Our next speaker will be Dr. Sepi Amin-Hanjani, who's a professor at the University of Illinois of Chicago, who's going to discuss advances in vascular surgery during the last year. Sepi. Can you-all see my slide or you see my slide preview window? You see the correct slide and my cursor there? Okay. Thanks, Fred, for that introduction and thanks to you and the organizing committee for the opportunity to participate in this session, which I always find to be a really illuminating and fun session myself hearing about the latest updates in our subspecialty areas. What I'm charged with is talking about trials updates in the vascular arena. I'm going to span a little more than this last year because there's been a couple of trials that have come out in press within the last couple of years since we missed the last AANS meeting that I think it's worth mentioning. I'll spend the time on stroke, on vascular malformations and aneurysms and subarachnoid hemorrhage and really try to just hit the high notes and the main conclusions of some of these studies that have been published or presented recently and really focusing on randomized clinical trials or meta-analyses of randomized trials that have some impact, I think, in our field. No disclosures that are relevant to this talk. I'm going to start out with acute ischemic stroke because this has really become the hot topic in cerebrovascular and particularly endovascular. Of course, this is on the heels of a lot of data that came out in the last few years from randomized trials showing the efficacy of mechanical thrombectomy for large vessel occlusion and those studies permeated quickly into guidelines demonstrating that patients within six hours of symptom onset from an LVO or large vessel occlusion benefit from mechanical thrombectomy and furthermore within guidelines demonstrating randomized studies where even delayed thrombectomy beyond six hours and up to 16 or 24 hours were effective. Now, this sets the stage for a collaboration that was presented at this year's ISC, International Stroke Conference meeting. This was a virtual meeting and this particular study, Aurora, that I'll mention, really tried to hone in on the patient subgroups who are treated in that delayed time window of six and 24 hours after initial presentation. This particular collaborative really looked to do an individual patient data meta-analysis, taking patient data from a number of randomized trials that had examined patients within this window to really examine pre-specified patient subgroups and provide really a even higher level of evidence for treatment of these patients with mechanical thrombectomy in this delayed time window. What did their results show? They really were able to emphasize the level of improvement in outcomes in patients who undergo the thrombectomy in that time window, a two and a half fold improvement in outcomes as measured by MRS at 90 days. Interestingly and somewhat paradoxically, when they looked at subgroups of patients randomized within 6-12 hours after presentation versus 12-24 hours, that later subgroup seemed to enjoy a better odds of improvement which is not as intuitive as one would expect to have seen in these results in that those presenting later we might expect would do worse. On the other hand, it may be that these patients who are being treated in that later time period are self-selecting themselves as folks with good collaterals who still have salvageable conumbra. That was an interesting observation from this collaborative that pulled together this individual patient data for meta-analysis. The overall conclusion, of course, was that this provided a stronger evidence base even for performing thrombectomy in this delayed time window, and really something that's becoming adopted as a standard for patients who are eligible based on the types of criteria used in those trials. Now, this is an older study that I wanted to mention, older in that it was presented at last year's International Stroke Conference and has been published in 2020, but I think is an area to keep an eye out for. This particular study, ESCAPE-NA1, was looking to see if there was additional benefit of using a neuroprotectant, specifically narinitide or NA1, in patients who are undergoing thrombectomy. This was designed as a multi-center, international, double-blinded, randomized study. Patients were stratified in the randomization by use of TPA. Of course, TPA is standard care for patients presenting within four and a half hours of stroke, and it'll become relevant why that stratification was important when we talk about the results. The trial enrolled over 1,100 patients, and in its primary outcome, which was modified Rankin score, 0-2, so a good functional outcome in 90 days, there was no difference in the two groups as far as those receiving neuroprotectants versus those that did not. However, when the stratified analysis was examined in those patients that did not receive alteplase, so the patients at the top of this figure, there did appear to be a signal almost significant for a difference between those receiving the neuroprotectant, having a higher odds of a better functional outcome at 90 days. Could this be just a spurious subgroup effect? Maybe not, because there appears to be some biological plausibility for why this effect may exist, in that alteplase can affect the metabolism of the neuroprotectant neurinotide, and therefore, in those who did not receive alteplase, who weren't candidates for it for whatever reason, they may enjoy a benefit of that treatment. Of course, this is a subgroup, and therefore, the overall conclusion of the trial is that there is no benefit to this therapy in conjunction with thrombectomy, but that this treatment effect may be present in patients that don't receive TPA and therefore needs further study. Now, along those theme of TPA and the need for it, or IV TPA or thrombolysis, which I mentioned is really standard of care, the really hot topic now is the idea of whether thrombectomy patients, those who are eligible for an LVO mechanical thrombectomy, even need to receive IV thrombolysis, i.e., do they even need bridging therapy, or should they just go for thrombectomy? I'll present a few studies in quick succession, all of whom were trying to address this issue of if it's necessary to give patients with LVO that are heading for mechanical thrombectomy, thrombolysis or not. The first of these studies that was published last year in the New England Journal was the DIRECT-MT trial. This was conducted in China in over 600 patients with LVO stroke within four and a half hours. Within that window, where thrombolysis could be administered and were randomized to receive or not receive that. This was a non-inferiority design, trying to show that there's no difference in providing that bridging therapy. The results of that study were positive, positive in that they did reach their non-inferiority threshold statistically, demonstrating in their conclusion that, at least in this population of Chinese patients, thrombectomy alone is non-inferior. It's interesting to note that that effect is not related to door-to-puncture time. You might expect that the benefits of not giving thrombolysis might be that they get faster to the angiosweep. But in all of these trials, door-to-puncture times were similar. Whatever effects are being seen are not a artifact, so to speak, of speed of thrombectomy. Now, the next study that examined this was a skipped trial published earlier this year in JAMA. This was conducted in Japan. Multi-center study, again, non-inferiority design. Again, patients with LVO stroke within four and a half hours, they did not meet their non-inferiority threshold. They were not able to claim that thrombectomy alone was non-inferior. Although when you look at the actual MRS 0-2 numbers at 90 days, it's very similar in both groups. Again, the door-to-puncture times were quite similar between the two groups there. Their conclusion, however, was that because of their failure to meet their non-inferiority threshold, they cannot conclude that the procedures, meaning thrombectomy with or without thrombolysis are equivalent. Next came the DEFT trial, a study in China again, which aimed to enroll 970 patients, but was actually halted early after they met their non-inferiority goal after enrolling only 234 patients. Here again, similar to the direct MT study, they found that their threshold for non-inferiority was met, demonstrating that thrombectomy alone was not inferior. Again, similar door-to-puncture times between the two groups. Their conclusion is that within a 10 percent confidence limit, they feel the treatment is non-inferior. Now, all of these studies were in Asian populations. What was presented at the International Stroke Conference this year was the one study from Europe, Mr. Clean No IV, where basically in a randomized trial in Europe, 539 patients were similarly randomized to get or not get bridging therapy. This was a slightly different design. Their primary analysis was actually focused on superiority, but they did do a secondary analysis for non-inferiority as well. In their results, they were not able to show either of those thresholds, meaning that the odds ratio crossed one, and therefore they were not able to show superiority, and neither were they in their secondary analysis able to show their threshold of non-inferiority. Even though that trial did not resolve the issue in this Caucasian population, the pooled data from all these studies really suggest that the true difference between bridging or not bridging is probably even Steven, so they say. There are still ongoing studies like SWIFT Direct that are going to inform this further so that ultimately this may make its way into the guidelines as to whether bridging thrombolysis should remain a standard of care or not. Now, what else do we have on the acute ischemic stroke front? There's been a couple of trials looking at mobile stroke units. This one published earlier this year was regarding the effect on outcomes of mobile stroke units. There's been a lot of discussions about how these units may improve stroke care by increasing the speed of stroke care delivery, but not a lot of data about how outcomes are affected, and certainly discussions about how the cost of these units might be prohibitive in a lot of communities. This particular study was performed in Berlin, where it was a non-randomized but prospective and controlled intervention study looking at patients who were brought in by a mobile stroke unit versus a conventional ambulance and enrolled a large number of patients, over 1,500 patients. They indeed found that the modified Rankin score favorable, which they defined as 0-3 at 90 days, was in fact significantly better. The percentage difference is small, but certainly significant with that high volume of patients in this particular cohort. They conclude that the MSU does in fact lower disability at three months in this population that was studied. Now, here in the US, the best MSU study was presented, the ISC meeting in February, and compared in a similar way the idea of outcomes at 90 days in TPA-eligible stroke patients. This was an alternating week cluster controlled study with blinded assessment at entry and outcomes, and it enrolled over 1,000 patients. And here, too, a benefit of the MSU group was seen. If you look at the 90-day outcomes, there was a benefit there in terms of improved functional outcome, and that's probably related to the higher proportion and speed at which interventions like TPA were administered to patients. And there, they conclude that there was substantially less disability for stroke patients who qualified for TPA by having been picked up by the mobile stroke unit versus conventional means, and they are still doing cost-effectiveness analysis, so further data will be coming out from the best MSU study. On the surgical front, there haven't been any new trials of decompressive hemicraniectomy for large hemispheric stroke, but there was a meta-analysis published this year that looked to combine individual patient data from seven randomized trials in almost 500 patients, and, again, really reiterated there is certainly decreased mortality and an increase in favorable outcome defined as MRS 0-3 with decompressive hemicraniectomy. Importantly, though, this meta-analysis re-emphasized that outcomes differ by age and by timing. Those greater than 60 don't necessarily fare as well, and delayed hemicraniectomy does not necessarily fare as well either, and they conclude that there's still uncertainty in older patients and the benefit of surgery is less certain if it's after day two following the infarction. And then on the stroke prevention front, the ACST2 study was just very recently presented at the cardiology meeting in Europe and published in Lancet soon thereafter, about a week ago. This was a large study comparing carotid endarterectomy and carotid stenting for asymptomatic carotid disease. And in this particular trial that was an open-label but randomized multicenter study, their overall results in a cohort of over 3,000 patients you can see in this table, the authors really focused on the notion that both CEA and CAS had a very low risk of perioperative events, less than 1% for death or disabling stroke as a periprocedural outcome. And then you can see that in subsequent non-procedural strokes, both procedures fared well. It is interesting that if you slice and dice these different kinds of outcomes in their published paper, if you take any stroke or death into account, you could argue that carotid endarterectomy, which is the red line, fares a little bit better, but none of that was significant. So ultimately the procedures seemed to be fairly equivalent, no superiority between one or the other for asymptomatic carotid disease. And the authors, again, really emphasize the low risk of disabling stroke or death. And note that the risk of subsequent stroke or serious stroke is about half percent per year. Of course, this doesn't address the issue of whether carotid endarterectomy and CAS are still superior in this era to modern medical therapy. And that's a question that the ongoing CREST-2 trial that's going on in the U.S. that's randomizing patients to CEA versus medical therapy and stenting versus medical therapy is aimed at answering and is recruiting currently for that. Now, moving on to vascular malformations, a couple of studies worth noting. I always hesitate to talk about ARUBA because I have so many concerns about its design and validity, but nonetheless, the ARUBA trial, which was a trial of AVM intervention versus conservative management published long-term results. This was a multicenter, non-blended, randomized trial. It was halted early after recruiting 226 patients. One of the critiques of the study among many was the short follow-up period of 33 months in the initial trial results. So the authors aimed to address that with a longer-term follow-up at 50 months. Arguably, I think for a disease like AVMs, 50 months is still not long-term data, but nonetheless and unsurprisingly, their results were similar with the intervention arm having a higher risk of a worse outcome at five years. And their conclusion was, again, that intervention is a higher risk of morbidity compared to medical treatment alone. But I would really emphasize the caveat that the critiques of the design of this trial make it such that such a conclusion is hard to be considered valid and is unlikely to permeate or change our management of AVMs in any substantive way. And one interesting study, a small study, but on a topic that's rarely looked at in trials is dural AFG and venous fistula. This particular study, the RESPECT-CVT trial, wasn't directly or primarily looking at AV fistulas, was really primarily addressing whether cerebral venous thrombosis can be treated with the Bigotran versus Warfarin. But as part of their analysis, they also examined whether there was evidence of new dural fistulas developing as a consequence of the cerebral venous thrombosis in a prospective trial of 112 patients. And really, they found that at least in that timeframe, no new dural fistulas were encountered in the study group, either on the Bigotran or Warfarin. And they conclude that really, there's not a need for routine follow-up after treatment of cerebral venous thrombosis because there's such a low incidence of developing dural fistulas, at least in a relatively short-term follow-up range. And then finally, onto aneurysms and subarachnoid hemorrhage. There hasn't been a lot of new trial data. I'll mention one study that I think is kind of interesting, at least in terms of its focus on a subgroup of aneurysms, MCA aneurysms, where there is still ongoing debate as to whether endovascular therapies have really matched surgical treatment. And this was examined by a group both in the CURES and ISAT-2 trials. So what the authors did is specifically pick out MCA aneurysms in those two trials. These are two randomized studies, CURES looking at unruptured aneurysms. Important to note that the primary endpoint of the CURE trial is failed treatment modality, hemorrhage or residual at one year. And for the ISAT-2 trial, which is a study of ruptured aneurysms where the primary endpoint is an MRS of greater than two. And when only the MCA aneurysms were examined in these two randomized studies for the CURES, which is again, the unruptured aneurysms, the primary endpoint was significantly better in the clipping. Again, primary endpoint being failure of treatment or residual or hemorrhage. But functional outcome was no different, at least statistically, meaning that both clipping and coiling fared similarly well as far as functional outcome. As far as the ISAT-2 trial looking at ruptured aneurysms, the functional outcomes, again, were not significantly different between clipping and coiling. But again, the occlusion of the aneurysm was better with clipping than coiling. And so the overall conclusion the authors propose is that both treatment modalities have similar clinical outcomes, but that treatment efficacy, complete obliteration of the aneurysm is actually better with clipping than endovascular treatment for this specific cohort of MCA aneurysms. And then one final trial in subarachnoid hemorrhage, the ultra early trial was published this year. This particular study was looking at re-bleeding after subarachnoid hemorrhage with the idea of administering tranexamic acid as an antifibrillinetic, as a strategy to reduce re-hemorrhage before aneurysms are secured. It was an open label randomized study in the Netherlands, recruited over 950 patients, and unfortunately did not show any difference in functional outcome at six months. And in fact, even the re-bleeding rates were not significantly different in patients who were administered tranexamic acid versus the control group. And therefore with those results, the conclusion was that the use of an antifibrillinetic routinely after confirmation of subarachnoid hemorrhage does not appear to improve clinical outcome. And in fact, did not even appear to improve substantially re-hemorrhage rates. So with that, I'll conclude this review of trials. And again, thank the organizers for the opportunity to give a synopsis of what's been going on over the last year or so in the cerebrovascular realm. Thank you.

vascular surgery

trials updates

acute ischemic stroke

neuroprotectants

thrombectomy patients

mobile stroke units