What is the reasoning behind the TRISCEND II trial?

So we're increasingly seeing patients with severe TR that are symptomatic that don't have good options. You know, surgery is very morbid. Medical therapy is often ineffective. So there's unmet need of trying to find a therapy that works for these patient population.

And you know, last year there was the TRILUMINATE study with edge-to-edge repair, and this is the first trial looking at transcatheter tricuspid valve replacement to treat symptomatic severe TR in patients who are felt to be at high risk or inoperable for surgery.

What was the study design and patient population for TRISCEND II?

These were patients that were seen by the local heart team. They were felt to be optimally managed on medications for their severe TR but remained symptomatic and were felt to be high risk surgical candidates. So these patients were then randomized 2:1 to either get transcatheter replacement with the Edwards EVOQUE system or continued optimal medical therapy, and we followed these patients.

The primary endpoint of the trial is a one year endpoint. There were a total of 400 patients: 267 in the EVOQUE arm and the remainder in the control arm.

What were the key findings?

For first, in discussing the findings, first thing is procedural results, right? We were able to successfully deploy the valve in over 95% of patients. The procedure time, the device time was under 60 minutes. Patients in general went home, 93% went home. Median length of hospital stay was three days, and all procedures were done from a femoral venous approach percutaneously.

In terms of the 30 day results, there was about a 3% cardiovascular mortality, there was a 1.2% conversion to surgery, which was three patients, and those were mainly due to RV wire perforations. And other safety events, importantly were, there was about a 10% rate of severe bleeding. Now, not all of that was access related, probably about half of it was some of the comorbid conditions in these patients. They're prone to bleeding, a lot of them are coagulopathic at baseline, so there were other bleeding events beyond vascular issues.

And then the other big safety event that we looked at is the requirement for new pacemaker, and that was about 24% in patients that didn't have a prior pacemaker. So that was another important safety signal.

So then between 30 days and one year, the safety events were comparable between the two groups. So there's an early safety hit with transcatheter replacement, but after 30 days we didn't see any other safety events.

So then when we look at the one year endpoint, the primary endpoint was a hierarchical composite of both clinical, including mortality, RVAD, and tricuspid valve intervention, as well as functional quality of life changes. And there was a hierarchical composite endpoint. The significance was calculated using Finkelstein-Schoenfeld and it was highly significant, benefiting transcatheter therapy with EVOQUE. To sort of look at the magnitude of the effect, we calculated a win ratio which was highly significant with a win ratio of 2.02. Now most of that win ratio was driven by KCCQ improvements, NYHA class improvements and all cause mortality improvements.

And then when we look at sort of all, obviously everyone looking at are there changes in mortality, and we look at the Kaplan-Meier curves for all-cause mortality, they numerically favored EVOQUE at one year, but there was no statistical difference. And we also did a landmark analysis, you know, because there's the safety event. And so if you look at 30 days to one year, you see these curves start to separate around six to eight months, and again numerically favoring EVOQUE but not reaching significance. Heart failure, hospitalization, similar, not numerically favors but not significant in the group.

Where we really saw the benefit was in functional status and quality of life improvements. And Suzanne Arnold has sort of presented, is presenting the data looking at KCCQ changes, and there was a pretty significant benefit of almost 20 points in patients that got transcatheter therapy with EVOQUE in terms of KCCQ improvement compared to those that were on control.

Were there any surprising or unexpected results?

The patient population is sort of a mix, and I think it's important for us to understand that the population of patients getting treatment is really quite varied, from atrial functional TR, to ventricular functional, to pacemaker leads. What's interesting is 40% of the patients that involved in this study had a pre-existing pacemaker. So these were patients, and so that's an important component that those are a lot of patients that don't get edge-to-edge. So I think that was important.

I also think we're early in this journey on tricuspid therapy, and we start looking at subgroups, and we look for interaction and in that power. But what was sort of interesting is patients that had massive or torrential TR, so patients that had worse TR got greater benefit, patients that had better RV function got greater benefit, patients that had a greater six minute walk at baseline got more benefit. So there are subgroups that are going to benefit, and maybe some of these benefits are going to actually translate to mortality benefits.

And I think before we say there's clearly not a mortality benefit, I think we need to understand it's a very heterogeneous population, and there may be patient groups that benefit, and that was sort of interesting. And so, as we start looking more into this data, we need to conduct more studies, better understand who's going to benefit. And I think we will better identify which patients need to be treated and are going to get the greatest bang for their buck.

What further study is needed?

I mean, I think this is the first trial of replacement. We need to understand, you know, there's a whole host of other devices that interact with the annuals differently that may have that, you know, we need to get the pacemaker rate down, right? We can't have a 24% pacemaker rate. And so whether that's screening patients, whether it's likely device iteration, procedural technique, all those things, I think we need to figure that out.

Anticoagulation is an issue. All these patients had to be on anticoagulation because you get leaflet thrombosis and thickening, and we've seen that from the surgical side as well. Now, is that lifelong? We need to understand that. Are there valve designs that can reduce that risk because, you know, anticoagulation comes with a price, and right now we need to anticoagulate. So that's another area of interest.

And obviously, we need to continue to reduce procedure complications, and that's going to come from device iteration, things getting smaller. We also need to better understand how to image. You know, we had a couple, we had 5% that couldn't get the procedure. Majority of those were due to imaging challenges. And so, you know, if we can sort of help sort through that, we can figure out, you know, maybe find a larger portion of patients that can be treated. And right now, this is a select population. We need to continue to figure out how we expand the population that can get treatment.