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Thank you. It's a great pleasure to be with you for this uh uh presentation on this mainstay of neurovascular practice. I'll be talking about antithrombotic therapies to prevent second recurrent strokes with an emphasis on antiplatelet therapy. Here are my disclosures and to start broadly, we know that about four out of 55 out of six strokes in the US are ischemic, the others hemorrhagic and the major mechanisms of ischemic stroke are large artery atherothrombosis, small vessel lacunar disease, which also is usually intracranial branch atherosclerosis, cardioembolic P fo associated and other entities. And these uh causes of stroke uh have thrombus formation via two main pathways. The white clot and the red clot pathway. White clots are platelet rich with some fibrin strands and they form in settings of high speed dy laminar flow and shear stress. Those are settings in which platelets are activated and aggregate and are best treated for uh thrombotic component. With antiplatelet agents. Red clots are erythrocyte rich. They form in areas of stasis in the veins in the nonbeating atrium. In afib, the driving force is the clotting protein cascade and they are the most effective treatments are anticoagulants that block the cascade. OK. So if we uh think about the best way to uh approach stroke prevention uh for recurrent stroke, we in our diagnostic work up will determine the likely mechanism of the index event. And if we think it's uh atherosclerotic, then uh that's a setting in which we have rapid flow over an irregular surface and platelets will be activated and we'll choose an antiplatelet strategy if we think it is uh due to stasis clotting as in atrial fibrillation, um then we'll choose anticoagulation as our strategy and thinking about the atherosclerosis and antiplatelet indication. This is really quite common. If you think about all the sources of atherosclerosis in the cardiac aorto cervical cerebral tree, you can have uh blockages arising from a in the aortic arch, the origin of the great vessels, the cervical internal and vertebral arteries, the intracranial arteries and the intracranial branch arteries, small penetrating vessels. So, about 50 to 60% of ischemic strokes are due to recognizable atherosclerosis of substantial degree. In addition, there is emerging evidence that a substantial proportion of so called cryptogenic strokes that don't have a definite identified mechanism are due to atherosclerosis. We uh big atherosclerosis is the recognized cause of a stroke when the feeding vessel is 50 to 100% narrowed by a plaque. But studies like this one in the embolic stroke of uncertain source category have found that uh patients who uh have anterior circulation ESIs strokes, uh much more often have minor plaques on the side of the stroke than they have in the other uh side of the carotid. And uh from the frequency with which it's more common. Uh the attributable risk can uh be determined. And it turns out that about one out of five of all ESIs strokes are likely due to nonstenosing uh mild uh plaque in the carotid arteries. So that expands the indications for anti atherosclerotic antiplatelet therapy. Another important aspect about antiplatelet therapy is uh the timing of recurrent strokes. When atherosclerosis is etiology, uh plaques when they cause a first stroke are in an unstable condition. They've uh had a thin fibrous cap that probably has recently ruptured, they have a large lipid pool. They um there's inflammatory M MP nine activity and uh that unstable state will persist for the next days and weeks after the first event. And so we see it in the graph on the right, the timing of recurrence drugs is front loaded with a very high risk in the 1st 3 to 4 weeks and then a much lower risk thereafter. Therefore, it's desirable to be aggressive with therapies in the 1st 3 to 4 weeks. Uh when uh there's a high risk of ischemic events. Uh there's a of course a risk of hemorrhagic events whenever you use antiplatelet agents and that risk stays about the same uh throughout this time period after in the 1st 3 to 4 weeks, aggressive therapy is usually uh justifiable for minor strokes and ti A s because the uh rate of ischemic events prevented will outweigh the bleeding events caused. But beyond one month, the, with the standard agents that we have um very aggressive antiplatelet therapy should be avoided. Uh because the bleeding events will now outweigh the ischemic events prevented. Well, let's turn now to individual agent classes that affect the activated platelet. And we have four main classes that are in uh clinical practice. The oldest of co course is the cox one inhibitor aspirin. Uh The uh uh pyperidine P two Y 12 antagonist are a major class including clopidogrel and tag the phosphodiesterase inhibitors uh that are antiplatelet and also vasodilating closta zole and Dipridamole and the GP 23 blockers, which are only available in uh IV formulation. So, are not part of uh long-term secondary prevention practice with aspirin. Uh a very helpful meta analysis from uh Peter Rothwell has shown that uh it is uh quite effective in the high-risk period. Uh The uh reducing uh the risk in uh early trials uh by more than half 2.4% to 1%. Aspirin alone, interest uh intracerebral hemorrhage in this early time period was low, no increased hemorrhage with low dose aspirin below 100 mg and mildly increased uh in patients on high dose aspirin 300 mg or higher. Long term. The relative risk benefit is less um a 13% reduction with aspirin alone long term. Ok. The major side effects of aspirin are familiar to all of us. Uh gi side effects, um peptic ulcers, gi bleeding sometimes that can be good cause it unmasks uh colon cancer and leads to early detection, but often it is uh can be a very adverse event, skin bruising and bleeding elsewhere, systemically, uh and allergic reactions and of course the bleeding in the brain uh that we talked about in the just prior to slide. Yeah. Well, next turn to the next agents to come into uh practice and uh talk about uh the p pyridines. Uh clopidogrel has been studied mostly as an addition to aspirin. Uh the um uh and so we're comparing clopidogrel plus aspirin usually to aspirin alone. And in uh trials, testing patients with uh the high-risk early period where double antiplatelet therapy was given for three weeks to uh after the stroke, up to three months after the stroke. You can see there was a uh nearly 30% reduction in ischemic stroke. Uh But uh a increase uh in uh hemorrhagic stroke that was nearly significant overall, there was an important reduction in any stroke because the hemorrhagic strokes at an absolute rate are occurring less often than the ischemic strokes. Uh But there was an offsetting uh increase in major bleeding uh systemically. Nonetheless, uh the uh overall benefit in any s stroke prevention is a substantial over aspirin alone. And uh clopidogrel plus Aspirin is the mainstay of treatment of patients with minor ischemic stroke or ti a in the early period in the long term period. Uh the uh was not a statistically significant benefit in reducing any stroke. Uh There was an increase statistically in hemorrhagic strokes that uh offset the benefits of uh preventing ischemic stroke and there was also and increase in major bleeding. So, uh bleeding risk is uh the constraint that we face uh with uh this standard combination therapy that we use in the early period, accepting some bleeding and that we avoid beyond the early period because of the bleeding. Another aspect of clopidogrel is the the presence of genetic resistance to clopidogrel uh is uh autosomal dominant uh uh feature if you have two copies, your poor metabolizer, one copy and intermediate metabolizer and pore metabolizes are frequent one and seven individuals in a Chinese population, one in 25 African Americans, one in 50 Caucasian patients and uh patients who have uh poor metabolizer status when they're on clopidogrel plus aspirin uh regimen have a 68% increase in ischemic stroke compared to those without this genetic condition for the adverse of effects of clopidogrel. Other than the increase in intracerebral hemorrhage that we've talked about. Uh there's bruising, uh nose bleeding, gum bleeding, pidogrel has even more bruising of the skin than aspirin. Major systemic bleeding can be diarrhea or constipation and uncommonly an allergic reaction. The other uh major uh agent in this class. Uh that's now used pretty widely is Ticagrelor, which uh has been tested in a variety of trials, uh most commonly added to aspirin. Uh and uh but also alone versus aspirin. Uh And here you can see uh in the first column, aspirin plus clopidogrel versus aspirin and a second aspirin plus Ticlopidine uh as a uh ticagrelor versus aspirin. And uh there's a suggestion of more bleeding with ticagrelor and uh generally similar uh benefit on ischemic stroke when it's added to aspirin as uh as with clopidogrel. Uh And uh head to head testing of the two, no, statistically significant difference of the double antiplatelet therapy combination. A plus T compared with A plus C um in stroke prevention, but an increased risk of bleeding. So, uh ticagrelor uh carries even more bleeding risk than uh than clopidogrel. Does it uh can be especially helpful when patients have genetic resistance to clopidogrel and will not benefit or not benefit substantially from clopidogrel. Uh then aspirin prostate cadre or is uh an excellent current option. The major bleeding, um systemic bleeding uh is of course, as we just saw a um important risk with uh can lower. Uh Another side effect is dyspnea, um which uh actually leads to discontinuation of the agent in one in 20 patients who uh mechanisms that are not completely understood, but it is a pretty common s side effect for the phosphodiesterase class of agents. I'm talking in detail about cilostazole. Uh There's also dipridamole. Uh these have vasodilator effects. In addition to anti platelet effects, cilostazole has primarily been tested in Asian populations versus aspirin as monotherapy. So, Losa isole alone versus aspirin alone for secondary prevention. Closo showed better reduction in ischemic stroke by 33% and better avoidance of intracerebral hemorrhage by 74%. So, a lesser bleeding risk with clozole is an a an important advantage of this agent. Although there still is bleeding risk, with regard to the combination of sua plus aspirin, it's an attractive combination. Uh because of the potential for maybe lesser bleeding than we see with uh clopidogrel or tag or plus aspirin. But too few studies have been completed to date and there's not uh evidence of statistically significant effect yet accumulated with oxazole as with all the antiplatelet agents. Systemic bleeding uh is uh important adverse effect. Uh A distinctive adverse effect is headache because it's a vasodilator. You get nitrate like vasodilatation, headaches, especially in the first days and first weeks on the agent. And uh up to 10% of patients have to stop the therapy. Uh because of the headache, heartburn and indigestion also may occur. There are a variety of other agents, just to briefly mention, uh prasugrel has uh high brain bleeding risk in uh general uh cardiovascular trials. And so it has not been tested in patients with stroke in detail because of that concern. The earliest agent Ticlopidine has neutropenia. So it's not really used in practice. Aranox is uh similar. The the diridone effect is similar to clozole. Uh But because there's fixed dosing um has to be given with aspirin, it's hard to use as flexibly as salota in the US. And the G 2 D3 agents, the oral formulations turned out not to be effective. So they're only available as IV agents. Keep with this landscape of current antithrombotic therapy. We see that there is a benefit in preventing ischemic stroke with intensified antithrombotic therapy. But an offsetting increased risk of causing brain and systemic hemorrhage with intensified antithrombotic therapy that makes the potential of uh an agent like a in dean uh very uh compelling. Uh if we have an agent that prevents intraluminal thrombosis, that uh occludes vessels but does not prevent um wall defect thrombosis that keeps vessels from bleeding. Uh We uh would then be able to have an intensified antithrombotic therapy that uh prevented ischemic stroke with no or little increased risk in hemorrhagic stroke uh allowing uh more aggressive therapy to be brought to bear both in the high-risk early period and in the moderate risk long term period. So, um the factor 11 A inhibitors appear to uncouple hemostasis at the vessel wall and thrombosis in the lumen in this manner. Um And uh that is the reason uh for the excitement about uh potentially adding them. Uh two are the therapeutic armarium. There's a variety of evidence that supports factor uh 11 inhibition as a uh promising uh target for agent development. Um in knockout mice, uh when uh the uh um factor 11 is knocked out, they are protected from thrombosis without bleeding. Um uh The agents that in animal models um uh provide factor 11 inhibition show this desired uh antithrombotic effects without increased bleeding time. Uh Very interestingly that individuals born with factor 11 deficiency, uh uh human uh individuals who have been observed to have a reduced incidence of uh both venous thromboembolism and stroke um and uh occasionally hemorrhage, but no major increase in hemorrhage during their lifetimes. So, this is a target that has been validated, not just in uh animal models but in humans with uh this living uh genetic condition. Um the early work in uh uh with agents that uh uh are targeted on factor 11 has been encouraging and has led to the phase three trials that are currently underway including for adding this as an agent for secondary stroke prevention. So, that's an overview of um our current landscape of antithrombotic, especially antiplatelet therapy and one potential avenue uh to improve our antithrombotic approach in the future. Thanks very much for your attention.