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 Brian Kopp, Surgical Trauma ICU Pharmacy Specialist at Banner University Medical Center in Tucson, Arizona. 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. 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 SCCM, CPP, JC, and hashtag PharmICU. SCCM provides the following disclaimer. This presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement, or opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are those of the presenters and do not necessarily reflect the opinions or views of SCCM. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion, or other information that may be mentioned. 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 Samuel Gundling, PGY-2 critical care resident at University Hospitals Cleveland Medical Center in Cleveland, Ohio. Our second presenter is Erin Chase, PGY-2 critical care resident at Augusta University Medical Center in Augusta, Georgia. And our third presenter is Sammy Marquart, PGY-2 critical care resident at Loyola University Medical Center in Maywood, Illinois. And now I'll turn things over to our first presenter. Thank you, Dr. Kopp, for the introduction. My name is Samuel Gundling, and today I will be presenting on the optimal sedation in patients who receive neuromuscular blocking agent infusions for treatment of acute respiratory distress syndrome. Acute respiratory distress syndromes, which I will refer to as ARDS, is an acute diffuse inflammatory form of lung injury. The 2019 ARDS guidelines provide recommendations based on expert opinion for patients based on the severity of ARDS. These guidelines recommend certain therapies based on the severity of ARDS. Today I will be discussing a study regarding the use of paralysis in patients with ARDS. Approximately 10 to 15% of patients requiring mechanical ventilation in the ICU suffer from ARDS, and about one-third to one-half of these patients die in the hospital. However, the reduction of mortality associated with ARDS over the last 20 years has improved due to the advancement of treatment options. In patients with ARDS, adjunctive treatment with paralysis can help reduce ventilator dyssynchrony and associated lung injury. However, paralysis carries certain risks and requires deeper sedation, which may further increase mortality. The ACQIRISIS trial was a landmark trial that studied the use of paralysis in patients with ARDS. This study included patients with severe ARDS, and they compared patients who received flat rate paralysis to patients who received placebo. Patients in each group received the same level of sedation, and they found a reduction in mortality in patients who received paralysis compared to the control group. They also did not find a difference in any safety outcomes. What they concluded was paralysis improved 90-day survival in patients with severe ARDS. The ROSE trial was a second recent landmark trial that investigated the use of paralysis in patients with ARDS. The ROSE trial was designed to be consistent with the ACQIRISIS trial using the same paralysis agent and the same dosing regimen. The key difference in the ROSE trial was the use of light sedation in the control group, which was consistent with current practice recommendations at the time of this study. The ROSE trial found no difference in mortality at 90 days between the two groups. They also saw a higher incidence of adverse events in patients who received paralysis. The researchers ultimately concluded that the use of paralysis in ARDS does not reduce mortality and is associated with an increased amount of adverse effects. So comparing these two landmark trials, the ACQIRISIS trial showed an improvement in 90-day mortality compared to patients receiving placebo with the same level of sedation. And then on the other hand, the ROSE trial showed no reduction in mortality in patients who received paralysis. Also, a lower positive end expiratory pressure was used in ACQIRISIS compared to the ROSE trial. And lastly, prone positioning was used more often in the ACQIRISIS trial compared to the ROSE trial. The study I'm looking at today is the optimal sedation in patients who receive neuromuscular blocking agents infusions for the treatment of acute respiratory distress syndrome. This was published in Critical Care Medicine in July of 2021. This was conducted at a single academic hospital network, and it was a retrospective study that occurred between 2008 and 2019. The primary outcome was in-hospital mortality, and the secondary outcomes include ventilator and ICU free days and vasopressor dose. Adult mechanically ventilated patients with ARDS were included in the study. Patients were excluded if they had a high risk for volume overload, had comfort care measures, or had missing data. So, this study utilized a mediation analysis to assess the direct and indirect effects of exposure on an outcome. In this study, the researchers investigated the effect of paralysis exposure on in-hospital mortality. They believed the proportion of deeper sedation indirectly mediated the negative effects of paralysis on in-hospital mortality. The proportion of deeper sedation was defined as a Richmond agitation and sedation scale of negative two or less, and the proportion of deeper sedation was also defined as a Riker sedation agitation scale of two or less. Bootstrap-bang resampling was used for the primary mediation analysis to assess the indirect effects of deeper sedation. To achieve power of 80%, this study required 3,419 patients. Other analysis performed include a multivariable logistic regression, linear regression, and negative binomial regression, and the results of these analyses were reported as adjusted odds ratio, adjusted coefficients, and adjusted rates ratios with 95% confidence intervals. To validate the accuracy of their approach, the researchers performed 100 chart reviews to identify patients with ARDS. Looking at our baseline characteristics, there were 3,419 patients with ARDS that were included in the original cohort. There were 16.8% of patients that received paralysis, and 83.9% of the patients in the original cohort did not receive paralysis for the treatment of ARDS. These patients differed by age, Apache score, positive end expiratory pressure, plateau pressure, and PA to FiO2 ratio. However, after propensity score matching, the baseline patient characteristics were similar between these two groups. There was a higher percentage of patients with severe ARDS that received paralysis compared to patients who had mild or moderate ARDS in the paralysis group. Looking at agents used for paralysis, a majority of these patients received cis-atriturium compared to different paralyzing agents. However, the specific dosing regimens were not reported. Patients who received paralysis had a significantly longer duration of deeper sedation and a higher proportion of deeper sedation within the first week after ARDS diagnosis. The duration of mechanical ventilation was also longer in patients who received paralysis. The mean duration of paralysis was 1.8 days. The graph below shows the percentage of patients receiving deeper sedation over the first week after ARDS diagnosis. The percentage of patients receiving proportion of deeper sedation was significantly higher in patients receiving paralysis within the first seven days after the ARDS diagnosis. So inpatient hospital mortality occurred in 43.5% of patients who received paralysis and in 32.7% of patients that did not receive paralysis. And this was the primary mediation analysis that they conducted. First, the investigators demonstrated that paralysis was or had an impact on in-hospital mortality. They used a model that did not include the proportion of deeper sedation as a potential confounder. In this model, paralysis was significantly associated with increased mortality. In the second step, the investigators added patients with a proportion of deeper sedation as a potential mediator to the primary covariate model. The addition of the proportion of deeper sedation to the model abolished and eliminated the association of paralysis and mortality. Finally, the investigators performed their mediation analysis. They calculated the influence of paralysis on the deeper portion of sedation. Next, they calculated the influence of deeper sedation on in-hospital mortality. Then they calculated the mediating effects of the proportion of deeper sedation. They found paralysis was significantly associated with a higher proportion of deeper sedation. In turn, deeper sedation was significantly associated with in-hospital mortality. The effect of paralysis on in-hospital mortality was completely mediated by the indirect effect of proportion of deeper sedation. Patients who received paralysis had significantly fewer ventilator free days and fewer ICU free days compared to patients who did not receive paralysis. The use of paralysis was also significantly associated with an increased vasopressor dose. The study conducted the mediating effects on proportion of deeper sedation on the secondary outcomes. Ventilator free days and ICU free days were mediated by the proportion of deeper sedation in patients who received paralysis. However, vasopressor use was not mediated by the proportion of deeper sedation in patients who received paralysis. The study performed a subgroup exploratory analysis on patients who exclusively received higher proportion of deeper sedation. These patients had a RAS of less than negative three or a Riker sedation agitation scale of less than two. There were 1,539 patients who received deeper sedation. 28.9% of these patients received paralysis and 71.1% did not receive paralysis. And in the patients who received deeper sedation, the use of paralysis was associated with a lower in-hospital mortality. In a separate subgroup analysis, investigators conducted a one to two propensity score based analysis that matched patients who received paralysis and those who did not receive paralysis. This subgroup analysis confirmed that a high proportion of deeper sedation mediated the effect of paralysis on in-hospital mortality. The study also looked at a different subgroup of patients who had a PA to FiO2 ratio of less than 150. Having a PA to FiO2 ratio of less than 150 was part of inclusion criteria for both the accuracies and ROSE trial. In these patients, deeper sedation mediated the effect of paralysis in-hospital mortality. The author concluded high proportions of deeper sedation was associated with increased mortality. However, they also concluded deeper sedation mediated the effects of paralysis on mortality, ventilator-free days, and ICU-free days. Lastly, they concluded paralysis was beneficial in patients requiring deeper sedation for ARDS. The study's hypothesis was clinically relevant because two previous landmark trials have been conducted on the use of paralysis in patients with ARDS. However, these studies had different results potentially due to different sedation regimens. This study was also published after a recent sedation and paralysis guidelines were published for ARDS. Naturally, a limitation of the study was the retrospective design as it leaves potential for information and recall bias. However, this study was able to achieve power with the size of the study population. Similar to the flaws of a retrospective analysis, a mediation analysis design has the potential of unidentified confounders. A strength of this study was the propensity score matching to adjust for baseline differences. Another strength of this study was they did a subgroup analysis on patients who were included in the accuracies trial and the ROSE trial. Another strength of this study was it used similar outcomes of previous landmark trials. However, there was no safety-related outcomes measured regarding sedation or paralysis. The study included a large number of patients that were similar to previous landmark trials and had similar inclusion and exclusion criteria. Lastly, the study was conducted at a single hospital network, which provides weak external validity. It is also hard to apply these findings to different institutions' practice as the sedation and paralysis regimens were not reported in this study. So the clinical interpretation of the study is patients with ARDS receiving paralysis, a high proportion of deeper sedation is associated with increased mortality. The proportion of deeper sedation mediated ventilation in ICU-free days, however, vasopressor use is not mediated by deeper sedation. Lastly, deeper sedation should be minimized after paralysis stops. Based on this study, my takeaway points are paralysis should only be used in patients who require deep sedation for the treatment of severe ARDS. The study was able to find deeper sedation as a potential mediator for the different findings between the two landmark trials, ACQUIRIS's and the ROSE trial. In the future, further studies are needed to determine the benefit of paralysis for patients with severe ARDS. To conclude, recently a new rapid practice guideline has been published on the use of paralysis. These guidelines are consistent with the findings of the study where paralysis should be reserved for patients with ARDS requiring deeper sedation. My first polling question is, are the results of this study likely to change your current practice related to paralysis and deep sedation? So, a majority of you responded with no, which is not surprising as there were several flaws with this study, including not reporting their sedation or paralysis dosing regimens. Moving on to polling question number two, so what paralysis regimen is currently used for ARDS at your institution? So, majority of people responded that they use a titrated train for cis-atropurium regimen followed by different paralysis regimens. Thank you for attending my presentation. At this time, I will take any questions from the audience. Yeah, thank you for that presentation, Dr. Goepp. I'm interested, you talked about, you know, future research and how you would design a trial. I'm interested in what you would want to, you know, in terms of the next steps, since we do have at least somewhat conflicting data with the ROSE and the acuresis trials, what would be maybe a thing that you would change on a future prospective randomized control trial? So, what I would look for in a study is for it to be a multi-center study. That way, external validity could be applied to practice across different institutions. I would also want it to be a prospective study, which would be difficult to implement. And I would also want to look at different dosing regimens of paralysis. And I would specifically want to look at patients who received deeper, patients who received similar sedation regimens. So, that's what I would look for in a ideal study on paralysis and sedation for ARDS. Yeah, this one should go pretty quick here. I got a question from the audience. The question is, is this pre-COVID, the study in terms of when it was completed? Yes, that's an excellent question. So, this study was conducted from 2008 to 2019. So, this study was conducted right before the pandemic hit. So, these patients did not include patients with COVID-19. All right. That concludes our Q&A question session for this. Thank you, Samuel Gundling, for your presentation. Thank you. Before we move on to our next presenter, we would like to ask a brief polling question regarding today's attendance to gain a better understanding of our overall attendance to ensure continued support of this Spotlight on Pharmacy webcast. And now I'd like to introduce our second presenter, Aaron Chase. Hi. Thanks for the introduction. Yeah. I'm Aaron Chase. I'm a PGY2 at Augusta University Medical Center, and today my presentation is on the CHARLI study or nebulized heparin for patients with or at risk for acute respiratory distress syndrome, or ARDS. Just to give a little background on ARDS, roughly a quarter of ventilated patients that develop will develop ARDS, so it's a very common disease state for patients that are mechanically ventilated, depending on which publication you look at. You get a few different numbers, but it is a pretty high rate of patients. Also, the patients that do develop ARDS have a mortality rate. Up to 50% of patients will die that develop ARDS in the severe range. And then the people that do survive and leave the ICU, a lot of them have typically a poor functional outcome due to multi-organ dysfunction and lung dysfunction and just their ICU stay, and it's a pretty long recovery. There are only a few therapies that have demonstrated and improved mortality and decreased that rate, like dexamethasone, low tidal volume ventilation, and conservative fluids. However, a large gap in the literature and our treatment of these patients is that nothing has been shown to prevent, no specific drug has been shown to prevent the development of ARDS for patients who are at risk or speed up the long-term recovery once they survive and leave the hospital. So that's really why this study was conducted to look at these two endpoints. A little bit of background on why the authors may have chosen the regimen that they did. So it's nebulized heparin. So to the right, we can see here is an alveoli. And if you look towards the right of this diagram, you'll see fibrin deposition in a hyaline membrane. This is a hallmark of ARDS. What the fibrin does is a few things. It gives macrophages a place to sit and kind of facilitate inflammation, which is a big portion of ARDS, but these fibrin sheaths also can cause microthrombi in the tiny vessels and the capillaries around the alveoli, which is a bad prognostic indicator in itself for ARDS and its severity. These fibrin sheaths also decrease overall elasticity and compliance of the lungs, which is bad for a patient on the ventilator and also bad for long-term sequelae of ARDS when they're trying to recover and they don't have their full lung function. Heparin specifically targets fibrin deposition and the fibrin clot formations. So that's the mechanism behind why it may work if you inhale heparin for ARDS. The investigator study hypothesis was nebulized heparin will decrease the development of ARDS in patients at risk, and then for patients who have ARDS or are at risk, it will speed up their self-reported recovery at 60 days at those at high risk for developing ARDS. The interventions that they chose, as I mentioned before, was heparin, and it was 25,000 units, so a fairly large dose nebulized every six hours for up to 10 days or until they were extubated, and then a placebo of 5 mLs of normal saline every six hours in the same fashion. This was a multicenter, randomized, double-blind, and placebo-controlled trial, and it was conducted in Australia at nine hospitals. They included patients who were adults and they had to be mechanically ventilated. They also had to have a P to F ratio of less than 300 on randomization, so already some sort of lung damage and oxygenation issues going on. They also had to be intubated within 24 hours prior to randomization, so it was very early in their course of mechanical ventilation so that we can get to them early and prevent any damage that may happen or have already happened. They excluded patients with any kind of coagulopathy, uncontrolled bleeding, or heparin allergy, so anything that would preclude you from receiving heparin normally. And then patients with ECMO, chronic dialysis, and nerve damage were also excluded, among a few other things that may change a patient's perception of their functional outcome, which was their primary outcome. The investigator's primary outcome was a physical function score at 60 days, and it was through the SF-36, which SF-36 is a scale of 0 to 100. It's a survey that a patient takes, so it's a patient-reported outcome on a scale of 0 to 100, and it has several sections. Some of these include perceptions of one's own health, limitations in their activities of daily living, emotional well-being, social functioning, and also their perception of their pain. So this was the primary outcome, and the investigators stated that a 10-point reduction would be a clinically relevant change in this score. Some of the select secondary outcomes that they did pre-specify were new development of ARDS at day 5 via the Breland criteria, decrease in the Murray Lung Injury Score, or LIS, at day 5. And the Murray Lung Injury Score is a score of 0 to 4, 4 being the worst, and above 2.5 being considered a severe lung injury. Some others were duration of mechanical ventilation and length of ICU stay or ICU days. The safety outcomes that they assessed were bleeding, specifically pulmonary bleeding with any deterioration of function, and then heparin-induced thrombocytopenia as these patients were receiving nebulized heparin. Before the study, they did do a power calculation, and they found that they need 256 patients for 80% power and a type 1 error of 5%. The analyses were all done with intention-to-treat principle, which is good. So we are able to be a little bit more confident if we did see a benefit. And then depending on the type of data and type of variable that they had, they conducted the appropriate tests in their analyses. The patient demographics are seen here. So patients were roughly a middle-aged population, average about 58 to 59 in each group. They're about 60% male, and the baseline P-to-F ratio on randomization for both patients who had ARDS and patients who didn't have ARDS but were at risk was 185. So this falls within that moderate severity of lung injury. About half of the patients were at risk for ARDS, and about half of the patients actually had a diagnosis of ARDS, so we had a pretty heterogeneous population here. And then the Murray Lung Injury Score for at-risk patients was lower than the patients who had verified ARDS, which is to be expected. It's also notable to mention that the causative factors of ARDS, or the risk factors for those who are at risk, were primarily pneumonia, with about 70% of patients having pneumonia, 15% having sepsis, and then 15% having other causes. The average APACHE score in this cohort was about 24 to 25, which correlates to about a 40% mortality to give you an idea of how sick this population was. Moving on to their outcomes, the primary outcome the investigators did not find any difference, no significant difference at least, in the SF-36 score at 60 days between those who received heparin or placebo. They did not meet that 10-point drop in SF-36 score. However, they did see some interesting things with the pre-specified secondary outcomes, such as new development of ARDS at five days. What they found is that patients that received the nebulized heparin actually developed ARDS less than those who received placebo, and you can see the hazard ratio here is 0.46. They also saw that there was less deterioration of the Murray Lung Injury Score, with a between-group difference of about 0.1 points on the Murray Lung Injury Score. For other efficacy outcomes, they did not see any difference in length of stay, ventilator outcomes, or mortality. And all the safety outcomes were similar. There was no difference in major bleeding or deterioration from pulmonary bleeding. However, APTTs were significantly higher in the patients who received the inhaled heparin. Overall, I think this trial was well-conducted and well-thought-out. So there were several strengths of it. One, of course, is that it's a randomized controlled trial, so we can establish some kind of causality from the results. And then one of the really big advantages, I think, is that this is one of the first trials that focuses on long-term recovery and prevention of ARDS, which is very important because, as I mentioned before, this is a large gap in the literature. There's a lot of focus on how do we reduce mortality in patients that have ARDS, but if we can prevent it, then we don't have to focus on that. So I would applaud the authors at looking at prevention of ARDS. And then these groups were really well-balanced via the baseline variables. There were, however, some limitations, one of the big ones being it's a heterogeneous population with about half having ARDS and then half being at risk, so it kind of muddies the picture of what we're looking at. It may have been better to split these up into two different trials. Also, the primary endpoint may not be the most revealing, as it is a patient, a very subjective patient-reported function of their well-being and their health, which is very important, but I think that it would probably be better to have a more objective lung function score, such as a pulmonary function test, to go along with it as a composite to really let us know how did heparin affect the lungs and the pulmonary function, because this is how we would think that it would affect it. And also 60 days was their primary endpoint for recovery of function. And this seems a little bit early, as when people leave the ICU, especially ARDS patients, it can take several months for them to really recover a lot of their function. So potentially pushing this endpoint out a little bit further could be appropriate. And then the other were positive secondary outcomes. These weren't adjusted for multiplicity, so we have to take them as exploratory outcomes and can't exactly take them as they are. So it needs a little bit more analysis, in my opinion. At this point, I would like to do some of my polling questions. So first one's easy. Question one, true or false, patients who received nebulized heparin had a better functional score at the end of the study period at day 60. All right. Sounds good. So most of us got this right. One person picked true, so you weren't listening, but that's all right. But, yeah, so they did not see a difference in the functional score at day 60. Next, let's see. All right, so question two, this study reported a significantly lower rate of ARDS development in at-risk patients. So based on these results, currently nebulized heparin should, A, be recommended for prevention of ARDS in mechanically ventilated patients, or B, may prevent ARDS in patients but needs some future studies to evaluate it so we can be really sure. Great. So everybody picked the answer that I would. I think that there are, it is really promising that we did actually decrease the development of ARDS in this trial, but because there were relatively small groups and it wasn't adjusted for multiplicity, it really needs to be replicated in larger trials for us to apply this to practice. So I agree. All right, so the primary takeaways from this, I believe my conclusions are not enough evidence to really recommend use at this time, whether it be for functional score or for prevention of ARDS. However, these exploratory secondary outcomes really do warrant more research and are pretty exciting. If we calculate the number needed to treat from what the authors reported, there's only a number needed to treat of seven with heparin with relatively low risk to prevent one case of ARDS, which is a disease with high mortality and morbidity. So once future trials are conducted, this could be a really promising intervention. So I think the next steps would be a similar study, but with more objective assessments of the primary outcome, whether that be pulmonary function tests alone or pulmonary function tests in conjunction with a functional score, and then possibly assessment of ARDS prevention specifically as a primary outcome, because if we prevent it, then we don't have to treat it. And that concludes my presentation, and I can take any questions that anybody has. Thank you, Aaron. It looks like we got a couple of questions here from the audience. First question is asking to comment on the dose that heparin shows in, since it appears as though it was much higher than some of the data with particularly burn inhalation injury. Yeah, so I did realize this is a very large dose of heparin. This is essentially what comes in a bag of heparin that will infuse in patients. There are some preliminary studies that show why they use this, and they have some preliminary data. And it is higher than the burn data. I believe they use only 5,000 units there. But what they got this dose from were some, not dose finding, but I don't know what they call the study, exploratory studies. And they did develop this dose from that in a similar study and saw benefit with it. Okay, looks like we got time maybe for one more. Have you seen literature using other thrombolytics for this or anticoagulants, and do they feel they might prove to be better or have better benefit? So, I haven't really seen any literature for nebulized, like other nebulized anticoagulants. If we're thinking things like low molecular weight heparins or things with lower molecular weights in general, I think it may be a little bit more dangerous and maybe have a few more bleeding episodes because they're smaller molecules. While heparin's large, so there would be a little bit more of systemic absorption. Because even we saw in this trial, there was a good bit of systemic absorption because the average APTT was higher in the heparin group versus the placebo, and heparin's a giant molecule. But no, I have not seen any other literature about other antithrombotics. Anything specifically with thrombolytics? Oh, thrombolytics. Yeah. No, no, no. Sorry, I misunderstood. No, I have not seen anything with thrombolytics specifically. I think this may be the last question here. Do you have information on the PTTs in the treatment group? What were they? Yeah, so what they reported in the treatment group, let me look back, I think it was significant, but it was 69 versus 51 is what they reported in the heparin group versus the placebo group. I agree and appreciate that, Aaron. This concludes our Q&A session. Thank you again, Aaron Chase. Now I'd like to introduce our final presenter, Sammy Marquardt. Thank you for the introduction, and good afternoon, everyone. My name is Sammy Marquardt, and I am a PGY2 critical care pharmacy resident at Loyola University Medical Center in Maywood, Illinois. The journal article I will be presenting today is the effect of endovascular treatment alone versus IV alteplase plus endovascular treatments on functional independence in patients with acute ischemic stroke, otherwise known as the depth-randomized clinical trial. The objectives of my presentation include to first, describe the role of IV thrombolytics and endovascular treatment in acute ischemic strokes. Two, review the literature on IV thrombolytics with endovascular therapy compared to endovascular treatment alone. And then three, interpret the results and applicability, strengths and limitations, and the final conclusions of the trial. The two reperfusion therapies of proven benefit in acute ischemic strokes are IV thrombolytics, such as IV alteplase, and mechanical endovascular thrombectomy. The 2018 and recently updated 2019 AHA and ASA guidelines recommend the use of IV alteplase in all eligible patients. In addition, the guidelines recommend the use of alteplase even if mechanical thrombectomy is being considered. Mechanical thrombectomy is indicated in patients only with large artery occlusions. Previous literature suggests equivalent effects on endovascular treatment alone versus endovascular treatment combined with standard alteplase treatment. The first trial that I'd like to review is the DIRECT-MT trial that included 656 patients in a multi-centered, randomized, non-inferiority trial. And they compared endovascular treatment alone versus combination therapy with alteplase and endovascular treatment. The patients included had internal carotid artery, or ICA, and middle cerebral artery, or MCA, M1 and M2 segment occlusions. And this trial found that endovascular treatment alone was non-inferior to alteplase regarding the functional independence, which was defined as a modified ranking score of zero to two at 90 days. The next study is the SKIP trial, which included 204 patients in a multi-centered, randomized, non-inferiority trial. It also compared endovascular treatment alone to the combination therapy of alteplase plus endovascular treatment. Patients in the IV thrombolytic arm received alteplase at a dose of 0.6 mg per kg, which is one dosing scheme approved in Japan, but is lower than the standard 0.9 mg per kg dose used elsewhere. The patients included had ICA or MCA, M1 segment occlusions only. The trial failed to demonstrate non-inferiority on the primary outcome of proportion of modified ranking score of zero to two at 90 days. So the results of these studies lead to the question on if there is benefit to the use of IV thrombolytics in eligible patients prior to endovascular intervention. The advantages to IV thrombolytics is possible improved reperfusion with the combination of both pharmacologic and mechanical dissolution of the class, whereas the risks lie in the increased risk of hemorrhage and the higher unnecessary treatment costs. So I'm going to pause here for my first polling question. Would the patients at your institution undergoing thrombectomy still offer IV thrombolytics if eligible? Okay, and it looks like 62% of you guys answered A, which is likely 80% of patients are still being offered ibuprofen ombilitics, even if undergoing thrombectomy, which is a very interesting answer. And I would like to say that by the end of my presentation that this trial will probably add more evidence out there as to whether we should be offering these patients ibuprofen ombilitics or not. Okay, so the trial we'll be presenting is the DEFT trial. And the hypothesis of my trial is that endovascular treatment is not inferior to combined alteplase plus endovascular treatment on functional independence in patients with proximal anterior circulation occlusions treated within 4.5 hours of onset of stroke symptoms or last known well. This trial set out to address the gap in the literature on the effects of these two therapies on more difficult 2-3 occlusions and also the difference in fixed non-inferiority margins that were present in previous studies. The DEFT trial was a multi-center, prospective, randomized, open-labeled trial conducted across 33 stroke centers in China. Patients included arrived with symptomatic anterior circulation ischemic stroke with onset of symptoms within the last 4.5 hours. The patients required a CT or MRI-confirmed ICA or MCA M1-only occlusion and then were randomized to alteplase plus endovascular treatment and then or endovascular treatment alone. Patients were assessed on their functional independence at 90 days and there was a central evaluation on the primary outcomes in which these evaluators were blinded to treatment groups. Patients in the combined treatment group received standard alteplase at a total dose of 0.9 mg per kg and then all the patients received endovascular treatment consisting of the options listed here under endovascular treatment. The patients included in the trial were all adults with symptoms onsets of 4.5 hours and they had to be randomized into the trial within 4 hours and 15 minutes of their symptom onset. All patients were required to be eligible to receive alteplase and needed an inclusion of the ICA or MCA M1 segment conferred by CT or MRI imaging. Patients excluded were CT or MRI evidence of hemorrhage, mass effects, cerebral vasculitis, AVMs or aneurysms. In addition, they were excluded if they had a modified rating score of equal to or greater than 2, arterial disease that would prevent the thrombectomy to reach the target vessel, pre-existing neurological or psychiatric diseases, and occlusions of multivascular territories or MCA M2 occlusions. Patients with a life expectancy of less than 6 months were also excluded. The primary outcome of my trial was that functional independence at 90 days defined as a modified rating score of 0 to 2. The secondary outcomes evaluated were the rate of excellent outcomes or a modified rating scale score of 0 to 1, quality of life, and disability. The secondary outcomes also evaluated vessel reperfusion on CT or MRI imaging within 48 hours and then changed an NIH score from baseline to 24 hours and 5 to 7 days. The post-hoc analysis performed looked at the rates of successful reperfusion before endovascular treatment and the rates of asymptomatic and symptomatic intracranial hemorrhage. The sample size was calculated to be 970 patients, which took into account 80% statistical power and a 5% attrition rate. The sample size of 970 patients was broken down to a five-interim group sequential analysis plan, and the first interim analysis was performed after 20% of the sample size completed their 90-day follow-up. The proportion of patients achieving functional independence for the endovascular thrombectomy alone group exceeded and crossed the pre-specified boundary that was determined for early termination, which the steering committee accepted the recommendation to conclude the trial at that point. The sample size calculation and non-inferiority margin for the primary outcome was made assuming that 43% of patients in both groups would achieve functional independence at the 90-day follow-up, and this was according to previous studies. Among the patients comparing endovascular therapy to the combination therapy, the lowest proportion of patients deemed to achieve functional independence was 33% in the endovascular treatment group. So, taking the difference of the lowest proportion of benefits seen at 33% in other studies compared to the assumed 43% average, the non-inferiority margin was set at a difference of negative 10% as the clinically relevant limit for the outside bounds of the confidence interval. We also looked at adjusted odds ratio for the primary outcome, and the secondary outcome used logistic, original logistic, or linear regression model, and a Kaplan-Meier method for mortality. Moving on to the results of the trial, the baseline characteristics between the two groups were similar. The differences I like to highlight was the pre-stroke modified ranking score of 1 was higher in the combination group in comparison to the endovascular treatment group alone. In addition, the arrival to IV alteplase time was 61 minutes in the combination treatment group, and then the arrival to puncture time for endovascular treatment was similar between the groups, with the combination group receiving around a 40-minute delay from the start of alteplase to the beginning of thrombectomy. At the 90-day follow-up, 54.3% in the endovascular treatment alone group compared to 46.6% of the patients in the combination group achieved functional independence at 90 days, with a difference of 7.7%. Now, the lower bound of the confidence interval here at negative 5.1% was greater than the pre-specified non-inferiority margin of negative 10%, which demonstrated that the endovascular alone group was not inferior to the combination treatment group. None of the secondary outcomes differed between the groups significantly. However, you can see the endovascular treatment alone group had a greater percentage of patients with excellent outcomes at 90 days, defined as a modified rating score of 0 to 1. In regard to the safety outcomes, mortality and rates of symptomatic hemorrhage were similar between groups, and interestingly, the rates of asymptomatic intracranial hemorrhage and clot migration were higher in the combination group compared to the endovascular treatment group alone. So, the authors' conclusions were that the endovascular treatment alone is not inferior to IV alteplase plus endovascular treatment on 90-day functional independence. The authors compared the rates of 90-day functional independence between groups in previous trials as well and found them to be similar. The reasons for any differences in the primary endpoint between trials was potentially due to decreased frequency of the ICA occlusions, the more favorable collateral status, and the exclusion of MCA-M2 occlusions that were present in our trial. The authors also emphasized the rates of intracranial hemorrhage among the combined treatment group were pretty similar between other published studies. The strength of the trial was the design as a multi-center randomized trial, and the primary outcome that is patient-centered with the modified rating score is another strength of this trial. The baseline characteristics were well-balanced between the groups, and the sites were experienced with endovascular therapy, another benefit of the trial. Also, the outcome assessors and radiologists were blinded to the treatment groups. In addition, there were no patients lost for a 90-day follow-up. Some limitations to the trial include that it was stacked early for efficacy at the first interim analysis, which does create the potential for overestimation of the effect size. It also had a liberal and broad non-inferiority margin at 10%, and this has not reached a consensus in the clinical community and may lead to concerns about the robustness of the study results. Another weakness is the median time from hospital arrival to IV alteplase of 61 minutes, which is more than the goal time of door-to-needle of less than 60 minutes. The trial was a multi-center trial, but across China, which means that there was an uncertain generalizability beyond Asian patients, who, as a population, has a higher incidence of intracranial atherosclerotic disease compared with Western populations. And finally, the difficult-to-treat ICA occlusions were not as common in this trial compared to others, which may overestimate the treatment effect as well. The disadvantages to consider between both therapies is the availability of thrombectomy and how it is limited to centers that offer and are experienced with performing thrombectomies. In addition, the time to puncture with thrombectomy typically is longer than the time to start IV thrombolytics, whereas the disadvantages to IV thrombolysis are increased risk of hemorrhage, increased cost, and there's a controversial benefit of IV thrombolytics that this study and previous studies are beginning to reveal. And then in this trial, the factors that may have possibly favored the benefits seen in the endovascular treatment alone is the rate of clot migration and asymptomatic intracranial hemorrhage seen in the combination group. So my takeaway points begin with the design of the study. The non-inferiority design allowed the trial to prove that endovascular treatment alone is just as good as combination therapy. Although the liberal and broad non-inferiority margin of 10% does not have a consensus in the clinical community, this is something to take into consideration when evaluating the results of this study. In addition, it's important to consider the limited generalizability of the study to the Western population as well. The study did determine that thrombectomy alone has equivalent benefits to combination treatment, which may influence clinical practice. The practice at the institution I work at, I've noticed a trend to the use of endovascular treatment alone in comparison to IV thrombolytics with endovascular treatment. And then in terms of next steps to advance our clinical practice in the treatment of acute ischemic strokes, I think it would be interesting to compare the IV thrombolytics connected place with combination therapy with endovascular treatment versus endovascular treatment alone. And then at the conclusion of my presentation, I would like to pull my last question, which is, have you noticed at your institution a trend towards a change in practice in the recent years? Okay, it looks like the majority of you guys said the answer C, that you are still seeing endovascular treatment plus connective lace being used. Okay, and that is the conclusion of my presentation, and I'm available to take any questions, and thank you all for being here today. It looks like we're just about out of time here, but does any of the audience have a quick question they want to type into the question section? Looks like nothing's coming across, so you must have done a great job, Sammy. So, appreciate all the input. This is gonna conclude our Q&A session. Again, appreciate your presentation, Sammy Marquardt. Great job. Thank you so much. Thank you. Yeah, thank you to all our presenters today and the audience for attending. Please join us on third Friday of the month from 2 to 3 p.m. Eastern Standard Time for the next Journal Club Spotlight on Pharmacy. That concludes our presentation today.

sedation

acute respiratory distress syndrome

ARDS

neuromuscular blocking agents

ACURISIS trial

ROSE trial

mortality

nebulized heparin

functional independence

endovascular treatment