Thank you. My name is, for those of you who came in the room late, my name is Dr. Michael Bloch. I'm a hypertension and vascular medicine specialist from Reno, Nevada. And I think, you know, whether you're an interventionalist or a non-interventionalist alike, we have to look at that data that Dr. Cohn just shared with us and recognize that that's just unacceptable, right? A 50% rate of control for hypertension in this country is simply not something that we should accept. And I've spent the last 25 years of my career going around the country, around the world for that matter, and telling providers that they got to get patients to eat better, to lose weight, to exercise, and to take more medicine. And quite frankly, that simply, that paradigm has not worked very well. I'm not suggesting we don't still do those things, but it's very clear to me that we need other therapies. And I think as we evaluate these other therapies, including renal denervation, this is the question I've been asked to talk a little bit about today, it's a very important one. It's really what magnitude of blood pressure reduction do we need to see from these therapies to really move the needle, to have a meaningful clinical effect such that we should move them from being an investigational drug to something, or an investigational intervention to something that we use in more routine clinical practice. So that's really the question I'm going to spend the next 10 minutes or so discussing with you. Here are my relevant disclosures. And as I said, this is really kind of a complicated question if you get into the weeds with it. Which blood pressure are we talking about? Office, ambulatory, home? What time period are we looking at? Are we looking at 24-hour? Are we looking at daytime? Are we looking at nighttime? A blood pressure reduction as compared to what? You'll see data reported as compared to a patient's own baseline, as compared to a sham control, as compared to other active therapy. And for how long? We've seen data looking at short-term. We've seen data looking at long-term. And there are a lot of different potential confounders that will affect the answer to that question. How much blood pressure reduction do I need to see in a given patient to move the needle? You know, some of those that are important are the presence or absence of background medications, certain comorbidities, background cardiovascular risk really matters, as does baseline blood pressure. And I could spend a lot of time talking about every one of these. I won't bore you and put you all to bed by doing so. But I do just want to highlight the last one, baseline blood pressure, because I do think that's important to keep in mind when we look at trials of antihypertensive therapy because often when we're comparing one study to another, we're really looking at apples versus oranges because those patients have different baseline blood pressures. Just as an example, here on this slide you see data from the RADIANCE clinical trial program, three clinical trials using ultrasound renal denervation. This is pooled data looking at daytime ambulatory blood pressure control as compared to placebo. And this is looking on the left side are patients who had lower blood pressures coming into the study, and on the right side are patients who had higher blood pressures coming into the study. So if you look at the bottom graph there, what you see is that patients who had higher blood pressures coming into the study, as an absolute millimeters per mercury, had a greater reduction in blood pressure. This was seen in this trial. This was seen in lots of different antihypertensive trials. So when we talk about trying to compare one study to another or one group of studies to another, all of these factors are important, including looking at the baseline blood pressure. So one way to answer that question, how much blood pressure reduction do we need to move the needle? One way to look at that question is to say, well, there's a bunch of things that we commonly use to treat high blood pressure. These are things that are super, super well accepted. What kind of data do we have in terms of how much each of them lower blood pressure? So this is looking at drug therapy, pharmacologic therapy. This is from a meta-analysis looking at these drugs as monotherapy, mostly short-term reductions in blood pressure. And as you can see, each of these classes lower systolic blood pressure. This is office blood pressure, about 10 mm from baseline on average. With monotherapy, first blood pressure agent is going to lower by about 10 mm as compared to a patient's own baseline. But remember, it depends as compared to what. If you look at placebo in these studies, placebo, when it was available in these studies, lowered blood pressure by 4 mm. So if we're looking at placebo-controlled reductions in blood pressure, it's about 6 mm, office from baseline. That's short-term data. What about longer-term data? This is a slide that comes from the Blood Pressure Lowering Trialist Collaboration published last year. This is a meta-analysis of essentially the 21 clinical trials that prove that drug therapy works to treat hypertension, prove that drug therapy actually lowers cardiovascular events. If you look at these trials and you look at the difference between active therapy and placebo out past a year, the difference between active therapy and placebo was about 5 mm. That's what we see when we use a therapy to treat blood pressure out past a year, including issues with adherence and all sorts of other issues that happen. It's about 5 mm, and we've said that this is enough that it reduces cardiovascular events in these clinical trials. That's patients usually with monotherapy. What about when we talk about add-on therapy? Because mostly we're talking about renal denervation and other investigational therapies as add-on to a background of medications. So that's a potential confounder. And so I would say that all of us in this room probably feel that spironolactone is a very valuable drug for patients with apparently treatment-resistant hypertension. As a hypertension specialist, I have described my job as follows in the past. I open a door to an exam room, I say spironolactone, I close that door, and I go to the next room. We use a lot of spironolactone in resistant hypertension. It's very much, you know, the standard of care for treatment-resistant hypertension. There's good things about it. There's bad things about it. How did it become the standard for that as the fourth-line medicine essentially after ACD therapy? Well mostly from the Pathways II study. So this was patients who were already on triple drug therapy. Spironolactone added to that regimen, lowered blood pressure by about 12 mm as compared to baseline. But compared to placebo, it was about 9 mm. And compared to these other drugs, remember we said it's better than bisoprolol and doxazosin. We want to use it instead of those drugs. That was because of 4 mm. So the point I'm making is it doesn't take that much blood pressure reduction for us to move the needle and say that something becomes the standard of care. I think the other way to look at this, and Dr. Cohn already showed this slide, I'll expand on it a little bit, is what are we really trying to do at the end of the day with blood pressure reduction? We're trying to affect people's lives in a positive way by reducing their risk of cardiovascular events. And what we've seen in meta-analyses is if you take trials that have looked at more aggressive versus less aggressive therapy, and there's two different meta-analyses that are on this study. An older meta-analysis that looked at a 10 mm drop in blood pressure, that's what's shown in blue. But I really want to focus on that newer meta-analysis that was published just a couple of years ago that looked at 5 mm of mercury. This is over about four years. If you lower blood pressure by 5 mm of mercury as compared to placebo or a different active therapy, you reduce cardiovascular events by 10%, you reduce stroke by 13%, heart failure by 13%, MI and other ischemic heart disease by 8%, and cardiovascular death by 5%. Really meaningful reductions with 5 mm of this is mostly office blood pressure as compared to the other less aggressive arm. This was irrespective in terms of relative risk reduction. This was irrespective of baseline blood pressure or underlying history of cardiovascular events. That is as a relative risk reduction. But I think an important point to keep in mind is that patients who have higher blood pressures, patients who have a previous history of cardiovascular disease or who have other cardiovascular risk factors are at higher absolute risk of disease. So when we start looking at the value of some of these interventions, even though the relative risk reduction is going to be the same 20%, if you're starting at a higher absolute risk, you're going to see greater bang for your buck in terms of actually number of events reduced by lowering for 5 mm. So in conclusion, you know, I started by saying I think this is a really complex question. I think in conclusion I want to sort of end with this slide that says maybe it's not that complex at all. This is actually not the first time we've looked at this question. This was one of the questions that we looked at in the HEART Consortium, which is a hypertension academic research consortium group. Dr. Kanzari, who's sitting right in front of me, chaired this committee. And this was one of the questions that we asked. We asked, you know, in the beginning here, before we had clinical trial results, what kind of results did we want to see before we said that these therapies, device therapies in particular, renal denervation, would be something that should move to routine clinical practice. And our answer was pretty much the same whether you looked at ambulatory, office, or home. We figured if you can lower blood pressure by about 5 to 10 mm as compared to baseline, that would have clinically meaningful results for our patients, and I think that's consistent with all the data that I showed you. So thank you very much for your attention.

hypertension

blood pressure reduction

clinical effect

antihypertensive drugs

cardiovascular events