Kendal Williams, MD (Host): Welcome everyone to the Penn Primary Care Podcast. I'm your host, Dr. Kendal Williams. So, we're here for our second part of our discussion of stroke with two stroke experts, Dr. Christina Blum, the Medical Director of the Primary Stroke Program at Penn Presbyterian, and Kristy Yuan, Associate Professor of Neurology, who is a stroke neurologist as well, practicing at HUP and Pennsylvania Hospital. Christina, Kristy, thank you for coming back.

Dr. Christina Blum: Absolutely. Happy to be here.

Dr. Qingyang (Kristy) Yuan: Great to be back.

Host: So, in the first one, we covered a lot of ground. We talked about the pathophysiology of stroke, the various mechanisms. We talked about the imaging and how that's changed. And then, we talked about some of the big changes in terms of how how you initially manageD stroke with an eye towards the therapeutic benefits that can be achieved with thrombolytics and now increasingly with stent retrievers and mechanical thrombectomy and so forth. So, that was a great discussion, and there's a lot going on in that area.

Now, me as an internist, even if I were a hospitalist, now I'm a primary care physician, but when I was a hospitalist, I would generally be getting these patients now out of the neuro ICU onto my service. Or the other patient population I would see are patients that were not candidates for initial stroke therapy because they're either outside the window or there are other issues that led them not to be candidates and they come to my service directly.

So, I want to start there, start with a patient who is coming out of either acute therapy with thrombolytics, and is now coming to the floor or just an acute stroke that wasn't a candidate. Christina, you see these patients all the time. What are the key elements that you want an internist to know as we're managing these patients?

Dr. Christina Blum: Sure. So, when approaching a patient that's coming to you either from the emergency room or out of the neuro ICU, I think it's important to think about three main buckets. The first is neuroprotection, and we'll go through those components. The second is what workup has been done that's been directed towards figuring out the mechanism. And as we discussed in the previous episode, the mechanism of the ischemic stroke or TIA guides our secondary prevention. And then, the third is the early medical management and then kind of looking ahead to secondary prevention.

So, with neuro protection in general, for any stroke mechanism, we always want to think about the area of the brain that's irreversibly infarcted or the area at risk or, if someone's had a TIA, then there wouldn't be any area of the brain that's been infarcted, but there still might be a risk of having a subsequent stroke.

And so, in general, if we're within the first 24 hours, we position the head of the bed flat. There's not really a lot of strong high-level evidence for this. There was one negative randomized control trial awhile back called the HeadPoST trial that was negative, that was comparing flat position versus non-flat position in patients with ischemic stroke, but a more recent trial specifically showed benefit in patients who had large vessel occlusions who were awaiting thrombectomy.

But the general idea is that, if tolerated, if you have the patient flat, maybe there's going to be more blood flow to the brain, and this may be more relevant if someone has a hemodynamically significant stenosis supplying their stroke and some people might be more sensitive to position. So, keeping in mind someone's pain level or aspiration risk, we usually do head of bed flat as tolerated for the first 24 hours. But I'm usually quick to liberalize that because we don't want to get in the way of getting evaluated by physical therapy, speech, et cetera.

And, the next is glycemic control, that's really important. So, severe hyperglycemia can be associated with worsened risk of neurologic deterioration or even hemorrhagic transformation, particularly after thrombolytic therapy. Normothermia, and then importantly, permissive hypertension.

And so, if someone receives thrombolytic therapy for the first 24 hours, their blood pressure goal is less than 180 over 105. However, if a patient did not receive thrombolytic therapy, we let the blood pressure essentially kind of do its thing. And so, what's happening at the level of the stroke is that, if you remember autoregulation, when a brain is not seeing blood flow, the blood vessels try to dilate to preserve blood flow. And when a stroke occurs, that ischemic tissue loses its capacity to autoregulate and the blood vessels are kind of maximally dilated and can't do anything else. And then, there's an area at risk around the brain where there still might be some capacity to autoregulate, and that's called the penumbra.

And so, what we don't want to do is, if someone comes in with ischemic stroke symptoms and a systolic blood pressure of 200, there might be a reason why their blood pressure is that high, or maybe they were chronically hypertensive and not taking their blood pressure medicines in the first place, and we don't want to artificially lower them or give them a medicine they weren't taking, because that can actually precipitate ischemia.

And so, this kind of disruption in the acute period after ischemic stroke usually is maximal within the first 24 to 72 hours, give or take. And so, we do permissive hypertension up to 220\/120, and this is, of course, as allowable from a cardiovascular standpoint, depending on, you know, if there's something acute cardiovascular going on with the patient.

And it's not that we're pushing the patient to that level. Like, if they're clinically stable at a blood pressure of 140, when they're having their stroke, we're not going to push them higher. If the patient is higher, it's okay. We will only treat if it's above that level. And then, eventually, we kind of slowly bring it down. And this is really important. As I mentioned before, sometimes, if we start meds too quickly in the acute period, that can sometimes put someone at risk for completing their infarct, although other times it could be just the natural history. So, I would say that's like neuroprotection.

And then, if a patient has not received thrombolytic therapy, we discussed last time, early antithrombotic therapy with antiplatelets as being a form of an acute treatment. And so, the patient gets started with aspirin or aspirin and Plavix depending on different criteria which we can get into.

And then, the third is kind of what tests are being done to explore the mechanism of the stroke. So, brain and vascular imaging, cardiac workup, et cetera, which we can go into.

Host: Yeah. Kristy, I want to ask you if there's anything to add to that. But I also want to throw another question your way and that is when do we start the antiplatelet therapy? Is it started in the emergency room bay, in terms of aspirin in particular, or is it something that we're doing later?

Dr. Qingyang (Kristy) Yuan: Yeah, I think if someone is not getting thrombolytics, we start it right away as soon as possible. And last time, we reviewed some cases where patients would get aspirin and Plavix loaded, and those are usually TIAs and minor strokes. And so, we do try to start that right away. If patients undergo a thrombectomy, they have frank blood in their brain, then we could hold it for a period of time. But we do try to start that right away.

And I think like it's beneficial in the hospital if they're first dose of aspirin to be a full dose 325. And then, it probably doesn't matter much beyond that, whether they're going to be on 81 milligrams. And the longer you kind of go from that acute period, the less of a difference the aspirin load would make. And so, we generally would then transition into 81 milligrams of aspirin.

Host: And just 81. And you're comfortable with 81 long-term, especially in the dual antiplatelet therapy mode, I assume.

Dr. Qingyang (Kristy) Yuan: Yeah. After their 21 days, they go to aspirin 81. You know, Christina started to allude to certain situations where we might do aspirin and Plavix for longer, and that gets into what we find in the workup. And so, she mentioned vessel imaging. That's one of the primary things we would do. They probably already have gotten those scans from the ER, vessel imaging, maybe a CTA or MRA head and neck, or maybe carotid ultrasounds.

And if someone has a large vessel stenosis, particularly intracranial severe atherosclerosis in the region of their stroke, we have good evidence that perhaps months of aspirin and Plavix together or some combination of aspirin dual antiplatelet therapy may be more beneficial than single antiplatelet therapy initially, but then followed by probably single antiplatelet therapy long-term.

So, there are situations outside of the TIA minor stroke, mainly severe intracranial atherosclerosis that could benefit from longer-term aspirin and Plavix or dual antiplatelet, but still not lifelong. So, that's one of the situations.

Host: So, I got into that, when we sort of structured the outline of our podcast, we though that we would talk about medications in the context of secondary prevention, but because this starts so early in the process, you know, potentially even in the ED, I wanted to kind of talk about antiplatelet therapy upfront.

And as you noted, aspirin, and then for those that are eligible, minor stroke and TIA, that this is the new thing, right? You get dual antiplatelet therapy, aspirin and Plavix. And then if they have intracranial atherosclerosis, they're getting it even longer. Three months? Is that right?

Dr. Qingyang (Kristy) Yuan: Yes.

Host: Three months, yes. And then, let's just finish this topic. Do you care what we choose after that? Because we're going to now go down to single antiplatelet therapy, do you care if it's aspirin, Plavix, ticagrelor? What do you think about the balance of those three?

Dr. Qingyang (Kristy) Yuan: I would say that technically, long-term, there's no single antiplatelet that is better than another for a secondary stroke prevention. But there might be situations where one is preferable over the other. So, if someone has, let's say, intracranial atherosclerosis and they had a stroke while on aspirin, after they get months of dual antiplatelet therapy, you might consider switching to Plavix. You might consider other combination therapies for longer-term. For example, there is a aspirin/low-dose Xarelto combination from the COMPASS trial, that is more so for large vessel stenosis below the neck, carotids included. I mean, carotids and everything below the brain. So, that's something to consider longer term in that particular situation. But I think Plavix, for patients, if they've got CAD, if they got PAD, maybe that's a better consideration, especially if they had a stroke already on aspirin. The American Heart Association actually has some guidelines surrounding aspirin 325 long-term for intracranial atherosclerosis. So then, instead of aspirin 81, full-dose aspirin could also be a consideration.

And typically, in my practice, I would say if someone has intracranial athero, had another stroke while on aspirin after the dual antiplatelet therapy period, I might consider checking a Plavix response test, the genetic polymorphism CYP2C19, to see if they are a good Plavix responder. And if they are, then I might switch them to Plavix.

Dr. Christina Blum: Yeah. it's just to kind of add to that, it gets a little tricky, and I think that's what's fun about stroke is that it's a little nuanced. And so, yeah, as Cristy said, any monotherapy could be an acceptable option eventually. I think that aspirin's more recognizable to patients. And so, it's, like, easier to tell patients to take it.

And there isn't any actual high-level evidence that guides us beyond the acute period. And in the trial where aspirin and Plavix were compared head to head for secondary stroke prevention, CAPRIE, they were essentially equivalent, but there was a trend towards benefit not significant for Plavix, but it was probably driven by the patients with peripheral vascular disease, as Kristy had said. And there is also a subset of patients that could be resistant to Plavix, whereas resistance doesn't really occur with aspirin.

So, it is a little bit nuanced. But if you look at the AHA guidelines, or you read UpToDate, for example, aspirin and Plavix are both kind of acceptable options for monotherapy long-term, and Aggrenox, which is not really used as much anymore. And in some Asian populations, cilostazol has been studied. And then, there's also Ticagrelor monotherapy, which has been looked at in the minor ischemic stroke, high-risk TIA population. And ticagrelor could be considered if you've done a thorough workup of a mechanism and a patient continues to have a small vessel subtype stroke, or maybe something due to athero and they're doing everything they can to optimize their other risk factors, and maybe they're Plavix-resistant, then you could maybe consider that in that situation.

But whenever anyone has a stroke on whatever therapy that they're on, the first question is not, "Did they fail their medicine?" It's, "What's the mechanism of the stroke and what's going on with their other risk factors?"

Host: Yeah. So, many of these strokes are going to be atherosclerotic in origin, so we're going to be dealing with antiplatelet therapy. Let's get into workup, though, because not all strokes are atherosclerotic in origin. And we need to sort that out. We don't know that for sure often when they come to us.

So, I want to ask about some typical studies that are ordered. We order an echo, we put patients on telemetry, primarily because—well, two reasons for telemetry. One is, I think, that there is increased ventricular arrhythmia risk in patients with stroke, but also because we want to see if they have declared themselves as having atrial fibrillation. And then, we often order an echo. Sometimes we consider a TEE depending on the circumstance.

But before we get to that, I want to ask about the imaging. Because when I was a resident, it was echo, carotid dopplers, I mean, ones we could put a stamp and check the boxes. But now, we're getting people that have already had a CTA. They've already maybe even had an MRA. And I want to ask you, by the way, when you would do an MRA, because so many people get CTAs, because it's quick, right? You can do it in the ER bay. And it helps drive your thinking about stent retrievers and so forth, but okay...

So, is it sufficient to do the CTA to get the vascular imaging I'm going to need for decisions long term? And second question is, when are you doing an MRA in addition or instead of?

Dr. Christina Blum: Great question. So, CTA of the head and neck, or MRA in the head and neck, both actually provide similar information of the anatomy of the head and neck vasculature. Carotid Dopplers image the arteries in the neck, which are mainly the carotids, but you can get the direction of the velocities of the verts in the back. But the carotid dopplers, of course, are not imaging the intracranial vessels. And so, yes, you're right. Back in the day, the first pass kind of stroke workup was carotid Dopplers, maybe an MRI, aspirin, send the patient on their way. But a lot has changed.

And so, just to review, we have our three main categories of mechanisms. So, small vessel disease, large artery disease, and cardioembolism, and then we have other causes. And that includes embolic strokes of undetermined source or other causes such as cervical artery dissection, hypercoagulable states, et cetera.

But usually, when someone's coming in to the emergency room, they will end up getting a CTA because that's the acute study of choice, and they may already be in a window where the hospital is following their stroke activation protocols. But if not, you can do either an MRA head and neck or a CTA head and neck. I prefer a CTA head and neck because you get a little bit of a better view of the aortic arch and the takeoff of the vessels, and you can see calcifications, which is a marker for athero. So, you're not going to get that specific information with an MRA, although you might visualize intracranial calcifications of the vasculature on a non-con head CT.

MRA head and neck takes longer to acquire, and the patients might be limited by pacemakers or claustrophobia. There's evidence that it's not as harmful as people used to think to give contrast in the case of renal disease, and that used to be kind of larger hesitation for CTAs, but it is radiation. So, each study has its pluses and minuses.

MRI also has some additional sequences. So, sometimes we do vessel wall imaging, or we can do fat-sat sequences for dissection. So, there's some additional sequences that sometimes you can add on to MR. And if you're in the non-acute period, it's easy and the patient can tolerate a long study, then it's easy to get the brain MRI plus the vascular imaging all at once.

So, usually, our study of choice is going to be head and neck vascular imaging with a CTA head and neck, or MRA head and neck. The main time where you might be okay with carotid Dopplers could be maybe someone has known AFib and you just need to make sure that their carotids are open because that's the one thing that will change your management. But particularly with young people or really anyone, you want a good picture of the head and neck vasculature because you're looking for both intra and extracranial atherosclerosis. And intracranial or extracranial atherosclerosis carries the highest risk for early recurrence. And so, you want to know the status of the vessels as soon as possible.

And to add to your question about imaging, the brain MRI is important because that characterizes the stroke distribution and location, which informs us about the mechanism.

Dr. Qingyang (Kristy) Yuan: Yeah, I think, Kendal, your question about different modalities of imaging is particularly interesting when we're talking about carotid imaging in the neck. And I would say that's one situation where we would get probably at least two modalities of imaging. So if someone gets a carotid ultrasound that is, you know, 70% stenosis, you might want to confirm that with a CTA, which sometimes can estimate lower levels of stenosis compared to the carotid ultrasound, just depending on different factors, or if there's heavy calcifications, it might overestimate the degree of stenosis.

In that situation, the MRA actually subtracts out the calcifications. And so, MRA for the neck, even though it can be a harder study to acquire with no movement, perfect pictures, all of that requires a lot of perfection. It might be a quite accurate study for a measuring degree of stenosis. The CTA, like Christina said, can give us different morphologies a litle bit better if there's like a carotid web, if there's carotid dissection, if there is tortuosity, if there's fibromuscular dysplasia. So, things that a carotid ultrasound might not offer.

Dr. Christina Blum: Yeah, that's a great point. I would say whenever we are evaluating the degree of carotid stenosis and considering a candidate for intervention, I always like to test and I would say my preferred combination might be a contrast-enhanced MR neck, and then the carotid ultrasound to evaluate the plaque and the plaque morphology. But yes, always two tests when we're thinking about carotid revascularization.

Host: That's interesting. So, carotid ultrasounds have not gone away. They still have value. Yeah.

Dr. Qingyang (Kristy) Yuan: They absolute have great value. And I think, especially for a carotid stenosis, they can give us the dynamic features that we don't get with the other studies and whether there is mobile components, and whether there's heterogeneity, certain things that we can better tell on ultrasound.

Host: Yeah. The next thing we're ordering is an echo. Christina, do I need to order an echo with a bubble?

Dr. Christina Blum: That's a great question. So, in most cases, I would say you want to default to no, but we can kind of tease that out a little bit. So, an echocardiogram is generally indicated in any patient with ischemic stroke or TIA, and that's to look for a few things. Number one, rule out any obvious clot. Number two, to look for structural heart disease. So, looking for LVH, which might give us information about whether the patient's been living with hypertension, wall motion abnormalities, ejection fraction, the size of the left atrium, et cetera.

 The presence of a PFO usually is going to be clinically relevant in someone who is younger, who has an unexplained embolic-appearing stroke. And so, that's our category of ESUS or embolic stroke of undetermined source. So, if someone comes in and has a small cortical infarct or maybe an infarct in more than one vascular distribution, or maybe a cerebellar infarct because cerebellar infarcts can be from a couple of different mechanisms, and you've looked at the vessels and you don't see any evidence of hemodynamically significant stenosis supplying that stroke territory, so that would be greater than 50%, or you don't see any obvious drug use or a dissection or something else clearly going on, the patient's young and has no other known vascular risk factors, that's where the PFO becomes a little bit more clinically relevant. And so, that's what the bubble study will look for.

So, I would say the age cutoff you can think about is up to age 60. But depending on where you work, like, for example, at our institution, a lot of our younger patients have a lot of risk factors. And they're not young when they're in their 40s and 50s. So, we kind of have to approach each case and consider, if we find a PFO, what are we going to do with that information? Is it really going to change our management?

But we do like to see contrast-enhanced echos, particularly if the stroke appears embolic or if someone has a trop elevation or some sort of EKG abnormality. So, the contrast on a regular transthoracic echo will improve your ability to look for left ventricular thrombus.

Host: If you have an embolic stroke, because it's clearly embolic, it's involving multiple territories, you know there's an embolic cause, and the TTE, the transthoracic echo, even with contrast imaging, is negative, then do you recommend a TEE to look for a source, or are you happy with that?

Dr. Christina Blum: Yeah. So, again, it depends. So if someone is younger and has no other vascular risk factors and the stroke appears embolic, then our threshold to do a TEE is lower, for sure. So, I would say we approach it on a case-by-case basis. And you might actually get different answers from different stroke neurologists. My threshold to do a transesophageal echo might be different from Kristy's and might be different from someone else's.

But I would say, generally, we think about it under the age of 60, if someone has an embolic stroke of indeterminate source. However, if we're looking for endocarditis, that would be a situation where we're going to go to a TEE regardless of what else is going on. And then, we're always going to be thinking how is it going to change our immediate management. So, if someone has no atrial fibrillation, then an echo is not really going to change our management in that case.

Host: I understand that 30% of the strokes are in this ESUS category, right? Undetermined source, embolic stroke of undetermined source. I think that's right, about 30% of the ischemic strokes. And so, we're left with this question of where did this come from? How did it arise? AFib is always a concern. And I know there was a study that showed a higher percentage than expected of patients who got long-term monitoring after having an ESUS event or actually had AFib. And so, it's led us to start to think about doing longer term monitoring when we discharge patients, right? Has it now become standard? It's not standard for all strokes, right? Is it just standard for ESUS strokes? Or maybe it is standard for all strokes?

Dr. Qingyang (Kristy) Yuan: Yeah. Sure, I can answer. So, I think that definitely for ESUS, even if they are a younger patient, unless you highly suspect some other mechanism, you can truly definitionally only call them ESUS after you did some kind of monitoring. That could be a week of telemetry, that could be a few days of telemetry. But generally, we like to see longer. And if we're going to order ambulatory cardiac monitoring, we generally order 30 days, to start with.

And I would say sometimes, if you have someone who is older, you think they might have more chances of having AFib, maybe their LA is dilated, maybe your chances of finding something on the ambulatory monitor is higher, you would go with the two-week or 30-day monitor. But for a younger patient, maybe less than age 65, less than age 60, they don't have those features, sometimes we can go straight to loop recorder placement, just to monitor them for longer.

And if you do detect AFib in those situations, there's sort of an entity of like AFib after a stroke, that may occur as a result of stroke or it just occurs because you have some kind of atrial cardiopathy, may not actually be the cause of stroke. But it's an emerging field, but generally get anticoagulated if AFib is found. And I think in certain situations, you might go for shorter monitoring.

Host: Let's say you do detect AFib, Kristy, and you know the patient needs to go on anticoagulation long term. What's the timing of starting that? I mean, we talked about, in ischemic stroke, aspirin and Plavix, you start very early. But history of AFib comes in with embolic stroke, they weren't on anticoagulation before, they're going to need it now. When do I start it?

Dr. Qingyang (Kristy) Yuan: So, if you detect AFib on an ambulatory monitor, you start it as soon as you find it. Because generally, by then, it already would have been, like, weeks, from their time of stroke. If we're talking about this patient is still on your inpatient hospital service, Kendal, and they have a smaller size stroke, we have better criteria now in the last few years saying you can start it within one or two days. If it's more of a moderate-sized stroke, then maybe three days, three to four days. If it's a larger size stroke, maybe seven to 10 days. We used to start them much later for a larger size stroke because of the fear of hemorrhagic transformation. But there's less of that risk documented recently. And so, we generally are starting anticoagulation sooner.

Host: Yeah. It probably helps that we're not using heparin and Coumadin anymore either. Have you had any experience managing inpatient heparin? You know, you get these very high PTT values. And so, it's very hard to sort of dose it correctly. And so, I think with the DOACs that we can start, it's a little easier because the risk is generally lower.

So, I'm going to be sending my patient for an echo. I'm going to be looking for a potential source of an embolic stroke, whether it be an endocarditis or maybe they have a clot in their heart or some other thing. I'm going to be looking for atrial fibrillation. Those are basically going to determine whether I'm going to put somebody on an anticoagulant.

if they don't fall into that category, meaning I have a clear cause of stroke that is sensitive to anticoagulation, then I'm going to be going down atherosclerotic pathway and I'm going to be treating them to prevent another atherosclerotic-related event with aspirin and, as we noted, the dual antiplatelet therapy in certain circumstances.

But I'm also going to be adding a statin, right? And a high-dose statin, right? And so, going back probably a decade or more, we know that starting Lipitor at high-dose, 80 milligrams, atorvastatin, has been the standard of care. I don't know if that's changed in terms of whether or not you can be flexible with your choice of statin or you still prefer Lipitor. When I was in training, we would measure the LDL and we'd decide whether they needed it. And then, I think it was a SPARCL trial—you can correct me—came out that said, "No, 80 milligrams right away makes a huge difference in that short period of time after a stroke." Any comments on my sort of quasi summary there?

Dr. Christina Blum: Yes. You're right, it was the SPARCL trial. That was the landmark trial looked at Lipitor and its benefit in segmentary stroke prevention, and showed a small but significant absolute risk reduction, over several years for ischemic stroke.

And Lipitor 80 was what was used in the trial. But our standard practice is any patient with an ischemic stroke, regardless of the degree of athero. But generally speaking, when we're thinking of any athero or if they have an elevated LDL, they should get discharged on a high-intensity statin, so Lipitor 40 or 80 or Crestor.

The exception would be a patient who has completely clean vessels, is young, and we're thinking about a different stroke mechanism as you mentioned, or someone, say, with a spontaneous cervical artery dissection, which would heal spontaneously over time, and they'll just get an antiplatelet.

And so, high intensity statin, definitely, when we're talking to patients, we're talking about a few things at once. We're talking about the mild blood thinning medicine or the strong blood thinning medicine, the high-intensity statin, we're talking about blood pressure control, glycemic control, lifestyle changes, it's a whole package.

And statins not only have lipid-lowering benefits, but of course, they help with plaque stabilization. And so, we're not only treating their—you know, in general, especially if we think the mechanism is due to athero, we want that LDL extremely low in particularly high-risk patients below 55. But we're not just treating to level, we're treating to mechanisms. So, even if their LDL improves, we don't want them to come off of a statin entirely. That's something that would be long-term for them.

Dr. Qingyang (Kristy) Yuan: Just to pop in here, probably the primary care doctors also have heard of this, like, very hot off-the-press new lipid guidelines from March of this year. We used to just target our LDLs to be less than 70, for usually all-comers of stroke and European Cardiology societies have changed that to be lower.

And I think, just recently, our lipid societies have recommended LDL less than 55 for anyone who's had a heart attack or stroke or clinical ASCVD. I think whether you have athero or not as a mechanism of your stroke, we do try to target LDL even lower now, maybe between the 50 to 70 range, may be below 55. But certainly, if you've got athero as mechanism or diabetes or other high-risk features, it'll be less than 55.

Host: This has been very interesting, that it's evolved. And we've had Dan Soffer and other colleagues on, Doug Jacoby, to talk more about this. And I've learned a lot about cholesterol plaque from the SPARCL trial in terms of how it works so quickly, because you wouldn't think it would make such a big difference, but it really does stabilize these plaques early, and that really educated me partly about just this power of statins and how they work very quickly.

I want to circle back to blood pressure, because we talked about it in the context of patient coming right onto the floor out of the neuro ICU or up in the ED. But now, they're leaving the hospital, and we know that control of blood pressure is a key element of preventing that next stroke. My practice had always been, I think, 72 to 96 hours, which roughly approximates when they're about to leave the hospital. But how do you approach blood pressure? Let me just leave it open-ended.

Dr. Qingyang (Kristy) Yuan: Are we talking about when they leave the hospital, blood pressure?

Host: Well, how do you approach it, short-term and long-term, because you don't want to drop it too quickly, right, Kristy?

Dr. Qingyang (Kristy) Yuan: Yeah. As far as blood pressure goes beyond that first few days of acute period, even to when they may be first visit the PCP in their office one to two weeks later for a post-hospitalization visit, if they have large vessel occlusion or significant intracranial atherosclerosis as their mechanism, you might want at least two weeks of permissive hypertension. That doesn't mean that it's definitely two weeks, you know, give or take, it doesn't mean that they have to be off of all their blood pressure meds for two weeks, it just means that you're carefully, gingerly, trending them downwards. And so, they might leave the hospital with just one or a very low-dose blood pressure med, and maybe the first doctor they see out of the hospital is their primary care doctor. So, we especially rely on primary care doctors to kind of carry forth that permissive goal. Maybe for the first two weeks of maybe slowly go up on the dose of one blood pressure med and, after two weeks, add back another blood pressure med, slowly go off on that. It might take a month to get them back to the eventual goal of, for the most part, less than 130/80.

If they have significant, maybe even multi-vessel large artery athero, and they feel symptomatic or litheaded or a get return neurologic symptoms when their blood pressure is very low, then we might sometimes allow long-term blood pressure to be slightly higher, maybe in the 110s and 140s range for some very high-risk patients. But I do think for that particular population, it's going to be a slow move back to normal.

Even for, let's say, a small vessel disease stroke patient, if they're seeing a primary care doctor, let's say within seven days of having a stroke, they might not be at their normal blood pressure yet. And that could be okay, but they're going to be more quickly moved towards normalizing that blood pressure. And so, they might more quickly add back their blood pressure medications as an outpatient.

Dr. Christina Blum: Yes, the large vessel and small vessel subtypes, I would say, that permissive hypertension plan is extremely important. And usually, on the inpatient side, when I'm seeing these patients, we're recommending permissive hypertension to the max up to around 48 to 72 hours, and then pending ongoing clinical stability, a plan to gradually lower. So, if a patient actually was taking all of their three or four blood pressure medicines when they came into the hospital, they are not likely leaving on all of them, and it has to be a very gradual process, as Kristi said.

And the small vessel disease mechanism in particular, the natural history of that stroke is that sometimes as they pick off their perforators, they can complete their infarct even up to a week. So, sometimes, we have had patients get discharged on day three, after their stroke, and they have just mild symptoms, but then they complete their infarct a week later. And the very first thing that we check is what was going on with their blood pressure, in addition to their sugars. Were they taking their antithrombotics, et cetera?

And unfortunately, that sometimes is just the natural history. But very important, especially with the chronic hypertensives and they have reduced, compliance in their vessels to be very gradual with the blood pressure lowering over time. So, the most important modifiable risk factor for stroke is high blood pressure. But just because we want the blood pressure normal, long term doesn't mean we want it normal at the beginning, and that's what we explain to patients.

Host: Yeah. And just to highlight, because repetition is the mother of learning, the ones you have to be most careful with dropping too quickly are the intracranial athero and the small vessel ischemic patients, right? Those are the ones you're most careful with.

Dr. Christina Blum: Yes. And extracranial disease as well.

Host: Extracranial disease as well. So, carotid disease, others. Where there may be a flow-limiting lesion, right? But in general, I think, the others, though we may not be as permissive, we're also not lowering it quickly no matter what. We're gradually doing it, which is the way we do it in primary care. I put somebody on an antihypertensive. I don't have them come back the next day to get their blood pressure checked. I see them in a couple weeks or four weeks. And I think that mode is appropriate in this setting.

Dr. Christina Blum: Yes.

Host: Yeah. Before we leave, I wanted to jump back to one point, Christina, that were talking about earlier about anticoagulation in the setting of ESUS, so embolic stroke of undetermined source. And there was some interest, I highlighted that we found that more patients than we expected were in AFib, and there was some interest to going ahead and empirically anticoagulating patients in the setting of ESUS. But I understand that didn't quite pan out, is that right?

Dr. Christina Blum: That is correct. So, there have now been three randomized control trials that have looked at DOACs versus aspirin for secondary prevention for patients with ESUS. The first was RE-SPECT ESUS, and then NAVIGATE ESUS, and then ARCADIA. And RE-SPECT ESUS looked at Pradaxa versus aspirin and NAVIGATE ESUS looked at Xarelto versus aspirin. And the rate of stroke was similar in both groups, and there was more bleeding in the DOAC group.

The more recent ARCADIA trial looked at Eliquis versus aspirin, but they were also trying to select patients with ESUS who also had one additional biomarker of left atrial cardiopathy. So, either a prolonged P wave terminal force, moderate to severe left atrial enlargement or an elevated BNP. And unfortunately, there was also no difference between Eliquis and aspirin. However, Eliquis did not have an increased risk of bleeding.

So, we actually don't have high-level evidence to support. Like, if you see someone with a stroke and you think it's embolic, and you really want to anticoagulate them, you don't actually have strong evidence for that in that particular patient population. But it gets a little different if someone maybe has an underlying malignancy that's associated with hypercoagulable state, or someone has a demonstrated clot elsewhere, or someone has another history that might make you worried about an underlying hypercoagulal state, or if this is their second or third event, then it becomes a little trickier. But for a first event, then it would be the antiplatelet approach that we already discussed.

Host: Very quick, Kristy, I actually wanted to go back to one point you had said earlier, you had mentioned a combination drug of antiplatelet and anticoagulant, I think it was Xarelto and Ticagrelor or aspirin and Xarelto—it was aspirin and Xarelto. What circumstance would you use that drug?

Dr. Qingyang (Kristy) Yuan: Yeah. So, that's based on a COMPASS trial looking at aspirin versus aspirin and 2.5 milligrams twice a day of Xarelto in stroke prevention in those with some at least moderate degree of peripheral artery stenosis, and periphery includes neck, carotid, vertebral, coronary, and peripheral artery disease.

And it's important to note that that combination is not an acute therapy. So, it's not like our Plavix load, aspirin load, even Ticagrelor load. I would say for patients who have maybe moderate carotid stenosis, or they've got some coronary disease, or maybe they've got aortic arch athero, which is also below the neck, and they've already undergone three months of asprin and Plavix for large artery athero-related stroke, then I might consider this combination long-term. And this is, like, based on also if they're also not having bleeding complications, renal disease, and all of that.

There is a trial going on right now called CAPTIVA to look at different dual antithrombotic combinations, aspirin/Plavix, aspirin/ticagrelor, aspirin/low-dose Xarelto for stroke prevention, kind of comparing dual head to head three ways. And that's ongoing, But I have to say that the aspirin/Xarelto combination, ... that arm has been paused because of some risk concerns, and this has not panned out the COMPASS trial in terms of the bleeding risk wasn't outweighing the benefit. But I think intracranially, I would be a little bit careful prescribing that combination. And extracranially, I might consider that long-term.

Host: Interesting. That's interesting. You're kind of changing my world here, because I always separate out, you know, atherosclerotic with antiplatelet therapy from the thrombotic and anticoagulation. So, you're mixing them up, and I'm interested to see how that pans out.

So, what do you tell patients as they're leaving the hospital? You know, the family's all gathered around the bed. You've been in this situation hundreds of times, their loved one has just experienced a stroke, and they're asking you about what are they going to be able to do. And I think we should do a separate podcast. The two of you have recommended an expert to come on to talk about this, but I wanted to just get your input on what you tell patients in that scenario of what they can expect through the rehab process and so forth.

Dr. Christina Blum: The one thing I think it's important to emphasize first with patients is that they understand why they had the stroke, their specific risk factors for stroke and what medications they're going out on. Stroke education in general is an important piece and explaining to them exactly what's going on with their body and how that is due to the stroke that they had so that they understand.

I think I also set expectations, because depending on the situation, if someone has very significant deficits, it's not so much getting to the point where they may not be there anymore, it might be working with the deficits or living with the deficits that exist, and then also making sure that they understand signs and symptoms that should prompt them to come back. And then, I'll hand it over to Kristy, who can talk more about the rehab and recovery piece since she sees these patients in the outpatient setting.

Dr. Qingyang (Kristy) Yuan: I think, even at the bedside, the families are often wondering, like, "Will he walk again? When can I go back to work?" And I do encourage them to take it day by day. There are some people who improve quickly after the first day and they might have a better prognosis.

There are people who've just had a large stroke and everything and lots of comorbidities and everything is against them, so I might be a little bit more guarded. But I would try to get them a trajectory of natural recovery of stroke, which is that in the first three months, you get the greatest level of recovery, better even with physical therapy and therapies.

In the first six months, from three to six months, you can still get recovery. Then beyond that, you can still get recovery. And I think that, previously, we had thought about stroke recovery as a more narrow window of maybe the first three months or first six months. So, particularly in young patients, they can look very different one-year later. And I think there's a number of things influencing that.

I would be hesitant in telling patients, "Yes, you can walk," or, "Yes, you're going to do this." I would just say, "I would know more at three months, at six months, at one year. But that it is a promising sign that your loved one has improved this quickly already in the first 24 hours."

And I think that with recovery, a lot of things influence that. So, I think having social support, and obviously socioeconomic factors help with that. Treating mood symptoms help with recovery. Over 50% of patients after stroke will have changes of mood, either depressed mood or sometimes increased agitation. And treating those mood symptoms does improve outcomes in whichever way that fits, whether it's psychotherapy, other outlets, whether it's medications.

Host: I think there was a trial a few years back in sort of starting Lexapro in this population. It had some benefits, but I haven't really followed that literature since.

Dr. Christina Blum: The FLAME trial was the original trial. And eventually, there have been several conflicting. And ultimately, it didn't hold, but I think that, as Kristy said, there are comorbid mood conditions that occur. And it's a life-changing event to have a stroke. And so, treating any comorbid mood issues is important, I think, to help with someone's recovery and motivation to participate in rehab, et cetera.

Dr. Qingyang (Kristy) Yuan: I just wanted to highlight. with the FLAME trial, was just actually looking at SSRI, specifically fluoxetine for motor recovery. So, that's been kind of disproved. But I think it is still beneficial for treating mood symptoms, as it relates to recovery. So, not using SSRIs for motor recovery but, if they are depressed, to treat their depression.

Host: So, I can stay here for the next hour asking you questions, but we don't have time for that, so we're not going to do. I did want to highlight one thing you had said, just about education.

One of the things I found in my career is that we often talk over patient's heads, and we use terms. We all came to medical school not knowing a language about the human body and the pathophysiology. We learned this language, and then we don't really know how to speak about it outside of that language. So, we have to create other ways of doing it. And, everybody in their career, if they're going to be good at patient education, is going to learn how to do that. And it sounds dumb at first. I use all kinds of analogies about pipes and clogging of pipes and everything else. But it's really important to help people understand and be able to be faithful to these therapies moving forward, so that they need to understand exactly why they're taking these drugs and what benefit they're having with them. So, I wanted to emphasize that point.

Dr. Christina Blum: Absolutely. I completely agree. And, you know, the patient has to be empowered understand going on with them and however we can get them to understand. Sometimes we might even show them the picture of the brain and kind of walk through it with them, and that can help too.

Host: Well, thank you so much for spending two hours talking about stroke. We covered a lot of ground. And as I said, we even left some stuff on the table that we didn't have time to cover. So, maybe, hopefully, we can have you back and go more firmly into the outpatient environment and talk about some of the presentations that we see and how to work through those.

So, I want to thank Christina and Kristy for being on the Penn Primary Care podcast, and I want to thank the audience for coming again. Please come again next time.

Dr. Christina Blum: Thanks so much, Kendal.

Dr. Qingyang (Kristy) Yuan: Thank you.

Host: Yeah, it was great.