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Host Samantha Gambles Farr, MSN, AG-ACNP, FNP-C, RNFA, is joined by Roman Melamed, MD, to discuss the comparative effectiveness of reduced-dose versus full-dose alteplase for acute pulmonary embolism, focusing on patient outcomes and complications. They will highlight study findings on significant improvements in hemodynamic and respiratory parameters in both groups, with a lower rate of hemorrhagic complications in the reduced-dose group (Melamed R, et al. Crit Care Med. 2024;52:729-742). Dr. Melamed is a critical care intensivist and director of the Pulmonary Embolism Program at Abbott Northwestern Hospital in Minneapolis, Minnesota, USA, and an adjunct associate professor at the University of Minnesota.
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Transcript:
Dr. Gambles-Farr: Hello and welcome to the Society of Critical Care Medicine Podcast. I’m your host, Samantha Gambles-Farr. Today I’ll be speaking with Dr. Roman Melamed, MD, about the article, “Safety and Efficacy of Reduced-Dose Versus Full-Dose Alteplase for Acute Pulmonary Embolism: A Multicenter Observational Comparative Effectiveness Study,” published in the May 2024 issue of Critical Care Medicine.
Dr. Melamed is a practicing critical care physician with over 20 years of experience. He currently serves as an adjunct associate professor at University of Minnesota. He is also a fellow of the American College of Chest Physicians. He is currently the director of the Pulmonary Embolism Program at Abbott Northwestern Hospital, and he also serves as the director of critical care research in the same facility. Dr. Melamed, thank you so much for being here. Before we start, do you have any disclosures to report?
Dr. Melamed: No disclosures.
Dr. Gambles-Farr: I’m so happy you’re here today. You are so well versed to speak to this conversation. Reading your article, I was very intrigued about something that we all, as critical care clinicians, have to manage at some point or another in our practice. We all know that pulmonary embolism is a significant cause of morbidity and mortality in critically ill patients and that patients can present with multiple signs of shock. They can require CPR, and all these things lead to long-term mortality if not treated quickly and appropriately.
I feel like, with your background, this is the exact study that needed to be done and the exact person, along with your other colleagues who are listed on this paper, to take on this study. I’m very happy to have you here as an expert to discuss your findings of this paper. Could you speak a little bit to past research that we’ve seen as it relates to PEs and the utilization of alteplase historically?
Dr. Melamed: Yes, thank you. And thank you for asking me to comment on this paper. The field of pulmonary embolism is quite complicated, and we’ll start with just a reminder that we deal with several types of pulmonary embolism, including massive or high-risk PE, which is associated with hypotension or shock; submassive or intermediate-risk pulmonary embolism that is not associated with hypotension but has some high-risk features such as right ventricular dysfunction, positive biomarkers, or signs of altered gas exchange; and low-risk PE. For each of these types there are treatments. The common treatment accepted for all of them is systemic anticoagulation, typically with unfractionated or low-molecular-weight heparin in a hospitalized patient.
In patients with massive or high-risk PE, systemic thrombolysis has been shown to improve outcomes, including mortality. In patients with intermediate-risk PE, it’s less well established. The majority of them can be treated with systemic anticoagulation alone, but there is a subset of these patients who are right on the verge of decompensation, still not being hypotensive but having significant RV dysfunction, evidence of some hemodynamic instability presenting significant tachycardia or altered gas exchange that prompts physicians to look for additional interventions in addition to the anticoagulation.
This is where the systemic thrombolysis comes in. In general, we have two regimens for the thrombolysis. The full-dose regimen is 100 mg of alteplase administered over two hours. It’s an FDA-approved regimen based on a fairly old study that compared alteplase to urokinase in patients who were getting angiograms and showed improved outcomes. However, there is no dose titration study for the alteplase. And, while systemic thrombolysis can improve outcomes, it can be associated with hemorrhagic complications.
A randomized controlled study published in 2002 showed that systemic thrombolysis in patients with high-risk submassive PE reduced the risk of clinical decompensation. In this study, there wasn’t any significant increase in hemorrhagic complications. However, a more recent randomized controlled trial called the PEITHO study also confirmed that thrombolysis reduces the risk of clinical decompensation. However, there were a significant number of hemorrhagic complications.
There is also some evidence that a lower dose of alteplase, such as 50 mg as opposed to 100 mg, may result in similar outcomes but less complications. That’s the reason that we wanted to look at the real-world outcomes in large health systems and try to compare full- and the reduced-dose alteplase.
Dr. Gambles-Farr: Right, because we understand that having papers like this is so important as the next phase because of all the work that, as you mentioned, has been done before. But there have not been a lot of studies looking into that phase two, comparing the amount of medication that’s being given and how that can impact complications such as hemorrhagic complications. In doing the study, you had some inclusion criteria that included some propensity scores. Can you speak a little bit to that?
Dr. Melamed: Yes. The cohorts who received full- versus reduced-dose thrombolysis, as expected, were somewhat different at baseline. In general, as clinicians, we instinctively tend to give higher-dose alteplase to patients with higher disease severity, especially those who have massive PE with hypertension or shock. Therefore, in order for us to compare the two dose regimens, in addition to just comparing the groups at baseline, we had to balance the groups. This was done by propensity score weighting that took into account multiple variables in patients in both groups, and balanced the reduced- and full-dose alteplase quite nicely, allowing us to compare the outcomes.
Dr. Gambles-Farr: There was a large amount of detail that you guys put in your data research in comparing and looking at medical records using the EMRs to look at comorbidities, the issues that the patients had prior to them presenting, the issues that they had while they were hospitalized. That information I felt was very detailed to really give a good idea of not just the number of patients but what the patients actually had as chronic illnesses prior to their PE. I felt like that was a very detailed aspect, and it’s very well detailed in all of the tables that you have within the paper.
Moving on to kind of shifting the findings, we’ve talked a lot about research in the past, why you felt like this was so important, but then also talking about your inclusion criteria. Maybe discussing some of the findings, which we’ve kind of already alluded to, but giving those specific findings that you guys had as a result of your paper.
Dr. Melamed: Yes. We were able to include 284 patients, 98 treated with a full-dose and 186 treated with a reduced-dose alteplase regimen. About a third of the patients had massive PE and the rest had high-risk submassive PE. In general, the baseline characteristics in Table 1 show just a reflection of our practices. Who gets what dose regimen? As I mentioned, as expected, patients with massive PE tended to receive a full-dose regimen more often. But in the weighted cohorts, after the balancing by the propensity scoring, there was no significant difference.
Overall, we looked at the abnormalities in the troponin and lactate levels. We looked at the anticoagulation or antiplatelet agents prior to the administration of systemic thrombolysis, trying to see if those were somehow factored into the development of the complications. So, overall, we felt that the propensity scoring was successful. We were able to achieve a fairly balanced group of patients for comparison.
Dr. Gambles-Farr: I think that that’s an important aspect to think about in critical care when we’re managing these patients is that sometimes the medication that we’re actually giving them may not be the main reason why they may have these complications. Sometimes it’s the timing of the medications they were on before or the medications that they may be on after that medication that could increase their complications as well, particularly with like alteplase, heparin, and all those other medications that we utilize in the ICU.
As with any type of research paper, there are always limitations to our studies that we perform. What were some of the limitations that you found as you moved forward in your study?
Dr. Melamed: The main limitation was the retrospective observational study design, that we were limited to what we had in the charts. The study was done over a fairly long time period, about nine years. Over this time period, the electronic health records have evolved so we were limited in terms of getting all the comprehensive data in some cases. We were specifically limited in echocardiographic data, just because of how things get reported. We certainly wanted to have more echocardiographic data but had to limit our reporting to what we had. Therefore, this wasn’t the main aspect of the paper.
All the potential confounders that come with the retrospective design, manual chart review, which we had to do a fair amount, just because it is almost impossible to figure out all the complications from the ICD coding, because many times they are not coded at all. We tried to do as good a job as possible, and every complication was reviewed by two researchers. In case of disagreements, they were discussed, and we tried to come to a solution. But those were limitations.
Dr. Gambles-Farr: The interesting part that I found in reading this is that your study went all the way into December 31, 2020, and we know that we were in the depths of COVID during that time. So I wonder, during COVID, we did have an increase of DVTs, and I wonder if that had any impact. And that could be another study that could potentially come later on as an adjunctive thing, because a lot of our patients were having DVTs and some PEs as a result of COVID. That’s something that could also be looked at perhaps as a retrospective study as well.
Dr. Melamed: This is a good point. We did not collect COVID data for this study, but it is a good point, and we noticed increased VTEs during the COVID epidemic.
Dr. Gambles-Farr: Yeah, that was just me. You know, just what you see in clinical practice a lot of times will affect kind of what we think of could be the next gap that we have in research, right? So that just popped into my mind just now, thinking about, that was a whole year, well, not quite a whole year of COVID, because in the United States, we kind of started in March.
But definitely pursuing and continuing this research article, as you are more than likely dealing with actively sick patients among multiple institutions, such large-scale data mining and looking into charts, that’s commendable to have been able to do that and gather so much information, despite your limitations, of course.
I think, finally, and just kind of talking about everything that we’ve discussed here, you know, everything that we do, we’re trying to improve patient outcomes and give the best evidence-based medicine. What do you think overall needs to happen and how can we invest the findings that you have into our everyday practice of what we’re doing? Then what can we do moving forward to help improve patient outcomes as they relate to alteplase and acute pulmonary embolisms?
Dr. Melamed: The study provides information on the way systemic thrombolysis works. I think one of the important messages is that alteplase does work. We were happy to find that our clinical bedside impression was confirmed with the data analysis. What we found at the eight-hour time mark after alteplase administration, we measured blood pressures, and heart rate, and shock index, and respiratory rate, and all these parameters improved in both full- and reduced-dose alteplase regimens and in propensity-weighted cohorts as well.
That’s good news that just confirms that this treatment works in the appropriate patient population. The other message I would say from the paper is that both regimens work pretty similarly. This is based on our finding that the mortality and discharge outcomes were pretty much similar in both groups in reduced- and full-dose alteplase.
This was, in a way, good news to us because we have a little more ground to using the reduced-dose alteplase if we feel that it is a safer regimen. We also found that it basically confirmed the previous research that mortality mostly happens in patients with massive PE. If we look at the differences in mortality in massive and submassive PE in our studies, they’re pretty striking.
The majority of deaths happen in massive PE, so we know our high-risk patient population and can be probably a little bit more selective in submassive or intermediate-risk patients. One of the main findings that we feel is of value to our practice is the analysis of hemorrhagic complications. We noticed that hemorrhagic complications happen more often with full-dose alteplase as compared to reduced-dose. This was statistically significant in the unweighted cohorts, especially for major extracranial complications.
Once we looked at the weighted cohorts, the differences were still pretty significant. For major complications, it was 7.1% for full-dose, 1.3% in reduced-dose. Because the number of events wasn’t that high, it didn’t reach statistical significance. The number of intracranial hemorrhages luckily was not that high. We had three. Two of them happened in a setting of extra-supratherapeutic anticoagulation. It’s not an inconsequential number but provides some important information of what to expect.
And the finding that there are some other factors associated with complications will probably give us some guidance in terms of what are the ways to reduce them. We found that about a third of patients who develop complications had an invasive procedure. It was either a vascular access procedure or some kind of surgery. So, understandably, these patients are at higher risk and probably need extra attention to minimize the complications.
Also, the vast majority of patients who develop complications were on systemic anticoagulation with heparin. And over a third of them had heparin in supratherapeutic levels. That points to another direction to reduce complications, such as being cautious with heparin titration in these patients who receive alteplase and trying to avoid high levels of anticoagulation. We all know that the half-life of alteplase is very short but it can leave behind a post-thrombolysis coagulopathy affecting our ability to clot, thrombocytopenia, low fibrinogen levels. These are things that could potentially be monitored and also direct us to ways to potentially reduce the complications.
Dr. Gambles-Farr: Just hearing your descriptions, I’m hearing what we’ve been talking about this entire time. But then also, and just knowing that you are the director of the pulmonary embolism program there, it sounds like there are at least two additional papers that could come out of just this paper by itself. You know, phase two, looking at the different dosing of alteplase in a more applicable way in patients who are moving forward but then also looking at adjunctive anticoagulants that are used and how they’re monitored, associated with alteplase as well.
It’s such an important thing for us to have these important discussions about risk stratification when it comes to these patients as they’re receiving these medications because of the complications. But like you said, three is not a high number, but it’s still significant because the patients can have really bad outcomes as a result of it.
Dr. Melamed, thank you so much for coming on the podcast today and discussing your paper. I feel like it’s very on par with the things that we need to be thinking about in critical care medicine. Is there anything that you wanted to end our discussion on?
Dr. Melamed: Thank you for inviting me to this podcast. It’s been a pleasure. I’ll just summarize our findings that, to us, it feels like the alteplase is an effective method of reperfusion therapy in pulmonary embolism patients who need reperfusion. However, patient selection is the key because, as we know, especially in a group of submassive or intermediate-risk patients, the majority of them will not decompensate and will do well just with anticoagulation.
Finding this small group of patients who benefit from reperfusion and whose benefits substantially overweigh their risk is the challenge. So patient selection is the key, and ways to reduce potential complications such as cautious heparin titration therapies afterward, avoiding invasive procedures, and probably additional studies that focus more on the optimal dose regimens and ideally prospective studies that would not have the limitations of the retrospective analysis.
Dr. Gambles-Farr: Excellent thoughts, and thank you for that powerful ending. Dr. Melamed, thank you so much for joining us again. This concludes another episode of the Society of Critical Care Medicine podcast. If you’re listening on your favorite podcast app and you like what you heard, consider rating and leaving a review. For the Society of Critical Care Medicine Podcast, I’m Samantha Gambles-Farr.
Announcer: Samantha Gambles-Farr, MSN, AG-ACNP, FNP-C, RNFA, is a nurse practitioner intensivist in the Department of Trauma, Surgical Critical Care, Burns and Acute Care Surgery at University of California San Diego Health. She is also adjunct faculty at University of San Diego Hahn School of Nursing and Health Science in its nurse practitioner program.
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