Stroke Alert June 2022

On Episode 17 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2022 issue of Stroke: “Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage” and “Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns.” She also interviews Dr. Bruce Campbell on his article “Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy.”

Dr. Negar Asdaghi:         Let's start with some questions.

1) Is vitamin D that golden key to recovery from intracerebral hemorrhage?

2) Endovascular therapies seem to have prevailed where thrombolytics have failed. In the era of fast and furious thrombectomy, what is the role of pre-thrombectomy thrombolysis?

3) And finally, 20 years of clinical research has failed to demonstrate the superiority of anticoagulation over antiplatelet therapies for treatment of patients in sinus rhythm with low left ventricular ejection fraction, and yet, our practice patterns have not changed. Why do we remain resolute in prescribing anticoagulation despite the lack of evidence?

We're back here to tackle the toughest questions with our Stroke Alert Podcast because this is the latest in Stroke. Stay with us.

Dr. Negar Asdaghi:         Welcome back to another extremely motivating Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The June 2022 issue of Stroke contains a number of interesting articles. As part of our Advances in Stroke, we have two articles, one on the topic of cost-effectiveness of stroke care to inform health policy and the second on the current state and the future of emerging stroke therapies. As part of our Original Contributions category, we have an interesting study by Dr. [Ben] Assayag and colleagues from the Department of Neurology at Tel Aviv Sourasky Medical Center, where we learned that just over 10% of patients with TIA and stroke developed post-traumatic stress disorder, or PTSD. Higher presenting stroke severity, preexisting white matter disease, and having anxious coping styles are risk factors for development of post-stroke PTSD.

Dr. Negar Asdaghi:         In another Original Contribution, by Dr. Daehoon Kim and colleagues from Yonsei University College of Medicine in Seoul, South Korea, we read with interest on the topic of whether or not we should be anticoagulating frail patients with atrial fibrillation. In this large population-based cohort, which included patients with atrial fibrillation older than 65 years of age with frailty as defined by a score of equal or greater than five on Hospital Frailty Risk Score, we learned that despite their frailty, patients with atrial fibrillation still significantly benefit from oral anticoagulation therapy. In this study, those treated with anticoagulation had lower net adverse clinical events as compared to those untreated. We also learned that direct oral anticoagulants provided lower incidence of stroke, bleeding, and mortality over Coumadin. This paper really provided practical information on treatment of frail patients with atrial fibrillation. So, I encourage you to review these papers in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Bruce Campbell from University of Melbourne in Australia on an especially timely topic, that is the role of intravenous thrombolytics prior to endovascular therapy. Dr. Campbell is a leading authority on the topic, and his interview does not disappoint. But first, with these two articles.

Dr. Negar Asdaghi:         In the setting of intracerebral hemorrhage, or ICH, aside from the primary brain insult that occurs at the time of hemorrhage, secondary brain injuries continue for days and sometimes to months mostly due to the pathological response of the brain to byproducts of hematoma lysis or RBC degradation products. Today, the majority of spontaneous ICH cases are not surgically evacuated, so we rely on the body's own ability to clear blood for hematoma clearance, and obviously the faster the clearance, the better the outcome. Erythrophagocytosis by monocyte-derived macrophages contributes to hematoma clearance and ultimately to the functional recovery from ICH. So, it's conceivable that therapeutic approaches to enhance the endogenous erythrophagocytosis can potentially improve ICH outcomes. Vitamin D has been known to have variety of functions within the central nervous system, and it turns out that it may also be one such therapeutic option to improve the much needed erythrophagocytosis in intracerebral hemorrhage.

Dr. Negar Asdaghi:         In the current issue of the journal, in the study titled "Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage," a group of researchers led by Dr. Jiaxin Liu from the Department of Surgery at Queen Mary Hospital at the University of Hong Kong studied the effects of oral vitamin D administered two hours after the induction of hematoma in a rodent model of ICH using direct collagenase injection into the striatum of the mouse. Eighty-nine young mice and 78 middle-aged mice were included in the study and randomly divided into three groups. Group one were sham-operated mice; group two, ICH mice treated with vehicle, which was corn oil; and group three, vitamin D-treated ICH mice. In the third group, 1000 international unit per kg of vitamin D diluted in corn oil was administered orally using a pipette two hours after the induction of ICH to mice, and then daily afterwards. And here are their top three findings of this study.

Dr. Negar Asdaghi:         Number one, vitamin D-treated mice did better than vehicle on two neurobehavioral tests that were completed in the study. On the cylinder test, treatment with vitamin D significantly alleviated the asymmetric usage of four limbs at day seven, and vitamin D elongated the duration that the mice could run on the accelerated rod at day 10 on the rotarod test.

Dr. Negar Asdaghi:         Number two, in terms of hematoma resolution and perihematoma edema, it's an issue that we deal with, with ICH, they used MRI imaging for edema measurement on T2-weighted images, and then sacrificed the mice and used digital quantification of hematoma volume with fresh brain specimens. And they found that treatment with vitamin D significantly alleviated both the ICH-associated brain swelling on MR and resulted in significant reduction in hematoma volume on the fresh brain specimens when compared with the vehicle-treated group at day three and day five.

Dr. Negar Asdaghi:         And finally, their third main finding is in terms of erythrophagocytosis. So, the pathway that is mediated by the monocyte-derived macrophages is an endogenous pathway, that is, PPAR-γ (which stands for peroxisome proliferator-activated receptor γ) and its downstream scavenger receptor CD36 mediated. This pathway is essential for directing the endogenous erythrophagocytosis. Using flow cytometry, they found that vitamin D-treated mice had more mature macrophages expressing the scavenger receptor CD36, which was not expressed by the undifferentiated monocytes.

Dr. Negar Asdaghi:         Western blot analysis confirmed that vitamin D treatment increased the tissue levels of CD36 and the upstream PPAR-γ levels in the brain at day five after collagenase model. Locally, vitamin D-enriched phagocytes that were positive for PPAR-γ and CD36 in the perihematoma regions. So, in summary, vitamin D increased the number of mature macrophages rather than undifferentiated monocytes in the perihematoma region and accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. So, bottom line is that in vitamin D, we have a simple, accessible, and well-tolerated agent to improve both the ICH outcomes and enhance hematoma resolution, but this we all observed in rodents. So, we stay tuned with interest to find out whether the same success will be seen in humans treated with vitamin D after intracerebral hemorrhage.

Dr. Negar Asdaghi:         Patients with depressed left ventricular ejection fraction, or low EF, are at risk of development of ischemic stroke even if they remain in sinus rhythm. The optimal antithrombotic treatment for these patients is still unknown. Over the past two decades, we have a number of randomized trials studying the efficacy of oral anticoagulation, predominantly Coumadin, over aspirin therapy in prevention of all forms of stroke, that is ischemic and hemorrhagic, and death in patients with a low EF in sinus rhythm.

Dr. Negar Asdaghi:         The meta-analysis of WASH, HELAS, WATCH, and WARCEF trials showed that treatment of low ejection fraction patients in sinus rhythm with Coumadin does reduce the subsequent risk of stroke, but it comes at the cost of a higher major bleeding risk in this population. The COMMANDER HF clinical trial published in New England Journal of Medicine in October 2018 studied whether low-dose rivaroxaban at 2.5 milligram BID was superior to placebo in patients with recent worsening of chronic heart failure, reduced ejection fraction, coronary artery disease, but no atrial fibrillation, and very similar to its prior counterparts, it did not show that rivaroxaban was associated with a lower rate of combined death, myocardial infarction, or stroke as compared to placebo. But very similar to prior studies, it also showed that rivaroxaban-treated patients had a lower risk of subsequent ischemic stroke. This poses a conundrum for stroke neurologists treating patients with this condition, especially after they present with an embolic-appearing stroke. So, the question is, how often do we encounter this situation, and what do we do in routine practice? We know that when there is equipoise, there's practice variation.

Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm," Dr. Richa Sharma from the Department of Neurology at Yale School of Medicine and colleagues examined the prevalence of heart failure with sinus rhythm among hospitalized patients with acute ischemic stroke and the physician's practice patterns with regard to the choice of antithrombotics in this population.

Dr. Negar Asdaghi:         So, let's look at their study. The study was comprised of five separate study cohorts of hospitalized acute ischemic stroke patients in the Greater Cincinnati Northern Kentucky Stroke Study for the year 2005, 2010, and 2015, and then four additional academic hospital-based cohorts in the United States during different timeframes. These were the Massachusetts General Hospital from 2002 to 2016, Rhode Island Hospital from 2016 to 2018, Yale-New Haven Hospital 2015 to 2017, and Cornell Acute Stroke Academic Registry from 2011 to 2018. All of these cohorts combined contributed to the 19,155 total number of patients in this study, which included over 14,000 patients that had documented left ventricular ejection fraction. Amongst those, 1,426 had a depressed EF and were included in this study. The investigator obviously excluded those with documented atrial fibrillation and flutter. And so the sample size for this analysis was 805 patients. And here are their main results.

Dr. Negar Asdaghi:         The overall prevalence of this condition, that is low ejection fraction and sinus rhythm, among hospitalized acute ischemic stroke patients was 5%. It varied slightly between the different cohorts in this study from 4 to 6%. In terms of the antithrombotic treatment patterns, this information was available in close to 500 patients in the cohort. Overall, 59% of patients were discharged on an antiplatelet treatment alone, and 41% on anticoagulation. But these percentages significantly varied between the different institutions and was as low as 22% in one of the cohorts and as high as 45% in another cohort.

Dr. Negar Asdaghi:         So, what were the factors that were associated with the use of anticoagulation at discharge? They found that the absolute percentage of left ventricular ejection fraction and the presenting NIH Stroke Scales were associated with anticoagulation use. That is, the lower the percentage of EF and the higher the presenting NIH Stroke Scale, the more likely physicians were to discharge the patients on an anticoagulation in univariate analysis, but in multivariate analysis, only the study site and presenting NIH Stroke Scale over eight were independently associated with anticoagulation use.

Dr. Negar Asdaghi:         Now, interestingly, 2002 to 2018, which was their overall study period, was a time during which some of the largest and neutral randomized trials on the topic of anticoagulation versus antiplatelet were published, including the WATCH and the WARCEF trial. But the authors found no temporal variation in anticoagulation practice patterns before and after the publication of the results of these trials. So, it appears that we didn't change our minds. So, overall, we have some important takeaway messages from this study. We learned that 5% of hospitalized acute ischemic stroke patients have low left ventricular ejection fraction and remain in sinus rhythm without atrial fibrillation. Today, over 40% of patients with this condition are anticoagulated at discharge despite the results of the randomized trials, but the practice is widely variable among different institutions, and a higher presenting NIH Stroke Scale is a significant predictor of anticoagulation use at discharge in this population.

Dr. Negar Asdaghi:         Almost 20 years after the approval of intravenous thrombolysis for treatment of patients with acute ischemic stroke, endovascular therapy was approved for treatment of select ischemic stroke patients with a large vessel occlusion. The two treatments are, therefore, entangled, as one was the standard of care while the second one was being tested. Therefore, all endovascularly treated patients enrolled in randomized trials would've received intravenous thrombolysis if eligible. Now, with the overwhelming success of endovascular therapy in achieving reperfusion in areas where IV thrombolysis has drastically failed, there're still critical questions regarding the added value of IV thrombolysis to endovascularly treated patients. The critical question remains as to whether eligible ischemic stroke patients who have immediate access to endovascular thrombectomy should receive prior IV thrombolysis, or should we skip the thrombolysis step altogether and just move to the angio suite as fast as possible. And there are, of course, arguments for and against each approach.

Dr. Negar Asdaghi:         In this issue of the journal, in an invited topical review titled "The Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy," we learn about these arguments as the authors go through a comprehensive review of the current literature on this issue. I'm joined today by the first author of this review, Dr. Bruce Campbell, to discuss this paper. Dr. Campbell absolutely needs no introduction to our Stroke listeners. He's a professor of neurology and head of neurology and stroke at Royal Melbourne Hospital, University of Melbourne, in Australia. He's a pioneer in the field of acute stroke therapies and acute neuroimaging. He has served as the lead investigator of multiple landmark randomized trials, including EXTEND-IA and EXTEND-IA TNK, and holds multiple leadership roles. He's the clinical director of the Stroke Foundation and co-chairs the Australian Stroke Guidelines Working Party and the coordinator of the National Brain School Training Program for Neurologists in Training. And, of course, last but not least, he's my friend. So, I'm delighted to welcome him to our podcast today. Top of the morning to you, Bruce, 6:00 a.m. in Melbourne. That's quite some dedication. Thank you for being here.

Dr. Bruce Campbell:       It's great to be with you. Thanks for the invitation.

Dr. Negar Asdaghi:         Congrats on the paper, really exciting topic. So, let's just start with this question as part of a case. We have a patient with an M1 occlusion, a large clinical syndrome presenting two hours out from their symptom onset, and we are at a hospital where the angio suite is ready. What are some of the benefits of basically spending time in giving IV thrombolytics first rather than quickly going to the angio suite?

Dr. Bruce Campbell:       I think a key element of this case is that the patient has presented directly to a hospital with immediate access to thrombectomy. Thrombolytic used in drip-and-ship transfer patients really isn't controversial, and the recent randomized trials excluded them. So, the debate's all about this context of bridging thrombolytics in patients presenting directly to a comprehensive stroke center. And you mentioned spending time giving lytics, but in fact, if you do things in parallel, that shouldn't be the case. It shouldn't delay thrombectomy if you go and give thrombolysis.

Dr. Bruce Campbell:       So, the general principle is that getting the artery open faster by any means is better, and IV thrombolytic certainly has the potential to open the artery before thrombectomy in a proportion of patients, perhaps not that many, but it may also facilitate the thrombectomy. So, in the randomized trials, reperfusion after the thrombectomy was significantly better when patients had had bridging thrombolytic despite a low rate of pre-endovascular reperfusion. Other reasons for giving the lytics are the potential safety net it provides if the thrombectomy procedure is unexpectedly delayed or fails to get the artery open, and there's also this potential for lytics to dissolve distal embolic fragments and perhaps improve microvascular reperfusion.

Dr. Negar Asdaghi:         So, great. So, let me summarize for our listeners what you mentioned. First off, so these are arguments in favor of giving lytics. As you mentioned, we're not really wasting time. These processes occur in parallel, so it's not like we're wasting time in giving a therapy that is potentially not as efficacious as thrombectomy is. And number two, we have improved the possibility of early reperfusion, perhaps, with the lytics. And if there are some fragments or distal clots that thrombectomy wouldn't have reached, then the lytics would. And then also there is also the chance that the thrombectomy might have failed in difficult access, and so on and so forth, and at least the patient has some chance of revascularization with the lytics. So, if these are the arguments for giving lytics, what are the arguments against giving lytics in this scenario?

Dr. Bruce Campbell:       The main argument is the potential to reduce both the intracerebral and systemic hemorrhagic complications. There's also potential cost saving by skipping thrombolytics. That's probably more relevant in low-resource settings, particularly when relatives may have to pay for the thrombolytic before treatment is initiated, and that can be burdensome and also potentially delay the thrombectomy. There's a theoretical concern about thrombus fragmentation with lytics and potential migration of the clot out of reach of the thrombectomy or to new territories. But final reperfusion, as I mentioned, was, on average, better with the patient having a lytic on board in the randomized trials.

Dr. Negar Asdaghi:         Perfect. And I want to highlight this issue of thrombus fragmentation because I think our readers will read more and more about this idea of, as you mentioned, fragmentation will potentially make an accessible clot for thrombectomy inaccessible. But I see that later in our questions, we're going to address that as part of the findings of randomized trials as well. So, these are some of the arguments for and against. And before we go to the randomized trials, I'd like to get an overview of what we knew as part of observational studies and non-randomized studies prior to more recent randomized trials on this topic.

Dr. Bruce Campbell:       There've been a couple of nice systematic reviews and meta-analyses of the observational data, and notably in most of these studies, the direct thrombectomy patients had contraindications to lytics, and that introduces confounding factors that are difficult to adjust for. For what that's worth, the functional independence, mortality outcomes were better in the bridging patients. Hemorrhage rates weren't always higher with the lytic, and one study by Jonathan Coutinho in JAMA Neurology for the SWIFT and STAR studies showed the opposite despite them having really careful adjustment for all the confounders they could think of. And the meta-analysis by Eva Mistry in Stroke did not detect a difference in symptomatic ICH between the direct and bridging strategies. One thing that should be less affected by the patient characteristics would be the technical efficacy outcomes, and it was interesting that in the observational data, the patients who'd had bridging lytic had higher mTICI 2b-3 rates and also fewer device passes.

Dr. Negar Asdaghi:         Okay. And now we do have further information with all of these new randomized trials. So, why don't we start with some of the earlier studies, the three, SKIP, DEVT, and DIRECT-MT, and start with those studies first before we move to some more recent European trials.

Dr. Bruce Campbell:       SKIP was performed in Japan, and it used the lower 0.6 milligram per kilogram dose of alteplase that's standard there, and DEVT and DIRECT-MT were performed in China. All three of them showed numerically similar functional outcomes with slight trends favoring direct thrombectomy. SKIP had a smaller sample size and did not meet its non-inferiority criteria, and the other two trials did meet their specified non-inferiority margin, but it could be argued those margins were overly generous. If you think about non-inferiority trials, we generally try to set a margin for non-inferiority such as lower 95% confidence interval for the trial intervention would sacrifice up to 50% of the reference treatment effect. And it's difficult to estimate the effect of alteplase in this specific population. But if you think of the Emberson meta-analysis of alteplase, overall zero to three hours alteplase versus placebo has a 10% effect size and mRS 0-1, three to four and a half hours of 5% effect size. And we regard that as clinically important. So, half of 5%, 2.5%, is a lot tighter margin than any of the direct randomized trials employed.

Dr. Negar Asdaghi:         So, Bruce, let me recap what you just mentioned. Two out of the three earlier trials seem to suggest that perhaps skipping IV therapy is the way to go rather than bridging as these two trials met the non-inferiority criteria if we believe that non-inferiority margins you mentioned. And now we have a couple of more trials, more recent trials. Can you tell us about these trials please?

Dr. Bruce Campbell:       MR CLEAN-NO IV in a European population did not demonstrate non-inferiority, and the point estimate slightly favored bridging. Interestingly, in that trial, the symptomatic intracerebral hemorrhage risk, which was one of the main drivers for trying this strategy, was 5.9% in the direct and 5.3 in the bridging group. So, there's no hint of benefit from dropping the lytic on that metric. SWIFT-DIRECT was more selective in only enrolling internal carotid and M1 occlusions, which had a lower chance of early recanalization with lytic. But the protocol also specified giving the full dose of lytic. In the other trials, it seems the alteplase infusion was often stopped once the patient was in the angio suite, so the full dose may not have been delivered. And despite very low pre-endovascular recanalization in that selected group in SWIFT-DIRECT, the end of procedure reperfusion was significantly better in the bridging group, which is a consistent finding across the trials and suggests that the lytic may improve the thrombectomy outcome.

Dr. Bruce Campbell:       DIRECT-SAFE, the final of those trials, was interesting in that the patients were enrolled roughly 50:50 from Australia, New Zealand, versus Asia. And in contrast to the original three randomized trials in Asian patients, DIRECT-SAFE found a significant benefit of bridging lytic in Asian patients. So, it'd be very interesting to see the results of the IRIS individual patient data meta-analysis, but we may not find a difference in Asian versus Caucasian patients despite those initial trials and despite substantial differences in the prevalence of intracranial atherosclerosis, which has often been proposed as something that would increase the risk of having bridging thrombolytic on board.

Dr. Bruce Campbell:       The original study level estimate of symptomatic hemorrhage had a borderline significant 1.8% absolute reduction in the direct group. Whether those data were not all core lab adjudicated and the final analysis may show a smaller difference than that. Notably, given that trend with symptomatic intracerebral hemorrhage, mortality did not differ significantly, and, in fact, the trend favored bridging patients. So, the symptomatic hemorrhage slight trend into increase did not translate into any hint of increased mortality.

Dr. Negar Asdaghi:         So, Bruce, a lot of information, and I need a recap for me. So, let me try to recap some of the things you said, and please jump in. So, so far, the newer data really basically don't show us any convincing evidence that skipping is the way to go, and direct endovascular we really don't have data in favor of going directly to the angio suite. And the jury is still out regarding an increase in the symptomatic intracerebral hemorrhage rate amongst those that actually are pre-treated with IV therapy. Is that correct?

Dr. Bruce Campbell:       That's correct. So, none of the three recent trials met their non-inferiority margins. And again, we had this issue of relatively generous non-inferiority margins, and the symptomatic hemorrhage, it would make sense that there's a small difference, but it's not really been borne out in the data to be statistically significant at this stage. And again, this individual patient data meta-analysis is keenly awaited to get the most accurate estimate on that.

Dr. Negar Asdaghi:         So, while we wait that, I'm going to digress a little bit and ask you a question that's not addressed in the paper that you have in this issue of the journal, and that's the CHOICE trial. So, by now, we have the results of CHOICE trial. Do you mind first give us a brief overview of what CHOICE was and how you feel that the results of CHOICE would affect this field of direct versus bridging in general?

Dr. Bruce Campbell:       CHOICE is a very interesting study in that it tested giving the intra-arterial lytic at the end of a thrombectomy procedure that had achieved an mTICI 2b or better, which is what we traditionally regarded as angiographic success. The idea was to improve microvascular flow, and that may be the case. The trial was terminated early due to logistic reasons and showed a very large effect size that requires replication. The subgroup analyses are interesting in that the benefits seem to mostly accrue in patients who'd not already had intravenous lytic.

Dr. Bruce Campbell:       So, perhaps giving the IV lytic before thrombectomy can still benefit patients after the thrombectomy, as well as achieving early recanalization in a proportion of patients and perhaps facilitating the thrombectomy. The other issue to address with the DIRECT trials is that with the exception of a few patients in DIRECT-SAFE, the comparator was alteplase and not tenecteplase. And we have data from EXTEND-IA TNK that tenecteplase bridging is not just non-inferior, but superior to alteplase bridging. There's an ongoing Brazilian trial of exactly that, tenecteplase versus the direct approach, which will be very interesting.

Dr. Negar Asdaghi:         So, great, Bruce. I just want to repeat this segment again for our listeners. So, CHOICE is a very interesting study, looked at giving intraarterial alteplase to patients after endovascular therapy was completed and after they'd already achieved the complete and successful revascularization, and the trial was terminated early because of logistic reasons. So, we have to keep in mind, this was a smaller study, early termination, but the effect size was pretty large in favor of giving lytics.

Dr. Negar Asdaghi:         So, what you mentioned is interesting, and I think that it's really worth paying attention to, that the majority of the benefits seem to have occurred from intraarterial thrombolytics in patients that have not been given intravenous lytics prior to endovascular therapy. So, in other words, you need some sort of lytics either before or after the endovascular thrombectomy to achieve that ultimate improved outcome. So, moving forward now from the randomized trials that we have on bridging versus direct thrombectomy, you have mentioned in the paper some interesting subgroups that may benefit or not benefit as much from bridging versus direct thrombectomy. Do you want to elaborate a little more about those subgroup analyses?

Dr. Bruce Campbell:       The idea of precision selection or individualized treatment is being talked about a lot given there didn't seem to be much overall difference between strategies in the randomized trials, but it's important to note that the randomized trial actually disadvantages the bridging group by delaying lytic until the patient was firstly confirmed eligible for thrombectomy and then consented and randomized. Putting that aside, if we could identify a subgroup who clearly benefit from skipping lytic and, importantly, identify them without delaying lytic for those who likely benefit, that's clearly attractive.

Dr. Bruce Campbell:       Currently, I'd say we have not identified that kind of subgroup, and the planned IRIS individual patient data meta-analysis will be critical for that. Patients with a large ischemic core are one potential group where there's a high risk of bleeding hypothesized. To date, there is no definitive data to indicate the risk is lower with the direct approach. Patients who need stents certainly may benefit from not having a lytic on board because they often need adjuvant antithrombotics that could increase the bleeding risk. But the question there is whether we can confidently identify those patients before the procedure, and I think that's unclear at this stage. Patients with really large clot burdens and proximal occlusions have sometimes been said not to benefit from IV lytic based on the low rates of pre-endovascular reperfusion, but the randomized trials really hinted other benefits like this potential facilitative thrombectomy. So, that hypothesis may be insecure as well.

Dr. Negar Asdaghi:         And how about age? Have you come across and has there been any signal towards an impact or interaction between age and benefit from pre-endovascular thrombectomy and thrombolytics?

Dr. Bruce Campbell:       It's an interesting question because age has not generally been a treatment effect modifier in previous stroke studies with thrombolytics and thrombectomy, and the individual direct thrombectomy trials that have reported subgroups haven't shown any convincing heterogeneity by age. There's certainly no indication that older patients are at risk from bridging in what I've seen so far.

Dr. Negar Asdaghi:         So, this question comes up in clinical practice all the time, that a person's older, perhaps more atrophy, more vascular risk factors and white matter disease, and they're more prone, so to speak, of having a symptomatic intracerebral hemorrhage. So, what you're saying is, from the data we have, there's really no signal in favor of withholding pre-thrombectomy lytics in this population. So, it's important to know this. Bruce, what should be our final takeaway message from this study?

Dr. Bruce Campbell:       I tend to agree with the recent European Stroke Organization and ESMINT guideline that for now, patients should receive lytic as early as possible and in parallel with the decision to perform thrombectomy such that neither treatment delays the other. I think if we can identify a subgroup that benefits from direct thrombectomy, and that's confirmed in the individual patient data and meta-analysis, and we can identify them without disadvantaging the majority of patients, and also that the ongoing improvements in IV lytic strategies don't render the existing trial data obsolete, then we may, in future, skip lytic for some patients, but we are not there yet.

Dr. Negar Asdaghi:         So, that's amazing, Bruce. We look forward to reviewing the paper and individual data meta-analysis and interviewing you, hopefully at a better hour your time, on that. Thank you very much for joining us on the podcast today.

Dr. Bruce Campbell:       Thanks again for the invitation. It's been great talking to you.

Dr. Negar Asdaghi:         Thank you.

Dr. Negar Asdaghi:         And this concludes our podcast for the June 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including three very interesting images that are presented as part of a new article type, Stroke Images, and a special report in Comments and Opinions section on "Bias in Stroke Evaluation: Rethinking the Cookie Theft Picture." June is the month of Pride, and in spirit of equality, we hope to do our part to reduce all biases in stroke processes of care, diagnosis, and outcomes as we continue to stay alert with Stroke Alert.

Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.