morning everyone thank you for joining here inside and outside and thanks for allowing us to be part of the medicine meeting still or forcing us perhaps but it's nice to to be we we we having a a sequel to our last uh miniseries on on on stroke so today we have um episode two and it's about uh anti regulation after stroke what does it say who who when what it's a it's a topic that is in flux constantly so Dr sandan CH is our senior register he's recently now basically reviewed the literature that's changes um quite rapidly and there's always uh new studies coming out but she's going to bring us up to date on that and it's a probably relevant to to most of us sitting here and on online so thanks um um Sani for doing that and bringing us up to date with anti culation post talk all right good morning everyone I'm sandani as mentioned um and today I'll be talking about anti anti-coagulation poststroke okay so the main thing that I'd like to cover because it's quite a dense topic um I'd like to cover who who are the people or the patients who are indicated to get anti-coagulation after stroke what what is the best um medication that we should give or the anti-coagulation type as well as when is the optimal time to start anti coagulation of the stroke so just giving a back story um I mean when it comes to stroke we talk about whether it's an INF or Hemorrhage so you can get cerebral inunction um whether it is a cardioembolic thing that happens or EOS scerotic um event that happens or intracerebral Hemorrhage or sagid Hemorrhage so then when it comes to the iology these are also important as to directing us what mode of um secondary prevention we'll be using so the toast classification in 1999 1993 sorry was looking at um essentially the causes of stroke whether it's one a large artery atherosclerosis two is it a small vessel occlusion or is it cardioembolic which is the main um reason why we here today to talk about that as well as other um determined causes such as cervical Artery Dissection and um there used to be a term called cryptogenic um stroke so that Encompass three main things the first being um patients who are not necessarily fully worked up so maybe they pass away way before the time um for us to get you know an optimal workout for them or is it patients who have maybe two or more possible causes so somebody maybe who has atrial fibrillation and then they might also have um atherosis L Vel so you're not necessarily certain what caused it and then there was a third group so the third group is now termed isas and we'll come to that that is a group of usually young patients who are fully worked up and then um you can't necessarily find a CA so we we'll talk about that now so our role essentially will come here the iology figuring out what is it that caused the stroke as well as the secondary prevention so the last talk that we spoke about as profet Prof Moran mentioned um was with regards to antiplatelet therapy after strokes but today we'll be talking about anti-coagulation so coming to who so um there is this slide and towards the end there'll be another slide so I encourage us to ask questions and to interact when these slides come up the who what and where all right so according to ton at and his colleagues um they established a list of what are the indications for anti-coagulation so firstly we know about anti phospolipid syndrome and where there's question marks that's where we now start to um review what literature says so cical Artery Dissection was on this list but as we'll come to know it might not be an indication for antiag Atri fibrillation as we know um as well as left atrial of ventricular thrombus um and then also things like mechanical left ventricular assist device left ventricular ejection fraction of less than 35 I put a star there so that we can discuss about that as well as well as valvular heart disease and then the question mark in front of esus so why do so isers essentially stands for embolic stroke um with undetermined Source right so we'll we'll cover that just now okay so why do we give anticoagulation so essentially um the movement had gone to looking at the actual thrombus right so mayic describes a thrombus as a gel like substance that is made up of um comprises of fibrin platelets red blood cells um vecta as well so when coming to sorry about that the thrombogenesis so that picture on the right looks at um thrombogenesis that happens in the arterial system as well as in the Venus system so then um when looking at the arterial system um you see how the atherosclerosis happens in the coronary arteries even in the koted arteries um and then this essentially can lead to a stroke when it's es schic heart disease so the pathogenesis there would be quite chronic you have recurrent endothelial injury that then recruits platelets to come to play um and then the platelets predominate in the arterial system as in the Venus system it's a low pressure system and this is hypothesized to also happen in the heart um in cases where patients have maybe atra fibrillation or a dynia in the heart low pressure system in the Venus or in the cardiac and then the clot then becomes a rich of fibrin and then trapped arthroses so um taking it back not back towards indas um and his colleagues they then postulated that you have to consider red thrombi versus white thrombi depending on the thrombogenesis pathway so the red thrombi um as mentioned would be in a low pressure system and it would likely respond better to anti-coagulation as opposed to the white thrombi which BAS basically um will be predominant um from the local plagues that activation and aggregation to the formation of the white thrus and therefore antiplatelets would be um the best to consider so this is basically summarizing what I just said but there was a um uh Mr Clean registry biobank that looked at the composition of a thrombi so they basically did thrombectomies on these patients and then they assessed what type of clot you'll get and the reason why um we considered or they used to consider embolic stroke of undetermined source as uh some as patients who would benefit from anti regulation is because this were the findings from the Mr Clean registry so as you can look um on the x-axis it looks at non-cardioembolic cardioembolic and undetermined so remember undetermined used to fall was cryptogenic right and then one of the things was embolic stroke of undetermined source and you can see how there's similarity so essentially the red box here in this bar whisker plot um basically looks at the arthrite component and then higher up you see the fibrin and platelets and you can see how I don't know if I have a pointer here but between the cardioembolic and undetermined they look quite similar and that's how they then hypothesized that maybe the embolic stroke of undetermined Source would have a similar thrombus composition and thus they would benefit from anti-coagulation okay so in this in continuing as to who are the patients who get anti-coagulation one of the uh diagnosis would be cervical Artery Dissection in fact when I started what we used to do when a patient had cervical or at least your hypothy that this person's got cervical Artery Dissection you wanted to move fast to confirm this diagnosed so you can start anticoagulation however studies suggest otherwise so when you have an intramural um when you have cical Al dissection you can have an intramural hematoma that can cause stenosis or vsel occlusion you can then get a consequence of cerebral inunction um whether it is from the hemodynamic mechanism of a clude or an artery artery embolization so then there was a ctis group it was a randomized control trial that um looked at 250 patients with this extra extra cranial koted and vertebral Artery Dissection they compared the use of anti-coagulation and antiplatelets in these patients and what they found is that there is no significant difference between the treatment arms also there's a low recurrence of stroke up to one year yeah so then the American Heart Association guidelines changed in that antiplatelets are not considered to be infera so you can use antiplatelets in these patients so this is the reference of the study I'm talking about and in addition in 2021 we had the treat CAD um study which basically showed the same thing so there was now two randomized control trials that show that antiplatelets are really not inferior okay you talk about the ises that I've been referring to so this term was coined in 2014 it basically refers to large vessel Strokes so it's embolic so it's not launa Strokes not the small ones um and 70% of all esic Strokes that typically happen in Yang essentially become ises after we've worked them up extensively so the rate of recurrence of a stroke is 4 to 5% a year and these are a list of the hypothesized cause so you have an esus you work them up you can't figure it out what is the cause this is a hypothesis list that they have now established so could it be an atrial um cardiopathy left ventricular disease covert atrial fibrillation patent foramin noal valvular heart disease eerotic plug or cancer since it causes a hypercoagulable state so this is a lovely illustration um that is is taken from dios at L um not only does it show these seven hypothesized causes but it's got color grading at the back so this color grading at the back we see red that goes down to White and remember we spoke about red thrombi and white thrombi so in the red background these patients are more likely to have a red thrombi as opposed to going to the white side they're more likely to have a white thrum so now um there were many proposed mechanisms of um esus being embolic as you have seen in the previous image most of them are cardiac pathologies um proposed and then there was now um studies comparing um likely the likely response to anti-coagulation in these patients so you then had the navigate um that looked at rivan um and as well as the respect trial That Was Then conducted to assess if there's a benefit of anti-coagulation over aspirin in these patients and it was found that there is no benefit to anticoagulate over to giving aspirin in a patient with esus provided you didn't find I mean um whether they have Atri fibrillation or not so then the is trial no significant difference between the effect of the biger Tran and that of aspirin on the risk of recurrent stroke among the esus patients the incident of major bleeding was not more for the deig train group um and clinically more relevant non- major bleeding events in the de train group so that's also a reference to the study and then what about atal fibrillation so um Atri fibrillation also hypothesized um but in these cases if you are quite suspicious of Atri fibrillation then we have to prove it before we can give anti-coagulation so initially it was considered that most important underlying mechanism of esus however Rand randomized control tries on prolonged cardiac monitoring so outside of doing um an ECG and a 24-hour halter they then had um these studies that were looking at cardiac monitoring for a longer period of time so we had the crystal AF um the embrace the find if and it found that with the Embrace had higher rate of atra fibrillation detection than Crystal AF and that AF may be detected in 30% of eers during long-term followup so it does show that long-term cardiac monitoring in your esus patients you might pick up atrial fibrillation in these patients and then what about atherosc plugs so with atherosc plugs in the um aortic Arch cerebral or inter cranial arteries um remember they fall on through onto the white colored end of the spectrum so they more likely to do well on giving them um antiplatelet therapy in fact um there needs to be more randomized control trial but essentially navigate e say the cared plug found on the epsal to the esic stroke instead of on the collateral side um so here I mean we don't really have much randomized control trials if we were to use anti-coagulation here so we still stick to using antiplatelets and then when it comes to atrial cardiopathy so this is essentially um there's an absence of a thrombus in this case there's just atrial cardiopathy so thrombi may form in disease left atrium even in the absent of AF so in the event that there's a thrombus then it would be beneficial to give anticoagulation however um there's no strong evidence to start anti population as yet and then what about patent foren or value so the question here when it comes to patent for Ram Val is um is this a direct cause is it a risk factor or is it an incidental finding right because we are basically trying to see um the potential mechanisms that can happen when somebody has a PFO so you can have a paradoxical embolism that develops maybe somebody's got a DBT and then it migrates up paradoxic embolism or in clot that for that forms um or even an arhythmia that can form in these patients and um a powerful marker is that usually if you find a non-incidental PFO um at a young age that's when you would consider doing something about it um so as mentioned the consideration the age of the patient the morphology of the PFO um yeah so in Isa what they found also in addition to the patent forino valy in Isa over 60 is it showed that they had a lower risk of having recurrence of a stroke however there were other trials that um suggested that especially in younger patients in the event that you find a PFO it would be beneficial to maybe close it as well as give them anti platel therapy so these recent trials percutaneous device closure reduces the risk risk of further stroke recurrence with an acceptable complication rate so then from 2017 the mass at Al looked at the patent forment of value closure giving anti-coagulation versus anti plent after the stroke after closing the P Pon for Valley as well as in 2017 they also looked something similar and in 2018 as well um but okay wait sorry but then shows like PFO closure plus antiplatelet therapy can lower risk of stroke recurrence so yeah and then what about cancer so with cancer in esus there's an increased stroke risk um it varies by the cancer stage as also by the type you find that in your lung cancer patients it's more likely um to have higher risk stroke there's several pathologies whether it's a hypercoagulable state whether the tumor embolizes mechanical compression of vessels um and so on and then here with the randomized control trials that were done it is unclear if there is a role for anticoagulation in these patients okay and also as um to mention when it comes to hemorrhagic stroke you mainly focus on anti-coagulation inter cranial hemorrhages it's already I mean if the patient already had an indication so let's say this person has got atrial fibrillation and they were on anticoagulation and then they now develop an INT cranial Hemorrhage No Ex Associated and then so essentially here um I should have put it later actually um talks about how nox um so novel oral anti-coagulation agents are um better right they have a decreased chance of bleeding risk compared to wering so um reinitiating oral anti-coagulation compared to no treatment significantly reduces the risk of anemic stroke okay so this is the slide I was talking about that encourages us to talk about this indications um so these are the proposed answers based on what I've just talked about that one conditions with potential high risk of cardiogenic re-embolization is um these are the patients who will have used thought anticoagulation is esus so just having an embolic stroke of undetermined Source doesn't mean you have to start anticoagulation and then atra fibrillation you have to start antiphospholipid and dissection so my question to you and also to maybe the Cardiology team is is a ejection fraction of less than 35 an indication to start anticoagulation in a person who's had a stroke alone of um in patients have very poor injection infection under 30% you do see spontaneous and you do have some that strong okay thank you yes [Music] thank you thank you just repeat that Dr for the online okay so according to uh the Cardiology Department there is no um indication essentially if a just has an ejection fraction that is less than 35 um and at this point unless if there is a thrombus basically that's the gist of it there's been a trial um that also showed this okay so to ask that so that we mention that spontaneous I's it smoke that you see on the you don't consider that anymore as an indication not on it own all right I think and no other source curation then you might say there's a all right so now going on to the what so what basically um we looking at what agents would you use um as into coagulation so we're taking it back to the international stroke trial um and this stroke trial not necessarily that we're using it to help guide decisions now but it gave us Insight onto um things that we're doing today so this trial looked at nearly 20,000 stroke patients were randomized within 14 days of stroke onset and they were treatment arms where there was no anti-thrombotic therapy given there was parental hippin and then there was ES spring that was given um and basically this graph on the left looks at on the x-axis you looking at the treatment groups so the Hein and the aspirin that was given and then on the Y AIS we're looking at the the outcomes and when you look at the hpin um you find that the it did reduce the I mean the risk of a recurrent esic strob but there was Major Hemorrhage that happened more likely in these patients as opposed to the the aspirin group um so we found that I mean parental anticoagulation reduces the risk of stroke however the risk benefit ratio between having a recurrent stroke or having a bleed you found that they were more likely to bleed and there was no overall benefit of starting anti-coagulation early which we'll talk about when we get to the Wi but the main gist of this is how um it helped us direct that the treatment option to consider um was that IV Hein in given early was considered um dangerous or had adverse effect um in fact there was also a r study but the main purpose of this is to determine the timing to give anticoagulation so the reason I'm mentioning it here under what is that um there were different treatment groups um they had about 1,000 29 patients 766 were given anti-coagulation 263 no anti ulation and they were then treatment ons where they gave low molecular weight Hein alone or they gave werin or do or lower molecular weight um hpin followed by werin and the findings here under the what is that dox was noted to reduce risk of bleeding as opposed to giving low molecular weight Heparin alone or followed by an oral anti-regulation so basically looking that that looking at that we found that dox had a reduced risk of bleeding as opposed to lower molecular weight hpin and then that's not supported so then between warrin and the direct oral anti-coagulant warrin is still considered safe and effective um major bleeding risk of 1.3 per year and then um just 37% relative risk reduction of stroke compared to just giving antiplatelets and then um basically looking at the anti-coagulant in this case um basically that the dox are effective in stroke prevention and have half the risk of intracranial hemorrhage as opposed to um uh wering so in fact I so basically this is quite repetitive but it's repeating what I just said now but outside of that there were also um phase three randomized control trials um that were looking and comparing whether to use werin or to use the nox so novel direct anti-coagulants were introduced in clinical practice in TW 2008 and they either you know you can reduce the coagulation through direct inhibition of factor 10 a or 2 a and it decreases thrombin formation and fibrinogen conversion to fibrin um the nox were then noted not to be inferior to werin um as mentioned these trials the relay rocket AF Aristotle engage AF um in fact there was a meta analysis looking at this and this is basically a table I mean the purpose of this is not necessarily to look I know it's quite a busy slide but to look at all these trials that were done comparing D TR and warer in and relay rocket looking at River roxan and werin Aristotle aaban and werin and um showing that these oral anti coagulations are not inferior options to werin and that werin can be actually uh actually nox can be a a great um anti-coagulant that we should consider in patients who have had stroke and um this I mean this Forest plot is basically looking at this meta analysis comparing the efficacy and safety of these new oral anti-coagulation anti coagulant with Waring in patients with atrial fibrillation in fact what to note is that a lot of these studies were done in patients with at fibrillation and then you see that the data that's falling on the right of the mint line favors the use of warrin and that on the left favors the use of nox um and what you can see there is under the efficacy that um these nox are able to reduce the recurrence of having an es schic stroke um but also under the safety they have a lower risk of in cranial Hemorrhage and that's why we like them per se because they have a less um profile for Adverse Events so then under the what um for nonventricular fibrillation you find that dox are better than werin and in our case we then use um oral anti-coagulant as first line therapy in these patients Prof do you have any addition here okay all right and then we at the last section of the talk we're talking about timing so timing is also something critical to establish because you don't want to start too early um and then offer the risk of bleeding or hemorrhagic transformation or start too late and risk the chance of somebody having another stroke so those are the issues that we want to determine or that I essentially at play here is determining um or rather trying to to you know that balance between early anti pulation and later um so there has been a lot of Trials here and as you can see there's been a timeline going back from way from 1997 as mentioned in the international stroke trial remember where they at IV Heparin and aspirin coming back to currently when they ongoing trials so we'll just go through some of them so the international stroke trial as mentioned um this has led to the common practice of delaying initiation of anti-coagulation after stroke for the first two weeks so that was the initial decision wait don't start anti-coagulation after that person just had a stroke if it's indicated wait for at least two weeks but this was in 97 and then we moved on to 2013 where we had the European hot um Rhythm Association that then proposed a new um rule of how to look at it they spoke about the one 312 days rule so this essentially says that in a case that a patient has maybe a transient esmic attack you can start anti-coagulation after one day that's the one if the patient has a mild stroke then you can start after 3 days if it's moderate you start after 6 days and if it's a severe stroke you start after 12 days um and here the EV evidence that large infacts are more likely to grow um undergo hemorrhagic transformation than small infacts came to play because if it's larger you're likely to wait longer right and then um we then had the American Heart Association um in 2018 revised also in 2019 it was considered reasonable to anticoagulate within 4 to 14 days but in this case I mean 4 to 14 is also a broad window do I start at four or do I start at 14 but then we had to now consider um the the factors that influence you starting at 4 or at 14 so this is basically a summary of studies on early initiation of anticoagulant therapy um in patients with recent Atri fibrillation so this here you have um this table that basically summarizes these studies so from the top these are observational studies so they were not randomized control trials they were just prospective observational studies that influenced that 4 to 14 day start um and this basically in that graph shows that they were following these patients up for 19 days however what one must note about these trials is that they only worked on mild Strokes so people with an Nies of about um 3 to 8 and then they started anti-coagulation from day four to 5 so they don't necessarily do it on large um Strokes per se in these trials so it was the NOC ISP the samurai EnV a and the um and here this was basically a summary of the findings that they found so this included patients with recent esmic Strokes as mentioned um and then it found that early D treatment right so looking here um at the first so looking at the x-axis the first study that was done in 2016 the Noak ISP um was looking at the the risk of having recurrent es schic stroke it was still there however intracerebral intracranial hemorrhage was lower was on the low lower end but also considering that they were looking at patients with mild Strokes so they found that starting anti coagulation earlier was now an option because they had less risk of bleeding however you'll ask okay what about the third uh 2017 study so I mean here also is that yes there is a higher intracranial cerebral bleeding the r Noak um however the anti-coagulation in those cases was started at day three and it's not necessarily known if I mean if it was a direct impact from the anti-coagulation because this B these bleeds were only picked up as 30 days it could still be um but uh so basically the just the reasons why we started between 4 14 was because of these studies and now uh looking at that 4 to4 Gap one needs to consider what then increases your chance of bleeding so then the consideration of um these factors came to play so you have the factors that are associated with hemorragic transformation there are multiple factors but we'll be focusing on the size and the type of infact so you see that patients with a larger embolic territorial um infact are more likely to bleed as opposed to patients with the small or launa um type infact so this then um it's a nice illustration as looking what considers it to be as mild moderate and severe INF so this basically shows that you know your mind yes you have to consider your NHS score your aspect score on presentation but this is a nice illustration so if it's a minor infal it's less than 1.5 CM moderate it's less than a third of a large vessel territory um or deep MCA territory and then SE would be a complete involvement of the territory um or Pell and deep or if it's in the posterior circulation or like the cerebellum here or the brain stem if it's more or equals to 1.5 CM so then the recommendations as the years went on now included the type or the size of the infa in considering when do you start anticoagulation so this is um the eso kolinsky stroke update recommended considering the infa size so then mild stroke and small infact you could it would be reasonable to start ulation by day four and then moderate stroke and medium infacts consider it studying starting anti culation by day s and severe stroke we still are on the side of caution waiting however this was low quality evidence weak strength of recommendation um and then as the timeline goes um now in 2020 we then looked at the cardiovas the Canadian cardiovascular society which you know if anything as we go down these slides they basically have the same theme um you have here that if it's a TIA within 24 hours so looking at the top of the flowchart patients with AF and acute esic stroke it considers is that a TIA is it a mil stroke moderate or severe and then as you go down it considers the timing in which you need to start anti calulation so with a TIA it's within 24 hours essentially going back to what the Europeans or the Europeans said that tiia one day M stroke same three so you basically have the 13 six2 again um but here they um they will add other things that as a clinician you need to consider um when deciding this same in 2021 um you then had the European heart rhythm Association but here they now um made it important to consider brain Imaging so it's the same sequence of you have the brain Imaging if there's no hemorragic transformation is it a TIA is it mild moderate and severe but what's interesting here is that they considered that if in the case of a Moder and S it would be beneficial to repeat a CT Brain before starting so um exclude hemorrhagic transformation by brain SE to your MRI less than one day before starting the so this was an addition to consider doing repeat Imaging um and then lastly when it comes to these um flowcharts is that because they saw that starting an regulations earlier had less adverse effect they now started to push it even further so you then had this combined data from prospective Registries in Japan these are not randomized control trials but um they basically uh open the path to working on um randomized control trials that try to push starting even earlier so they then proposed that now instead of considering 1 3 6 12 how about we consider 1 2 3 4 um and because of the outcome from observational studies it B it birthed this rule um so what is the optimal timing so I mean it also comes um there are ongoing randomized control trials the Optimus trial the elen trial but I do have feedback from the El trial timing trial as well as thought that early anticoagulation might still have benefits and prevent stroke recurrence as well as prevent systemic arterial embolization and then that do Works offer a significantly lower risk of bleeding compared to other anti coagulates potentially allowing for earlier initiation and preventing recurrence so um as mentioned this is basically the ongoing trials you have the Optimus trial um that basically wants to look at starting in the early group less than four days which is basically consider 1 two 3 4 or later 7 to 4 days um as well as the elen this is a Eland trial that was published last year actually so this looked at starting um anti-coagulation early um within 48 hours if you have a mild or moderate stroke or by day six or seven if you had a major stroke that was the early treatment group and then the late treatment group looked at starting it at the 3612 okay and the primary outcome that they got was um combination of so the primary outcome was looking at whether this person's going to have a recurrent stroke are they going to have systemic embolization major extracranial bleeds or vascular death so that was the primary outcome looking at these different groups and the adverse outcome was more likely to happen in patients who had earlier initiation that later initiation so this wasn't favorable to starting earlier in the 124 So currently um at least with us um you would still consider the 13 612 or you'll get expert opinion okay and then um this then ALS so uh to finish I'm basically adding in what about patients with hemorrhagic Strokes so rein reinitiating oral anti-coagulants so say somebody's got atrial fibrillation as the prime example and then they have a bleed um when do you initiate so there's no relevant guidelines or randomized control trials available as yet however the optimal time is basically at least four weeks in those patients according to um American Heart Association reinitiate at least four weeks after the inter cranial Hemorrhage um or in some Nationwide retrospective study in 2022 they looked at maybe between six to 8 weeks um of this and this graph basically depicts the reasoning behind this um so looking at the why it accesses the risk and then the x-axis is the days to restart so we focusing on the bleeding risk so the the red line as well as the clotting risk so at least waiting two weeks because that's where they cross there by day 16 so delaying anti-coagulation resumption after inter cranial Hemorrhage for at least two weeks usually restarting after around four weeks so as you can see they don't have a set timing as to when you can start but when there's a bleed at the initial presentation you'd wait longer so we are uh so the proposed um answer as to when is the optimal time there are many guidelines with similar themes the American Heart Association don't recommend early or urgent anticoagulation in acute es schic stroke you need to consider the size of the infact and the severity of the stroke and then we need results from randomized control trials and we need our experts in our departments to help us thank you [Music] yes