Perfect. Thank you, Keith. And yes, I think we're doing pretty good here in terms of time. So there was one question that came in in the chat that had to do with markers of procedural adequacy. So I would be glad to defer to a cardiologist on our panel, or I can take that one. What do you think about markers that say enough ablation has been delivered in the interventional suite, whether it's radiology or cardiology? Michael, you're the only one. I'd be happy to. There you go. Thank you. I'm over the age of 40, so I struggle with Zoom. But yes, I'm not an interventionalist myself, but having worked closely with the interventionalists here in our community and doing some of these studies, I think it is pretty clear that we don't have an on-the-table marker that is ready for prime time. It would certainly be nice to have one that was clinically easy to use and useful in discriminating patients who you're done denervating versus those you're not done denervating. And I think there's a lot of work that's going to be done in this in the future, but as of now, there's really nothing that's available to us that's ready for prime time, or even close to it, in my opinion. Any other comments? I'll add two things to that very quickly. The one predictor of the response that says you gave adequate denervation was the height of the blood pressure in the first place. The early trials, which enrolled people with systolic in the 180 range, they had the biggest reductions in blood pressure. We were hopeful that renin activity might be a marker for who will and who will less likely respond to denervation higher renins. Maybe they have a better response. There's a little data to support that, but it's not ready to be the definitive test to pigeonhole patients in terms of their likelihood for prediction. Eric, did you want to add anything? Because I saw you on mute. I was just going to say, you know, I agree exactly with Michael's side and your comments. And, you know, the only other addition I was going to make is we saw some recent data about your resting heart rate. You're based on heart rate as a predictor for response as well. People have a higher resting heart rate tend to have a greater response to renal denervation. But I think Michael kind of nailed it on the head that we don't know when we're done in the lab yet. We've kind of been guided by the device itself and when it times itself. And, you know, I think that there's a lot to learn in terms of how we denervate, which will come with time and experience. And, you know, one thing, Ray, if you look within simplicity three, the phenotype that I described in the African-American cohort trend towards more obesity, more females, more diabetes, history of previous heart failure, stroke, those are often low renin patients. They didn't control for sodium intake. And I don't think renin levels were actually measured or calculated. So we may have a phenotype there that we need to do more study and studies going forward that may actually describe the benefits. Perfect. Second question is about the efficacy of RDN on patients in renal failure or on dialysis. I'll take first crack at this since I have this little card from the ASN that seems to think I managed to get through the board certification process. And it turns out that much of that data has been done in Europe or Canada. But in terms of renal failure, first of all, it's safe. So the change of kidney function over time does not worsen as a result, even if impaired in the first place. Most of the current studies cut off at GFR around 45. But the folks in Regina, Canada, did a large study, looked out two years and did not find a worsening in the decline in GFR of people that had GFRs in the 20 and 30 range. And it works. It works about the same as what we've already shown you. It's not huge, but it's not tiny either. It does have an effect. And for dialysis, the only issue about dialysis is that for radiofrequency ablation, you're relying on the blood flow in the kidney artery to cool. Because what renal frequency and ultrasound do, they heat the tissues up. That's how it works. Nerves are sensitive to that heat. And so you've got to cool down stuff. Well, the ultrasound catheter has an internal cooling mechanism, but radiofrequency requires blood flow in order to have that 37 and a half degree blood cool down the 70 degree burn that was just created by the application of radiofrequency energy. That said, the study from Erlangen, Germany, actually did dialysis patients. Caution to the wind here. So what if they don't have much renal blood flow? We're going to do it anyway. It's a small study, single center, but it actually found an even better degree of reduction. And so it was published in Clinical and Experimental Nephrology in 2019. I just happened to have it on the side screen here. So I think from what we can see, no love lost here. You can actually enroll kidney patients when and if that's absolutely necessary. But I don't think you're going to see FDA approval for that if FDA approval is granted in the U.S., because we're not studying that population in any sort of randomized clinical trial that I know of at this time. Next question is, do you think renal denervation predisposes to orthostatic syndromes? So Naomi, would you like to take a crack at that one since I see you're both unmuted? And so far, we've been kind of ignoring you a little bit. So I'm going to undo that little bit of socializing. I'm happy to open with that and also really happy to thank everybody. It's great to be here and to have listened to everything. And just I would like to take a minute to reiterate the importance of innovative therapy for hypertension, apart from the fact that it's incredibly prevalent affecting one in two adults. That's really a lowball estimate. If we're lucky enough to have reached middle age without hypertension, we know from the Framingham study that our chances are over 90% of developing high blood pressure in our lifetime. So it's rather inescapable. We know that current available therapies are not working. And those of us who see patients with hypertension all day every day know that it's really tough to get patients to take their medications. The reality is, whether they cannot or will not, many of them simply do not take their medications. So I think that we're really fortunate to be in an exciting time right now to have a robust, rigorously performed set of positive trials to guide us. And it's time to educate providers and patients and to disseminate and prepare. So I'm really excited about this. I mean, the last time we had a new therapy for hypertension was in 2007, when Eliscarine was improved. Yep. So we're going back, I can do math, 14 years before we had a new therapy. So I think the answer to that, I gave myself a little bit more time because the answer to the question posed is rather shorter, that we have really no evidence that there's an increased in orthostatic hypotension with this therapy. Okay. I'm going to skip the question on platelet therapy, since there is a question about single or dual. Actually, let me talk to one of the cardiologists because, unfortunately, I don't get to treat these people because of the whole COI thing, being on Medtronic's global exec committee. But I know that they do something. So Eric, can you or Keith address, or Michael, address the issue about antiplatelet therapy after renal denervation, arguing that you just traumatize the renal artery and maybe there's a risk for either clotting or either atheroprogression. What do you think? My overall concern about thrombotic risk after renal denervation is low. I think there's been exploration in terms of needing antiplatelet therapy for a duration of time. But overall, we traumatize vessels frequently and have not seen clear thrombotic events outside of when we really leave behind implanted devices. I don't know if Keith or Michael have anything to add to that, but that's my general approach for this therapy. I think it's important to recognize, too, if we follow the data, follow how these clinical trials are designed, they're not requiring antiplatelet therapy in the clinical trials that we have. And without seeing much in the way of renal artery stenosis, literally you can count on one hand the number of cases of renal artery stenosis. And actually, you can leave off a couple of fingers of renal artery stenosis that we've had in our clinical trial program to date. Obviously, we need to see what happens over the long run, but so far, so good. I agree with that. The European consensus was that it's safe and effective up to three years. And the procedural duration, how long does it take if you're in the intervention as opposed to the sham group? I think intervention adds 20 to 35 minutes because you've got to do the burns and you've got to do them on both sides. And if it's radiofrequency, you're doing the branches as well. But I think it's roughly an hour to an hour and a half in most patients with ephemeral approach. Does that ring true? That sounds about accurate. I think that there are going to be modifications to that that might make that quicker. There's been exploration into using alternative sites like radial access that might decrease some of the procedure-related time burden for this. And then also the other consideration is if there are accessory vessels that need to be denervated, that might add a little bit of time additional to the procedure. But I think the hope is to keeping this to a two-hour procedure or less. And I think that is well within the likely frame we'll see when this emerges to practice. I would also say that so far we've seen that there is a learning curve, right? And that the more you do it, the faster you are. And obviously, as anybody who does interventions knows, the longer patients in the lab, the more the chances that there's going to be adverse events. So I think that once again, just speaks to consolidating the experience in particular communities rather than having every interventional cardiologist or interventional radiologist in the community doing a handful of procedures, really trying to consolidate the experience to a handful of procedurals. The next question is incidents of procedural complications, including renal artery injury and stenosis. I'm glad to defer on this, but I actually published something on this, so I'm glad to also take first crack. So we looked at roughly 5,000 people followed roughly two years. The incidence of renal artery stenosis requiring both looking at this person angiogram and dropping in a stent, there were about 25 cases or so over the two years amongst that. The rate was 0.2% for long-term, and most of them occurred within the first six months, and the vast majority within the first year after denervation. So it's an uncommon thing. And the other thing is if you look in the HTN-3 paper, one of the few bright spots in the paper was the safety profile. The safety profile had been established from things like the coral study and others that had a renal intervention that happened to be angioplasty with a stent. But one of the safety bars here, the goals, was to be at or below intervention trials that were ethically conducted in the U.S. and other places. And it turns out the overall complication rate, so far as I know, is in the single-digit percents, and it's usually things that you can imagine with ephemeral puncture. There's going to be some bleeding and bruising, one of those common things, and they rate these things with TIMI levels, and I don't understand that, but I know that it's supposedly accurate. Occasional pseudoaneurysms, and once in a while, an intra-procedural complication, like a wire in the wrong place or a ruptured vessel, but you're on the table, and they usually have no bad outcomes except an extra bit of hardware is left behind to seal the crack. So Eric, did I cover that okay? Yeah, I think that's a fantastic overview. I mean, the trial programs have been vigilantly looking at late events, including renal artery stenosis as a consequence of denervation, and that frequency is incredibly low, and so most of any of the risks seem to be upfront and more procedure-related, like any procedure with access site complications and an engagement of the renal artery, and those, again, in the right hands tend to be very infrequent. So the safety seems to not be as much as you can see in these webinars a concern or a consideration with this procedure, which is a very fortunate and rare event for an invasive therapy. So thank you all for listening, participating in this webinar. Again, thanks to Medtronic for sponsoring it, and thanks to our panel members for being part of this Thursday evening. We hope you've learned something in the process, and thank you and good night from the Fillmore East.

renal denervation

hypertension treatment

predictors of response

renal failure

innovative therapy