outcomes for patients with nmda receptor Encephalitis have not changed over the last decade we need your help to Reaper newly diagnosed nmda receptor encephalitis patients who may be eligible to participate in the nih-sponsored extinguished trial the extinguished trial is now enrolling new nmda receptor encephalitis patients to learn more search extinguish trial at clinicaltrials.gov or call the extinguished hotline at 844 for brain five [Music] this is Jose Mourinho editor-in-chief of the neurology family of journals the neurology podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients thanks for listening and have a great week [Music] hi and welcome to the neurology podcast this is Dan Ackerman from St Luke's Health Network and today I have the pleasure of speaking with tan Nguyen from Boston University about her paper titled dual anti-platelet therapy versus all the place for patients with minor non-disabling acute ischemic stroke the Aramis randomized clinical trial Tom thank you so much for joining us on the podcast today Dan thank you so much for having me and I also want to acknowledge the principal investigator of the trial who is puishing Chan he was the brainchild behind this Aramis trial wonderful well thank you Dr Chen as well because this is a great study now there are so many important things in this paper for us to unpack but one thing I just want to get off the bat this idea of minor non-disabling stroke could you just talk to us a little bit about how you defined minor non-disabling stroke and how does this affect your clinical practice from day to day so minor non-disable stroke was defined in the Aramis trial as patients who presented with acute ischemic stroke with an ni Stroke Scale of five or less and they had to have one point or less on the NIH single item scores such as motor Vision language neglect and you couldn't score in the Consciousness item because we were worried that would be a potential stroke mimic or a patient with encephalopathy so that was excluded and then the study treatment had to start within four and a half hours so if these patients met these criteria they were automatically considered for the trial and then in terms of the non-disabling component that was a little bit trickier because we had to ask the patient or their family if the patient wasn't able we had to ask them to what degree with this deficit that they present with might interfere with their activities of daily living their Hobbies or their work and so that was a very important component of selecting if patients would be eligible for this trial because as you know this is a very controversial population for consideration of autoplays versus other therapies absolutely I think in our practice from day to day it's very easy to be pigeonholed a little bit by The anide Stroke Scale and the ni Stroke Scale is wonderful as a tool but recognizing that patients who score zero on The Stroke Scale may still be symptomatic and those symptoms could still have a major impact on their life having a method like this to pick out those patients for whom the symptoms would still be disabling in their eyes and having that open communication about how important the symptoms are to the patient does a great job of really reinforcing that early doctor-patient relationship since we're trying to deal with this rapid decision making and helps us to orient ourselves in terms of altar Place versus other potential therapies I love that and to write on your point Dan even though you could be included with an nihs of one point on the motor scale so say you had a drift if that was going to be potentially disabling to the patient meaning you know I need to play violin or I need to play My Piano then they probably would not have been included in the trial now in this trial this this was a non-inferiority study comparing all to place versus dual anti-platelet therapy so tell us about the results what did the trial teach us it pivots on the point that the ninds trial the initial trial that demonstrated that TPA was effective in patients presenting within three hours they were excluding patients with rapidly improving or minor strokes and so this set the bar for who you should treat with TPA or not and then in 2011 we saw some data coming out from get with the guidelines there was a paper I remember as a resident Eric Smith and Lee schwam looking at these patients with rapidly improving minor strokes and a significant proportion of them had pretty poor discharges they didn't do well on discharge criteria from get with the guidelines and so this spurred some interest in looking at these patients in more detail so we fast forward to the IST trial the international stroke trial where they compared all to place versus routine medical management in patients with all kinds of stroke and then they focused specifically on patients with minor strokes so ni Stroke Scale five or less and so Dr katri performed this very nice analysis and what she found was that in these subgroup of patients where they had minor stroke defined as an IHSS of five or less there seemed to be a treatment benefit of giving out to plays by approximately nine percent absolute benefit of getting better outcomes better excellent outcomes which in their study was defined by the Oxford handicap scale so they took that equivalent as like the Mrs zero to one and some guidelines building on these early data were stating that you could consider giving alteplays to patients with minor non-disabling strokes so the early 2018 I believe aha guidelines and then the Chinese guidelines also said that it can be considered it wasn't a strong recommendation however but it was in the guidelines so in our psyche when we're seeing these patients in the ER we're always asking when was your last known well and what are your deficits and so even these patients with minor symptoms they're being considered for autoplay so that's why we wanted to see well can we compare these patients with dual anti-platelet and this idea of dual anti-playlet really emerged as you know from the point in the chance trials both trials showing that stabbed was better than aspirin alone in these patients with minor ischemic stroke Tia and reducing the recurrent event rate so Dr Chen and colleagues wanted to study this by a non-inferiority design well maybe the Dual ante platelets are not inferior to altar plays and then we can prove that it's good enough to give these patients debt if it was true and so the findings in the study were that indeed after enrollment of I think 700 patients we found that dual anti-platelet therapy in these patients was non-inferior to alter place and we met the non inferior your border margin on the confidence intervals and so we exceeded that and so that's why in essence this was a positive study showing that patients overall did quite all right with dual anti-platelet therapy compared to intravenous ultiplase if they presented within four and a half hours and in terms of the proportions there were about 93 percent who had Mrs 0 to 1 in the dad group and 91 percent had mrs01 excellent outcomes in the ultiplase group so pretty strong data to show that that is non-inferior and we weren't seeking a superiority signal so even though the number was higher in debt I don't think we can say it being Superior thank you so much for that background that's outstanding it's a real master class and reminding us how we got to where we are in current treatment okay so based on this study we're suggesting that dual anti-platelet therapy with aspirin and Clopidogrel is not inferior to systemic thrombolysis with IV ultiplates according to the standard protocol at 0.9 milligrams per kilo maxing at 90 milligrams that's right again this was a study conducted purely in China so of course the question of how transportable are these data outside of China is another big question and obviously we can look at the parallels with the chance trial which came out earlier than the point trial so these were the Dual anti-platelet trials and when chance came out showing that adapt was Superior to single aspirin then the world was waiting for Point meaning they said we're not going to change our practice because this was in a Chinese population so let's see what point shows and indeed Point showed a very similar pattern and so the fact that there's some similarities in outcomes between chance and point I think you can potentially speculate that that might be the case for these patients between depth and intravenous ultiplase so it's a speculation it's not hard evidence but in short of that it is some evidence that could give you some reassurance as you're making these decisions seeing these patients in the ER yeah I really couldn't agree more I remember when chance came out and sort of waiting for point and then later on we saw thales coming out and the fact that those populations are really quite similar to the population in this study would suggest that maybe those concerns over generalizability are not as significant as we originally might have thought them to be we'll have to see as the data continues to mature but I think it's a really great point that you made and speaking of chance in point there was some variability in a post-chance and point world with regard to the Dual anti-plated therapy that's chosen in particular to your load with 300 versus 600 milligrams of Clopidogrel and typically maintaining that for three weeks in this study the choice was to load with 300 milligrams of Clopidogrel in addition to aspirin and to maintain that combination for two weeks why was it organized that way this was drawn from the previous data from chanson Point obviously chance uh loaded with 300 milligrams and then continued dual antiplatelet versus aspirin for 21 days and then point loaded with 600 milligrams so they they went more aggressive on the treatment up front and then went with I believe was three months of dual antiplatelet versus aspirin and so in chance what we noticed is there was no increase in Hemorrhage rates between the Dual anti-platelet versus the aspirin group whereas in points there were excess hemorrhages in the adapt group not necessarily ascribable to the 600 load but that's what was observed and so because there's a signal of potentially higher hemorrhagic risk with this regimen than we just wanted to keep with the bare minimum going with the 300 milligram load and the question is why would you go with a 600 and the potential answer is because when you go with 600 you get to a therapeutic level faster to being therapeutic on the anti-platelet regimen but maybe 300 is good enough so that's why in Aramis we went with 300 with regards to the question about duration in the chance study they looked at the duration do we really need to go out to the 21 days that chance went out to and so they did a sub study in neurology and they looked at this and they found that the turning point was about 10 days after which the benefit risk benefit ratio between dual antiplatelet versus single antiplatelet converged and so that's why in Aramis we did not want to increase the risk of hemorrhagic events we wanted to maximize the potential effect of dual antiplatelet and so we limited this to the two-week regimen based on that sub study of the chance trial I really appreciate that insight into the thinking as the trial being designed and I think that kind of information is really helpful for how to apply these study results to the patients that we're seeing today with this particular study did you notice any challenges in the safety arm in comparing the bleed rates of systemic altar Place versus dual antiplatelet therapy that's always the greatest concern is bleeding that weighs heavily on us every time we give drugs to these patients and so in terms of symptomatic Hemorrhage which is what we are most concerned about between ultiplase and dual anti-platelet there was essentially no difference although numerically there were more event rates in the ultiplase arm so 0.9 percent of patients had a hemorrhagic event that was symptomatic compared to 0.3 percent but still that's not significant and if you look at any bleeding events then this was significantly higher actually in the altiplase a group of five percent compared to the Dual ante platelet which was 1.6 so that was significantly different in terms of any bleeding events but for what we are always worried about the symptomatic hemorrhages it wasn't different thank you for that so a little bit as we might expect there was some excess bleeding in the altar Place group but not symptomatic Hemorrhage now anytime we're talking about acute ischemic stroke it's important that we remember that there are going to be some patients with stroke mimics in our treatment groups that's just the nature of the Beast and they say if you have never treated someone with a stroke mimic you're just not treating enough stroke patients do you think that these results inform our treatment of patients particularly those with stroke mimics in any particular way and how was this dealt with in the study if at all every day we're always wondering are we treating a mimic right because we're not getting MRI routinely on these patients because there is no time so really your decision to treat is based on the clinical presentation the history and the exam and so inevitably you will be treating mimics and I certainly have in my practice as for Aramis they included patients based on the clinical presentation and also there was an Imaging criteria of demonstrating ischemic stroke on CT or MRI and so to what degree patients had either modality I would have to dissect in the the details of the protocol but suffice to say that in real world you're not necessarily going to know if you're going to be treating a mimic up front unless it's obvious and they have other medical history like a prior migraine that's complex so you may not know that up front in Aramis unfortunately we didn't have a special section for the mimic patients because most of patients were already confirmed by Imaging when you look at the consort diagram there were two patients that were excluded by the fact that there was no stroke on MRI so I think this was a very refined population of hard stroke meaning Imaging confirmed stroke so unfortunately that was not well addressed in the Aramis trial suffice to say even though it wasn't addressed what you can think is if you have a potential mimic that exactly meets or mirrors the criteria of Aramis you might feel reassured that okay well I may not want to go aggressive and give all to plays because of the bleeding risk but if I give adapt I may not be harming the patient either or taking away a potential benefit of giving them TPA so you might have some reassurance based on that a rhombus trial very reasonable in particular sometimes the more so-called minor or less disabling stroke cases are the ones where we're more concerned about mimics patients who present with a severe clear stroke syndrome that localizes very well to one an area of the brain most often are indeed experiencing a stroke but at times when we have a little more of that wiggle room in patients who have more mild symptoms that we could attribute to multiple potential causes that's where the mimic population is really centered so I really appreciated your explanation I also really liked the secondary endpoints and the subpopulations in this study and in particular those patients who presented to the clinical trial group with minor stroke or minor non-disabling stroke but also large vessel occlusion could you comment a little on how that group did in particular and any other subgroups that you feel were particularly important to bring out yes that was actually a reviewer question which is great because it's the naturally the question that everyone wants to know so we had to further delve into the data and look at patients who had the data on large artery occlusion and as you can imagine because the entry point of these patients are patients with minor stroke they're not obliged to undergo CTA from the outset in clinical practice because guidelines say you don't have to treat patients less than an age of six so naturally because of that we don't have a lot of data represented on the presence of large artery occlusion I think it was only present in 36 of the 700 patients in the study and so this is largely underrepresented and when you look at the confidence intervals I don't think we can say very much as to whether autoplays or adapt is better but that we need more data unfortunately there will be data that's already being studied by the Calgary group Dr Sheila Coots is looking at this via an international trial with Tempo looking at thrombolysis for these patients with minor stroke and large vessel occlusion so I think we'll learn a lot more there as some of the advanced vascular Imaging continues to come into the mainstream and certainly at many hospitals that becomes part of that initial stroke evaluation it's going to be a really important question to continue to address and consider for patients who have minor symptoms but evidence that they may be at higher risk for worsening compared to your average patient with minor symptoms that does not have a large vessel occlusion but really that gets down into the nitty-gritty of some very specific patient situations 10 this study was done in China but of course stroke is a worldwide problem and there are huge differences from one country to another with regard to Health Care Organization health care resources and particularly in low and middle income countries there can be a major impact on someone's care with regard to the cost of treatment could you speak a little bit about how this study could be useful in different settings and some of the feedback that you have gotten from people around the world with regard to these results what I didn't realize when we released this paper was the reaction from colleagues in lower or middle-income countries where they welcomed this study because of the potential ramifications for patients in terms of cost of treatment where in some countries patients do have to pay for all to plays and it can be a significant cost to them versus aspirin and Clopidogrel which might be a lot lower cost compared to the intravenous analytic so in patients where you have that potential controversy or that equipoise where they might meet the aromis criteria giving them dual anti-platelet would offer some reassurance that this is a okay treatment to offer these patients and they're not offering inferior treatment than autoplays because representing with stroke-like symptoms and that the families could rest assured and the patients could rest assured that the outcomes are likely going to be excellent whether or not you go on adapt or intravenous altar place kind of a attenuating the intensity of resources of the cost of the drug and the Aftercare of these patients in the first 24 hours in an intensive care unit setting or a step down unit when we talk about cost to the patient and to their family as well as the cost to health care in general it can be much higher with altar Place versus aspirin plus Clopidogrel in all sorts of different settings and because acute ischemic stroke is such a time-sensitive crucial emergency it can be very easy to be a little bit more blind to those costs compared to the average neurologist treating patients in other kinds of settings so keeping that in mind and particularly recognizing the difference from country to country is just really crucial I think overall this is a very elegantly done study and it's really going to help inform our treatment and really is a great next step after chance and point and thales to help us understand the best way to treat patients with minor stroke and minor non-disabling stroke anything else that you wanted to bring out and summarize about the study yeah I just wanted to draw out the fact that when you look at the NIH tiers grading from zero to one to three and four to five subgroups there was a bit of a signal for the patients with nihf four or five seeing potentially a signal for all to plays being better than dual anti-platelets so I just wanted to mention caution for these patients where they accumulate NIH points because they may not be as disabling as we think and so I think this is obviously a moving Target and a population we just want to be careful about before we apply our criteria to liberally I think this study really helps to drive home the point that it's not a one-size-fits-all kind of approach to stroke hair and that we need to be able to take this data and apply to each patient as an individual and make sure we understand the stroke symptoms they're experiencing in the context of their lifestyle and what are the potential risks benefit and alternatives to systemic thrombolysis in that setting I I really think that this was exceptionally well done thank you so much again for talking with us today again we've been discussing the paper titled dual anti-platelet therapy versus altar place for patients with minor non-disabling acute ischemic stroke the Aramis randomized clinical trial which appeared in the June 2023 issue of Jama thanks so much again thank you Dan [Music] this is Stacey Clark your podcast editor if you've enjoyed the podcast please take a few moments to subscribe rate and review the neurology podcast through Apple podcasts Google podcasts Spotify or wherever you listen and remember you can always head to neurology.org backslash podcast for our full list of past episodes where you can also search by keyword in your podcast app for any neurology specific topics if you want to learn about