And Ashkan, you recently presented the ENRICH-AF trial, and you alluded to the results of this trial, you know, showing a reduction in ischemic stroke risk, but increase in intracranial hemorrhage with anticoagulation after intracranial hemorrhage in patients with atrial fibrillation. So what are your thoughts and how easy it is to deliver the message to clinicians and healthcare providers?

Ashkan Shoamanesh

The first kind of message and take-home point from ENRICH-AF is that we cannot necessarily assume that what we see in safer populations, such as those trials that were conducted in populations where prior intracranial hemorrhage were excluded, necessarily generalizes to patients who are higher risk, and in particular those with intracranial hemorrhage. So as you indicated in the ENRICH-AF trial, we identified that the overall effect of standard dose of edoxaban, 60 milligrams, dose adjusted to 30 milligrams daily on the primary efficacy endpoint of stroke or systemic embolism, stroke encompassing both ischemic and hemorrhagic, was neutral. And the devil was into the details. There was about a 43% reduction in ischemic stroke, but this was offset by a three-fold increase in hemorrhagic stroke. We additionally saw a two-fold excess in our primary safety endpoint of ISTH major bleeding. And this held true for both intracranial hemorrhages and non-intracranial major bleedings. And concerning, there was a four-and-a-half-fold excess risk of fatal bleeding with edoxaban versus non-anticoagulation medical therapy. A couple of nuances that are worth appreciating in our trial was that the control arm consisted of either no antithrombotic therapy or single antiplatelet therapy at a discretion of the clinician, and about 52% of the population was selected to receive single antiplatelet therapy as part of the control arm. And then once two-thirds of the population had been enrolled, the safety review by the DSMB led to exclusion of patients with lober ICH or convexity subarachnoid hemorrhage, where the DSMB identified what they termed an unacceptably high risk of recurrent intracranial hemorrhage with patients assigned to the edoxaban arm. When we look at the rates of intracranial hemorrhage stratified by ICH location, we see that the annualized rate of recurrent ICH and the lower ICH or convex subarachnoid group, which, of course, in a population where the average age is close to 80 years, is predominantly due to underlying cerebral amyloid angiopathy, that the rate of recurrent IH was about 7.5% on edoxaban versus about 3.5% in the control arm. And I think the more concerning statistic is that close to 90% of the intracranial hemorrhages occurring on edoxaban in the subgroup were fatal, whereas none of the bleeds occurring in the control group in this subgroup were fatal. In contrast, in patients with subdural bleeds or non-lower ICH, the annualized rate on edoxaban was about 2.4% versus 1.1% to 1.2% in the control arm, and the proportions leading to death were similar between the edoxaban and control arms. So overall, really, our trial suggests that in unselected intracranial hemorrhage survivors with atrial fibrillation, standard dosing anticoagulation with edoxaban does not lead to net benefit, but really that individualized treatments, perhaps such as selecting safer subgroups of intracranial hemorrhage survivors, such as those arising from hypertensive arteriopathy or arterial sclerosis, and there may be benefit. And something else we identified in a subgroup analysis worth discussing is that for our primary safety endpoint, we identified the significant heterogeneity on the basis of indicating either the 60 or 30 milligram dose of edoxaban. All the excess and ICH major bleeding was observed in those that indicated the 60 milligram dose as opposed to the 30 milligram dose. This is tempting to suggest that 30 milligram dose may be a favorable option in this population or a lower dose of a DOAC. The overall treatment effect at a primary efficacy endpoint and those who indicated a 30 milligram dose suggested maybe a 30% reduction in the composite endpoint of stroke systemic embolism. Having said that, it’s worth noting that we did not randomize patients to receive the 60 or 30 milligram dose, and it may just be baseline imbalances that led to indicating one dose over the other and that led to these differences that were observed. So that is a hypothesis-generating observation, certainly not a definitive result to guide practice.

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Aristeidis Katsanos

Thank you so much, Ashkan. These are very important points, and thanks for all the insights into the ENRICH-AF trial. As we’re reaching to the end, Peter, I would ask you, as I always ask in our previous webinars, if you can kindly summarize the three most important takeaway messages from these webinars for our listeners.

Peter Kelly

Delighted to do so, Aristeidis. I think it’s a really exciting time to be in the field of secondary stroke prevention. I mean, we’ve heard in the discussion over the last little while about several new avenues, really promising avenues and different ways of thinking about our patients to improve the prevention of further cardiovascular events in them. So probably closest to clinical application at this point are the factor XI inhibitors and a really promising therapeutic avenue there. And as Ashkan mentioned, I think over the next decade, I’m very confident we’ll work out the right recipe of these for patients with different stroke subtypes. I think inflammation is a brand new area to target. We’re just scratching the surface of it at the moment in patients with stroke. And I should also, of course, comment on the COVASC-ICH trial, which is looking at anti-inflammatory therapy for late secondary prevention in patients with hemorrhage. And speaking of which, I think the shift in our thinking in recent years, where we are starting to think of patients who survive an intracerebral hemorrhage holistically and in the round as being both at risk of further hemorrhagic events, but also ischemic events, is a really important change in the way we are thinking. And again, opens up the possibility of testing many different candidate prevention agents in this group of patients, which I expect will lead to real benefits down the road. And finally, for ESUS, I think we need to do better in terms of selecting outpatients who may benefit from direct oral anticoagulants, but also perhaps factor XI inhibitors. So this will be a really exciting area to watch in the coming years.

Aristeidis Katsanos

Thank you so much, Peter, for this comprehensive summary. So in today’s discussion, our experts highlighted the unmet needs in secondary stroke prevention, presenting novel treatments currently being evaluated in clinical trials, and also discussing the opportunities and challenges of implementing new therapies for stroke prevention in clinical practice. Thanks to all of you, our panelists, for the insightful and engaging discussion. But most importantly, thank you for all of us joining today and looking forward to see you in our next webinars. Thank you so much.

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Aristeidis Katsanos: Research Grants from HSFC, CIHR, Brain Canada, HHS, HAHSO; Consulting fees for Diamedica Therapeutic Inc and Bayer Inc.

Ashkan Shoamanesh: Co-PI of OCEANIC-STROKE sponsored by Bayer AG; PI of ENRICH-AF, an investigator-initiated study with unrestricted grant-in-aid from Daiichi Sankyo, LTD.

Mike Sharma: The OCEANIC-STROKE trial was funded by Bayer. Funds were paid to my institution. I have served as a consultant to Bayer.

Peter Kelly: Advisory boards: Bayer, Novartis.