Thanks, Rob. For full disclosure, I did not put this together. I'm presenting to you slides from the principal investigator, Pierlis Wissam-Jaber. These are slides he presented at TCT, so everybody can get it straight from a horse's mouth. So let's go ahead and get started, though. So what's the background and why was Pierlis performed? Well, first of all, the largest pulmonary embolism trial performed in the past of advanced therapies for PE was the PITO trial, which everybody remembers from 2014, randomized 1,000 patients to systemic thrombolysis versus anticoagulation alone. Since then, there have not been pivotal randomized trials evaluating advanced therapies, but the field of catheter-based interventions has significantly grown. And obviously, the field of catheter-based interventions has fallen into two large categories, catheter-directed thrombolysis and large-form mechanical thrombectomy. These are in heavy utilization and increasing utilization in the US and Europe. Thus, there was a need to perform a comparative study to determine the relative risks and benefits of the two therapies. So the Pierlis trial is the first trial to compare these two interventional based therapies against one another, ideally with clinically relevant endpoints. Who are the patients enrolled? Well, they are your typical ESC intermediate risk patients. They largely had positive biomarkers and then preserved blood pressures, were symptomatic and had central clot with RVs that were larger than their LVs on an initial CT scan. You can see that the main thing that folks were excluded for were things like limited life expectancy, inability to anticoagulate, or PA pressures greater than 70 millimeters of mercury on hemodynamics because there was concern that this actually represented a different phenotype, that of chronic or acute on chronic PE, which was not the goal of the study. 550 patients were randomized equally between catheter-directed thrombolysis and large-form mechanical thrombectomy. And we'll present primary endpoints, which are largely short-term or in-hospital endpoints, but also 30-day outcomes were collected, which have some importance to the interpretation of the study. A couple of minutes on how the primary endpoint was designed and how to interpret it. A so-called Winn ratio was utilized. The Winn ratio aims to do the following. You take patient one, let's say in catheter-directed thrombolysis, and you then compare them to patient two, to patient one in large-form mechanical thrombectomy for the first component of the Winn ratio, all-cause mortality. If one of the patients survives, I'm sorry, if one of the patient dies, then the other patient gets a Winn. If not, they tie and you move down to intracranial hemorrhage. And you do the same thing again as you work your way down to assign either a Winn or a tie in a hierarchical manner, moving through these five endpoints. The beauty of this, and then you go ahead and take patient one in catheter-directed thrombolysis, and you repeat that process for patient two in large-form mechanical thrombectomy. And straight down the line, where every patient in catheter-directed thrombolysis gets compared to each patient individually in the large-form mechanical thrombectomy arm. What are the advantages of a Winn ratio approach? Well, there are several. The first is that it does allow you to create an actual hierarchy of endpoints, as you see here, because if you're higher up in the Winn ratio, you're evaluating that endpoint more than those endpoints that are lower. Secondly, it dramatically increases your power to see differences, because the total amount of comparisons is very large, based on how I described to you the methods there. And then thirdly, it enables you to mix dichotomous endpoints, all-cause mortality, intracranial hemorrhage, which are yes-no questions, with sometimes endpoints that are more health services-based, or in this case, health care utilization-based, and that's that last endpoint of the ICU admission and length of stay. You'll see in other types of scenarios where folks might use things like New York Heart Association classification, which is a categorical endpoint, which has four categories to it, not just a yes-no, but you can factor that into a Winn ratio by putting it in as part of your endpoints and still determining a Winn or a tie based on these categories. So these are the potential advantages of the Winn ratio. However, it is important to recognize that when it comes to Winn ratios, you want to look at the total Winn ratio, but you also want to go ahead and look at the components and how they're compared to one another. And in the peerless trial, each of the individual components of the Winn ratio is a pre-specified secondary endpoint that was analyzed individually in the trial. Who was enrolled? Well, a typical PE population, mean age of about 60, and happily, there was almost 50% of the patients were women. There was about 20% to 25% that were African American, and you can see the average BMI was 36. This kind of mirrors, I think, what most of us would think about from a PE patient standpoint. The RVLV ratio is about 1.3 on the initial scan. Importantly, the patient population ended up being extremely low bleeding risk. You can see there was only 4% with relative contraindications to thrombolysis, and in fact, even these contraindications, I think most of us would see as maybe not even being a true relative contraindication. They included four patients, for example, who had gotten a low molecular weight heparin, which I use routinely on all my PE interventions. They included patients with hemoglobins in the nines because the hemoglobin less than 10 was considered a relative contraindication. So even the 4% is an overestimate for what the contraindications to lytics were, I would argue. So this was truly a low bleeding risk population. That wasn't the initial intent of the trial, but it ended up being what the investigators were willing to randomize. What was done in the catheter-directed thrombolysis arm? The majority of patients were treated with ECOS. However, that still was only 60% of them. You can see about 30% were treated with the old-school Crag-McNamara or Unifuse catheters, standard infusion catheters, and then some other devices were used in a small percentage, perhaps the Thrombolex device in a few patients. But this was largely a study of ECOS, 60%, about two-thirds, and old-school Crag-McNamara and Unifuse catheters, about one-third. No specific TPA protocol was dictated, but you can see what was done here. It was done at operator and institutional discretion, and the total TPA dose for patient ended up being an average of about 16 milligrams in the catheter-directed thrombolysis arm. Not surprisingly, procedure time was a little bit shorter in catheter-directed thrombolysis, but actually the treatment catheter times were much longer because patients were largely put in ICUs and had indwelling catheters and fused in their lytics as we often do. You can see that the primary endpoint represented what was considered a large win for large-form mechanical thrombectomy with a win ratio of five. That win ratio mean there were five times more wins for large-form mechanical thrombectomy than catheter-directed thrombolysis as you worked your way through that process that I mentioned. However, when excluding the ICU utilization component, you can see that the win ratio dropped to 1.34 and did cross unity. That was a pre-specified secondary endpoint. So that's the four-component win ratio that's noted there. So this is excluding the ICU care piece. And then I think when you delve deeply into each of the individual components, which is extremely important, mortality is extraordinarily low, only one in-hospital mortality in the whole trial, unbelievably low, just one out of 550 patients, much lower than we predicted in the intermediate risk population. Intracranial hemorrhage, also very low, about a half a percent all throughout the trial. So not really a risk in either case for catheter-directed thrombolysis or mechanical thrombectomy. Major bleeding rates, dead even at 7%. Also, I think most would say reasonably low and equal across therapies. The difference, the only difference ended up in the fourth endpoint in clinical deterioration and or bailout therapy. We'll talk more about that in a second, where there were 15 events in the catheter-directed thrombolysis arm and five in the large-bore mechanical thrombectomy arm. That was technically statistically significant. Now then, naturally, in the post-procedural ICU utilization piece, there was a lot more, there was almost universal usage in the catheter-directed thrombolysis arm, where almost everybody went to the ICU and then ended up staying a bit longer. Whereas in the large-bore mechanical thrombectomy arm, this trial did demonstrate that it was safe to send many of these patients to the floor. There was no dictate in the trial to tell institutions how to treat their patients after the procedure, but I think we all know that in the U.S., we tend to put catheter-directed thrombolysis patients in the ICU. In this trial, you know, roughly 60% of patients ended up not in ICU after large-bore mechanical thrombectomy. As far as this important endpoint of clinical deterioration or bailout, it has two separate components. The first is clinical deterioration. This, I would argue, is a hard endpoint in the sense that it was a pre-specified endpoint that included things like you see on the left. Cardiac arrest, respiratory failure, worsening hypotension that required pressors, increased oxygen requirements that were noted that were significant, and true respiratory failure needing, you know, high flow oxygen, non-invasive positive pressure ventilation or intubation. I think this is probably a fair way of describing what clinical deterioration is. There were 10 events in the catheter-directed thrombolysis arm and four in the mechanical thrombectomy arm, but that obviously on its own does not meet statistical significance. Importantly, the timing of those events was different. All four of those events happened in the lab for a patient with large-bore mechanical thrombectomy, whereas the 10 events in the catheter-directed thrombolysis arm happened in the kind of 24 to 48-hour period after the procedure when patients were largely in the ICU. The second part and the slightly more controversial piece is in this escalation to bailout therapy. There's some subjectivity here, naturally, because operators were allowed to make a decision that they thought patients were not clinically improved enough, and in that case they offered potentially another advanced therapy. In this case, most of the catheter-directed thrombolysis patients were offered large-bore mechanical thrombectomy afterwards. Still only six patients out of 276, so certainly not common, but it was offered that many times. Large-bore mechanical thrombectomy, one of the patients was treated afterwards, I believe with systemic thrombolysis. That was the escalation to bailout therapy in that group. Again, some subjectivity here, and it's worth discussing that in further detail with the panel, which I know will be interesting to talk about. Major bleeding, I mentioned, only seven percent in each arm, and I don't think there's much more to say about that, honestly. It was not an impressive end point. Perhaps it was driven a little bit in the catheter-directed thrombolysis arm by a few more transfusions. Finally, it's important to look at two final end points. First is the 24-hour visit secondary end points, which were largely dyspnea-based end points based on scoring systems given to the patient or measurements of the respiratory rate, and also RV functional end points. The majority of these, you can see five of these six end points, very early at 24 hours, were statistically significantly in favor of large-bore mechanical thrombectomy, and additionally, there was a little bit less of a hospital, there was a little less hospital readmissions. You can see the 30-day all-cause readmissions was a bit lower with mechanical thrombectomy, eight percent versus three percent with large-bore mechanical thrombectomy, but then finally, at 30 days, those same end points I mentioned to you, which showed a difference at 24 hours, MMRC, dyspnea scale, NYHA, and then a couple of other quality of life scores, they all were now equalized between the two groups. So we see this bit of a signal towards a difference at 24 hours versus 30 days in terms of some of those functional end points. And we'll go ahead and stop there and just mention that obviously, peerless, as we all know, is the first randomized trial comparing these two therapies. I think I covered many of the potential limitations. It's non-blinded, the CDT care was not standardized. We know about issues with ICU, which I'm sure we'll delve into, and I think it's important to talk about the bailout piece and what we mentioned. And it is, importantly, a low bleeding risk population. This doesn't necessarily apply to a high bleeding risk population. It technically did meet its primary endpoint. However, it's important to take that into context with the secondary endpoints that were mentioned. And I'll stop there and let Rob take back over.

Peerless trial

pulmonary embolism

mechanical thrombectomy

catheter-directed thrombolysis

Winn ratio