Hello, everyone, 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 Catherine Beach. I'm a clinical pharmacy specialist in the cardiovascular ICU at Atrium Health Wake Forest Baptist Medical Center in Winston-Salem, North Carolina. I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log in to mysccm.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a question and answer after each of today's speakers. To submit questions throughout the presentation, 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 live discussion on Twitter, following hashtag fccmcppjc and hashtag PharmICU. Please note the disclaimer stating that the content to follow is for educational purposes only. And now I'd like to introduce your speakers for today. Each will give a 15-minute presentation followed by a Q&A. Our first presenter today is Megan Cook, PGY-2 Critical Care Pharmacy resident at Brigham and Women's Hospital in Boston, Massachusetts. She will present on haloperidol for the treatment of delirium in ICU patients. Our second presenter is Austin Willett, PGY-2 Critical Care Pharmacy resident at Charleston Area Medical Center in Charleston, West Virginia. She will present on safety and efficacy of prophylactic levotriazetam for prevention of epileptic seizures in the acute phase of intracerebral hemorrhage, or the PEACH trial, a randomized, double-blind, placebo-controlled Phase III trial. And our third presenter is Anissa Sula, PGY-2 Critical Care Pharmacy resident at Philadelphia College of Pharmacy in Philadelphia, Pennsylvania. She will present thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke, an open-label, blinded-outcome, randomized, non-inferiority trial. And now I'll turn things over to our first presenter. Thank you so much for that introduction today. I'll be focusing on haloperidol for the treatment of delirium in ICU patients. Starting off with some brief background information, delirium is characterized by disturbances in attention and awareness and can be classified as hyperactive, hypoactive, or mixed. Delirium is common in critically ill patients, occurring in up to 50% of patients hospitalized in an ICU and is associated with worse outcomes. The 2018 PATIS guidelines emphasize the importance of non-pharmacological interventions and recommend against the routine use of antipsychotics for the prevention and treatment of delirium, but they do mention that short-term use of antipsychotics may be beneficial in select patients with significant distress related to delirium or agitation. The risk factors outlined by these guidelines include benzodiazepine use, blood transfusions, older age, dementia, prior coma, pre-ICU emergency surgery or trauma, and then greater APACHE and ASA scores. Moving into some of the previous trials investigating haloperidols used for ICU delirium, in the HOPE ICU single-center trial, patients were randomized to haloperidol or placebo, and the primary outcome of delirium-free and coma-free days was not significantly different between groups. Lower rates of agitation with haloperidol were seen, and the investigators concluded that haloperidol could be safely used for acute agitation. The REDUCE multi-center trial investigated prophylactic haloperidol versus placebo for ICU delirium and found no difference in survival at 28 days between groups. Authors recommended against prophylactic haloperidol. And then the MIND-USA was a multi-center trial in which patients with delirium were randomized to haloperidol as a prosodone or placebo. Nearly 90% of patients included had hypoactive delirium at randomization, and there were no significant differences found in the primary outcome days alive without delirium or coma or in secondary outcomes, including 90-day survival. This brings us to our first polling question. What is your preferred IV antipsychotic in critically ill patients? Options include A, haloperidol, B, droperidol, C, olanzapine, or D, other. So that brings us to kind of the study that we'll be diving a little bit deeper into today, the AID-ICU study by Andersen-Randberg and colleagues, which aimed to investigate whether treatment with haloperidol would lead to a greater number of days alive and out of the hospital compared to placebo in critically ill patients with delirium. This trial was a randomized, blinded, parallel group and placebo-controlled trial that was conducted in 16 ICUs in Denmark, Finland, the United Kingdom, Italy, and Spain. Treatment occurred from June 2018 through April of 2022. Patients were included if they were at least 18 years old, were acutely admitted to the ICU, and had positive screenings for delirium with the CAM ICU tool or the ICD-SC. Exclusion criteria are outlined on the slide and include contraindications to haloperidol, antipsychotic use in the ICU prior to inclusion, non-applicable delirium assessments, involuntary hospitalization, and alcohol-induced delirium or delirium tremens, among others. For interventions, patients were centrally randomized in a one-to-one ratio to either haloperidol 2.5 milligrams IV three times daily or matching placebo. Randomization was stratified according to trial site and delirium motor subtype. At the discretion of the involved providers, additional as-needed doses of the trial interventions were allowed. In addition, for uncontrollable delirium, rescue medications could be administered, including propofol, benzodiazepines, or alpha-2 agonists. Patients were able to receive these agents for alternative indications during the trial without them being considered rescue medications. And then the patients were screened twice daily for delirium. If two consecutive assessments on the same day were negative, the intervention was paused and then could be resumed if delirium was detected again. The primary outcome for this study was days alive and out of the hospital within 90 days post-randomization. Components of the primary outcome, mortality, and hospital length of stay were also analyzed individually for secondary outcomes, along with days alive without delirium or coma, days alive without mechanical ventilation, the number of serious adverse reactions, and the number of patients using rescue medications, and the number of days of use. The investigators calculated a sample size of 1,000 using 90% power and a 0.05 level of significance to detect a 15% lower incidence of the primary outcome, correlating to a combined effect of 8% greater mean number of days alive and out of the hospital for the haloperidol group compared to placebo. The primary analysis was intentioned to treat, but they also did per-protocol analyses and reported results from both. In the primary analysis, linear regression was used to estimate the adjusted mean difference between groups. The investigators bootstrapped 95% confidence intervals with 50,000 resampling iterations used in the bootstrap, and the Kryger-Jensen and Lange test was used to estimate the p-value. For secondary analyses, binary logistic regression, linear regression, and Poisson regression models were used. In addition, the primary outcome was analyzed in pre-specified subgroups for trial site, delirium motor subtype, ICU admission type, sex, age, risk factors for delirium, and disease severity defined by the simplified mortality score for the ICU or SMS-ICU scores. In terms of results, 1,000 patients were initially enrolled, and after post-randomization exclusions, 501 patients remained in the haloperidol group and 486 in the placebo group. The median age and rates of males and females were similar for both groups. Highlighting some of the risk factors for delirium that were present, the most common risk factors were receiving benzos in the hospital before randomization, active tobacco smoking, and alcohol overconsumption. There were slightly higher rates of alcohol overconsumption and benzodiazepine use in the hospital in the haloperidol group, and slightly higher rates of benzodiazepine use before hospitalization in the placebo group. Coexisting conditions were collected for the SMS-ICU prediction score. Slightly higher rates of COVID-19 were observed in the placebo group at over 10% compared to 7.4% in the haloperidol group. Approximately two-thirds of patients were hospitalized in the medical ICU compared to the surgical ICU. The placebo group had a greater number and proportion of patients in the medical ICU. Over 60% of patients included were using mechanical ventilation at randomization. Slightly more patients in the haloperidol group required vasopressor or inotropic support within 24 hours prior to randomization. Mean SMS-ICU scores were similar between groups with a score of approximately 35, correlating to a predicted 90-day mortality rate of about 80%. The last thing I want to highlight here from the baseline characteristics are the delirium motor subtypes at randomization for the included patients. Over half of the patients included had hypoactive delirium with 55.3% in the haloperidol group and 54.1% in the placebo group. The remainder had hyperactive delirium at randomization. Regarding doses received, the median daily dose for haloperidol was 8.3 milligrams and 9 milligrams for the placebo group with median cumulative doses of 32.5 milligrams for both groups. Over 70% of patients received at least one as-needed dose of their assigned intervention. Use of rescue medications appeared overall greater in the placebo group with slightly higher rates of alpha-2 agonist and benzodiazepine use in that group compared to the haloperidol group, which had slightly higher rates of propofol use. There is not a significant difference found between groups for the primary outcome of days alive and out of the hospital at 90 days with a mean of 35.8 days in the haloperidol group and 32.9 in the placebo group and a p-value of 0.22. This remained consistent across subgroup analyses as demonstrated in the force plot. When looking at the components of the primary outcome individually, the rates of death at 90 days were significantly lower in the haloperidol group at 36.3% compared to 43.3% in the placebo group. The difference in overall survival over the course of the trial is illustrated in the figure on the right side of the slide. There are no differences in mean length of stay between groups. Other secondary outcomes were also not significantly different between groups as shown here. The authors concluded that the use of haloperidol in ICU patients with delirium did not lead to a significantly greater number of days alive and out of the hospital at 90 days compared to placebo. This brings us to our second and final polling question. What total daily dose of haloperidol do you see most often in critically ill patients with delirium? A, less than 10 milligrams, B, 10 to 20 milligrams, C, 20 milligrams or more, or D, you don't use haloperidol? Oh, so I'm seeing 10 to 20 milligrams, which is interesting thinking about kind of what we saw in this study with eight to nine milligrams being the median and then pretty low overall cumulative dosing as well. But we can move on and move on to our critique. Here we go. So moving on to discussion and critique, inclusion and exclusion criteria seemed appropriate overall. The incidence of antipsychotic use prior to admission and randomization was not reported, leaving the potential for unreported imbalances between groups. They also excluded patients in whom delirium couldn't be adequately assessed, which makes sense, but it means that patients with language barriers and deaf, blind, and aphasic patients were excluded, limiting applicability of results to those populations. While the delirium motor subtypes were similar across groups, more than half of the population included had hypoactive delirium, making it difficult to draw conclusions on the benefits of antipsychotic use from this cohort. The delirium subtype was also only assessed at randomization, so the fluctuations that we can see between subtypes and mixed presentations were accurately represented in this analysis. The intervention and control groups were overall well-balanced at baseline, but I did want to highlight some small differences that could potentially impact results. In terms of the reported risk factors for delirium, more patients in the haloperidol group consumed alcohol excessively and had used benzodiazepines in the hospital before randomization, which could have impacted the ability to see a difference in outcomes related to the incidence of delirium. The placebo group included more patients with COVID-19 and more patients hospitalized in the medical ICU compared to the surgical ICU, which could indicate a more acutely ill population and could contribute to the difference seen in the 90-day mortality outcome. However, this is counteracted by more patients requiring vasopressor or inotropic support in the haloperidol group, and average SMS ICU scores of approximately 35 for both groups. A more acute scoring system, such as the Apache score, could have been useful here, especially knowing that higher scores have been associated with increased risk of delirium. Other baseline characteristics that may have been helpful to see include other risk factors for delirium that are reported in the 2018 PATIS guidelines. The indication for hospital admission and ICU admission could have also provided useful context. Other things that weren't reported by the investigators that could impact outcomes and interpretation of the results include sedation requirements, especially since patients were allowed to receive the rescue medications for indications other than delirium, and pain scores and associated opioid requirements, knowing that uncontrolled pain could contribute to delirium and other negative outcomes. Nonpharmacological interventions for delirium were also not reported and could limit the ability to see differences in our delirium outcomes. Moving on to interventions, having a placebo-controlled group adds strength to the trial design. The overall dosing of haloperidol used in the trial was fairly low, with maximum doses of 20 milligrams set per day and a low, medium, daily, and cumulative doses for both groups. The idea of underdosing in the trial is further supported by the fact that approximately three quarters of both groups required one or more PRN doses and may have contributed to not seeing differences in our outcomes. Significance wasn't reported, but there were numerically higher rates of rescue medication use in the placebo group, particularly with benzodiazepines and alpha-2 agonists. The doses of rescue medications and the method of administration, particularly for benzodiazepines, may have been useful information as well. The endpoints used in this analysis were patient-oriented and clinically meaningful, but may not be solely representative of the effects of haloperidol or antipsychotics in general. While there was a significantly lower rate of death at 90 days in the haloperidol group, it's hard to say that that reduction in mortality was directly related to the antipsychotic and not related to other confounding variables. In addition, other endpoints of potential interest that weren't evaluated in the analysis include things like hospital readmission rates, delirium subtype fluctuations over time, and the incidence of patient family and staff stress related to delirium, among others. For statistics, the sample size was just under the calculated threshold of 1,000 to meet 90% power, making the study technically underpowered and increasing the chance of a type 2 error. In addition, for the power calculation, it was assumed that haloperidol would lead to a 15% lower incidence of in-hospital mortality and shorter hospital admission time compared to placebo, which may have been an overzealous assumption since previous data hasn't found such an effect. Both intention-to-treat and per-protocol analyses were utilized, with intention-to-treat analyses increasing external validity. Overall, it seems like the statistical tests used to analyze the data were appropriate. The number needed to treat can be calculated for the mortality outcome and comes to 15, meaning that 15 patients would need to be treated to prevent one additional death. While that number is fairly low, haloperidol is likely not going to be blanketly used to decrease mortality in patients based off of these findings. When comparing to previous trials, there were lower rates of hypoactive delirium included in this analysis, which is better, I suppose, but we're still including a pretty good portion of a population that's known not to benefit from antipsychotics. Like the previous trials discussed, this trial did not find a difference in the number of days patients were without delirium for those receiving antipsychotics. However, this analysis did demonstrate a reduction in mortality with the use of haloperidol, which is not consistent with the previous data discussed. I personally don't see the results from this trial changing present practice. I think they further support that the routine use of antipsychotics in all critically ill patients with delirium isn't generally recommended, but again, thinking back to guideline recommendations, could be considered in select patients with more agitated and hyperactive delirium. The results from this study, particularly the difference seen in mortality, are hypothesis-generating and indicate the need for additional larger international studies using doses of antipsychotics that are consistent with those used in clinical practice, specifically in patients with hyperactive delirium to investigate the role of these agents. Thank you. I'm happy to take any questions. All right. Thank you so much, Megan. I think you brought up a lot of really great points regarding the strengths and some of the limitations of this study in general, kind of their overall trial design and patient population assessed. If you were to design a trial to maybe essentially answer this finally once and for all, what would you change relative to what they did in this trial if you were repeating a similar assessment of antipsychotic use for delirium? That's a great question, and I think there's kind of a lot of pieces that go into answering that question. I think one of the biggest things that stands out here and from a lot of the data that looks at delirium is the subtype. Obviously, we know that hypoactive delirium is not benefited with antipsychotic use and that the benefits are, if there are benefits, it's typically in hyperactive delirium. So I think I would really want to focus on that. And since there are fluctuations, that's also something that's really hard to do by selecting patients at randomization that have hyperactive delirium. They're not always going to have that kind of manifestation of the delirium. But I think that would be one thing. And then at least reporting kind of the fluctuations that you see and maybe the incidence of hypo versus hyperactive delirium, which of course would have many challenges in and of itself. I think another thing, another big thing for this trial is the dosing of the haloperidol. I mean, when I start, if I was going to use haloperidol in a patient, usually it's more frequently than three times a day, usually Q6 to start and as needed for delirium or agitation more so. And then higher doses, like my typical starting dose is probably five Q6, so 20 milligrams, where they had a maximum set at 20 milligrams per day. So I found that interesting as well. So I think kind of focusing on that. And then also the agent used with haloperidol maybe not being my preferred parenteral antipsychotic, but of course could be an option. Yeah, those were a lot of the same thoughts I had when reading through this trial as well. I think one other population that I would maybe exclude from randomization would be those with the significant heavy alcohol use, just because of maybe some confounders or impacts those might have on overall delirium management and being able to determine what the cause of delirium is. But I think those are some really great, really great points. We do have one question in the chat. It asks, how will this change your practice for hypoactive delirium and or hyperactive delirium? I honestly don't find it changing my practice at all, which isn't great when we kind of analyze these studies, but I think in terms of managing patients with hypoactive delirium, I think the focus is still going to be on non-pharmacological measures, knowing that antipsychotics probably aren't going to be helpful. And then in terms of hyperactive delirium, I don't think that this is going to make me favor haloperidol in patients necessarily because of that mortality benefit. I don't see that that was maybe the most representative of the antipsychotic. So I honestly don't think it's going to change my practice at all. I don't know if others feel strongly that this will change their practice, but that's how I feel. I agree with that sentiment. I think we've been waiting to see data that really shows positive outcomes and have yet to see anything really robust in that arena. I guess the last question I have for you before we move on, do you believe that this primary outcome is the most appropriate to study for this question that we're asking? Or do you think that future studies could maybe address a different clinical endpoint? Yeah, I think that was another big thing with this study is that it was like they're looking at mortality in patients where we probably are, we're trying to investigate the use of haloperidol for delirium. So to me, I think the primary outcome should probably be focused on that, reducing delirium. And then the other outcomes like mortality and hospital length of stay could be more secondary as a result of the reduction in delirium, hopefully. So I don't think it was the most representative of the antipsychotic use. Wonderful, thank you, Megan. All right, now I would like to introduce our second presenter, Austin Willett. Good afternoon, everyone, and thanks for joining today. So today, as previously discussed, we're gonna be covering and discussing the PEACH trial. So this discusses the safety and efficacy of prophylactic levotirastatam for prevention of epileptic seizures in the acute phase of intracerebral hemorrhage, a randomized double-blind placebo-controlled phase III trial. A little bit about background. So we know that spontaneous non-traumatic intracerebral hemorrhage, or ICH, accounts for about 15% of all strokes and affects two million people worldwide each year. Epileptic seizures are a common complication of the acute phase of ICH with the incidence of early seizures after ICH reaching about 30% when subclinical seizures are diagnosed by continuous EEG. But we know these are difficult to detect without this modality, given the likelihood these seizures are being clinically unrecognizable. Some studies suggest early seizures might be associated with hematoma expansion and worse neurological outcomes, which we'll discuss soon. However, conflicting data to this observation exists, thus leaving a gap in our current knowledge. Overall, randomized controlled trials supporting the use of antiseizure medication as primary prevention among patients with ICH are overall scarce, and current guidelines do not recommend prophylactic antiseizure treatment in this setting. The efficacy of primary antiseizure prophylaxis on the occurrence of clinical and electrographic seizures have never been assessed in the acute ICH setting. Looking at previous literature, Engerman and colleagues in 2019 published a systematic review and meta-analysis observing prophylactic antieleptic drugs among adult patients with spontaneous ICH are not associated with improved neurological function during long-term follow-up. On the contrary, Sheath and colleagues in 2015 published a observational study observing that antieleptic drugs are not independently associated with poor outcome in patients after acute spontaneous intracerebral hemorrhage. And Spilhoff and colleagues in 2019 also published a meta-analysis observing prophylactic AEDs were not associated with improved short-term or long-term outcomes in patients after acute spontaneous intracerebral hemorrhage. As far as the hypothesis of the PEACH trial, the hypothesis was prophylactic levotiracetam will reduce the risk of early seizures in patients with acute ICH. When thinking about levotiracetam overall, we know that its mechanism in seizures is pretty much unknown. However, theorized to deal with calcium channel blockade, GABAergic modulation, as well as synaptic vesicles and modulation of neurotransmitter receptors. But we do know that it comes with an overall relatively favorable adverse drug effect profile. As far as methods of the PEACH trial, the study design was a parallel group, double-blind, randomized, placebo-controlled phase three trial. The location was in three stroke units in France, one secondary and two tertiary hospitals, which took place between June 1st of 2017 to April 14th of 2020. The intervention, randomized in a one-to-one fashion, was levotiracetam 500 milligrams IV every 12 hours versus placebo. And as IV was transitioned to enteral after 48 hours based on swallow evaluation or as able. Duration of treatment overall was six weeks, 30 days at full dose, which was 500 milligrams twice a day. With gradual tapering over the final two weeks as noted in the study protocol. As far as endpoints, the primary endpoint was occurrence of at least one clinical seizure within 72 hours of inclusion or at least one electrographic seizure recorded on continuous EEG. Secondary endpoints or key components thereof were number of seizures on continuous EEG and median duration of seizures. And the number of seizures on continuous EEG and median duration of seizures noted if they occurred. Change in NIH stroke scale score between inclusion and 72 hours, one month and three months. As well as change in modified ranking score between inclusion and three months, six months and 12 months. And the stroke impact scale score at three months, six months and 12 months. Change in ICH volume between inclusion and 72 hours as well as one year mortality. Patients were randomized via a web-based system and stratified by medical center and baseline NIH stroke scale score. As far as study population or inclusion, patients were greater than 18 years of age presenting with non-traumatic spontaneous supertentorial mild to moderate ICH within 24 hours after initial symptom onset. Key components or exclusion criteria were NIH stroke scale score greater than 25, ICH caused by or suspicious of trauma etiology, vascular malformation, hemorrhagic transformation of acute ischemic stroke or tumor. History of epilepsy or current use of AED. History of severe depression or psychotic disorder. Known terminal illness or the occurrence of seizure between inclusion and initiation of treatment drug. In this case, Levotir's 10. As far as statistical analysis, assuming a proportion of patients with at least one seizure, 35% for placebo and 10% for Levotir's 10, utilizing the alpha of 5% with 80% power and a 10% estimated loss to follow up, the patients needed to meet power in this trial was about 52 patients per group. However, recruitment was prematurely stopped after 48% of the recruitment target was reached. Due to low recruitment overall and cessation of funding, keeping in mind that this took place primarily amidst the COVID-19 pandemic. Looking at baseline characteristics, I have noted some key differences here overall, but patients assigned with Levotir's 10 were older. So we see 77 and a half or 66 and a half, as well as have had a higher pre-stroke modified Rankin score, higher proportion of diabetes and hypertension and more patients were taking antithrombotic treatments before ICH. Regarding imaging data noted on the right, ICH location was more often lower and ICH baseline volume was lower in the Levotir's 10 group. Looking at seizure related outcomes, the primary efficacy outcome of clinical or electrographic seizure in the first 72 hours was statistically significant and different. So Levotir's 10 was three out of 19 or 16% versus 10 out of 23 and 43% for placebo. So lower in the treatment group. Looking at this infograph noted in the article, A, B and C, A was the number of patients with at least one acute clinical or electrographic seizure, B, the number of electrographic seizures and C, median duration of seizures were all lower in the treatment group receiving Levotir's 10 and all statistically significant. For functional outcomes, we can see that number of seizures on continuous EG and median duration of seizures were lower in the treatment group or Levotir's 10 group. However, we note no other differences in secondary outcomes on this slide. As far as stroke impact scale score at three, six or 12 months, change in ICH volume between inclusion and 72 hours, the NIH stroke scale score between 72 hours, one month and three months, inclusion in those three instances and as well as no difference was observed in the modified Rankin score between inclusion and three, six and 12 months. Looking at safety outcomes for at least one serious adverse event, there was five noted in the treatment group and nine noted in the placebo group. Looking below, we can see that the most common treatment emergent adverse drug effects noted as Levotir's 10 versus placebo, headache, pains and fall with headache and falls being more common amongst the treatment group and pain being more common amongst the placebo group. Most frequent serious adverse drug events were neurologic deterioration due to ICH, so one in the Levotir's 10 group versus four out of 25 in the placebo group and severe pneumonia was very similar. No treatment related death reported in either group. As far as the author's conclusion, they stated that Levotir's 10 might be effective in preventing acute seizures in ICH. Larger studies are needed to determine whether seizure prophylaxis improves functional outcomes in patients with ICH. Looking overall at the critique and the good and bad throughout this trial, looking at specifically design and statistics, the positives, this research question definitely identified a gap in the primary literature and sought to answer a question that we'd all like to definitively know the answer to. This is also a multi-center study, so three different institutions in France and it is a randomized placebo-controlled trial. Continuous EEG reduces the clinician bias and determination of clinical seizure. However, we know that it does not eliminate it, but I do think that that was carried out in the most appropriate way. As far as what we can improve on, of course, the sample size did not meet power as the study was stopped early and severe intracerebral hemorrhage was not included, so therefore, we cannot extrapolate results that were found in this trial or subsequent trials that might be devised in this fashion. To that part, we can't take these results and extrapolate them to that population. As far as population overall, the clinically relevant and appropriate inclusion-exclusion criteria were utilized as well as relevant past medical history reported, and I thought it was interesting that they did report treatment compliance as well. As far as things we can improve on, again, a small patient population. There was a higher pre-stroke modified Rankin score in the levotirsotium group and there were definitely imbalances noted in demographic and baseline characteristics between groups that we have previously discussed. Looking at interventions, appropriate prophylactic dosing of levotirsotium was selected based on currently available evidence and levotirsotium has an overall favorable adverse drug effect profile compared to its colleagues or counterparts in the anti-elliptic agent category. As far as things we can improve on for interventions, recruitment was based on continuous EEG recording in a tight time schedule, and that is challenging. The authors did note that missing data was noted upon the analyzation process. And expertise and resources available within each institution may be variable depending upon what type of institution that you work at. Endpoints assessed were appropriate and clinically relevant in observation of levotirsotium group have having fewer patients with seizure and number of seizures may be clinically significant as well as the neurologic deterioration due to ICH was higher in the placebo. However, this could also be clinically significant. However, we must note that we have to interpret this statistical significance with caution given sample size was not met and the study overall was not powered for functional outcomes. Takeaway points, levotirsotium displayed a safe adverse drug effect profile with possible efficacy at preventing the occurrence of seizures post ICH. The number of seizures observed during continuous EEG recording was higher in the placebo group than in the levotirsotium group and seizure duration was longer. An adequately powered RCT is needed to determine whether seizure prophylaxis improves functional outcomes in patients with ICH. And as always, we must keep it in the back of our mind that the 2022 AHA and ASA guidelines state in patients without seizures that this intervention is likely not beneficial. And this will be the first polling question. How often is seizure prophylaxis utilized in the acute phase of non-traumatic ICH at your institution? In simplicity, the first answer, greater than 75% of the time. The second, greater than 50%. Rarely utilized or we never utilize seizure prophylaxis in ICH. So for time's sake, we will move on to the next polling question, which follows this. I would say in our institution, it's gonna be very patient-specific. However, I would say we likely fall on the greater than 50% category. How often is continuous EEG utilized as standard of care after acute non-traumatic ICH at your institution? Again, first option, greater than 75%, then greater than 50%. Utilize it only in specific patients. For C, they never utilize it. And the last option, continuous EEG is unavailable in my institution. Perfect. So, I'm seeing 81 percent for utilized continuous EEG in specific patients. I would say that's the exact same way that we review this. And with that, I will take any questions. Excellent. Thank you so much, Austin. We do have a couple of questions in the chat, but I'll go ahead and read those. The first question is, given differences between the groups, why do you think the incidence of seizures was so high in the placebo group, presumably if not from the absence of prophylaxis alone? I would say, personally, just looking at the overall baseline demographics, I would think, you know, if we exclude the fact that they're not receiving anti-epileptic agents, I think that we might be able to contribute to the baseline hematoma volume that was present given it was doubled versus the levotirostim group. The things that usually come to mind that trigger our clinicians to sort of pull the trigger on seizure prophylaxis in these patients are going to be things like location-based area like low bar, as well as hematoma volume at baseline. So I would say if we're looking at 15 to 30 milliliters of hematoma volume at baseline, as well as younger age, comatose. So I think any of those factors sort of come into play. For this specific trial, I think I would probably lean more towards the baseline hematoma volume. And you started to comment on this, but this leads nicely into one of the next questions that's wondering, how would differences in hemorrhage location affect the study endpoints? Yeah, and I would think that as sort of, you're right, as I sort of previously elaborated on, I would expect that the location, especially low bar, would increase your likelihood of likely seeing a seizure or a seizure occurrence. So given the fact that the Levotiristam group had 42% versus 19% low bar involvement, that would be the main area that I would likely be looking out for or seeing if there was any location like that noted that would impact my decision on whether I would recommend against or for seizure prophylaxis. Thank you. I'm going to jump in quickly for the sake of time. There's a couple of different questions asking about the duration of the intervention. So what is your assessment of their six-week treatment duration and how that possibly compares to other trials or other similar prophylactic efforts? Yeah, I would say this is probably one of the biggest variabilities throughout trials. Again, I would say at our institution, very clinician-specific, I think that they erred on the long side of treatment duration. I would say most frequently in my practice that I see about seven days would be a typical duration that we would utilize seizure prophylaxis in this patient population. So I do think that they treated longer than what I would typically see. However, this is variable across different trials. All right, thank you so much, Austin. That concludes our Q&A session for this trial. And now I would like to introduce our final presenter for the day, Anissa Sula. All right, good afternoon, everyone. Today I'm going to be presenting on the SWIFT Direct Trial, Thermectomy Alone versus Intravenous Alteplase plus Thermectomy in Patients with Stroke, an open-labeled blinded outcome randomized non-inferiority trial. So as we are all familiar with acute ischemic stroke, it occurs when there's deficient blood and oxygen supply to the brain. There are two main types, being thrombotic or embolic etiology. As for treatment options, it includes thrombolytics such as alteplase or tenecteplase, and then also mechanical thrombectomy for larger vessel occlusions. Today we will be focusing more on TPA and thrombectomy. For background, major trials previously have shown that thrombectomy plus IV TPA is effective for acute ischemic stroke. Previously the SWIFT prime trial was performed in 2015 that looked at TPA alone versus TPA plus thrombectomy. This trial saw that TPA plus thrombectomy significantly reduced disability at 90 days. Other secondary endpoints included functional independence, which favored the TPA plus thrombectomy group, which was also statistically significant. And they also saw no significant differences in 90-day mortality, as well as no differences in symptomatic intracranial hemorrhage. And again, previous trials have all been pretty similar with these outcomes. Now the question today becomes whether thrombectomy alone is equally as effective and safe as IV TPA plus thrombectomy. And this question still remains kind of uncertain. Looking at some of the current literature, it's really limited in what has been previously conducted. Looking at two trials that were conducted in China, the DIRECT-MT trial and the DEVT trial, they both showed that thrombectomy alone was non-inferior to thrombectomy plus TPA. In contrast, two trials that were performed in Japan, the SKIP trial and the MR-CLEAN and OIV trial, could not show non-inferiority between these two groups. When looking at these trials, there were considerable differences between them, including their population, stroke ideology, and different types of occlusions that were included, as well as their organization and how these studies were performed. Again, whether thrombectomy alone versus thrombectomy plus TPA is non-inferior to one another still remains controversial. This takes us to the SWIFT-DIRECT trial that we will be diving into today. This trial looked at thrombectomy alone to see if it was non-inferior to IV TPA plus thrombectomy in patients who were directly admitted and presented with acute ischemic stroke. This study was a investigator-initiated, multi-centered, prospective, randomized, open-label, blinded outcome trial. It occurred in 48 tertiary centers in Europe and Canada, and patients were assigned in a one-to-one ratio. The intervention group was the thrombectomy alone, and then the control group included patients who received IV TPA plus thrombectomy. In regards to masking, this was open-label to the treating physicians, but blinded to all personnel assessing the primary outcome. Patients were included in the SWIFT-DIRECT trial if they were equal to or greater than 18 years old, had clinical signs of acute ischemic stroke, had occlusions of the intracranial ICA, first segment of the MCA, or both, which had to have been confirmed with CTA or MRI. This also included patients who were eligible to receive IV TPA within four and a half hours, as well as patients who were eligible to undergo thrombectomy within 75 minutes. The study also included patients who had a NIH SS score of greater than or equal to five and less than 30. Patients were excluded from the SWIFT-DIRECT trial if they had an acute intracranial hemorrhage, contraindications for IV TPA, had a in-hospital stroke, were pregnant at the time, renal insufficiency, or had advanced dementia or substantial pre-existing disabilities. Patients were also included if they had early signs of severe tissue loss, which would have been confirmed by CT, MRI, or a score of four or more on the ASPEC scale. The primary endpoint of the SWIFT-DIRECT trial was a score of two or less on the Modified Rankin Scale at 90 days. Secondary endpoints included mortality, degree of disability on the Modified Rankin Scale at 90 days, change in the NIH SS score between admission and 24 hours, quality of life at 90 days, significant reperfusion, and also safety endpoints, which looked at serious adverse events such as bleeding and symptomatic intracranial hemorrhage. As for statistical analysis, the investigators of this trial set a non-inferiority margin of 12%, a power of 80%, and the primary outcome was analyzed using a one-sided significance level of 0.05 with a 95% confidence interval, which was similar for secondary outcomes, but it used a two-sided significance level of 0.05. Moving on to our results, so a total of 408 patients were included in this trial. In the thrombectomy alone group, the median age was 73 years, and in the thrombectomy plus TPA group, they had a median age of 72 years. It was evenly split between males and females, and that was similar for both groups. When looking at the NIH SS score, both groups had a median of 17 with a similar interquartile range. When looking at the pre-stroke modified Rankin scale score, we can see here that almost all patients belong to a score of 0 or 1, meaning that these patients were all functionally independent before coming into the hospital. Just to note, there was one patient with a score of 4 in the thrombectomy plus TPA group. When looking at baseline occlusion site, this study only included patients with an ICA or M1 stroke, and we can see here that about one-third of patients belong to the ICA occlusion group, and about two-thirds of patients belong to the M1 occlusion group, which is the most common type of occlusion for acute ischemic stroke. Moving on to our primary result, we can see that in the thrombectomy alone group, 57% of patients reached a modified Rankin scale score of 0 to 2 at 90 days, and in the thrombectomy plus TPA group, 65% of patients achieved that score at 90 days. There was an adjusted risk difference of 7.3%, and the lower limit of the one-sided 95% confidence interval was 15.1, crossing the non-inferiority margin of 12% that was set for this trial. As for secondary results, there was no statistical difference between mortality at 90 days, no difference between modified Rankin scale score at 90 days, as well as a change in the NIHSS score. For other secondary results, such as significant reperfusion, there was a statistically significant increase in reperfusion per the thrombolysis in cerebral infarction score in the thrombectomy plus TPA group, which was statistically significant. Lastly, for the quality of life dimensions, all the dimensions, such as mobility or able to take care of all activities throughout the day, were not statistically significant between the two groups. As for safety results, looking at symptomatic intracranial hemorrhage, 2% of patients underwent thrombectomy alone, and 3% of patients in the thrombectomy alone group, 3% of patients who had a symptomatic intracranial hemorrhage received IV TPA plus thrombectomy. This was a risk difference of 1%, and there was no difference between these two groups. For serious adverse events, there was also no difference between these two groups and different types of bleeding. The authors of this study concluded that thrombectomy alone was not shown to be non-inferior to IV TPA plus thrombectomy in patients presenting with acute ischemic stroke due to large vessel occlusions such as the ICA and M1 occlusions. The authors also concluded that there was decreased reperfusion rates that were seen when IV TPA was omitted before thrombectomy. As for my critiques for this trial, positive critiques included that this was a randomized trial. It was multi-centered and included 48 tertiary centers in both Europe and Canada. It was an intention to treat analysis, meaning that all patients who were randomized were included in the analysis. Both groups had similar baseline characteristics, increasing the internal validity of the study. And lastly, there was appropriate endpoints that were chosen. As for the negative critique, focusing on generalizability, this study only included the intracranial ICA, first segment of the MCA, or both types of occlusions, so this may not be generalizable to different types of occlusions such as our M2 or basilar artery occlusions. There was only one type of stent or thrombectomy device used in this trial, so this may not be generalizable to different types of stent retrievers. And lastly, all of the tertiary centers that were included in this trial were comprehensive stroke centers and had low times to alteplase administration, less than 55 minutes, and also had thrombectomy compatibility. So this may not be generalizable to institutions that are not comprehensive stroke centers and need to transfer patients to other institutions. And lastly, looking at a potential bias, this trial was funded by the Medtronic Research Grant, which was the only type of device used in this trial. Some clinical takeaway points, thrombectomy plus IV tPA should be considered the main stay of treatment for patients with acute ischemic stroke, especially for intracranial ICA and M1 stroke. Early thrombectomy plus tPA may increase reperfusion in patients and should not be omitted if eligible. Using tPA concomitantly with thrombectomy may not increase the risk of symptomatic intracranial hemorrhage. And lastly, more randomized controlled trials need to be completed. These are my references. And our first polling question is, which thrombolytic is currently being used for acute ischemic stroke at your institution? All right, so I can see here that looks like 61% of the people here today are using Tenecteplase at their institution, which is similar to what we are doing here at Cooper Healthcare. Second polling question, does your institution currently offer a thrombectomy for large vessel occlusion or acute ischemic stroke? All right, and we can see here that it looks like 84% of people today said yes, which is very similar to what my institution does as well. All right, and with that, I can take any questions the audience may have. All right, thank you so much. What is your assessment of their choice of primary outcome? Yeah, so I thought that the trial investigators chose an appropriate primary outcome for this trial. So it was pretty similar to what previous trials had also chosen. But using the modified Rankin scale, we can see how functional or the degree of disability patients have after they have their acute ischemic stroke, which I think is important not only for assessing the patients themselves, but also their quality of life after. So I thought the primary endpoint that they chose was appropriate. Thank you. And based on the high percentage of connected place use, do you think these results can be generalized to that agent as well? Yeah, that's a great question. That's something I thought about when putting this together. So there have been some studies that have been published. One of the bigger studies was the EXTEND-IA-TNK trial, which actually looked at tenecteplase versus alteplase before thrombectomy. And they actually saw better outcomes with patients who received tenecteplase and more significant reperfusion as well. So there have been some other smaller trials that have been looking at tenecteplase with thrombectomy as well. And everything so far seems like it is showing similar or even better outcomes. So I think we can definitely take some of the things we've seen in this trial and kind of use some of the outcomes we've seen here with tenecteplase before thrombectomy as well. And that's currently what we do at my institution. And we've seen some good outcomes for patients. All right, thank you so much. For the sake of time, we will go ahead and conclude the Q&A. Thank you again, Anissa, for that presentation. To conclude, I wanted to thank all of our presenters today and everyone in the audience for attending. Please join us on the third Friday of the month, 2 to 3 Eastern Standard Time, for the next Journal Club Spotlight on Pharmacy. And with that, that concludes our presentation for today. Thank you so much.

critical care pharmacy

haloperidol

delirium

levatiracetam

epileptic seizures

intracerebral hemorrhage

thrombectomy

alteplase

stroke