Chapters Transcript Video Anticoagulation Following Ischemic Stroke and Intracranial Hemorrhage Elisabeth B. Marsh, M.D. presents at the Johns Hopkins Department of PM&R’s Grand Rounds on May 21, 2019. So let me uh do a little bit of introduction um today for the PM and R department uh Grant Brown, we have uh Doctor Elizabeth Marsh to, to present uh So it's a great pleasure and honor to, to have uh Liz. That's how we I know you. Um So let me take you uh tell you a little bit about uh about Liz Marsh. She is uh an associate professor in the Department of Neurology and I'm gonna read it because there are many titles. Um very recently, she became the Vice Chair of Clinical Operations at the Neurology Department at Bayview. Uh She's the Director of the Comprehensive Stroke Center and up in Bayview uh which is uh one of the stroke excellence programs in, in Maryland, one of the two, the this hospital and are the only two. So it's easy to keep track. Um She is the director of the John Hopkins Bao Stroke Intervention Clinic or call it Basic. Um She's a associate program director of the Neurology residency uh here in Hopkins and the director of the Hopkins Inter Hemorrhage Center. Um So uh has uh trained in, she's a true Hopkins person. She started her education here undergrad. Uh Hawkins is a medical school here, Hawkins residency fellowship and remain as a, as an attendant. So, um I don't think she can talk much about something else happening outside Hopkins. Um But maybe she can. So, uh Elizabeth interest obviously is in a stroke uh ne in stroke neurology. And uh she has written more than 40 publications. She has uh received funding from uh federal and non federal agencies and some foundations and she's very involved in, in research and, and training education neurology. So, with that, thank you so much for coming and joining us today. Thank you for having me. Fair warning. I tend to walk, so I'll try to behave and stay right here. Um So thank you for that introduction. Oh, wait a minute, there we go. So I don't really have any disclosures for this talk. Um But I do ask that you keep in mind that I am a stroke neurologist. I know many of you from the floors here as well as at Bayview. Um So what you're gonna hear is the bias of a stroke neurologist which may be slightly different than the bias of A P MD or the bias of a rehab physician. Um So just keep that in mind, but I'll try to be unbiased. All right. So today I wanna talk a little bit about restarting anti coagulation, which is something that you guys uh hear a lot. I was just with the residents and that was one of the questions that came up that we kind of pushed for later. Um But rest starting anti coagulation in patients either have primary intercerebral hemorrhage or a stroke with or without hemorrhagic transformation. And how we kind of think about the risks and benefits and the timing that surrounds that. Uh We'll talk a little bit about the scope of, of the problem dealing with uh inter creal hemorrhage and then the data or lack of data that exists. Uh And then we'll really get into the clinical application and talk about the different factors that you can be considering. And that will include some of the data that we've gathered here at Hopkins uh that help inform uh risk of bleeding both with hemorrhage as well as after TP A and some of the other questions we talked about earlier. Um And then finally, I'll let you know about a score that or a tool that's available to you on your iphone. Uh If it's helpful, uh Although the neurologist often when you consult them will, will give you that information as well. Let's talk a little bit about interest hemorrhage. I was telling the residents earlier that uh it can get confusing. So we talk about stroke and when we say stroke, it means ischemic or hemorrhagic. But most of the time, at least as neurologists when I say stroke, I mean ischemic. So for the rest of the talk, if I say stroke, I mean closure of a blood vessel and if I mean hemorrhage, then I say in intercranial hemorrhage, um overall, the incidence of hemorrhage in the general population is much smaller than stroke, which is a good thing because it's much more deadly. Um but it does increase significantly and it increases significantly, especially with warfarin uh up to 2 to 3 per 100 person years, hemorrhage is something that affects both the old and the young and our population is certainly getting older. So they're at higher and higher risk. And like I said, hemorrhage is really the deadliest form of stroke because you initially not only have bleeding but have significant swelling that can cause herniation and death. Uh So patients often look much worse with the same size hemorrhage than they do with a similar stroke early on. Uh the bleeding, uh risk is twice as high on Coumadin. So when somebody comes in with a hemorrhage, if they're on Coumadin, their risk of having a poor outcome is significantly worse, probably because their risk of bleeding and of continuing bleeding is worse. Um And many people have indications for anti coagulation. Now, so the risk of coming in with a hemorrhage or of having their stroke turn into a hemorrhage continues to increase. So this is an important topic to be talking about and thinking about. Um in addition, though, we know that we need anti coagulation for stroke prevention right, patients have mechanical valves and atrial fibrillation. So, balancing that risk and benefit in your patient, uh it can be tricky. We also have new agents. So, Warfarin, we know a lot about and we will talk about its risks and benefits. But now we have new agents that are easier to use and are becoming more attractive and more patients are willing to take. So again, the number of patients that are on anti coagulation continues to rise. So let's start with where we were a few years ago with prior data for restarting anticoagulation after hemorrhage and stroke. Let's start with hemorrhage. So initially, all we had were actually a few uh small case series to go on. Unlike the cardiac literature, the stroke literatures, stroke and hemorrhage literature is a little bit behind. So we have to do a lot of case looking at case series and a lot of extra extrapolation to figure out risks and benefits. In 2007, the American Stroke Council took a lot of these and put them together and, and used a meta analysis and, and determined that 7 to 14 days after IC H was the optimal time to restart anticoagulation. Um And there was a mayo clinic proceeding that assembled a panel of experts. They all sat down, they looked at the literature and they said, yeah, all right, 3 to 10 days following IC H and high risk individuals. So people that needed to be on a blood thinner, seems like the reasonable thing. And that's where our data was about 10 years ago, which is unfortunately, you know, we talk about things, oh, we're gonna restart at this time when you actually think about where the data comes from. You'd be surprised at the data or lack of data. In many cases, it's often expert panel or, or consensus in 2010 maid and colleagues actually published one of the first Multi Center and it was a retrospective cohort analysis of nearly 3000 patients who presented with IC H. And what they did was they looked at patients um and um who were restarted on warfarin. Uh and that were warfarin associated hemorrhages. And then they looked at the odds of having a stroke and the odds of having a hemorrhage to try to determine the best time to restart anti coagulation. So 234 of those uh nearly 3000 patients were warfarin associated hemorrhages, but only 100 and 32 survived the first week. So like I said, hemorrhage can be really deadly. 45 of those were started on warfarin. Um And what they found was that the optimal time to restart anticoagulation, unlike the prior consensus statements was 10 to 30 weeks after patients presented with their bleed, which sounds like a lot longer, right? So why was this data so different? And that's not what we do now. So what was going on here? Well, and colleagues had a bias toward lower uh risk indication. So they had a lot of patients in their study that had atrial fibrillation and we'll get to it a little bit later. But what do we know about atrial fibrillation? The stroke risk is high over a year, over two years, over five years, but not tomorrow or the day after. So, the risk is an accumulative risk. Unlike bos where if you leave a patient off anticoagulation for a couple of days with a valve, your stroke risk is really high, right? So including a lot of individuals with atrial fibrillation in that population kind of skewed the data in the in the direction of of it being safe to wait a lot longer. Whereas patients with um with valves were actually far more likely that of those 45 patients that got restarted to be restarted on anticoagulation much sooner. So the population was a little bit different. Um along those lines, data that came out a little bit after that by Clason and colleagues showed that there was, oh, there we go. That there was actually uh a relatively low risk after someone presented with hemorrhage of restarting anti coagulation. Uh that the risk of uh of of having complications such as bleeding was higher or the patients that, that did get restarted. And it was uh they had more thrombo ays when they weren't restarted. So that kind of fits with what we know right. You don't restart patients on their in a coagulation. A small portion will go on to have a stroke, you restart them on their blood thinner and a small portion will go on to have a bleed. Right. That makes sense. That's not entirely helpful, but at least it's intuitive. And then this Danish registry came out that again, looked at patients with a fib and you can say, well, why did everybody keep looking at a fib? It's because that's the biggest group of patients that we have that requires an a coagulation, right? And they're often recruited for cardiac studies. So it's very easy to take that and then take that data and find out information for stroke and hemorrhage. Um And what they found was similar to what we know that when you anti coagulate, the risk of stroke goes down over time and you can see it goes down a little bit if you start antiplatelet dead and it goes down even more if you start anti coagulant. But the risk of recurrent hemorrhage goes up with a G. So then what ended, what people ended up doing is they, they put data together, right? More numbers gives us more data. So people love meta analysis and that was where we were, where we were really left in around 2010 or so. And in fact, here at Hopkins, we did a nice meta analysis and we determined that high risk individuals should be started on anticoagulation. Uh um and that they had a high risk for stroke and that we should wait a few weeks after and then start them. Probably the best data that you guys have heard about came from this study here, um where the 7 to 8 weeks is thrown around and, and this came from a study um uh from 2005 to 2012 that looked at uh uh 2600 19 ic H survivors with atrial fibrillation. And uh and found that when patients were started within the seven to week, 7 to 8 week time period, they, they had a little risk of hemorrhage and, and a lower risk of stroke. And that seemed to really be the sweet spot. So now often we'll put in our recommendations that a patient presents with a hemorrhage. They have a a risk for uh um uh for they, they have an indication for anti coagulation and start 7 to 8 weeks after. So it's good to have data, right? It's good to have these studies. But I just told you that each of them has weakness. A lot of them just included atrial fibrillation patients and all patients aren't different, right? And we all practice and need to think about our patients as individuals. So what goes into really weighing the need for the risk and benefit of anticoagulation and that's what I want to spend. A lot of the rest of the time talking about and how we think about that need and why some of the recommendations are going to be different. And the things uh the really the key factors of the key players that go into this decision are ideology of the, of the bleed. Why did they do it? Is there a trigger? What's the indication for anti coagulation? What is the agent that we're going to use? So, is one safer than another in helping me to mitigate that risk and then other risk factors. So should anti coagulation be restarted at all? Right. There's a group of people that think that once a patient bleeds, we're done no more anti coagulation. Maybe that's true for some patients. And then how long do we wait? So let's think about the ideology of the hemorrhage. So for me, I'm always looking for a precipitating factor. So a patient comes in with a blood pressure of 200 that doesn't necessarily tell me that their blood pressure is out of control at baseline because every hemorrhage patient comes in with a blood pressure of 200. That's how they present. But being able to get a little bit more history and hear that they have uncontrolled hypertension makes me happy. Not because they have uncontrolled hypertension, but because I have a trigger and I have something that I can modify that will then decrease their risk. The same is true for trauma, right? If they fell, I know why they had the hemorrhage or if their inr is super therapeutic and is four, I know what led to their increased risk. The person that comes in that's inr is 2.5. Right where it's supposed to be, that always takes their blood pressure medications and that had no other precipitating event. I cringe because I don't have anything to modify. That's gonna help me to decrease their risk. If I start them back on anticoagulation, it doesn't mean I don't, but I certainly don't feel as good about it. Right. I don't have anything to modify. I also look at underlying vasculopathy and what do I mean by that? So we talked a little bit with the residents earlier about imaging. We didn't talk about this one. So up here, this is gradient echo imaging and you can see these little black dots that's hemorrhage or micro bleeds. It doesn't tell me whether they're new or old because little black dots can happen when they're babies or when they're adults and it looks the exact same but the pattern does help me. So these deep bleeds in here are a classic hypertensive pattern when I see a gradient echo that looks like that. I know that person's had hypertension a good long time. When I see these micro bleeds here in the cortex, I get a little bit nervous because that's where Amyloid tends to hang out. People start to have a little bit of dementia, they come in and on their gradient echo, they have these micro bleeds that are more cortical patients that have amyloid angiopathy have a known risk of incredibly high recurrence, both for micro and macro hemorrhages. So, a patient that has an IC H due to amyloid is not someone that I would restart on anticoagulation. We're gonna think about it for everybody else. But for me, that's a hard stop because the odds that they're going to present with another hemorrhage and then it's gonna be a huge hemorrhage and kill them is incredibly high. And any type of, of risk, uh prevention for ischemic stroke is gonna pale in comparison to that risk. So, one of the first things I think about is did amyloid play a role and are there modifiable trigger risk factors? Ok. Does that make sense? So I thought about the hemorrhage risk and I thought, and I thought about why they had their hemorrhage and now I need to think about why they need to be in coagulated, right? Is it worth it? Um Are they 99 years old and, and really, really sick and it's not going to make a big difference over time or, or do they have a risk factor? So, indication for anti coagulation informs both when and whether I restart anti coagulation. So some of them are really easy, right? Somebody has AD VT or a pe they have active clot. I don't have a choice right. Then what I can say to you as a neurologist is who we're between a rock and a hard place. I'm really nervous they're gonna bleed and we'll talk about how I quantify that. But you know what? You have no choice. You got to go ahead and restart it. They have a, they have AD VT, right? And maybe they're not a filter candidate or they have a pe, you got, you got to put them on a blood thinner um or they have a mechanical valve. So the risk of stroke with mechanical valve uh pro protect particularly a mit valve is incredibly high. The cardiologist range anywhere between allowing a patient to be off one versus four days before they start to get a little bit anxious. Um So I really have to start thinking about, ok, how long can I wait to restart a patient on anticoagulation with a valve? Um And, and what am I gonna tell the patient and the team about their risk? Because holding it really is not, it is, is not an option in these individuals, but that's a little different than some of these other risk factors, right? And we started to talk about uh some of them earlier, but atrial fibrillation is the big one. And by far you could see in the studies, the major reason that patients are on anticoagulation, you're gonna see far more patients with a fib than you're gonna see with mechanical valves. And here the picture is a little bit less clear. Right. So we know based on their chads too or their chads valve score, what their risk on a daily basis or on a yearly basis is for having a stroke from atrial fibrillation. But again, remember it's an accumulated risk over time. So you may have a patient who is high risk overall, who I wanna restart anticoagulation on. And that's my stroke bias. Right. So a lot of primary carers are like, oh, they're 90 I don't want to start, I start everybody on anticoagulation because a a 90 year old that has a stroke is gonna die from their stroke. Um But we'll talk about that in a second. But the chads basque score, the chads two score tells me about their risk and makes me decide whether or not I'm going to start them. But again, I'm thinking longer term, not necessarily four or five days after their hemorrhage. So this is what I was getting to with, with stroke uh due to uh atrial fibrillation. The problem when people have strokes due to atrial fibrillation is the strokes aren't little. So when you have a stroke that's due to a cardioembolic event because the heart's not beating properly, right? A big clot forms, it's not like the little clots that form in the, in the blood vessels that go to the brain. They cause problems, but they're smaller, right? They're often a scatter shot. These clots are big they lodge in the MC A, they lodge in the AC A, they lodge in the Basler and they cause debilitating strokes. So, if I can prevent that with anticoagulation, then that's gonna be my preference. And I understand people bleed, but their strokes are devastating when they stroke due to atrial fibrillation. There have been lots of trials uh for primary prevention if you like alphabet soup and secondary prevention showing the um uh the effectiveness of anticoagulants predominantly warfarin here. But we're accumulating uh do studies. Uh Currently heart failure is a little bit trickier. OK. So we have a strong indication for atrial fibrillation. But what do we do for heart failure patients? So this is based on the worst study, the worst stuff study came out a couple of years ago and it looked at all patients with heart failure with ejection fractions of 35% or less. And it followed them over time. It didn't care whether you'd had a prior stroke or not, but it looked for the risk of recurrent stroke. OK. And half, about half of the population was on an anti platelet and half of them were on a blood thinner. And this group had not had evidence of atrial fibrillation. Although they were, they weren't screened intensively, they didn't have loop recorders or anything implanted, but they hadn't had any history of AFI and when they followed them over time, they found that for both groups, for the group on aspirin and Warfarin. The recurrence of stroke was small or the stroke period because some of them were primary strokes, initial first strokes. But that after about four years, you can see that the Warfarin group did better. They had less strokes which tells us how, how I interpret that graph is that if your patient is gonna be around for four years or more, there starts to be a benefit for warfarin in decreasing the stroke risk. And remember we're talking about big clots because they're coming from the heart again. Now, I do have to point out that they're small, right? There's a small benefit and a lot of primary carers don't think it's worth it, which is reasonable. But the subgroup analysis that looked at patients that had had strokes. So for secondary prevention was much stronger and that's the group of patients that I see. So I tend to push hard for people that have already had strokes with heart failure to be restarted on anticoagulation. But I don't look at it like a mechanical valve or even a fib because the data is not as strong. It isn't there. You see how we're starting to slowly decide what our threshold is for saying someone needs to be anti coagulated versus not and starting to think about time. OK. How does the choice of anticoagulant help me decide uh what uh what my treatment plan is going to be or, or, or what am I thinking about, well, we now have three, Heparin cumin and the do ax, uh, that are available to us not to make everybody cringe about their biochemistry, but to take us back. So Heparin is a glyco amino glycan. Um, and I won't ask anybody about the, the clotting cascade. Um, but the nice thing about Heparin is that it's able to be stopped and able to be reversed. Right. You can turn it off immediately when they're on a Hepburn drip and you can reverse it with protamine, which is great. Uh There's also the low molecular rate form. Uh Unfortunately, it's in the form of shots which a lot of patients don't like. Um but uh but uh the nice thing about heparin is it's metabolized in the liver. It binds the plate leads in the plasma proteins. This is in comparison to Warfarin, which is nice because it's an oral form. But, and has other advantages. So we know a ton about warfarin because it's been around forever. We know the good, the bad and the ugly, right? And there is bad and ugly, right? It, it interacts with a lot of medications, it interacts with a lot of foods. Uh, patients have to have their INRS monitored. So there's a lot of things that aren't going for it, but it is an oral pill and we do know what to expect and we do know how to monitor it and we can give vitamin K to reverse it. So all those things are, are good things, then we have the new agents, right? And just to get everybody on the same page because I know I always have to think about where they work, they work very differently, right? So we have, which works on uh which blocks uh ability to convert Fino to fiber, which you need for clots. And then we have the 10 A inhibitors which also uh interfere with that pathway. So that fibrinogen is not being, not being converted to fiber. And, and no, and clot is, is, is not building, not been forming. So the bigger was first approved in 2010 and it's a pro drug. And the nice thing about it is that it acts on thrombin and it has a relatively short half life compared to warfarin and there's no need for monitoring, which is the reason the patients like it so much, it acts quickly. So you give it, it starts working and now there's an antidote which we'll talk about in just a second. The problem with bigger is that it's uh predominantly renally excreted. So if patients have renal impairment and a lot of ours do, um that can be an issue. Um And in the past, some of the other similar medications had some side effects uh that, that didn't make it ideal, although debit seems to be to be fine, what a lot of us prefer are the factor 10 A inhibitors. Um And there's three of them now, although the top two are really the ones that are mainly used Rivera and Apixaban that were approved in, in 2011 and 2012. They're also uh early available and they have a very predictable um onset and, and plasma concentration and they're not affected by age renal disease, hepatic disease, any of those things, they still don't require monitoring. They have a short half life and a rapid onset, but they don't have an antidote, which at least not yet. Although the pharmaceutical companies are working on them. The, um, the issue with that and, and the way I think about that is, is that they actually have a lower bleeding rate because probably because they keep people in that range as opposed to having fluctuating levels of inr and cumin, it's antidotes. Vitamin K. That's not actually how we treat a cumin hemorrhage. Right. When someone comes in, uh, with, uh a cumin related hemorrhage, we do give vitamin K, but that takes hours to days to actually work, we give PC C and other clotting factors. That's the same thing we, for the 10 A inhibitors. So patients get really agitated and, and some doctors do as well that there's not an antidote yet and I think we'll all feel better when there is, um, that that's approved and, and used routinely. Uh, there's certainly some that are very close. Um, but it's less of an issue for me as a stroke neurologist because again, we treat this the same way that we treat a cumin hemorrhage. And we know based on the literature so far that these patients actually do better, probably because they're in range more, right. Uh, more frequently than the CID in patients who, well, that didn't go well, anyway, these trials, uh, uh, these were, uh, big trials just showing that, uh, for the AX, which they're not, no ax anymore because they're not new enough. So now they're direct instead of being new, um, uh, they were effective in preventing recurrent stroke. So, how do I think about these three classes of medications or these three medications in when I'm gonna choose an anti coagulant for someone that's had a hemorrhage? Ok. And I'm gonna restart well. So, for Heparin, right. It's pretty, it's pretty straightforward. It's, it's easy. You can turn it on, you can turn it off. So, if you're really worried about somebody bleeding, it's great. It's a great way to hedge your bets. Oh, they have a mechanical valve. I really think they need to be on something. Let's try it. We'll rescan them, we'll make sure that they're not expanding. I can turn it off rapidly. I can reverse it. Right. For coin, it has its benefits too. I like the fact that I can start it and that the inr isn't therapeutic right away so I can start it on discharge and somebody that I'd like to wait a few more days to be in, it coagulated and it will slowly drift up into therapeutic range. We certainly do that. I think we've sent plenty of patients to rehab with you that way. Right. Where we're watching the inr drift up. Um, we know how it's gonna interact. We, but we do need frequent monitoring and then there's the, the, the no, a right that have less therapeutic, uh, less interactions and and are immediately therapeutic and easier to monitor. Uh but we don't have the antidote. We're gonna put this all together at the end and we're gonna do some cases and see how each of these pieces fits into our decision making about uh when to start anti coagulation, if to start and what we're gonna use. The last piece is other factors that, that increase the risk of hemorrhage, right? And this is where we have more accumulating data. So what's specific to my patient? All right, what do they have? And there have been a few scores that have tried to quantify that. So the has blood score from the Euro heart study as well as the hemorrhages score, try to say what, what about this patient? Is it their platelets? Is it their renal failure? Is it their kidney uh liver function that makes them more, more likely to bleed? And what does that bleeding risk look like? The problem with all of these studies is that they, they don't have many in intercranial hemorrhages, they have G I and gu hemorrhages because they're from uh atrial fibrillation studies. No study was dedicated exclusively to uh risk factors for IC H and that came to uh one of the reasons for a project uh that we looked at in neurology where we wanted to know and this was in ischemic stroke patients, ok. Um But we wanted to know what factors made them more likely to bleed. So we've talked a little bit about hemorrhage patients where we know they've already proven that they've bled. Um But in the way we think about them and when we restart anticoagulation, but what do you do with the ischemic stroke patient? Who they probably had their stroke because they have atrial fibrillation. And now they need to go back on what are factors that inform our understanding there. And that's the group that we looked at. And then we tried to see if, if we could also apply that to uh primary inal hemorrhage. So we took 100 and 43 patients with acute ischemic stroke and we uh 100 and 17 of them were anti coagulated. They got restarted in the hospital for high risk reasons and 26 were not. And what we found was is that the hemorrhage rate actually wasn't that different between the two groups? It was slightly elevated in the, in the anti coagulated group. But that you can see that the symptomatic hemorrhages occurred in that anti coagulated group, which makes sense, right? So you start somebody on a blood thinner and most of the time in these patients, it was warfarin and their risk of having a symptomatic hemorrhage is higher. But what were factors that helped us to know what the likelihood of that was? And when we did our analysis, what we found was that the NIH stroke scale score, which is a good surrogate for how big the stroke is, right? It measures stroke severity, you get more points. Um For, for the things you can't do, you can't let your arm, you get four points. Um You can't look in all directions, you get points uh and renal failure, which was interesting and what we and we're gonna talk a little bit more about. So another word about volume just dividing our, our cohort into turtles of volume. So um smaller and larger strokes, the larger your stroke, the higher your risk of having uh symptomatic hemorrhage. So your risk of hemorrhage actually increased 14% for every 10 ccs of ischemic tissue. And we talked about this a little earlier with the residents. But why is that? It's because when you close off a vessel and brain tissue dies, all of the little vessels that feed it become friable, they're damaged, right? They're not getting um uh um they're at higher risk to be leaky and higher risk to, to have hemorrhagic transformation. When you actually start sending the blood. So this makes sense. What was interesting, although intuitively also uh can make sense is that renal impairment was in, was associated with a higher risk of of in intercranial hemorrhage. So, patients that had no renal impairment had a 20% risk of any conversion. And when you have a big stroke, a little bit of, of hemorrhagic transformation, a little bit of conversion. A little bit of oozing is actually quite common. It doesn't cause new symptoms, but it's quite common just because those vessels are friable, whether or not it causes problems, helps us to categorize it as asymptomatic or symptomatic. Ok? Um But your odds ratio of having any bleeding goes up by 1.5 if you have mild renal impairment. So your GFR is a little bit, a little bit poor and MO and goes up 2.8. So nearly three fold if you have moderate renal impairment. So your GFR is less than 30. Ok. So another risk factor for um uh for patients having more of that using and that allowed us to actually create a score. And a lot of times you hear this from the residents called the the hemorrhage risk stratification score or the score. And it allows us to actually say to you look, this patients had a stroke, we know they need to be on a blood thinner, but this is their risk of having hemorrhage or we don't know if they need to be on a blood thinner, we're weighing the risks and benefits. What's the risk of stroking? Let's compare that to what we know the risk of hemorrhagic transformation is. And this score uses stroke size renal failure and age as its variables. And it's actually available as a, as an app that can actually quantify for you again, based on those factors, what the percentage likelihood of bleeding is. And I find it really useful to be able to talk in actual numbers, whether to a physician or to a patient, right? Because have you ever, have you ever tried to give a patient advice and said, well, it's the risk is small and they're like, what do you mean by small, you know, small, you know, small, well, small as in 5% small as in 10%. What does that actually mean? And this is a nice way to help quantify that we actually validated the score at a new cohort. Um uh and found that it was helpful in predicting. So it wasn't just the cohort that we developed it in. And then we started looking for other areas where renal impairment was important and how that helped to inform our uh uh um uh what we know about bleeding risk. And we looked at patients with TP A and somebody asked me about this earlier. So we actually looked at our entire population treated with IVTP A uh over several years and found that uh um 18 of the treated, uh eight of them bled and three of them with renal failure, blood. So, a higher risk and when we went back and did a retrospective analysis of, of 224 patients presenting with symptoms. What we found was that uh the uh craine greater than one was a big predictor of a 5.5 fold increase in symptomatic hemorrhage in patients that got TP A. So you can see here that the patients, you can't see that to the patients, the symptomatic hemorrhage significantly increased if they had TP A. So our average bleeding risk for TP A is about 5 to 6%. But patients with renal impairment were certainly on the high end of that, which is important. But the other important thing to note because people get worried is that patients without renal impairment, their risk of bleeding was like 1%. So, not only do patients with renal impairment do a little bit worse, but your risk is really almost negligible if you don't have renal impairment, if you get TP A, which is important. And I think clinically useful, we also found that renal impairment makes the risk of having big hemorrhages as opposed to little hemorrhages far more likely. And this has been uh shown in the literature. Um And, and is consistent with some of the things, uh such as the Rotterdam study, which showed that a decreased GFR was associated with a four fold, increase in hemorrhagic but not ischemic strokes. And to some studies, looking at micro bleeds. So remember those tiny little areas in dialysis patients, they tended to have more than non dialysis patients. And where does that come from? Well, it may come from the fact that uh that uh when you're remic, your platelets don't work. Ok. There's, there's um a platelet dysfunction that we don't quite understand but that we know occurs or the inflammatory cascade that occurs also inhibits uh antiqua or inhibits coagulation factors. So, after we found that uh renal failure and volume were important in hemorrhagic transformation. We wanted to go back to our initial question about whether or not it was important for primary hemorrhage as well. And what we did is we looked at a group of patients with small vessel disease, be a small vessel disease puts you at risk. Uh Those patients can either get la coons, right, which are ischaemic strokes or they can have deep hemorrhages. And we wanted to see what the um uh the effect of renal disease does it make you more likely to have ischemic or hemorrhagic disease? And what we actually found was that there were factors that were more predictive of one versus the other. So, patients with similar vascular risk factors with small vessel disease were more likely to present with small deep hemorrhages if they were older, if they were African American, and if they had micro bleeds and they were more likely to present with small vessel la coons if they were female and had more extensive white matter changes. And you can see that for this renal impairment didn't go either way, probably because it's a risk factor for both. Ok. So what does that help us to um to understand and, and what is um kind of the, the unifying um the unifying themes here? So, in patients who present with an acute stroke, who also need to be on a blood thinner age stroke volume and renal impairment are the most important factors in thinking about what their risk is for bleeding. And that those who are on anticoagulation, who you do have to put on, don't necessarily have a higher risk of bleeding, right? Remember those two numbers were pretty similar, but they're more likely to be symptomatic to have oozing, that's symptomatic and causes a worsening exam. So something to think about patients that are given TP A when they have a creatine, that's greater than one. Their risk of having a symptomatic hemorrhage is higher though not ridiculously high, still within treatment, the National guidelines. But that those who don't have an impaired creatinine have a very low risk of bleeding. And in patients with long standing hypertension that we see those who are older African American and have micro bleeds are more likely to end up coming in with a hypertensive hemorrhage as opposed to a hypertensive lagoon. And why is that important why I told you at the beginning, right, that those hypertensive hemorrhages actually don't do as well early on, right? The la coons, they can cause problems, they can cause a hemiparesis. But IC H is a far more deadly illness, particularly early on. So how do we apply all that? We know about the risk factors that are important for hemorrhage, both primary intracerebral as well as hemorrhagic transformation and think about restarting the in a coagulation in our patients. Let's do a couple cases. All right. So I have a 68 year old guy who has a history of hypertension and a mechanical microvalve. So high risk he comes in with a 30 cc hemorrhage and an inr five. Ok. So what do you guys think pros versus cons of anti coagulating period about the ideology of his hemorrhage? What do you think? Was it triggered? Are there things we can modify the inr was super therapeutic? Great love it. How about the indication for anticoagulation? Does he need to be anti coagulated? Yeah, he has a valve, right? I'm with you. How about other risk factors? Hm. He doesn't have a whole lot of them. Ok. So what do you want to use? He has an active hemorrhage but a valve. How about some heparin? Right? Ok. So he's only a day out. Ok. Over time those friable vessels start to heal but not at 24 hours. But I don't want to wait that long. Right. Or how long do I want to wait? He has a valve. I don't want to wait more than a couple of days. So I would start heparin in as long as cardiology will give me. Right. 342. What, whatever they're comfortable with but not very many, less than a week. Ok. So I take as much time as I have let it heal as much as I can and then I would restart and then I would start heparin and I'd watch him very carefully. Does that make sense? Let's try another one. So I often will. So I rescan for symptoms, for symptoms. Absolutely. For hands down first thing. And then usually after they're therapeutic for 24 hours, I'll rescan them. Also. The problem with that is that what are you gonna do with that information if they've expanded a little? Are you gonna stop? Right. So, you gotta know what you're gonna do with the information you have. We do it because we want to know. But you just, but it's something to think about, right? If they're asymptomatic and have expanded just a bit, are you gonna wait another like six hours and scan again? Right. So then it becomes a little bit dicey, but I tend to rescan after 24 hours because it is a person I'm worried about. Yes, sir. I know because, well, because theoretically if somebody does expand their risk of expanding further is high Well, then I'd probably rescan in six hours and make sure that it stayed stable. I would serial scan. But you're right. You're opening, you're opening Pandora's Box. But I do worry and if they're high, I mean, that guy has an active hemorrhage, I'd be hard pressed to find a neurologist who wouldn't scan it 24 hours. But you do have to think about what you're going to do with the results. Uh, so if, if it expanded just a little bit, oh, if it didn't scan, I would. No, no, no. If I scan once it's stable and then if they're symptomatically the same, I don't scan again because again, what are you gonna do? Right. But symptoms. Absolutely. The other thing. And I'll just say this here while we're talking about scanning. Um, I often like to get a baseline scan period, especially, um, with big strokes because again, we talked about how a lot of them ooze the worst ever is to send somebody out and say, just start your anti coagulation and then somebody gets a headache or somebody gets delirious and you scan them and there's a little bit of blood and you have no idea if it's just because they were, they have a big stroke and it's the natural course or because you started their anti coagulant. So, for that reason, you'll often see us, we'll get a baseline scan before we send them right on their way out the door. And it's ok if they have a little bit of hemorrhagic transformation. But that tells me it's there when they're looking good or looking the way I send them to rehab. So that in rehab, when somebody fluctuates or has an issue, you know what to compare to because it does, it's a very natural thing to have a little bit of hemorrhagic transformation in those big strokes over time. All right, let's try another 1, 78 year old woman. She has atrial fibrillation. So think about her long term, short term stroke risk on Coumadin who comes in with a 50 cc hemorrhage. OK. So pretty big with, with some uh involvement of the ventricles after she fell. Her inr is 2.5. So in range and she has a normal blood pressure. Ok. So the ideology of the stroke, what do you think she fell? Love it? Great. Does the iron r help you, man? Wish she'd been therapeutic? No, she's, but she's therapeutic, right? And her blood pressure is normal. OK. How about indication for anti coagulation? She is a fit so good reason, right? But not necessary for right now. OK. How about other risk factors? She's she's falling. OK. So what do you know about anti coagulating someone who falls? What do you know about the risk? This is again, I'm putting on my stroke neurologists hat. The primary carers don't like it. So there's a, there's actually a really nice paper and I can send it to you um in looking at patients with a fib um and the anticoagulation, you have to fall every day to make your risk when you have an elevated chats vask score. To be fair. I think actually they did it with chats two scores. But to make your risk of having an intracranial hemorrhage, now we're not talking Gigu. So separate issue happens more frequently but to make falling and having an IC H outweigh the risk of again having a large stroke. So something to think about and every patient is different and there are certainly patients who fall all the time who maybe you're thinking about not doing it in but in general don't use a fall like that as an excuse not to anticoagulate a high functioning individual. Think about it. But don't, but, but there's significant repercussions to that long term. OK. So what agent do you want to use in her? So which is, yeah, I think restarting her on whatever she was on before would be absolutely reasonable. So I think Coumadin or a no, you know, I don't feel um when do you wanna do it? Do you wanna do, do you wanna use now, do you wanna use, do when, when do you wanna do this? So she has a Yeah. So I think wait, waiting, you know, I, I would even wait longer than that, right? That, that paper that came out that saying, you know, 6 to 7 weeks, 7 to 8 weeks with a primary hemorrhage, although it was triggered would, would not be unreasonable. So certainly waiting week and into her rehab stay. Um, and you'd probably get some kind of recommendation right around, you know, 1.5 to 2 months in thinking about restarting here. That would be entirely reasonable. But see how she's not gonna get the Hepburn, she's gonna kind of get uh a different course. How about this one? I have an 88 year old man with an ejection fraction of 25%. So he meets heart failure criteria who comes in with a left MC A syndrome and this is a diffusion scan. So remember bright is a cute stroke. This is a new stroke happened in the last week. There's a big cut off here. No left MC A, right. So he has heart failure and had a big stroke. So ideology of IC H. Well, he doesn't have an IC H. OK. Uh How about his indication for anticoagulation? What do you think his heart failure? It's not the strongest, right? I told you there's certainly there's some data that Coumadin is better than aspirin, but aspirin does. OK. So it's not the strongest. It's certainly not a hugely compelling reason. How about his other risk factors? We don't know much. Well, we know we can calculate his her score, right? So we know the guy is 88. He's old. We know, the guy has a humongous stroke. I didn't tell you his, his renal function, but those two things alone can make his her score his likelihood to have any hemorrhagic transformation almost 60% which is huge, right? So he's a guy that I would use aspirin on, right? I don't think the benefits outweigh the risk. So in summary, weighing the need for anti coagulation versus the risk is really important and that helps you to answer the questions about should anti coagulation be restarted at all? And then when do you restart it acutely? And if so how do you do it? Do you use heparin? Do you just let the, the inr slowly go up? Um And, and the ways to think about that is really to think about the ideology of the hemorrhage, whether it was precipitated and there's something that you can modify and the indication for anti coagulation, whether it's emergent, whether you gotta do it today or in the next couple of days because they have a valve also thinking about the agent and these other risk factors and not forgetting about the importance of general impairment, um which a lot of our patients have um uh with that, I think I'll stop and I'm happy to take any questions about this or about other stroke related topics. I know. Um There, there's a lot of uh a lot of discussion. Uh We had some great discussion with the residents about some other questions and I'm happy to talk about them. So I, so how much um the size of the stroke, how much brain you have left after you had these strokes, your decision of moving on to negress prevention. So you, you, you really show there the natural stroke the more likely your risk for breathing, but also the less piece of brain that you have left to work with and, and, and then you have seen the race, you assume that the person also will have more complete. So, is that part of the conversation when you start thinking? Well, so I think that that would be, you know, absolutely reasonable in thinking about an older individual. So like someone who's 90 who wasn't good before their stroke that has atrial fibrillation and comes in with a humongous stroke, they've already taken out, you know, a and what, what exactly, how long are they going to be left to really reap the benefits from being put on an antiqua? And I think that's a perfectly reasonable thing to think about. As opposed to the 45 year old who came in with a hemispheric stroke, they have a lot of potential to recover and a lot of years left to potentially have an increased risk. Um So no, I think that that's a very good thing to think about. Yes, great. Um So obviously, there's another group of patients that we can have like last D program and it's obviously a different issue than anyway. But is there any data out there about when it safe? So in general, DVT prophylaxis is fine to start as soon as. So we talked about how it's 24 hours after IVTP A. But it's fine to start once you've shown that if they're hemorrhage, that the hemorrhage is stable. Um And that stroke fairly acutely. Um The risk of DVT is incredibly high in the patients Uh because the brain, you know, for hemorrhage, the brain doesn't like the fact that it's bleeding. So it actually becomes procoagulant to some uh to some effect. Plus you're immobilizing people. So their risk of clot is very high. So we start DVT prophylaxis as soon as we show the clot is stable or it's not the clot, the um the blood is stable. Mhm And often within the next day. Yeah. Yes, sir. So, um you, you talked about old people and number of adults. Are there any special uh consideration for pediatric patients who might have a like on this nomination? Oh, that's a great question. So, the arterial venous malformations are a different bird altogether. So they are incredibly high risk. They're in a high pressure system, right? So when you put an artery in a vein next to one another and and it starts pumping in uh the we cringe about anticoagulated those individuals uh without having them fixed. We uh I usually don't, they're incredibly high risk to bleed there any other rewarded medical situations that would argue against coagulation? For example, this is uh oh department, in fact. So I think so, he's asking about co morbidities. So I think it's about um that factors into the discussion about how long the uh how long you have to be on a medicine to reap the benefits of the secondary prevention. So, if their Parkinson's is so bad that they, that they only have, you know, six months to a year left. That's, um, then probably that person isn't going to achieve significant benefit. If you're thinking about it from a false perspective at some point once they're wheelchair bound, they're not falling anymore. Right. So, so that almost makes it easier. Um So, so I think having that trade off also having a family discussion about what would be worse. So, is a major stroke worse than, you know, some of these other alternatives because thinking about um, a big stroke from atrial fibrillation is gonna put that the patients done. They're in a nursing home, they're not leaving, um, weighing that against, you know, some of these other risks and putting that in perspective for the family so that the family can think about some of these things. They are hard discussions. There's not an easy right answer, but there are certainly things to be thinking about. Yes, sir. Is there any special consideration for the, um, do require like, and I'm sorry, you and, uh, have a history of have a history of uh micro. So there is you any special for certain someone has to like new brand? That's a great question. So let me uh answer two questions, one you didn't ask but almost asked. And the other one you did. So as far as micro bleeds and TP A, so you are correct that if you look at patients that have been scanned, that their bleeding risk is higher with TP A if they have more than 10 micro bleeds. However, it is still incredibly low and not at all worth scanning patients with Mr Prior to determine whether they have micro bleeds. I want to say that again because otherwise it's going to be, oh Liz Marsh said we shouldn't, we shouldn't give patients with micro bleeds. TP. It is an incredibly low risk still. But there is some data to show that if you have more that, that their risk is higher of having hemorrhagic conversion with TP A. If patients have hemorrhagic transformation with TPA, I certainly think about um uh those things a little bit differently. So who has hemorrhagic transformation usually big strokes? Right? So the smaller strokes don't have conversion as much as the bigger strokes do. So it factors into my analysis. Well, I knew big strokes bled anyway. And yes, once you bled, then am I gonna probably wait even just a little bit longer? Sure. Um The same thing for it, they have a lot of micro bleeds. Um, that in and of itself doesn't, unless they're in the spot for amyloid doesn't factor in quite as much. But what if they've proven that they bleed? Right. Once you've proven you're, you've done something, you're kind of showing that that's the path you're on. So that's, that's, um, I'll give you an example. A patient with atrial fibrillation, right? You put them on anticoagulation, they have a hemorrhage, you take them. So they have never had an ischemic stroke. They've now shown you they've had a hemorrhage. So you, you waffle a little bit and think again, you look for modifiable risk factors. Maybe that person's inr was six. Great, then I might restart them if their inr was right where it was supposed to be. And um and, and they had a hemorrhagic transformation on therapeutic Warfarin. That's a harder decision because they've shown you that they're a bleeder, not a Stroker. Um And that piece of history does have um something at least a small part in, in, in decision making. There aren't right answers. That's a good thing and a bad thing. Uh It's, it's, there's a lot of gray but thinking about how to approach the gray so that you're consistent and so that you have a frame of reference is really important and, and, and why doctors are important, right? Otherwise you could just plug it into an algorithm and it would tell you it would spit out and tell you what to do and how to do it right. But there's clinical decision making involved. That's great. Thank you. So, uh it is a new call for the texting only works standards. Yeah, I can't really. Yes, thank you. So. Created by
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