Latest / CRITKNOW / Middle Meningeal Artery Embolization for Chronic SDH: STEM trial
Transcript
- Bharath Kumar: Hello everyone, welcome back to Crit Now. This is Bharat Kumar and I'm joined by my co-host Ramesh Benkatraman. Before we start off with today's episode, a reminder to comment, like, subscribe, and share if you've been enjoying what we've been doing. This will help us reach a wider audience. Thank you. In today's episode, we are shifting gears and moving to neurocritical care. And we're going to be talking about an intervention that is becoming more common across neurointensive care units. I'm referring to the embolization of the middle meryngeal artery for subacute and chronic SDH. And we'll be talking about the STEM trial that specifically evaluated this intervention. We'll also discuss a couple of other trials and summarize the body of evidence that is lookated that's looked at MMA embolization. Ramesh will kick us off by talking a little bit about the background and the rationale for embolizing the middle meningeal artery in these patients. Over to you, Ramesh. Ramesh: Thank you. Thank you, Bharath. I think exciting to be part of the next podcast here. So quickly jumping onto the topic, I think today we'll talk about the rationale of why we do middle men's gelatine embolization. So I think before we go on into the study, I think we need to understand that acute SDH, pathophysiology is slightly different than chronic SDH. Acute SDH usually is traumatic and usually happens because of vascular disruption in the dural vasculature. causing a collection there and that needs to be evacuated if clinically indicated. Previously, chronic SDH was thought to be related to bleeding from the bridging veins and therefore, people accumulated over a period of time rather than acutely and suddenly. But what recent evidence has kind of shown is that chronic SDH is because of multiple microbleeds that happen over a period of time. purely because of a lot of neovascularization that happens in some kind of inflammatory state of the dura matter and then this blood accumulates over a period of time. So if you think of the dura, there's an outer and an inner membrane. The inner membrane is just collagen and fibroblast and really doesn't do a whole lot, but the outer membrane can get neovascularized from whatever. inflammatory response that happens locally and if you have a little bit of a bleed that triggers further inflammatory response and further neovascularization and leading to multiple small chronic microbleeds that happen over a period of time and evidence is very clear that this neovascular is basically being supplied by the distal branches of the middle meningellar tree and hence the concept of trying to embolize the middle meningellar tree so that you can prevent these microbleeds from happening in the future attenuating the blood flow to the neovascular surface of the outer membrane of the dura matter and therefore minimizing recurrence or reaccumulation of this STH over a period of time. So there has been an emerging body of evidence that has evolved at least in major trials over the last couple of years with people specifically looking at this intervention as a way of minimizing recurrent bleeds and need for recurrent interventions of chronic STN. So that would be the basic rationale for why we would be studying this intervention now. So over to you Bharath, I think this is a very important study, lot of papers coming out in this particular aspect and this is something that we will be seeing in the near future. Our center already does quite a bit of these middlemen gelatina embolization. So I thought it would be worthwhile discussing this paper. So over to you Bharath. Bharath Kumar: Yeah, thanks Ramesh. And I think that's fascinating pathophysiology that you highlighted. in fact, people have tried to evaluate steroids and so on and so forth in the context of chronic SDH, right? And and this is a disease that you know has significant morbidity as well, right? The ri the need for recurrent surgeries and coming back to the hospital, neurological outcomes and so on. Okay, coming to the STEM trial, this was the this was an international multi-center open label trial. I want to at the outset make an important point that this trial was funded and operationally conducted by a company called BOLT, who's the maker of the liquid that was used for embolization. The liquid itself is called Squid. And BOLT had a pretty you know sort of deep involvement in the conduct of the trial, in in assisting with analysis and and so on. So the population that the trial included is symptomatic patients with symptomatic chronic SDH, more than 10 millimeters in thickness on imaging. And they had definitions for when they would consider it as chronic. So if it was more than 50% isodense or hypodense as compared to the cortical gray matter on imaging. they excluded patients that had a MRS of more than one at baseline. So any degree of you know deficit at baseline, they excluded those patients. They excluded patients that had a craniotomy, you know, if they already had a craniotomy. and in this trial, you could be randomized if you had SDH on either side or also if you had it on both sides. So that that is something that's important to note. now in the intervention before before the intervention, before the randomization, in fact, the team, the team, the clinical team managing the patient was asked to record what the intent of treatment is going to be, whether it's going to be surgical or medical. And once this was recorded, then the patients were randomized to undergoing brittle meningulatory embolization or not. and and obviously MMAE was performed as an addition to the standard treatment. In case the patient was being considered for surgical intervention, the embolization would be performed prior to the surgical intervention. and the agent they used is called Squid. It's also one of the ethylene vinyl alcohol copolymers. And the comparator here, of course, is standard treatment, meaning no middle meningal artery embolization. Patient, of course, can get surgical or medical treatment in the control arm as well. The surgery itself, if patients underwent, would be either a bar hole or Or they use something called a subdural evacuation port system or a SCPS. So that was the nature of the surgery. The outcome is a composite efficacy outcome. And I'm gonna remind our viewers, listeners that we have discussed composite outcomes in previous episodes of our podcast. there's also a blog on composite outcomes at ccmevidence.blog. So the outcome that they used is recurrent or residual chronic SDH, measuring more than 10 millimeters at 180 days. This is based on imaging. And then the second component was reoperation or surgical rescue within 180 days after intervention. The indication, remember, was at surgeon's discretion. So that's important to note. Or the third component was major disabling stroke, MI, or death from neurological causes. So there are three components: one is the imaging recurrence, one is the surgical decision to reoperate, and then there is some safety sort of signals around stroke, MI, and death. So that's the composite outcome. And then I'm gonna take a couple of you know maybe seconds to talk a little bit about how they ascertain the outcomes because this is again important. The imaging outcome was actually, I mean, there's no blinding in the trial. There were independent groups assessing the imaging outcome, but it's important to note that the agent itself is radioopaque, so there is no way of blinding. so even the person assessing the imaging knows whether they got the intervention or not. And the decision to operate, as I said, was already left to the surgical team. So this is the way they assess the outcome. Now the sample size, STEM was powered to detect a 17% absolute reduction in the primary outcome. One may argue that that's very optimistic. And they had otherwise a 90% power, you know, 0.05 alpha pretty standard. the another important point here is that they were not powered for shretum level analysis, meaning they were not powered to look at effects within the surgical group and the non-surgical group. So this is the approach that they took, Ramesh. That's the that's a summary of you know what they did in terms of the PICO. Ramesh: Okay, now that's a quick nice summary Bharath. So let me just quickly go on to what they found. So as you said, this is a 32 center multi, know, multi center trial happening in the US in and around New York. They enrolled 310 patients overall, of which 149 received embolization and 161 were in the control arm. If you just divide the 310 patients into surgical and non-surgical, 189 were in the surgical group, 121 in the non-surgical group. And among the surgical group, 91 had embolization and 98 were in control arm. And among the non-surgical group, 58 were embolized and 63 were in the control arm. It is important to say that the original power analysis that you mentioned Bharat was for 286 patients, but only 264 completed. the entire study protocol, which means they need to go through whatever limb they are randomized to, then they need to get the clinical and the imaging follow-up at 180 days. So only 264 were able to do that. data was missing in about 15 % of the patients overall. 15 died from non-neurological causes, so they were eliminated, and hence the primary outcome was evaluated only in 249. from 286 power we were down to 249. So I think the results have to be looked in with that piece of information in mind. So if you look at the patient population, I think it seems very reasonable. The mean age was around 73. Most of them were men and 9 to 11 % of the people were alcohol users. 35 to 45 % of the patients were either on anti-platelets or anti-coagulants, which is what we would normally see. The right sided bleeds were more common than left and as you mentioned they included bilateral bleeds and that comprised of somewhere around 15 to 20 percent of the patients. The original inclusion criteria the SDH has to be at least 10 millimeters. So, the average size was anywhere between 15 to 20 millimeters across all the patients and there was about a 3 to 5 millimeter midline shift. in the neurological imaging, initial neurological imaging. So I think the groups were well balanced. They seem to represent the patient population that you and me would probably see, Bharath, in terms of this particular disease. The primary outcome, which you said, is the recurrence or the re-accumulation or the persistence of an SDH of more than 10 millimeters at 180 days was 16 percent in the embolization group versus 36 percent. So, they got an absolute disc reduction of around 20 percent. The second outcome is re-exploration or re-operation requirement within 180 days was 10 percent in the embolization group versus 30 percent, another again 20 percent absolute disc reduction. However, the third outcome which is know mortality related to neurological causes, MI and new strokes, was similar between the two groups. It is I think 2 and 3 percent between the two groups. So that was not particularly different. One point I would like to point out is if you look at the surgical group and the non-surgical group, the difference is predominantly seems to be driven in the non-surgical group Bharat. In the non-surgical group, the embolization had a 19 percent event rate versus the control arm at a 56 percent event rate almost like no. two and almost three times or so in terms of the event rate. If you look at the surgical group, there was only 14 versus 23. So the separation was not huge in the surgical group, but in the non-surgical group, the primary outcome separation was huge and that probably drove the absolute differences in the primary outcome between the two groups. So that's a quick summary of what happened in terms of how the trial went through. Now going to you, what did you think about the trial and my one particular question for you Bharat is that we talked about stratification. If you actually looked at this paper here, the stratification was not done the way it should be. Patients initially, the surgeon said surgery or non surgery, but then the patients were randomized after that. That's not how stratification would generally work. So for the sake of our viewers, Bharat, could you tell us what stratification is? How was it done and how was it done in this trial and are there problems with the way stratification has been done in this trial? Bharath Kumar: Yeah, no, thanks. Thanks, Ramesh. Thanks for summarizing the results. and also, you know, pointing out that it is actually the in the non-surgical group that the benefits seem to be, you know, sort of most pronounced. coming to your question on stratification, yeah, I think they did something very different and very interesting. so normally when you're doing a large randomized control trial, let's say you know tens of thousands of patients, usually your baseline characteristics are you know, well matched and it's very it would be uncommon to end up with an important prognostic factor being imbalanced, right? that's that happens when you do a large trial. Now when you do smaller trials, just by sheer bad luck, you can end up with a key prognostic factor being you know imbalance between the two arms that could be age, that could be illness severity, that could be, you know, any of these variables that that are prognostic. And typically we know that trials will stratify by site, meaning to make sure that there are no center-specific effects. So they will try to stratify by site, by age, and then you know the other variables. And what we mean by stratification here is that you try to ensure that for certain key variables the balance is maintained. Meaning, if you're stratifying by center and age, for example, you will first go to each center, and within each center, you know, the patients will be further randomized into medical management or surgical management or MMA embolization or surgery in this case, right? I mean, no embolization. so this will ensure that which in each center as well, there is a balance in terms of the number of patients that get either of the interventions. This usually takes care of center effects. Similarly, you can do that for age, age less than 18 or more than 18, or whichever age less than 60, more than 60. So you can create strata thereby ensuring that within those strata, the patients are comparable with respect to their baseline characteristics, and we don't end up with you know unequal numbers or major imbalances with respect to those key prognostic factors. Usually, trials will stratify by two to three factors because over stratification can also become a problem. So normally, I mean, I would have expected that here they would have stratified by surgery or no surgery and then randomized to embolization versus no embolization. Which would have made the two groups absolutely comparable, the patients that get surgery versus those that don't get surgery, they would be exchangeable. Therefore, interpreting the treatment effects would become easier. Now that's not what they did here. Here they asked the clinician to first decide what will be the treatment option. And obviously, there is a you know clinician bias across different centers. There's going to be a clinician subjective decision on who will get surgery, who will get medical management, and then they start the randomization process. So this is a bit problematic in the sense that it it doesn't really serve as true stratification. So the two groups within the stratum aren't necessarily exactly comparable. And as you s as I mentioned earlier, they did also not power the trial to make sure that they Ramesh: Mm-hmm. Bharath Kumar: would capture the Shratom specific effects. So I think this was an unusual decision. and and I'm not sure what the reason was. They could have done it as a a true stratified randomized control trial. I mean it it doesn't take away from the main outcome and we'll of course talk about the the caveats and interpreting the main outcome, but you definitely should not read too much into stratum specific effects in any case. that is sort of what I would summarize. Ramesh: No, I think this is kind of a pseudo-statification that they have evolved without, like you said, Bharath Kumar: Yeah. Ramesh: it's kind of usual for people to do it. They could have ideally stratified the way you described earlier. Bharath Kumar: Yeah. Ramesh: going through the results Bharath, I felt it's a well-done trial, number one, because I think this is a question, important question that needs to be addressed. I think they have gone about it in the right way. Their inclusion-exclusion criteria seemed right on that I would agree that are clinically relevant. Their primary outcomes are all clinically very, very relevant in terms of need for surgery, expansion, or persistent of hematoma and death. My thoughts are it's a very well done study. There are some limitations of the study. Number one, for me, the patient dropout and the loss of data seems to be a big red flag for me. So you enroll 310 patients and the primary outcome was adjudged only in about 249 patients. And not all of them had all the data. So there was a lot of imputation of the data that happened even in those 249 patients. So one, that to me is a red flag. But to be fair, the authors in their discussion clearly say it was during the COVID when the study started. The patient population is very old. 180 days is too long for the patients to be showing up and all of that stuff. All of that makes sense. But still a dropout rate of 15 % with data imputation kind of makes me be a little skeptic about the data. That's number one. Number two, like you said, even though the outcome assessors, at least imaging assessors were blinded, you can't really blind them, right? I mean, you said the embalasing agent is radio opaque and they can actually figure it out. So the outcome assessment may not have been as objective as one would think based on reading the paper. So that is the second thing that I would think of. And the third thing that I would be a little wary about is the primary outcome being driven predominantly in the non-surgical group. That's something that you would expect, right Bharath? If I went and did something to the subdural hematoma, then adding a second intervention may not actually yield me two bigger results. But if I did nothing to somebody and then went and did one intervention to plug a blood vessel, then that group would benefit more. So. I think the outcome is predominantly driven in the non-surgical arm than the surgical arm. So I think these three to me are the main kind of points that I would say probably the biggest limitations of this study and the results have to be interpreted with these three things in my mind. What about you Bharath? Any other points that you think we should discuss? Bharath Kumar: No, I I agree with all the points that you raised. I wanted to sort of emphasize again that I would have been happy if the if the funder was not involved in had did not have such a deep involvement in the trial. typically we want the funder to not have an involvement in the design, in the analysis. but obviously this is a this is a trial that's sort of driven by the funder, right? So that that always you know brings some concerns. again, I shared your concern about the indicator. For rescue or resurgery being left to surgical discretion, as you pointed out, if if my patient has received no embolization, I'm more likely to operate that group, right? In the in the control arm, right? So, and interestingly, in the in the multiple components of the outcome, the outcome is primarily being driven by that component, right? The Ramesh: Mm-hmm. Bharath Kumar: massive difference in that component and in the medical or non-surgical group. So both of this opt. To me, it would reduce the magnitude of the effects they are seeing. this doesn't change the result. I mean, there is probably a benefit of middle middle manager embolization if you take the overall cohort, but I think the amplitude or the magnitude of that difference would come down. And there is a slightly higher death rate in the treatment arm, maybe not statistically significant, eight versus five percent at 180 days, which the authors have acknowledged. those are, I guess, sort of my major concerns. Again, as I said, it doesn't take away from the key result, but there are we should take it with maybe a couple of pinches of salt rather than just a pinch of salt. Ramesh: No, agreed. All your points are very, very valid. Yes, I think there is a signal, but the signal may not be as strong as the authors claim it to be in terms of the benefit. But again, like we always discuss, Bharat, any study shouldn't be looked at in isolation. We need to look at other studies, the pretest likelihood that this results goes along with or goes against previous test results. And we need to put all of those together. There are at least been two to three studies that have looked at the same question Bharat. I think the first one that we could probably discuss is the EMBLICE trial Bharat. So could you just tell the Bharath Kumar: Yeah. Sure. Yeah, so Ramesh: audience what you actually did in that trial? Bharath Kumar: Yeah, yeah, embolizes this trial that again was published around the same time as as STEM. There were actually a series of three trials that came sort of close to each other, all in the New England Journal of Medicine. and this trial was also from the United States, which compared middle manager embolization with surgery versus surgery alone. So slightly different to the STEM trial. the inclusion criteria is very similar, so I won't talk about that in detail. The intervention they use something called Onyx, different to squid, but it also has the same polymer, the ethylene, villain, alcohol polymer, but a different agent from a different company. and in this case, the patients could get the embolization done before or after surgery. So up to 72 hours, so it you know, patients were allowed to have it even after surgery. The primary outcome was recurrence or progression requiring surgery. so that was their primary outcome. Again, unfortunately the funder involvement here is as deep as in the STEM trial. this is also an industry-driven trial. there was one thing concerning about what they did in embolize that I want to bring out. they had they had a planned interim analysis, and their initial sort of decision or pre-specified rule was that if the chance of showing superiority is less than 34, 35, or 37 percent, they would stop. Actually, when they did the interim analysis, it was only 34%. But at that point, for some reason, they say no, no, we will not look at the ITT population. Let's look at the modified ITT population, in which the conditional power is something like 72%. Using that, they say no, no, we now increase the sample size. They increase the sample size from 200 to 400, and then at the end, the result is statistically significant. So they show a decrease in the primary outcome, it's 4% versus 11%. so Also, a trial that's a bit concerning because they change things you know in between. but there is a signal again in the trial. Ramesh: Yeah, but if you bring that point of intention to treat, found in this trial too, in the STEM trial too, they talk about an intention to treat and a modified intention to treat. Traditionally, intention to treat is once you randomize to the arm, you kind of use the same numbers to go ahead and do the analysis. Here, the definition of intention to treat is going to be patients who have consented and randomized. And in terms of modified intention to treat, it is going to be patients who are consented, randomized and actually got the intervention. I think again, they have done a little bit of, you know, I would say data mining there in terms of how they define intention to treat and modified intention to treat to get to the results. The signal was pretty similar in both groups. So that kind of is reassuring in this trial, but that's something that I would know alert the audience about when they read these papers in terms of how to look at it. The other trial, Bharath Kumar: Absolutely. Ramesh: I think the only big trial that was not funded by any company is the Magic MT trial, I think done in Chinese population, large number of patients, 772, almost double of the other two trials that they had looked at. They used the embolizing agent ONIX compared to the squid agent in this particular trial. And there they looked at the rate of hematoma recurrence and progression within 90 days rather than 180 days. And again, pretty much similar population. And there they either did a burr hole or a conservative management and then went on to embolization versus control. There they found that the embolization group had a recurrence of 6.7 % versus the control group at 9.9%, which was not statistically significant. So like you mentioned, there is a signal, but probably the amplitude of the signal was not as big as the study showed. So that's pretty much what the MAGIC-MT trial did. So I think we need to look at this trial in the light of the other two big trials. And there's a recent trial, M-Protect, which basically looked at smaller size particles to embolize to prevent some of the complications that may happen. And there is a reason AHA consensus that recommends using MMA embolization as an adjunct to the current standard level of care, whether it is surgical or non-surgical at this point of time. those are all the... kind of the cumulative evidence and consensus statements we have at this point of time. I think for the audience here, we are going to bring in an expert in our next Beyond the Evidence session next week. We'll get a senior neurosurgeon and a neuro-interventional consultant who would be giving us more insights into when and how this is going to be done and what his take is on these studies and in terms of practice. So over to you, Bharath, what is your final answer in terms of MMA embolization for chronic SDH? Where do we stand right now? Bharath Kumar: No, thanks Ramesh. I I I think it's it's a bit interesting, you know. This is sort of not the main point, but to say that, you know, you see that when there is a large academic trial, the results are no longer as impressive as what the funded, you know, the industry driven trials are. So I think that's something that we have seen in other fields, in other cases, right? yes, there is still a signal, as you pointed out in in in the Chinese trial as well, but the ma magnitude of benefit seems to be coming down. There are also some differences between these trials and who included patients with craniotomy versus not. And I think we'll get a little bit of insight, as you said, when we talk to our neurosurgical and neurointerventional colleague. So, my own takeaway is that you know, it's probably worth considering middle manager artery embolization. you know, I think the benefits are probably not as much as what the manufacturers of the liquid want us to believe, but there is a signal towards benefit. probably in in in specific patients, I would You know, I would think about you know this procedure. I also would be interested to know what you know what are the cost effectiveness data, you know, and and so on and so forth. Because then the benefit is not huge. You're also keen on knowing what's the cost, what's the it's it's a procedure. Then there is the drug, there is the anesthesia, there's so many aspects, right? the risks that come from undergoing the procedure and so on. so those are my Big big sort of takeaways. Ramesh, what did you think and and how would it sort of what how does it influence your practice? Ramesh: So from an intensivist point of view who takes care of neurocritical care patients, would say I think we should consider it as a treatment modality in patients with chronic SDH on top of standard care. If a patient undergoes surgery and is a surgical candidate. and has got high risk of recurrence. They are on antiplatelets, anticoagulants, multiple comorbidities that would preclude you from doing repeated surgeries. I think this is a no brainer. Just go ahead and do an embolization, minimize the risk of having any recurrence and move on with it. If no intervention in standard group, I really don't know how to go about giving this. think probably the decision would be nuanced. and individualized in terms of looking at the risk factors of waiting and watching versus doing some intervention versus none. Looking at the amenability to embolization in terms of the neurovascularity or the feeding vessel. And then there are some articles that talk about dangerous collaterals. If there are other collaterals coming from elsewhere and not from MMA, then maybe embolizing this may not be helpful. So I think the decision has to be nuanced. there a neuro interventionist has to take a call on a case to case basis. But this is definitely a therapy that I would keep in the back of my mind, not only bur holes or no evacuation of hematoma anymore. I think this is something that should be discussed with the neurosurgeon and then taken forward in high risk patients for sure. Bharath Kumar: Thanks. Thanks, Hamish. I think the point that you made about you know risk factors, I think it's important to see if we if if if there is any way of knowing or predicting which patient is likely to benefit the most, right, from this procedure. That I think would be interesting. I'm looking forward to hearing the surgical or the neurointerventional view on this. but I think you know, again, a good trial overall, STEM, but also the rest of the trials and and and advancing the field. So to that extent, very, very important. On that note, we will stop this episode. thank you all for listening, viewing, and again a reminder to please like, comment, subscribe, share, spread the word. Thank you so much. Bye bye. Ramesh: Thank you all. See you in the next session with the expert. Thank you. Bye-bye.