Thrombolytic Dosing in PE: Versus Series

This episode of Pharmacy to Dose, the Critical Care Podcast, is proudly sponsored by QAZ. QAZ is a family-owned, researched-focused, sustainable pharmaceutical company accredited with both B Corp. and a benefit corporation status. QAZ is making global changes that benefits patients, providers, and healthcare organizations with forward-looking and impactful initiatives. QAZ appreciates the integral role that clinical pharmacists play in patient care and are proud to support this community. To learn more, visit qaz.pharmacy-to-dose.com. Again, that's c-h-i-e-s-i.pharmacy-to-dose.com. The Critical Care PRN is dedicated to fostering the role of critical care pharmacists as essential members of the multidisciplinary patient care team. The Critical Care PRN's goal is to optimize drug therapy outcomes by promoting excellence and innovation in clinical pharmacy practice, research, and education. For more information, including how to become a member, go to critprn.accp.com. Again, that website is critprn.accp.com. Welcome to Pharmacy to Dose, the Critical Care Podcast, a partner of the ACCP Critical Care PRN. And I'm your host, Nick Peters. Wherever you are and however you are listening, thank you. And our second episode of the Versus series features special guest Lauren Igniri. As we argue, what is our preferred strategy for thrombolytic dosing in pulmonary embolism or PE? So I'm defending full dose thrombolysis whereas Lauren is backing reduced dose thrombolytic treatment. So we're going to go through three different categories or scenarios debate the best treatment strategy. And I should clarify, we're discussing all-to-place dosing regimens until we get to our bonus round arguing which is our preferred thrombolytic agent in PE, all-to-place first to next to place. So each of us, we highlight a landmark study for each topic to help kind of back our argument. And then once you listen to the episode, go to @Pharmacy2Dose on Twitter or X to vote for the ultimate winner of the Versus series episode. But for now, let's get this debate settled with our second Versus series, thrombolytic dosing in PE. Starting right now. I'm very excited to introduce our special guest. And I guess I'd have to say maybe opponent for the next 60 to 75 minutes or so. And that is Lauren Igniri. Now, Lauren is a critical care clinical pharmacy specialist at Cooper University Healthcare. You can find her on Twitter or X at @eligniri_PharmD. Lauren, welcome. How are you doing today? Great. I'm really excited to be here and attempt to defend out-to-place 50. It is going to be such a blast. You know, one of the things the listeners will see in the reference list for the Versus series is that, you know, Lauren has written a review article on this exact topic. It's why her name instantly came to my mind to come into this Versus series, only the second ever. So you're one of two to come on. This is a great idea. Now, let's kind of review the ground rules for ourselves and the listeners and make sure everyone's on the same page. So it's the thrombolytic dosing in PE Versus series. So Lauren and I will compare full dose, meaning 100 milligrams versus reduced dose, meaning 50 milligrams, all to place for a QPE in three specific patient populations. So high risk or massive, intermediate risk or also known submassive and then in cardiac arrest. Each of us will have a little closing argument, then we'll have a bonus round where we argue the best agent. So in each of these categories, we'll have a maximum of five minutes to make our case and then two minutes to make a rebuttal. So who has who. So as Lauren said, she has the reduced dose, the 50 milligrams thrombolytic dosing and she is team all to place for the dosing agent. And I have the full dose 100 milligram thrombolytic dosing and hashtag team to Nectaplace. Yup. So T and K. And each of us is using or focusing on one article to make our case. So we shared which articles were going to be the backbone of our argument ahead of time, but that's it. No other sharing of notes, thoughts, or anything. So and then reminder after the episode is released, you the listener have the chance to vote for the winner for the medical question with no true answer on social media at pharmacy to dose. Lauren, anything else we need to cover or say kind of before we get started here? No, I think that's it. That's perfect. So why don't you go ahead and hit in the leadoff position for us talking about the use of reduced dose thrombolytics in high risk PE. All right. Thanks, Nick. So before I begin to defend the out to place 50 milligram dose in high risk PE population, I think we should probably review some of the history surrounding thrombolysis in PE first. For all of our listeners out there, we should all be aware that the use of litics in PE is based off of pretty low level evidence, especially when considering the agent that had been studied prospectively was streptokinase, even though we more commonly utilize out to place or even connect to place in some situations in more modern times. So back in 1995, there was a prospective study of eight patients. That's right, eight. With PE associated cardiogenic shock where patients received 1.5 million IUs of streptokinase over an hour and heparin bolus followed by heparin infusion, followed by heparin infusion, and that was compared to heparin alone. And these patients were really sick. So they had evidence of hypotension. They had elevated pulmonary artery pressures. They were in cardiogenic shock and they had markedly reduced PAO2s in the mid-40s. But the study investigators had to stop the trial after only eight patients were enrolled because all four in the heparin-only group died within three hours of randomization compared to zero in the thrombolytic heparin group. So interestingly, these four patients that died, they had severe artery myocardial infarction and massive PE identified on autopsy. So this is really what has prompted the use of thrombolytics in this patient population. Due to the increased risk of death scene when thrombolytics are withheld or delayed in high-risk PE, it's unlikely and it would be unethical to perform a future randomized controlled trial comparing more modern thrombolytic therapies such as alpha-placer to nectoplace in conjunction with anticoagulation versus anticoagulation alone. So thereafter, studies evaluating the more modern agents are largely based from registry data. Emperor was a prospective multi-center observational registry that described the diagnosis, treatment, and outcomes of patients that presented to the ED with acute PE. And out of a little under 1900 patients with confirmed PE, 33 patients were licensed in the ED and 12 received lysis after hospital admission. The majority of these patients received deltoplace. And what's important from this is that out of the 20 patients that had confirmed PE that died, only three received thrombolytics, but their deaths were not attributable to any bleeding complications. And a limitation of this study or this registry in general is that they don't describe the doses of thrombolytics used. So that being said, despite these low quality evidence, guidelines have continued to recommend in more modern times the use of the fibrin-specific second and third generation thrombolytics including out-of-placer to nectoplace over first generation because of their more favorable administration and pharmacokinetic profiles. So for out-of-place specifically, the dosing of 100 versus 50 has been largely based at the provider discretion over the years based on the full assessment of the patient's risk versus benefit and really thinking about the individual patient's opportunity for improvement with lysis. And full versus half dose was recently evaluated by the melamed study. This was a multi-center retrospective observational study that evaluated the characteristics, outcomes, and complications of patients with PE and really determined whether full or reduced dose regimens were appropriate. This was done at a tertiary care hospital and 15 community academic medical centers in the Mayo Health system. Notably, patients who had cardiac arrest or required ECMO support were excluded and 98 patients ultimately received the full dose, which was defined as 100 milligrams over two hours with 186 patients receiving reduced dose. And this was defined as either giving 50 milligrams IV over two hours or a 10 milligram bolus over a minute followed by 40 milligrams over the two hours. And their primary outcome was all-cause and PE-related mortality or hemorrhage within seven days of out-of-placed administration. So what did this group find? Well, notably, this study included both patients with massive and submassive PE. And I'll just point out that in this particular study, about one-third were classified as having massive PE or high-risk PE. Their propensity-matched analysis in the massive PE cohort found no significant difference in PE related mortality at seven days between the full dose and reduced dose groups. And that number was around 10.9 or 10.6% in either group. So pretty significant risk for mortality anyway, but not different between the two doses. So regardless of the dose, there were also significant improvements in shock index, blood pressure, heart rate, respiratory rate, supplemental oxygen requirements between both groups. But here's where I really want to point out some exciting news. So when evaluating the entire cohort of massive and submassive PE, there was an 11.5% absolute risk reduction in all hemorrhagic complications with the reduced dose compared to the full-dose regimen. So also, importantly, major extracranial hemorrhage occurred in 1.1% of patients who were receiving 50 milligrams versus 6.1 receiving the 100 milligram dose. And this was statistically significant. Now, we have to talk about some limitations with this study. So an important limitation is that there is likely significant selection bias. There's always this perception that patients who are sicker are going to need the higher dose. And this is what was seen in the baseline characteristics. So patients receiving the full-dose regimen were more likely to have massive PE than those in the reduced-dose regimen. And then the reduced-dose regimen had more submassive PE. Those full-dose patients had significantly lower blood pressures, higher heart rates, higher peak respiratory rates and higher SOFA scores than the patients receiving the reduced dose. Additionally, they were more likely to be mechanically ventilated or require vasopressor support. But when I think about these baseline differences in the observational study, this likely reflects real-life practice where there often lies that perception that the sicker patient needs more drug because they're unstable and they need lytic. But in my mind, this observational nature makes it highly generalizable to the dosing decisions that are made in real life. Now, on the flip side, a major strength of the melamed study is that they had propensity scoring performed for their patient cohorts. And after propensity score waiting, the full and reduced-dose alkylase groups were well balanced with regard to the key differences in the baseline characteristics. So that being said, for many years, I diplomatically defended the 100 milligram dose. And when speaking with my providers, many of whom I consider close friends who genuinely enjoy these collegial discussions with their pharmacist, I would often say, if you're going to do it, do it all the way and give 100 milligram dose. After all, the patient's hemodynamically unstable or just about ready to decompensate. But this study does give me pause to think about this dosing strategy a bit more. And maybe we should really be using less drug to achieve the same outcome and reduce the risk for major bleeding complications. I think many of us struggle with, what do I do with the patient who looks fine from the door, but some of their objective data are starting to move in the wrong direction and indicate badness may be happening very soon? Or what about those frail patients where a bleeding complication will most certainly result in significant morbidity or even mortality? A lot of times we just say, I'm just going to give 50 milligrams and try to avoid badness. And honestly, I think this paper can help support that decision with more evidence now. The skeptic in me really wanted to believe that there had to be something left to help defend the 100 milligram dose after dissecting the high risk PE patient population from the entire cohort. But alas, when you compare the two dosing strategies in either just the massive or the submassive PE cohorts, there's no difference in PE related mortality and significantly less bleeding. So with that, I have become a supporter of the reduced dose out to place for high risk, massive PE. That was a great argument. That was a great argument. Let me a couple things that we let's come back to. You said it, those full dose patients were much sicker. I don't need to highlight what that means. Phasopressors, respiratory support, you already said it. Now, the difference in bleeding right was only in that unweighted analysis. But before we even look into the weighted analysis, let's go ahead and pop into supplemental table two. And that looked at independent risk factors. And it did it in the unweighted cohort. So just looking at everybody and they found dosing was not an independent risk factor for those hemorrhagic complications. And that one independent risk factor was an invasive procedure 30 days afterwards. I was kind of shocked by that to be completely honest. But then when we go back to that match cohort, no difference. And even in the unweighted, the difference was in major extra cranial hemorrhage. Now I looked at what that meant, and bleeding in scary spaces is one of the big things. But one of the other things is a hemoglobin drop of two points or more. How often does that happen in our sick patients, patients that we're giving thrombolytics to? I think that could happen all the time. One other thing, supplemental table one, because we're looking at RV dysfunction, right? That's looking at the echo and things. That's one of the big things. Both regimens had improvement in their RV function. But I would say the full dose seemed to have it to a higher degree. They both brought down to 7%. The full dose had higher. It's my only argument going through, but it's a strong case for the 50 milligrams who knew that a study that was highlighted on this podcast would then come back to fight against me in a versus series. So this is a cruel twist there. But that's a strong, strong work for the 50. Hard to disagree with that, especially your line about they're sick. We need to give them more drugs. That kind of hurt. That was a good line there. Because that's an argument I think we, I've joked about before. So Touche, very, very good point. Thinking about my argument for our full dose, 100 milligram dose. And one of the biggest things to think about is it's going to focus on the need for treatment escalation. So let's stay in critical care medicine. Let's go back to 2018. Let's dive into the research article, half dose versus full dose alteplase for the treatment of pulmonary embolism. Featuring pharmacist, first author, friend of the pod, Tai Kaiser for the Colorado pulmonary outcomes research group. So multi center. And like Lauren highlighted, a database study, like a lot of these, especially in high risk patients are so premier database, collecting data over five years from January 2010 through December 2014. And it looked at 50 versus 100 milligrams alteplase for acute PE treatment in ICU patients. And the primary outcome was the need for treatment escalation. So that meant in like a higher level of care in the ICU, right. So initiation of vasopressors, are you giving more thrombolytics? Do they need to get catheter directed treatments, ventilation, CPR, et cetera. Now, the unweighted baseline characteristics in E table one, showed that when you just look at it in that timeframe, over four times as many patients received 100 milligram alteplase, only about 20% of the study cohort received the 50 milligram regimen. And that 50 milligram regimen, it was younger, less comorbidities. When you look at the unadjusted analysis, about half the mortality rate, right. So I think that goes along with that idea that you're less sick, you need less thrombolytics, but we'll continue. So table one, and then continued in E table two, it describes the characteristics once they were matched. 25% on vasopressors, about 17% mechanically ventilated. So some critically old patients. But what I want to, what I want to bring attention to in these cohorts is when you look at the percentage of patients that were brought in from the unmatched cohort to the matched cohort. So only about 18% of the 100 milligram group is included in the matched cohort, and 78% of the 50 milligram group is included. So I want to point that out. It's probably some sort of bias. I tried to Google what specifically it would be, and I couldn't exactly find it. Feels like that's important to just point out. Maybe it's not, but I feel like it is. Now, the primary outcome was significantly higher in patients who received the 50 milligrams compared to the 100 milligrams treatment. And this was driven by an increase in additional thrombolytic or catheter directed treatment. So 54% in that 50 milligram group needed treatment escalation with about a quarter of those needing more alteplase, right. So probably that extra 50 milligrams. And we're thinking about our modern day usage of thrombolytics. I think the goal is to avoid the need for treatment escalation. And I think that's what the 100 milligram dose did a better job of. And I think, you know, the 50 milligram group, they were less critically ill, and it was just less used in general, especially in those high risk PEs. All right, that's my argument. Lauren, come in and come in and rebut. What are your, what are your thoughts on that? Yeah, well, getting to your comment on how the propensity matching, you know, selected only, you know, smaller fraction of the 100 milligram dose and the 50 milligram dose nearly 80% were included in the in the match cohort. I'd like to believe that they picked the best 100 to make 50. I'm just kidding there. I just thought I had to. But in all, in all seriousness, you know, I think that the propensity matching is a strength of this study in that it demonstrates that the half dose had similar rates of in hospital mortality and major bleeding. Now, the need for treatment escalation, this was, I'll be honest, was always some of my argument to continue using the 100 milligram dose. But when you really drill down to see, you know, what was indicators of decompensation, the need for new vasopressors, the need for assisted ventilation, and the need for CPR, this was the same, whether it was the 50 milligram or the 100 milligram dose. So those percentage of patients in each cohort that went on to meeting those interventions was the same. So what was actually different was the need for secondary thrombolysis or embolectomy after alteplase administration. Interestingly, surgical embolectomy was similar between the two groups. So what do I take from this? You know, due to the nature of the study design, pulling data from the premier database, which is voluntarily reported, it's nearly impossible to determine whether that catheter directed therapy was preplanned, or the patients ultimately progressed and decompensated and then continue to need catheter directed therapy. I'll say anecdotally, and this is, you know, the best evidence obviously anecdotal, but some of our interventional cardiologists kind of like performing catheter directed therapy after some systemic litic has been given. They feel it really helps facilitate the clot retrieval. Dr. Eliottis always says it makes the clot like jelly and easier to suction out. So I don't know, maybe they liked the fact that these patients got 50 and they'd have a really awesome chance at retrieving a big gooey clot and it would be very satisfying and also potentially help improve that patient's morbidity and symptoms of breathlessness within the first month following their PD. So with that, I don't know. Yeah, no, you know, I'm in trouble. I'm in trouble when you were like, oh, yeah, I see your side. That's what I like to do when you like commiserate with me. That's how you know you're about to lay the hammer. So listeners, this feels like this could be bad for me right here, but let's go. We're going to do a little, a little snake in terms of who goes first. So let's shift into the, into our discussion in the intermediate risk. I'm going to go ahead and take the lead on this one. And similar to my big point in high-risk PE patients, the major focus is going to be on reduction of treatment escalation. And, you know, Lauren highlighted that a lot of this data is large multi-center studies, sometimes registry studies over a long period of time. But the study I'm using for the defense, this is a full court press using our March Madness theme right now, because it's the highest quality to this point. And it's the 2002 New England Journal of Medicine article, Heparin plus alteplase compared with Heparin alone in patients with submassive pulmonary embolism, aka the MAPIT. It's M-A-P-P-E-T-T-3 trial. And I'm trying to pronounce it differently because you're going to hear the MAPIT trial with Lauren. And I'm trying to, this is not me trying to say it wrong. It's just a, they're very, very similar acronym. So the MAPIT three trials. So this randomized placebo controlled multi-center study. Wow. I know 49 centers in Germany. So they enrolled patients with what they defined as submassive PE, but their definition as to who they enrolled is actually pretty accurate in terms of how, what we consider intermediate risk right now. So they had confirmed PE with RV dysfunction and or evidence of pulmonary hypertension seen via echo and all patients were hemodynamically stable. So obviously there's going to be some differences, but the overarching idea that intermediate risk is where you have some echo or RV changes in your hemodynamically stable. That's what these patients were kind of thinking about 2002 to 2024. So patients are randomized to either TPA plus heparin versus heparin plus placebo, right? So thrombolytic plus anticoagulation versus anticoagulation alone. So all patients got a heparin dose. Looks like they got a fixed regimen titrated up to a baseline PTT. And then the TPA regimen, 10 milligram bolus followed by 90 milligrams given over two hours. So primary composite outcome in hospital mortality or clinical deterioration, just like the seaport trial, we just talked about kind of same things, vasopressor treatment, rescue thrombolysis, intubation, et cetera. 256 patients enrolled similar baseline characteristics mean systolic in the 130s, systolic blood pressure and around 30% had some baseline RV dysfunction. Now, compared to heparin alone, ultimately significantly reduced the incidence of the primary outcome in hospital mortality or clinical deterioration. And there was no difference in in hospital mortality, but it was driven by the need for treatment escalation specifically that secondary thrombolysis. So, you know, the patients in that thrombolytic group, they had a higher probability of 30 day event free survival and only one incidence of major bleeding in the thrombolytic cohort six in the entire study. Now, you're instantly going to see that and you're going to be like, well, it's a huge limitation. There's no way that that's real. And I, there's letters to the editor, if you look at the New England Journal of Medicine article detailing that same thing. And I think this speaks to, you know, was a little lower than we expected probably. But that's why you have strict inclusion and exclusion criteria when you're using high risk medications like thrombolytics. And table three, it details the independent risk factors for the primary outcome. And first and second, respectively, are the presence of arterial hypoxia and the treatment with anticoagulation alone compared to heparin and alteplase respectively. So, similar to the high risk study, right, the use of thrombolytic treatment, specifically 100 milligram multiply, it decreased the need for further thrombolytic treatment later in the hospitalization. And why is 100 milligrams the best? This is a randomized placebo controlled trial. It's some of the best evidence we have about using these agents in general. So if we're going to try to use evidence based medicine, I would argue that it's the 100 milligram dose from this 2002 New England Journal of Medicine study. All right, go ahead and give, try to give her a bottle, I guess, Lauren, because that's, I'm just saying that might be a tough one. I mean, you do have a very strong study. But I think this might be a good segue into really talking about, you know, I want to preface the intermediate risk PE with the fact that, you know, routine use of reperfusion therapy is not recommended in all intermediate risk PE, right? So that's really important to acknowledge. There's a high risk of leading complications. I think that's pretty undeniable at this point in time. But select patients with intermediate risk PE may benefit. And, you know, you did a nice job highlighting those at highest risk. As a pharmacist, as a critical care pharmacist, we really do need to be familiar with the nuances of who would benefit from lysis and then the strengths and limitations of not only guideline recommendations and then the primary literature. But, you know, being part of that team and helping identify the patients who might benefit from lysis. People who have patients who present with PE and RV dysfunction, troponin elevation, elevated spessy scores, one or more, high lactate above two, if there's a large concomitant DVT, BNP elevations, or have a shock index greater than one, you know, these are folks that probably should be monitored very closely and would benefit from lysis. And, you know, as we are discussing today, much controversy exists surrounding the choice of which thrombolytic to give and the dosing strategy, especially in this intermediate risk population. One other thing that I'll point out, especially since we will be kind of pulling in some older studies is like the nomenclature of massive and submassive PE and the differences in how we describe high risk and intermediate risk now. So, you know, back in the day, a massive PE or an intermediate or I should say submassive PE was generally described as how many lobes the clot sort of, you know, interfered with or, you know, was infiltrating because we don't really describe massive and submassive PE that way anymore. In fact, we're looking more for hemodynamic stability or instability as the defining factor. But anyway, with that being said, I do want to go back and talk about the MOP it trial now, not MAP it, MOP it, O not A. This was a prospective open label study that evaluated what is called quote unquote the safe dose of alteplase in PE. So, I'll just keep saying safe dose so that our listeners can, you know, associate that with the 50 milligram dose. And what they did was they evaluated the 50 milligram dose or .5 meg per gig for those patients weighing less than 50 kilos in 121 patients with symptomatic PE in more than two or more lobes. So, again, this was a middle sized PE back in the day that would be considered intermediate risk. Now, there were some patients that got, you know, smaller doses than 50 milligrams. But if the dose was 50, they generally were administering it as a 10 milligram dose over one minute and then gave the additional 40 over two hours. And what we see here, alteplase significantly reduced the incidence of pulmonary hypertension or recurrent PE out at 28 months. And this was very different between groups. So, the use of that 50 milligram dose resulted in pulmonary hypertension or recurrent PE in 16 percent of patients compared to 63 percent. Importantly, there was no bleeding events that occurred in either group. So, I think this again further highlights that the 50 milligram dose is safe. And, you know, so to kind of rebuttal a little bit in how some people may say, well, those definitions used in this study are a little bit old school. I think it's important to point out the incidence of pulmonary hypertension at baseline. It was very high in this study cohort compared to prior literature. And I think that this really indicates a sicker population, even though like in order to be included in the study, they just had to have PE that was involved in two or more lobes. Just for discussion points, on admission, the pulmonary artery systolic pressures were like in the 50s on admission. And then, just after 48 hours of getting the thrombolytic, this dropped to 34 and then out at six months was in the low 30s and 28 months in the high 20s. So, I think, you know, this demonstrates that the 50 milligram dose was, you know, very effective at reducing pulmonary artery pressures. A couple other things that I want to point out about this study is that, you know, no bleeding was noted in the study population. And nearly 80% of patients in the alteplase group received inoxaparin, one meg per gig, every 12 hours and not heparin infusion. So, despite the use of anoxaparin, which has that perception of an increased risk for bleeding because of its longer duration of action compared to heparin, no major bleeding events were associated with its use in conjunction with 50 milligram dose of alteplase. Now, you know, as I mentioned before, an important limitation of the study is that the presence of RV dysfunction was not a requirement for inclusion compared to MAPIT, but the presence of pulmonary hypertension indicates an ill population. Now, I don't want to throw anyone for a loop here, but what about an even lower dosing strategy, especially in this intermediate PE risk population? Do I hear quarter dose? Anybody? Well, thankfully, there was recently a study published. It was a single center prospective cohort trial at a tertiary university hospital in Turkey. It included 37 consecutive patients with massive PE. But when you actually look at the types of patients that were in that study population, that probably more is in line with what our current intermediate risk definitions are. These patients were receiving 25 milligrams of alteplase and they received it over six hours. So, they got low and slow infusions. Now, this was a pilot study and it's certainly just hypothesis generating. But when you look at the mean pulmonary artery pressures, these baseline mean pulmonary artery pressures in these patients were about in the mid 50s at baseline and after receiving just 25 milligrams dropped into the mid 30s. And they also found that the right to left ventricle diameter, the RV to LV ratio went from being 1.37 down to around one, which is important to note that means RV dysfunction is improving. And this decreased significantly after the administration of this low dose. Importantly, no major bleeding or stroke was observed. There was one in hospital death and two additional deaths within six months. But no cases of pulmonary hypertension were identified during follow up. And of course, it's just a pilot study. But I think this just highlights the fact that we know that these patients need lysis and we just need to figure out what the right dose is. And maybe it's even less than 50. So I'll leave it there. That is why we called it the reduced dose group. Man, I didn't expect you to bring that out low and slow such a great nickname of that too. All right, a couple things a couple now you brought up lovin ox love that you did. I like to this study did did do lovin ox. Now they capped it at 80 milligrams. So I don't know about you in New Jersey, but if we're capping 80 kilos in Indiana, most people aren't getting that one mig per Kig that are coming in. Now they did get they didn't get lovin ox. So I do agree that does make an argument. But now this study's primary outcome was looking at the development of pulmonary hypertension. And I'm just unclear. Do we if we saw rates that are of greater than 50%, I think we would see some long term benefits. If all to place really did reduce the amount, we would see some outcome differences. If that was the case. And I'd also want to see differences in like what treatments or care they received in the hospital. There's none of that. And it's funny. You look at these two studies we talked about. It's such a trip back in time because mop it 2013 the map it 2002 warfarin was their standard of care in my trials two and a half to three and a half. Here was two to three. So I'm wondering like, did they just have a shy person uptight trading a kumitan in one of the groups? And that's why the length of stay was was higher. You know, the 50 milligram right, it reduced pulmonary hypertension rates and the length of hospital, the length of stay. My question would be, would the 100 milligram have done even more and done even better? I guess we'll never know. That's true. We may not. I don't want to go back to those kumitan days. I'm happy with my dox. No, yep. Yeah, the it's an art, not a science. I'm completely fine not doing all that. Although gone are the days of the kumitan clinic, right? Where you'd have to, you know, you always have to do the finger sticks on those poor ladies. It's your third try. You're just like, I'm so sorry. I promise I'll get it this time. I feel like we're neck and neck going into our into our final kind of platform here. We've looked at high risk. We've looked at intermediate risk. So Lauren, talk about reduced dose thrombolytics in cardiac arrest. Sure, let's get going. So not to confuse acronyms even more. Now we're going to talk about the PIA PET study. So make sure we keep all these things straight. So, you know, when thinking about cardiac arrest, it's estimated that anywhere between two and 10% of cardiac arrests are attributable to suspected or confirmed PE. And, you know, certainly we need to continue with our standard ACLS resuscitation pathways. But the use of thrombolytic therapy, especially when we know that the patient has a PE, maybe, you know, super important in altering that patient's trajectory. So certain CPR guidelines recommend adjunctive thrombolytic therapy, or even surgical embolactomy or mechanical embolactomy as emergency treatment options. But, you know, we've all been there at the bedside. We just want to be able to try to like break that clot up as quickly as possible. And let's focus on quick, okay, because that's what we want to do. We want to get rid of it. So that being said, you know, the best dose about place to administer still remains controversial in this population. So let's talk about the PIA PET study. This was a single center report of 23 consecutive patients. And all these patients developed cardiopulmonary arrest due to a pulsus electrical activity. And they had CPR, you know, performed per standard ACLS. But all of these patients presumably had PE arrests due to massive PE. In terms of like where these patients lived when they, you know, presented. So 17 patients came in through the emergency department. Two were in the ICU, one patient was on the floor, three were in the radiology department, probably terrible and sucks to be that, you know, dealing with that down there. But in the 20 patients where PE was diagnosed by CT pulmonary angiography, we're going to talk about some of their outcomes. So of these patients, 16 were diagnosed with PE before administration of alteplase, and four after the administration of the alteplase. Notably, all of these patients had elevated troponins, BNP, RV enlargement, RV hypokinesis, that baseline. And what these patients received was alteplase 50 milligrams as an IV push over one minute, followed by a flush while CPR was ongoing. I will note that it's quite easy to draw up the alteplase as 50 milligrams. In this study, they noted in their emergency department that alteplase was kept at the site in 100 milligram bottles. They were readily available for use. They would mix it, they would draw half of that vial into a 50 ml syringe, or I guess at the time it was probably 60 ml syringe, but you know, that's just some pharmacy nerd humor for you. And then they would also be able to run that to the ICU as a stack call when, you know, the patients were in need. With administration of TPA, return of spontaneous circulation and hemodynamic stability, which was defined as a systolic greater than 100 millimeters of mercury and a palpable pulse, of course, was achieved following two to 15 minutes after administration of TPA in all, but one patient. So, you know, that's pretty good statistics there, if you ask me. Within 30 hours, 21 patients were extubated and changes in the RV to LV ratio and pulmonary artery systolic pressures showed decreases over time that were statistically significant. No bleeding occurred at the 22 month follow-up, which I think is also very important. Honestly, would I expect someone to bleed at 22 months? Probably not, but like probably more important in the first week. They didn't have any major bleeding events that were reported. Now, another thing that I thought was kind of interesting about the study, there was no formal quality of life instruments uniformly utilized in this study because, you know, this was a little bit old. But interestingly, all surviving patients reported a return to before event functional capacity without any restrictions, which could be attributable to PE. That's pretty good. So, significant limitations exist with the small non-randomized study. But I think that we see efficacy, we see no major bleeding events. And because of this, you know, I think we are in good hands with using this 50 milligram dose. And I think with that, I'm going to leave it in Nick's hands to try to defend 100 milligram dose. I'm going to try. Now, I got to, we got to come back here because, you know, I just need to note the first study, the melamide study, it excluded cardiac arrest patients. So just want to say reduced dose, no cardiac arrest there. Now, it's kind of a, it feels like a case series or almost like a protocol justification because the, it's a 23 consecutive patients on whom our group was consulted. So it's not even every patient with a PE that underwent cardiac arrest. The impressive thing, time from CPR initiation to TPA administration, six minutes. That's amazing. No bleeding at all. I'll tell you what, that may be amazing. Six minutes. I want other people doing my chest compressions, if that's the case, because I understand how you're getting litics and at least six or even longer minutes of compressions. No bleeding. I don't know. It just feels like if this doesn't, we don't have this luxury when we're actually using thrombolytics in cardiac arrest. Like the idea of giving it six minutes. I mean, sometimes, you know, you mentioned the 50 milligram administration reconstitution. I'll get into that teaser here, but it is not that easy that compared to the 100 milligrams. So it's just impressive. And I just feel like if we're actually thinking more pragmatic real world of what we do, I don't think this is it. That being said, the idea of giving it IV push, I can't push back on that. It's a great idea. I support that. Use that. So I can't push back on that because we'll get it. That's one of the biggest limitations of mine. The idea of infusions, you want to use it, get it quick. I get that. But it feels like this is like a, an ideal circumstances using this. And like when we actually use it in real life, most of the circumstances or patients wouldn't be these. That's kind of my thoughts on it. All right. All right. So let's go ahead and get started. Let's go ahead and get started. This episode of Pharmacy to Dose is proudly sponsored by Keezy, providing innovative pharmacologic therapies for over 85 years. Keezy is committed to supporting the clinical pharmacist community and the patients you serve to learn more. Visit keezy.pharmacytodose.com. Now looking in cardiac arrests, now before we even get into, into my study, I want to talk about reconstituting these. And if you've been on the stroke team, reconstitute the 100 milligram alteplase, you know, it's got the two, it's got the diluent, the product, it's got the adapter that you hook into it. It's nice and easy. If you've ever had to do the 50 milligrams, they do not have the adapter. So it's actually, you think it would be easier, but it's actually more complicated unless your shop does something different where you have 50 already available, you pre-mix adapter, whatever. But doing that without an adapter is not that easy because then you're like, you're, if you have 50 or 60 CC syringes, right? A lot of times you're, you're going around getting five tens, right? Trying to bring out all the diluent, trying to bring it back in. It can be a nightmare. Okay. So we're just, that was just practical putting it together, 50 milligrams of little dicing. Now let's get into my trial. Now I just want to say, it's probably the worst evidence of any type of trial to support an argument that I will make. You'll understand why I'm done, but my argument, it's going to shift gears from treatment escalation to patient selection and using the correct patients here. Now, first things first, you may be wondering, why have I never heard this study? Well, because the Canadian trial has no trial nickname. That's what we've learned today. If your trial has a nickname, there's 100% more change that we will remember it because I didn't know about this study until we kind of dug into this. So this is, we're back in 2002, we're back in the New England Journal Medicine and it's tissue plasminogen activator in cardiac arrest with pulseless electrical activity. So again, Canadian randomized double blind placebo controlled trial. I mean, on the surface that sounds like an amazing study, right? So they enrolled adult patients with PEA. Now this is a very, very important caveat to how they enrolled patients with PEA. PEA needed to be present at some point. And when you think about the average CPR lasting 60 minutes, they likely had PEA at some point, right? When you're in a resuscitation that long, your rhythm or especially in a non shockable rhythm will likely present itself. But 22% initially had acystole and 24% had a shockable rhythm. So let's set the stage for what kind of trial this was 233 patients enrolled mainly out of hospital 96 due to paramedics. They were randomized to 100 milligrams of TPA or placebo. So the 100 milligrams is given over 15 minutes while CPR continued. And then they made sure it was mandated in the protocol that once they gave it, CPR was continued for at least 15 minutes after the infusion cessation. That feels important. That's a point that when we're thinking about using litics, especially if we're trying to argue maybe against it, you're like, Hey, we're gonna have to continue this for X minutes long after we give this, right? That's a huge point probably taken from this study. I did peeking, I didn't find that anywhere else. Now the patients in this trial had, I can't think of a more incredibly poor prognosis. The average duration was 60 minutes. One went as long as 395 minutes. You look at the interquartile range. That's crazy. 20% of patients achieved Rosk. Two thirds of them passed away at the scene. Literally one patient survived. So what did this trial show? Nick, why are you even talking about this study? You're making the argument for 50 milligrams. I might get to why I think this makes the argument for 100 milligrams. And when you review so many of the trials looking at thrombolytics and cardiac arrest, I think you a lot of times will have a selection bias. I think when we actually look at our real world use of thrombolytics in cardiac arrest, I think more often than not, we suspect it. I don't think we have as confirmed a PE when we're debating thrombolytic therapy as in cardiac arrest as we do because I think if it's a known PE, I think you're, it's less of an argument. It's more of when are you going to do it? Maybe what dose, but I think you're always going to look at like it's a little easier. And in this study, only 42 of the patients had an autopsy and one patient had a PE. So that's like a rate of like 4% of this study or something. And with it being undifferentiated, I think this makes the argument even more compelling to use 100 milligram TPAs. So undifferentiated cardiac arrest. So what are our two of our biggest reasons why we would use it? MIPE, that MI dosing is 100 milligrams. And I think probably bending the rules by bringing in an MI patient into this argument. But if we're looking at undifferentiated cardiac arrest, right, and we're thinking PE, this would also be what you might say a two, one treatment, two possible indications. Now, with this study, I found a difference. If they gave it earlier, maybe what if they didn't mandate giving 500 ml of fluid before they started thrombolytic treatment? That's a true story. What if they administered patients who like survive to the hospital? Maybe. But for now, I think the argument is to use 100 milligrams of TPA to maximize its chances of efficacy in this population while looking to use it earlier and in a much more selective patient population in cardiac arrest than the Canadian research trial did. I know that was a rough one for me. I think I was neck and neck. And I think I just I think my horse tripped on the on the back stretch there. Okay, so Nick, it sounds like you want to redo this study, because clearly giving this full dose of 100 milligrams, whether it was from PE arrest due to an MI or PE didn't matter because they all died anyway. And getting back to your comment about the reconstitution of the 15 milligram vial, it is kind of a pain. But if you get the glorified pencil case box and make yourself a kit for your hospital, you can have all the supplies that you'll need at the bedside. And this is something that we actually do at my institution. So we do have out of place kits that are dispensed with the code team when they're needed for in hospital cardiac arrest. And then in the ED, we have nearly 24/7 coverage now with pharmacists, and they have a box of goodies with all the different types of litics. And I won't segue into connected place just yet. But yes, we have we have all the things. And I do remember how to mix out the place. And I do know it's kind of a pain in the butt. Anyhow, that being said, if I had to give my bedside nurse who is attempting to, you know, quadruple task, a bag of 100 milligrams at all the place and said here, find a place to infuse this for 15 minutes while someone jumps on the chest, she gonna look at me and say no, no chance and draw it up in a surrender self and push it. So I think that the practicality of using the 50 milligram dose as an ID push is quite important. And then, you know, perhaps the answer lies somewhere in between these two studies, you know, in the the Canadian study, they insured that CPR was continued for 15 minutes. I think in real life, we often use that same strategy with after administration of a bolus of alteplase, we do ensure that we continue CPR for 15 and 20 minutes to ensure that the alteplase has time to work and circulate and get to the clot and start breaking it down. So I don't know, perhaps it's a draw, something in between is probably appropriate for cardiac arrest. But that's really all I got. Honestly, the Canadian study is pretty abysmal. There's a lot of limitations with that study, unfortunately. And I know I didn't present necessarily the highest level of evidence either, but the truth lies somewhere in between that. And if my patients walked out of the hospital and did calculus, I think 50 milligrams is pretty good. We talked about high risk, intermediate risk, cardiac arrest. Now, right, it's like we're watching our favorite crime show, we get our two minute closing argument, we're lawyers here now. So, Lauren, what's your what's your closing argument for the jury for the audience, the listeners as to why reduced dose thrombolytic dosing is the answer? All right, well, here we go. So in my mind, the more recently published melamed study not only provides evidence to support the use of the low dose thrombolytic therapy in high risk PE but also in intermediate risk PE. At the end of the day, the risk of bleeding was markedly reduced with the use of the 50 milligram dose and the outcomes were the same. Of course, those with massive PE or high risk PE, you know, had a higher mortality compared to intermediate risk PE, which is what we would expect. But there was no difference between the 100 or the 50 milligram group in the propensity matched analysis. Additionally, thinking about the cardiac arrest population, you know, I think we kind of just drilled it down. We probably more practical going to be able to use the 50 milligram dose as an IV push. And then, you know, outcomes may be improved. I think you bring up a really great point about, you know, thinking about whether this is a suspected versus a confirmed PE. Certainly in a confirmed PE, we want to fix the PE and get rid of it. So it makes sense to use lytic in that situation. But I think the 50 milligram dose, you know, is more practical and likely has, you know, very good outcomes for those who actually have pulmonary embolism. So getting back to with our intermediate risk population, you know, again, talking about the melamed paper, but also I want to like remind the group and highlight the MOP it study, you know, these patients had pretty significant pulmonary hypertension caused by their pulmonary embolism. And we saw, you know, significant reduction in pulmonary artery pressures after administration of lytic at 50 milligrams. And I think overall, we're getting our best bang for a buck in terms of balancing efficacy and safety with the lower dose. And potentially in the future, we may find even lower doses are more appropriate. But, you know, the jury's still out on that. I can't believe I got to follow that. Okay. So my closing argument for full dose thrombolytic treatment. So I want to highlight two things not talked about until just now I left it for the closing. But the only FDA approved treatment regimen for the management of a QPE is the 100 milligram alteplase dose given over two hours. And the recommendations from the chest guidelines in patients with acute PE associated with hypotension, we suggest system systemically administered thrombolytic therapy. And when a lytic agent is appropriate for PE, current evidence supports that thrombolytic therapy should infused into a peripheral brain, less than or equal to two peripheral brain a peripheral vein over at least two over a less than or equal to two hours at a dose of 100 milligrams. So thinking about our three categories, here, and I mentioned that and everyone needs to read this, the Journal of Pharmacy Practice published in 2020, I want to quote Lauren's own article here in high risk patients for patients who present with massive PE thrombolytic therapy with alteplase 100 milligrams over two hours should be administered, couldn't have said it better. Now for intermediate risk patients, when we are using thrombolytics in these patients, we are wanting to avoid treatment escalation. We don't want them to continue getting sicker. That's what we're worried about. And that's what the 100 milligram alteplase dosing regimen has shown. And then when using cardiac arrest, one of our most vulnerable patient populations, I want to use the regimen studied in maybe a semi poorly designed study, but it was a randomized double blind fashion, which is the 100 milligram alteplase. So reduced dose thrombolytic treatment sacrifices efficacy in the name of safety. But in today's use of thrombolytic treatment, I think if we're concerned enough to administer thrombolytics, do we want to sacrifice anything from an efficacy perspective? I would say no. And that is my argument for full dose thrombolytic treatment in acute PE. All right, let's get into our bonus round. That was unbelievably fun, by the way, and diving into this evidence, I hope everyone realizes it is shaky at best when you actually look into into the studies and things like that. So this was, at times felt very, very challenging. But let's get into our thrombolytic agent of choice. And I just want to say, Lord already talked about how easy it was for Tenectaplace to get reconstituted. So I didn't even have to say anything. So I am team Tenectaplace, Lauren's going to take TPA and alteplase. So all right, I'll go ahead and take the start here. And I've highlighted before the ease at which you can reconstitute Tenectaplace compared to alteplase. That is no argument, you can't. The first time I did it, you think you're missing four steps, because it's that easy, right? Now, the Lauren's going to kind of talk about two studies here. So I'm also going to talk about two kind of studies here. And that's the patho and the troika trial, thinking about evidence comparison alone, two of our best studies to date, prospective, multi center randomized double blind, a little over 2000 patients enrolled. They looked at the use of it in Tenectaplace in intermediate risk PE and out of hospital cardiac arrest. So when you're thinking our ends of the spectrum, it's about as wide and big as it gets. I think it's strength. And up to this point, we've just been comparing doses of the same agent. There haven't been any comparison of Tenectaplace or alteplase or anything that's been showing an improvement in outcomes with the specific agent. Now, alteplase has been studied longer. That will be an argument. It's one of the first agents. But having this having more lower quality evidence, does that mean that one treatment is superior to another? Right? It's like the office quote, do you want a little bit of really good pizza or a lot of kind of good pizza? I want a little of really good. And there's been a large movement in using Tenectaplace for acute ischemic stroke. And in the hope of having one thrombolytic agent and formulary, I think there's sufficient evidence as it relates to the safety and efficacy with using Tenectaplace as our thrombolytic agent of choice, which would include for the acute management of PE. All right, Lauren, that was my argument for Tenectaplace. Why don't you make the push for why alteplase is actually the answer? Okay, well, before I go in and start supporting alteplase, I think we have to talk some shade about Tenectaplace. So while you're correct, the Python study was the largest study of thrombolytic therapy in PE, specifically intermediate risk PE. This was a double-blinded randomized trial containing just over 1,000 patients. With patients that had PE, they were complicated by right ventricular dysfunction, elevated troponin. And these were real intermediate risk PE patients that probably needed lysis. And they were randomized to receive either the weight-based Tenectaplace or placebo in combination with heparin. Now, although Tenectaplace was associated with a significant reduction in death or hemodynamic compromise at day seven, the hemodynamics was what really drove this difference in the primary outcome, and there was really no difference in death at seven or at 30 days. Now, the number needed to treat here is 34. Let's compare to the number needed to harm because this is a little exciting. So unfortunately, compared to placebo, Tenectaplace increased major extracranial bleeding at day seven. And this was nearly a five-fold increase or almost a six-fold increase. And it also increased the risk of stroke with 10 hemorrhagic strokes occurring in the Tenectaplace group comparing to one in placebo. So if I'm doing my calculations correctly, I'm pretty sure the number needed to harm is 20. So the number needed to harm is less than the number needed to treat. So I don't know about Tenectaplace at this dose. And I will give you that because let's think about the ischemic stroke population, right? So we've all or many institutions have transitioned to using Tenectaplace for stroke, but not at MI dosing, right? So there had been dose-finding studies in the stroke population and my two cents here, somebody with a grant that needs to go and run with this. I think that Tenectaplace at a different dose needs to be studied in intermediate and in massive PE. Although massive, I guess we can't really do prospective randomized clinical trial, but you know, the intermediate risk PE. And that's really what I think we need so that we can potentially use an easier to reconstitute agent in this population. Now, I'm also going to compare this to the melamet study. So when thinking about major extracranial hemorrhage in the melamet study, the 50 milligram dose had a 1.1 percent risk of hemorrhage and 6.1 percent major extracranial hemorrhage occurred in the 100 milligram dose. So in this study, the melamet study, the rate of extracranial hemorrhage with 100 milligrams of alteplase was comparable to weight-based Tenectaplace from the pytho study, but the 50 milligram dose of alteplase was similar to that of the anticoagulation only group in the pytho study. So that being said, I feel very strongly about the bleeding complications with Tenectaplace. And I think this is where the role for alteplase lies. And perhaps I should have made this argument even in my alteplase 50 support, but I really believe that, you know, at this point in time, especially for this intermediate risk population where the risk versus benefit needs to be weighed because they're not as ill as a massive PE population, I think really alteplase is the winner compared to Tenectaplace. Now, let's segue a little bit and talk about the cardiac arrest population. So thinking about patients without a hospital cardiac arrest that received Tenectaplace versus placebo, this was, there was a double-blind multi-center study done in Europe that randomized just over a thousand patients with witnessed out of hospital cardiac arrest to weight-based Tenectaplace or placebo as an adjunct to pre-hospital CPR. But it was terminated early because there was an interim analysis that showed no difference in survival, risk, hospital admission, 24-hour admission, blah, blah, blah, all those things. If we didn't even survive, there's no way there's a neurological or meaningful neurologic outcome. But the rate of intracranial hemorrhage was nearly seven-fold higher in all comers that got Tenectaplace. So I don't know about that. I think at this time, it's unknown, you know, whether Tenectaplace has a role in PE. I, again, I already alluded to this before. I think there needs to be a better dose-finding study for pulmonary embolism. And with that, I think we are left with using Alteplace until we can figure out an appropriate dose of Tenectaplace in PD. All right. I think Lauren may have just schooled me in both dosing and agent, but this was unbelievably fun to the listeners. You're going to be able to go right as you're listening to this. Go vote for who you think won the battle that'll be on Twitter or X at Pharmacy2Dose versus Ceres, looking at thrombolytic dosing in a QPE. Lauren, can't thank you enough for coming on. What an awesome, I mean, unstructured, just truly coming in and having fun talking about a topic like this. You were amazing. I hope the listeners reach out to you @eligniri_farmd, but appreciate time, expertise, and energy coming on here. I really appreciate the opportunity to speak about PE. It's a topic that's super important to me. It's kind of a fun little end note. Anytime I've written test questions about pulmonary embolism and lysis, there's always someone that kind of resonates with me in a patient case. So, you know, sometimes you have to experience one to be able to learn, read, and write about it. So, be on the lookout for that. Well, Lauren, thanks so much. Appreciate it. All right, friends of the pod. Listeners, you know what to do. Vote on social media, Twitter or X at Pharmacy2Dose to determine who the ultimate winner in the thrombolytic dosing in PE versus series is. Definitely let Lauren and I know what you thought at Pharmacy2Dose, TO2Dose, or via email, [email protected]. The reference list with the landmark articles we kind of highlighted, as well as some of those others that are featured in the podcast episode description, as well as at pharmacy2dose.com, the website. But until next time, I'm Nick Peters, this is Pharmacy2Dose, the Critical Care Podcast. Thanks for watching. I hope you enjoyed it. I'll see you in the next one. Bye.