On Episode 21 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the October 2022 issue of Stroke: “Oral Contraceptives, Hormone Replacement Therapy, and Stroke Risk” and “Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage.” She also interviews Dr. Shadi Yaghi about his article “Direct Oral Anticoagulants Versus Vitamin K Antagonists in Cerebral Venous Thrombosis.”

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

1) Do hormone replacement therapies or oral contraceptives increase the risk of stroke? And if yes, does the age of the individual or the duration of therapy modify this risk?

2) Should survivors of intracranial hemorrhage who have atrial fibrillation be treated with antithrombotic therapies for secondary prevention of stroke?

3) And finally, what is the anticoagulant of choice for treatment of cerebral venous sinus thrombosis?

We have the answers and much more in today's podcast as we continue to bring you the latest in cerebrovascular disorders. You're listening to the Stroke Alert Podcast, and this is the best in Stroke. Stay with us.

Welcome back to another amazing issue of 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. The October issue of Stroke covers a number of timely topics. As part of our October Literature Synopsis, we have a nice paper by Dr. Farida Sohrabji and colleague, which summarizes three recently published animal studies to evaluate the association between small vessel ischemic injury and either development of Parkinsonism or the future risk of Parkinson's disease. These studies looked at how ischemia, specifically involving the lenticulostriate arteries, can modulate the nigrostriatal dopaminergic pathway and ultimately lead to Parkinsonism.

As part of our Original Contributions, we have the results of a small randomized trial out of Korea, which was led by Dr. Yun-Hee Kim from Sungkyunkwan University School of Medicine in Seoul, where we learned that doing 20 sessions of transcranial direct current stimulation for about 30 minutes for each session at home can improve post-stroke cognition. This was found to be specifically effective in patients with post-stroke moderate cognitive decline. Now, transcranial current stimulation can be given using a handheld device at home, and if truly proven safe and efficacious in larger studies, can dramatically change the landscape of stroke recovery in cognitive rehabilitation.

I encourage you to review these articles in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Shadi Yaghi from Brown University. Shadi will walk us through a systematic review and meta-analysis of published studies to compare the safety and efficacy of direct oral anticoagulants to that of vitamin K antagonists in patients with cerebral venous sinus thrombosis. Our devoted Stroke Alert Podcast listeners recall that we did cover this topic in our March podcast when we reviewed the results of ACTION-CVT, a multicenter international study that was led by none other than Shadi himself. I'm delighted to have him as a guest on my podcast today to talk more about the seminal study and all things cerebral venous sinus thrombosis. But first, with these two articles.

Millions of women worldwide use exogenous hormones, most commonly in the form of oral contraceptives and hormone replacement therapies. Despite the many different formulations of these drugs that are now available on the market, the two therapies are similar in that both combined oral contraceptives and hormone replacement therapies, or HRTs, contain various dosage of estrogen and progestin. Now, the principal difference between them being that the hormone contents of oral contraceptives are at high enough dosage to prevent ovulation, whereas hormone replacement therapies are considered more physiological as their aim is to return post-menopausal hormone levels to what they were before menopause. Well, by now, you must wonder how is any of this even relevant to vascular neurology? Well, the answer lies in the close relationship between hormonal therapies and stroke. But before we get to that, we have to review a few things.

First of all, it's long been known that the endogenous estrogen has strong and protective effects on the arteries. It promotes vasodilation and cell survival of the endothelial layer. It increases the endothelial mitochondrial efficiency and stimulates angiogenesis. In other words, endogenous estrogen is good for vascular health. And in fact, that's why we think that premenopausal women, in general, are at a lower risk of stroke as compared to their age and vascular risk factors–matched male counterparts. And to make things even better for estrogen, there's enough evidence to suggest that exogenous estrogen also does all of these good things for the endothelium. So, why are we even talking about an increased risk of stroke associated with use of hormonal therapies? The problem is, we have to remember that exogenous estrogen also does other things. It can increase the blood concentration of procoagulants, which, in turn, can increase the risk of thromboembolism, especially venous thrombosis. But there's still a lot of unknown on this topic. For instance, the majority of the prior research on the topic involves postmenopausal women using hormonal therapies.

Some of that research has actually suggested that HRTs may be protective against vascular events, while others showed the opposite. Well, we know that a majority of oral contraceptive users are actually much younger and use these medications premenopausal. So, there seems to be a lot of gaps in our current knowledge on the simple question of whether or not oral contraceptives and hormonal replacement therapies do, in fact, increase the risk of stroke or not. In the current issue of the journal, a group of researchers led by Drs. Therese Johansson, Torgny Karlsson, and Åsa Johansson from the Department of Immunology, Genetics and Pathology at Uppsala University in Sweden set out to fill some of these gaps with their study titled, "Oral Contraceptives, Hormone Replacement Therapy, and Risk of Stroke," as part of a large UK Biobank population-based cohort.

Just a bit about the UK Biobank. This was a large population-based cohort from 2006 to 2010 that included over 500,000 residents of the United Kingdom between the ages of 37 and 73. Participants at the time of enrollment would have extensive information collected from them through questionnaires, interviews, health records, physical measures, as well as some imaging and biological samples. Data on each participant was collected from the time of their birth all the way to the day of assessment, which is interesting, because the day of assessment would then count as the end of the follow-up for each participant. Now, for the current study, they included over 250,000 women of White race in whom information required for the study on whether or not they use hormonal therapies, duration of treatment, age at the time of exposure was available. And just a quick comment about their methodology. They analyzed their cohort once for oral contraceptive use and once for HRT use and compared each group to a reference group of either women who never used their set therapy or the number of years they contributed to the study prior to initiating that set treatment.

So, for instance, if a person started using oral contraceptives at the age of 21, all of the years that she contributed to the study before that age would count as non-exposed user years and were included in the control cohort. So now, on to their findings. A total of 3007 stroke diagnosis of any type were identified prior to the initial visit to the assessment center, which, as we mentioned, was the end of the follow-up in the study. Of these, 578 were ischemic strokes, 177 intracerebral hemorrhage, and 478 were subarachnoid hemorrhages. But as expected for any large cohort, over half of total strokes were self-reported as stroke of any type and could not be classified into any of the above subtypes. Now, let's look at the effects of oral contraceptives on the outcome of stroke. Overall of the women included in the study, 81% were classified as oral contraceptive users, while 19% reported never having used oral contraceptives at any point during the study. On the association between oral contraceptive use and the risk of stroke, at first glance, things looked OK. The hazard rates of any stroke for any stroke subtypes were not different between women who had used oral contraceptives as compared to those in the reference group.

That's great news. But when they looked deeper, they realized that the odds of development of any stroke was actually quite high during the first year after the initiation of oral contraceptives with hazard rate of 2.49 for any stroke, while there was no difference in hazard rates found during the remaining years of use and after discontinuation of oral contraceptive use. So, meaning that there was no lingering effects of oral contraceptives on increased risk of stroke after the first year or after discontinuing the medication. Now, on to HRTs. In total, 37% of women in the study had initiated HRTs at some point during the study, while 63% had never used this therapy. Here's the bad news. Overall, HRTs did increase the risk of stroke. An approximately 20% increase event rate of any stroke was noted among women who had initiated HRTs as compared to those who had not. When analyzing stroke subtypes, the use of HRTs was associated with increased risk of only the subarachnoid hemorrhage subtypes. We don't know why.

Diving deeper, in considering timing of HRT initiation, very similar to what was observed for the oral contraceptives, during the first year after starting the HRTs, the treatment group was twice more likely to suffer from any type of stroke, and the hazard rate was also increased for all three stroke subtypes that were available in the study. But, unlike oral contraceptives, the hazard rate of any stroke remains significantly high even after the first year of use, not just for those who continued HRTs, but sadly, even for those who discontinued the therapy. Though the risk remained high, the hazard ratio declined over time as we went further away from the first year when treatment was initiated. So, bottom line, if women had initiated HRTs at some point in their life, the hazard risk of any stroke increased significantly in the first year. That hazard risk did decline over time, but it always remained significantly higher than non–HRT users.

Now, what about timing of treatment in relation to the onset of menopause? Is the risk of stroke any different if women start on HRTs prior to or after their menopause? The answer is no. Initiation of HRTs was associated with an increased hazard rate of any stroke if it was started pre- or postmenopausal, but the risks were higher if the treatment was started prior to menopause. So, in summary, this large population-based cohort has truly given us some very important practical findings. We learned that both oral contraceptives and hormone replacement therapies do, in fact, increase the risk of stroke, an effect that was most notable in this study in the first year after initiation of both of these therapies, and in the case of oral contraceptives, was just actually limited to that one year alone. Why does this happen? I guess the easy answer is that these drugs, as we noted earlier, have an immediate prothrombotic effect, which gradually weakens over time.

That's one plausible explanation, but for instance, why HRTs increase the risk of subarachnoid hemorrhage is something we can't explain based on the prothrombotic effects of HRTs. So, we have to come back to the vessels, the impact of hormone therapies and estrogen specifically on the blood vessels, on the endothelial cells, the potential increase in blood pressure, especially early on in the course of treatment with these medications. And also, we have to think about the role these drugs may play in increasing inflammatory markers, providing a more suitable milieu for accelerated atherosclerosis, as to why these associations were noted in this study. And it's fair to say that we need more research on this topic in the future.

One challenging scenario that we commonly face in our daily practice is deciding whether or not we should resume antithrombotics in patients with atrial fibrillation who have survived an intracranial hemorrhage. The majority of intracranial hemorrhage survivors with atrial fibrillation actually have a very high CHA2DS2-VASc score, which means that they are actually at a very high risk of future ischemic stroke and systemic embolic events unless they're treated with anticoagulants. On the other hand, the risk of spontaneous intracranial bleeding is substantially higher in a person who has previously suffered from one, let alone if we treat them with anticoagulants. And to make matters worse, we have little evidence from the literature to guide us. So, in the current issue of the journal, in the study titled "Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage," a group of researchers from the UK led by Dr. Deirdre Lane, Professor of Medicine at the University of Liverpool, performed a much needed systematic review and meta-analysis of the available evidence on this subject.

I have to say that lately, it seems that we've been covering a few of these reviews in our podcasts, and we are just getting started. In fact, my next paper in today's episode is also a systematic review and meta-analysis. These papers are packed with details, a testament to the work needed to complete them, but I have to say that even summarizing these papers for a podcast has been a bit challenging. So, feel free to put me on pause, go get some coffee, and let's power through this one together. For their methods, they used the usual search engines looking for papers that included adults over the age of 18 with atrial fibrillation who had survived a non-traumatic spontaneous intracranial hemorrhage of any size, any type, and any location, be it lobar, brain stem, deep, cerebellar, subdural, epidural, or subarachnoid hemorrhage.

And very importantly, they included even those with evidence of microbleeds on neuroimaging. The intervention of interest was either long-term oral anticoagulation or antiplatelet therapy versus no antithrombotic use for the following three outcomes of interest: number one, recurrent thromboembolic events; number two, recurrent intracranial hemorrhage; and number three, all-cause mortality. Just a quick note that for this analysis, they excluded studies that looked at either short-term anticoagulation or non-oral anticoagulation use for any reason that was given to the patient other than for secondary prevention of stroke. For example, if a patient suffered from a pulmonary embolism and was treated with IV heparin or, for a short period of time after that, with oral anticoagulation, those patients or those studies were excluded from this meta-analysis. So, with this criteria, they pulled over 4,000 citations and abstracts, and finally included 20 papers that were published between 2015 and 2021 for a total of over 50,000 participants for this meta-analysis, very nice sample size.

Most of the papers included were observational cohorts, but in addition, we had two small randomized trials, and I want to take a moment and review these trials for our listeners. The first one was a small noninferiority pilot trial out of the UK, the SoSTART trial, that looked at any anticoagulant versus either antiplatelet therapy or no antithrombotics in this population, and the other trial was the Phase 2 trial, the APACHE-AF, that studied apixaban versus no anticoagulation after anticoagulant-associated intracerebral hemorrhage. A reminder that both of these trials were published in Lancet Neurology in 2021. And before we move on to the findings of the meta-analysis, it's worth noting that they had included a mix of patients, some were oral anticoagulant–naive, and some had developed their index intracranial hemorrhage while already on treatment with anticoagulants or antiplatelet therapies. OK, now on to their findings, as mentioned, we're going to review three outcomes of recurrent thromboembolism, recurrent intracranial hemorrhage, and all-cause death for the following three groups: group one, oral anticoagulant therapy versus no therapy; group two, oral anticoagulation therapy versus either antiplatelet treatment or no therapy; group three, comparing new oral anticoagulants versus warfarin.

So, for the first outcome of recurrent thromboembolic events in group one, when comparing oral anticoagulant therapy to no therapy, the study showed a significant reduction in thromboembolic events in favor of oral anticoagulation compared to no therapy. That's great news. Next, analysis of the studies that compared oral anticoagulation versus either antiplatelets or no therapy didn't show the same difference in prevention of embolic events in favor of either groups. Actually, no difference was noted between the two groups. Number three, now, in terms of comparing NOACs to warfarin, three studies had the information on this comparison, and they reported a significant reduction in the risk of thromboembolic events with NOAC as compared to warfarin. So, great news for oral anticoagulation overall, and especially for NOACs.

Now, on the next outcome. Our second outcome was a recurrent intracranial hemorrhage. Keeping in mind that they included some studies where the outcome was defined as any form of intracranial hemorrhage, meaning they included subdurals, epidurals, etc., and some studies only included the outcome of intracerebral hemorrhage. So, on to the first group, comparing oral anticoagulants to no therapy, the pooled estimate revealed no statistically significant difference between oral anticoagulant–treated patients to those who were not treated with any antithrombotics on the risk of recurrent intracranial hemorrhage. That's great news. Next, on our second group, for the same outcome of recurrent intracranial hemorrhage, comparing oral anticoagulants to either antiplatelet therapy or no treatment, they found that oral anticoagulation was associated with a higher risk of recurrent intracranial hemorrhage as compared to antiplatelets or no therapy. And finally, third group comparing new oral anticoagulants to warfarin for the same outcome, the risk of recurrent intracranial hemorrhage was significantly reduced in patients treated with NOACs as compared to warfarin. And now, we're finally on to our last outcome of the study, which is the outcome of all-cause mortality.

So, again back to group one, comparing oral anticoagulants to no therapy, this meta-analysis showed a significant reduction in all-cause mortality rate associated with oral anticoagulation. That's, again, great news. Next group, for the same outcome of mortality, comparing oral anticoagulants to either antiplatelet therapy or no treatment, they found no significant difference in the mortality rates between the two groups. And finally, comparing NOACs to warfarin, the pooled estimate showed that NOACs were associated with a significantly reduced risk of all-cause mortality. Amazing news for NOACs.

So, in summary, here's what we learned from this big study. Oral anticoagulation use after intracranial hemorrhage in patients with atrial fibrillation did significantly reduce the risk of thromboembolic events and all-cause mortality without significantly increasing the risk of recurrent intracranial hemorrhage. In general, new oral anticoagulants, or NOACs, are preferred to warfarin as they do prevent embolic events with a lower risk of recurrent intracranial hemorrhage. But, of course, we still have a lot more questions. For instance, would any of the outcomes mentioned above be different in patients with lobar intracerebral hemorrhage, a condition typically associated with amyloid angiopathy, which carries a high risk of development of intracerebral hemorrhage? Also, we have to keep in mind that the majority of the studies included in the meta-analysis were observational. So, there remains an urgent need for a larger randomized trial on this subject, and we have to stay tuned for more research.

Cerebral venous sinus thrombosis, or CVST, is an uncommon form of stroke resulting in headaches, seizure, or focal neurological symptoms due to either intracranial hemorrhage or venous ischemic infarcts. The rarity of the disease has made it difficult to study as part of randomized trials, so current treatment guidelines for CVST are consensus-based with much of the recommendations extrapolated from data on treatment of patients with systemic deep vein thrombosis. In general, based on the current evidence, the field agrees that a patient with CVST should be anticoagulated. The decision that is difficult and sometimes inappropriately delayed in the setting of acute hemorrhage in the brain. And not surprisingly, there's significant equipoise around the choice of anticoagulant, duration of therapy, and the role of heroic therapies, especially in the acute setting. Currently, there are a number of ongoing trials to address some of these issues. The direct oral anticoagulants present an attractive alternative to vitamin K antagonists for treatment of patients with CVST. This is partly because of their convenience of use.

But how do direct anticoagulants compare in safety and efficacy to the vitamin K antagonists in the setting of CVST is less known. In our March podcast, we reviewed the results of ACTION-CVT, which was a multicenter international study that compared the safety and efficacy profile of the direct oral anticoagulants to that of warfarin in routine practice. The study included over a thousand imaging-confirmed CVST patients from multiple centers in the US, Italy, Switzerland, and New Zealand. And if you missed it, no worries at all. We're here to review some of the results again, as in this issue of the journal, many of the ACTION-CVT investigators, led by Dr. Shadi Yaghi, present the results of a systematic review and meta-analysis comparing the safety and efficacy of DOACs, or direct oral anticoagulants, to that of vitamin K antagonists. I'm joined today by Dr. Yaghi himself to discuss ACTION-CVT and the current meta-analysis. Dr. Yaghi is a Director of Vascular Neurology at Lifespan and Co-Director of Comprehensive Stroke Center and a Director of Research at the Neurovascular Center at Rhode Island Hospital. Good afternoon, Shadi, and welcome to our podcast.

Dr. Shadi Yaghi: Good afternoon, Dr. Asdaghi. Thank you so much for having me.

Dr. Negar Asdaghi: Thank you. And please call me Negar. Congrats on the paper. Before we talk about the meta-analysis, can you please remind us of the results of ACTION-CVT and why the systematic review, in your opinion, was an important next step to that effort?

Dr. Shadi Yaghi: Thank you so much for having me and for bringing up ACTION-CVT. So ACTION-CVT is a real-world multicenter international study that used real-world observational data to compare the safety and efficacy of direct oral anticoagulants to vitamin K antagonists in patients with cerebral venous thrombosis. The reason why we did ACTION-CVT was, as you know, cerebral venous thrombosis is a rare disease, and it's hard to have large studies that would be powered enough to compare the safety and efficacy of direct oral anticoagulants to vitamin K antagonists. So, most of the studies that were done are small, retrospective. There's one randomized controlled trial, but most of them are underpowered to detect the difference between the two groups. So, we decided to do a large-scale international multicenter study using real-world data to compare the safety and efficacy of both.

Dr. Negar Asdaghi: OK, so we're glad you did. Let's start with the methodology of the current meta-analysis. Can you please give us an overview of the inclusion criteria for selection of the papers and the intervention and outcomes that you were interested in?

Dr. Shadi Yaghi: Of course. So, this is a systematic review and meta-analysis that included studies comparing direct oral anticoagulants to vitamin K antagonists in patients with cerebral venous thrombosis. The studies needed to have the two groups included, the direct oral anticoagulants and vitamin K antagonists, and they need to include at least one of the outcomes in our study to compare this outcome between the two groups. In addition, we included articles published in English, and we also included papers that had five patients or more in each group.

Dr. Negar Asdaghi: Perfect. So just recap for our listeners, in order to have been included in the meta-analysis, the paper had to have a reasonable number of patients, and you put that reasonable at the number five, and also they had to have at least one of the outcomes of interest reported in their papers. And those outcomes were either recurrent venous thromboembolism or recanalization rates. Right?

Dr. Shadi Yaghi: Correct. Yes.

Dr. Negar Asdaghi: Perfect. So with that, how many papers did you have to go through to come up with the current number of papers included?

Dr. Shadi Yaghi: That's a great question. We had a little over 10,000 papers, and then we went through a screening process. We used this tool that was developed by Brown University. It's called Abstrackr, and what you do is, we did the search and using several databases like PubMed, Cochrane, and then we included all these studies. We uploaded them in Abstrackr, and Abstrackr was utilized to be able to review all these abstracts and select studies that may or will probably qualify and then go through the studies and details that would qualify. So, we had about 10,000 studies with the initial search, and we had two reviewers go through each abstract, and from these 10,665, we excluded 10,411, and that left us with 254 studies. And then we went through these 254 studies in details. And then finally, we had 19 studies included that met our inclusion/exclusion criteria. And these 19 studies included three randomized control trials and 16 observational studies.

Dr. Negar Asdaghi: Incredible effort. So, three randomized trials in this meta-analysis and 16 observational studies. I think we're very ready to hear the primary outcomes.

Dr. Shadi Yaghi: Yeah, so, the primary outcomes were recurrent venous thrombosis, and that included recurrent venous thromboembolism like peripheral DVTs or PEs, for example, and including recurrent cerebral venous thrombosis. And we know that most of the events are recurrent VTEs, not CVTs, like probably about two-thirds to three-quarters were VTEs, and a third to a quarter were CVT. And then the other efficacy outcome is venous recanalization on follow-up imaging. And we found that direct oral anticoagulants and warfarin were not significantly different in the primary efficacy outcomes.

Dr. Negar Asdaghi: Thank you. I just want to repeat this for our listeners. So, you mentioned some important information here. First one was the fact that about three-quarters of recurrent events were actually systemic thromboembolic events rather than cerebral thromboembolism. So, an important outcome to keep in mind for our practicing physicians. And the fact that DOACs did the same as compared to vitamin K antagonist. So, I think you can already guess my next question, and that is, was there any compromise on the safety profile when using DOACs as compared to vitamin K antagonists in this meta-analysis?

Dr. Shadi Yaghi: Thank you. That's a great question. In ACTION-CVT, we found that there was a lower risk of major hemorrhage with direct oral anticoagulants compared to vitamin K antagonists. In this systematic review and meta-analysis, we didn't find a significant difference, but there were fewer events in patients treated with direct oral anticoagulants versus vitamin K antagonists. This did not reach statistical significance, but if you look at the raw data, it's kind of along the same lines as ACTION-CVT, so the risk of major hemorrhage was about 3.5% with warfarin, and that was about 2% with direct oral anticoagulants.

Dr. Negar Asdaghi: So, again, very important finding, and I want to repeat this for our listeners. So, important finding number one was that there was a superiority in favor of DOACs that you found in terms of a reduced risk of intracerebral hemorrhage in ACTION-CVT. You didn't find this superiority in the meta-analysis, but there was sort of a hint to perhaps lower risk of intracerebral hemorrhage in patients that were treated with DOACs. Did I get that right?

Dr. Shadi Yaghi: Yes, that is correct, and in addition, also major hemorrhage in general, and that included also ICH.

Dr. Negar Asdaghi: Oh, OK, so not just intracranial, but systemic hemorrhages as well. All right. Very good. So, I think my next question would be, why do you think that DOACs have a lower chance of causing hemorrhage?

Dr. Shadi Yaghi: Yeah, that's a really good question. This is not unexpected with DOACs as opposed to vitamin K antagonists. We saw these same trends in patients with atrial fibrillation. We saw improved bleeding profiles with direct oral anticoagulants as compared to vitamin K antagonists. And the risks were along the same lines that we found in patients with cerebral venous thrombosis in ACTION-CVT. Also in the VTE trials as well, there was also reduced bleeding complications with direct oral anticoagulants as compared to vitamin K antagonists. So, it was kind of reassuring to see the same results in patients with cerebral venous thrombosis.

Dr. Negar Asdaghi: Perfect, so kind of expected based on what we know from treatment of systemic conditions with DOACs. The next question I have for you is that in routine practice, treatment of cerebral venous sinus thrombosis almost always starts parenterally with either unfractionated heparin or low molecular weight heparin and then we switch to an oral agent. In the observational studies, did you find any differences in terms of timing of this switch or characteristics of the patients in whom vitamin K antagonists were chosen over direct oral anticoagulants?

Dr. Shadi Yaghi: Thank you very much. Most of the studies did not report these details. I think the one study, off the top of my head, that does report the differences in characteristics between the two groups is RESPECT-CVT. That's the randomized controlled trial comparing dabigatran to vitamin K antagonists. In this study, there was a treatment with parenteral anticoagulation for several days, I think seven to 14 days, prior to transitioning to oral anticoagulation. And this is generally my practice. I typically would treat patients with at least seven days or so parenteral anticoagulation, and once they're clinically stable, then I would transition them to oral anticoagulation, either vitamin K antagonists or direct oral anticoagulant.

Dr. Negar Asdaghi: And I think my next question is along the lines of this question as well. We have several direct oral anticoagulants now available on the market. What was the most common DOACs used for treatment of CVST in these studies, and did you note a preference for the use of any particular agent over others?

Dr. Shadi Yaghi: Thank you so much for the question. Anti-Xa inhibitors were much more common than dabigatran, and the anti-Xa inhibitors most commonly used were apixaban and rivaroxaban. It's in line with what we saw in ACTION-CVT as well, although most of the randomized controlled trials or the largest randomized controlled trial, RESPECT-CVT, used dabigatran, but overall people have been using anti-Xa inhibitors, more particularly apixaban, which was also in line with what we saw in ACTION-CVT.

Dr. Negar Asdaghi: But I think it's fair to say that we don't really have data on superiority of one over others. Is that fair?

Dr. Shadi Yaghi: Yes, that is correct.

Dr. Negar Asdaghi: OK, and so now, where are we at in terms of the future of studies on this topic? We have one ongoing randomized trial now?

Dr. Shadi Yaghi: Yes, we have one randomized controlled trial ongoing, and this is the SECRET trial, and it's looking at rivaroxaban versus vitamin K antagonists in patients with cerebral venous thrombosis. There's another study, it's a prospective observational study that's called the DOAC-CVT study. It's an international study also looking at real-world data prospectively to see if there's a difference in outcomes between the two groups.

Dr. Negar Asdaghi: So, we look forward to the results of those studies. Shadi, a follow-up question I have on this topic is, how long should a duration of therapy be in idiopathic cases of cerebral venous sinus thrombosis?

Dr. Shadi Yaghi: Thank you so much for this question. So, it's unknown at this point for how long should we treat. The key things from the treatment are first achieving venous recanalization, and second is preventing another venous thromboembolic event from happening. So, regarding the venous recanalization, studies have shown that there's not a lot of recanalization beyond four months of treatment. So, a lot of the recanalization really happens early, and continuing anticoagulation beyond the six-months interval, for example, in order to achieve further venous recanalization probably has limited utility. And the second important reason why we treat patients with anticoagulation is also to reduce the risk of a recurrent venous thromboembolic event or cerebral venous thrombosis.

And for that, if it's a provoked CVT, then I think usually it's three to six months. If it's unprovoked, up to maybe six to 12 months or even longer, depending on the profile. And if there's a persistent provoking factor, such as cancer, antiphospholipid antibody syndrome, then the treatment is lifelong or until this condition subsides. There's a lot of controversy about the duration of treatment. The European guidelines were very helpful in identifying the duration of treatment. Hopefully, also, we have some guidelines or at least a scientific statement by the AHA that also doles details out and provides some guidance to practitioners.

Dr. Negar Asdaghi: Shadi, what should be our top two takeaways from the current meta-analysis and also ACTION-CVT?

Dr. Shadi Yaghi: So, really, the top two from ACTION-CVT and the meta-analysis are, first is direct oral anticoagulants have a comparable efficacy to vitamin K antagonists in terms of recurrent venous thrombosis and achieving venous recanalization on follow-up imaging. And then the second point is direct oral anticoagulants are probably safer than vitamin K antagonists. We have to keep in mind that this data is based mostly on observational studies. And, as we mentioned earlier, we need more randomized controlled trials to support these findings.

Dr. Negar Asdaghi: Dr. Shadi Yaghi, it was a pleasure interviewing you on the podcast. Thank you very much for joining us, and we look forward to having you back on the podcast and reviewing this topic again in the future.

Dr. Shadi Yaghi: Thank you so much. I appreciate you having me.

Dr. Negar Asdaghi: Thank you.

And this concludes our podcast for the October 2022 issue of Stroke Please be sure to check out this month's table of contents for the full list of publications, including an important update from the European Stroke Organisation by Prof. Martin Dichgans.

I also want to draw your attention to this month's InterSECT paper, which is our International Stroke Early Career and Training section, to discuss the key topic of burnout and mental health amongst physicians, especially amongst neurologists and stroke neurologists. It's alarming to read in this article that neurology is one of the specialties with the highest reported rates of burnout syndrome, and stroke neurologists are at particularly higher risk than other neurological subspecialties. The article tackles some tough subjects, such as the barriers for physicians to seek help and important strategies to mitigate burnout and how to improve mental health in general. I think it's also timely to know that October is the Mental Health Awareness Month, and the theme for October 2022 is "Back to Basics." The basics of recognizing the burden of stress, anxiety, the burden of isolation and depression, not only on those who we take care of, but also on those who give care to us.

So, whether you're a stroke physician, a stroke caregiver, or whether you've been touched by this disease in some way or shape, please know that you are part of the stroke community and a part of our Stroke podcast family. Thank you for listening to us, and, as always, stay alert with Stroke Alert.

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.

Sailors, Caribbean Trade, and National Boundaries in the Late Nineteenth Century