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 Taylor Rue. I'm an inpatient staff pharmacist at Eskenazi Health in Indianapolis, Indiana, and I'll be moderating today's webcast. A recording of this webcast will be available to registered attendees. You simply log into mysccm.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers, so to submit questions throughout the presentation, type into the question box located on your control panel. You'll 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 the hashtag SCCMCPPJC 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 Alyssa Sykuta, PGY-2 critical care resident at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. Our second presenter is Michael DeCesar, PGY-2 critical care resident at the Johns Hopkins Hospital in Baltimore, Maryland. And our third presenter is Jennifer Hipskind, PGY-2 critical care resident at Centura Health St. Anthony Hospital in Lakewood, Colorado. And now I'll turn things over to our first presenter. All right. Thank you, Taylor, for the introduction. As Taylor said, my name is Alyssa Sykuta. I'm a PGY-2 critical care pharmacy resident at Thomas Jefferson University Hospital. And today I'll be discussing the ULTRA trial, looking at ultra-early tranexamic acid after subarachnoid hemorrhage. So just to provide some context, non-traumatic subarachnoid hemorrhages can be attributed to ruptured intracranial aneurysms about 80% of the time. Aneurysm re-bleeding is associated with very high mortality and poor prognosis for functional recovery in survivors. The risk of re-bleeding is reported in up to 13% of patients within the first 24 hours. And of these, about a third of re-bleeds occur within three hours and nearly half within six hours of symptom onset. Some factors associated with re-bleeding include longer time to treatment, worse neurologic status on admission, initial loss of consciousness, previous sentinel headache, larger aneurysm size, and possibly systolic blood pressures over 160. There are a few key ways in which we can optimize care for patients presenting with aneurysmal subarachnoids. The AHA guidelines suggest surgical clipping, endovascular clipping, and controlling blood pressure with titratable medications should be recommended to reduce the risk of re-bleeding. Blood pressure goals have not been well defined, but the AHA guidelines suggest it's reasonable to maintain a systolic pressure less than 160. For patients with an unavoidable delay in obliteration of the aneurysm, a significant risk of re-bleeding and no compelling medical contraindications, short-term therapy with tranexamic acid or aminoclerotic acid is reasonable to reduce the risk of early aneurysm re-bleeding. While anti-fibroanalytics have been studied in traumatic head injury, there's a gap in knowledge for their utility in aneurysmal subarachnoid hemorrhages. A 2002 randomized controlled trial looked at the efficacy of TXA use for subarachnoids up to 72 hours and found a significant reduction in occurrence of re-bleeding. However, it was underpowered to evaluate impacts on clinical outcomes. In 2013, there was a Cochrane review published which showed that TXA reduced bleeding in patients with subarachnoid hemorrhages but did not have any beneficial effects on clinical outcomes. This is because in most clinical studies, the potentially positive effect of a reduction in re-bleeding was negated by a concomitant rise in delayed cerebral ischemia. Shorter durations of treatment with TXA for less than 72 hours did show reductions in bleeding without an increase in cerebral ischemia, which is where that 2013 AHA guideline statement came from on the previous slide. So our first polling question, just to get a sense of what everyone does in their institutions, is do you routinely use anti-fibroanalytic agents such as TXA for management of subarachnoid hemorrhages? So it looks like 88% of you said no, 12% said yes. So we'll see after discussing this trial, whether that changes your mind at all. So the purpose of the ULTRA trial was to investigate whether ultra early short-term treatment with tranexamic acid or TXA improves clinical outcome at six months. The study was a randomized controlled open label multi-center trial at eight treatment centers for subarachnoid hemorrhage and 16 referring hospitals in the Netherlands. It took place between July of 2013 and July of 2019. They included patients age greater than 18 years who had been symptomatic for less than 24 hours and had a non-contrast CT confirmation of subarachnoid hemorrhage. They excluded patients specifically with perimesencephalic bleeding pattern and a GCS of 13 to 15 without loss of consciousness directly after ictus or focal neurologic deficit on admission. They also excluded patients with diagnosis of traumatic subarachnoid hemorrhage, ongoing treatment for DBT and PE, a history of hypercoagulability, pregnancy, severe renal failure and imminent death within 24 hours. Patients were randomly assigned one-to-one after a non-con CT approved diagnosis of spontaneous subarachnoid hemorrhage. They were randomized to ultra early TXA in addition to usual care or usual care only. For the TXA group, they received a one gram bolus of the drug followed by one gram every eight hours. And this was continued for a maximum of 24 hours or until the start of surgical or endovascular intervention, whichever came first. The 24 hour duration was based on that figure that most re-bleeds occur within the first 24 hours of aneurysm rupture. Of note, this is a different dosing scheme for TXA compared to recent trials, such as the CRASH trials and the STAMP trial in which those studies gave a one gram bolus followed by another one gram over eight hours rather than every eight hours. So a higher total cumulative dose. The primary outcome that the authors looked at was modified Rankin scale six months post-randomization. And in particular, they segregated the results into good versus poor clinical outcomes. They defined a good clinical outcome as a modified Rankin of zero to three. Secondary outcomes the authors looked at included an excellent modified Rankin at six months, which they defined as a modified Rankin zero to two, as well as all-cause mortality at 30 days and six months. Finally, they looked at a variety of safety outcomes. They kind of separated these into four main categories. So they looked at complications of subarachnoid hemorrhages including recurrent bleeding, hydrocephalus and delayed cerebral ischemia. They also looked at complications of treatment including periprocedural thromboembolism, infarcts related to procedure and periprocedural rupture. They looked at other complications including thrombosis, hemorrhage, hyponatremia, infection and seizures. And then finally, they looked at unexpected serious adverse drug reactions. Of note, delayed cerebral ischemia, re-bleeding and hydrocephalus are the safety outcomes that have been most heavily scrutinized in other trials looking at TXA for intracranial bleeding. A power calculation was performed based on an assumption that a good clinical outcome would occur in 69% of the control group and 77% of the TXA group through a reduction in the rate of re-bleeding from 17 to 3.9%. These numbers were based on previous studies that the authors had conducted as well as other previous studies. For their power calculation, they calculated that a sample size of 950 patients was needed to achieve 80% power to detect an absolute difference of 8% in good clinical outcome between groups. Analyses were based on intention to treat principles. Basic T-tests were used to assess descriptive variables. And for the primary outcome and secondary outcomes, multivariable logistic regression was used to calculate adjusted odds ratios for the influence of treatment center and potential differences in baseline characteristics. 955 participants were enrolled in the ULTRA trial with a mean age of 58 years and 67% were female. No major differences in the baseline variables were seen here. For those who may be unfamiliar, the WFNS score correlates with the degree of neurologic impairment assessed by GCS and motor deficits, with one being the least impairment and five being the most. So as you can see, there was a similar distribution between groups. I'd also like to point out that in 14% of the TXA group and 15% of the control group, no causative aneurysm was ever identified for their subarachnoid hemorrhage. The median time from ictus to first CT was 93 minutes. Median time from first signs and symptoms of subarachnoid hemorrhage to start of TXA was 185 minutes. And the median time to aneurysm treatment after CT did not exceed 90 minutes. And the median time to aneurysm treatment after CT diagnosis was 14 hours. In the attention to treat analysis, 60% of the TXA group and 64% of the control group had a good clinical outcome defined as that modified brankin of zero to three. There was no statistically significant difference between the TXA group and the control group in the overall distribution of scores with univariable ordinal shift analysis or adjustment for treatment center. Excellent modified rankin at six months defined as the score of zero to two was significantly lower with the TXA group than the control group. The odds ratio here was 0.73 favoring the control group. Additionally, all-cause mortality at 30 days and six months did not differ between groups. For safety endpoints, TXA had numerically fewer rebleeds prior to definitive aneurysm treatment, but this was not statistically significant. All other adverse events, including hydrocephalus, delayed cerebral ischemia, and thromboembolic complications during endovascular treatment were similar between groups, although seizures did occur more commonly in the TXA group. The author's conclusion was that in patients with CT-proven aneurysmal subarachnoid hemorrhage, ultra-early TXA initiated immediately after diagnosis for a maximum of 24 hours did not improve clinical outcome at six months. There are some strengths of this trial that are worth mentioning. First, it was the largest randomized controlled trial to date of use of TXA for subarachnoid hemorrhage, and the outcomes and design allow for meaningful application to patients in clinical practice. By assessing outcomes at six months, this really gives insight to the types of outcomes that our patients tend to care about, which are the long-term outcomes, and not many trials really look at this. However, I think there were a plethora of limitations for applying this trial to clinical practice. One is that the median time to TXA after CT-proven diagnosis was about three hours, and even in the randomized controlled setting geared for ultra-early start of TXA, it may still be too late to prevent a considerable proportion of re-bleeding, considering that half of all re-bleeds occur within three hours. Second, the modified Rankin score was the primary outcome in this study, and this particular score is known for poor inter-rater reliability, and it was done over the phone, which further complicates that. Finally, assumptions used for the power calculation differed from their actual results. So the number needed for the power calculated based off an assumption of good clinical outcome in 77% of the TXA group and 69% of the control, but in reality, they only found a good outcome in 60% with TXA and 64% with control, so it makes it difficult to interpret the statistical meaning of their study. Some other critiques are an unblinded randomization, convenient sampling, a large number of patients who did not have an aneurysm on angiography, and this can affect power and outcomes as well. Additionally, this was done in a single country, so geography, the Netherlands may have quicker access to CT or endovascular intervention, which may not be as generalizable to our patients in the US. For take-home messages, I think there are a few. One is that in the ULTRA trial, excellent modified Rankin was lower with TXA, which is difficult to explain given the lack of differences in adverse events between the groups, although the TXA group did experience more seizures. The second takeaway is that access to early aneurysm treatment may outweigh the reduction in re-bleeding risk by TXA. And ultimately, the results of this study add to the growing body of evidence that TXA is unlikely to provide any meaningful long-term benefit in patients experiencing bleeding, particularly in the setting of aneurysmal subarachnoid hemorrhage. I would not recommend using TXA in this patient population due to a lack of expected benefit. Let's bring this to our second polling question. Based on this study, would you recommend TXA for patients with diagnosed aneurysmal subarachnoid hemorrhage? A, yes for all patients. B, yes in certain patients, such as those who are not surgical candidates. C, no, not for any patient without another clinical indication. Or D, more clinical trial data is needed. Looks like 61% said they would not recommend TXA in this setting for any patient without other clinical indication. 30% said more clinical trial data is needed. And 9% said yes, they would recommend it in certain patients, such as non-surgical candidates. And with that, I'd be happy to take any questions at this time. All right, I'll go ahead and start off the Q&A with our first question. You discussed some limitations of the modified Rankin scale, like poor iterator reliability. So if you were to redesign the study, would you choose a different primary endpoint? If so, what would you choose? And if not, how could you improve upon the methods used for collecting this information? Yeah, that's a really great point. So the modified Rankin is known not to have great iterator reliability, and it's also a very subjective scale. Unfortunately, most of the studies looking at the neuropopulation and particularly these long-term functional outcomes, we really don't have a great alternative for the modified Rankin. And this is the scale that's used in most other studies. And so for the sake of comparison and standard in the literature, I don't know that I would use anything else. However, I think the importance of training a few particular people in doing the follow-up is definitely important. And I think that had they been able to bring patients back in, sometimes I think it helps to score them on the modified Rankin when you're able to actually see from a third-party standpoint how they're functioning, rather than doing it over the phone where a clinician can't use their own clinical judgment to make some inferences. Great, thanks. Our next question, is this data included in this study any better than the older data that we've previously seen with Amicar? So, I am not very familiar with the older data, particularly with Amicar. I do know that there was a study with TXA done in 2002 that was a randomized controlled trial. And the major differences between that one and this one was that there were actually a much higher incidence of bleed, both with TXA and without in this trial. I'm not aware of anything looking particularly at like TXA versus Amicar in this population, but I'd have to look into that. All right, and then our last question for you. There's a small number in each group that were on anticoagulants prior to the presenting to the hospital, but anticoag reversal, whether that be with four-factor PCCs or platelet transfusion was left to the discretion of the different institution. But that management info, from what I could find, wasn't reported. Do you have any thoughts on sites potentially administering both PCCs and TXA in this instance? And do you think that intervention could have impacted the results at all? Yeah, that's a really great point. So definitely differences in site management of those patients who were receiving anticoagulation prior and whether they chose to give another potentially thrombotic agent in addition to TXA, I do think could have impacted the results. I don't know. I also was unable to find any additional information on the breakdown of how many patients received four-factor PCC. So I don't know the extent to which that would have impacted results, but definitely a confounding variable that was not very well accounted for. All right, thank you so much, Alyssa. That concludes our Q&A session. 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 on this Spotlight on Pharmacy webcast. So if you would please fill out how many attendees are you viewing this webinar with? Just you, two to five people, five to ten people, or greater than ten people. All right, thank you all for answering that. Now I'd like to introduce our second presenter, Michael DeCesar. Thank you for the introduction. My name is Michael DeCesar, and I'm the current PGY2 critical care resident at the Johns Hopkins Hospital. Today I will be presenting on the association between incident delirium treatment with haloperidol and mortality. Starting the stage with some brief background information, delirium is described as a disturbance of consciousness and a change in cognition that develops over a short period of time and tends to fluctuate during the day. ICU delirium is associated with an increased morbidity and mortality, specifically longer ICU lengths of stay and long-term cognitive impairment. Delaying treatment of delirium may increase mortality. Incident delirium is delirium that occurs after ICU admission, whereas prevalent delirium is delirium occurring before or at ICU admission. Haloperidol, a typical antipsychotic, is commonly used in ICU delirium management. The PADIS guidelines from 2018 make conditional recommendations against the use of haloperidol to prevent delirium and against the routine use of haloperidol to treat delirium. What does the existing literature tell us about haloperidol use in delirium? In 2013, the HOPE ICU trial was published. This was a single-center, randomized, double-blind, placebo-controlled trial that evaluated 141 clinically ventilated patients in a mixed medical and surgical ICU. Patients were randomized to haloperidol 2.5 milligrams IV every eight hours or placebo. There was no difference in delirium-free and coma-free days between groups. In 2018, the MIND-USA trial was published. This was a multi-center, randomized, double-blind, placebo-controlled trial that included 566 patients with delirium prior to enrollment and acute respiratory failure or shock in a medical or surgical ICU. Patients were randomized to one of three groups, haloperidol, zeprazidone, or placebo. There was no difference among groups with regard to the primary outcome of delirium-free and coma-free days alive. And finally, the REDUCE trial was published in 2018. To note, the trial I will be reviewing in depth today is a post-hoc analysis of the REDUCE trial. The REDUCE trial was a multi-center, randomized, double-blind, placebo-controlled trial including 1,789 patients without delirium on ICU admission, an expected ICU length of stay greater than or equal to two days. Along with the standardized non-pharmacologic protocol, patients were randomized to one of three groups for prevention of delirium, haloperidol one milligram IV three times a day, two milligrams IV three times a day, or placebo. Of note, enrollment into the one milligram group was stopped early due to futility. Patients who developed delirium were encouraged to be treated with open-label haloperidol. There was no difference in 28-day survival between the haloperidol two milligrams IV three times a day group and placebo. These trials suggest that haloperidol does not reduce the incidence or duration of ICU delirium or mortality. Now we will dive further into the trial titled Association Between Incident Delirium Treatment with Haloperidol and Mortality in Critically Ill Adults by Dupre and colleagues published in Critical Care Medicine. The research question the authors were looking to answer was, when used to treat delirium not present on ICU admission or incident delirium, is haloperidol associated with reduced mortality? This differs from previous studies in targeting treatment of incident delirium specifically. Like I mentioned previously, this was a post hoc analysis of the REDUCE trial, a three-armed multi-center randomized double-blind placebo-controlled trial. For delirium prevention, patients were randomized to receive either haloperidol one milligram IV three times a day, two milligrams IV three times a day, or placebo. Patients were assessed three times a day from the time of ICU admission for up to 28 days for the presence of delirium, defined as a CAM-ICU positive assessment. If delirium was present, providers were encouraged to initiate open-label haloperidol at two milligrams IV three times a day and titrate to a maximum dose of five milligrams IV three times a day based on symptoms. Rescue sedative medications were permitted per provider discretion. The focus of this post hoc analysis was on the association of this treatment dose haloperidol and 28- and 90-day mortality. Included were adult patients with expected ICU length of stay of greater than or equal to two days and delirium not present on ICU admission, patients at risk of prevalent delirium or delirium present before ICU admission, and those in whom CAM assessment could be confounded or excluded, such as patients with acute neurological conditions, history of dementia or psychiatric disease, or alcohol abuse disorder. Patients with significant safety concerns were also excluded, such as those with a QTC of greater than or equal to 500 or patients with a history of ventricular arrhythmia within the last year. With regard to the statistical analysis, a multivariable Cox regression model was created for 28- and 90-day mortality. In this model, the authors controlled for several a priori determined factors expected to impact delirium, which included the total number of days with delirium or coma, age, admission severity of illness based on APACHE-2 scores, presence of sepsis, mechanical ventilation, and ICU length of stay. Additionally, several sensitivity analyses were performed to confirm association. A P-value of less than 0.05 was considered statistically significant. In the 489 patients from the reduced trial that were administered treatment haloperidol were mostly males in their late 60s with a higher acuity of illness based on admission APACHE-2 scores and a medium ICU length of stay of 9 days. Over 90% of patients that received treatment haloperidol were mechanically ventilated during their ICU admission, and over a third had sepsis. Almost all patients were delirious at some point in their ICU stay, with the majority also having at least one day of coma, defined as a RAS score of minus 4 or minus 5. The average daily haloperidol treatment dose was 2.1 milligrams and never exceeded 4.5 milligrams per day. Haloperidol treatment was administered on average for 6 days. Of note, only 10 patients continued haloperidol after ICU discharge. After controlling for the previously discussed risk factors for delirium, each milligram of treatment haloperidol administered daily to a patient with delirium was associated with a 7% decrease in 28-day mortality and a 3% decrease in 90-day mortality. When considering the interaction of time along with haloperidol dose, the association between haloperidol treatment and mortality decreased daily as haloperidol was administered later in the ICU course. To visualize these results, this is a graph looking at the dose and time-dependent nature of the association between haloperidol and 28-day mortality. To orient everyone, the Y-axis represents the daily hazard ratio for 28-day mortality and on the X-axis, ICU day. The horizontal bold black line represents a hazard ratio of 1. The sloped red line represents the daily hazard ratio with 95% confidence intervals. The strength of the association between haloperidol treatment and 28-day mortality decreased daily as haloperidol was administered later in the ICU course, depicted by the daily hazard ratio approaching 1 over time. The significance of the association was detected through day 19 as represented by the star, where the confidence interval crosses 1. The authors performed a plethora of sensitivity analyses included on this slide, adding additional factors to the core Cox regression model, the authors controlled for study arm allocation of the reduced trial for delirium prevention, the total haloperidol exposure from both prevention and treatment doses, mechanical ventilation as a potential marker for greater daily severity of illness, surgical versus medical admission type, and several time-varying covariates not listed on this slide. These sensitivity analyses resulted in no change in the direction or strength in the association between haloperidol and mortality. Additionally, the removal of the number of delirium or coma days from the core Cox regression model also did not impact the association seen, suggesting some potential reasons for the mortality benefit observed are independent of days spent in delirium or coma. The authors concluded that among patients without delirium at the time of ICU admission, the dose of haloperidol administered for the treatment of incident delirium and its symptoms may be associated with improved survival. The authors go on to mention that clinicians should not assume treating delirium and its symptoms with haloperidol will reduce mortality. The strength of this trial included robust statistical analysis, which included regression models controlling a priori for confounding variables that are known risk factors for delirium. Additionally, only patients with incident delirium were evaluated, which is in contrast to previous literature, which included patients with both incident and prevalent delirium or delirium before or on ICU admission. Patients were also managed with a standardized non-pharmacologic delirium prevention bundle, which has been shown to significantly reduce delirium that is now considered standard practice. Weaknesses or limitations of this trial include the inherent limitation of a post hoc cohort analysis, which introduces selection bias. Also within the parent trial, delirium symptoms were not characterized and daily RAS scores were unavailable. Without this information, we cannot determine if these patients had hypoactive, hyperactive, or mixed delirium, which may impact the decision to use haloperidol or other antipsychotics in clinical practice. Another limitation includes the haloperidol treatment dose titration, lack of standardization, with average daily doses not exceeding 4.5 milligrams per day. This dosing strategy may not be able to be generalized to widespread clinical practice. Lastly, other pharmacologic therapies that may impact delirium were not assessed, which may have impacted the results. My takeaways from this trial are that haloperidol treatment for incident delirium may be associated with improved mortality in a dose and time dependent fashion. This study differs from previous literature by evaluating treatment of incident delirium specifically and provides supporting evidence for haloperidol use in this setting. This study is hypothesis generating and prospective randomized studies evaluating incident delirium treatment and mortality are needed to confirm these results. My practice will continue, will be to continue treating patients with delirium symptoms with haloperidol or other antipsychotics in addition to non-pharmacologic approaches. This leads into my first of two polling questions. Prior to this post hoc analysis, studies have shown that haloperidol does not reduce delirium or mortality. At your institution, do you routinely treat patients with delirium with antipsychotics? A, yes, B, no. And it looks like about 80% of everyone said yes. And I think this is consistent with most clinical practice and would be consistent with my clinical practice that I've had experience with in the last two years. And my second polling question, at your institution, what initial dose of haloperidol do you routinely recommend for treatment of ICU delirium? A, 1 milligram, B, 2 milligrams, C, 5 milligrams, D, 10 milligrams, or E, other? And it looks like almost 60% answered with 5 milligrams. And that would also be my standard or routinely recommended dose of haloperidol. Obviously, if there are specific patient factors in play, that would potentially lead me to a reduced dose, which would be around 2 or 2.5. And with that, I'd like to thank everyone for taking the time to listen this afternoon and would love to open the floor to questions and discussion. Thanks, Michael. Your first question, the authors reported compliance to the non-pharmacologic delirium management protocol was fairly high, about 88%. How do you think that compares to global standards and do you think that had any impact on the applicability of the results? Sure. I don't have an exact percentage of what the global percentage, per se, would be to similar non-pharmacologic practices, but I would anticipate that it would be lower than that 88%. They mentioned that the specific factor within there was noise canceling strategies that were difficult to adhere by, which I would imagine would be the most difficult within ICUs because of all of the beeping and noises from different machines. And I think this, although that is the standard of practice, it could have had an impact on this trial, but to what extent, I'm not sure that I can make a leap to say. All right, thank you. Next question for you. What was the incidence of patients with a history of substance use disorder and specifically alcohol use disorder? If it wasn't reported, how would this affect the evaluation of delirium in the study? Well, alcohol abuse disorder patients were excluded, so that wasn't reported. And then specifically substance abuses, they did not report that as well. All right, and our last question for you. Was there any discussion of assessment of QTC prolongation, and do you think there's any value in implementing standardized telemetry or EKG assessment based on the study's intervention? The study did not consistently follow QTC monitoring, but that is something that I do think would be valuable, depending on the doses that you are using with haloperidol and any other concomitant medications that put you at risk for a prolonged QTC. So that is something that in my personal practice that I do monitor when there are patients that I believe that are at higher risk or have those concomitant medications that could lead to a higher risk. All right, great. Thank you. Well, that concludes our Q&A session for Michael. And now I'd like to introduce our final presenter, Jennifer Hipskind. Thank you, Taylor. So, again, my name is Jennifer Hipskind. I am the PGY-2 Critical Care Pharmacy resident at Centura Health St. Anthony Hospital, and I'm here to talk to you about the PGI-2 Critical Care Pharmacy resident at Centura Health St. Anthony Hospital, located in Lakewood, Colorado. Today, I'll be discussing the article titled Indexonet Alpha versus Four-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage. Indexonet Alpha was approved in the United States in 2018, and it is a selective anti-Xa inhibitor that acts as a decoy for the anti-Xa drugs to bind to, thus freeing Xa to promote hemostasis. Despite its approval, there's little guidance in making the clinical decision between using Indexonet Alpha versus alternative therapies, such as Four-Factor Prothrombin Complex Concentrate, or Four-Factor PCC, for the treatment of life-threatening bleeding associated with oral factor Xa inhibitors. The 2020 American College of Cardiology Expert Consensus Statement supports with a moderate recommendation that either treatment option may be used in managing bleeding in patients on oral Xa inhibitors, which leaves the question whether one agent is more effective than the other for reversal in various indications, such as intracranial hemorrhages related to anti-Xa agents, as both rivaroxaban and apixaban have been associated with intracranial hemorrhages at rates that range from 0.1 to 4%, as seen in previous clinical trials. The Annexa IV trial published in 2019 was a key prospective study that supported the approval of Indexonet Alpha for the reversal of Xa inhibitors. 352 patients were included who had received a Xa inhibitor less than 18 hours prior to a major acute bleeding event, and 64% of these patients had an intracranial hemorrhage. Patients received a bolus of Indexonet Alpha followed by an infusion, and the dosing was determined by which anti-Xa drug the patient received as well as the timing of the last dose. Excellent or good hemostasis occurred in 82% of patients who could be evaluated for hemostatic efficacy at 12 hours, and within 30 days, a thrombotic event occurred in 34 or 10% of patients. A retrospective study by Panos and colleagues published in May of 2020 sought to evaluate the safety and efficacy of both activated and four-factor PCC for factor Xa inhibitor-related intracranial hemorrhage. A total of 663 patients were included and assessed for safety outcomes, while 433 patients were evaluated for hemostatic efficacy, where the investigators observed excellent or good hemostasis in 81.8% of patients within 24 hours post-treatment. 25 patients had a thrombotic event, and most occurred within 14 days of PCC administration. Finally, a study published in July of 2020 by Barra and colleagues investigated Indexonet Alpha and four-factor PCC for reversal of rivaroxaban and apixaban associated specifically with intracranial hemorrhages. 18 patients received Indexonet Alpha while 11 were treated with PCC. It is worth noting that the patients in the PCC group had a lower median GCS score of 10 compared to those in the Indexonet Alpha group with a GCS of 15. For their results, good or excellent hemostasis occurred in 88.9% of Indexonet Alpha patients and 60% of PCC patients at 24 hours post-treatment administration. Good applications occurred in 16.7% of the Indexonet Alpha patients and 9.1% of the four-factor PCC-treated patients within 30 days of treatment. And now for our first polling question. Do you currently use Indexonet Alpha at your institution for the reversal of oral 10A inhibitor-related intracranial hemorrhage? So it looks like most people do say that they either never use it or they do not have IndexNet Alpha. And I will say that's probably in line with my experience as well so far, as I also do not have access to IndexNet Alpha. Due to the gap in literature comparing these two reversal agents, the authors of this study investigated the outcomes of patients and treated with indexnet-alpha or four-factor PCC to reverse intraparenchymal, subarachnoid, subdural, and other intracranial hemorrhages in the setting of apixaban or rivaroxaban. This was a retrospective single-center study at Yale New Haven Health System by Amar and colleagues. It included adult patients admitted from July of 2018 to April of 2019 for traumatic or spontaneous intraparenchymal, subarachnoid, subdural, and other intracranial hemorrhages. To be included, patients had to receive at least one dose of indexnet-alpha dosed for life-threatening bleed or four-factor PCC dosed at 25 units per kilo per dose with a maximum of 2,500 units per dose, and patients were excluded if they received both indexnet-alpha and four-factor PCC. The primary outcome was stable head CT scan at 6 hours and at 24 hours post-intervention administration. Each brain imaging study was independently reviewed by three experienced providers blinded to the treatments and outcome and rated for stability. Stability was defined as a similar amount of blood from one scan to the next. For intraparenchymal hemorrhages, the volume of the hematoma was calculated using the ABC2 volume estimation method and defined as an increase in volume of less than 6 mLs or 33% of the baseline volume. Secondary outcomes included good functional outcome at hospital discharge, incidence of thrombotic events, hospital and ICU length of stay, disposition at discharge, and mortality. Continuous variables were analyzed using the Mann-Whitney U test and categorical variables using either Chi-squared or Fisher's exact test. Logistic regression was used to adjust for age and sex. A subgroup analysis was performed in patients with intraparenchymal hemorrhage and further adjusted based on baseline hemorrhage volume. All analyses were performed using R software and a p-value of less than or equal to 0.05 determined statistical significance. For the results, a total of 44 patients presented with intracranial hemorrhage during the study period. 16 were traumatic and 28 were spontaneous, with the majority of the spontaneous hemorrhages being intraparenchymal. 28 patients were treated with indexinet alpha and 16 with four-factor PCC. There was no significant difference between the groups in the majority of the baseline characteristics, indication for anticoagulation therapy, the type of bleed, or the size of intraparenchymal hemorrhage volume at baseline. However, there were 11 patients, or 39%, in the indexinet alpha group compared to 1 patient, or 6%, in the PCC group on concomitant therapy with an antiplatelet agent. The primary outcome found no significant difference in proportion of patients with stable neuroimaging between the indexinet alpha and four-factor PCC treatment at 6 hours with a p-value of 0.71 and at 24 hours with a p-value of 0.15. This outcome remained non-significant after adjustment for age and sex. In the subgroup analysis of patients with intraparenchymal hemorrhage, there was also no significant difference in stable neuroimaging between indexinet alpha and four-factor PCC groups at 6 hours and at 24 hours. And overall, there was no difference in the degree of hemostasis achieved based upon hematoma volume at 6 or 24 hours. For secondary outcomes, they found no significant difference in the incidence of thrombotic events or in the number of patients with good outcomes upon discharge. This study aimed to fill a gap in the literature, which was comparing these two possible reversal agents that may be used for 10A inhibitors. The study population was inclusive of both traumatic and spontaneous forms of intracranial hemorrhage. However, there were more patients who presented with a spontaneous hemorrhage than traumatic, and a limited number of trauma patients received indexinet alpha. Further, the median GCS score of both groups was 14, so generalizability to the traumatic hemorrhage population and those with severely impaired consciousness may be limited. Additionally, there was a difference between the groups in percentage of patients also on antiplatelet therapy, with significantly more patients in the indexinet alpha group being on aspirin. The risk of intracranial hemorrhage is likely elevated in patients on both antiplatelet and anticoagulant therapy, and being on both may confound the reversal effect seen. Another limitation is the small population size, which also continued to get smaller after the initial presentation, as some patients were unable to have CT scans that could be evaluated at the 6 and 24-hour timeframes. This dropped the evaluated patients from 44 to only 27 that could be evaluated for the primary outcome by the 24-hour follow-up. This table shows a few results from each of the studies previously discussed, with our primary article highlighted with a red outline. When we look closer and compare the patient populations, there was a similar percentage of traumatic hemorrhage patients who received indexinet alpha in the original ANEXA-4 trial and in this new study, but a larger percentage was seen in the study by Barra and colleagues. The distribution of traumatic hemorrhages that received PCC ranged from 45 to 51 percent, so this was fairly similar across the studies. However, there was a wide distribution of type of hemorrhagic bleed found in the studies, so this was not listed out in this table. Overall, a similar mean or median GCS score of 14 was seen, with the exception of the four-factor PCC group in the Barra trial with a GCS of 10. For the treatment dosing, indexinet alpha was dosed the same in the three trials where it was studied, and a majority of patients received the lower-dosing regimen. Looking at the studies that assessed the use of four-factor PCC, better hemostasis was achieved in the PANOS trial, which also saw a higher average dose of four-factor PCC at 43.8 units per kilo, compared to the Barra study at 26.9 and this newest trial at 26 units per kilo. Overall, hemostasis results with four-factor PCC at the 24-hour follow-up ranged from 60 to 79.4 percent, which may have been influenced by the dosing used. For the indexinet alpha, hemostasis was achieved in anywhere from 82 to 88.9 percent of patients between 12 and 24 hours of follow-up, so there is some consistency seen in those results. Finally, the authors in this study found no statistically significant difference between the groups for percentage with stable neuroimaging. Looking strictly at percentage differences, there was a 7 percent difference between the groups with a number needed to treat of 16 at the 6-hour evaluation. This then changed to a 28 percent difference between the groups with a number needed to treat of 4 at the 24-hour follow-up. However, neither result was statistically significant at the conclusion of the study. Due to the small patient population, there is an increased risk for type 2 error in that there may actually be a difference between the two treatments, but the study was unable to detect it. And now for the second polling question. Based upon this study, would you use indexinet alpha for reversal of oral 10A inhibitors in patients with intracranial hemorrhage? A, more likely to use, less likely to use, C, use as adjunctive treatment after other reversal agents, or D, your practice is unlikely to change based on presented data. It looks like a majority of people, almost 60 percent, say that their practice is unlikely to change based on presented data, and then about 31 percent would be less likely to use indexinet alpha. In conclusion, the study was designed and executed well. There is no difference found between the groups, however, the small sample size limits the conclusions that can be drawn. Until further research is completed, I believe that it is reasonable to continue to use four-factor PCC as a cost-saving alternative to using N-dexnet-alpha for the reversal of oral 10A inhibitors. These are my references. And thank you for listening to my presentation. I'd be happy to open the floor for questions at this time. Thanks, Jennifer. Go ahead and start off your Q&A with the first question. One of the secondary outcomes they looked at was modified ranking score at discharge. How valuable do you think that information is to correlating clinical outcomes, and do you think there'd be any benefit to comparing data at three months versus at discharge? Yeah, that's a great question. The modified ranking scale at discharge was an interesting secondary outcome to look at, and it was one that was looked at in previous studies, so it was most likely that they were kind of mirroring what has been done in previous studies, but I do agree that looking at maybe patients' outcomes later at perhaps a three-month follow-up may be more beneficial than looking directly at the discharge timeframe. Thank you. Thank you. Next question. Based on the current data we have available, what four-factor PCC dosing strategy would you recommend? There's some debate between weight-based dosing and fixed dosing. What would you recommend based on the data we have available? Based on the data that was available and that I saw when looking through these various studies, it looked like a majority of the patients were receiving anywhere from 25 to 50 units per kilo. Everything was kind of weight-based, so none of it discussed the fixed dosing, and even in this trial, we had a fixed dose, but that was only for each individual doses, and patients could receive multiple doses of the four-factor PCC. I guess just based on this data, my own personal opinion would be to continue using the weight-based dosing. However, the fixed dosing does have its own benefits in being able to mix quicker and get to the patient in a more timely manner. Great, thank you. I don't see any additional questions in our chat box, so I believe that will conclude our Q&A session. Thank you so much, Jennifer. Thank you. Thank you to all of our presenters for presenting today. You guys all did a great job, and thank you to the audience for attending. Please join us on the third Friday of the month from 2 to 3 p.m. Eastern Time for the next Journal Club Spotlight on Pharmacy. That concludes our presentation for today. Thanks, everyone.

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