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It's a great pleasure to be here and to be able to share with you the exciting results of the specific stroke trial and think through with you its uh potential application in clinical practice. Should the results be confirmed in larger trials currently underway? Here are my disclosures and let's begin with a case. A 71 year old man awoke from sleep with left-sided weakness. Uh He arrived in uh by ambulance eight hours after last known. Well, and he has vascular risk factors of hypertension hyperlipidemia, uh no prior antithrombotic therapy, an N A stroke scale of three with mild face and arm paras and on the left and has this small right cortical lesion uh and in the right internal carotid artery, uh about a 50% atherosclerotic plaque. And uh what is the best approach to antithrombotic therapy in this patient? Well, uh the standard approach currently is to increase statins to maximum intensity, to treat with permissive hypertension for the 1st 24 hours and then resume BP control and to give aspirin plus clopidogrel uh for 21 days, the period of the greatest increased risk. And uh then monotherapy often with aspirin alone thereafter. And in this patient on the state of the art regimen, he had a recurrent stroke at day six. And we uh know that uh the uh rate of recurrent stroke in the active double antiplatelet therapy arms of the clopidogrel plus aspirin trials. Although statistically significantly and clinically importantly, lower than with aspirin alone still is substantial. Uh if the this regimen does not eradicate the occurrence of uh recurrent ischemic stroke. So with that, let's turn to the specific stroke phase two trial led worldwide by Doctor Sharman and Hart and published in the lancet in 20 22. The key design aspects were patients were over the age of 45 no upper age limit within 48 hours of onset of a noncardioembolic ischemic stroke. And we're planned to receive long term antiplatelet therapy uh because they had an indication for um for antiplatelet treatment, patient severity. In the first part of the trial was uh kept to uh patients with uh mild strokes and I stroke scales less than or equal to seven. it's a little bit more severe than just less than four or five as in some other trials. Uh but still um mild strokes and patients could not have received intravenous thrombolysis or endovascular thrombectomy. Then when uh uh safety analysis of the 1st 829 patients was completed and showed a very good safety record. In the second part of the trial. The last 979 patients. Uh The uh enrollment criteria were relaxed and you could get in if your anti-stroke scale was less than or equal to 15. Now, adding patients with moderate strokes to those with minor strokes and you could get in if you had been treated with intravenous thrombolysis or endovascular thrombectomy with a 24 hour interval. Since uh the reperfusion therapy, the treatment was continued for 6 to 12 months. So this is not just a short term trial but um uh a short and intermediate term trial and the conto concomitant therapy um uh for which the agent was added onto was standard antiplatelet therapy, which as we know can be double antiplatelet therapy or single antiplatelet therapy. And if it was aspirin plus clopidogrel, then that had to be used only for the first few weeks. So, uh this is a trial that tested cripple antithrombotic therapy in some patients who received two antiplatelet drugs. And this anticoagulant agent, the primary efficacy endpoint was symptomatic ischemic stroke and covert brain infarcts detected by MRI. So, um it's both overt and covert uh ischemic strokes and the primary safety endpoints was um standard uh definition of major bleeding plus uh bleeding that required a clinical encounter even though it was, did not meet uh the major bleeding criteria. And here is designed this as a phase two was a dose ranging study to determine uh both um you know, proof of uh uh evidence of uh potential benefit of the agent and also the best dosage to take on to a phase three trial. The doses were um 10 mg a day, 20 mg a day and 50 mg a day um as well as a placebo arm. So four arms each with about 450 patients, 1808 patients were enrolled at 100 and 96 sites in 23 countries. So this was a global uh and for stroke studies, a very large phase two trial for the primary efficacy outcome. Uh as you see here, there was not an observed effect, but these outcomes were driven by the MRI uh covert infarcts. And those very small infarcts may have different mechanisms of uh um pathogenesis than overt symptomatic infarcts when you look at actual clinical events, um recurrent stroke ischemic stroke or TI A was uh by point estimate reduced in all the dosage groups and statistically uh significantly reduced in the 50 mg uh dose group. Um And you can see a nice dose effect with an hazard ratio reduction for the point estimate by 8% for the 10 mg dose, 26% for the 20 mg dose and uh 36% for the 50 mg dose. In contrast, here are the bleeding outcomes for uh the each of the doses and the uh placebo group. Um You can see that for uh major bleeding, there was a mild I indication of an increase. Um for all bleeding, no difference between placebo and the active arm and for hemorrhagic transformation, uh there was um i in the brain, no significant increase in uh bleeding, either uh petechial hemorrhage or major hematoma. So this appeared to be a agent that added to a pretty aggressive uh antiplatelet regimen was uh showing strong signals of reducing ischemic stroke without increasing brain hemorrhage, maybe a little bit more major systemic bleeding, but not an increase in brain hemorrhage. If we uh think about um the subgroups analyses of this study. Um because uh another goal of this study was to identify the best patient population to bring to the definitive phase three trial. So, um after um looking at a variety subgroups, um a uh three in particular um were uh showing magnified treatment benefits uh and important to carry on into phase three. One was the presence of having uh coronary or peripheral vascular disease um or a prior stroke or ti A. So, having established atherosclerotic cardiovascular disease, didn't need to be positive of the index stroke just had to have aro somewhere and those patients had a magnified evidence of benefit. Another one is having a uh cortical infarct uh or a large deep infarct. So, a embolic topography infarct uh and conversely, those with just small, deep infarcts showed less evidence of benefit from uh this therapy. So, uh uh suggestion that uh lacunar stroke patients should not be included in the phase three trial. And then uh the uh the particularly magnified benefit in patients with actual imaging evidence of atherosclerosis in the cervical cerebral tree, either extracranial or intracranial atherosclerosis. Uh here, uh nearly 50% hazard reduction. And uh again, evidence that uh this agent is effective, particularly effective when treating atherosclerotic disease over or or overtly. And so, um based on specific stroke refinements in the patient population were made uh to determine uh the pivotal phase three Oceanic stroke uh trial entry criteria. Patients with lacunar strokes um singly uh were dropped. Uh and by patients with embolic topography, strokes, medical history of Afro or imaging evidence of Afro uh went on into the currently ongoing oceanic uh stroke trial. Um So oceanic is testing three quarters of the patient population that uh were in Pacific still a very substantial group of patients. So, if oceanic confirms the signals of benefit, we saw in specific stroke, it's um intriguing to think about how this would affect our uh clinical practice. And I have about five scenarios where I think adding an agent uh uh like acid deum um would be particularly helpful in clinical practice. Should it uh hold up as an agent that reduces ischemic stroke without increasing or minimally increasing in interval hemorrhage? And uh one aspect is uh the patient with a moderately severe stroke and, and uh the on the left, you see a patient with a uh divisional MCA infarct, too large to qualify for double antiplatelet therapy. Um And with uh uh because uh it's causing a moderate, not mild deficit. And in the get with the guidelines, Stroke National Registry, you can see uh we reported a distribution of presenting N I stroke scales in the country. Um and most strokes are mild to moderate. Um uh 45% of patients meet one definition of mild and anti scale of 0 to 4 on presentation. Uh but 39% of patients uh meet the specific stroke uh entry criteria that are beyond mild uh an a stroke scale of 5 to 15. So uh being able to treat patients like this would double the number of patients in whom we could give more than monotherapy acutely giving aspirin plus acid dein rather than aspirin alone during that initial highrisk period. Another is uh using uh combined therapy rather than monotherapy for patients with embolic strokes of in certain source ESIs where we have embolic topography as seen on the left but uh no to level uh uh etiology that can be said to very likely be the cause and on the right, you see uh some of the many causes of ESIs and recent data have showed the three of these are particularly common atherosclerotic plaques that are nonstenosing, minimally stenosing. Uh are accounts for 20% of ESIs strokes. P fo accounts for 20% of otherwise cryptogenic stroke and overt atrial fibrillation accounts for 6% of ESIs strokes. And you can see that overt atrial fibrillation would best be treated with an anticoagulant. Um P fo medically, we're eventually going to go to closure in younger patients. But while awaiting closure and in older patients, an anticoagulant regimen is likely better than an aspirin regimen because of the venous stasis clotting source of the strokes. Whereas for the an atherosclerotic plaques, uh uh agents against atherosclerosis would be best. And we know that monotherapy with um just an antiplatelet agent or just a doac uh did not show one agent being superior to the other in ESIs strokes. And uh we, we have not explored uh combination therapy in part because of the concern about substantially increased bleeding risk, adding a doac to an antiplatelet. But with acid dei, we have the potential to be able to add an anticoagulant to antiplatelets without excessive bleeding risk. And uh also with some benefit for atherosclerotic plaques in addition to the entities that um cause uh uh clotting cascade uh uh thrombosis to uh cause stroke. Uh So uh this uh could be a broad cover all the bases, uh antithrombotic treatment strategy in the patient with ESIs. Another setting is patients with unstable carotid plaques. Um The so-called hot carotid when patients uh prevent with uh uh cervical uh internal carotid artery. Um aro that has caused a stroke, uh they need to, to go to a carotid revascularization procedure. Uh it's gonna take at least several days before that can be done. And if they've had a major stroke, the surgeon may wish to wait a few weeks. And, uh, but these are patients who have large unstable plaques, thin, ruptured fibrous caps lipid pools, um, and a high rate of early recurrence and may have a second stroke before getting into the or unfortunately, we can't use double antiplatelet therapy during this high-risk period. Uh because of the risk of bleeding when patients do go to the or and surgeons don't want them on uh DAPT um uh because of procedural bleeding risk. Uh but it's uh quite uh likely quite possible that Sinex N added to a single anticla agent would provide enhanced protection during this early period without uh increasing the perioperative bleeding risk unduly. And here is a setting for which there's a nice data out of the Pacific study it itself. And that is uh patients with cerebral microbleeds. And on the left, you see, uh far left is a patient with many microbleeds due to a hypertensive arteriopathy all deep now on the right, a patient with many microbleeds due the cerebral amyloid angiopathy, all superficial. Uh These are patients with a pretty extreme burden of microbleeds. Um In specific stroke, the analysis was conducted of patients who had any one or more microbleeds. So uh lesser burden than, than this and that was very common. Uh Just over one third of patients in the trial had one or more microbleeds. And of course, these patients uh especially when you get up to five microbleeds or more are at increased risk of brain hemorrhage whenever you intensify antithrombotic therapy with our current regimens. But in the trial, as you see here, um in red are the patients who had cerebral microbleeds. And in blue are the patients who did not. Uh and you can see the rate of intracranial hemorrhage was not any higher in uh patients who received the high dose as index in um added to their single or double antiplatelet therapy compared to placebo. Uh while the risk of ischemic stroke um was in a favorably reduced direction. Then uh the, the last setting I'll talk about is in the staple of our practice of preventing recurrent stroke after an initial minor stroke or a tia A. And on uh the left here is a graph of the uh frequency with which recurrent strokes occur over the 1st 12 months after uh the index event, uh looking at those with symptoms lasting more than 24 hours or less than 24 hours. But both of these show a very front loaded risk in the first one month. This curves climb sharply uh but then a steady ongoing risk thereafter. So in those 1st 21 to 30 days, because of the very high risk in uh double antiplatelet therapy is the standard therapy in um uh in minor stroke in ti a patients, but it provides incomplete protection in uh in pooled analysis of point and chance double anti therapy reduced to 21 day risk from 7.8% to 5.2%. Which is an important reduction. But it means that one in 20 patients were still having a stroke within the first month after the index stroke. So we're not eradicating stroke with this regimen. So there's potential for further improvement by adding acid de in to double antiplatelet therapy. And that would give you a cat strategy, cripple, antithrombotic therapy rather than adapt double antiplatelet therapy strategy. And uh could uh help to further reduce this early recurrent ischemic stroke without major bleeding. Then in addition, you can see that uh from one month to 12 months, there is still substantial occurrence of um follow-up events. Now, in addition to uh the high-risk period, patients remain at substantial risk for recurrent stroke between one month to 12 months as you see here. Uh and during this time period, single antiplatelet therapy set is the current standard therapy but also clearly provides incomplete protection. So we have uh we're not able to use DAPT in these patients routinely because of the bleeding risk in this time period, outweighing the ischemic stroke reduction benefit. But there's a potential for that double antithrombotic therapy to be used as in Duin added to aspirin alone or added to clopidogrel alone. Um And uh in order to provide an intensified antithrombotic therapy compared with a single antiplatelet therapy um with uh out a major increase in bleeding risk. So, uh returning to the patient with whom we started our talks, the 71 year old man who came in and received double antiplatelet therapy and had a recurrent stroke on day six. Uh hopefully, uh in the not too distant future, we'll be able to add a in de in to the regimen um both early and late and his outcome will be event free. So uh with that, I hope that uh you share my enthusiasm for the potential that this agent class offers. Um And thank you very much for listening.