Hello and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine CPP section. My name is Jen Tharp, Critical Care Pharmacy Specialist at Johnson City Medical Center in Tennessee, and I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log into mysccm.org and navigate to the My Learning tab to access this recording. 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 on the bubble next to your choice. You may also follow and participate in the 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 the 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 Jacob Gregory, PGY-2 Critical Care Resident at WellSpan York Hospital in York, Pennsylvania. Our second presenter is Nicole Leshko, PGY-2 Critical Care Resident at Penn Presbyterian Medical Center in Philadelphia, Pennsylvania. And our third presenter is Mariam Naveed, PGY-2 Critical Care Resident at University of Chicago Medicine in Chicago, Illinois. And now I'll turn things over to our first presenter. Thank you very much. Good afternoon, everybody. My name is Jacob, and today we will be reviewing an article recently published in JAMA titled The Effects of Vasopressin and Methylprednisolone versus Placebo in Return of Spontaneous Circulation in Patients Within Hospital Cardiac Arrest. A brief background and review of cardiac arrest, there are four main rhythms associated with cardiac arrest. These are asystole, PEA, V-fib, and V-tach, which can be subcategorized into shockable and non-shockable rhythms. Recently, the American Heart Association and European Guidelines have published their algorithms as to how to approach each subgroup of rhythms. And as you can see here, it's a combination of shocking and medication administration. The medications administered for cardiac arrest are few. There is epinephrine for all rhythms. And then for our shockable rhythms, there is amiodarone and lidocaine. Using this information, the authors of this trial and previous trials have tried to attempt to see if there are any other medications that can be utilized to help increase our success in attaining ROSC. As we look into previous trials, there are two main trials titled the VSE trials, looking at vasopressin, steroid, and epinephrine. The first of these trials were published in 2009. It was really a proof-of-concept trial with a relatively small end of 100 patients, and this was done in a single center in Greece. These patients had no prior corticosteroid administration, and all patients suffered an in-hospital cardiac arrest. The intervention group was given vasopressin, 20 units, IV, along with epinephrine, 1 milligram, for every CPR cycle, notably up to five cycles, and only received methylprednisolone, 40 milligrams, during the first epinephrine administration. And only if ROSC was achieved did they receive 300 milligrams of hydrocortisone after the fact. The control in this group did receive standard of care of epinephrine, 1 milligram IV, per CPR cycle. The clinical outcomes included a benefit in ROSC, 81% versus 52%, survival to discharge with a difference of 15%, and a cerebral performance category score, incidence of a score of 1 to 2. This was collected, however, it was not reported. The findings of this trial proposed a, here we are, an additional much larger trial of three institutions, with a much larger end of 268 patients, and this was published in JAMA years later. Again, you'll find that the population was identical to the previous trial, as were the study designs, with the use of vasopressin and methylprednisolone, along with hydrocortisone after the fact. The outcomes from this trial did show, once again, a benefit in ROSC, as well as a benefit in survival to discharge, with a CPC score of 1 to 2. Understanding that there might be some benefit into using vasopressin and methylprednisolone, when updating the guidelines, the American Heart Association did acknowledge these trials, however, found that it wasn't completely consistent with other case reports that have been also published in the literature, and felt that a much larger, more robust trial was needed before making a formal decision as to whether or not vasopressin and methylprednisolone should be utilized in the setting of in-hospital cardiac arrest. Which really leads us to the current trial we're reviewing today, which was conducted by Anderson and colleagues. So once again, the purpose of this was to determine whether the addition of vasopressin and methylprednisolone will increase return of spontaneous circulation, when compared to placebo or standard of care, and the authors did feel that this addition would increase the opportunity of ROSC. Looking at the methods for this trial, the study design is nearly identical to those in the past, as were the inclusion and exclusion criteria, as you can see, they included patients 18 years or older, those who suffered an in-hospital arrest, obviously, and received at least one dose of epinephrine during their arrest. Reasons for patients to be excluded from this trial included an out-of-hospital arrest, known or suspected pregnancy, previous enrollment, those with DNR prior to arrest, or the use of mechanical circulatory system. Just to show everyone a figure of what the study design was, as you can see, it's identical to those we've previously mentioned from the VSE trials, with one administration of methylprednisolone 40mg once, with the first administration of epinephrine, along with vasopressin, with each epi administration up to five cycles. With the notable difference being, there was no 300mg hydrocortisone administered for patients who attained ROSC in this trial. The outcomes for this trial are obviously ROSC, but also survivability at 30 and 90 days, a cerebral performance category score, which for those of you who might not be familiar with it, it is essentially a level of function test where scores 1 and 2 are defined as individuals having normal living or living with sufficient function for daily living. Whereas for our quality of life assessments, they utilized the EQ5D5L index, which considers patient factors such as their level of mobility, self-care, ability to perform usual daily activities, pain or discomfort, along with anxiety and depression. Their statistical analysis, continuous outcomes were reported as means with standard deviations and 95% confidence intervals, and medians with interquartile ranges. Primary and key secondary outcomes were analyzed using a Fisher exact test. Looking at our patient population, as you can see, the average patient was in their 70s, male, and history of arterial hypertension, and a breakdown of their medical history, you can see is quite in line with most of our patients that we see here in the States. Oops, apologies. Cardiac arrest characteristics, you can highlight it in right here for you. You can see the majority of the patients were on floor. These were not necessarily, majority of these patients were not necessarily our ICU or ED population, as well as the most likely rhythm for cardiac arrest in these patients was PEA, and as you can see there was a slight difference between epinephrine administration and trial drug administration, with the average epi time being five minutes and direct trial drug administration being eight or nine minutes. Transitioning into the results and authors conclusions, the authors were able to show that there was a 9.6% benefit to receiving vasopressin and methylprednisolone over the standard of care, and this was statistically significant with the p-value of 0.03. However, secondary outcomes such as survivability, neurological outcomes, and quality of life assessments were not able to prove that, show benefit. A subgroup analysis that the authors did perform showed one interesting point, and this was the time from arrest to trial drug, as I have highlighted in red here. As you can see, patients who received the trial medication administration less than eight minutes, compared to greater than eight minutes, did have an improvement from 33 to 51%. This was not necessarily powered for significance, and I think this is thought-provoking and could be analyzed in future trials. As for the authors conclusions, vasopressin and methylprednisolone significantly increased the probability of RASC. There was no benefit in survival or neurological function, and there were no significant differences in adverse drug effects. As for my critique of the trial, I felt that the authors did a great job being consistent to the prior studies and incorporating standard of care. The outcomes they used supported the aims of their hypothesis. Their inclusion and exclusion criteria were appropriate based on prior studies, and there was a low risk of bias affecting the results of the trial from a study design perspective on the authors behalf. As for some opportunities for improvement, the authors did discuss in their conclusions that the outcomes of this trial may vary based on different regions throughout the world, based on Denmark having better cardiac outcomes than other countries. What I found in my review of the literature is that it's not necessarily a country or region specific outcome that changes. It's more so institution-based, as institutions within the same country can have widely different RASC attainment percentages, and not even the institution, but at an annual level as well. In addition, anytime human performance is assessed, we often do better when we know we're being assessed, so I feel that the outcomes in this trial, while definitely showed improvements, could have been inflated due to the CPR team at these institutions knowing that they were being assessed. In addition, while there were hundreds of patients enrolled in this trial, nearly twice as many were excluded. Of those excluded were our COVID patients in isolation, so the results of this trial wouldn't necessarily be extrapolated to that population. In addition, the study drug administration was delayed by three minutes, which may have impacted study results. And finally, the effect size was not adequate for the primary outcome to meet the 80% power requirements. As a result, vasopressin and methylprednisolone improved RASC without benefit in quality of life. Vasopressin and methylprednisolone's place in therapy for in-hospital cardiac arrest remains uncertain, and additional trials will be needed to prove benefit in RASC. As for my polling questions, I'm interested to hear everyone's feedback. Has your institution discussed the inclusion of vasopressin and methylprednisolone to crash carts in response to this trial or previous VSC trials? Okay, and that's pretty much what I was expecting. A large proportion of you said no. The 6% who said yes, I'd be interested to hear how those conversations went and what the ultimate outcome was, which I think will be addressed with our next poll question. So, does your institution incorporate vasopressin and or methylprednisolone in crash carts currently? Do you foresee a change based on this trial? Okay, so we have about, okay, so about 18% of folks are, well, so we have some yeses here. So we have 2% of folks who do incorporate it. I'd like to hear their thoughts and their success with it, as well as some folks who might be on the fence of transitioning to incorporating it. Again, just understanding their thoughts and what they thought about the trial and how that may encourage the use of vasopressin and methylprednisolam. Thank you all for your response. All right. Once again, I'd like to thank you all for attending, and at this time, I'd like to address any questions, comments from the audience. Thank you. For our first question, did the author state why they did not include the 300 milligrams of hydrocortisone post-arrest, and do you think that this difference between previous trials and this trial might be somewhat due to this difference? Thank you very much for that question. The authors did discuss in, I believe, the Supplemental Index why they did not include it. And the reason was they did not, I believe they did not believe that the 300 milligram of hydrocortisone had really much to do with the achievement of ROSC, and therefore, because that was the primary outcome, they felt it was best to omit it from the trial. Okay. Can you comment on the choice of the steroid used in this study, methylpred versus other steroids? You know, that's a real, that's an interesting question. Unfortunately, I did not look into that. If that individual would like to drop their email, I'd be happy to get back to them, or if I could. Okay. Thank you for your presentation, and this concludes our question-and-answer session. And thanks again to Jacob Gregory for his presentation. Before moving on to our next presenter, we would like to ask a brief polling question regarding today's attendance to gain better understanding of our overall attendance to ensure continued support of the Spotlight on Pharmacy webcast. How many attendings are you viewing this webinar with? With me, 2-5 people, 5-10, or more than 10 people. And now I'd like to introduce our second presenter, Nicole Leshko. Thank you so much. So, my name is Nicole Leshko, I'm a current PGY-2 resident at Penn Presbyterian Medical Center. I'll be presenting the effect of early sedation with dexmedetomidine on body temperature in critically ill patients. This was published by Grayson and colleagues in Critical Paramedicine in July of 2021. So, a little bit of background before we get into this presentation. Dexmedetomidine is a high affinity agonist to the alpha-2 receptor. As seen in the right-hand side of this picture, as dexmedetomidine agonizes the alpha-2 receptor, this prevents norepinephrine from being released. And so the potential direct alpha-adrenergic stimulation has been proposed to be the cause of dexmedetomidine's thermodysregulation, as the reduction in central neurotransmitters mediate hypothalamic temperature regulation and lower the shivering threshold. And in the literature, untreated hypothermia is associated with poor outcomes. This ranges from negative neurocognitive effects, multi-organ failure, and death. And so before we get into this presentation, I did want to quick ask the audience, have you heard of the association between dexmedetomidine and hyperthermia? Yes or no? All right, so it looks like the majority of the audience has heard of the association between dexmedetomidine and hyperthermia. And I will say that prior to my PGY-2 experience, this is not something that I had heard of. And before we get into the methods, I did want to go over the published literature, as it is imperative to better understand how the methods of this article were created. So in 2017, Grayson and colleagues, which is the primary author of the 2021 article I'm about to review, did publish a retrospective single-center cohort of around 10,000 ICU patients. And they observed patients with a temperature of more than or equal to 39.5 degrees Celsius and its exposure to dexmedetomidine. Dexmedetomidine did result in a 4.5 greater odds of achieving a body temperature of more than or equal to 39.5 degrees Celsius. And after the removal of several confounders, dexmedetomidine continued to be strongly associated with temperature elevations. In addition, they saw an independent association with a BMI greater than 35 kilograms per meter squared and in patients that were post-open heart surgery. In 2019, the SPICE-3 investigators published a prospective parallel group open-label trial of around 4,000 ICU patients. And they looked at, does dexmedetomidine have an effect on mortality for early sedation versus usual care? Ultimately, they found that there was no difference in 90-day mortality. However, the patients that were less than the mean age of 63.7 years did have a 4.4% increased risk of mortality at 90 days, which ultimately favored the usual care group. So in 2021, a post-hoc of the SPICE-3 trial, which is the trial I'm about to go over, was published. And the objective was to investigate the association between dexmedetomidine's use and hyperthermia. Again, this is a post-hoc analysis of 4,000 ICU patients enrolled in the SPICE-3 trial. And this was in four ICUs in both Australia and New Zealand. The hypothesis was early sedation with dexmedetomidine in critically ill, mechanically ventilated patients increases body temperature. They included adults that were expected to require mechanical ventilation for more than 24 hours from randomization and requiring immediate sedation. Patients that were excluded included invasive ventilation for more than 12 hours prior to enrollment and those that sustained an acute or suspected proven brain or spinal cord injury. Patients were randomized in a one-to-one ratio to dexmedetomidine or usual care. And the depth of sedation was assessed every four hours using the RAS scale. Patients were permissible for agitated delirium and routine benzodiazepine use was strongly discouraged. Patients were started with dexmedetomidine at an initial starting dose of one microgram per kilogram per hour, which ranged from zero to one. And physicians were able to up titrate to 1.5 micrograms per kilogram per hour. Of note, doses were capped at a weight of 100 kilograms. And if patients were unable to achieve the targeted RAS goal at the maximum infusion rate of dexmedetomidine, propofol was then initiated at the lowest dose to achieve the RAS goal as a secondary agent. The primary outcome was the mean body temperature from randomization to five days, ICU discharge or death. Secondary endpoints were collected from the time of randomization to five days, which included the highest body temperature, mild body temperature elevations, which they defined as more than or equal to 38.3 degrees Celsius. And for the rest of this presentation, I will be referring to that as mild. And for severe body temperatures, they looked at elevations more than or equal to 39 degrees Celsius. And for the rest of this presentation, I will be referring to 39 or more as severe body temperature elevations. This was an intention to treat study and all statistical analyses were appropriate for each data type. I did want to draw the attention to the fine and gray subdistributional hazard regression, as this statistical analysis is used to estimate the incidence of outcomes over time in the presence of competing risks. They compared this with a multivariable sensitivity analysis in which they adjusted for the baseline temperature, patient age, body weight, institution, the presence or absence of known sepsis, and the dose of dexmedetomidine. In addition, the authors performed a subgroup analysis of an age less than or more than 63.7 years, as this was the age that they saw the increased risk of mortality in the SPICE-3 trial. In addition, they performed a subgroup analysis with a weight more than or less than 120 kilos, as this was seen with an increased BMI in the 2017 Grayson publication. And lastly, they did a subgroup analysis in patients that had a presence or absence of known or suspected sepsis. Moving into the results of this presentation, the average patient was around 63 years old and was an 85-kilogram male with a PACI-2 score of 22, indicating moderate disease. Most patients did have suspected or proven sepsis, and the most common ICU admission was nonoperative in nature. The most common reason for ICU admission was a respiratory disorder, and patients were afebrile on admission. As for the patients that were exposed to dexmedetomidine, there was 351 in the intervention group and 28 in the usual care group. In the patients that were exposed, patients in the intervention group did receive an average duration of dexmedetomidine for three days versus two days in the usual care group, and the average dose, the daily dose and maximum dose of dexmedetomidine was about two times as much as that in the usual care group. For the primary outcome of the mean daily body temperature, they saw an absolute difference of 0.06 degrees Celsius, which was not statistically significant compared to the usual care group. For the secondary outcome, they saw a significant difference in the highest daily temperature with 0.12 degrees Celsius that was significant. Mild body temperature elevations was seen with a 10.6% absolute difference compared to the usual care group, and this calculated to a number needed to harm of 10. As for severe body temperature elevations, they saw an absolute difference of 6.9%, which was statistically significant with a number needed to harm of 15. This is a pictorial of the temperature on the y-axis, and on the x-axis, they looked at the data points and days from randomization on the x-axis. This shows that both the mean and peak daily temperature both fluctuate throughout the time from randomization. However, as you can see, after randomization to day one, they did see that the mean daily temperature was highest, and in addition, the peak daily temperature was highest. Of note, the peak daily temperature was what was statistically significant at day five. The cumulative incidence of both the mild and severe temperature elevations is seen here, and on the y-axis, they graphed cumulative incidence, and on the x-axis, they graphed the days from randomization. Drawing your attention to the left-hand side, looking at the incidence of at least one body temperature being a mild elevation, they did see a statistically significant difference when they looked at the gray list, which took into account the competing risks. This was continued to be seen on the right-hand side when they looked at severe body temperature elevations that was statistically significant from days of randomization at day five. For additional secondary outcomes, they saw that there was a significant difference in the multivariable analysis for the subgroup of a weight more than 120 kilograms. In addition, they saw that for each additional one microgram per kilogram per hour of dexmedetomidine, this increased the temperature by 0.03 degrees Celsius, of which was statistically significant. Lastly, they found no difference in the subgroup analysis for highest daily temperature, mild, or severe body temperature elevations. As for co-interventions related to body temperature, these were not statistically significant between groups, and this was true when looking at both the medications and interventions that may alter body temperature, including continuous neuromuscular blockade, neuroleptic medications, and receiving renal replacement therapy. So the authors concluded that there was no difference in the mean daily body temperature with dexmedetomidine compared to usual care. They also stated that the peak daily temperature was significantly higher in patients who received dexmedetomidine. However, this was a small magnitude of between group difference of 0.12 degrees Celsius. In addition, there was a higher proportion of patients who experienced both mild and severe hyperthermia in the dexmedetomidine group. This leads me to my second poll question for the audience. Based on the trial results, how likely are you to consider dexmedetomidine to cause hyperthermia? Very likely, somewhat likely, are you unsure, somewhat unlikely, or very unlikely? All right, so it looks like the audience does have a split, but the majority of the audience does feel that this is somewhat likely to be the cause of hyperthermia with dexmedetomidine. But overall, again, it does look pretty split, and I would agree, I am still unsure as well. So the reason that I am unsure is for several reasons. I believe that this is a great trial. The randomized control trial does increase the authenticity of association, and I applaud the authors for the balancedness between groups for those who received interventions, which may alter body temperatures, including neuromuscular blockade, renal replacement therapy, and neuroleptic medications. And ultimately, I do believe that the outcomes are consistent with the conclusions with previously reported literature, which does increase the validity of both the primary and the secondary outcomes. However, the reasons why I'm ultimately unsure include several of the limitations. I believe that the root of the temperature measurement was not standardized or collected, and our diagnosis of fever is dependent on our mode of measurement. Ultimately, I would have liked to see rectal measurements being the primary mode so that we can definitively conclude fever. In addition, the authors did not report other antipyretic medications, such as NSAIDs and cooling devices. And I believe that the exclusion criteria does decrease the external validity. The authors did exclude patients that did have a known or suspected spinal or brain injury, as well as, if you look in the supplemental, they excluded patients that did have primary care in a nursing home. And of course, alternative causes of fever related to our disease states and concomitant medications could have also been excluded. And this includes patients that are going through withdrawal, VTEs, beta-lactam antibiotics, or barbiturates, and then procedures and infections, which can all alter our body temperature. And lastly, correlation does not always equal causation. And I would have liked to see would stopping dexmedetomidine lead to the resolution of this high body temperature overall? So in conclusion, the exposure to dexmedetomidine did not result in a higher mean body temperature compared to the usual care overall. However, patients that were more than 120 kilograms displayed a significant increase in the mean body temperature with dexmedetomidine. And they did see a proportional relationship observed with higher infusion rates of dexmedetomidine, which was associated with higher body temperatures. The mode of the temperature elevation, use of cooling agents, and alternative antipyretic agents was not reported. And alternative causes of body temperature elevations were not excluded in this trial. Thank you so much for listening to this Journal Club, and I can open this to any questions. Thank you to Nicole. If you have any questions, please enter them in the control panel now. To start us off, what would you recommend for a facility that has dexmedetomidine on their therapeutic hypothermia protocol for shivering? Do they need to reconsider that agent, or do you feel comfortable leaving that as an option? Oh, that's a great question. So I guess my question is, so for therapeutic hypothermia, really what we like to do is obtain normothermia. And I think as long as the patient is obtaining the normothermia, you can definitely leave it on. But it is something I guess you should, could definitely consider in using alternative agents for sedation in those patients. Thank you. Oh, go ahead. Go ahead, it's okay. Do you know how many patients were exposed to propofol in the intervention group, and whether this may have skewed the results since propofol itself is associated with hypothermia? Off the top of my head, I do not know that. I believe that is reported in the supplemental, and I could definitely get back to whoever asked that question. But I believe that the majority of these patients were primarily maintained on only dexmedetomidine. Okay, that concludes our question and answer session. Thank you to Nicole Leshko. And now I'd like to introduce our final presenter, Mariam Naveed. Good afternoon, everyone. My name is Mariam Naveed, and today I'll be presenting the FREDA trial, a non-immunogenic recombinant staphylokinase versus alteplase for patients with acute ischemic stroke 4.5 hours after symptom onset in Russia, a randomized open-label, multicenter parallel group non-inferiority trial. This was published in September 2021 in Lancet. So to start off, over 80% of strokes are acute ischemic and may be managed with thrombolytic therapy. The two agents routinely used for the management of acute ischemic stroke are alteplase and tenecteplase. Listed here are the four major trials that led to the approval of these agents for the management of acute ischemic stroke. Starting out in 1995, we had the NINDS trial, which showed that TPA or alteplase administration within three hours of symptom onset improved clinical outcomes at three months. Subsequently, we had the ECAS3 trial published in 2008, which demonstrated a benefit of alteplase beyond the conventional three-hour window up to 4.5 hours. Then in 2012, we had the NOR test trial, which in which tenecteplase was found to be not superior to alteplase in improving functional outcomes at three months. And then finally, we had the 2018 EXTEND-IATNK trial, which found that tenecteplase was not inferior to alteplase in improving cerebral perfusion, as well as improving functional outcomes at three months. The agent we will be discussing today is Staphylocinase, which is a thrombolytic agent like TPA and tenecteplase. This agent was first isolated in 1948, but it was subsequently redeveloped with improved methods of purification to reduce the production of antibodies that patients receiving previous formulations were found to have. This agent does not have any proteolytic activity on its own. However, in the absence of a blood clot, Staphylocinase will bind to plasmin, which will then form a Staphylocinase-plasmin complex, which can then bind to fibrin to degrade clots. It has been found to have much higher fibrin selectivity than both alteplase and tenecteplase. Based on the results of the FREEDOM trial, this agent was approved in Russia for ST-segment elevation myocardial infarction as a 15 milligram IV bolus. The study showed that Staphylocinase had similar reperfusion patency, as well as fewer minor bleeding events compared to tenecteplase. This brings us to the objective of this current study, which was to assess the safety and efficacy of modified recombinant Staphylocinase compared to alteplase in patients presenting with acute ischemic stroke within 4.5 hours of symptom onset. Looking at the study design, this was a randomized open-label multi-center parallel group non-inferiority trial that was conducted in 18 clinical sites in Russia. The inclusion criteria initially included acute ischemic stroke with an NIHSS scale of five to 25 points. The protocol was after that adjusted according to the 2018 AHA-ASA guideline recommendations to include an NIHSS score of up to 25 points. So basically patients with scores of zero to four could also be included. Initially patients were included if they were aged 18 to 80, but after the protocol revision, patients over 80 years old could also be included, and the patients had to have onset of symptoms within 4.5 hours. Similar to previous stroke trials, exclusion criteria included intracranial hemorrhage, platelets less than 100,000, unknown time of symptom onset, severe strokes with NIHSS scores of over 25, and then seizures at stroke onset. Other exclusion criteria not listed here included rapidly improving symptoms, blood pressures of over 185 over 110, hypoglycemia, recent major surgery, et cetera. Patients were randomized one-to-one to receive Staphylocinase or Alteplase. Staphylocinase was reconstituted as 10 milligrams and 10 milliliters of normal saline, and was administered as an IV push over 10 seconds. Alteplase was administered as 10% as an IV bolus and 90% as an IV infusion as the standard of care as a 0.9 milligram per kilogram dose. Assessments were completed at one to 24 hours the day of administration, two days, seven days, 14 days, and 90 days post-administration, and assessments included vital signs, NIH stroke scale scores, modified Rankin scale scores as well as Bartell index scores. CT and MRI findings were also assessed, and this was assessed through the Alberta Stroke Program early CT score. And this is a score that determines middle cerebral artery score severity using available CT data, which can assess the extent of early ischemic changes. Looking at the outcomes of the study, the primary outcome was a modified Rankin scale score of zero to one on day 90. Secondary outcomes included a modified Rankin scale score of zero to one, an IHSS score of zero to one or a Bartell index score of 95 or more on day 90, and this was a simultaneous outcome. Other secondary outcomes included an IHSS score after 24 hours and on day 90, and then safety outcomes including mortality, intracranial hemorrhage, symptomatic intracranial hemorrhage as well as other serious adverse events. For statistical analysis, this study had a non-inferiority margin that was set at 16%. This was based on the SAFE implementation of thrombolysis and stroke monitoring study or SITS-MOS study. This study was done to confirm the safety and efficacy of alteplase after its European approval. And in this study, they found that the difference between alteplase and placebo was 16.9%. So based on this study, the authors set a non-inferiority margin of 16%. They needed a total of 168 patients to reach 80% power with a p-value of 0.05, and this was accounting for a 10% dropout rate. Continuous variables were assessed using the Mann-Whitney U-test and categorical variables were assessed using the two-sided Fisher's exact test. Just to briefly go over the scoring tools that were utilized in the study, this is the NIH Stroke Scale, which is a 42-point scale that quantifies neurologic deficits in 11 categories to quantify stroke severity. Higher scores reflect more severe deficits. And just to point out that the primary outcome and the secondary outcomes as well in our study were an NHSS score of zero to one, reflecting no symptoms or minor symptoms. Here is the modified Rankin scales. This is a six-point scoring tool assessing degree of disability or dependence after stroke, with higher scores indicating unfavorable outcomes. And in this study, the primary outcome was a modified Rankin scale score of zero to one, indicating no symptoms at all or no significant disability despite symptoms. And then finally, we have the Bartell Index of Activities of Daily Living scoring tool, which is a 10-item, 100-point scoring tool that measures the ability to form activities of daily living. Higher scores indicate more favorable outcomes. Looking at our results, there were a total of 385 patients that were screened, of which 336 were included in the study. There were 168 patients that received non-immunogenic Staphylococcinase and 168 patients that received Alteplase. We can see that over 60% of patients in the study were male with an average age of about 65. The average weight was about 80 kilograms with an average BMI of 27 kilogram per meter squared. The primary risk factor that these patients had was hypertension occurring in 95% of patients in both groups. Other risk factors that had fairly low incidence were diabetes at about 10%, hyperlipidemia at about 20 to 25%, and then smoking, 26% in both groups. Looking at the cardiovascular risk factors, the highest risk factor was atrial fibrillation occurring in about 30 to 40% in both groups. And then previous strokes and previous TIAs were fairly low incidence in both groups. Looking at the baseline stroke characteristics as well as the onset to treatment time, we can see that for these patients, the baseline NIHSS score was about 11, which indicates moderate severity of stroke. The baseline modified Rankin scale score was four, which indicates moderately severe disability where patients are unable to walk without assistance and unable to attend their own bodily needs. And then finally, the aspect score is also included here. This was done for 154 patients in the Staphylococcinase group and 151 patients in the Alteplase group. Both were 10, which indicates a good CT scan. For onset of treatment, the average time to treatment was about three hours in both groups. When this was split by less than three hours and three to 4.5 hours, the authors found that in the less than three hours timeframe, the average time was about 2.3 hours. And in the three to 4.5 hours time window, the average time was about 3.5 hours. Looking at our primary outcome for a modified Rankin scale score of zero to one on day 90, there was found to be no difference between the two groups. This was found to occur in 50% of patients in the Staphylococcinase group and 41% of patients in the Alteplase group with an odds ratio of 1.47. Looking at our secondary outcomes of the simultaneous outcome of the modified Rankin scale score of zero to one, NIHSS score of zero to one or Bartel index score of over 95 on day 90. This was also found to be not different between the two groups at 35% of patients versus 31% of patients. The other outcomes, including the NIHSS score after 24 hours, NIHSS score on day 90, as well as the modified Rankin scale score of zero to two on day 90, there were no differences in these between the two groups as well. The authors also assessed changes in these outcomes when considering body weight as well as the time of administration. And they found that these outcomes did not differ when considering body weight or the time of administration within the 4.5 hour window. This image describes the modified Rankin scale score distribution at day 90. As we can see, there is a higher proportion of patients in the Staphylococcinase group with higher modified Rankin scale scores. However, as previously discussed, there was found to be no significant difference in the primary outcome of zero to one in this study. Moving on to our safety results. The first safety result was mortality at day 90. This was found to be no different between the two groups as well at about 14% for both groups. The next safety outcome was intracranial hemorrhage, which was also not different between two groups at 17% versus 19%. The next outcome was symptomatic intracranial hemorrhage. This was an outcome that was taken from the ECAS-3 trial where patients were deemed to have symptomatic intracranial hemorrhage if the hemorrhage resulted in death or if the hemorrhage resulted in decreases in neurological impairment of up to four points on the NIHSS Stroke Scale. And we can see here that there was a slight numeric increase in the alteplase group, but this was not found to be significant as well. Finally, the authors also assessed the number of patients that had one or more serious adverse event. These could include cerebral edema, surgery, neurosurgery, acute MI, pulmonary embolism, having a new acute ischemic stroke or gastric ulcers. And we can see there was a slightly numerically higher incidence of serious adverse events occurring in the alteplase group. However, this was not found to be statistically significant. So overall, the authors concluded from this study that alteplase staphylokinase is non-inferior to alteplase for patients with acute ischemic stroke. Mortality, symptomatic intracranial hemorrhage, as well as serious adverse events did not differ significantly between the two groups. However, looking at the critique of the study, I had different opinions. So first, looking at the strengths of the study, this was a randomized controlled trial where patients were randomized one-to-one to receive staphylokinase or alteplase. Alteplase is one of the major agents that we use in the management of acute ischemic stroke. So this was a good agent to be compared against. The study included similar outcomes as previous stroke trials, which was also one of its strengths. And then the study included studying staphylokinase, which was a convenient option because it offers a flat dose of 10 milligrams, which can potentially simplify the management of patients with no need to weigh the patients, and then possibly a reduction in the risk of calculation errors. I do think there are several criticisms and weaknesses of this trial, firstly, starting off with the clinical relevance and relevance and the need for this trial. So we already have two agents, alteplase and tenecteplase, that have been very well studied for the management of acute ischemic stroke. And with the introduction in tenecteplase in the management of acute ischemic stroke, we do have an option that has been significantly easier to reconstitute and to administer. Tenecteplase is administered as an IV bolus. It does require a weight-based dosing. However, because it is administered as an IV bolus, it is significantly easier to prepare and requires less operational considerations than alteplase. Secondly, looking at the study design, this trial was an open-label design, which lowers the internal validity of this study. The emergency department staff were aware of which medications patients were receiving. Patients and investigators did not know which medications were being received. However, because the ED staff was aware, this could potentially affect some of the assessments that were done. Looking at the data analysis, this study included a very liberal non-inferiority margin of 16%. And this was created, as previously mentioned, by a trial that compared alteplase to placebo. Given that this study was comparing two thrombolytics, I think this was a very liberal and inappropriate margin. Previous studies had much more conservative margins that were used, particularly the studies assessing patients proceeding to thrombectomy had margins of five to 10% that were used. And so I think something similar to this would have been more appropriate to be used in this setting. Finally, this study had a lack of generalizability, which lowers its external validity. I'm starting off with the patient population. The study only included patients from Russia that were an average weight of 80 kilograms and a BMI of 27, which only had a high comorbidity of hypertension. However, we know in the United States, we have higher rates of obesity, higher rates of smoking, diabetes, as well as cardiovascular disease, which could affect the results as well and lower the external validity of the study. And then finally, looking at our outcomes, the outcome, similar to previous stroke trials, was the Modified Rank and Scale Scoring Tool, as well as the NIHSS and Barthel Index Scoring Tools. These are subjective endpoints and could vary depending on the investigator that's conducting the assessment and therefore could have led to variability in assessments as well as lower external validity. So overall, based on these weaknesses, my overall takeaways from this study are that Staphyloccinase may be a convenient thrombolytic for the management of acute ischemic stroke. However, because of the major limitations that we've previously discussed, I do believe that further head-to-head studies are needed to assess the efficacy and safety of Staphyloccinase compared to Alteplase and Tenecteplase, as well as its role in patients proceeding to thrombectomy. I would also be curious to understand in these future studies to better characterize the time that it takes for Staphyloccinase to be administered compared to Alteplase and Tenecteplase, since this is one of the major selling points that the authors mentioned as a reason for this agent being studied. This brings us to our first polling question. What thrombolytic agent is used at your institution for the management of acute ischemic stroke? Alteplase, Tenecteplase, or Alteplase and Tenecteplase? So it looks like majority of the audience selected Alteplase, followed by Alteplase and Tenecteplase. Moving on to our next polling question. Do the results of this trial impact your perspective on the management of acute ischemic stroke? The majority of the audience selected no, which I also agree with. And I'd be happy to answer any questions. Thank you. As a reminder, if you have any questions, please enter them into the control panel now. For our first question, kind of a hypothetical, so let's say your institution can no longer get alteplase, which is starting to become an issue, and this agent becomes also available in the United States, is this an agent that you would then consider for formulary? I think based on the available data that we have, this is the only trial studying this medication, and so I would feel more comfortable promoting the use and addition of tenecteplase to formulary and using tenecteplase instead of alteplase for the management of these patients. I think there's still a lot more studies that need to be done before we can say that this agent is effective and safe for the routine use of patients. Okay, thank you. And this will conclude our question and answer session. Thank you to our presenter, Maryam Naveed, for that presentation. Thank you again to all of our presenters today, as well as our audience for attending, and a reminder to please join us for our next Journal Club Spotlight on Pharmacy, which will be held on December 17th from 2 to 3 p.m. Eastern Time, and thanks again for joining us. That concludes our presentation for today.

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