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 Jenna Corvelli, a clinical pharmacy specialist in the medical ICU at the University of Rochester Medical Center in Rochester, New York. I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log into myfccm.org and navigate to the My Learning tab to access the recording. Thanks for joining us. 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, 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 SCCMCPPJC 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 Rachel Oh, a PGY2 critical care pharmacy resident at the University of Texas Southwestern Medical Center in Dallas, Texas. She will present on flugocortisone dose-response relationship in septic shock, a randomized phase 2 trial. Our second presenter is Joanna Nixon, a PGY2 critical care pharmacy resident at University of Kentucky Healthcare in Lexington, Kentucky. She will present on continuation versus discontinuation of renin-angiotensin system inhibitors before major non-cardiac surgery, the stop or not randomized clinical trial. And our third presenter is Hannah Frank, a PGY2 critical care pharmacy resident at University of Washington Medicine in Seattle, Washington. She will present adjunctive intravenous argatroban or eptifibatide for ischemic stroma. And now I'll turn things over to our first presenter, Rachel Oh. Thank you again for that introduction. As said, my name is Rachel, and I am the current PGY2 critical care pharmacy resident at the University of Texas Southwestern Medical Center in Dallas, Texas, and I will be presenting on the flu dress trial, which looked at flugocortisone dose-response relationship in septic shock. So, sepsis and septic shock are leading causes of both morbidity and mortality worldwide. As a component of treatment, guidelines recommend the use of steroids in septic shock, but questions remain regarding the benefit of steroids on various outcomes, as well as which agents to use. As a high-level overview of just some of the literature surrounding the topic of steroids in septic shock, an all-inclusive review is beyond the scope of this presentation. Various trials have looked at hydrocortisone alone, as well as hydrocortisone with flugocortisone, at doses of 50 micrograms daily in septic shock. When looking at even the earlier studies, shock duration has been shown to be reduced with the addition of steroids. However, only two studies have showed a mortality benefit, both of which being studies that investigated hydrocortisone in combination with flugocortisone. The COIT study in 2010 did also investigate the combination of hydrocortisone and flugocortisone, but did not find a mortality difference. However, the study was underpowered to detect a difference in mortality. Even with that information, there remains some uncertainty regarding the efficacy of hydrocortisone monotherapy and the additional benefit that flugocortisone to hydrocortisone may add, specifically in regard to its mineralocorticoid activity. One argument for the use of hydrocortisone alone is based off of the hypothesis that the mineralocorticoid activity of hydrocortisone at the doses given for septic shock are sufficient to activate mineralocorticoid receptors without concomitant flugocortisone administration. On the other hand, the rationale for the use of flugocortisone may be supported by various hypotheses, including the idea that although hydrocortisone has binding affinity to mineralocorticoid receptors, subsequent signaling pathways differ from those mediated by flugocortisone. Additionally, there also may be non-mineralocorticoid effects associated with flugocortisone activity, and there may be a component of downregulation of receptors as well. Of note, in recent years, several studies, including two meta-analyses as well as a retrospective claims-based study, support the use of a combination of hydrocortisone and flugocortisone, as benefit has been seen when looking at outcomes including ICU and hospital survival, shorter lengths of stay, and aligning with previous studies, a decrease in shock duration. Even with this newer data that may better support the use of flugocortisone, another question that arises is the optimal dosing. Earlier studies have noted that the pharmacokinetics of flugocortisone in the setting of shock are variable in terms of absorption, peak plasma levels, and plasma half-life, raising the question of if the originally studied doses of flugocortisone 50 micrograms is sufficient. Before we dive into our discussion of the trial, I have our first polling question, which is, do you routinely use flugocortisone for treatment of septic shock? Alright, so it looks like the majority of participants said no, which is what I've encountered in my practice, and what I've observed is that it's very provider-dependent. With that, that brings us to the FLUGRA study and its hypothesis and ultimate objective, which was to see if the addition of flugocortisone to hydrocortisone results in a shorter time to shock resolution and that this effect is dose-dependent. This was a multicenter, open-label, randomized-controlled Phase 2 trial conducted in Australia between April 2021 and April 2023. The study included adult patients with a documented or strongly suspected infection and at least two SERS criteria who were also receiving either non-invasive or invasive ventilation and vasopressor support to maintain a systolic blood pressure greater than 90, a MAP greater than 60, or an alternative target that was set by the treating clinician. Patients were excluded if they were known to be on long-term steroid treatment. If they had met all inclusion criteria for more than 24 hours, if there was a documented systemic fungal infection, or if death was deemed inevitable or imminent. Patients were randomized into four groups, either receiving hydrocortisone 200 mg per day alone or hydrocortisone along with flugocortisone with doses ranging from 50 micrograms daily, twice daily, or four times daily. Of note, the trial did not specify the administration details of hydrocortisone and whether it was administered intermittently or via continuous infusion. The study's primary outcome was time to shock resolution, which was defined as time from randomization to attainment of a clinical prescribed MAP target for more than 24 hours without the use of pressors. Secondary outcomes included recurrence of shock, ventilator-free days, maximum SOFA score, ICU and hospital length of stay, and death from any cause. Additionally, plasma flugocortisone levels at 3 hours and adverse effects were also investigated. In order to detect a 3 to 5 percent difference in shock reversal rate, a target sample size of 300 patients was needed to achieve a power of 70 to 80 percent. The primary outcome was analyzed using Cox regression, and secondary outcomes were analyzed using Fischer's EXACT test and T-test. Since there were three different intervention groups, investigators analyzed outcomes using a sequential approach and started with analysis of the control group against the flugocortisone 200 micrograms per day group, and only if that was found to be significant were analyses then performed on the next highest dose arm and so on. Otherwise, testing was stopped. Looking at the trial results, a total of 153 patients ended up being enrolled with around 40 patients in each group. Due to funding constraints and slow recruitment during the COVID-19 pandemic, the trial resulted in early termination, thus the total number of patients was below the number needed for power. In terms of baseline characteristics, they were overall balanced between the various groups. When looking at the overall cohort, the mean age was 60 years, and the majority of patients were male. Most of the patients enrolled were being treated in a medical ICU, and the breakdown of pressers has been included for your review. I did want to point out Metariminol because it is not available here in the United States, but it is a presser that works as an alpha-1 agonist. The time from start of presser use to randomization was approximately 15 hours overall, and the baseline SOPA score was 11. Moving on to our outcomes, first focusing on the primary outcome, which was again time to resolution of shock, the median time in all four groups was 3 days and was not statistically significant. None of the secondary outcomes, including 28-day mortality, were found to be statistically significant, and secondary outcomes were not found to be different between the groups either. For the pharmacokinetic portion of this study, 64% of patients had a flusocortisone concentration measured post-dose between days 1 and 5 of enrollment, and out of those patients, 97% had a detectable plasma level at hour 3. The median plasma concentration was 261 nanograms per liter, with an interquartile range of 156 to 334, but overall plasma concentrations ranged anywhere from 0 to 677 nanograms per liter, suggesting wide variability in absorption and or bioavailability. As we wrap up with a discussion, starting off with the strengths of the study, first it was a multicenter randomized trial, and overall baseline characteristics for patients were balanced between each of the different treatment groups. The study also incorporated early administration of steroids to capture patients earlier on in their shock course and potentially garner more benefit. And lastly, the primary outcome of resolution of shock has been one of the outcomes that has been shown to be significant with the use of steroids in multiple previous trials, so it was relevant to be the primary outcome of this phase 2 trial. In terms of limitations, given that this was a phase 2 trial, the sample size was small, so generalizability is limited. Along with that, the study was ultimately underpowered to detect the difference between the different flucocortisone doses on shock resolution, so it limits the conclusions that we're able to draw from those results. This was also an unblinded study, which may have introduced some bias, as the primary outcome was in part clinician decided. And lastly, for limitations, there was no standard definition for shock resolution that was outlined by investigators, making it provider-dependent and potentially increases the variability and thus the results. Overall, the authors concluded that there was no difference in time to shock resolution with various doses of flucocortisone, but the study was underpowered due to early termination. Additionally, to answer the second objective of this study, plasma concentrations of flucocortisone were found to be detected in the majority of patients regardless of dose. Thus, my overall takeaways from this trial are that as a single study, these results do not definitively support the use of flucocortisone for septic shock. However, when combining this study alongside the others that have been conducted, at this time, it seems that higher doses of flucocortisone may not be needed and that flucocortisone in 50 micrograms daily is likely adequate and still has the most evidence to support its use. So, in conclusion, it would be reasonable for any future studies to focus on solidifying outcomes based upon this dose before providing any stronger recommendations. That brings us to our second polling question, which is, based on the results of this study, would you adjust the dose of flucocortisone you use or recommend for septic shock? And it looks like participants either said no or not applicable, which is similar to the takeaway that I had shared in my conclusion and, again, seems consistent with the current Thank you all for your attention, and with that, I'm happy to take any questions. Well, thank you very much, Rachel. I do have a question here for you. What is your opinion on the timing of the drug levels? Do you agree with checking those levels at three hours post-dose, or would you have done that differently? I think that the investigators were trying to target somewhat of a peak dose, and so based off of previous studies, the half-life of flujicortisone can range anywhere from three to five hours, and so I think it was appropriate to check levels at that point. Okay, thank you. And I noticed you said that only 64 or 65 percent of patients actually had levels drawn. Did the authors mention any explanation for why so many patients did not end up having drug levels drawn? That's a great question. There was no mention of it in the discussion of the trial or in the supplemental material. If I had to guess, it might have been just resources, but that would be something that, if I were designing the study or changing it, would be something that I would consider in trying to get levels on all participants just to have more data. Okay, thanks so much. And seeing no other questions here, that concludes our Q&A session. Thank you very much, Rachel. And now I'd like to introduce our second presenter, Joanna Nixon. Hi, thank you for that introduction. Again, my name is Joanna Nixon. I am a PGY2 critical care pharmacy resident at the University of Kentucky Health Care, and today I will be discussing the STOP or NOT trial that looked at the continuation versus discontinuation of renin-angiotensin system inhibitors before major non-cardiac surgery. So, why this study is important? Many patients who undergo major surgery have a history of hypertension, diabetes, and heart failure and are often being treated long-term with a renin-angiotensin aldosterone system or RAS inhibitor, including ACE inhibitors or ARBs. The best strategy for managing these patients before major surgery is unknown, and there is little evidence from randomized clinical trials to adequately inform guideline recommendations. Currently, the available data for undergoing, for patients undergoing non-cardiac surgery is conflicting, and some data has shown that the continuation of RAS inhibitors is associated with intraoperative hypotension, leading to cardiovascular events and acute kidney injury. Whereas, on the other hand, discontinuing RAS inhibitors has been associated with postoperative hypertension and increased risk of arrhythmias and heart failure. So, the 2014 ACC guidelines for the perioperative management of RAS inhibitors in patients undergoing non-cardiac surgery recommends continuing ACE inhibitors or ARBs perioperatively is reasonable, and that is a class 2a recommendation. Whereas, the 2022 ESC guidelines actually split their recommendations based on the presence or absence of heart failure, and they recommend that patients with heart failure can consider perioperative continuation of RAS inhibitors, and this is a class 2b recommendation. Whereas, patients without heart failure can consider withholding RAS inhibitors on the day of surgery in order to prevent perioperative hypotension. The available literature up to this point in adults undergoing non-cardiac surgery has consistently shown lower rates of intraoperative hypotension when discontinuing RAS inhibitors preoperatively. However, there have been mixed conclusions in terms of the morbidity and mortality benefit, and results from these studies beg the question, does the continuation versus discontinuation of RAS inhibitors have an effect on all-cause mortality and post-operative complications after non-cardiac surgery? And before we get into today's study, the first polling question I have for the audience is, does your institution utilize a protocol to guide the management of perioperative RAS inhibitors for non-cardiac surgery? All right, and it looks like it is pretty evenly split, but about half of you are saying no. And we do not use a protocol at this institution either, but we do have perioperative clinical pharmacists who are very diligent in ensuring that these patients' medications get properly continued or discontinued before surgery. All right, so getting into the STOP or NOT trial, this was a investigator-initiated multi-center open-label randomized clinical trial that took place at 40 hospitals across France from January 2018 through April of 2023. Their objective was to evaluate the effect of continuing or discontinuing RAS inhibitors before non-cardiac surgery on 28-day postoperative complications. Doctors were randomized to continue their RAS inhibitor until the day of surgery or to discontinue their RAS inhibitor 48 hours before surgery. And it is important to highlight that they defined elective major non-cardiac surgery as a procedure with an expected duration of longer than two hours from incision to closure and an expected postoperative hospital stay of at least three days, which is based on a previous study called the RELIEF trial, which was published in 2018, and that trial assessed restrictive versus fluid liberal therapy for major abdominal surgery. So the primary outcome that they investigated was the composite of all-cause mortality and major postoperative complications at 28 days after surgery. And I have the definition of complications listed on the screen for you, but I did want to highlight that a cardiovascular event included acute myocardial infarction, arterial or venous thrombosis, stroke, acute pulmonary edema, cardiogenic shock, acute severe hypertension, or de novo cardiac arrhythmias requiring therapeutic intervention. And some secondary outcomes that they looked at included intraoperative hypotension, which was defined as immune arterial pressure less than 60 millimeters of mercury or patients requiring vasopressors. They additionally looked at the SOFA score on day seven, ICU length of stay, and hospital length of stay. And patients were included if they were 18 years or older and they were undergoing elective major non-cardiac surgery who had been taking ACE inhibitors or ARBs for at least three months before surgery. Of note, they stratified patients based on hospital site and their heart failure status. The following patients were excluded and I wanted to emphasize that the patients who required emergency surgery, which was defined as surgery required within 24 hours, and those requiring vasopressors before surgery were a major exclusion point from this study. And in terms of statistical analysis, 2,222 patients were required for 80% power to detect a 20% relative decrease of complications in the experimental group using a chi-square test. Now getting into some of the results, over 2,000 patients were included in this study with 1,115 patients in the discontinuation group and 1,107 patients in the continuation group. The baseline characteristics were pretty well balanced between the two groups. The median age of patients was about 68 years old. Most patients had a history of hypertension and I did want to point out that only 6% of patients in each group had heart failure, so an underrepresentation of patients with heart failure in this study. Additionally, 54% of patients were prescribed angiotensin receptor blockers and 46% of patients were prescribed angiotensin converting enzyme inhibitors, so a pretty even split between those two agents. Additionally, the most common type of surgery that patients underwent included abdominal surgery followed by thoracic, vascular, and urological, among others, and the median duration of surgery in this study was roughly 182 minutes. Like I mentioned, the primary outcome assessed a composite of all-cause mortality and postoperative complications on day 28, and this study did not find a statistically significant difference in the primary outcome. The between-group difference was 0 with an adjusted odds ratio of 1.01 with a 95% confidence interval from 0.82 to 1.24, which again was not statistically significant. And here is a breakdown of each of the individual components of the primary outcome. So looking at all-cause mortality, there was only a 1% mortality rate in both groups, 11% of patients in both groups developed an AKI, and 5% had an unplanned ICU admission, and lastly, 8% of patients in each group required reoperation or radiological intervention. Now getting into some of the secondary outcomes, I wanted to highlight the episodes of hypotension requiring vasopressors was statistically higher in the continuation group, with 54% of patients experiencing intraoperative hypotension compared to 41% in the discontinuation group, which is consistent with what other studies have found. Additionally, the median duration of hypotension was significantly longer in the continuation group at 9 minutes versus 6 minutes in the discontinuation group. However, this difference may not be clinically relevant, as the study did not observe any other differences in any of the other outcomes as a result of this. And ultimately, the authors concluded that continuing versus discontinuing RAS inhibitors did not result in any differences in postoperative complications in patients who underwent major non-cardiac surgery, suggesting that the decision to continue versus discontinue can likely be made on a case-by-case basis. Now getting into some of the critique of this study, some of the strengths I wanted to highlight is that this is the largest randomized control trial to date that assesses the continuation versus discontinuation of RAS inhibitors, and supports that either strategy appears to be safe. Additionally, various types of surgeries were assessed, which does enhance its generalizability, they assessed patient-centered outcomes, and they also had well-balanced baseline characteristics. And some of the limitations I wanted to point out is that they did look at a composite primary outcome, and they did not find a difference in their composite primary outcome or any of the individual components of the primary outcome. And some of the secondary outcomes that they looked at, I wanted to touch on as well. So one of the secondary outcomes that they looked at was sepsis, and this is likely not relevant because it's difficult to attribute sepsis to RAS inhibitor continuation versus discontinuation when patients are undergoing major surgeries and have other risk factors for developing sepsis. And then the SOFA score on day seven, again, was likely not relevant, and the study wasn't powered to assess this. And also the 28-day follow-up is likely not relevant, especially considering the median length of stay was about six days in both groups. So the investigators were unable to assess the patient's compliance to medications once they leave the hospital. So it's difficult to definitively attribute 28-day outcomes to any of the interventions made by the investigators. Additionally, there are some other outcomes that would have been worth assessing, in my opinion. For example, I would have liked to see a discussion on AKI and renal dysfunction, especially in the patients who did experience intraoperative hypotension. And it would have been nice to see the cardiovascular complications broken down by what type of cardiovascular complication, such as the incidence of de novo arrhythmias and or heart failure, especially in the patients who discontinued their RAS inhibitor. And additionally, the patients were not blinded, which could have introduced a little bit of bias into this study. And lastly, there is limited generalizability to patients with heart failure, given their underrepresentation in this study. And now this brings me to my second polling question. How do you manage perioperative RAS inhibitors for patients undergoing non-cardiac surgery at your institution? All right, it looks like there is a variable response here, which is pretty consistent with what I see in my practice as well. I think a lot of it has to do with patient-specific factors that I will get into on the next slide. All right, and just for my key takeaway points from this study, like I mentioned, ultimately the preoperative management of RAS inhibitors should be individualized based on patient comorbidities, indication of RAS inhibitors, so it's important to consider the risk of bleeding if patients are taking these medications for hypertension. We don't want them to discontinue their RAS inhibitor and then have a higher risk of bleeding after the fact, and additionally based on the type and duration of surgery. For example, there are risks of hemodynamic effects when you have longer surgeries, longer duration of general anesthesia, and the fluid shifts and blood loss that can occur throughout major surgeries such as abdominal surgeries. And additionally, this study was kind of in line with what other studies showed in terms of increased risk of intraoperative hypotension with continuing RAS inhibitors before surgery. However, again, this did not lead to any differences in any other outcomes, so likely not clinically super relevant. And I did want to point out as well that the new 2024 European Association for Cardiothoracic Surgery Guidelines were actually just published a week ago, and they have a recommendation that in cardiac surgery patients should continue or discontinue their RAS inhibitors based on the drug's half-life and on the individual characteristics of patients with comorbidities. So that is a change to their prior guidelines, and I'm curious to see what happens to the new guidelines in non-cardiac surgery. And thank you all for your time today, and I will take any questions anybody may have. Thank you for that excellent presentation, Joanna. I did notice that in the baseline characteristics, there were about a third of patients who were also receiving beta blockers and calcine channel blockers and or diuretics at baseline. Did the authors discuss whether or not any of these agents were held or continued, as they obviously could also influence things like hypotension or post-op effects? Yeah, that was a great question, and I actually had the same question as I was reading through this as well. I didn't see any mention of it in the discussion or in the supplemental material. However, I think this would have been worthwhile to assess, especially considering a large number of patients were receiving concomitant agents beforehand. Okay, thank you. And a second question for you. So I know you mentioned at the end there, thinking about individualizing our recommendations for patients with potential new guidelines, but how would you recommend continuing or stopping these agents prior to non-cardiac surgery? Are there any specific situations or patient populations that would influence that recommendation? Yeah, that's a great question. So I think I would recommend patients with heart failure to continue their medications, kind of like the 2022 ESC guidelines stated, and I think also patients with hypertension. I would take into account the duration of action of their acinibator, or I would probably recommend continuing some sort of agent, whether it's shorter acting than what they're currently on, just to prevent any sort of post-operative hypertension, arrhythmias, so kind of in line with what the current guidelines say. Excellent. Well, seeing no other questions, that will conclude this Q&A session. Thank you very much, Joanna. And now I would like to introduce our final presenter, Hannah Frank. Hello, everyone. Thank you for the introduction. As stated, my name is Hannah Frank. I'm a PGY-2 critical care resident at UW-Madison in Seattle, and today I'll be discussing the utility of adjunctive agents in patients receiving IV thrombolysis or acute ischemic stroke. As we're all very well aware of, I'm sure, acute ischemic stroke remains a leading cause of death and disability both here in the States as well as worldwide. And while we've had several advancements in therapy over the years in the treatment of stroke, our functional outcomes for these patients remain quite poor. As a means to improve these outcomes, there's been several agents that have been studied as an adjunct primarily to IV thrombolysis. However, some have been found to be harmful. There is some promising studies with our use of our Gotchervan as well as epistobatide. Just to quickly highlight, the current literature looking at both of these agents, and this is a study done specifically with our Gotchervan in patients receiving alteplase, where they found a trend towards improvements in overall modified Rankin scale scores as well as a similar incidence of adverse events and mortality compared to placebo. This was another study that was done on epistobatide in conjunction with a overall lower dose of alteplase compared to standard dose alteplase that had promising results overall with lower incidence of symptomatic intracranial hemorrhage and numerically better modified Rankin scale scores, but this is not statistically significant. In terms of where our current 2019 AHA-AHS guidelines for the early management of patients with acute and extreme stroke, where they land on these agents, they do specifically call out both epistobatide and our Gotchervan, however, have the caveat that the data is not well established and they don't have a direct recommendation or recommendation for the use of either of these agents. That then leads us into the study itself. The objective intervene is our Gotchervan or epistobatide for ischemic stroke study. The objective here was to evaluate the efficacy and safety of combining IV thrombolysis with our Gotchervan or epistobatide. This is a Phase III randomized single-blind adaptive control trial in the United States where they compared our Gotchervan, epistobatide, and placebo at those following doses there. As for randomization, it was quite unique. For the first 150 patients, they were randomized in a one-to-one-to-one style. For the subsequent 350 patients, they underwent this response adaptive randomization, where as new data was collected, there was an algorithm that determined whether or not one intervention had more promising results and then would randomize more patients into that treatment group moving forward. It's important to note that the same was true for the opposite. If patients were having poorer results overall, less patients would then be randomized into that group. Then over the 500-patient mark, they would then transition back to a standard either one-to-one or one-to-one-to-one ratio. Here's the inclusion and exclusion criteria for this study. I just wanted to call out specifically for our inclusion criteria. They included patients who either received alteplase or tenecteplase. However, these needed to be given within 3 hours of symptom onset, so could not have been at that extended four-and-a-half-hour mark. In terms of primary outcome, we had a primary efficacy and safety outcome here. For efficacy, it was a 90-day modifying Rankin score. This is a score ranging from zero, being functionally normal, to six, being death. These were then translated to patient-centered utility weights. These utility weights, a higher utility weight was used for the more optimal outcome, meaning that a score of 10 would be perfect health, and then zero could be death or worse than death. You can see the assigned weights here at the bottom, which were derived from previous studies that were conducted in the U.S. that utilized this type of outcome. As we can see, a score of zero or an MRF score of zero was associated with a utility weight of 10, and then going up to five and six had utility weights of zero. Primary safety outcome here was symptomatic intracranial hemorrhage within 36 hours of presentation at that definition. Some curtain and secondary outcomes to call out here as well, namely a change in baseline NAHS-IV, any intracranial hemorrhage or hemorrhage within 36 hours after randomization, and they also evaluated all-cause mortality at the 90-day mark. In terms of the statistical analysis, it was conducted in the intention to treat population. Interestingly, you'll notice that they adjusted the primary outcome based on baseline NAHS-IV, and they used what's called a Bayesian normal dynamic linear model, where here, theta-D represents the difference between modified or the expected modified Rankin score between the active treatment and placebo. Because they used what's called a vague prior, and because they used what's called a vague prior, this meant that if theta-D was a positive value, that would then denote a positive outcome. In order for a treatment group to be deemed effective, the posterior probability, or the PR value, would have had to be greater than or equal to 0.985. Moving into the results of the study here, as we can see, in terms of enrollment, we had 228 patients randomized into the placebo group, 59 patients in the argotraban group, and then 227 patients into the haptocipritide group. It's important to note, too, that the study here was stopped for futility after the first 500 patients had a 30-day follow-up. In terms of baseline characteristics here, just to call out, median age was around 68 years old, split pretty evenly between male and female sex. And then finally, to call out some key differences in the baseline characteristics, you'll notice that patients in the argotraban group were more likely to receive alteplase compared to tenactive place, and more of these patients had a large vessel occlusion, and more of these patients at baseline had a history of HIV-positive and more of these patients at baseline had a history of atrial fibrillation. As for differences in the haptocipritide group, you'll notice that prior use of antiplatelets before presentation was more common in this group as well. In terms of the primary efficacy outcome here of utility-weighted Vodafone Rankin scale scores at 90 days, you'll notice that there was overall limited difference, and with placebo having the most promising results overall. The PR values, notably, for argotraban was 0.002, and for episiphotide was 0.041, so not surpassing that greater than or equal to 0.985 that was required in order to deem either treatment group effective. In terms of the primary safety outcome here, which was symptomatic intracranial hemorrhage at 36 hours, you'll notice that there was also no difference in terms of percentages between each of these groups. Moving into some other pertinent secondary outcomes that were evaluated, you'll notice that for our 90-day Vodafone Rankin scores of either 1 or 0, as well as scores 0 through 2, based on the confidence interval for the argotraban group compared to placebo, placebo overall had better or more promising results here, whereas in the episiphotide group, you'll notice there was no difference between either of these. For pertinent secondary outcomes or differences that we noticed here, patients in the argotraban group did experience more intracranial hemorrhage, although not symptomatic at the 36-hour mark, compared to placebo in that episiphotide group, and then also we can see here that overall death from any or mortality of any cause at 90 days was higher in the argotraban group. And again, this is further kind of echoed by the fact that there were so few patients that were randomized into this group as a result of that adaptive randomization style. Here we can see the Kapler-Meier curve that they used for all-cause mortality just to get a peek at this further. So our argotraban group, just to call out, is this lighter gray value here, and as we can see, within the first week or so, the mortality rates are very consimilar. But as you can see, as the duration of time kind of continues over time, at around the 15-day mark, we see that ultimate drop in mortality. And as a result, the authors concluded that the use of IV anticoagulation or antiplatelet agents following thrombolysis for ischemic stroke is likely ineffective for improving functional outcomes. Moving into my own critique and understanding of the study results here, so as kind of to echo what the authors have said here, that argotraban and epizobatide were not shown to improve functional outcomes overall. And in fact, argotraban was shown to have higher rates of mortality as well as intracranial hemorrhage at 36 hours compared to placebo. Interestingly, in the manuscript, the authors do call out directly that the deaths within this group were not due to the drug. However, it did lack in an explanation of what those deaths were, not reporting out what the ultimate cause of mortality was, and leaves us a little confused on whether or not there was a specific trend in the types of mortality we saw in that group. Epizobatide had a much more neutral effect on functional outcomes and safety outcomes, but again, we saw that there was very little difference and likely not to be effective. In terms of strengths of the study overall, I felt that the study question was applicable to our current challenges that we have in the management of acute ischemic stroke. As I mentioned before, our functional outcomes for these patients remain quite poor. And so, based on the previous studies that we had saw, that indicated that there may be some benefit or at least safety data to show that argotraban or epizobatide may be helpful, but it's not quite as effective as we thought it would be. In terms of the patient population they selected for, I do think this is also applicable to our typical cohort that we see in our patients who do present with acute ischemic stroke here in the US, making it a bit more generalizable for the group, specifically for patients presenting with moderate stroke, as that was the most commonly presenting form of stroke. I do also want to call out the fact that I think it was a strength that they evaluated both patients who received alteplase and tenecteplase, as well as patients who did receive and did not receive thrombectomy. We've seen a lot of change and shift, I think, overall to prioritizing tenecteplase over alteplase, as well as trying to prioritize thrombectomy for patients who do qualify for it. So, I do think that was good that they evaluated that, as that was a change in practice that was happening at the time of the study. Another strength was the use of patient-centered outcomes here with the utility-weighted modified Rankin scale scores, however, with the caveat that this can still be considered a subjective scale overall. I do think that as we move forward with more data and more studies focusing on this original outcome, it will be interesting to see if those scores change. Moving into the limitations of the study, there were several. One of the bigger ones being that it was a single-blind design, meaning that the treating providers were aware of the assignment, which can certainly introduce bias into the study. They did blind both patients and their family members, as well as the physicians who were evaluating for functional outcomes. However, being that there was any unblinding in the study certainly could introduce bias. Unblinding in the study certainly could introduce bias. As I had mentioned before, as well, there were imbalances in the baseline characteristics in both the Argot-Gervain and the Epstein-Pesetai group. So, it makes it more challenging for us to say whether or not these differences could have contributed to the differences we saw in the overall outcomes and safety events. I do think it was a limitation, as well, that the etiology of stroke was under reported or was not reported in the study. It would have been interesting to see if a higher proportion of patients who, say, had cardiombolic stroke in one group or another could have affected the results of the study. As we saw previously, too, the census in the Argot-Gervain group was quite low, likely as a result of the adaptive response randomization indicating that there was a higher mortality rate in the Argot-Gervain group. And while this was meant to be a more patient-centered approach in terms of randomization, I do think it overall hinders the study in our ability to kind of evaluate what this actually means moving forward. Another limitation was that Argot-Gervain was administered at a flat dose rather than titrated to specific PTT values as it had been in previous studies. And although it was a relatively low dose overall, I do think it could have been beneficial to at least report out the PTT values to see if there was any trend towards those having higher PTTs and having a worse outcome overall. So, my overall key takeaway from the study here is that while I do think it was well-designed in regards to the targeted patient population that they selected for, there were several limitations in the study that I think impeded or confounded the validity of their results overall. As such, I do think this is unlikely to lead to any major practice changes. However, I do think it does raise concerns, potentially, with using Argot-Gervain for other indications within the specific patient population. And while I don't think that this is likely to lead to any practice changes, I do think that there's a possibility that in future stroke guidelines, we may see the results of this study reflected, particularly with a recommendation against using Argot-Gervain in the future. In terms of where to go from here and next steps in the literature, I do think it'd be nice to evaluate if there's any utility in patients not receiving thrombolysis with either alteplase or tenactoplase, almost using one of these agents as an adjunctive or a bridging therapy of sorts. It could be interesting also to evaluate utility in patients who received thrombolysis greater than three hours after the symptom onset, too, to see if there would be any change. Another important thing that I am looking forward to seeing in the future is kind of this transition to using utility-weighted modified rank and scale scores in the future clinical studies. And again, kind of evaluating what the overall American population and how they would kind of rank these modified rank and scale scores overall and seeing if that has any change. And I decided to leave my polling questions for last, so we'll get into those. First polling question for the group is, what is the primary thrombolytic agent that you use at your institution, either tenactoplase or alteplase? Okay, and so, as you can see here, the overwhelming majority of people are using Connect-A-Place at 92%, which is consistent with what I do at my institution as well. And we can see still a small proportion of institutions are also using Connect-A-Place too. So I'd say this is fairly consistent with what we saw in this study, although this practice change happened while the study was undergoing, or while it was going on. And then moving on to our second question here, which direct thrombin inhibitor does your hospital have on preliminary, either bivalrudin, argotrivan, or both? Okay, looking at the results here, it looks like the majority of institutions are indicating that they have both argotraban and bivalorudin on formulary. At my own institution, we actually only have bivalorudin, so had there been any difference with the argotraban or had there been any trend towards using argotraban, we certainly wouldn't have been able to do that. So I think it's interesting to kind of evaluate what different institutions have available to them in their toolbox and to see if that would have any effect on future studies overall. Okay, these are just my resources, and thank you all for your attention, and I'd be happy to answer any questions that you have. Thank you. First question is, thank you for going through some of the thoughts for future studies with regard to this topic, but I'm also curious, do you think there's any role for exploring other IV antithrombotic agents as adjuncts at this time, in addition to thrombolytics? Things like ivalerudin or terofenan or other drug classes? Yeah, I think that's a great question. I think primarily most of the data was looking at argotraben specifically, but knowing what we know about vivalerudin and its kind of probability to be within therapeutic range, especially compared to other agents like heparin and other things, it might be useful to see if there's any change that we can see with vivalerudin. As of right now, I'm not aware of any literature that's looking at that, but based on the results of this study, I imagine that will probably be limited, considering that they're from the same drug class. That makes sense. Thank you. And then my question actually was, I'm just curious about this utility weighted modified Rankin scale. I feel like I'm used to seeing mostly the standard MRS used, at least in classic stroke literature. Do you have any sense as to why the authors chose to use the utility weighted scale? Is there a benefit to using the scale over the standard one in clinical trials? That's a great question, and that's also a question that I had as well, and kind of digging into why this is becoming maybe more widely used in the literature. The authors specify that they just wanted to make it a more patient-centered approach, rather than looking at the overall just modified Rankin scale scores. And looking further to see if any other studies had used this approach, there was some interesting data indicating that depending on what utility weighted scale they used, or depending on whatever scores they decided to use, that could ultimately affect the results of the trial. So again, I think kind of moving in the future, making sure that we have a really solid understanding and a very consistent approach to assigning these scores will be very important if we choose to use these further. Okay, well thank you. I'm not seeing any additional questions. That will conclude this Q&A session. Thank you very much, Anna. And thank you to all of our presenters today, and 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. And that concludes our presentation today.

Webcast

Sepsis

Procedures

Neuroscience

Surgery

Stroke

Professional

Select

2024

FLUGRA study

septic shock

fludrocortisone

STOP or NOT trial

renin-angiotensin inhibitors

non-cardiac surgery

thrombolysis

acute ischemic stroke

individualized treatment