Hello, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine's CPP section. My name is Scott Allen, Critical Care and Emergency Medicine Clinical Pharmacist at the University of Utah Health in Salt Lake City, Utah. 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 the 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 live discussion on Twitter following hashtag sccmcppjc and hashtag PharmICU. Please note the disclaimer stating that there is content to follow, that the content to follow is for educational purposes only. And now I'd like to introduce your speakers for today. Each will give a 15-minute presentation followed by a Q&A. Our first presenter today is Kaitlyn Rousseau, PGY-2 Critical Care Pharmacy resident at Atrium Health Wake Forest Baptist in Winston-Salem, North Carolina. She will present on bivalerogen plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention, a randomized trial. Our second presenter is Kelsey Tate, PGY-2 Critical Care Pharmacy resident at Carilion Roanoke Memorial Hospital in Roanoke, Virginia. She will present on comparison of four-factor prothrombin complex concentrate and indexin alpha for reversal of pixaban and ribaroxaban in the setting of intracranial hemorrhage. Our third presenter is Evan Wright, PGY-2 Critical Care Pharmacy resident at UCSF Medical Center in San Francisco, California. He will present nighttime dexminutambion for delirium prevention in non-mechanically ventilated patients after cardiac surgery, a single-center, parallel arm, randomized, placebo-controlled superiority trial. And now I'll turn things over to our first presenter. Thank you for that introduction, Scott. I'm excited to share the BRITE-4 trial with you all today. Before we jump into the trial, I wanted to give a brief overview of the agents we're going to be discussing today. First, heparin, which we are all familiar with, potentiates antithrombin 3, thus inactivating thrombin in factor Xa. The half-life of heparin is around 60 to 90 minutes, and it is metabolized hepatically. Bivalirudin, on the other hand, is a direct thrombin inhibitor with a half-life around 25 minutes, and it is metabolized via proteolytic cleavage. Because bival is roughly 70% metabolized by this proteolytic cleavage, with the remainder being renally metabolized, you'll see that we do dose adjust for renal dysfunction. But the primary patients to really be concerned about using bival in is our patients with heart failure, with a reduced ejection fraction, or any other disease where you might have a lower flow rate or pooling of blood, because when this happens, proteolytic cleavage can metabolize bivalirudin in that area of pooling blood, and eventually lead to thrombosis in that region. Now that we know which agents we'll be discussing, let's review the guideline recommendations for PCI in STEMI patients. Here I am referencing the European guidelines, since they have been updated most recently. PCI should be performed within 12 hours of symptom onset, and less than 120 minutes from STEMI diagnosis. Guidelines offer unfractionated heparin, Lovenox, and bival as anticoagulant options, but make the recommendation that heparin should be used routinely, and bival should be considered in patients with HIT. And then lastly, the guidelines do not comment on a post-PCI bivalirudin infusion. They only say that routine post-procedural anticoagulation is not indicated after primary PCI, unless the patient has a separate indication for anticoagulation, whether that's full-dose or prophylactic. So with that in mind, let's move on to discussing the previous literature that led to this trial. First we have the HORIZONS AMI trial. This compared bivalirudin to heparin with GP2B3A inhibitors and found that bival reduced 30-day rates of major bleeding and all-cause mortality, but it did increase the rates of acute stent thrombosis compared to heparin. Next we had the HEAT PPCI trial, which showed that unfractionated heparin reduced the incidence of major adverse ischemic events without increasing bleeding complications compared to bivalirudin. However, bivalirudin was associated with an increased risk of stent thrombosis. Next we had the FIRST BRITE trial, which showed that bivalirudin with a post-PCI infusion reduced bleeding events without increasing the risk of major adverse cardiac events or cerebral events or stent thrombosis compared to unfractionated heparin with or without tarofaban. Next we had the MATRIX trial, which showed that bivalirudin and unfractionated heparin had similar rates of MACE, composite death, MI, and stroke. However, bival was associated with a lower cardiovascular mortality and bleeding, but a more definite rate of stent thrombosis. Lastly, we had the VALIDATE SWEETHEART trial, and this showed no difference between bivalirudin and unfractionated heparin with respect to mortality, major bleeding, or stent thrombosis. Both the MATRIX trial and the VALIDATE SWEETHEART have many limitations, which we don't have time to discuss today, but these results should be taken with a grain of salt compared to these first three trials. So up to this point, you can see that the literature has gone back and forth about which agent should be used in our STEMI patients undergoing primary PCI. And with the increased rate of stent thrombosis, many institutions have moved to using heparin for PCI, but with bivalirudin being the agent with a potential mortality benefit, there was really a need for a well-designed trial comparing these two agents for this indication. And before we move on, we're going to go ahead and jump into the first poll question, which anticoagulant is used at your facility in STEMI patients undergoing primary PCI? I will tell you that at our institution, we are primarily using heparin for our STEMI patients who are undergoing PCI. Okay, so let's go ahead and jump into the BRITE-IV trial. This was an investigator-initiated, open-label, randomized controlled trial that was conducted in 87 clinical centers in China, and it was designed to evaluate the safety and efficacy of bivalirudin compared to unfractionated heparin in STEMI patients undergoing primary PCI. Patients were included regardless of age, and they had to be experiencing a STEMI within 48 hours of symptom onset or having a planned primary PCI. Patients were excluded if they were unable to receive PCI or if they received thrombolysis, anticoagulation, or one of our GP2B3 inhibitors before PCI. After inclusion, patients with STEMI undergoing primary PCI received DAPT with aspirin and clopidogrel or ticagrelor, and then they were randomly assigned one-to-one to receive unfractionated heparin monotherapy or bivalirudin with a post-PCI high-dose infusion for two to four hours. Bivalirudin was dosed according to ACTs, and it was preemptively dose-reduced in patients who did have renal dysfunction. Tirofaban was reserved for thrombotic complications in both groups during PCI. The primary outcome was a composite of all-cause mortality or BARC type three to five occurring within 30 days, and the secondary outcomes that are listed on this slide and included major adverse cardiac events or cerebral events, stent thrombosis, and bleeding. And the statistical analyses used with respect to these outcomes were appropriate. Included patients were around the age of 60 and were predominantly male, and you can see the average dose of heparin on this slide is around 5,570 units. And then in the bivalirudin group, it's important to note that all patients who received the agent received a post-PCI infusion for approximately three hours. Similarly, the rates of hypertension, type two diabetes, and previous stroke or MI were similar between groups. 60% of patients had a Killip class one, meaning they had no clinical signs of heart failure. And then patients in both groups did receive Tirofaban with the majority being given via the intracoronary route and the remainder being given as an IV infusion. And then lastly, I do wanna point out the DAPT regimens that were used in this trial with around 34% of patients receiving Clopidogrel and 65 to 66% of patients receiving Ticagrelor. Since Prostugrel is not available in China, no patients received Prostugrel in this trial. The primary endpoint was a composite of death from any cause, death from cardiovascular causes, and bark type three to five bleeding, and does favor by Valirudin. This is primarily driven by a decreased rate of death from any cause and a decreased rate of bark type three to type five bleeding. However, I do wanna point out that the bark type three to type five bleeding occurred in less than 1% of patients in both groups. And notably, the Heparin group did have significantly more type three bleeds, which means they had more overt bleeding with a hemoglobin drop that potentially required a transfusion. Reinfarction and stroke rates were similar between the different groups, but interestingly, stent thrombosis was significantly lower in patients who received by Valirudin, which is different from all of the previous literature or some of the previous literature that we reviewed at the beginning. And then lastly, by Valirudin was shown to reduce the net adverse clinical events, which included major adverse cardiac or cerebral events and bark type three to type five bleeding. There were 19 pre-specified subgroup analyses conducted with almost all of the 19 subgroup analyses favoring by Valirudin. And while the authors claim that these three subgroups that I've listed on this slide favored Heparin given their P-value, you can see from the forest plot that these claims are not substantiated as you do see the lines crossing that center line. And that red box, I really wanna hone in on the Killip class, which I think is one of the most interesting of these subgroups, because it makes sense that these patients with lower cardiac output states would potentially benefit from the use of Heparin over by Valirudin given its mechanism of metabolism via proteolytic cleavage as we discussed previously. And then lastly, the Crusade score is a bleeding risk score that stratifies patients with insomnia who are undergoing anticoagulation and just helps determine their risk of bleeding. In summary, this trial did have a very large sample size that was powered to detect a difference in their composite primary endpoint of death and bark type three to five bleeding. And they also had a short time to intervention, which is mostly representative of our patient population, while still allowing for patients to present within 48 hours as the guidelines would suggest. This trial also has a strong internal validity and design. And most of the patients had primarily radial access PCI, which is known to decrease bleeding risk in this patient population. Weaknesses of this trial include the patient population because given this location of the study, the baseline characteristics reflect a different patient population than what is likely found here in the US. So that limits its generalizability to certain patient populations. Another limitation that the authors even note is that they did not adjust the secondary endpoints for multiple comparisons, which increases the risk of a type one error. Next, as we discussed, these three subgroup analyses were touted as favoring heparin, but as you saw, the forest plot does not clearly favor heparin. They also didn't evaluate for HIT diagnosis in patients with acquired thrombocytopenia, which could have affected adverse outcomes associated with heparin. And next, there wasn't reported monitoring of the therapeutic efficacy of heparin or bivalorudin after the procedure, despite bivalorudin having that extended infusion. And then lastly, I wanna address the stent thrombosis outcome. The authors reported more stent thrombosis in the heparin group, which is different from the primary literature. Despite this difference, the authors don't provide any more information about the patients who experienced stent thrombosis. For example, in the bivalorudin group, were these patients who had low cardiac output states or did they receive that post-op infusion for a shorter duration, et cetera. And moreover, I think it's difficult to draw conclusions regarding the subacute stent thrombosis rate, as these are likely not due to anticoagulation post-PCI. Because we know that skill level and experience play a really large role in the success of stents. And so some of these thrombosis could have been related to a mechanical issue like improper placement, because some of the included institutions who contributed very low numbers to the patient population may have had less experience or even just seen lower volumes of PCI patients and perform this procedure less frequently. So with that in mind, I would like to talk about some clinical application pearls. So bleeding outcomes in PCI are multifactorial and they can be related to CKD or the interventionalist skill, the use of GP2B3A inhibitors, the use of femoral access, et cetera. And then bleeding is an independent predictor of mortality post-PCI. So having an agent like bivalorudin, which showed a decreased rate of major bleeding may lead to a practice change. And then next, the ECT or the echo and clotting time is the gold standard for bivalorudin monitoring. And while it's not routinely something we do in clinical practice, it would have been helpful in the trial to use this monitoring to better assess the efficacy of bival. And then lastly, there is substantial evidence that links CYP2C19 loss of function alleles with poor clinical outcomes among patients who are receiving clopidogrel for ACS. And that's particularly in those patients who are undergoing PCI. So with over 50% of patients of Asian descent having more than one of these alleles, this could have impacted the results of this trial given the patient's population and the location. Overall, I do think that we could see some practice change as a result of this trial. And I really look forward to seeing the next iteration of the guidelines to see if they make any different recommendations in light of BRITE-4. So with that in mind, I have our last poll question here. Which agent would you prefer to use in a patient with a low cardiac output or low flow state who is undergoing PCI? Great. I totally agree. I think heparin is the better option in this patient population, given the metabolism of bivalirudin. Thank you guys for your time. I'm happy to take any questions. Thank you, Caitlin. I would like to ask you a question. When I was looking through the different characteristics of the patient populations, I noticed that there were more patients in the heparin group who had multivessel interventions. I was wondering if you thought that that may have had any impact on the results, particularly with, for example, mortality and things like that. I think that's a great question. I mean, we talked a little bit about how important interventionalist skill is. So if they're having multivessel interventions and placing stents in multiple vessels, I do think that that could have potentially impacted the results. I would have to go back and look at exactly what percentage of patients did have multivessel disease. But I do think that's a good point and something to definitely keep in mind. Excellent. Thank you. I had another question for you, if you don't mind. Again, looking at the differences between the two groups and thinking about the patients that I see in my practice, I found it interesting as well that the ACT between heparin and bivalirudin were different. So heparin was lower at 267 versus 321 on average versus bivalirudin. And we know that with heparin, that is pretty close to the typical target you would expect for monitoring after a dose. I'm just wondering what your thoughts are on if the higher ACTs with bivalirudin may have impacted the efficacy more towards that group or not. Yeah, that's another great question. And I think that's that kind of leads into something that I've been thinking about the whole time with this trial, which is like, are we comparing just an intraoperative heparin versus bival or is this, you know, extended infusion versus not extended infusion? And I don't think that there's, it almost seems like we're comparing apples to oranges since we are having another agent that is continuing for a longer period of time. And so I think with that in mind, it would be nice if they had included those ACT values longer for a longer duration so that we could have seen the duration that patients were therapeutic because I do think that that could potentially be the reason that this trial is favoring bivalirudin because they did have therapeutic anticoagulation levels for longer than the heparin group. Excellent. Thank you. All right. I don't see any other questions. So we will move on. Thank you. That concludes our Q&A session. Thank you so much, Caitlin, for your presentation. Thank you. Before moving on to our next presenter, we would like to ask a brief polling question regarding today's attendance to gain a better understanding of our overall attendance to ensure continued support of the Spotlight on Pharmacy webcast. All right, and now I'd like to introduce our second speaker, second presenter, Kelsey Tate. All right. Thank you, Scott. As Caitlin just went over anticoagulants, I feel like it's only fair that I flip the switch and now talk about reversal agents. So today we'll be looking at the roles of both four-factor prothrombin complex concentrate or PCC and indexonet alpha in reversing oral anticoagulants in the setting of an intracranial hemorrhage. So to provide a little background, oral factor 10A inhibitors or DOACs have become widely used for a variety of indications, as we know, including treatment of VTE and non-valvular atrial fibrillation. They require less therapeutic monitoring than our vitamin K antagonists, such as warfarin, and they have been shown to have comparable efficacy rates along with lower rates of major bleeding. There are several DOACs out there, as you can see from the ones I have listed on the screen, with both apixaban or Eliquis and rivaroxaban or Xarelto kind of being our two workhorses for this group. Although DOACs have been associated with lower rates of major bleeding, that risk is not zero, of course. In the setting of intracranial hemorrhage, the annual rate of anticoagulant-associated bleeding is about 50% lower in patients on a DOAC compared to those on a vitamin K antagonist. As you can see, that 50% reduction is reflective of a very low incidence overall. However, I'd like to point out that the mortality rate of intracranial hemorrhages are usually well over 40, approaching 50%. And if patients do survive, they are certainly at risk for severe disability, which is why it is imperative to achieve hemostasis and prevent progression of that bleed in order to improve our patients' outcomes. These DOACs can be reversed, usually by two primary agents, the first one being our four-factor prothombin complex concentrate, or PCC. PCC is derived from human plasma, containing of factors 2, 7, 9, 10, as well as protein CNS. And it is FDA approved for the reversal of vitamin K antagonists with acute major bleeding or for the need for urgent procedures. However, it is often used off-label for DOAC reversal and is actually recommended within the 2016 Neurocritical Care Guidelines for ICH. And dexanet alpha, on the other hand, is a recombinant modified factor Xa protein indicated for the reversal of either epixaban or rivaroxaban in the setting of a life-threatening or uncontrolled bleed. Data surrounding the use of these two agents continues to grow, but certainly there are limitations and few prospective studies comparing the two against each other. Which brings us to the intent of the study I'm talking about today, which was to compare clinical outcomes in patients taking either epixaban or rivaroxaban who experienced an intracranial hemorrhage and were then subsequently reversed with either PCC or indexanet alpha. Before I dive too deep into the study, I am curious to see how many people have indexanet available at their institution. So I'm seeing a good majority of patients or people do not have INDEXA available on their formulary, a few with restrictions. I would say that's kind of what I was expecting to see. We currently do not have it on our formulary as well. It actually just went up to P&T quite recently for the second time for another review and we decided against adding it to formulary. INDEXA study was a single center retrospective descriptive cohort study conducted at a level one trauma center and tertiary referral hospital between January of 2015 and February of 2021. All adult patients receiving either PCC or INDEXA were for DOAC associated intracranial hemorrhage were included in the analysis, and those ICHs were diagnosed via a CT imaging. Only patients with ICH due to other DOACs or if they were receiving DOAC reversal due to non-ICH bleeds, patients who received other hemostatic agents or clotting factors, or patients who underwent surgical intervention prior to study drug were excluded from the analysis. The primary outcome was either excellent or good hemostatic efficacy at 12 hours post-reversal, and this was defined as either a less than 20% increase for excellent or greater than 20 but less than 35% increase in the hematoma volume compared to baseline at the 12-hour mark. There were multiple secondary outcomes as well, including the change in hematoma size, a patient's functional status at discharge, the need for a surgical intervention. There were a few safety outcomes, including any thrombotic event within 28 days, as well as all-cause mortality. And then lastly, the authors looked at discharge disposition as well as lengths of stay. Patients were given either a weight-based dose of PCC at 50 units per kilogram, maxing out at 5,000 units for the dose, or they were given indexa according to the product labeling as seen here in this table. So there was either a low dose or a high dose, and that was kind of dependent on which agent they were receiving and what time their last dose was. But this is consistent with the product labeling. For statistical analysis, baseline characteristics and categorical variables were expressed as counts or percentages with either Chi-square or Fisher's exact tests. Our parametric continuous data was expressed as means using a t-test, and the nonparametric continuous data was expressed as medians using the Mann-Whitney U-test. And of course, significance was set with an alpha of 0.05. So this brings me to my second poll question real quick, which is what type of dosing scheme for PCC is used at your institution? All right, seeing a good mix of both weight-based and fixed dose, I think this is somewhat a hot topic right now at various institutions. Currently, Carilion did recently switch over to a fixed dose of 2,000 units. We have some internal data here supporting similar hemostatic efficacy rates between a weight-based and a fixed dose, and then we also saw a substantial cost savings. Diving into some of our baseline characteristics, a total of 70 patients were included in the analysis, with more in the PCC group compared to INDEXA. There were no significant differences between these groups, and I've highlighted a few of the interesting characteristics here. So this population was slightly older, with a median age of 80 years, and more patients in the INDEXA group were taking apixaban over rivaroxaban. About two-thirds of patients were anticoagulated with the indication of atrial fibrillation, and nearly half of the population was also receiving concomitant antiplatelet therapy, with aspirin being our most common agent there. Lastly, median GCS upon presentation was 13 and 12 for each group. Only 21 patients from the PCC group and 12 from the INDEXA group were included in our primary outcome analysis. That's because patients with either a subarachnoid hemorrhage or intraventricular hemorrhage were excluded, along with patients who did not have either follow-up CT imaging or if they underwent surgical intervention after reversal. As you can see, hemostatic efficacy was achieved in 75% of patients with INDEXA, and almost 67% of patients in the PCC group, although this was not significantly different between the two. As far as safety outcomes go, there were no differences amongst the two groups as well, with about 20% of patients experiencing a new thrombotic event within 28 days. This was defined as either a new VTE, whether that was a DVT or a pulmonary embolism, cerebrovascular accident or TIA, myocardial infarction, or cardiovascular death. When broken down, all eight patients in the PCC group did experience a VTE, while four out of the five in the INDEXA group had a VTE, and one unfortunately died from a cardiovascular cause. When looking at our secondary outcomes, the need for additional hemostatic agents or surgical intervention after reversal was similar between both groups. Functional status was assessed at discharge and was also similar between both groups, reflecting severe disability, with a modified Rankin scale score of 5, a Glasgow outcome scale score of 3, and a cerebral performance category score of 3 as well. 28-day mortality was similar at about 40% in both groups, which is somewhat aligned with what we would expect for an intracranial hemorrhage. Lastly, median lengths of stay were similar between both groups, with about three days in the ICU and a week total in the hospital. Most patients were then discharged to either a rehab facility or a skilled nursing facility, which fits with the severe disability that we saw, as only about 11 patients were actually able to be sent home. Overall, the authors concluded that there was no significant difference in outcomes between patients who were reversed with PCC compared to those who were reversed with INDEXA. Achievement of excellent or good hemostasis was about 70%, which is consistent with some of the previous literature, looking at hemostasis anywhere from that 6 up to 24-hour mark. There were certainly a couple limitations to this study. It did include a limited sample size of only 70 patients, and then from there, only 33 of those patients were actually included in the primary analysis. The inability to calculate an accurate hematoma volume for those subarachnoids or intraventricular hemorrhages, as well as the lack of follow-up CT imaging, did hinder their ability to include more. Furthermore, there was no power calculation reported, but the authors did state that this study was not powered to detect a difference in the primary outcome. This study, also being retrospective in nature, certainly made it difficult to fully collect some of the pertinent data, such as information regarding blood products and quantities administered after DOAC reversal. Additionally, data was only pulled from their institution, so any kind of information regarding readmissions to outside facilities may have impacted the results, kind of regarding those long-term outcomes or thrombotic complications. And then lastly, this study was restricted to patients with intracranial hemorrhage, so that kind of makes it difficult to generalize these data to other patient populations that may be experiencing life-threatening bleeds for other reasons. In summary, this study suggests that PCC and INDEXA are both suitable choices for DOAC reversal and achievement of hemostatic efficacy. Safety concerns are similar for both, as rates of mortality and thrombotic complications were similar. However, I would like to see some larger prospective trials in order to compare the efficacy of PCC and INDEXA for DOAC reversal in possibly some alternate patient populations. As far as future directions go, I would like to point out that there is another study from INEXA underway right now, the INEXA-I trial, that is looking at INEXA versus standard of care for patients presenting with ICH and life-threatening bleeding that do require a standard of care. So I am kind of curious to see the results of that study with standard of care likely including PCC now, and kind of seeing how the two agents compare against each other at that point. But I think this study, along with some other retrospective studies out there, is certainly just one more drop in the bucket, kind of supporting the use of PCC or INDEXA for DOAC reversal. And with that, I would like to thank everyone for their time, and I would be happy to try and answer any questions you may have. Great. Thank you, Kelsey. The first question that we have from the audience is, do you think an 18- to 24-hour time point would have shown the same outcomes? I mean, it's kind of hard to say. There's some studies out there looking at, you know, some of the INEXA studies looking at the rates of, you know, 10A levels rising after the drip was turned off. So it's hard to say, you know, if in 24 hours that same level of hemostasis might be achieved. You know, I think it's certainly, I think you still would have seen some benefit from either agent at the 24-hour mark, given what we see here in this study at 12. Great. Thank you. So with only 12 patients in the INDEXA group, do you feel like there are enough patients there that we can draw really any conclusions from this study? Do you feel like this added to the literature in your mind? I think, I mean, that's a fair question. I think it's certainly hard to draw any conclusion from a study with only, you know, 12 patients in one group. I think that's hard to apply that to a, you know, a wide audience and say this is a practice-changing result that we found. I do think it adds to some other literature that does support the efficacy of INEXA. So I think because we have that other literature also saying the same or showing the same benefit, I feel kind of comfortable with these results. But I do think that's certainly a limitation with only having 12 in the group. It's kind of hard to draw a solid conclusion from this study by itself. Excellent. Thank you. All right. I don't see any other questions. So we'll move on to our next presenter. Thank you so much, Kelsey. Thank you. Now I'd like to introduce our final presenter, Evan Wright. Thanks so much, Scott. So hi, everybody. I'm really excited to be here. We heard some great presentations on some hematologic topics, but I'm going to change gears a little bit and talk a little bit about ICU delirium. So excited to present my journal, Nighttime Dexmedetomidine for Delirium Prevention in Non-Mechanically Ventilated Patients After Cardiac Surgery or the MINDS Trial. So I have no conflicts of interest or sponsorships to disclose. And the objective today is to analyze the outcome of the MINDS Trial, describe the role of dexmedetomidine in improving delirium management in critically ill patients post-cardiac surgery, and discuss common institutional practices regarding the use of pharmacologic agents for delirium in critically ill patients. Here are some abbreviations that you're going to see throughout the slides and that I will be referring to as we go through this discussion. So diving right into it. Delirium occurs in around 10 to 30 percent of our older adult patients post-cardiac surgery. These numbers are even higher for some of our non-surgical patients. And we know delirium is associated with long-term cognitive deficits, prolonged hospitalization, increased mortality and morbidity, a number of various side effects for our patients in the ICU, as well as a substantial cost to the U.S. healthcare system. And it's always something we struggle with as clinicians trying to manage for our patients in the ICU. We know that the PATIS guidelines do not currently recommend any pharmacologic therapy for the management of ICU delirium, and really first-line agents are to consider non-pharmacologic therapy. And while many institutions around the country, including ours, try very hard to implement non-pharmacologic therapy, this can always be very challenging for specific patients in the ICU. And so we really have been looking for are there good pharmacologic agents that we either have found or we can use to try to help with this for our patients and reduce their delirium and improve their outcomes. So one such option is dexmedetomidine or Presidex, which many of you are familiar with, an alpha-2 adrenergic agonist. And it's emerging as a potential option for a number of reasons. And I think one of the main ones that's cited in a lot of the literature is that it can mimic non-REM sleep and actually help, from a neurophysiologic standpoint, help the body recover as if you were getting appropriate sleep. Many of us are familiar with it, obviously used as a sedative medication for many of our intubated or non-intubated patients. And so this is really where this trial dives into this emerging literature of is this helpful and in which patient's population specifically. So the authors of the MINDS trial really looked at two old trials that had conflicting results. And that's really where they wanted to dive into the literature and figure out, okay, really what is going on here and how can we use dexmedetomidine for our patients? And so the first trial was a trial from Su et al. back in 2016. This was a randomized double-blind placebo-controlled child done in China at two different centers. And so they had a large patient population that was specifically non-cardiac surgery that were both intubated and non-intubated. And they ended up using dexmedetomidine, a continuous IV infusion, at 0.1 mics per kg per hour. And they started that on admit for patients to the ICU and then continued it for about 24 hours or until post-op day one at 800. And their primary outcome was the overall incidence of delirium at seven days. And as you can see here, they really found a dramatic improvement for the patient population that was started on dexmedetomidine versus those that were given a normal saline placebo. This trial didn't dive deeply into or didn't do a great job in analyzing the subgroups to see was this mainly a benefit in intubated versus extubated patients. And it was hard to tell if this would translate to other surgical patient populations. So insert kind of our next big trial from Turin et al. in 2020. They wanted to specifically look at the cardiac surgery patient population. Seeing the results from the previous trial in 2016, they thought if we do a multicenter randomized controlled trial and we look at patients undergoing cardiac surgery with cardiopulmonary bypass, which is a risk factor for worsening delirium post-operatively. Using a similar format where they use a continuous infusion of Presidex, 0.1 mic per kg per hour started before surgical incision and then titrated up to 0.4 mics per kg per hour post-operatively for 24 hours after the start of the infusion, comparing that to a normal saline infusion. And they were looking at actually a combined primary outcome of both reducing post-op AFib as well as reducing delirium for these patients at post-op day five or on hospital discharge. They, unlike the previous trial, actually found that the Presidex group had higher rates of ICU delirium comparatively to the placebo group and that the patients in the Presidex group had higher rates of serious hypotension. So they did not see that same benefit that you saw in the previous trial. And that really brings us to the MINDS trial where the authors were saying, okay, for the cardiac surgery patient population, is this beneficial? And so specifically, this trial wanted to look at patients that were already extubated and also wanted to look at kind of a novel dosing of dexmedetomidine, which we will get into when we talk about the methods of this trial. So the MINDS trial was a single center randomized placebo controlled superiority trial of about 394 people. You can see the inclusion criteria here. Notable exclusion criteria are renal or liver dysfunction, which they defined as being on dialysis or having a child Q score greater than five. Any previous ICU stay within a month or prior cardiac surgery within the past year. And then as this trial was done from 2017 to 2021, and unfortunately, the COVID pandemic hit right in the middle of it, they did exclude any patients that were COVID positive in this trial. Looking further at their methods, patients that met inclusion criteria were randomized one-to-one to receive either dexmedetomidine one mic per KG up to a max of 80 mics as a one-time 40 minute IV infusion nightly at 2100 for up to three nights after being extubated post-operatively or a matching placebo. The primary outcome that they were looking at was delirium occurring on post-op day one assessed using our CAM ICU delirium tool. And they did a modified intention to treat protocol for any patients that did not meet pre-specified dropout criteria. So the pre-specified dropout criteria are in this red box here, but they're specifically any patients that needed a second surgery or had a complication, any patients that was intubated for more than 12 hours post-operatively, or once again, any patient that became COVID positive or had COVID symptoms. The secondary outcomes focused mostly on patient-centered outcomes, looking at the severity of the delirium using the CAM severity scoring system, ICU and hospital length of stay, and then also all-cause mortality in the hospital and at some pre-specified time points. Additionally, they wanted to assess cognitive assessments as well as quality of life for patients. So they also did an abbreviated Montreal Cognitive Assessment or MOCA scoring tool at those same pre-specified time points, as well as use the PROMIS survey system to assess patients' quality of life. So from a statistical standpoint, went through a lot of this already, but they really did this modified intention to treat. They had a sensitivity analysis specifically looking at their per-protocol cohort, where they excluded some of their missing data. They did do a logistic regression comparing between controlling for the randomization strata, excuse me. And then they also did a Kaplan-Meier curve specifically looking at delirium through up to post-op day three. So diving a little bit into our table one and our background characteristics, the groups were relatively well-balanced. The patient population was majority male and majority Caucasian. The average age was around 69 for patients meeting their inclusion criteria. The majority of patients were well-balanced in terms of their cardiac comorbidities and cardiac history. You'll notice the patients did not have any delirium at baseline and were relatively low risk. And then you can also see here their MOCA scores as well as the PROMIS survey scores were relatively even between groups. And as a reminder, for those of you less familiar, the MOCA scoring system is from zero to 22 with zero being poor cognitive function and 22 being optimal cognitive or great cognitive function. So additionally, looking kind of at their surgical characteristics, their cardiopulmonary bypass time was very similar between groups as well as the surgical procedures that were being done. What's very interesting and something to keep note as we start to talk about the results was that the majority of patients actually only received study drug on day zero or day one. As you can see, up to 80% of patients only received doses on those days. And then by days two and three, a large portion of patients did not receive repeat doses of the intervention or placebo. So diving into our primary outcome. So really this outcome of delirium on post-op day one, you can see our percentages 8.5% in the placebo group versus 2.9% in our dexmedetomidine group. This was a statistically significant difference. The delirium severity, however, was no different between groups. Additionally, kind of the primary secondary outcome, they looked at post-op delirium on day three. This difference was not maintained. So there was a decrease in delirium from the Presidex group to the placebo group. However, it's not statistically significantly different. We'll talk a little bit about why this may have occurred. Additionally, the delirium severity at day three was also not statistically significant. Looking at our secondary outcomes, you can see both groups had very similar lengths of ICU stay, length of hospital stay. And actually none of our clinically significant secondary outcomes had statistical significant difference between groups. In-hospital mortality and kind of our mortality at the pre-specified endpoints as well, there was no difference. Additionally, for our assessment, cognitive assessment tools not seen here, but the MOCA scores as well as the PROMIS surveys also had no difference between groups. The only outcome that was different between groups was actually one of their pre-specified safety outcomes, which was need for additional norepinephrine or vasopressor therapy. And there was a statistically significant difference in our dexmedetomidine group when compared to placebo with the dexmedetomidine group needing higher amounts of vasopressor therapy during the study. So seen here is the Kaplan-Meier curve for them. Really, you can see the kind of large difference here on day one, which is exactly what the study found. But then that difference disappears relatively quickly over days two and three. So the authors drew the conclusion that dexmedetomidine is reasonable as a prophylactic treatment to reduce postoperative delirium in this low-risk cardiac surgery patient population. And they really went on to kind of speculate that this kind of novel dosing strategy of giving a single bolus or a single large dose may help improve drug utilization and compliance, and actually may be an option in the future if we do have some oral agents that come out that are similar in efficacy to IV dexmedetomidine. So diving into this trial a little bit in terms of strengths, this was a randomized double-blind placebo-controlled trial with very strict controls, which did a great job at trying to remove bias. It did have great patient-centered outcomes, really looking at patients' cognitive function scores, looking at some of the PROMIS surveys to tease out real impact in terms of if this reduction in delirium actually had clinical outcomes for our patients, especially long-term, because we know that's one of the major complications with ICU delirium for our patients. They were very adherent to their pre-specified drop criteria for both groups. And then interestingly, this is a relatively novel dosing strategy used at least in an ICU patient population. Bolus doses of dexmedetomidine are used sometimes surgically or postoperatively to help manage both sedation and analgesia sometimes. But this is relatively rare and has not been studied really in a large trial yet for using this type of dosing strategy, specifically when looking at trying to prevent and control ICU delirium. Some of the limitations of the study is a relatively small sample size. And the only reason I put that is because it actually was underpowered for the primary outcome. They hoped to get about 190 patients in both groups. And in the actual modified intention-to-treat protocol, they had slightly less than that. This, in combination with the low incidence of ICU delirium when comparing it to a lot of the other major studies in the literature, suggests that possibly the difference in the primary outcome could have occurred more so by chance or from other factors than maybe due to the intervention itself. Again, this was a single center study with a relatively homogenous patient population, which really decreases the external validity. I know at our site here, our patient population for cardiac surgery looks very different than some of the patients seen in this trial. They did have a relatively short window for extubation. And actually, the majority of patients that were dropped for the drop criteria was due to being intubated for longer than 12 hours postoperatively. And then interestingly enough, and kind of the most controversial maybe part of the trial, was their missing data imputation strategy was a little bit interesting. And so this was really in the supplementary materials, but they had about 30 patients total that they did not include, that were randomized, received study drug or placebo, that they did not include in the primary outcome analysis. And if you actually include those patients and count them as CAM-ICU positive, which is usually standard in our intention-to-treat model, they actually would not have had a statistically significant difference between groups. Additionally, for post delirium on future days, so post-op day one, two, or two, three, if they had missing data, they actually used the only value. So if they had missing data on post-op day one, they would actually look at post-op day two. And if that was positive, they would just assume that it was positive on post-op day one as well. And so this may have biased the outcome, and so it makes it very hard to assess, especially those longer delirium at post-op day three or the delirium rates at post-op day two. It makes it very hard to assess those because it's unclear if those patients, if they were just including outcomes previously, and if those patients were actually delirious or not. So kind of some key takeaway points from this trial. This single nightly one-time dose of dexmedetomidine IV post-extubation may reduce the risk of delirium on post-op day one, and it may help reduce the delirium in the ICU, specifically for this low-risk cardiac surgery patient population. However, personally, I would not change practice based on the results of this trial, as I do think this trial has poor generalizability due to kind of a very specific patient population. And I do think there were some intricacies with the trial protocol that makes it hard to extrapolate these results to other centers or to other patient populations. So future directions, and I think this is probably the most exciting part, is that this is a very, very hot topic right now in the literature and just in the ICU in general. And so there's over 20 trials right now looking at Presidex specifically for the management of delirium in the ICU on clinicaltrials.gov. Five of these trials are specifically looking at this exact patient population. So hopefully we can assess those trials in the future and see how their results compare to what we've seen here. And for me personally, I think some of the big questions that this trial asked for me is that we really do need large, randomized, controlled trials really looking at some of the key questions. And the ones that I had were the difference between a continuous infusion and this kind of nightly dose, one-time dose of IV dexmedetomidine. The benefit that we're seeing if this is more in our non-intubated versus intubated patients. Dexmedetomidine for sleep specifically. So is that really where we're seeing the benefit? Is that what's helping these patients reduce their ICU delirium because it's benefiting their sleep? And then lastly, can we apply some of these results to other patient populations that we see in our ICUs? So now a few quick polling questions just to get all of your inputs. So does your institution use dexmedetomidine IV for the management of ICU delirium? Yes, at a continuous infusion. Yes, at a single intermittent infusion. Or no, we do not use IV dexmedetomidine for ICU delirium. Okay, great. So I see the majority of people do not use dexmedetomidine for ICU delirium, but there is a small group that is using continuous low-dose infusion, which I know we do have some literature out there that does support using this in some of our ICU patient populations, especially in the overnight. We do not yet at UCSF, but it is cool to see that that is emerging as more of this data comes out. And then as a follow-up question, what other therapies does your institution utilize for the management of ICU delirium? All righty, and we have a great mix of answers here, which I would say melatonin and atypical antipsychotics being the most common, that is, I think, relatively common that we see here, too. We have tried hard to implement a non-pharmacologic order set here at UCSF as well, but it's clear that this remains a challenging issue that we're all dealing with, and trying to find optimal strategies is something that I know we all continue to work on going forward. Great. Well, thank you all so much for your time. I appreciate it, and I'm happy to answer any questions that you have. All right. Thanks, Evan. I've got a couple for you. The first question that I had was, when I was looking through the study design, I didn't see if the authors mentioned any use of melatonin or other sleep agents in either patient population. So the first question, part of this question is, did they have that and I just missed it? And if they didn't, do you feel like that would impact the results, potentially, if they didn't even control for any of that? Great question, Scott. They made brief mention to that being up to provider team discretion, but they did not comment or control for that in any way, from what I could tell. I absolutely think that impacts what we're seeing here, as I kind of hinted at, but I didn't want the audience to draw conclusions. Part of my thought, clinically, is that I think Presidex is providing benefit to sleep, and that may be the difference that we're really seeing in managing delirium. And so I do think that those absolutely could have confounded or kind of interacted with some of the results that you're seeing here, and I wish that's something they did control for, despite I know that that can be very challenging. But yeah, they made a comment that it was up to provider discretion, but there's no, none of their data, none of the supplementary has anything about what those drugs were, what those doses were, and what that looked like. Perfect, thank you. The second question that I had was in regards to the day one versus day three development of ICU delirium. I found it really interesting, just thinking about the patient population that I usually work with. You know, you have these patients that were relatively quickly extubated, so you would think would be lower risk for ICU delirium, and then they found significant differences in the day one compared to the day three. And I was wondering if you felt, or what your thoughts were, on the clinical significance of the difference there. So is there a meaningful difference in having patients who are not developing ICU delirium at day one versus day three? Yeah, I think that's a great, I think that's a really good question. I guess more to distill the question, because I guess it could be a little confusing. Do you feel like the effects from dexmedetomidine are persisting, or is this just more related to the fast extubation in these patients? I think it's likely more related to the fast extubation more than anything, and I do think it's also related to other non-pharmacologic therapies. So likely with fast tract extubation, these patients are working with PTOT, right? They're engaging with family, or they're doing other non-pharmacologic rehab, and that's likely maybe more of the benefit that we're seeing, more so than the dexmedetomidine itself. That would be my initial interpretation of the data and the difference that we do see there, but I think it's, once again, very hard to know right now, and that's why I'm excited that so much literature is on the horizon for this, because I think diving into that and really trying hard to control for some of those other factors is going to be great to see if this really has efficacy for these patients, and it is an option that we can use going forward. Excellent. Thank you. All right. That concludes our Q&A session. Thanks, Evan. Thank you. And just an overall thank you to all of our presenters today and for 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, and that concludes our presentation today. Thank you.

Journal Club Spotlight

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randomized trial

bivalirudin

heparin monotherapy

ST-segment elevation myocardial infarction

reversal

intracranial hemorrhage

delirium prevention

cardiac surgery