SCCM Pod-526 CCM: Alteplase Dosing in Pulmonary Embolism
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Hello, and welcome to the Society of Critical Care Medicine podcast. I'm your host, Samantha Gamble-Sfarg.

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 multi-center 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 the 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 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. And before we start, do you have any disclosures to report?

No disclosures. I'm so happy you're here today. You are so well versed to speak to this conversation and 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 lend to long-term mortality if not treated quickly and appropriately. And so 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. And so very happy to have you here as a 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?

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 a low-risk PE. For each of these

types of their treatments, the common treatment accepted for all of them is systemic anticoagulation, typically with unfractionated or low molecular rehab 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 a significant tachycardia or altered gas exchange that

prompts physicians to look for additional interventions in addition to the anticoagulation. And this is where the systemic thrombolysis comes in. In general, we have two regimens for the thrombolysis. The full-dose regimen is 100 milligram of L-teplase administered over two hours. It's an FDA-approved regimen based on a

Fairly old study that compared alteplase to urokinase in the 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 control study published in 2002 showed that systemic thrombolysis in patients with high-risk submassive PE reduced the risk of clinical decompensation. And in this study, there wasn't any significant increase in hemorrhagic complications.

However, a more recent randomized controlled trial called PYTHO study also confirmed that the thrombolysis reduces the risk of clinical decompensation. However, there was significant number of hemorrhagic complications. There is also some evidence that lower dose of alteplase, such as 50 mg as opposed to 100 mg,

may result in similar outcomes, but less complications. So that's the reason that we wanted to look at the real world outcomes in large health systems and try to compare the full and reduce those alteplies.

Right, because we understand that having papers like this are so important as the next phase because of all the work that, as you mentioned, has been done before, but there has not been a lot of studies looking into that phase to 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? Yes. The cohorts that 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 who

with higher disease severity, and especially those who have massive PE with hypotension or shock. And 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.

And this was done by the 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. There was a large amount of detail that you guys put in your data research that

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. And so that information I felt was very detailed to really give a good idea of not just the amount of patients, but what the patients actually were suffering with as chronic illnesses prior to their PEs.

So 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 kind of 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. Yes. So we were able to include

284 patients, 98 treated with full dose and 186 treated with reduced dose alteplase regimen. About a third of the patients had massive PE and the rest had a high-risk submassive PE. In general, the baseline characteristics in Table 1 shows just a reflection of our practices.

who gets what dose regimen. And as I mentioned, as expected, patients with massive PE tended to receive 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

troporin and the lactate levels. We look at the anticoagulation or antiplatelet agents prior to the administration of the 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.

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 ICU.

As with any type of research paper, you know, there's always limitations to our studies that we perform. What were some of the limitations that you found as you moved forward in your study? The main limitation was the retrospective observational study design. We were limited to what we had in the charts.

And 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 the old

the comprehensive data in some cases. We were specifically limited in the echocardiographic data just because how things get reported, and we certainly wanted to have more echocardiographic data, but had to limit our reporting to what we had, and 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...

quoted at all. We tried to do as good a job as possible, and every complication was reviewed by two researchers in case of some disagreements. They were discussed, and we tried to come to a solution, but those were limitations.

The interesting part that I found in reading this is that your study went all the way from into December 31st, 2020. And we know that we were in the depths of COVID during that time. And so I wonder, during COVID, we did have an increase of like DVTs. And I wonder if that had any impact. And that could be another study that could potentially come back.

later on as a adjunctive thing, because, you know, a lot of our patients were having DVTs and some PEs as a result of COVID. And so that's something that could also be looked at perhaps as a retrospective study as well.

This is a good point. We did not collect COVID data for this study, but it is a good point. And we have noticed increase that VTE is during the COVID epidemics. 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 along multiple institutions, such a large scale crisis.

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 is

needs to happen and how can we invest the findings that you have into our everyday practice of what we're doing and then what can we do moving forward to help improve patient outcomes as it relates to alteplase and acute pulmonary embolisms.

The study provides information on the way the systemic thrombolysis works. I think one of the important messages is that the alteplase does work, and we were happy to find that our clinical kind of bedside impression was confirmed with the data analysis.

So what we found at an eight-hour time mark after the alteplase administration, that we measured blood pressures and heart rate and shock index and respiratory rate, and all these parameters improved in both full and reduced those alteplase regimen and in propensity-weighted cohorts as well. So 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. And this is based on our finding that the mortality and discharge outcomes were pretty much the

similar in both groups in reduced and full-dose alteplase. So 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 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. So the majority of deaths happen in a massive PE. So we know our high-risk patient population and can be probably a little bit more selective in a submassive or intermediate-risk patients. And 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 the full dose alteplase as compared to the 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 a full dose, 1.3% in a 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 supra-therapeutic 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. We'll probably give us some guidance in terms of what are the ways to reduce them. We found that about a third of patients who developed complications had an invasive procedure. It was either a vascular access procedure or some kind of a surgery. So, understandably,

These patients are at higher risk and probably need extra attention to minimize the complications. And also, the vast majority of patients who develop complications were on systemic anticoagulation with heparin. And over a third of them had

in the supratherapeutic levels. That points to another direction to reduce the 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. So these are things that could potentially be monitored and also direct us to ways to potentially reduce the complications.

Just hearing your descriptions, I'm hearing what we've been talking about this entire time. But then also in just knowing that you are the director of the Pulmonary Embolism Program there, it sounds like there's 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 that 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, it's not a high number, but it's still significant because the patients can have really bad outcomes as a result of it. Dr. Milliman, thank you.

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?

Thank you for inviting me to this podcast. It's been a pleasure. I just summarize our findings that to us, it feels like 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 are substantially overweight their risk is

the challenge. So patient selection is the key and ways to reduce the potential complications, such as cautious heparin titration therapies afterwards, avoiding invasive procedures, and probably additional studies that focused more on the optimal dose regimens and ideally prospective studies that would not have the limitations of the retrospective analysis.

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. Samantha Gambles-Farr, MSN, NPC, CCRN, RNFA, is a nurse practitioner intensivist at University of California, San Diego Health in the Department of Trauma, Surgical Critical Care.

Burns and Acute Care Surgery. She also serves as adjunct faculty at University of San Diego Hahn School of Nursing and Health Science in its Nurse Practitioner Program.

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