Hello, welcome to today's Journal Club, the Spotlight on Pharmacy webcast, which is supported by the Society of Career Care Medicine CPP section. My name is Russ Roberts, I'm a Clinical Pharmacy Manager at Massachusetts General Hospital and also the Program Director for the PGY-2 Career Care Residency, and I will be moderating today's webcast. Recording of this webcast will be available to the registered attendees. Log into mysccm.org and navigate to the My Learning tab to access the recording after the meeting. Thanks for joining us today. A few housekeeping items before we get started. There'll be a question and answer session after each of today's speakers. To submit questions throughout the presentation, please type them into the question box located on your control panel. You 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 also 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 speaker will give a 15-minute presentation followed by a question and answer session. Our first presenter today is Sarah Schumacher, who is currently a PGY-2 Critical Care Pharmacy Resident at University of Iowa Hospitals and Clinics in Iowa City, Iowa. She will present on nasoidophore antiseptic versus mupyricin antibiotic in the setting of chlorhexidine bathing to prevent infections in adult ICUs. Our second presenter is Kaylee Hall, a PGY-2 Pharmacy Resident at University of Mississippi Medical Center in Jackson, Mississippi. She will be presenting on intravenous levothyroxine for unstable brain-dead heart donors. And our third presenter is Anthony Phan, who is a PGY-2 Critical Care Pharmacy Resident at Harris Methodist Hospital, Fort Worth, in Fort Worth, Texas, and he will be presenting on tranexamic acid in upper gastrointestinal bleed in patients with cirrhosis. And now I'll turn things over to our first presenter. Hi, everyone. Thank you for having me today. Today I'll be talking about the article nasoidophore antiseptic versus nasal mupyricin antibiotic in the setting of chlorhexidine bathing to prevent infections in the adult ICUs. A little bit of background on this topic. So healthcare-related associated infections in the ICU are a fairly common thing that we see throughout the country. And most commonly, we do see staphylococcus aureus, which is a common ICU pathogen that causes about 23% of ICU infections in North America. And this can cause a wide spectrum of infections, which include ventilator-associated pneumonia, bloodstream infections, as well as surgical site infections. Previous trials that have looked at mupyricin is the REDUCE MRSA trial, which was published back in 2013. It was a pragmatic cluster randomized controlled trial, and this trial included three different groups. They had MRSA screening, which then led to isolation if they were positive for MRSA. They had another group, which had targeted decolonization, which was the patients who tested positive were decolonized. And they also had a third group, which was universal decolonization, which everyone received the mupyricin. The results of this trial, they did find that universal ICU decolonization was superior to universal screening, followed by either contact precautions or targeted decolonization. It did have a reduction in MRSA clinical cultures by 37%, as well as a reduction in all-cause bloodstream infections of 44%. And this trial concluded that universal decolonization was superior to the other methods. As for what is the ICU standard of care when it comes to decolonization, a 2021 survey was sent out by the National Healthcare Safety Network to 5,000 US hospitals, which then showed that universal ICU chlorhexidine bathing was adopted in about 63% of ICUs, and then universal nasal decolonization was adopted in about 37% of ICUs. So this leads to my first audience question, and what I want to know is what infection prevention or decolonization techniques has your institution implemented? And select all that apply if you are using more than one. So the results look like that contact precautions, about 68% showed that you guys are using that, as well as second place is screening followed by decolonization. So universal decolonization, only about 32% responders showed that this practice has been adopted at your institution. So today's trial also called the Mew-Pearson Iodophor Swapout Trial. What they wanted to assess was whether Iodophor antiseptic works as well as nasal Mew-Pearson for preventing Staphylococcus aureus clinical cultures in ICU patients who are also receiving daily chlorhexidine bathing. So this trial was a cluster randomized non-inferiority trial. It was a multi-center study, including HCA hospitals. And this group is the largest private inpatient provider in the United States, which primarily consists of community-based, but it does range on the size of institution from small to large tertiary medical centers. So 137 HCA hospitals were included, which included 235 ICUs. Enrollment for this trial was from November, 2017 to April, 2019. The interventions of this study, there were two different groups. The first group being the Iodophor Chlorhexidine Group, which was Iodophor swabs, which were the 10% povidine-iodine swabs to the bilateral NAERS twice daily on ICU admission for five days, combined with the daily chlorhexidine bathing. The other group was the Mew-Pearson Chlorhexidine Group, which was topical Mew-Pearson ointment to bilateral NAERS twice daily on ICU admission for five days, also combined with daily chlorhexidine bathing. There were different study periods throughout this trial. So there was a 24-month baseline period in which all patients in all of these hospitals received Mew-Pearson and chlorhexidine as this was adopted as their standard of care back in 2013 after the reduced MRSA trial was published. And then this followed a four-month training period and phase-in period from May, 2017 to October, 2017. And this included the training as well as implementing the Iodophore component for that study group. And then, which followed an 18-month intervention period, which was November, 2017 to April, 2019. And then the outcomes were compared, compared the intervention period in this trial to the 24-month baseline period. The study criteria include, sorry, for the inclusion criteria, it included US HCA hospitals with an adult ICU, all patients within the all-adult ICUs, including patients who were less than 18 years old and greater than 12 years old. As for the exclusion criteria, they excluded ICUs with an average length of stay less than two days, as well as HCA hospitals not able to transfer or merge data for the trial. As for the outcome, so the primary outcome looked at the number of participants with ICU-attributable Staphylococcus aureus clinical cultures from the baseline to intervention period. And then the secondary outcomes included the number of participants with ICU-attributable MRSA clinical cultures, as well as the number of participants with ICU-attributable bloodstream infections. And what this trial defined as being ICU-attributable, they defined it as occurring greater than two days from admission into the ICU through two days following ICU discharge. As for the statistical analyses of this trial, for the sample size, they had an 80% power to detect non-inferiority of the Iodophore chlorhexidine group compared to the Mupiricin chlorhexidine group. And they had a hazard ratio of 1.1 for the primary outcome. As for the analyses, they had an as-random unadjusted analyses, but they also had an as-treated model, which did have excluded patients who did not receive two doses of the study treatment. And then they also had post-hoc analyses, which compared the intervention period of the current trial to baseline and intervention period of the reduced MRSA trial. Looking at the results of this trial, as for patient characteristics, so like I said, 178 HCA hospitals were assessed for eligibility and 137 hospitals underwent randomization. As for the Iodophore chlorhexidine group, 69 hospitals were in this group, which included 122 ICUs, which were then included in the as-randomized analyses. And also comparing the baseline and intervention period comparing the baseline and intervention period between the number of admissions and the number of ICU attributable days in the Iodophore group. As for the Mupiricin chlorhexidine group, 68 hospitals were included, which included 111 ICUs in the as-randomized analysis, and then the baseline and intervention period numbers of admissions and ICU attributable days. For baseline characteristics, all patient characteristics were similar across groups between baseline and intervention periods. And I did want to note that this was a mixed ICU population, so it did include surgical, medical, cardiac, and neurosurgical patients. And then as well as the adoption of the assigned intervention group that did differ between groups. And one thing I did want to point out as for the adherence between the baseline and intervention period, for the intervention period and the Iodophore arm, they did see a decrease with this arm in the intervention period. As for our outcome measures of this trial, so for the primary outcome, they looked at the 24-month baseline period comparing the 18-month intervention period. So for the Iodophore chlorhexidine group in the baseline 24-month period, they had 4.3 raw events out of 1,000 ICU attributable days. And this compared to the five raw events out of 1,000 ICU attributable days, which showed a clustered hazard ratio of 1.17. As for the mupiricin chlorhexidine group in the 24-month baseline period, they had four out of 1,000 ICU attributable days. And then in the 18-month intervention group, they had 4.1 raw events out of 1,000 ICU attributable days. This did have overall clustered ratio of 0.99, which did show non-inferiority between Iodophore. That did not show non-inferiority between Iodophore chlorhexidine and mupiricin chlorhexidine. So they did have a p-value of less than 0.01. So they were unable to show non-inferiority between the Iodophore and the mupiricin groups. As for the secondary outcomes, the ICU attributable MRSA clinical cultures was a similar outcome between the Iodophore and mupiricin groups, where that they were unable to show non-inferiority between the Iodophore and chlorhexidine groups. But as for the ICU attributable bloodstream infections, this did show non-inferiority between the Iodophore and mupiricin groups with a p-value of 0.84. Looking at the durability of clinical effect, so this looks at comparing the mupiricin groups that were in the reduced MRSA trial and what the cumulative hazard ratios of all of the outcomes had. So the primary outcome of Staph aureus clinical cultures, they did see a significant decrease even in the mupiricin chlorhexidine group later in our trial in 2017 through 2019. And that showed similar between the secondary outcomes as well of MRSA clinical cultures, as well as all bloodstream infections between comparing the reduced MRSA trial to this trial. So the author's conclusions were that nasal Iodophore antiseptic did not meet criteria to be considered non-inferior to nasal mupiricin, and results were consistent with nasal Iodophore being inferior to nasal mupiricin. Going into the discussion of this trial, a few strengths that I noted was that this is relevant to current practice. We do have a lot of sick patients in the ICU that are there for different reasons. And getting an infection, a healthcare associated infection, can set back their course quite a bit. So if there's any way that we can prevent this from happening and being successful at it, it can be a big intervention that we can have on our ICU patients. This was also a very large study population in which they included a wide variety of different ICU settings from smaller hospitals to tertiary care centers. And I do believe that they had appropriate outcome measures when they looked at reducing MRSA clinical cultures in the ICU. When it comes to weaknesses of this trial, one thing that it did not note was any resistance rates of mupiricin. And that's something to keep note that there are different mupiricin resistance rates throughout the country and whether this intervention may work in one part of the country and may not work as well in others. The next thing I noted was the cost of medication as well as nursing administration time. So in our part of the country in Iowa, Iodophor can range anywhere between 13 to 16 cents per swab. And mupiricin can go anywhere between 51 cents to $3.89 per one gram of ointment. So that's something to keep in mind if this is something that we do see that we want to continue doing that there is a cost associated with it. And then adherence to study medications, we did see that adherence with the Iodophor group in the intervention period was lower than the mupiricin group and whether this had anything to do with the results of this trial as well. And then one thing I wanted to note was the reliability of the MRSA nasal PCR at the institution I am at. We highly rely on the MRSA nasal PCR for deescalation of vancomycin in a patient who may not have an MRSA pneumonia. And so whether or not if we are decolonizing our patients with mupiricin or Iodophor, if this is something that can even be relied on anymore or if we're gonna be stuck with vancomycin until our cultures grow out. So my key takeaways for this trial is Iodophor chlorhexidine did not meet criteria for non-inferiority compared to mupiricin. Mupiricin resistance rates do differ and there has been a study that has shown it can be as high as 81% in some parts of the country. And resistance increases with repeated exposure. So one thing to keep in mind is if we have patients who have recurrent admissions into the ICU, if we are doing this upon each admission, if this can increase resistance that way. And then the last thing being the reliability of the MRSA nasal PCR for deescalation of antimicrobials and whether or not we will be able to continue utilizing this if we are decolonizing all of our patients. This leads me to my second audience question, which is based on the results of this trial, are you inclined to implement universal decolonization with mupiricin chlorhexidine? So the results of this polling question, the top answer was no at 44%, possibly was 40%, and then yes was 16%. So the majority being no or possibly for this implementation of universal decolonization. I wanted to thank you all and I'm happy to answer any questions. And if you have any questions, please type them in the question box. So I can start with one. Great presentation. Thank you. I think it's conflicting whether or not the dual should be the standard. I guess, can you comment a little bit more, do you think IDA4 had a fair shot? And should we continue to look at IDA4 as a formulation over Mipiracin, given some of the concerns about resistance rates that you brought up, even though the UHC hospitals or HCA hospitals, sorry, showed that their before and after were pretty much similar? Yeah, so I think if IDA4 got a fair shot, and in this case, since the adherence was lower in the intervention group, I feel like it could have played a role in not having as many or having more ICU attributable MRSA cultures. And so I believe that, you know, we could continue to try to look at IDA4 because if we are seeing increasing resistance rates of Mipiracin, then in future trials, we might not be able to see quite as well as a response to Mipiracin if there's increasing resistance. I think it's hard to play out, you know, without a trial, just looking at CHG by itself versus the dual agents, and I think that's where we're lacking in data. So hopefully that'll be coming. But in terms of IDA4 versus, you know, Mipiracin, do you think there'd be a difference if the IDA4 also might be formulated differently, meaning, you know, if the ointment stays in the NAERS more contact for a more effective killing versus a swab of liquid that, you know, it's kind of dependent on how the nurse puts it in the NAERS as well? I think that also could play a big role if the swab just wasn't the right formulation for the IDA4 to show the same clinical effect as Mipiracin, because definitely, you know, maybe the ointment does stay along longer, and so I definitely think maybe the formulation could also be something that the study found to be why they found it to be not considered to be non-inferior. Perfect. Well, hopefully we'll see a CHG trial versus the dual and see how others on this call can be convinced later on if that information comes out based on your poll. Anyway, this includes our Q&A session for this first journal club. Thank you so much, Sarah. Okay. Now, I'd like to introduce our second presenter, Kaylee Hall. Thank you. So, I'll go ahead and get started. In 2023, the Organ Procurement and Transplantation Network reported over 46,000 transplants, with more than 16,000 of those coming from deceased organ donors. This includes nearly 5,000 heart donations, with the majority of heart transplants coming from donors who had been declared brain dead. Brain death is a catastrophic event that results in severe systemic disturbances, with the main goal for successful organ donation being to first normalize and then maintain normal physiological conditions. Just some brief background pathophysiology. Acute brain death is associated with a catecholamine release that can cause a bunch of different issues, including acute left ventricular failure, arrhythmias, a decrease in your cytosol levels, insulin antidiuretic hormone, and thyroid hormone, with a reduction in thyroid hormone leading to myocardial energy depletion and ultimately shock, with supplementation of thyroid hormone being thought to improve hemodynamics by increasing inotropy and then also increasing chronotropy. Now despite lack of high-quality evidence, thyroid supplementation has been recommended by consensus guidelines and is frequently administered in deceased donors. It is recommended to be considered for patients who are hemodynamically unstable or for potential cardiac donors with abnormal left ventricular ejection fraction. They also remark that both T3 and T4 are acceptable replacement therapies, with T4 being the most common agent utilized. That is our levothyroxine, and it is typically dosed at 10 mics per hour. Okay, my first polling question. How often do you utilize IV levothyroxine in brain-dead organ donors? Okay, so the results of the poll are 43% said all of the time, 37% said sometimes, and that's kind of what I was expecting. So the majority of organ procurement organizations are saying that they do utilize levothyroxine in brain-dead organ donors. So to look at some previous literature, I'll start with a study by Sellam et al. in 2007. This was a retrospective review of brain-dead patients that successfully donated organs, and what they found was that patients who received T4 had significantly more organs procured. Then in 2009, there was a prospective randomized double-blind trial that looked at T3, methylprednisolone, either both or one of each, or placebo. They found that there was no effect on heart retrieval rate or improvement in donor circulatory function. Then in 2020, Pellet et al. did a retrospective review of heart transplant recipients and looked at donors who had received T3 or T4 and found that thyroid hormone therapy to be associated with an increased risk of early graft loss. So despite this lack of high-quality evidence, thyroid supplementation has been recommended by consensus guidelines. And these authors wanted to look at this a little bit further and investigate their hypothesis that intravenous levothyroxine would increase the rate of hearts transplanted from hemodynamically unstable brain-dead organ donors being considered for heart donation. This was a multicenter parallel group randomized trial of 15 organ procurement organizations in the United States from December 1, 2020, to November 6, 2022. They included patients with a declaration of death due to neurological criteria, aged 14 to 55 years old, with a weight greater than or equal to 45 kilos, and who were hemodynamically unstable. They excluded patients whose heart was not being considered for transplantation and who received thyroid hormone within the past month. They had a one-to-one randomizations where patients were randomized within 24 hours either to receive levothyroxine at 30 mics per hour or normal saline at 30 mils per hour for a duration of 12 hours. They did have this 12-hour limit, but they could be decreased or discontinued early set by these pre-specified parameters, including hypertension, tachycardia, arrhythmias. Also, levothyroxine could be extended at the discretion of the OPO. So the patients who were randomized to receive levothyroxine, that could be continued. And also, levothyroxine was available for patients on normal saline as well after their 12 hours of normal saline. That was discouraged, but it was prospectively tracked. Looking at their primary outcomes, they had a primary efficacy outcome of transplantation of the donor heart and a primary safety outcome looking at graft survival at 30 days. Secondary outcomes included other organ transplantation, duration of vasopressor support, proportion of donors weaned off vasopressors or inotropes at the end of 12 hours, and vasopressor requirements after 12 hours. They also looked at the initiation of levothyroxine or normal saline in the time to echocardiography and incidences of adverse effects. So looking at their baseline characteristics, baseline characteristics were similar between the two groups with no difference in age, weight, median vasopressor inotrope score, which is a score that they utilized in order to quantify the vasopressors that the patients were on, and time to brain death to start of infusion and median free T4 level. So I will note that their median free T4 level was one in both groups with a normal free T4 level being 0.9 to 2.3. So only about 38% of their population had a thyroid deficiency upon randomization. Looking at their trial infusions, the sign infusion was started in 98% of the levothyroxine group and 92% of the saline group. Levothyroxine was weaned before 12 hours in 14% of the levothyroxine group, and open label levothyroxine was utilized beyond 12 hours in the levothyroxine group, 50%, and 12% in the normal saline group. The median free T4 level at the time of organ recovery was 1.4 in the levothyroxine group, which was about 40% increase from their baseline and remained one in the saline group. Looking at the percentage of primary outcomes of transplantation of donor heart and graft survival at 30 days, you can see that looking at transplantation of donor heart here, the levothyroxine group is in the light blue color and the normal saline group is in the dark blue color. There was about a 55% of transplantation in the levothyroxine group compared to a 54% or 53% in the normal saline group of transplantation of donor. So there is no statistically significant difference between the transplantation of donor hearts between the levothyroxine and the normal saline group. Looking at graft survival, there was also no statistically significant difference between graft survival between the levothyroxine and the normal saline group as well. Now looking at there's some secondary outcomes, this is a Kaplan-Meier curve looking at the proportion of patients who continue to receive vasopressors over hours since the infusion was initiated. So looking at this, you can see that's the percentage of patients who are still requiring vasopressors and there was no difference in the time to wean off of vasopressors within the two groups. You can look at that a little differently by looking at this here. There is looking at their vasopressor inotrope score. So that's what's graphed here on the y-axis. And then hours since the study drug infusion was initiated across the x-axis. So by looking at this, you can tell that at hour 12, there was no difference in vasopressor requirements at hour 12 at the end of their infusion or at by the end at the time of their organ recovery. Here we have a forest plot of the subgroup analysis of heart transplanted, which was their primary outcome. And as you can see overall, I'll reiterate this again, there was no difference between the levothyroxine and the normal saline group when it came to heart transplanted. And looking at their subgroup analysis, when they were separated by their left ventricular ejection fraction from their first echocardiogram, so separating them to patients who had an abnormal or less than 50% ejection fraction versus normal ejection fraction, they also found no difference in patients who received levothyroxine versus normal saline. They also looked at this from brain death to trial infusion of less than or equal to 12 hours versus greater than 12 hours, and again, they found no difference. Looking at adverse events, the number of donors with adverse events was significantly higher in the levothyroxine group compared to the saline group. And this was most true with severe hypotension with 26% or 26 cases in the levothyroxine group and 5% in the saline group. They also had a significantly higher incidence of tachycardia as well. So in conclusion, in this randomized trial of hemodynamically unstable brain-dead heart donors, there was no benefit to the treatment of IV levothyroxine in terms of heart's transplanted hemodynamic stability or donor cardiac function. There were some limitations though, so they did allow for open label use of levothyroxine. So in that levothyroxine group, 50% of their patients did continue to receive levothyroxine past that 12-hour mark, so they were receiving more than allocated for. And even in the normal saline, even though it was small, still 12% of them received levothyroxine, so that could skew the data a little bit there. Another limitation was that they did not have donor management standardization. So this was a large trial over 15 organ procurement organizations, and because of that, they didn't have the same protocols, and the authors did mention that all the patients received glucocorticoids, but the dosing for that was different based on their organ procurement organization. Additionally, the median baseline free T4 level was within normal range, and so it wasn't really looking at a population of patients who were thyroid deficient, and they did not assess T3. So some takeaway points, levothyroxine in hemodynamically unstable brain-dead heart donors does not increase the rate of heart transplantation or graft survival, and this does have major clinical implementations. A donor registry report reported about 78% of organ procurement organizations utilizing levothyroxine, which was a little bit more than you all reported, but still a significant number. But still, as always, future research is needed in this area. So my second polling question, after reviewing the results of this study, how would this change your utilization of levothyroxine? 40% said no change, and 45% said they will decrease utilization. And this is kind of what I was expecting. Oh, and 10% said that they'll stop legothyroxine utilization. So, this is kind of consistent what I was thinking with more people having a decrease in their utilization. And yeah. Are there any questions? So, now, thank you for the presentation. We'll have a couple of questions. So, I guess, can you just comment on the standardization of the protocols and if that changes what the outcomes would be? Meaning, do we standardize insulin use, glucocorticoids, and do you think that would have changed? And that's probably why people are on the fence. And my next question is, it seems like maybe a certain population, this might be a niche in, those obviously who are deficient in thyroid hormone. And so, do you think we should just, for certain patients, check the thyroid, and if it's normal, then we can actually forego this, or that wouldn't be the recommendation either? I'm curious your thoughts. At this point, I don't think that I would recommend that, even in patients who do have a low thyroid level. They also, I didn't present that data, but they did a subgroup analysis of that as well. And they found no difference in their primary outcomes in patients who had a less than 0.9 of their T4 level. So, they did a subgroup analysis of that and found no difference. For your first question, looking at if there was standardized protocols, all patients did receive glucocorticoids, and I'm sure they received insulin as well. Even though it wasn't standardized, I think that it was probably still appropriate to make these conclusions without the standardization of those other regimens. Perfect. I know this has already caused some controversy at a lot of sites, basically more data, and we don't have time to discuss the T3 versus T4, but we'll leave it at that. So, this concludes our Q&A session. Thank you again, Kaylee. Now, I'd like to introduce our final presenter, Anthony Phan. Hi, everyone. I will go ahead and get started. Okay. So, for some background information, acute diabetes is a pretty common cause of death worldwide, where we can see up to about 10 percent mortality rate, and it can be even higher in patients who have a history of bleeding and the bleeding occurred again. Majority of this bleeding comes from upper GI bleed in this patient. However, in the setting of acute decompensated cirrhosis, typically, these GI bleeds are due to poor hypertension. So, typically, you will see patients coming in with esophageal or gastric viruses are the most common cause, and mortality are pretty high in this patient as well, especially for those who have childhood class B and C. So, with cirrhosis, there's this local and systemic hyperfibrinolysis, where it can interfere with the patient body's own ability to form hemostasis and healing at the site of bleeding. So, with that, that comes with the hypothesis that maybe TXA can work as an antifibrillic agent in this patient population. So, just looking at previous data, so we have two meta-analysis. The first one is done in 2021, where they're looking at 13 different random mass control trials, where they're comparing using TXA versus placebo, and the dosing are kind of variable between different studies. But what they're trying to do is that they're trying to see whether the rate of continued bleeding was significant with TXA. There was less urgent need to go back to endoscopy intervention, and there are significant difference in mortality in patients getting TXA as well. However, in this random mass control trial, there's a dropout rate in this patient, and a lot of the studies are small, so when they account for all the drop rate, that's kind of where they see the improvement in the patient mortality benefit. So, it doesn't really answer the use of TXA in this patient. In a second meta-analysis done in 2022, where they compare high-dose TXA versus low-dose TXA, and they see that patient who's getting high-dose TXA doesn't have any reduction in bleeding or mortality, and they actually see an increase in adverse event, especially in VTE, pulmonary embolism, and seizures as well. Looking at low-dose infusion, they actually didn't see any difference in mortality. However, they do see some reduced risk of re-bleeding and need for surgery. Now that we know some background from this meta-analysis, one thing you want to also keep in mind is that these two meta-analysis doesn't include a very big landmark trial called the HOTED trial, which I'm going to talk about next. So, in this, the HOTED trial, it is a pragmatic multicenter international placebo control trial done in 15 countries. For this population, they're looking at patients with upper GI bleed, which consists of 90% of these patients, and patients with lower GI bleed. And the time of bleeding to onset of randomization was about 22 hours. So, for the intervention, the patient will receive TXA at 1 gram IV over 10 minutes as a loading dose, followed by a 3-gram-consumed infusion over 24 hours, versus placebo, which is just an NS infusion. So, with this study, the thing to be important is that about 45% of these patients are having gastroparesis bleeding as well. So, looking at the result, they did not see any difference in death from bleeding at five days for these patients, and they also see no difference in all-cause mortality, which was their original outcome. At the end, they did not see any adverse events associated with this patient, including thromboembolic or seizure event. So, knowing this background information, which they said didn't really clearly answer the question whether we can use TXA in patients specifically with gastric varices or cirrhosis. So, that kind of comes to the topic of my journal club, which is the use of transamic acid in upper gastrointestinal bleeding in patients with cirrhosis. So, in this study, it is a single-center randomized control trial that was done by Department of Hepatology and Liver Transplant in New Delhi. It is funded by the same research institute as well, and its objective is to evaluate the efficacy and safety of TXA in treatment of acute upper gastrointestinal bleeding in patients with advanced cirrhosis. So, for the intervention, they randomized patients to receive the TXA of placebo at a ratio of one to one, where the patient will receive one gram of loading dose for a 3-gram infusion over 24 hours versus placebo. And I appreciate that they actually used the methodology from the HALTIC trial for us to see how they can be replicated. So, the patient will receive standard management, including receiving antibiotic if they have concern for sepsis or SBP. Patients actually get telepressin initially on admission within 30 minutes, and if there's a contraindication, they will receive somatostatin instead, and all these patients will receive IVPPI as well. Then after all the baseline collected, the patient will be followed up to assess for controlled bleeding and re-bleeding until discharge and up to six weeks, and the beta blocker also gets started for the patient from day six and onward. So, for the inclusion-exclusion criteria, they include patients who are older than 18 years old with advanced liposurosis defined as childhood class B or C, and the patient has to have an present with an upper GI bleed within the 24-hour onset. They exclude any non-steroid patients, like ulceration patients, and if you have a gastrointestinal tear, patient with childhood class A, unknown allergy to TXA, or any evidence of DIC. So, for their primary outcome, they want to see what is the proportion of patients five-day treatment failure, and they further define that pretty clearly in their methodology. So, treatment failure defined as absence of controlled bleeding, re-bleeding within five days, or death or need to change in therapy, which is a kind of more compulsive outcome for this. Our first secondary outcome, we're looking at failure to prevent bleeding after five days, need for salvage therapy, blood product use, ICU and hospital length of stay, adverse drug event, and overall mortality and bleeding-related mortality. So, for the statistical analysis, they need about 600 patients, assumed for the 5% drop rate, to have an 80% power to detect a 7.5% difference between treatment group with an alpha of 5%. For their categorical and continuous variable are appropriate. If they need to use type, square, official exact test, and T-test, and Mann-Whitney test. Any missing data would deal with multiple amputation approach, which I think all those are appropriate. So, looking at our result. So, the study recruitment was conducted between October of 2020 to November of 2022. They were screening 794 patients with suspected advanced cirrhosis, and there are about 300 were randomized into each treatment group. So now, looking at our baseline characteristic, there was no difference in terms of sex, age, clinical feature, hematologic, and biochemical parameter. So, on average, we have an average baseline characteristic of 51 years old, male, with a history of previous various bleeding, and had a ligation before as well, and about 50% of these patients are on beta blocker. The source of bleeding mainly stemmed from esophageal varices, and most common initial endoscopic therapy were done in these patients are band ligation. Looking at these patients' childhood class and male score, they're basically similar. However, when I did some calculation, I noticed that these patients have about 6 to 20% mortality based on their male score, which is not as severe of a patient as I thought they would include in the study. Looking at the patient time to get into the hospital, so these patients coming to the hospital and getting endoscopy about three hours, and they don't need time to receive TSA or the placebo within 15 minutes, which is pretty quickly. And then about roughly 20% of these patients will receive antibiotic to help treat any underlying infection, et cetera, going on. So, looking at our primary outcome, we see that TSA shows a significant reduction in 5-day treatment failure compared to placebo. When I study further, I break it down to whether the patient suffered from varicose vein bleeding from ulcer without ulcer, the results show a significant reduction with TSA compared to placebo. For their secondary outcome, I still did not see any difference in overall outcome, including adverse event, mortality, or hospital mortality. I did see a significant reduction in hospital length of stay, and there's a significant less readmission in patients receiving TSA. Re-bleeding after five days post-TSA or placebo was significantly better in TSA group as well. So, with that, the author concluded that TSA significantly reduced the risk of, reduced the failure of control bleeding by five days in each patient. However, there was no difference in five days or six-week mortality between treatment group. And also, they don't see any difference in adverse event in this patient as well. So, for some critique, so this is a, so this is a well-written study. It can help fill some of the gap of the clinical evidence that was missing. And they're actually trying to attempt to replicate a landmark trial with the appropriate methodology, which I appreciate as well. They have a well-balanced baseline characteristic and a well-defined definition for their outcome. For some limitation, it may not, there may be some limited generalizability to the general population. Even if it's a single center in New Delhi, they use telepresence as their anatropic. Compared to us, we probably use mesopressin or octreotide. And they did not examine alternative dosing compared to the previous study. With that, they also did not look at any long-term mortality benefit in this patient as well. So, it's kind of hard to see whether the patient may be passed away due to further bleeding or from the underlying disease they have, like infection, or they just have high mortality after that. So, with that, for my conclusion, this is also a well-designed study that provides additional information that gives us some idea where we can use TXA in acute upper GI bleed. And if we give this TXA early in this patient, we'll have favorable outcome, especially in those with advanced cirrhosis. I did it with different subconcerns of adverse effects, including VTE, PE, or seizure. So, I would recommend using TXA in patients with advanced cirrhosis, patients with acute GI bleed, and maybe not any patients who have childbirth class A. So, with that, it comes to my first polling question. Do you or your colleague currently recommend TXA for different indications outside of traumatic hemorrhage? That's it. I see, yeah, majority of time at my institution too, we mostly use TXA intramural hemorrhage. Maybe there's some post-mortem hemorrhage, but other than that, I don't see a whole lot of uses after, aside from that. And then, so what would you or your colleague recommend to patient admitted to ICU or ED for TXA from now on? Only specifically for acute GIP, I'm sorry for missing that. Okay, so a lot of people are still using the dosing regimen for traumatic hemorrhage. For me, if I have a patient who's coming in with advanced cirrhosis, I probably still want to stick with the trial that we have and would do 1 gram, or 10 gram, and then the 2 gram over 24 hours. So with that, that's the conclusion of my presentation, and I will open the floor for any questions. Thank you. All right. Thank you, Anthony. Do you think, I know based on the poll and then your recommendation, that we should be using these in all patients with an upper GI bleed with cirrhosis, or from what it looks like from the study and what's done here in the U.S. versus maybe where this was done, can you discuss the intervention of TIPS and how that factored into the patients that should receive this therapy or should not receive this therapy real quick? So looking at the study over there, actually any patient who come in with a GI bleed, they actually have a preemptive consent form where they want to proceed with TIPS or not. I did not have a chance to talk over there, but there was about 6 patients out of 300 was okay with doing TIPS afterwards. So even that TIPS is not commonly done in a whole lot of patients, I feel like there will be some difference in patient outcome with regards to that. Yeah. I think that's one of the most notable things is we do a lot of TIPS here in the U.S. Maybe it depends on who's on this call right now, certain centers. So the question is, if you're going to TIPS, should you get this? Or maybe it's you see if you're not going to TIPS, then maybe you can get this. Again, that's just one of many questions I have. Okay. Thank you again. This concludes our Q&A session for this last presentation. So thank you again, Anthony. Thank you so much. So with that, I want to thank all of our presenters today, and also all of you, the audience, and staying past a couple minutes over as well for attending these presentations means a lot to us. Please join us on the third Friday of the month from 2 to 3 Eastern Standard Time for the next Journal Club Spotlight on Pharmacy for some more robust discussion and presentations. This concludes our presentation for today. Again, thank you so much.

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