On Episode 10 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the November 2021 issue of Stroke: “Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke” and “Treatment-Associated Stroke in Patients Undergoing Endovascular Therapy in the ARUBA Trial.” She also interviews Dr. S. Claiborne Johnston about “Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack.”
Dr. Negar Asdaghi:
1) What is the net ischemic benefit derived from combination of ticagrelor and aspirin treatment in patients with mild ischemic stroke or transient ischemic attack?
2) Is the ischemic stroke in patients hospitalized with COVID-19 associated with the rise in biomarkers of inflammation and coagulopathy?
3) What are the characteristics associated with periprocedural stroke in patients treated endovascularly for an unruptured AVM?
We'll discuss these topics and much more at today's podcast. Stay with us.
Dr. Negar Asdaghi: Welcome back to the 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. For the November 2021 issue of Stroke, we have a large selection of topics, from peanut consumption reducing the risk of ischemic stroke, and the decline in the rate of progression of coronary atherosclerosis in patients on a Mediterranean diet, to how the efficacy of endovascular thrombectomy diminishes in patients with more pervious thrombus composition, which I encourage you to review in addition to our podcast today.
Dr. Negar Asdaghi: Later in the podcast, I have the distinct honor of interviewing Dr. Claiborne Johnston from Dell Medical School at UT Austin on his latest work with data from the THALES trial to clarify the net ischemic benefits derived from a combination of ticagrelor and aspirin therapy in comparison with the risks of hemorrhage associated with this treatment in patients with mild and moderate stroke and TIA. But first with these two articles.
Dr. Negar Asdaghi: COVID-19–associated ischemic stroke, or CAIS, is a new term that, unfortunately, stroke physicians need to be familiar with. While acute ischemic stroke can occur in parallel from, say, traditional causes of stroke in patients infected with coronavirus, ischemic stroke and other thrombotic events, such as myocardial infarction, pulmonary embolism, deep vein thrombosis, and acute limb thrombosis, can occur in the setting of overt hyperinflammation and subsequent coagulopathy that is observed in patients hospitalized with severe COVID-19 illness.
Dr. Negar Asdaghi: Elevated D-dimer, although quite non-specific, has emerged as a marker of COVID-19–associated coagulopathy, but whether an elevated D-dimer in isolation or in combination with various other inflammatory and coagulation markers is associated with development of acute in-hospital ischemic stroke in those hospitalized with COVID is not known.
Dr. Negar Asdaghi: So, in the current issue of the journal, in the article titled "Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke,” Dr. Charles Esenwa from the Department of Neurology at Montefiore Medical Center and colleagues did an interesting analysis of over 5,000 patients with COVID-19 who were admitted to one of the Montefiore Health System hospitals between March 1, 2020 and May 8, 2020. This was a retrospective analysis, so they had to work with the available biomarkers for each patient and use a machine learning cluster analysis of these biomarkers to divide the patients basically based on five biomarkers to four clusters.
Dr. Negar Asdaghi: The following five biomarkers were chosen by this machine learning cluster analysis. These included CRP, D-dimer, LDH, white BC, and PTT. So, they had to come up with some arbitrary rules to exclude biomarkers that were either missing in over 30% of their population, and they also excluded those patients that were hospitalized for a long period of time, and they chose a 30-day hospitalization and over. And they also only used the first reading for each biomarker. Again, these were arbitrary rules that were set forth by the authors, and they found some alarming findings. When they clustered patients based on similarities in these biomarkers, they came up with predicted models for combined thrombotic events and acute ischemic stroke.
Dr. Negar Asdaghi: For example, in the cluster where the patients had the highest mean values for CRP, D-dimer, LDH, and white BC, and a relatively low PTT, these patients had the highest prevalence of acute ischemic stroke. They had the highest prevalence of in-hospital strokes and severe strokes and highest percentage of total thrombotic events. In contrast, the cluster with the lowest mean of all of these five biomarkers had no cases of in-hospital acute ischemic strokes; they had the lowest prevalence of composite, all thrombotic events, and patients had the least severe complications.
Dr. Negar Asdaghi: So, they also tested the effects of biomarkers individually for prediction of acute ischemic stroke. And it turns out that when they used a lone marker, only D-dimer again was associated with acute ischemic stroke. Very interestingly, D-dimer was specifically elevated in those COVID-19 patients in whom the stroke was ultimately classified as cryptogenic.
Dr. Negar Asdaghi: So, what does that mean? That means that it's more likely that a stroke had occurred in the setting of severe COVID-19 hyperinflammatory response, and less likely associated with other classical causes of stroke.
Dr. Negar Asdaghi: So, what did we learn overall from this study? Well, hospitalized COVID-19 patients with a combination of high CRP, D-dimer, LDH, and white BC, and slight reduction in their PTT, had a 4.5-fold increase in the risk of in-hospital mortality and a fivefold increase in the risk of in-hospital stroke as compared to the COVID-19 patients with the lowest mean values for all the five biomarkers mentioned above. So, important information to keep in mind as we treat hospitalized COVID-19 patients, and we await more prospective data on this topic.
Dr. Negar Asdaghi: Arteriovenous malformations, or AVMs, are congenital vascular lesions that are associated with long-term excess mortality and morbidity, essentially almost all related to their risk of intracerebral hemorrhage. Roughly half the patients with brain AVMs present with intracerebral hemorrhage, resulting in a first-ever hemorrhage rate of about 0.5 per 100,000 person years.
Dr. Negar Asdaghi: Annual risk of hemorrhage is estimated at 1 to 4% for all comers with AVMs, but varies significantly, and can be as low as 0.9% in patients with unruptured, superficially located brain AVMs with superficial drainage, but may be as high as over 34% in patients with ruptured, deeply seated brain AVMs with deep venous drainage. So, treatment would entirely be dependent on the type of presentations and characteristics of each patient with an AVM.
Dr. Negar Asdaghi: Whether unruptured AVMs should be managed clinically or treated either endovascularly or surgically is the subject of the ARUBA trial that is a randomized trial of unruptured brain AVMs. The enrollment of ARUBA was halted by the study's DSMB board, but medical management was found to be superior to treatment arm for the primary outcome of symptomatic stroke and death.
Dr. Negar Asdaghi: Since then, there's been a lot of focus in the literature and comparison of outcomes between treated and untreated patients with unruptured AVMs, but less has been published on characteristics of patients who suffered from periprocedural stroke, an important part of the primary outcome of ARUBA. So, in the current issue of the journal, we have the study titled “Treatment-Associated Stroke in Patients Undergoing Endovascular Therapy in the ARUBA Trial.”
Dr. Negar Asdaghi: Dr. Joshua Burks and colleagues from the Department of Neurosurgery at the University of Miami and colleagues evaluated 64 patients with unruptured AVMs enrolled in the ARUBA trial who underwent endovascular treatment as part of the trial and looked at the characteristics of those who suffered a perioperative stroke, defined as a stroke recorded at or within 48 hours of intervention, as this would represent a direct procedure-related complication rather than sequelae of, say, treated or partially treated AVM itself.
Dr. Negar Asdaghi: All patients who initiated endovascular intervention, including attempted interventions in cases where therapy was aborted secondary to technical or anatomical limitations, were included regardless of randomization or subsequent withdrawal from the study beyond 48 hours following the intervention. So, what they found was that 16% of interventions resulted in stroke, 11% hemorrhagic, and 5% ischemic strokes. And they had no perioperative mortality, which is good news.
Dr. Negar Asdaghi: In univariate analysis, they found many factors that were more commonly seen in patients that suffered from perioperative stroke as compared to those who did not have a stroke perioperatively. Those factors included, for instance, female sex. Over half of these patients were female. Close to half were enrolled in France. And over 40% of those who suffered a stroke in the perioperative timeframe had Spetzler-Martin grade two AVMs.
Dr. Negar Asdaghi: When they accounted for all confounding variables, they found that endovascularly treated unruptured AVMs that are supplied by the posterior cerebral artery cortical feeders and those with Spetzler-Martin grade two and three had a higher perioperative stroke risk as compared to their counterparts without these characteristics. Interestingly, there are also significant geographical disparities in the risk of stroke in that patients treated in the United States or Germany had a significantly lower stroke risk than patients treated in other countries.
Dr. Negar Asdaghi: So, what did we learn from this study? There are patients and lesion characteristics that increase the risk of stroke associated with endovascular treatment of unruptured AVMs. The current study suggests that AVMs with cortical arterial feeders from posterior cerebral artery and those with grade two and three Spetzler-Martin were associated with a higher risk of procedural and periprocedural stroke.
Dr. Negar Asdaghi: And very importantly, as with every surgical intervention, the risk of a procedure is operator-dependent, as well as center-dependent. And these are important factors to keep in mind as technology evolves and more treatments become available to decide whether to keep or to refer patients with unruptured AVMs to a more experienced center.
Dr. Negar Asdaghi: Patients with mild ischemic stroke and transient ischemic attack are at high risk of having recurrent ischemic events, especially in the immediate aftermath of their symptom onset. Early diagnosis and initiation of secondary preventive measures, such as antiplatelet or anticoagulation therapies, in the appropriate setting considerably reduce this recurrent risk.
Dr. Negar Asdaghi: Multiple randomized trials have shown that as compared to treatment with a single antiplatelet agent, dual antiplatelet treatment is more effective in reducing the risk of stroke and other major vascular events in the TIA mild stroke population, a benefit that comes with an expected increase in the risk of hemorrhage.
Dr. Negar Asdaghi: THALES trial is one of the latest trials to determine the efficacy of dual, which is combination of ticagrelor and aspirin, versus mono-antiplatelet therapy, that is aspirin alone, in eligible patients with non-cardioembolic acute ischemic stroke and TIA. Now, it's important to keep in mind that the primary outcome of THALES is a composite of stroke or death, which included both ischemic and hemorrhagic events.
Dr. Negar Asdaghi: Now, it's important to understand that while in the setting of a clinical trial, combining the risks associated with dual antiplatelet therapy, which is hemorrhage, and the potential treatment benefit, that is reduction of recurrent ischemic events, is appropriate as part of the outcome selection. In routine practice, this type of primary outcome can obscure the actual trade-offs between the benefits of dual antiplatelet treatment and its inherent hemorrhagic risk.
Dr. Negar Asdaghi: So, in this issue of the journal, in the study titled "Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack," the THALES investigators led by Dr. Claiborne Johnston sought to separate the ischemic benefits of combination of ticagrelor and aspirin therapy from its hemorrhagic risks in patients enrolled in the trial.
Dr. Negar Asdaghi: I'm joined today by Professor Johnston to discuss the findings of this paper. Dr. Johnston absolutely needs no introduction to the stroke community and our readership. He's a Professor of Neurology at Dell Medical School at the University of Texas at Austin. He's a leader in the field of cerebrovascular disorders, has served as the primary investigator of multiple randomized trials and large prospective studies to evaluate the preventive treatment outcomes in TIA and mild stroke, and has pioneered the development and validation of predictive models for recurrent stroke in this population. He's authored over 700 peer-reviewed manuscripts, has won several awards for research and teaching, and is recognized for his leadership in the field of medicine and healthcare.
Dr. Negar Asdaghi: Good morning, Clay. We're delighted that you could join us on the podcast.
Dr. S. Claiborne Johnston: Well, thank you. It's wonderful to be here. Thank you for having me.
Dr. Negar Asdaghi: Thank you. So, THALES is an exciting new addition to the most recent trials of dual antiplatelet therapy that studied mostly the role of clopidogrel and aspirin combination therapy. Can you please start us off by telling us why did we need a new trial in a very similar patient population?
Dr. S. Claiborne Johnston: Well, the primary reason was, yes, clopidogrel works in combination with aspirin in the setting, but clopidogrel is actually a prodrug. It requires conversion in the liver to its active form. And polymorphisms in CYP2C19 and Cyt P450 pathways are really common and associated with an inability or limited ability to convert that prodrug into its active form. So, there are a number of people who may not benefit much, if at all, from clopidogrel. So, it's kind of surprising that it works as well as it does.
Dr. S. Claiborne Johnston: Ticagrelor doesn't have that problem. It's not a prodrug. It acts directly on the P2Y12 inhibitor. And so, the hope was that we would have a more consistent and pronounced effect on risk reduction in patients after TIA and mild to moderate strokes.
Dr. Negar Asdaghi: Primary efficacy outcome in THALES was different from the primary efficacy outcome chosen for the POINT trial, that was major ischemic events and death from ischemic vascular events, and that of the CHANCE trial, that was a combination of ischemic and hemorrhagic strokes in 90 days. Can you please tell us about the thought process behind choosing this particular primary efficacy outcome in THALES?
Dr. S. Claiborne Johnston: Yeah, so this was encouraged by the regulatory authorities. And so the primary efficacy outcome in THALES is all stroke, hemorrhagic and ischemic, and all death, hemorrhagic and ischemic. And we teased apart just the ischemic etiologies in POINT.
Dr. S. Claiborne Johnston: The rationale was that we were including all the major outcomes that the drug could impact. The problem is that people forget that it includes hemorrhagic events, and then they weigh that efficacy outcome against the safety outcome. And so there's confusion. There's sort of double-counting of safety elements in doing that comparison.
Dr. Negar Asdaghi: Okay, great. And now, before we hear about how you disentangled the two safety and efficacy outcomes, can you please remind our listeners about the primary results of THALES, which was published obviously a few months ago?
Dr. S. Claiborne Johnston: Yeah, sure. So, it showed that the combination of ticagrelor and aspirin works. It reduced the stroke and death by about 17% over the 30-day period of treatment. So robust effect. There were some increased hemorrhages, and looking at severe hemorrhage as defined by the GUSTO definition, there was almost a fourfold increase, but it was tiny in absolute terms of 0.4% increase.
Dr. Negar Asdaghi: Okay. So, now it's very important, as you mentioned, this disentangling of recurrent ischemic, again, safety from efficacy outcomes. Your current study that is published in the November issue of Stroke clarified these results. And we're excited to hear about those results.
Dr. S. Claiborne Johnston: That's right. So, there were two problems with the way people have interpreted the results of the THALES trial. One is this entanglement of safety events and both efficacy outcome and the safety outcome. The other was the use of relative risks as opposed to absolute risks, because a high relative risk for a rare event is less important than a small relative risk for a more difference between more common events. And so we wanted to deal with both of those issues.
Dr. S. Claiborne Johnston: So, we defined new outcomes that were not entangled. So, we defined major ischemic events, similar to what we had done in POINT, and then we defined major hemorrhage as being basically irreversible hemorrhage, and compared outcomes in the two groups. And what we found was that when we did it that way, for every 1,000 patients treated, we avoided 12 major ischemic events and produced three major hemorrhages. So, about a four-to-one ratio of ischemic benefit to hemorrhage risk. And that was true at various cutpoints for disability.
Dr. S. Claiborne Johnston: So, if we said, "Okay, yes, you had an event, and are you disabled at last follow-up at 30 days?" Then if we said that, there was also a four-to-one difference in disabling events, ischemic versus hemorrhagic. And if we said a two or greater, so moderate disability or worse, it was the same ratio, four-to-one.
Dr. Negar Asdaghi: Okay, so four-to-one ratio of benefit. That's an important number to keep in mind. Also reassuring to see that this net clinical benefit or net clinical impact of the combination of therapy was practically the same across all the pre-specified subgroups in the trial. Were you at all surprised by the subgroup analysis?
Dr. S. Claiborne Johnston: Well you know if you do enough subgroup analyses, you're going to find differences, right? And thankfully, we have the looking at interaction terms to keep us honest, but even so, you look at 20 and you're going to have some significant interaction terms, as well. But yeah, it was reassuring that the effects were so consistent across groups.
Dr. S. Claiborne Johnston: I think there's been a tendency to over-interpret results from subgroup analyses. We don't have any evidence to suggest that we should be doing that here. I'm sure we can pick out groups that do better, and we've done that actually. The group with atherosclerosis does particularly well, but is that a chance event or is that real? I think we just have to be super-cautious about subgroup analyses.
Dr. Negar Asdaghi: So, absolutely. One of the subgroups that I'm personally very interested in is just the time subgroup. So, all of the patients in THALES were enrolled within the first 24 hours, and the subgroup analysis did not show that there were any differences in terms of the net benefit between those that were enrolled earlier, within the first 12 hours, and those that were enrolled later, between 12 and 24 hours. But in routine clinical practice, we often see patients with TIA and mild stroke actually presented to us later than that timeframe entirely. Should we be giving them dual antiplatelet treatment?
Dr. S. Claiborne Johnston: That's a great question. So, we did an analysis in POINT where we modeled out, would we still have an important significant net benefit if we had started the trial later? And we didn't start the trial later, right? So, this was just pretending like anybody who had an event early on was not in the study in starting at a later timepoint and modeling that out. And basically what we found was that for out to three days, there was still a benefit. And, in fact, if you look at that data and look at those tables, you could even say, even out to five days.
Dr. S. Claiborne Johnston: I would say it's not unreasonable to do that given that the risks are so small and they're going to be even later with later treatment. But I would say, too, that even though we're not seeing greater impact within that first 24 hours versus 12 to 24, it just makes sense with event rates being as great as they are early on that if you don't treat with a preventive medication before an event occurs, it doesn't work. So, it just makes sense that as much as possible we ought to treat people as early as possible after their events.
Dr. Negar Asdaghi: Very important findings and things to keep in mind. I want to ask you about the top two takeaway messages from the study.
Dr. S. Claiborne Johnston: One is that there's a favorable benefit-to-risk ratio for ticagrelor/aspirin in mild to moderate actually ischemic stroke and high-risk TIA from THALES. So that would be number one.
Dr. S. Claiborne Johnston: And then number two is watch your endpoints carefully. Think carefully, too, about whether balancing safety to efficacy events really makes sense and also whether focusing on relative risks really makes sense. I would encourage us, even though our journals tend to push us towards relative risks and we're more familiar with those, I'd encourage us to get more comfortable with using absolute risks in the way we look at data, but also in the way we talk to patients about their impact.
Dr. Negar Asdaghi: Fair enough. I remember a few years ago, you visited us here at the University of Miami to deliver the annual Cerebrovascular Scheinberg Lecture. And you had mentioned that the idea of dual antiplatelet therapy treatment of patients with TIA mild stroke had come to you many years back when you were still in training, but it took many years for that idea to turn into reality, into randomized trials, and now translated into clinical practice.
Dr. Negar Asdaghi: At the time, if you recall, this was right before you went to Europe to present the primary results of POINT at the European conference. And the trial results were not publicly available, so you were sworn to secrecy. You couldn't tell us about the results. It's been a few years since then. You've already completed yet another trial on this topic. Can I ask what's next for you and your team as it pertains to acute treatment of patients with TIA and mild stroke?
Dr. S. Claiborne Johnston: Well, there are a few things. So, CHANCE-2 is a really interesting trial. My role in that was peripheral, just really advisory, but it's an exciting trial. So, basically it's looking at people with those CYP2C19 polymorphisms that I mentioned before, people who don't rapidly and readily convert clopidogrel to its active form, and randomizing them to clopidogrel versus ticagrelor.
Dr. S. Claiborne Johnston: So, it's going to give us some head-to-head data on the two drugs and the people who may benefit the most from ticagrelor. And that is complete, and that will be published in the next few months. So, I that's going to be an important trial in people's thinking about how best to approach these patients.
Dr. S. Claiborne Johnston: The second is, you know, we're not done. We still have a 5% risk of events, even in those three dual antiplatelet therapy. And so we need more agents. And we need to think about secondary prevention extending to other groups as well, just as you said, longer periods of time, more severe strokes, people after thrombolysis/thrombectomy. Those are big groups of patients at extreme risk for secondary events, and we have no agents and no data right now.
Dr. S. Claiborne Johnston: I would be concerned about dual antiplatelet therapy in those patients, just given what we've seen about the risks of hemorrhage in the existing groups, which are again manageable and shouldn't change people's decision about treatment. But for the groups I just mentioned, risks of hemorrhage start to get greater. And so one worries about whether dual antiplatelet therapy's the right thing or whether other agents make more sense. So, yeah, we're interested in looking at other agents, some novel, for those other indications as well.
Dr. Negar Asdaghi: Professor Johnston, thank you for your time, and we look forward to covering more of your research in the future.
Dr. S. Claiborne Johnston: Well, thank you. It's been a pleasure.
Dr. Negar Asdaghi: Thank you.
Dr. Negar Asdaghi: And this concludes our podcast for the November 2021 issue of Stroke. Please be sure to check out the November table of contents for a full list of publications, including two important topical review articles, one on thrombus composition after thrombectomy, and one on pearls and pitfalls of perfusion imaging in acute ischemic stroke, as advanced neuroimaging continues to play a critical role in decision-making for acute stroke therapies.
Dr. Negar Asdaghi: Now, speaking of advanced neuroimaging and the immense role that neuroimaging plays in our day-to-day practice, let's take a moment as we end our November podcast to remember how the concept of medical imaging first began over 120 years ago with the discovery of X-ray by German professor of physics Wilhelm Röntgen.
Dr. Negar Asdaghi: On Friday, November 8, 1895, while experimenting with electricity, Röntgen accidentally discovered a new kind of rays that he referred to as X-rays. He soon realized that X-rays were capable of passing through most substances, including the soft tissues of the body, but left bones and metals visible.
Dr. Negar Asdaghi: One of his earliest photographic plates of his experiments was a film of his wife Bertha's hand with her wedding ring clearly visible. This was the first time that the inside of human body was seen without performing surgery.
Dr. Negar Asdaghi: From Röntgen’s first X-ray image to the advanced neuroimaging that we review today on our portable devices, I can't help but wonder, what will your accidental discovery on a Friday fall afternoon in November do to advance the field of science and stroke 100 years from now, as we continue to stay alert with Stroke Alert.
Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2021. 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.