So, you know, I think the one aspect of what you presented and Dave followed with is, you know, we don't have anything in the cardiovascular space with this level of evidence with sham control. And I think the challenge there, though, is that we're not used to looking at the impact of a sham arm, right? And I think Mike did a nice job of kind of highlighting that in the discussion about monotherapy and what a placebo does. So when you talk about this, and I know you've spoken about this a lot, how do you put into the context of the absolute benefit of renal denervation versus the change between the sham arm and the control? Yeah, it's a common problem and less so, as David so eloquently put, probably when you're talking to patients who probably think that 8, 10, 12 millimeters sounds great to them. But when I was speaking to my other colleagues, honestly, in my cardiology division, the first question that, or the first thing that's often said, even today, despite all the data you just saw presented is, oh yeah, it's that thing that didn't work in that trial 10 years ago, right? And so they're not up to date. So I think we all, I'm glad we're educating people in this forum, but we have to really be ambassadors of making sure people understand that there's been, you know, we just presented, I think, six consecutive randomized trials, there's been more with sham that demonstrate benefit here. And then the second thing, though, that's mentioned is, oh, how much are you getting out of it? And that's the key argument that you mentioned, is that when you're putting it up against a sham in a closely followed experiment, and using ambulatory blood pressure monitoring, everything about that is going in a direction of reducing what the perceived absolute benefit would be of the therapy. And actually, if they are following these patients in their offices, just checking however they check or ask them to take their blood pressure and bring it in, likely this is gonna be much larger. And that's kind of what is shown. And that's what their mind is attuned to, is those kinds of changes, but you're trying to reorient them to what things look like in a clinical trial setting. And nobody has more experience than Debbie with that. I don't know if you agree with some of that, with AVPMs and... Just a quick comment, just generally. So I don't know, there's other data, not in renal denervation, but at AHA there were two studies presented with Baxterostat and aprositantin. These are two drugs for resistant hypertension, and they both really showed impressive reductions in blood pressure, but the placebo groups also had huge reductions in blood pressure. So I think when you're measuring this against a sham and a placebo, you can't really predict how people are gonna react. So you have to take that into account, I think, particularly with the spiral on study, the latest one. We couldn't predict it. Yeah, and I think that's where the Global Simplicity Registry, GSR, fills in a lot of the needed evidence here, is that we're seeing now reductions in the teens over years in real-world practice. And so if you tell me that my patient in the controlled experiment versus a placebo is gonna have a 5-millimeter reduction, okay, we can all argue the value of that, and we've tried to show you some value proposition here, but if you say now in a real-world experience that if you have renal denervation, and you go through your clinical practice, and you're seeing that that patient now in one year and two years has a 15, 20-millimeter reduction, whether that's them doing something different in their lifestyle, plus renal denervation maybe with the med, that's still a big change compared to what we're doing in clinical practice right now, which is not getting anywhere near that, I promise. In my practice, I'm not. Maybe, Mike, hopefully, you are with your spironolactone, but... No, no. I'm not. And like I said, I'm just... We need new therapies, but just... The way I think about it is I've been a big proponent of using ambulatory blood pressure monitoring for these clinical trials and using a sham group for these clinical trials, right, in order to prove that there's a difference in blood pressure. Not to prove the magnitude of the difference, but to prove that there's a difference in blood pressure. Ambulatory blood pressure monitoring is a great tool for clinical trials. It increases your sample size. It standardizes your methodology. It gets rid of the white-coat effect. It shows data at daytime and nighttime, but unfortunately or fortunately, it's not something we use all the time in clinical practice. So when I'm asked that question by my colleagues, what should my patient expect in terms of blood pressure control, I think that the number I choose to share, the clinically meaningful number is office as compared to baseline, because that's how we've done other antihypertensive trials and that's what the patient sees. So that's kind of how I... What's that number that you say, then, when you get asked that? What would you say? What do you say? On average, you will expect... Yeah, somewhere close to 10 millimeters of blood pressure reduction. That's usually the number that I use. I don't know if... To date, there have been actually nine sham-controlled randomized trials of renal denervation therapy. So just to put it in perspective, it's a far greater standard that we've held PFO closure or transmyocardial laser revascularization for those old enough like myself to recall this or one PCI trial of sham-controlled. And although AVPM is definitely a step forward in some instances from office, it's not without its own fallibility, too, because even in the sham control groups in op-med studies, you can see a four to five millimeter change in AVPM in either direction just through follow-up as well. I think that the increasing awareness of hypertension and hypertension trials, though, brings us to a point where we start to think about how we view hypertension in general. Yes, it's one thing to say this is the world's largest leading cause of global death and disability, but rather than being number five on your list of problems on your epic charting, it really needs to come to the forefront. We start to revisit how we think about hypertension in the context of what we've done for diabetes. So think about initially several decades ago, you would prick your finger and you would measure your blood glucose. Then we transitioned to this hemoglobin A1c, which is a representation of your blood sugar over the preceding six months. And now there are device technologies that can measure your blood sugar continuously and even adjust therapy accordingly. And I think we see and we have this concept of glycemic control and time and therapeutic and time and target range. This is all just starting to transition now to hypertension. We'll have the advent of continuous monitors or more frequent monitoring. Home blood pressure monitoring is something that we haven't emphasized in the community as well. And so even amidst ambulatory blood pressure and its limitations in the United States, at least, I think there are other opportunities for us to think about how we view hypertension and the hypertension burden itself. And I'm going to throw one more question at you before we tie up the session. You said nine SAM-controlled trials. I think we've got a really nice representation of that. How much more data do we need? You know, I think that we have a great plan of more studies and there's value to them expanding to different clinical groups that haven't been studied. How much more data do we need in this space to feel confident? I think, I mean, this is speaking from my own opinion, of course, but I think for both technologies we have enough evidence to date to move forward into clinical practice given the efficacy, effectiveness, and safety of these technologies. I think for newer technologies, as we've described in the HART document, it's still important to think about proof of principle, proof of concept, off-med studies, if they can be performed. There are some evolving technologies, surgical mediated technologies and others in which SAM control might not be the most acceptable step forward, so we'll have to think creatively about those. But for renal denervation technologies, I think we'll then see forthcoming approvals based on, perhaps, non-inferiority trials rather than on superiority to a SAM control. I'll just point out that, in my opinion, I agree with everything David said, as always, but where we are with who's been studied, I would say that, you know, we're where we need to be. So as far as moving things forward, patients who haven't been in these studies, CKD rises high on the list here. We know that's a huge coexisting condition. And then secondly, more personalization of the therapy, I think. I think those are the two things that really strike me as huge areas forward. We can be even more informative to our patients that maybe we do expect a patient who walks in front of us to get 20 millimeters in an ABPM, but we have to start proving that.

evidence

renal denervation therapy

blood pressure

clinical trials

ambulatory blood pressure monitoring