This part of it, we'll talk about therapies for acute PE, when to do what. And my disclosures haven't changed in the last five minutes, so it's the same disclosures. And so let's start by looking at what are we doing now for management of our patients with pulmonary embolism. And this is ESC risk stratification. This is AHA. Most of us do use the ESC risk stratification. So if you have a low risk PE, where there is no RV dysfunction, no abnormal biomarkers, most of us would do anticoagulation alone. If you have intermediate risk patients, whether it's low intermediate or high intermediate risk patients, where there is a combination of RV dysfunction and or abnormal biomarkers, again, most of the contemporary practice is to manage them with the anticoagulation alone. And if you have a high risk PE, where the patients are hemodynamically unstable, the standard of care seems to be systemic thrombolytics or other advanced therapies. So let's start with that framework. That's the contemporary management of what is commonly used around the country and also globally. So in terms of therapeutic options for patients with PE, we have anticoagulation. We have systemic thrombolytic therapy. We have catheter-based therapies, which can be catheter-directed thrombolysis or mechanical thrombectomy. And then you have surgery. And all of these therapeutic options have trade-offs. I mean, anticoagulation clearly has a risk of bleeding. And the other trade-off with anticoagulation alone is in most of the practices around the country and also globally, the most commonly used anticoagulation is unfractionated heparin. So this is data from our hospital where we looked at the time to therapeutic range of anticoagulation in patients who are sent for mechanical thrombectomy. I'm sure you guys all relate to this. Patient comes to the ER diagnosed with acute PE. They start a heparin drip. And for the next few hours or a day or two, people think that they're treating those patients. So what we did was to say, how many of these patients are actually therapeutic? And by the time we took them to the cath lab, many times it was 8 to 12 hours later. And you can see only 14% of these patients were therapeutic on anticoagulation when they got to the cath lab. So in other words, we start an infusion. We think that we are treating the patients for PE, but most of them are sub-therapeutic. And in fact, what we showed, if you look at the therapeutic range, which is in green, many of these patients on unfractionated heparin are either very high on the 10A levels or sub-therapeutic. So supra-sub-therapeutic anticoagulation is very common. And because of this, ESC guidelines would recommend that if the anticoagulation is initiated, low molecular weight heparin or Fonda is recommended for most patients. But interestingly enough, this is not commonly followed in most of our practice. Moving forward to the next option, systemic thrombolytics, the trade-offs are again, bleeding, and the dreaded complication is intracranial hemorrhage. What about systemic thrombolytics? I mean, we all know maybe in high-risk PE we should be using lytics, but what about in patients with intermediate-risk PE? There have been a number of small randomized trials, this is a meta-analysis, six randomized trials comparing lytics versus anticoagulation with 71% being intermediate-risk patients. And interestingly, what was shown in this analysis was if you use lytics, there is a decrease in all-cause mortality, but this lytics actually increased intracranial hemorrhage and also increased major bleeding. And this is one of the main reasons why systemic lytics is not standard of care in intermediate-risk PE, although there is a reduction, at least in this meta-analysis of a reduction in mortality. So now moving on to our next option, which is catheter-based therapies, we have catheter-directed thrombolysis, where instead of systemic lytics, we are using less TPA, which is delivered locally over a period of time. But interestingly enough, even though the bleeding is substantially lower than systemic lytics, there is a risk of bleeding because you are using lytics. And even though the intracranial hemorrhage rates are much lower than systemic lytics, there is still a chance that there is a risk of intracranial hemorrhage. The other big problem I have with the lytic therapy for acute PE is what's shown on this slide. This is one of my days. I did a pulmonary thrombectomy, and I also had a patient present with STEMI. So you can see the clot burden. I'm not sure if you guys can see. This is from the STEMI patient. Okay, so this is the clot from the pulmonary emboli. This is from STEMI. The reason I show this is for multiple reasons. Let's compare fibrinolytic therapy for STEMI and acute PE. The thrombus burden, as shown in the other slide, in STEMI patients is relatively very small, whereas in acute PE, it's substantially larger. What about the age of the thrombus? We know STEMI, there is a plaque rupture, there is clot formation. So the thrombus is very fresh. It's a few hours. In acute PE, I would say that the term acute is a misnomer because most of the PE may be acute, but the clot is rarely ever acute. So it's always started with the DVT in most cases and embolized, so it's usually a couple of days to a couple of weeks old. So there is all this fibrosis going on in that thrombus. So it's an older thrombus in an acute PE. And we know from plenty of STEMI data that the efficacy of thrombolytic therapy decreases with longer time from symptom onset. So we say best within 60 minutes. But here, for acute PE, we're using the lytics, even though the clot may be several days to several weeks old. We looked at some of the data comparing the efficacy and safety of all of these therapies in patients with acute PE. And this is a meta-analysis randomized trial where we showed for short-term mortality, the best therapy was catheter-directed thrombolysis. If you want to reduce major bleeding, the best therapy was anticoagulation alone. So in other words, CDT will have a high risk of bleeding. And again, if you want to reduce intracranial hemorrhage, it was anticoagulation alone. That leads us to mechanical thrombectomy, which offers lytic-free options for these patients. So are they data for catheter-based thrombectomy versus anticoagulation alone? No RCT power for clinical outcomes. We'll hear later about the number of clinical trials in the pipeline. They're all being single-centered trials, which have shown the benefit of CDT, CBT at improving surrogate outcomes, RBLV ratio, pulmonary pressure, symptoms, and quality of life. And we've also published data using, this is observational data from National Readmission Database. We looked at catheter-based therapies in patients admitted with PE, both high-risk PE and intermediate-risk PE. This is hypothesis generating, suggesting that catheter-based therapies are potentially reducing hospital death, 90-day all-cause readmission, and also VTE-related readmission. Let's switch quickly to high-risk PE, and I want to show this ESC guidelines. So if you have a high-risk PE, patients are unstable, ESC guidelines would say systemic thrombolytic therapy is recommended for high-risk patients at class one level of evidence B. And you wonder, where is this class one coming from, and its level of evidence B? The class one comes from this randomized trial. So this is a trial done in the 90s. This trial had patients with massive PE, there were only eight patients. Patients were randomized to unfractionated heparin or streptokinase, and if you were randomized to unfractionated heparin, everybody died. If you got streptokinase, nobody died. Eight patients, trial was stopped, and this is the strength of evidence. So I think this is very, very important. If you ask people who are treating PEs and say, where is the data for lytics, they will think that there is some data, but this is all the data we have for systemic thrombolytic therapy in massive PE. There have been other studies, this is the FLAMES study, non-randomized, looking at high-risk PE patient, low-trevor arm, where everybody got mechanical thrombectomy, compared to a context arm where they could get any of their standard of care. And interestingly, what was shown is, in the high-risk PE, the low-trevor arm had the lowest mortality seen in any trials of massive PE so far. And of course, this has led to a randomized trial called the Persevere trial among the steering committee, so patients will be randomized to mechanical thrombectomy or standard of care in massive PE, hopefully we'll have more data from that. And our observational study in high-risk PE also suggests potential benefit of catheter-directed therapies over standard of care in these patients. So just to summarize in terms of choice of therapies in acute PE, I think for low-risk PE, it makes sense to continue anticoagulation alone, but I think the choice of anticoagulation, specifically a low-molecular weight heparin and potentially transitioning them to orals, I think would be critically important. For intermediate-risk PE, I mean, I have catheter-based therapy, I'm kind of biased towards mechanical thrombectomy. I think it is, being an interventional cardiologist and what we do with acute MI, I favor a lytic-free approach, but potentially you can use catheter-based lytic therapy for peripheral thrombus, and also potentially you should avoid that in high-bleeding-risk patients. There's also a role for embolectomy, we'll discuss that later. For a high-risk PE, I mean, we have moved away from lysing all patients unless they're actively coding. We offer mechanical thrombectomy in these patients, but hopefully ongoing randomized trials will provide further insights. Thank you for your attention. Thank you.

pulmonary embolism

risk stratification

anticoagulation

thrombolytics

thrombectomy