Hi, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine's CPT section. My name is Jessica Ward. I'm a clinical pharmacy specialist in critical care at Cleveland Clinic, and I'll be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log in to mysccm.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in live discussion on Twitter, following hashtag SCCMPPJC and hashtag PharmICU. Please note the content to follow is for educational purposes only. And now I'd like to introduce our speakers for today. Each will give a 15-minute presentation followed by a brief Q&A. Our first presenter is Sarah Stallworth. She's a PGY-2 critical care pharmacy resident at Duke University Hospital in Durham, North Carolina. She will present on the safety and efficacy of push-dose vasopressors in critically ill adults. Our second presenter is Sydney Dobson. She's a PGY-2 critical care pharmacy resident at St. Vincent Indianapolis Hospital in Indianapolis, Indiana. She will present on the impact of factor Xa inhibitor reversal with prothrombin complex concentrates in patients with traumatic brain injuries. And our third presenter is Sakita Yagnala. She's a PGY-2 critical care pharmacy resident at Mayo Clinic School of Health Sciences in Rochester, Minnesota. She will present intravenous metoprolol versus daltiazem for atrial fibrillation with concomitant heart failure. And now I'll turn things over to our first presenter. Thank you so much for that introduction and thank you everyone for being here for my presentation today. As we all know, there's been an increasing use of peripheral vasopressors for administration, peripherally vasopressors for acute hypotension, and their use has been growing over the past decade. Phenylephrine and epinephrine are the two most common push-dose vasopressors utilized and they have a rapid onset of action of about one minute. They do have some potential adverse effects, which we know, so reflex bradycardia with phenylephrine and then tachyarrhythmias with epinephrine. When reviewing the literature, you can see that the existing studies that are out there are all pretty much retrospective cohort studies, so we really don't have randomized control trials looking at safety and efficacy of these agents. From an efficacy standpoint, we can see that these agents increase blood pressure transiently. And then when it comes to safety, there's some discordance among these different studies as to how often adverse events occur with these agents. When looking at the different concentrations, you can see that phenylephrine comes in one concentration, so 100 micrograms per mil. And then just a quick reminder that epinephrine comes in different concentrations, which can lead to potential for dosing errors. So our push-dose epinephrine or double dilute epinephrine is 10 micrograms per one milliliter compared to our co-dose epinephrine, which is 100 micrograms per milliliter. So there is a 10% increase in concentration with the co-dose epinephrine compared to our push-dose epinephrine we'll be talking about today. The study that I'll be reviewing today was published in the American Journal of Emergency Medicine in August of 2022. The objectives were to describe push-dose vasopressor practice patterns in critically ill patients and assess efficacy and safety of push-dose vasopressors for the treatment of acute hypotension. This was a single-center, retrospective cohort study in a large academic medical center. And the study period was from June 2018 through July 2020. The institution that was examining these vasopressors, they used a specific push-dose vasopressor protocol that was implemented in 2015 at their institution, where they had two different vasopressor options, so specifically push-dose phenylephrine as well as push-dose epinephrine. And both of these agents were stored separately in all automated dispensing cabinets in the ICUs and the emergency department. So that at this institution, they did not practice bedside push-dose pressor dilution or preparation. Also, their protocol noted that epinephrine should be used preferentially over phenylephrine in patients with cardiac dysfunction at baseline, so an ejection fraction of less than 40%. For their inclusion criteria, they included adults that received at least one bolus of push-dose vasopressor. They excluded patients that were pregnant, received phenylephrine for epistaxis or priaprism, those with missing vital sign data, as well as patients who received push-dose vasopressors in the operating room or other procedural areas, and then patients that received both phenylephrine and epinephrine in a single episode of acute hypotension. For their study outcomes, they were looking at efficacy defined as a 25% increase in systolic blood pressure post-administration of push-dose vasopressor. And they divided groups into responders and non-responders for each push-dose vasopressor pending this 25% increase. Their secondary outcomes, they looked at adverse effects for safety, as well as hospitalization outcomes and mortality. For their statistical analysis, the statistical methods were appropriate for a univariate analysis. And for their multivariable logistic regression model, they analyzed variables that would be associated with push-dose vasopressor response. And when choosing these variables, they used a mixture of a priori and backward variable selection. 3,175 patients were evaluated for inclusion in this study. And the most common reason for patients not being included in the study were due to administration of push-dose vasopressors in the OR or procedural areas. And then our epinephrine and phenylephrine patients were broken down into responders and non-responders based on the primary endpoint. When first looking at the baseline characteristics of phenylephrine broken down by responders and non-responders, we can see that patients who responded to phenylephrine were all in We can see that patients who responded to phenylephrine were older, had higher baseline Apache 2 scores, received more continuous vasopressors 60 minutes prior to push-dose phenylephrine, received less inotrope therapy, and received higher doses of push-dose phenylephrine per episode. When broken down based on patient location, there were significantly more responders in the emergency department and fewer responders in the ICUs. We can also see, looking at patients with baseline cardiac dysfunction, there were several patients that received phenylephrine over epinephrine in several instances despite the protocol ongoing at the institution. And then, as expected, patients who got more continuous vasopressors and higher doses of push-dose phenylephrine had more blood pressure response. When looking at baseline characteristics for phenylephrine, we can see that more Caucasians responded to push-dose epinephrine and responders also had higher Apache 2 scores and received more continuous vasopressors 60 minutes prior to push-dose epinephrine. For the primary outcomes, 55.9% of patients in the push-dose phenylephrine group achieved greater than or equal to a 25% increase in systolic blood pressure, and then 71.9% achieved this primary outcome in the epinephrine group. First, I want to just emphasize the baseline blood pressure parameters between responders and non-responders for both the push-dose pressors. So, looking at phenylephrine and epinephrine, you can see that in the non-responder groups, the mean arterial pressure was significantly higher at baseline compared to those who responded to push-dose pressors. And, as expected, there was a statistically significant increase in systolic, diastolic, and mean arterial pressure after the receipt of push-dose vasopressors. When looking at our secondary outcomes, we can see that the most common adverse effect across both push-dose vasopressor groups was hypertension. When focusing more on the responders and non-responders and the differences between these two groups with push-dose phenylephrine, highlighted in red, we can see that there were significantly more cardiac arrests within 60 minutes of receiving push-dose phenylephrine in responders. The responders required more continuous vasopressors, and ICU and hospital length of stay were longer in non-responders. Interestingly, if we look at the push-dose epinephrine groups, there were not highlighted any significant differences between responders and non-responders, and this is likely due to being underpowered secondary to a smaller sample size. When looking at the multivariable regression analysis per predictors of push-dose vasopressor response, we can see that receipt of crystalloid boluses, as well as packed red blood cells, were associated with a lack of phenylephrine response. A potential explanation for this could have been that these patients were adequately managed with preload expansion, and I think this just highlights the importance of resuscitation in acute hypotension, so maybe these patients didn't need push-dose vasopressors after this volume resuscitation. And then when looking as well, we can see that administration of any sedative was associated with phenylephrine response. So this could be possibly because of that suspected peri-intubation hypotension that we expect patients to possibly develop when administered induction agents during rapid sequence intubation. And then looking at predictors of epinephrine response, we can see that history of congestive heart failure was associated with response to push-dose epinephrine, but I do want to note the wide confidence interval with that variable. The authors concluded that push-dose phenylephrine and epinephrine were safe and efficacious in treating acute hypotensive episodes in adult critically ill patients outside of the operating room. For my critique, this was a large sample size study. They evaluated multiple settings outside of the OR, so multiple ICU settings, as well as the emergency department. They did collect data on agents known to impact hemodynamics, so that being like crystal aboluses, blood products, albumin, sedative agents. And then they also did evaluate the presence of cardiac dysfunction when looking at phenylephrine and epinephrine responders. So I thought those were all strengths of the study. When it comes to limitations, of course, their retrospective design likely is not the best likely impacted the results. There was likely limited documentation in the healthcare record, as well as during these acute hypotensive episodes, there was likely a lower amount of documentation in these high stress situations. In addition, selection bias, of course, with the retrospective study design. And then I want to emphasize the likelihood of confounders in this study, so all those agents that could have influenced hemodynamics in these patients. So crystal aboluses, blood products, albumin, etc. While they did collect data on these agents in which patients received them, there was a lack of doses and amounts of these variables that could have definitely impacted the outcomes of hemodynamics. In addition, I already kind of alluded to this on a previous slide, but the high baseline mean arterial pressure of non-responders. So the baseline map of non-responders was 76 and 75. So I don't think these patients would have qualified for push dose vasopressors in my current practice. In addition, there was a lack of consistent adherence to the push dose vasopressor epinephrine in cardiac dysfunction. So we saw that several patients with an ejection fraction of less than 40% received phenylephrine. In addition, there was a lack of push dose pressor indications mentioned in the study, despite this being a primary objective to describe push dose pressor practice patterns. So really, the authors only discussed peri-intubation use, so I would have liked to see a little bit more discussion as to where these other push dose vasopressors were being utilized. And then finally, I think a lack of comparison between push dose phenylephrine and epinephrine when it comes to a primary outcome of efficacy and safety data was a limitation of this study. And I think it would have given us more information than using the primary endpoint as our comparator. So for my conclusions, based on this study and previous literature, I think push dose vasopressors do increase blood pressure transiently. And I think we've seen that in this study and previous studies. I think based on this study, we can say push dose phenylephrine may be safe. We only really saw that the major adverse effect associated with push dose phenylephrine was hypertension, which was decently rare. And antihypertensives only had to be administered in four patients. But I do think based on this study, it's harder to draw conclusions on the safety of push dose epinephrine with their smaller sample size and lack of ventricular arrhythmia assessment for adverse effects. From a safety standpoint, I think this study does highlight the need to eliminate bedside mixing of push dose vasopressors for reducing errors and adverse events. I also think it highlights the importance of separation of these agents in the omni cell, as well as separating different epinephrine concentrations, as well as labeling these epinephrine concentrations with epinephrine, the concentration, and then possibly in all caps, code dose epinephrine or double dilute epinephrine, and then also utilizing best practice alerts where we can. So as nurses are pulling them from the omni cell, getting alert, is this epinephrine being used for cardiac arrest? Yes or no. And then I think optimizing push dose vasopressor practice guidelines. So while this institution did have a practice guideline, in the article, they didn't really mention that there was a clear definition of what hypotensive was. So I think making sure to outline specifically what is qualifying a patient for receipt of push dose vasopressors and what is hypotension. And then finally, determining the specific indications and locations for push dose vasopressor use. So utilizing these in transport versus just in the brief time it takes a nurse to set up an IV vasopressor infusion versus peri-intubation periods and procedural areas. For future directions, there's an ongoing clinical trial looking at push dose epinephrine in pediatric patients. So I'm excited to see the outcome of that. And then I think our remaining questions include patient populations that benefit most from push dose vasopressors, comparative efficacy and safety between the two agents because there wasn't really a comparison with the study, and then long-term clinical outcomes after receiving push dose vasopressors. And that brings me to my first polling question. At your institution, do you stock push dose vasopressors in automated dispensing cabinets? If so, which ones? And our options are no push dose vasopressors stocked, phenylephrine only, epinephrine only, or both phenylephrine and epinephrine. And I'll just go ahead and say at our institution, we stock only push dose phenylephrine in our automated dispensing cabinets. So it does look like, based on the poll, that push dose phenylephrine is the most commonly stocked vasopressor in omni cells. So I think this study did have some important points when highlighting the potential dosing errors that could come with administering and mixing push dose epinephrine at the bedside. So I think I'd like to see more studies when it comes to using push dose epinephrine in patients with baseline congestive heart failure and reduced ejection fraction, as well as should we be considering other ways to store this push dose epinephrine to eliminate these dosing errors. With that, I'll move on to my next polling question. Does this publication, along with existing literature, change your opinion about the safety of push dose vasopressors in the critically ill population? So yes, I feel comfortable with use in acute care settings only. I am willing to consider using them now based on this literature. I'm still concerned with the safety, but open up to reviewing more literature and no push dose vasopressors. And it looks like the majority of responders said, yes, I am comfortable with use in acute care settings only. And I would also say this, I agree with this, and I think they can be helpful in using them for temporizing patients with acute drop in blood pressure, just for nurses to have enough time to go grab a vasopressor in case they need it. So I think it's a good idea to use push dose vasopressors in acute care settings only. And vasopressor infusion, as well as transporting critically ill patients, using them in procedural areas, and then that peri-intubation hypotension we might see with induction agents during rapid sequence intubation. And let's see. With that, I'll accept any questions. Thank you. So there are a couple of questions in the chat. You've alluded to this a little bit, kind of as you've gone through your polling questions, but does this study specifically impact your personal likelihood of utilizing push dose pressors in clinical practice? I think, personally, based on this study, I don't think that this necessarily influenced a change in practice for me, as we are already stocked push dose phenylephrine in our omni cells currently here. And the efficacy that I saw with the study, as well as the adverse effects, really don't change my practice, because I see efficacy when utilizing these agents. I know that, acutely, they would increase blood pressure, and we do see that with patients. So I think I feel comfortable using phenylephrine in specifically the setting of just using it to transiently increase blood pressure in a scenario where I can't actively have an IV infusion of continuous vasopressor running at that exact moment. So it's more of a temporizing measure. And I think I was happy to see the large inclusion of IV phenylephrine push dose pressor utilization in this study with a still limited adverse effect profile. So that made me feel a little bit more comfortable with use. Thank you. I'm going to, there are a couple of other questions in chat, so I'll ask you one other one pretty briefly. But the next question says, if the phenylephrine responders had a statistically significant increase in arrest compared to the non-responders, do you think that that may be a signal for CG concerns? I think it's hard to say based on this study. I do think that that is notable, but I also think it's hard to say specifically when looking at responders and non-responders in this study, because if we look at their baseline mean arterial pressure, I think you can clearly see that the patients that responded to these push dose vasopressors were sicker at baseline. And then I think when looking at the epinephrine group, it's hard to really say if there was a difference between responders and non-responders just because of the low sample size. So I think it's hard to say just based on knowing baseline that the patients who responded were sicker at baseline. Great. Thank you so much. That concludes our Q&A session. We really appreciate your presentation, Sarah. 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. And to ensure continued support of the Spotlight on Pharmacy webcast. So if you could just respond with how many attendings you are viewing this webinar with, whether it's just yourself, 2 to 5 people, 5 to 10 people, or more than 10 people today. All right, great. Now I'd like to introduce our second presenter, Sydney Dobson. Thank you, everyone. Yes, thank you for the introduction. My name is Sydney Dobson. I'm the PGY-2 Critical Care Pharmacy Resident at St. Vincent, Indianapolis. And today I'll be discussing the article titled Impact of Factor Xa Inhibitor Reversal with Prothrombin Complex Concentrate in Traumatic Brain Injuries. By the end of this presentation, you should be able to explain the difference between four-factor PCC and activated PCC and describe the effect of PCC and factor Xa inhibitor reversal in intracranial hemorrhage. Two guidelines mention the utility and dosing of PCC and factor Xa inhibitor reversal. The 2016 Critical Care Medicine Guidelines suggest administering four-factor PCC or activated PCC at a dose of 50 units per kilogram. Several years later, the 2020 Journal of the American College of Cardiology came out with guidelines recommending to administer indexin alpha. If that was not available, then to administer PCC or activated PCC, again, at that dose of 50 units per kilogram. These guidelines also mention that it's reasonable to administer four-factor PCC at a fixed dose of 2,000 units and with limited data, there are more institutions turning to this strategy as well. PCCs are products containing vitamin K-dependent clotting factors. They're highly concentrated and prepared from plasma. The article discussed today will be utilizing four-factor PCC or K-centra and activated PCC or FEBA. The only difference between these two products is the activation of factor VII in FEBA. You may be asking yourself if there is a difference between four-factor PCC and activated PCC in terms of efficacy. The CEO and colleagues in 2021 helped answer this question. Their primary objective was to analyze the efficacy and the safety of activated and four-factor PCC to prevent hematoma expansion in patients taking apixaban or rivaroxaban. This is a multi-center retrospective study. 67 patients were divided up into three categories. They either were divided into categories that received activated PCC, patients that received low-dose four-factor PCC, which was defined as a dose of 30 units per kilogram or less, or high-dose four-factor PCC, which was 30 units per kilogram or more. What they found was that all three of these groups, almost 90% of patients received excellent or good hemostasis achieved. And so they concluded that both activated PCC and four-factor PCC appear safe and equally associated with hematoma stability. And that's what brings us to our article that we'll be discussing more today, again, titled Impact of Factor Xa Inhibitor Reversal with PCC in Patients with TBIs. The primary objective of this study was to describe the effect of PCC as treatment for factor Xa inhibitor associated intracerebral hemorrhages in patients with TBIs. Patients were included in this study if they were adults 18 years or older, presenting with an acute TBI and taking a Pixaband or a Rivaroxaband. Patients were excluded if they had a spontaneous intracranial hemorrhage or if they had any known coagulopathies. Patients were then divided into two groups. The reversal group were patients that received either activated PCC, four-factor PCC, or a combination of the two. And our no-reversal group were patients that did not receive any of these products. The primary outcome of interest was hemorrhage stability. This was defined as no new or worsening hemorrhage on repeat imaging within 48 hours of admission. If a patient had multiple CT scans done during that 48-hour period, it was based on the initial and the first repeat CT scan. Secondary outcomes of interest included the degree of hemorrhage progression, in-hospital mortality, discharge disposition, ICU length of stay, and thrombotic events. This slide represents some of the statistical analysis that were completed. After evaluating for normality of patients, the data was analyzed with continuous or categorical data. I'd also like to note that propensity score matching was completed based on age, abbreviated injury scale of the head, and the Charleston Comorbidity Index. The matching was conducted with a greedy-slash-nearest-neighbor approach. Of the 593 patients screened, 115 were included in the unmatched cohort, and 84 were included in the propensity score-matched cohort with 42 patients in each group. The majority of patients were female, and the mean age for both groups was mid-70s. As you can see here, the GCS score for both groups was around 15, which would represent a mild TBI. The most common mechanism for screening was the use of a CT scan. The most common mechanism of injury was fall from standing, with about 80% of patients in each group. And epixavir was the most common factor-10A inhibitor that was utilized. I'd also like to point out that they did look at how long it had been since the patient took their last dose of medication, with about 50% of patients in each group with a last-known dose time that was unknown. Other categories were less than 12 hours, 10 to 12 hours, 12 to 24 hours, or within 48 hours. In terms of hemorrhage types, the majority of patients had subdural hemorrhages, and only about 2% to 4% of patients in each group had an epidural hemorrhage. 10% of patients in the no-reversal group had a midline shift, compared to a little over 20% of patients in the reversal group. However, this was not statistically significant. In terms of PCC dosing that they utilized, the majority of patients did receive activated PCC. The mean dose for this was around 30 units per kilogram. Two patients received four-factor PCC. And again, for those two patients, the mean dose was around 30 units per kilogram. And two patients did receive both products. And when combined, their dose was around 50 units per kilogram. As a reminder, the guidelines do suggest the 50 units per kilogram for reversal of intracranial hemorrhage. However, again, some institutions are moving to more of a fixed dose, which may account for this lower dosing mean. In terms of the primary outcome of hemorrhage progression, 10.8% of patients in the no-reversal group and 15% of patients in the reversal group saw hemorrhage progression. And this was not statistically different. Other secondary outcomes in terms of hemorrhage progression volume-wise, for MLs, the group that had no reversal saw a hemorrhage progression of zero ML compared to the no-reversal group, which saw a hemorrhage progression of one ML. In terms of ICU length of stay, numerically, this did not differ between patients, but due to the difference in interquartile range, you do see a statistically significant difference here. And for thrombotic events, only one patient in the study had a thrombotic event. They were in the reversal group and they had a DVT. And in-hospital mortality did not differ between the two groups. Discharge disposition was categorized as home, home with services, long-term care facility, skilled nursing facility, or other, and none of these differed significantly between the two groups. The authors of this study concluded that this pragmatic study was unable to identify any impact of PCC administration on hemorrhage stability. However, the Factor Xa inhibitor reversal strategy demonstrated safety when compared with supportive care in this patient population. I identified several strengths of this study. I appreciated the balanced groups of the study. I think the propensity score matching helped with this, even though the unmatched cohort groups were fairly balanced as well. I think it is a strength that they included patients that had activated PCC and four-factor PCC. Unfortunately, it wasn't a very even split with the majority of patients being on activated PCC, but this helped with the numbers a little bit. And then lastly, I think their primary outcome was very appropriate. We know that hemorrhage progression leads to poor prognosis, and so assessing that, the reason that we give reversal agents is to prevent this, and so I believe that was appropriate. However, the study did have limitations. It did lack diversity with the majority of patients being white females in their late 70s. Additionally, the majority of patients had TBIs that were mild, really limiting the generalizability to patients with moderate or severe TBIs. They also have low PCC dosing averages. Again, if your institution is one that uses maybe a fixed-dose strategy, this may not be a limitation for you. For an institution that really tries to use the 50 units per kilogram, this may be viewed as a limitation. Additionally, if you're an institution that uses four-factor PCC opposed to activated PCC, this may be a limitation for you. However, with that previous literature, we discussed in the background section, we see that these are fairly similar and show similar efficacy and safety, so this may not be a limitation. And again, we have to acknowledge that it is a retrospective study with small groups where the dosing could not be controlled. When I thought about the clinical interpretation of this study, I really broke it down into three different thought processes. First was the hemorrhage progression. They saw that 4.2% more patients in the reversal group experienced hematoma expansion. However, this group did start with larger hematomas and a higher percentage had taken their DOACs within the last 24 hours compared to the non-reversal group. Research has found that larger initial hematoma volumes do lead to expansion more often. However, I would like to note that the initial hematoma volumes of these two cohorts were relatively small to begin with, really just five and eight ml, so very tiny. These results were not statistically significant and I don't really consider them to be clinically significant either, especially taking into consideration my next point, which was the intracranial hemorrhage volume change. These results show that the reversal group experienced a median hematoma expansion of one ml compared to zero ml in the no-reversal group. This data was not available on everyone. More patients in the reversal group were included in this particular analysis compared to the non-reversal group. In the end, I do not believe that a one ml increase in intracranial hematoma volume, which already began small to begin with, is clinically significant. And finally, for thrombotic events, in terms of safety, the number needed to harm for a thrombotic event was 5,000, showing that giving PCC is not likely to cause severe safety events. Since patients in this study received lower than recommended doses per the guidelines, it is hard to generalize this data to guideline recommendation dosing. However, other studies have looked at this and have not found a significant difference in thrombotic events. Taking all of that into consideration, my conclusion was PCC may not be necessary to prevent hematoma expansion in patients taking DOACs with a mild TBI or a small hematoma volume. However, if it is given, it's unlikely to cause any significant harm to the patient. I believe further studies should include a more diverse patient population and focus on patients with moderate to severe TBIs with larger initial hematoma volumes. One of my polling questions is, I am curious of what agent or dosing strategy you utilize at your institution for the reversal of factor Xa inhibitors. Do you utilize a fixed-dose PCC strategy, weight-based PCC strategy, indexin-alpha, or some other strategy such as PCC plus Novo7? Okay, yeah, so I'm not as surprised by this. It looks like the majority, about 50% of people utilize a weight-based PCC dosing. I do think just hearing from different colleagues across the pharmacy world, this is where we're moving. And then the second most common was a fixed-dose PCC. So it looks about 80% of our participants today use PCC in some type of dosing, followed by 10% of indexin-alpha patients. All right, and our next polling question. There we go. In patients with a mild TBI, a GCSF-15, and DOAC use, would you recommend a reversal agent? Okay, all right, so I am a little surprised by these results. I did think that more participants would choose yes in this. I think right now, given this data, it is something to think about if we are really using these agents, if we really need to be using these agents in these patients. And so I think as more data comes out about the fixed-dose and maybe patients using, or institutions using like 10A levels, I think that this will be a big discussion moving forward on using our resources properly in these patients. So that's, yeah, it's great to know. Thank you. All right. All right, and at this time, I'd be happy to answer any questions from the audience. Great, so there's a nice question from an audience member. It says, what do you think about the differences that exist in definitions of ICH expansion across the available studies? Example, absolutely no worsening in the bleed compared to up to 35% expansion is effective. Yeah, I think that's a really great question. I was actually just pondering that today when I was just reviewing this a little bit more. And the question kind of came in my head of, well, what is hematoma expansion? And if you just search that, you do, you get a very wide plethora of definitions. And so I think that makes it really hard to analyze data. And as more data comes out, I think it would be beneficial as a kind of healthcare community, if you will, if we were able to kind of solidify that definition a little bit more. One that I saw was, one study looked at hematoma expansion and their definition was it had to grow by 20% and one was it needed to be more than 30 mLs. And if that were the case, none of these patients would have had hematoma expansion. So I think it just makes it a little bit more difficult to analyze the data. But I also think it shows us a little bit more like generalizability for real life because every radiologist is going to read every scan differently. Whether, you know, if it's just a neurologist who's looking at it, everyone will read that a little differently. So I think it's a challenge to interpret the data, but I also think it kind of shows us what it's like in real life to be interpreting this as well for patients. Yeah, thank you. Another question is when it comes to kind of assessing thrombotic events, do you know if the authors looked at occurrences that may have happened once the patients left the actual hospital facility while they were with like long-term care or still nursing facility? I noticed it didn't seem like they reported the like duration of stay. So I'm wondering if there may have been some detection bias there. Yeah, I think that's a great question. I also did not notice a timeframe. So I would assume in that case that it was probably in hospital thrombotic events. I know that the one was a DDT, but they did assess other thrombotic events like PEs and that just no patients had those. So yes, in reading this, I was assuming that they were just analyzing in hospital events. And so I think it would have been interesting to see if we had looked at long-term, longer term, I should say thrombotic risk. Yeah, great, thank you. I definitely think if you look longer, it also introduces the question of like, whether the calculation was restarted or not and the timing, which is a whole other thing. So thank you so much. Thank you. All right, so that concludes our Q&A. Now I'd like to introduce our next presenter, and that concludes our Q&A. Now I'd like to introduce our final presenter, Nikita Yevnala. Thank you. All right, so today I'm gonna be taking a look at a retrospective study by Koppenhanger and colleagues titled IV metoprolol versus diltiazem for atrial fibrillation with concomitant heart failure. A little bit of background. So we're all well familiar with AFib, with RVR. It affects over 1.2 million people per year in the United States and is really the primary reason for over 500,000 ED visits, so a very prevalent arrhythmia. First-line management for atrial fibrillation with RVR is usually going to be rate control agents, whether it's beta blockers or non-dihydropyridine calcium channel blockers like diltiazem. While the guidelines themselves don't really provide much preference on one over the other, what I think a lot of more recent retrospective, smaller cohort studies have shown is that perhaps calcium channel blockers like IV diltiazem, when compared to beta blockers, provide a higher incidence of rate control, perhaps a faster time to rate control, and a more profound reduction in heart rate compared to some of our beta blocker agents. And perhaps this might be a reason why in the emergency department or the ICU, we might use diltiazem first. That being said, there comes a caveat with diltiazem that we should be avoiding this agent in patients who have AFib and concomitant heart failure. We recognize that patients with recent ischemic events and who have lower ventricular ejection fraction, there's really no mortality benefits seen with diltiazem and non-dihydropyridine calcium channel blockers, and there's likely a potential harm given its known negative inotropic effects. That being said, a lot of this data was really seen in more patients who had received diltiazem chronically. And there's limited data comparing the clinical outcomes between IV beta blockers and IV calcium channel blockers to manage AFib with RBR acutely in congestive heart failure patients. Two more recent studies that have been published that try to take a look at this question is by Hershey and colleagues and Hashbrook and colleagues. What they looked at were heart failure patients with reduced ejection fraction, comparing them with each other to patients who received metoprolol versus diltiazem. When they looked at heart rate control, they really found no difference in heart rate control defined as a heart rate less than 110, but there were some confounding differences in the Hashbrook group where they did find that patients who received diltiazem actually had greater congestive heart failure symptoms defined as needing oxygen or inotropes within four hours of receiving IV diltiazem. So with this question still up in the air of which agent's better for AFib patients with congestive heart failure, I did wanna pull the group first and foremost to see what your practice is like. What is your rate control agent of choice in patients who present to the ED with AFib with RBR and known congestive heart failure, or if you don't practice in the ED, in your ICU? All right, majority of answers look like IV metoprolol, which really doesn't surprise me because I would say prior to reading this study, I felt the same way, and you'll kind of figure out perhaps after this study if I still feel the same way or not. I think a caveat to this question is the fact that I say known congestive heart failure, and so I think for me it also might depend on whether it's reduced ejection fraction or preserved ejection fraction. All right, so diving into the study itself, the study designers essentially thought out to ask the similar question. We wanted to look at comparing the rates of successful heart rate control and the adverse events between IV push metoprolol and IV push diltiazem in patients who came into the emergency department with AFib with RBR and known congestive heart failure. The way the study designers defined the primary outcome was looking at heart rate control defined as heart rate less than 110 beats per minute at 30 minutes after administration of IV agent and secondary outcomes looked at heart rate control at 60 minutes and at the time of discharge or transfer from the emergency center. Other effectiveness outcomes included time to heart rate control, reduction in heart rate control, and additional agents that were administered. Safety outcomes included bradycardia, hypotension, a new oxygen requirement, or change in the ejection fraction on the patient's subsequent echo. This study was a multicenter IRB-approved retrospective study, and so they initially included patients who presented to emergency center in AFib with RBR and were treated with either IV metoprolol or diltiazem, excluding patients who had heart failure exacerbation on admit, if they received other antiarrhythmic agents prior to the IV metoprolol or diltiazem dose, or if they had missing hemodynamic data. All these patients included needed to have documented heart failure, which they really identified by looking at echoes from the past 12 months prior to their emergency center admission. Ultimately, they were able to identify about 59 patients who fit the cohort for IV metoprolol and 134 patients who fit the group for IV diltiazem. From a statistics standpoint, continuous variables were compared with the Mann-Whitney U test, and for categorical variables, they were compared with the Fisher's exact test. Taking a look at some of the overall baseline characteristics of patients, we can note that majority of patients were a little older, around 73 years old. Majority of patients were female, and the vast majority of patients were white. Looking at the congestive heart failure classification, what I do want to point you towards is the fact that many of these patients had HEF-PEF or reduced, and not HEF-REF. When thinking about the concern for IV diltiazem in our congestive heart failure patients, I would make the argument that it's more of a concern in our HEF-REF patients. And so when we interpret the primary and secondary safety outcomes, important to recognize that many of these patients had preserved ejection fraction heart failure. In addition, many of these patients had chronic AFib at baseline, and many patients were taking beta blockers, which could also confound our results and something to keep in the back of our head when interpreting. Notable vitals at baseline, we can see that patients who were in the diltiazem group tended to have higher heart rates compared to those in the metoprolol group. While statistically significant, I would argue that this is likely not clinically significant but just interesting to take a note of. Diving further into our results, when looking at the dosing practices at this institution, I did wanna point a couple of things out. From a metoprolol standpoint, the most common dose that was reported was five milligrams IV push times three, about five minutes apart. From diltiazem specifically, it was interesting to see that the most common dose was about 10 milligrams given twice between 15 minutes and then perhaps starting a diltiazem infusion. Important to recognize that perhaps this institution utilized a fixed dosing strategy of diltiazem compared to perhaps other institutions were prioritizing the 0.25 milligram per kilogram dosing. Taking a look at our primary and secondary efficacy outcomes, we can see that at 30 minutes after IV push infusion, we recognize that percent of patients who achieved heart rate control really was no different between those who received metoprolol versus those who's received diltiazem. The same persists for heart rate control at 60 minutes. Interesting enough, at emergency center discharge, patients who received diltiazem pushes and perhaps were transitioned to chronic diltiazem therapy did have significantly higher achievement of heart rate control. Taking a look at some of the more nuanced outcomes, we can see that diltiazem definitely decreased heart rate to a more significant amount compared to metoprolol. And it also had a faster time to heart rate control. Both being statistically significant, I think this is also relatively clinically significant because when we're in the ICU or the ED, we certainly are sitting and watching that monitor to see if the patient's heart rate will be controlled and 15 minutes can seem like a long time. Also important to recognize that patients who received IV push metoprolol, about 17% of them actually crossed over to the diltiazem group, recognizing that these patients were still included when we're looking at the primary and secondary efficacy and safety outcomes. Overall, for any of the safety outcomes, including hypotension or bradycardia, there really was no difference between patients who received metoprolol or diltiazem. The study authors also did a subgroup analysis looking at the primary and secondary outcomes in patients who had HEF-PEF compared to HEF-REF. The efficacy outcomes essentially were similar between the both groups. Two things I wanted to highlight was that patients who had HEF-PEF tended to have more hypotension when they received diltiazem. Patients in the HEF-REF group actually had increases in their ejection fraction in both groups, those who received metoprolol and those who received diltiazem on subsequent echo check during their hospitalization. But patients who got metoprolol tended to have higher increases in the rejection fraction compared to those who received diltiazem. It's hard to really make meaning out of this data when we had such few patients who actually had HEF-REF to begin with, but just an interesting finding to report. Ultimately, authors concluded that both metoprolol and diltiazem seemed to show similar efficacy to control heart rate at 30 minutes, perhaps diltiazem having a faster time to heart rate control and having a greater reduction in heart rate control compared to metoprolol. Study designers postulate that given the findings of their study, diltiazem may be safe and effective in patients with AFib with RBR and congestive heart failure. All that being said, let's talk a little bit about the strengths and weaknesses of this study. I think from a strength standpoint, their exclusion criteria was fairly appropriate, excluding patients who have acute decompensated heart failure and attempting to avoid some confounders with patients who received antiarrhythmics prior to these rate control agents. The patient population is fairly generalizable and many of their methods were comparative to previous retrospective studies, though I would have hoped that they would have excluded patients in the metoprolol arm who did cross over to a diltiazem arm as this might have confounded our results. Overall, the endpoints measured were clinically applicable, recognizing that when we are in the ICU and ED, we are staring at that monitor, looking at that heart rate going down to less than 110, and from a safety standpoint, these are some of the most common safety concerns we have with IV diltiazem. From a weakness standpoint, I think really the biggest thing that I thought was a weakness was that this study looked mostly at heart failure with preserved ejection fraction patients. We know that the concern with diltiazem is more so seen in those who have ischemia-related reduced ejection fraction, and so I was hopeful that we'd perhaps have a higher N number for that, but unfortunately we did not. Majority of these patients had chronic AFib and were on prior to admission metoprolol, and I think this is important to recognize because perhaps it could have affected the results of how frequently patients responded to one agent over the other. Naturally, this study being a retrospective chart review comes with its own retrospective limitations. Admin timing discrepancies could have been off. The patient's most recent echo from the past 12 months might not have been indicative of that patient's current heart failure status, and naturally, providers might have had some drug selection bias on initial administration of the agent itself. The last limitation that I wanted to address was the diltiazem dosing and infusion strategy. Many patients might have received diltiazem infusions after the 30-minute mark, which could have affected the time to actual rate control, perhaps with the infusion providing a faster time to rate control. The diltiazem dosing was also interesting to note, as many patients had received 10 milligrams, but the average weight of this patient population was about 80 kilograms. If we were to take guideline recommendations of dosing diltiazem at 0.25 milligrams per kilogram, we can see that these patients perhaps should have received a higher dose of about 20 milligrams of dilt. They still had similar efficacy, but I think from a safety standpoint, it's hard to really extrapolate. This leads me to my second polling question. I am interested to see which IV diltiazem dosing strategy you typically use for acute rate control in patients with AFib with RVR, as this is an area of controversy. Is it weight-based dosing, fixed dosing, does it depend, or neither? All right, majority of patients about, or not patients, participants show weight-based dosing. I will say at our institution at Mayo Clinic, our order set provides weight-based dosing, but in the ED, or if you're just going to order IV diltiazem, we have different options for weight-based versus 10 milligrams versus 20 milligrams, good to know. All right, so overall, does this study really impact my practice? I would say globally, reading this particular study did not change how I feel towards using IV diltiazem in our HF-RF patients. Overall, I think it's important to recognize perhaps one dose of a 10 milligram IV diltiazem bolus in a patient who we don't know has HF-RF potentially is not going to hurt them as long as they're not in acute decompensated heart failure. But I think what's more important to take away is that once we give that IV bolus and they respond to it, the next step naturally is going to be to start an infusion and then put them on a chronic medication for diltiazem. And that clinical inertia is what's going to be harmful in the future if the patient goes home on an oral diltiazem agent. That being said, I think for the most part, when I think about IV dilt versus IV metoprolol in our AFib patients, I 100% would agree with the majority of the audience even before reading the study that those who have HF-RF or those who have severe HF-RF, those who have increased proponents or acute coronary syndrome, absolutely would still stick to IV metoprolol. In the case that we know patients don't have HF-RF, if they have PEPF and we're not concerned for acute decompensation, perhaps IV diltiazem is just a faster agent and a more significant potent agent to utilize for the reduction of heart rate in AFib. Overall, my final takeaways, I would say that both IV metoprolol and diltiazem have shown to be effective for acute heart rate control in our congestive heart failure patients. While diltiazem has the benefit of an infusion and likely seems to provide greater reduction in heart rate, I will still admit that there is limited evidence to support its safety in the setting of acute decompensated heart failure, those who have left ventricular ejection fraction of less than 40% and in the setting of acute coronary syndrome. Additional studies will be necessary to evaluate its safety in this patient population. With that, I'm happy to take any questions. I have a question for you, just kind of curious in your global perspective, what role amiodarone might play in the management of AFib in your CHF patients? Yeah, that's a great question. What role amiodarone plays? So I would say that naturally we start with a rate control agent and there's not many times where I've, you know, attempted metoprolol and then diltiazem and then amiodarone, usually we'll start with a rate control agent, either one, whether it's metoprolol or diltiazem and if that doesn't work, then we're kind of jumping over to amiodarone and so I would say from like a second line option standpoint rarely are we crossing between metoprolol and dilt, we're just going to attempt one rate control agent and then move over to amiodarone as a second option. Thanks. A couple of questions have come in. This says, are you utilizing magnesium at your institution for AFib and did the study report on mag youth? Oh, that's a great question. So we, I mean, I would say for like the treatment of AFib, we're certainly giving magnesium upfront, making sure mag levels are greater than two and so from that standpoint, we're absolutely making sure electrolytes are adequately repleted. The study themselves, they have not reported on IV magnesium use and the electrolytes and some of those other confining factors. So I think that's a really great point to recognize that we don't really know what triggered the AFib versus what their electrolytes look like and anything like that in these patients. Great, and then one final question for you. Do you personally take patients prior to admission home rate control medications into account when you're choosing between dilt and metoprolol? Yeah, I would say so. I mean, irrespective of their congestive heart failure or anything like that, but if a patient is on metoprolol at home, I would say that that's something that's been working for them and so that's likely the agent that I'll try first and I know that in prior studies that have kind of looked at what factors influence someone to start IV metoprolol versus IV diltiazem, it is what they take chronically at home. So I would absolutely say that that does impact the agent that I decide to start. Great, thanks so much. That concludes our Q&A session. All right, so I would just wanna say thank you again to all of our presenters today and to all of our audience members for attending. Please join us again on the third Friday of the month from 2 to 3 p.m. for the next Journal Club Spotlight on Pharmacy. That'll be March 17th from 2 to 3 p.m. And that concludes our presentation for today.

critical care pharmacy

push-dose vasopressors

factor Xa inhibitor reversal

prothrombin complex concentrates

diltiazem

atrial fibrillation

metoprolol

heart failure symptoms

rate control