Hello, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine's CPP section. My name is Katherine Smith, a clinical pharmacist in the Surgical Trauma Critical Care Unit at Maine Health Maine Medical Center in Portland, Maine, and I will be moderating today's journal cast. A recording of this webcast will be available to registered attendees. If you can just log into mysccm.org and navigate to the My Learning tab to access the recording. Thank you for joining us today. A few housekeeping items before we get started, there will be a Q&A after each of today's speakers. To submit questions throughout the presentation, please type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in a live discussion on Twitter, following hashtag SCCMCPPJC and hashtag PharmICU. If you're able to advance the slides, I think there was some information for the audience. So this is the example of the polling and also where you can find the question box for to submit questions. For the next slide, please note that there is a disclaimer that the content to follow is for educational purposes only. And now I would like to introduce your speakers for today. Each will give a 15 to 20-minute presentation followed by a Q&A session. Our first presenter today is Emery Johnson, a PGY-2 critical care pharmacy resident at Maine Health Maine Medical Center in Portland, Maine. He will present on angiotensin II and thromboembolic events, a systematic review. Our second presenter is Nedra McCarthy, a PGY-2 critical care pharmacy resident at the Mount Sinai Hospital in New York City, New York. She will present on safety and efficacy of early versus delayed acetylsalicylic acid after surgery for spontaneous intrafeveral hemorrhage in China, the E-START study. And now I will turn things over to our first presenter, Emery Johnson. Awesome. Thank you for that introduction, Dr. Smith. Once again, my name is Emery Johnson. I am the PGY-2 critical care pharmacy resident here at Maine Health Medical Center in Portland, Maine. Today I'll be talking about angiotensin II and thromboembolic events, a systematic review. So hopping right into it, angiotensin II, as we know, was recently approved back in 2017 by the FDA for refractory distributive shock. However, there's some upcoming literature looking at use and other indications like vasoplegia, status post-cardiac surgeries, and antihypertensive medication overdoses. But the overall mechanism of action of angiotensin II, if we think back to our pathophysiology days, is that it works in the renin-angiotensin-aldosterone system. So I've provided this nice little image here by the manufacturer of Geopressin that we're branding angiotensin II. And so as you can see in the normal pathway, we have angiotensin that's converted into angiotensin I with renin. And then following the normal pathway, it will be converted into angiotensin II with the use of angiotensin-converting enzyme. Once it is converted to angiotensin II, it will bind to our DT1 receptors, which result in vasoconstriction, aldosterone, and vasopressin release, and also some increasing norepinephrine release as well. However, during our distributive shock patients or our severely shocked patients, we will actually see a de-escalation in this angiotensin-converting enzyme. So we'll have this really high ratio of angiotensin I to angiotensin II, which leads to an elevated renin level to promote and get more angiotensin I to the system, but hopefully flood the remaining angiotensin-converting enzymes to make angiotensin II. And so that's where this medication comes into play, just to replete any depleted exogenous angiotensin II. So with all that background information, we'll hop into our first audience poll. Oh, there are my animations, which is going to be, for what indications do you use angiotensin II at your facility? Is it just for vasopressor-refractory distributive shock, for vasoplegia due to cardiac surgery? Both indications, or is there another indication that it's used for? Okay, I've seen a lot of vasopressor-refractory distributive shock, which makes sense. That's what the FDA label is saying. We actually, at our facility, just adopted it for vasoplegia due to cardiac surgery in response to the hydroxycopolymer shortage. So we actually got some pretty good response from our cardiac surgeon. So maybe with more information that comes out with this indication, you might see the adoption of this agent in other hospital facilities. Yeah, kind of the same trend. I'm curious what the other is, though. I wonder if you can drop it in the chat and see as we move forward, I'm curious what these other indications are for angiotensin II. But I'll move along just to save some time. So the biggest question we're here to answer today is, what is the proposed mechanism or why is there a thromboembolic risk on the FDA label? So looking at these four pillars of angiotensin II, the overall consensus is that angiotensin II impairs thrombolysis and increases thrombin formation. So the four main pillars here, and these are all usually derived from past studies in the early 2000s looking at hypertensive patients and seeing the response with like ACE inhibitors, ARBs, and how they have a reduced risk of thromboembolic events compared to angiotensin II. So we have tissue remodeling, inflammation, endothelial dysfunction, and oxidative stress. But looking further into endothelial dysfunction, which is where like our AT2 receptors are going to be, or AT1 receptors are going to play the most in, is near platelet activation because platelets have AT1 receptors on them and vasoconstriction. Within these subcategories, there are some trends that we'll see. So for vasoconstriction, we'll have a decline in nitric oxide, and then we'll have a decrease in our prostacyclins. But for our platelet activation, we actually see an increase in our plasminogen activator inhibitor type I and the decrease in our tissue plasminogen activator. This really comes into play when we're talking about the conversion of plasminogen into plasmin and then subsequently the breakdown of fibrin into fibrin degradation products. So our PA1 is going to inhibit TPA, and on top of the inhibition of this, we're seeing a further decrease with angiotensin II. And so we're not going to get this conversion from plasminogen to plasmin, and so we're going to have these fibrin clots just kind of hang around and aren't being broken down. So this is the proposed mechanism. I say proposed because, like I said, a lot of these, all this data is derived from hypertension studies back in the early 2000s. It's not from any study that has come after the Geopressa approval by the FDA in 2017. So this is what we're suspecting is the cause, but we're not 100% clear on it just yet. But looking at the actual numbers of this thromboembolic risk. So we're having some different information between the ATHOS-3 trial and the FDA label. So the ATHOS-3 trial itself, which is the trial that kind of spearheaded angiotensin II to where it is today, doesn't actually record the events in the supplemental data or in the actual article. However, if you look at the FDA label, they went back and did a clinical analysis or clinical review of the research itself, and they found there was about, there was 21 patients for about 12.9% of thromboembolic events in the AT2 group compared to 8 people or 5.1% in the placebo group. And breaking that down even further, looking at deep vein thrombosis, there were 7 patients in the AT2 group versus 0 patients in the placebo group. So it kind of raises the question, how prevalent or how concerned should we be with this thromboembolic risk with angiotensin II? Fortunately for us, there have been multiple studies that have been published since the ATHOS-3 trial, each documenting their own rates of thromboembolic events. So the overall goal of this article is to evaluate all of these articles, synthesize any existing literature, and seeing that there's an association between angiotensin II with their thromboembolic events. Hopping into the methods of this article, so it's a systematic review of literature from various databases, including PubMed, Scopus, and Central, using key search terms angiotensin II with or without the Roman numeral, Geopreza, which is the brand name of angiotensin II, and then LJPC501, which is the study drug name. They did look at bias within these trials, so they used the ROB2, or the Risk of Bias 2 score, and the ROBINS1 tool, or the Risk of Bias Non-Randomized Studies of Interventions, to assess bias throughout the various designs of these trials. So ROB2 being for randomized control trials, and then ROBINS1 being for our non-randomized studies. Looking at our inclusion criteria, we looked at trials that specifically used synthetic human sequence angiotensin II, which is what Geopreza is, looking at any kind of thromboembolic event, and as far as patient population, looking at any type of shock, whether that be vasodilatory or distributive, kind of in the same line there, or perhaps cardiogenic, they didn't really specify or narrow it down, but as we'll see, the majority of these patients are going to be in vasodilatory or distributive shock. As far as our exclusion criteria, anybody less than 18 years of age or less, any preclinical reviews or animal studies were excluded, any alternate angiotensin II formulations were removed, and then if there was no thromboembolic event complications listed as an outcome, it was also excluded as well. And we'll move to the next slide. Okay, so looking at how they got down to their population, which ended up being seven studies, so they did an initial search of 2,336 studies, removed the duplicates, came out to be 647, and then left giving us about 1,689 patients for records to be screened. 1,666 were excluded following those exclusion criteria as listed in the previous slide, and then leaving us with 23 trials remaining. And then within those 16, we had, or within those 23, 16 were removed due to either not having a non-comparator study design or no thromboembolic event outcome data being recorded, leaving us with our final seven studies, which are included on this page here. So as you can see on the left-hand side, I've included the studies and their publication dates, just to focus you in on some of the primary columns. So we have our design, as you can see, only two of the seven studies were actually randomized control trials, the rest of which were non-randomized studies of interventions, and even within those, we have two being, or we have four being retrospective and then one being prospective. So right off the bat, we're seeing a lot of heterogeneity within these trial designs themselves. Looking at the actual populations, we see the majority of them were admitted for ICU for shock. We do have some cardiac surgery mixed in along with some COVID-positive patients requiring some sort of mechanical ventilation, once again, increasing the amount of heterogeneity within these trials. Finally, looking at our primary outcomes, we see a vast variety in different outcomes, most of them being hemodynamic response, feasibility outcomes, looking at morphinethine equivalent doses or MAP response at various time intervals, maybe death at 28 days, 30-day mortality rates, and we're just looking at serum crabbing levels at seven days. Once again, just kind of painting the picture that a lot of these trials, or all these trials looking at them as a whole, are very different between one another, the only thing being similar is the actual intervention and just the controls being the standard of care. So we need to keep that in mind when we're talking about the critiques for the trials moving forward. Looking at the actual number of thromboembolic events, so this is from the published data that was listed on this article itself. So as you can see, our ATHOS-3 trial, or Kana and colleagues, reported about eight thromboembolic events, three being VTE, and then five being ATE, and when we do a summation of all these other trials, we see about 50 counts being VTE with 64 being ATE, bringing our total to about 114 thromboembolic events recorded, bringing us to about 20.2% across all studies. In contrast, again, under controls, we have 22.1%, so very similar, almost one-to-one. However, when we look at the FDA-reported thromboembolic events, this actually brings our number to 21, with seven being VTE, and then an unrecorded amount for the arterio-thomboembolism. For this trial, there was insufficient detail to subcategorize these actual arterio-thromboembolic events on the FDA-accounted ATHOS-3 trial, but what does this actually do to our total summation of all these events? Brings our percentage to 22.5 compared to 22.1, so almost a one-to-one, if not a one-to-one percentage across the controls in the angiotensin 2 group, so it kind of raises this question, is there an actual increased risk of angiotensin 2 leading to these thromboembolic events? I do want to draw your attention to this clinical review by the FDA. This was actually pulled by the FDA's analysis of the ATHOS-3 trial, which was given a report in this study, but I just wanted to clear the time here for an FYI. So as we see here in this column, we have those 21 thromboembolic events that were reported by the FDA, and the seven here being those DVT, but as we can see, looking at the further breakdown, we have acute myocardial infarction, jugular vein thrombosis, arterial occlusive disease, peripheral artery thrombosis, just to name a few. So just to answer the question from the last slide, they weren't able to subcategorize, but we were able to find this clinical review and further see and stratify how this was broken down. I also thought this was quite interesting, looking at the placebo group, compared to our LJPC group, it actually has one event of cerebral ischemia and cerebrovascular accidents compared to our LJPC group, which actually had zero. One caveat to this data, after looking further through the clinical review, the authors also reported that the timing of these events weren't all synonymous. The average time was about four days after the start of angiotensin 2, and just thinking back to the AFL-3 trial, the duration of angiotensin 2 was a max of 48 hours, so we're seeing these events about 24 to 48 hours after the stop of angiotensin 2. So just something to think about moving forward, keeping it in the back of your head when we're assessing these thromboembolic event rates. Looking at our bias risk that was performed by Caragata and colleagues, so this bias is just looking at our non-randomized control trials, as you can see, overall it's relatively low bias, except when we get to our fifth column here with the AFL-3 trial, that's probably due to excluding the actual rates or the event number in the published study, so that's why you have this some concern, which is swaying our overall bias in this study. So overall it's looking pretty good, low level bias, however, when we get to our non-randomized studies, you see bias starts to creep up, the majority of which being in our confounding group or our D1 column, so a lot of the studies didn't really identify some of the confounding variables or address the confounding variables in looking at these venous thromboembolic event rates. For example, Bird and colleagues being a very critical bias risk, that's because they recorded four thromboembolic events, but two of the four were actually patients that received some form of recombinant factor VII, so thinking about how that could also promote venous thromboembolism, there could be some overlap or it could have occurred after this factor VII was given and maybe not after this angiotensin II was given. None of the trials actually discussed or recorded the events of these thromboembolisms in contrast to when angiotensin II was started or stopped, so that leads to a whole other confounding variable itself. And I just want to point out the Smith and colleagues trial, for example, was looking at 30-day mortality as its primary outcome, so thinking when angiotensin II was started and when these venous thromboembolism rates were recorded, was it a week after angiotensin II was stopped, was it during the actual infusion of angiotensin II, or was it on day 28 of their 30-day period of monitoring these patients? We're not quite sure, and they didn't really record that information in the study, so we're seeing a lot of bias throughout these non-randomized control studies. But overall, just going to our critiques, looking at our strengths and limitations, this was the first trial to actually look and do a systematic review of numerous trials that looked at VTE event rates with angiotensin II. An overall relatively moderate sample size, about 1,400 patients were looked at throughout all seven studies, and in my opinion, I feel like they adequately assessed the bias using correct tools for the appropriate kind of studies that they were looking at, the ROV-2 and the ROV-1. As far as limitations go, we had a lot of bias within these non-randomized control trials, and a lot of these trials didn't actually look at thromboembolic complication as a primary outcome. When I was doing a deeper dive into these studies, a lot of these trials just recorded the VTE rates as the patient's clinical status decompensated, so it was more of a spontaneous search. It wasn't like a prospective, a continuous assessment of the patient to see if they were developing a VTE on this agent. One of the things as well is they talked about there was not a lot of data to subcategorize those arterial thromboembolic events within this study, but there was a clinical review by the FDA that's available online, so I kind of wish they looked into that further to guide their analysis. I kind of alluded to a couple slides back and throughout this study, there was a lot of heterogeneity between the trials regarding the angiotensin II indication, its exposure, as well as the definition for venal thromboembolism. A lot of the studies did not include a definition. They just reported if the patient had a VTE or not. There was one trial that mentioned what they used to actually assess for the VTE, while others just omitted that in their methods and within their supplemental data as well. But overall, looking at our take-home points from this trial, we saw the conclusion that there are comparable rates of thromboembolism between our angiotensin II and our comparative groups in various trials. However, given the severity of our patients that are going to be starting with angiotensin II, they're going to be critically ill at baseline just due to being on multiple pressers, being sedated, intubated, so they're already at a higher risk of developing VTE, so I don't see a reason to withhold or to adjust any protocol at this time for VTE prophylaxis. With the elevated risk of bias, it's kind of hard to draw a conclusion from this trial alone, which kind of leads to our next take-home point. I think future studies should definitely closely assess these VTE rates to see if they're actually something to be concerned about, or are these just going to be more because of the critical illness of the patients, or is it actually due to the angiotensin II itself? So maybe something that's more prospective, maybe a co-primary outcome along with MAP for blood pressure response, or norepinephrine-equivalent doses that are being down titrated with the start of angiotensin II, maybe having a co-primary outcome of VTE events, and just prospectively assessing our patients for the development of any form of clot as they proceed through their treatment on angiotensin II. And with that, we'll go to our next audience poll, which is, in your facilities that utilize angiotensin II, have you had to adjust your VTE prophylaxis protocol? Or within your angiotensin II protocol, have you added a special column for VTE prophylaxis? For our facility, we require patients to be on some form of chemoprophylaxis if feasible and if appropriate. I'm seeing a lot of no's in the chat, which makes sense. I completely agree with that. Awesome. And then I guess with that, I'll open it up to any questions that y'all might have. Yes, Emory, thank you for that excellent presentation. I have the questions up in the chat, so I will just go ahead and read them for you. First, we have an attendee that responded to your polling question, the first polling question for the other indication. And this attendee had selected other because they do not have angiotensin II at their institution or regional healthcare system. So probably would have been a good answer to have in there since we do know due to the cost of medication, many hospitals do not carry this on formulary. Very true. Yeah. The second question I see is a question regarding the Smith study, which is one of the studies in the systematic review. Why do you think they had so many thromboembolic events? Was it a result of the way that they screened the patients? Good question. I think it might be due because they were, I think I can see why they might have more compared to other studies. Aside from just like the naturals, like population size being larger compared to the other studies, I think it's like 271 within the angiotensin II group compared to the next biggest, which is the ATLAS-3 trial at 163. So it could be a component of just having a larger population size. It could also be because they might have been, they could have been prospectively looking at VT rates, didn't really specify in the trial. So I'm just kind of drawing from a, I'm just like hypothesizing, but the only thing I can think of right now is just the population size. But I can definitely go back and do a deeper analysis of the Smith II trial and see what they found. But my initial assumption would probably just be compared to the other trials, there's a higher population. So maybe just correlation wise, probably seeing a higher amount in the Smith II trial compared to our other ones, compared to the other ones. Thank you. The next question is, what do you make of the variable use of prophylaxis and treatment with anticoagulation? It makes it hard to conclude anything from this data about risk of clots. Exactly. I mean, especially since we don't know what each hospital, what these trials were using based on like heparin dosing or lovinox dosing, or is it really adjusted appropriately or was it adjusted appropriately based on the patient's BMI or weight? So it's definitely hard to, as another layer of, so it's making it hard to extrapolate from this trial. So definitely agree. So probably adding like a future study looking further into like how were the, how was prophylaxis added on? Was it at the start or was it during admission in the ICU? What was the timeframe and administration of the first dose of like your prophylaxis medication? What dose were you using? And just correlating that to a patient's body habitus or renal function and seeing how it was dosed, if it was dosed appropriately or not. I'm not sure if that answers your question about the BMI assumption of it. Okay. And there's one more question. Is there any signal that the rates of VTE in patients on angiotensin II may be dose or duration dependent? Yeah, that's a great question. When I was looking through that clinical review, they did, it was just for the ATHOS-3 trial, they didn't mention there was no correlation between the rate or the dose from what they saw. So I'm inclined to say there wasn't, there isn't a correlation between it, but I think it's a great question and something we can look further into with future trials just to kind of confirm or corroborate what the APHIS-3 researchers saw when responding to this clinical review by the FDA. Okay, well, thank you, Emery, for your excellent presentation and answering all of those questions. Awesome, thank you for having me. I appreciate it. Okay, before moving on to our next presenter, we would like to ask a brief polling question regarding today's attendance to gain a better understanding of our overall attendance to ensure continued support of this Spotlight on Pharmacy webcast. The poll today is how many attendees are you viewing this webinar with? And please select one. Is it just you? Are there two to five people viewing with you, five to 10, or greater than 10 people? Thank you for responding. It looks like many of you are viewing as a group, which is always the best way to do it so that you can discuss amongst yourselves these studies and the questions that are presented. Okay, so next I would like to present our second and final presenter, Nedra McCarthy from Mount Sinai in New York. Good afternoon, everyone. Thank you so much, Dr. Simit, for that introduction. So as mentioned before, my name is Nedra McCarthy, and I am the current PGY-2 in critical care at the Mount Sinai Hospital in New York. And today I'll be discussing the article titled Safety and Efficacy of Early versus Delayed Aceta Salicylic Acid After Surgery for a Spontaneous ICH in China, which is also called the E-STAR trial. As it relates to this presentation, I do not have anything to disclose. Some objectives for this presentation are to discuss the controversy regarding restarting Aceta Salicylic Acid, and just for short, I'll be just referring to it as aspirin from here on out, in patients who are at high risk for major ischemic and vascular events following spontaneous ICH. In addition, I want to review literature on the optimal timeframe for resuming Aceta Salicylic Acid for ICH. And finally, to evaluate strengths and weaknesses of the E-STAR trial and discuss its applicability to clinical practice. So one of the major controversy in stroke management is actually the timing to restart an antiplatelet therapy. Oftentimes, antiplatelet agents are usually discontinued or held during the acute phase of ICH to prevent re-bleeding. However, antiplatelet agents are necessary for patients who are high risk for ischemic and vascular events for secondary prevention. And to optimize patient outcomes and benefits, one has to weigh the risk of re-bleeding post-spontaneous ICH, and surgical procedures must be weighed against the risk versus benefits to ensure that we can optimize outcomes. And to date, no optimal timing has been established for restarting an antiplatelet agent in these patient populations. Both American and international stroke guidelines weekly recommend starting anti-thrombotic agents post-spontaneous ICH to prevent thrombotic events while balancing the risk and benefit. However, they both highlight the need for stronger evidence and do not specify an ideal time for initiating or restarting these agents. Safety studies on restarting anti-thrombotic agents are really limited. However, in 2019, the E-STAR trial was the first randomized trial that was designed to assess this clinical dilemma. The objective of the trial was to assess the impact of antiplatelet resumption on ICH recurrence and prevention of vascular events. The primary outcome was fatal or non-fatal recurrence of symptomatic ICH up to five years. The study included 537 adults who were 18 years and older with confirmed ICH who were on anti-thrombotic agents. Patients were randomized to either continued antiplatelet therapy or had it withheld. The study suggested that early resumption of antiplatelet therapy after ICH did not demonstrate a significant increase in the recurrence of ICH compared to stopping it. And this was with a P-value of 0.06. However, one of the drawbacks for this trial was that it included variable timing of restarting antiplatelet agent. And this time range ranges from two to 76 days. And this trial did not focus on neurosurgical patients or patients who were at a high risk for ischemic or vascular events. In 2023, another retrospective chart review tried to provide some clarity to this clinical controversy. And this time the trial main objective was to compare the safety outcome of restarting antiplatelet therapy, 30 days or less versus restarting it 31 days to a year. And the primary outcome was recurrent ICH. The study included adults age 20 years or older with confirmed ICH and who were on antithrombotic agents. The study found that early resumption was actually safe as delayed resumption regarding its effect on recurrent ICH. However, again, just like the E-STAR trial, the patients who underwent neurosurgical intervention of the ICH were not a focus of this trial. So given the limitations of the restart trial and that retrospective trial that I just presented to you with broad time ranges to resume antiplatelet agents and that the focus was not on neurological patients or patients who were at high risk for ischemic and vascular events, it kind of paved the way for the trial that we'll be looking at today, which is the E-STAR trial. This trial was published in the Lancet Neurology Journal in December, 2024. The primary objective of this trial was to evaluate if early antiplatelet therapy after surgery or spontaneous ICH reduces major cardiovascular, cerebrovascular or peripheral vascular events without increasing bleeding risk. It was a multi-center prospective open label blinded endpoint randomized clinical trial that took place across eight stroke centers in China. Patients were actually screened between May 1st, 2021 to May 1st, 2023. And eligible patients were randomized in a one-to-one ratio. Patients were assigned to receive 100 milligram of aspirin on either day three or day 30 post-surgery. All patients continue to take aspirin up to 90 days and all patients receive standard medical care for a blood pressure management in spontaneous ICH according to the American Heart Association guidelines and other international guidelines. The study included adults age 18 years to 70 years with non-traumatic spontaneous ICH who underwent neurosurgical hematoma evacuation and had a high risk for ischemic or vascular events. And these were namely patients who had a history of cerebral infarction or TIA, a history of CAD or MI, a CVD risk 10% or more, or a capillary scale score of two or more. Patients were excluded if they had a major cardiovascular, cerebrovascular, peripheral vascular events occurring after ICH, but prior to randomization. If they had a history of coagulopathy, they had treatment with an anticoagulant prior to the ICH or if they had a history of atrial fibrillation among others as listed here on the slide. The primary outcome of this trial was new measure ischemic cardiovascular, cerebrovascular or peripheral vascular events within 90 days. And this was confirmed by imaging and ultrasound findings. Secondary outcomes include death within 90 days of the surgery in hospital death, modified ranking scale of zero to three at 90 days. And they also assess safety outcomes which looked at rates of bleeding. And this was defined based on the bleeding academic research consortium classification, looking specifically at type two, type three and type five bleeding events. The study required a sample size of 250 participants to achieve 80% power and to detect a 50% relative risk reduction. All appropriate statistical tests were utilized within this trial. And a two sided P value of less than 0.05 was considered statistically significant. So as it regards to enrollment, a total of 7,323 participants were screened with only 269 meeting the inclusion criteria. Of these, 134 were randomized to receive aspirin on the third day, while the remaining 135 were assigned to receive the aspirin on day 30. So as it relates to baseline characteristic, the mean age across both groups were 60 years with 97 to 98% of the participants being Chinese. Approximately 22% of the patients were on antiplated therapy prior to spontaneous ICH and over 60% actually underwent minimally invasive surgery. Now looking at the results, the primary outcome. So this slide actually is a distribution graph where the first three colored sections indicate the composite primary outcome. And the individual color within that section indicates how the different components influence the composite outcome. And we can clearly see from this graph that early initiation of aspirin actually resulted in a lower ischemic and vascular event when compared to patients who started it at a later date on day 30th. And this is further illustrated in the table below where major cardiovascular, cerebrovascular or peripheral vascular events at 90 days was 20% in patients who started or initiated aspirin on day three compared to 31% in patients who started or initiated aspirin on day 30th. And something I also want to bring to your attention as it regards to the composite endpoint, the DVT between both groups actually comprise majority of that composite endpoint. The absolute risk reduction for this study was 11% and the number needed to treat was 10. Now looking at the secondary outcomes, something I wanted to highlight from this slide is that death within 90 days of surgery was statistically higher in patients who started aspirin on day 30th compared to patients who started it on day three. And for the bleeding events between both groups, it was not statistically different where the P values were all greater than 0.05. So what did the study conclude? So the study concluded that starting aspirin on post-operative day three in patients with spontaneous ICH who underwent surgery reduced major cardiovascular, cerebrovascular and peripheral vascular events without increasing intracranial bleeding compared to starting on day 30. And now I'll go into the critique, my critique for this trial. So overall, I think it was a well-needed study that was designed to address an ongoing clinical dilemma. One of the major strengths of this trial I think is the fact that it was a multicenter randomized clinical trial. And it actually included patients who were high risk for ischemic and vascular events who would likely benefit from the intervention. However, as it regards to weakness for the population, over 90% of the participants were Chinese, which limits its applicability to the US, which has a more diverse population. However, even though majority of the participants were Chinese, it makes me somewhat comfortable in accepting the safety findings within this trial, given that patients who are of Asian background are at a higher risk of recurrent bleeding after ICH. In addition to that, more than 60% of the patient actually underwent minimally invasive surgery compared to 40% who had major surgery. As it relates to the intervention, I think clinically appropriate drug and dose was used, given that based on the American Heart Association stroke guidelines, a dose of aspirin 75 to 100 milligram can be effective for both primary and secondary prevention of ischemic events. In addition to that, all the patients within this trial receive guideline recommended blood pressure management for patients who present with spontaneous ICH. As it relates to weakness for intervention, only one antiplatelet agent was evaluated and there was a short follow-up duration, which provided us really no data beyond 90 days on late onset adverse side effects compared to what was studied in the RESTAR trial. The RESTAR trial allowed participants to be on multiple antiplatelet therapy and they did follow patients up to five years. As for the endpoints, I think clinically appropriate endpoints with objective means of diagnosis was a strength. Also the time points for resuming or initiating antiplatelet therapy was appropriate. Some unpublished data, which was actually cited by the trial, showed there is an increased risk of recurrent bleeds within 72 hours and studies that have been published to date actually showed that there's an increased risk of stroke within the first few days to weeks following surgery after ICH, the most critical period in the first 30 days. So using those time points of three days and 30 days, I think that was clinically relevant and important and I think that was a strength. As it regards to weaknesses of the endpoints, assessment of adherence relied on subjective data from the Morisky Medication Adherence Scale and it's unclear why DVT and PE was included in the primary outcome given that we are utilizing an antiplatelet agent and we would not be expecting to see that much reduction on vascular events with an antiplatelet. And to confirm this weakness, the rates of DVT prophylaxis was not reported in this trial. For statistics, efficacy and safety analysis were performed on the intention to treat population and the study actually detected that 11% absolute risk reduction as opposed to the calculated 50%. So for my takeaways or my conclusion from this trial, initiating or restarting aspirin by post-operative day three in patients presenting with spontaneous ICH and at a high risk of post-operative major cardiovascular, cerebrovascular peripheral events appear safe and effective. The benefit of starting aspirin in low-risk patient is however unknown given that this study only assessed and included patients who are at high risk for ischemic and vascular events. And I believe that additional studies is definitely needed in a more racially distributed population and patients who have a history of coagulopathy. And in addition to that, even though this study was not powered for mortality, it is kind of reassuring to see that mortality rate was lower in the early start group compared to the patients who started it on a later date on day 30. And now we'll go into our first polling question. And it reads, at your institution, what is the current timeframe to restart an antiplatelet agent in patients who present with spontaneous ICH and have a high risk for ischemic and vascular events? And I see some responses coming in. I think majority of persons are indicating that it varies with additional persons saying within 30 days. Okay. And a few persons are actually indicating within three days, but majority varies. Okay, understandably. Thank you. And moving on to our second polling question. Would you make any changes to your current practice based on the results of the E-STAR trial? I think majority of the responses are going towards no. All right, still majority say no. Okay, thank you so very much. And maybe you could share in the chat as to your hesitation towards implementing this in practice. Okay, that's all I have for you today. Thank you so very much for listening. No, I do welcome any questions or feedback. Neidra, thank you so much for that in-depth review of this trial. You did a great job. There's a couple of questions in the chat, so I'm gonna start reading those. One attendee said, great presentation. Thank you for clarifying the primary driver of significance in the primary outcome. Did the researchers account for the impact of COVID-19 on hemostasis given that the recruitment window was actively during the pandemic? And fortunately, reviewing their supplemental and protocol, I didn't see where it was mentioned. I agree, I don't recall them mentioning it in the trial unless they tucked it into the appendix somewhere where we didn't see it, but what do you think is the relevance of that question? Why would we be concerned about the COVID-19 status? So the COVID-19 as it relates to patients presenting with spontaneous ICH or just in general for treatment? I suppose for the outcomes that they were studying in terms of cardiovascular and thromboembolic events. Okay, yeah, so that would be a confounder within itself because patients who do present with COVID-19 were at an increased risk of vascular events. They had to be initiated on DBT prophylaxis if there were no other contraindications, so that would confound the results considering that they also added DBT and PE a part of their composite endpoint. Yes, thank you. Another question, it's kind of two parts. So I think getting to your first polling question about when aspirin is initiated, this attendee asked how long do your teams typically recommend holding aspirin right now? Why do you think they chose 30 days instead of a shorter timeframe? So this particular participant works in the neurocritical care unit and typically sees teams hold aspirin for one to two weeks and very rarely longer than this. He felt that you did answer the question of why they decided to do 30 days based on the unpublished data, but he continues to ask the question of why not compare it to current practices, which is more likely one to two weeks after ICH. So could you repeat the first part of the question, please? Basically, they chose 30 days based on this unpublished data to look at aspirin initiation, but in this particular attendees practice, they typically see it held one to two weeks as opposed to 30 days. And so why not evaluate more current practice rather than looking at a longer duration of holding? Okay, thank you. So just to clarify the unpublished data, the recommendation came from the unpublished data as regards to the 72 hours. They had assessed the risk of recurrent bleeding events and it was seen to be highest within that first three days post-surgery. As it relates to the increased risk of stroke, it has been studied and it has been noted currently that there's an increased risk of stroke within the first few days to few weeks post-ICH with the highest within that 30-day period, hence the reason why they lean towards the 30 days as opposed to doing it earlier. Thank you. I don't see any further questions from our audience. However, if you have any, please post them. One question I had in particular, you touched on the generalized disability of the data with it primarily being Han Chinese, but they excluded patients who were over 70 years old. And if you come to Maine, you'll learn that we're a very old state. And so I'm curious why you think they excluded that population and how generalizable is the data overall to the American population aside from the ethnicity of the patient population? Yes, interestingly enough, I tried to dig into a little bit as to the reason they may have excluded patients who were over the 70 years old. They didn't mention it in their rationale or in their protocol, but I was looking at the patients who would possibly be candidate for certain neurological interventions. And there are some studies that have attributed age being a poor outcome for certain neurological interventions being greater than six to nine years of age. So that would be my thought process given that their inclusion criteria had to be patients who underwent certain neurological interventions and they had very neurological interventions, major neurological intervention craniotomy was one of them. And so that was the only limitation I saw where age being older than 70 years old would have played as more of a hinder to getting these neurological interventions. That makes a lot of sense. Thank you so much for looking into that. And then for your second polling question about making changes at our institution. I wonder if, from me personally, looking at the patient selection and how only about 3% of those who were screened were actually enrolled. And the fact that we do very little minimally invasive surgery for our ICH cases, I think this may have been the limitation to really making any practice changes based on the results of this trial, but it is certainly very interesting and hope to see more data come out and maybe not so selective on neurosurgical populations. Right, yes, I do agree that maybe including patients who would be older, who have some history of coagulopathy because it did exclude patients who had amyloid disease. So having a general inclusion would probably give us a better answer, try to answer or address this clinical dilemma with some more clarity. Okay, well, I don't see any further questions in the chat. So I think this concludes our Q&A session today. Thank you so much, Nedra, for that excellent presentation. And in conclusion, I'd like to thank our presenters today, both Emery and Nedra, for volunteering to provide this information and presenting very educational presentations for us. I'd also like to thank the audience for attending. Please join us on the third Friday of the month from 2 to 3 p.m. Eastern Standard Time for the Next Journal Club Spotlight on Pharmacy. Looks like it will be March 21st, 2025. And that concludes our presentation for today. So thank you very much and happy Friday, everyone. Thank you so much for having me.

Journal Club Spotlight

Pharmacy

Critical Care Medicine

Angiotensin II

Thromboembolic events

E-START study

Aspirin administration

Intracerebral hemorrhage

Webcast

Neuroscience

Intracranial Hemorrhage

Anticoagulation

Pharmacology

2025

Professional

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