Good afternoon. I am Ryan Weispfenning, Managing Vice President and Head of Medtronic Investor Relations. Welcome to the investor briefing here at the American Heart Association Annual Scientific Sessions in Chicago. Thanks to you that are here in the room with us today. Appreciate you coming to Chicago, and also a big welcome to those that are joining us around the world today on our webcast. Go to the next slide. Before we get started, I want to note that we could make some comments that may be considered forward-looking statements, actual results might differ materially from those projected in any forward-looking statement. Additional information concerning factors that could cause actual results to differ is contained in our periodic reports and other filings that we make with the SEC, we do not undertake to update any forward-looking statement. I encourage you to go back and read this slide.
The slides we are presenting today will be available for download shortly after the completion of today's event on our website at investorrelations.medtronic.com. I want to note that we're in our quiet period following the end of our second fiscal quarter, thus we won't make any qualitative or quantitative comments about the quarter, including topics such as sales, market growth, or market share, or taking questions today beyond the Ardian business. We plan to update you on our Q2 earnings call, which we expect to hold two weeks from tomorrow on Tuesday, November 22nd. While today's event is about Ardian, I do encourage you to check out the three-year results from the PROGRESSIVE-AF study that were presented as a late breaker today at AHA and published in the New England Journal of Medicine.
These data show that Medtronic cryoablation significantly reduces AF progression and is a superior initial treatment compared to drug therapy. You can read more by clicking on the business and regional news at news.medtronic.com and reading our news alert from today. Back to Ardian. Today is a big day for our renal denervation business, as a little over an hour ago, we issued a press release on our ONMED trial data and the data were presented here at AHA today. Sorry, one second. To provide insights on our Ardian data, we have Jason Weidman, Senior Vice President and President of our coronary and renal denervation business, and Dr. David Kandzari, Chief of Piedmont Heart Institute and Cardiovascular Services, and lead principal investigator of the SPYRAL HTN-ON MED study. Here's the agenda for today's event.
Jason will make some introductory remarks on our Ardian program. Next, Dr. Kandzari will discuss the six-month ONMED clinical results. Jason will come back up to provide an outline of our commercial and regulatory strategy for renal denervation. We'll take questions from the audience. With that, I'll turn it over to Jason to make some introductory remarks. Jason.
Okay, thanks, Ryan. Good afternoon. Thanks, everybody, for being here. We're super excited to talk about Medtronic's renal denervation program, as well as our go-forward plans to really help the billion-plus patients out there that have hypertension. I think I'll start by saying that, despite running the ONMED trial during an unprecedented global pandemic, we were actually pleased to see the results of this trial and that it validated the blood pressure-lowering effect of Ardian. When you look at the most common blood pressure measurement used in clinical practice today, office blood pressure measurement, we saw a statistically significant and clinically meaningful reduction in blood pressure for Ardian versus the control. While we did miss the primary endpoint in ambulatory, we think those results are clearly explainable.
Via the ambulatory measurement, you did see a reduction in blood pressure with Ardian, but we also saw an unexpected reduction in the sham, but that was due to medication increases and COVID's impact on the ABPM testing environment. Dr. Kandzari will talk about this in more detail here in a few minutes. Across all of our studies, really importantly, the Symplicity blood pressure procedure has demonstrated excellent safety and resulted in absolute blood pressure reductions that are remarkably consistent. I think what's great about this is that the consistency of the results is both in the short term and the long term. This is a big opportunity for us.
Our view of the market potential has not changed, if you look at our target segments that we'll reach over time, we look at this and we say that when we see that just 1% penetration of the target market segments results in greater than $1 billion of market opportunity in the long term. Of course, the first step in getting to that market is regulatory approval, that's why we're super excited today to announce that we did file with the FDA our PMA for the Symplicity Spyral device. I can tell you, we are very confident in the totality of our data, obviously, that includes our already reported positive pivotal trial, the OFFMED study. The last thing I'll note is that we are preparing for market launch, preparing to build this market, and investing to continue to lead in the future.
I'm just going to spend a little bit of time. I think it's worthwhile making sure we're all grounded on hypertension here. Obviously, hypertension impacts more than 1 billion people worldwide. It's the largest contributor to death, there's over or about half a trillion dollars in direct spend in the healthcare systems across the globe. We know consistently from the clinical literature that very small reductions in blood pressure confer pretty significant benefits. If you look at the data in the literature, just 2 to 5 millimeters of mercury in absolute office systolic blood pressure that drops will give you about a 10% reduction in cardiovascular adverse events. Drugs certainly work, but people just don't take them.
Right now, if you look across the globe, only one in four people have their hypertension under control, and about 50% of people stop taking hypertension medications at one year. We very much believe that Ardian is a solution. It's very safe. It's a simple procedure without a permanent implant, and its always-on effect can help to lower blood pressure and/or lessen the drug burden. This then results in a pretty enormous opportunity. Again, starting with 1 billion patients overall, but we definitely see this technology first being utilized in those patients that are of the greatest need. If you focus on the left side of the screen here, in our world, those patients, the sickest patients, are the resistant, uncontrolled hypertensive patients.
Over time, we would expect to move to the right of this slide and start to access more and more of these patient segments. As I said, when you look at these segments on the screen, 1% penetration results in more than $1 billion of market opportunity. I can tell you, we strongly believe that we have the right device to access this market. The Symplicity Spyral device is a one-size-fits-all catheter, can be used in all different vessels. It was definitely designed to maximize patient applicability. We also believe very strongly in the ease-of-use advantages of this device. That includes very simple setup. It's just plug and play. It has six French guide catheter compatibility, which is really important to physicians, and it has excellent deliverability that allows it to get through torturous anatomy into whatever vessel you need to.
I think the most important thing that I want to hit about our program here is that we have a tremendous amount of clinical data, positive clinical data in support of this therapy. In fact, I would call this an unprecedented amount of positive clinical data for a therapy that is not yet approved. If you look at the published literature, we have more than 12,000 patient years of positive published data, with the Medtronic renal denervation system. We continue to enroll new trials to support this therapy. I think with that introduction, and ending on the clinical piece here, I think that's a great time to introduce Dr. David Kandzari. As Ryan said, David was the PI of our trial and has been part of the program and this renal denervation journey for about 10 years.
You'll be able to walk everybody through the ON-MED results, specifically as well as some of the totality of the data.
Thank you, Jason. Terrific. Good evening, everyone. This is a welcomed opportunity to be with you this evening. Perhaps it's not uncommon in many instances at a meeting like AHA to have a program that didn't meet per se, its primary endpoint, yet there's much to celebrate here from the SPYRAL HTN-ON MED program. As Jason introduced, renal denervation has traveled a very storied path over more than the past decade, from the Symplicity HTN-3 study that now, in fairness to it, has some validation from our recent three-year publication in the journal "Lancet," to a succession of sham-controlled randomized trials demonstrating quite consistent findings. Indeed, we have now to date in the space of renal denervation therapy, nine sham-controlled randomized clinical trials. No other device technology, cardiovascular medicine or otherwise, has been held to such rigor and to such a standard.
All of these studies, uniquely, even with two different technologies, two different modalities of renal denervation therapy, have all consistently demonstrated meaningful reductions in blood pressure with renal denervation therapy, despite some variance with the sham control group. Jason had asked that perhaps we just begin very briefly by sharing with you something perhaps many of you are familiar with, but the methodology in terms of how we perform these trials with regard to catheter-based device therapies for renal denervation and hypertension altogether, with regard to the endpoints of the ambulatory blood pressure and the office systolic blood pressure. Specifically, ambulatory blood pressure is an endpoint that we've transitioned to based on our early experience from the Symplicity HTN-3 study. It is more commonly used indeed for research. It is representative of the burden of hypertension over a 24-hour period.
Specifically, an individual wears this monitor for a 24-hour period, during which time every 30 minutes in the waking hours, the blood pressure is assessed, and every one hour during the nighttime hours. We have pre-specified criteria for what constitutes a valid reading of the ABPM. ABPM, by averaging the blood pressure over 24 hours, expectedly for most of us, our blood pressure goes down when we're asleep, is typically lower on average than the office systolic blood pressure during waking hours. It is susceptible, though a bit less than office blood pressure, to variance and compared to the office blood pressure. By all means, the ambulatory blood pressure can vary from individual to individual from time to time. We've observed this, in fact, in our OFF-MEDS clinical trials in which patients are not taking antihypertensive medications.
We can see, for example, zero to three months, that there are some individuals whose ambulatory blood pressure increases three to five millimeters mercury, and others in the absence of medicines who change over this short time period as well. Of course, you can manipulate the ambulatory blood pressure too through lifestyle changes, whether you're taking medicines or not, whether you stop smoking or start exercising or weight loss or other interventions as well. In comparison, office blood pressure is by far the most commonly used metric to inform clinical decision-making when you and I are in the clinic as patients, and certainly when I see patients in clinical practice, as many other healthcare practitioners worldwide. It is the office systolic blood pressure and office diastolic blood pressure too that serve as the criteria for societies and guideline endorsement recommendations for target goals.
It's not an ambulatory blood pressure goal. It's an office systolic blood pressure goal as targets for defining hypertension and how to treat hypertension worldwide. Moreover, the office blood pressure really has been the primary endpoint for many other sentinel clinical trials, the SPRINT trial being one such example. A major trial that has highlighted the benefits of more intensive blood pressure lowering that invite therapies like renal denervation therapy to the space for more intensive blood pressure lowering. Those trials have been based on office blood pressure as well. To summarize from our presentation earlier this afternoon of the SPYRAL HTN-ON MED study.
To begin with, oftentimes overlooked because of the intense focus on blood pressure reduction, but quite consonant with the totality of data with radiofrequency energy delivery, as Jason shared with more than 12,000 patient years of experience, that this therapy and this trial, compared not only in the randomized cohort but also with a pre-specified goal, compared with a performance goal of over 250 patients treated with renal denervation, proved exceptionally safe. There were no major procedural complications, no major clinical adverse events. Once again, we continue to survey these patients through imaging at six months follow-up. Although it always has been a theoretical concern, we see no occurrences of renal artery stenosis, for example, which, to be fair, is really case reportable if it were to occur.
Despite the absence of reduction, which we'll talk in much more great detail with regard to 24-hour ambulatory blood pressure compared with the sham, the blood pressure reduction for office systolic blood pressure remained remarkably significant and remarkably consistently significant across all elements of the trial. Recall, this is a Bayesian analysis, so we combine, if permissible, if the data match and align, we can use up to 80 patients in the initial pilot randomized trial, which demonstrated at six months a significant reduction in office systolic blood pressure. We combine that with the expansion cohort of 257 patients. Herein, even in the expansion cohort, we see a significant reduction in office systolic blood pressure.
The absolute magnitude, which we'll soon discuss in a few moments, is almost to the decimal point, extremely consistent with what we've achieved with renal denervation in many prior sham-controlled randomized clinical trials. Unusually, unexpectedly, the ambulatory blood pressure, however, did not mirror the significance with regard to the office blood pressure reduction. To be sure, the ambulatory blood pressure reduced by a clinically meaningful amount. The absolute reduction, of course, 6.5 millimeters mercury in this clinical trial. The comparison with the sham control group was missed with regard to statistical significance. I don't mean to amplify that absence of difference more, but even a two-millimeter reduction in ambulatory blood pressure is what many drug therapies may be approved on, in fact, today. Not in this case with regard to statistical modeling.
In the expansion cohort, as mentioned, renal denervation therapy was effective at reducing blood pressure by 5.9 millimeters mercury in the expansion cohort. This is the 24-hour ABPM, but it was a 5.8 millimeter reduction in the sham control group. What's very different, for example, from our nascent experience with renal denervation, for example, in the SYMPLICITY HTN-3 study, is that we have now the fidelity, the granularity of clinical trials to really understand what was occurring in the sham control group. I don't think there's any debate in the medical community, does renal denervation work from this clinical trial? The reduction in the ABPM and office blood pressure, as I've shared, is exactly identical and consonant with previous trials. It's really now what's going on with the sham control group here. We have two observations from the study that provide insight to it.
One is that more than 80% of the patients in this expansion cohort experienced their follow-up during the COVID pandemic, and we identified quite statistically significant but meaningful differences in the patterns of ambulatory blood pressure between patients enrolled during the COVID period versus the pre-COVID period. These differences occurred for daytime ABPM, nighttime ambulatory blood pressure, and even 24-hour ambulatory blood pressure. It tells us in some ways that there's something different about this COVID patient population. Certainly, this is not unique to this study, as we've seen even here today at the AHA or during the AHA, other studies for iron supplementation and others showing some COVID effect and COVID sensitivities being employed in the clinical studies.
I think the even more striking, even more relevant and tangible issue is that there are quite remarkable differences in medication changes between the sham control group and the renal denervation group in this expansion cohort that we didn't witness in the prior sham-controlled randomized pilot study that were observed in the expansion cohort that significantly favored the sham control group. Specifically, as I presented earlier this evening, 22% of the patients in the sham control group had a net change in their medicines, meaning either an escalation of medication number or dose and not decreasing their medicines prior to the ascertainment of the six-month endpoint, compared with only 2% of the patients in the renal denervation group.
That's a tenfold difference, all of those changes occurred despite a protocol that mandates no changes in medicines and patient compliance, it all occurred before the ascertainment of the primary endpoint. Finally, as I shared with you, the absolute reductions that we observed, again in this trial with renal denervation, are quite consistent with previous studies. As introduced earlier, and sharing with you in a bit more detail, although we observed statistically significant differences in the ONMED pilot randomized study with regard to ABPM and office blood pressure at six months. Again, in the ONMED expansion group, no significant differences compared with the sham, but definitely a reduction of 5.9 millimeters of mercury, and then a significant difference even in the ONMED expansion group with regard to office systolic blood pressure.
Again, across the pooled analysis, across the individual components of the study, statistically significant reductions in office systolic blood pressure. As I've also shared with you, 80% of the patients were followed in the expansion cohort during the COVID pandemic. Just to recall, per protocol, to share with you how these studies are performed, and this is not unique to this study, is that for a blood pressure assessment during clinical follow-up, a patient is asked not to take your medicines that morning. You come into the office, and you have the office blood pressure initially assessed, then there is witness pill intake. Then the application of the 24-hour ambulatory blood pressure is performed.
If a patient, for example, is taking a higher number of medicines or a higher dose of medications, it's going to be even more amplified after the witness pill intake for the ambulatory blood pressure assessment. As I shared with you, too, in the pre versus the during COVID enrollment population, the during COVID enrollment population was quite sizable, approaching nearly 200 patients, that we saw very striking differences in the patterns of ambulatory blood pressure as well, not just for the overall 24-hour period, but for daytime and nighttime as well. This, again, may reflect behavioral changes in patient patterns, that have been described elsewhere in the context of the COVID pandemic.
Most striking, as I've also introduced, is that despite similarity in the baseline number— in the medication number and medication burden at baseline, medication burden representing medication number, dose, and class. Despite similarity at baseline by the process of randomization, there emerged very quickly, at three months and at six months, even amplified at six months, statistically significant differences with a higher medication number and burden in the sham control group. Again, all of which occurred prior to the six-month ascertainment of the primary endpoint. We confirmed this importantly by drug testing, by drug testing with urine and serum assays. This is, I think, highly explainable for the sham control reductions that we observed in this clinical trial.
In many ways, to me, it tells you that at least for ABPM, but certainly not for office systolic blood pressure, one can escalate his or her medicines to try to get to a similar but not greater reduction in blood pressure with escalation of medicines. It's at the cost of a higher medication number and burden. We know that's an independent predictor of adverse events. As we'll soon discuss, that's likely not sustainable from our experience of clinical trials, both from renal denervation and even trials like the SPRINT study. We observed this tenfold difference in the expansion cohort in medication changes that would favor a reduction in blood pressure, even more striking in the Black ethnicity population, representing nearly 20% of the study population.
The sham control group had 55% of those patients randomized to sham, experienced an escalation in drug number and/or dose with no reductions in their medicines, compared with, for example, 21% of patients who experienced in the renal denervation group, a decrease in their medicines in that subgroup. If you have an opportunity at home to measure your blood pressure and it's looking better, even though you don't know your treatment status, you start to take less medicines, perhaps. Alternatively, if your blood pressure remains high or is even going higher, you're more likely to increase your medications as well, or maybe a provider outside of the trial is willing to do so as well.
Indeed, about one in five patients in this study were taking more medicine that was even on their prescription list in this trial as well as I shared in our discussion panel this evening. Renal denervation therapy, once again, consistently not only reduces blood pressure observed in this trial and reduces significantly office systolic blood pressure, it also won, so to speak. It won with the win ratio. We have shown this in previous studies with medications as well, that when we look in a hierarchical analysis and consider it of the opportunity for renal denervation to reduce blood pressure, also perhaps to reduce the medication burden, which is quite clinically meaningful to patients, again, it's a predictor of non-adherence, that renal denervation in this therapy won with 27,000 patient comparisons.
I'm happy to, perhaps in discussion, if anyone is interested, describe to you the methodology for this. We compare patient to patient to patient across this trial 21,000 times to look at who won versus ABPM reduction and who won versus medication reduction and renal denervation in this case won. As I've also introduced the absolute blood pressure reductions, whether it's in the context of medicines or in the absence of medications, call that in the off-med setting, including the off-med's pivotal trial that demonstrated success compared with sham control. We were remarkably consistent, demonstrating nine to 10. The patient survey of real-world practice and patient-like patients that would be enrolled in the clinical trials like on-med and off-med. Those absolute reductions are at least consistent at 13 millimeters mercury. Even in the HTN-3 study, now with even longer-term follow-up, those reductions are consistent as well.
As I shared though, the strategies that we've observed in patients who have not been treated with renal denervation therapy in our trials, like the long-term follow-up of Symplicity HTN-3 and the ON-MEDS pilot study now both through three years of follow-up, both of which have been published in the journal "Lancet," demonstrate that for those individuals who do not get renal denervation therapy and remain persistently hypertensive, there is, if not anything, a waning efficacy with their medications over time, that their blood pressure control, if anything, erodes and goes even higher despite the escalation of medicines in an effort to reduce blood pressure. This is also the instance recently published within the past month in the SPRINT trial, a pivotal landmark trial that changed guidelines practice for more intensive blood pressure lowering.
It shows that blood pressure goes down in the intensive group during the trial period, during the Hawthorne effect, the period of surveillance. Thereafter, following these patients over longitudinal follow-up temporarily, there's this progressive erosion in their blood pressure control, and it actually returns to that of the standard therapy group with higher blood pressure, and they lose all of the clinical benefit of the 20% mortality reduction that was identified earlier in this trial. I think as a final data element to share with you before returning back to Jason, again, what is unique about this effect with renal denervation is indeed, as Jason introduced, this always-on effect that we see as disparate with medications with regard to the pharmacokinetic profiles, the dosing regimens, and certainly with patient adherence.
We see this always-on effect, this 24-hour always-on effect with renal denervation therapy, that in trials like HTN-3, trials like the ON-MEDS pilot study now through three years, not only is there durability in the blood pressure reduction and persistent safety, importantly as well, but the blood pressure reductions, if anything, are modestly amplified over long-term follow-up. Very importantly, this is not explainable by an increase in medication dose or number as it is in the control groups. Thank you, Jason.
Great. Thanks, David. I'm just going to spend a couple of minutes here on the regulatory and commercial strategy so you know what our plans are going forward. Most importantly, as I mentioned at the start, we did file the final module of our PMA today, so that went in today. We have been working with the agency collaboratively for some time now, for several years. As part of that, we've actually used a modular submission strategy. What that means is that, in fact, four of our five modules for our submission had previously been submitted and at this point, are preliminarily closed out. We'll continue to answer FDA's questions as they come, and we'll continue to work collaboratively with them.
As I said at the beginning, we're very, very confident in the totality of our data supporting this submission, and that does include, obviously, the pivotal study, the off-med study, as well as our other randomized trials and our registries. Moving on to thinking about market development here. If you look at Medtronic over the last 60 years, I would say the one thing, or there's many things, but one thing that Medtronic has been consistently very good at, it's creating new markets and building them. We know how to do this. This is something we do well, and we're ready to do this again with hypertension. There is a lot of activity that's been ongoing that's going to enable us to do this, that will enable us create demand, actually convert that demand into procedures and execute, and ultimately for us, sustain our leadership position.
As I mentioned, there's a lot of activity ongoing right now, I'll call your attention to a few things that I think are particularly important. One is that obviously for a new procedure like this to ultimately get great market adoption, it's going to need to be incorporated into the medical guidelines. Really the first step there is to mobilize the physician and the KOL community around support for the therapy. Support for renal denervation. We've been spending a lot of time over the past few years doing just that, I think a great example of how that's going well is that in the past two years, 12 separate physician societal consensus statements have been published across the globe in support of renal denervation.
This is really the precursor to guidelines, we're well along that path of what we need to do in order to eventually get into the guidelines. A couple other things I'll call out. One is in relation to our trials with something that you may not know is that the vast majority of the on- and off-med patients in our trial, they actually got into the trial through direct-to-patient recruitment, we did most of that digitally. Even if you look at just the select markets we went to across the country to run these campaigns, obviously aligned with our trial sites, we had over 150,000 patient opt-ins. I think that gives you a little bit of an idea of how interested patients are in finding an alternative treatment for their hypertension.
The learnings that we got during those processes are definitely applicable to the commercial setting and something that we'll just transfer over as we have commercial approval. Another thing to note is that we do have great relationships with our coronary sales force, with interventional cardiologists. We plan to have them sell and support renal denervation going forward so we can take advantage of those relationships and their knowledge of the hospital systems. However, we do plan to augment that with a separate therapy development field organization, that organization will be focused 100% on Ardian. Think of that as being very akin to what Medtronic and Edwards did with their therapy development organizations to build the TAVR market. Moving on to reimbursement. This is, I think, clearly one of the largest barriers, it'll take time. It's different all around the world.
What I will say is that we have the most experienced and the best people at Medtronic working on this, we are spending a lot of time trying to ensure we have success. If I focus on the United States, we have been meeting with CMS as well as large commercial payers for some time now. Ardian is not going to be a new thing or a surprise to them. If you think from the CMS perspective, there's likely to be multiple routes to coverage, we'll be prepared for all of those different routes. From a private payer perspective, this is going to be a situation where we need to go one by one by one by one with every commercial payer. Frankly, I would expect that every specific coverage decision and the associated timing will be pretty heterogeneous with all of these commercial payers.
Last thing I'll mention in the U.S. is coding and payment. These are pretty process-driven, we've done all of the steps we need to do, we'll be in good shape by the time we launch. In Europe, we do have approval, indeed, reimbursement has been a bit of an obstacle. Payers in Europe are very different country to country, one thing I would say that's fairly consistent is most of them do look to the guidelines, as I mentioned earlier. In Europe, the predominant guidelines are the ESC guidelines. I think what's very important to note is that the last update to the ESC guidelines was in 2018, and those guidelines actually say that renal denervation should only be used in a clinical trial setting. Obviously, that's going to hamper adoption.
As I mentioned before, we're working with the physicians to try to get those guidelines updated. We feel confident that during the next update, they will be in favor of renal denervation. Unfortunately, the next scheduled update for the ESC guidelines aren't until the fall of 2024, it's a little ways away. The only other thing I'll note here in Europe and the situation there with reimbursement is that generally payers care a lot more about economic evidence than they do in some other parts of the world. Now that we have our full data package complete, it allows us to move forward with our cost-effectiveness analyses. We have some plan here for publication over the next, or I'll just call it in the near term.
What I can tell you is that we will fall within or we expect to fall well within the acceptable thresholds for cost-effectiveness. Last thing I'll note is we are investing heavily in our pipeline as well. As I said earlier, we're very, very confident in the Spyral device. We think it's the best device out there, we also know that devices can get better, we intend to make them better. We have four active pipeline programs right now, we have over 75 people working on Ardian product development, that'll ramp to well over 100 as we get into the next calendar year. We fully intend to be the technology leaders in this space in the long term. Okay. Just before we head to Q&A, I just want to reiterate the key takeaways here.
For me, first and foremost, hypertension is a global health crisis. Patients desperately need, they want new solutions. Overall, if you look at the overall Medtronic data across multiple trials, it is very, very strong. It indicates that renal denervation can be this always-on hypertension solution that patients are looking for to lower blood pressure and or to reduce medication burden. We know that renal denervation provides clinically meaningful, absolute blood pressure reductions that are very consistent, as Dr. Kandzari showed, and they're durable. This is an incredibly safe procedure. Again, we filed for our PMA today, this is a multi-billion-dollar market opportunity, we're committed to leading in the long term. Thank you.
Okay. Thanks, Jason. Go to the first question here, Chris.
Thanks, appreciate you guys taking the time tonight. Chris Pasquale from Nephron. Dr. Kandzari, a couple questions for you. The focus on office BP specifically, I find that a little interesting. It's sort of like a dietician saying, "I only care what you ate for lunch on Monday," when clearly the rest of the week matters, and the goal is to get blood pressure down consistently for these patients. If changes in medication were really the culprit around the ambulatory blood pressure measurement, why do you think those didn't show up in the office comparison? Did you look at the subgroups that had no changes in medication regimen?
Thank you for those questions. I'm just trying to recall all of them in order. I like the analogy of the dietician, except to say that whether it's office or ambulatory blood pressure, ambulatory, even then, is just 24 hours of the day of a year, right? It still has its limitations. Instead of, to your point, though, instead of office or ambulatory, really, the goal is to look at a more continuous following of patients with regard to, for example, office blood pressure, as we've done in a concept called time in therapeutic range, where we're kind of taking the analogy of glycemic control in diabetes and looking at the long-term burden of hypertension, in this case, glycemic control in diabetes. We've shown, though, that in comparison to patients not getting renal denervation in these trials, the time in target range is substantially better.
Moreover, we've shown in the Global SYMPLICITY Registry that intuitively, the greater time you spend in target range by office systolic blood pressure translates to lower risks of death, stroke, and heart attack as well. That's a brief comment about ABPM versus office. I would also say, too, that in this trial, office blood pressure, the sham group is also affected. Recall, they have a five-millimeter reduction in their office systolic blood pressure when in theory, they should not have any reduction as well. The changes in medication certainly affected office blood pressure too, but to a lesser extent because of the protocolized way of after witness pill intake. The next morning too, the patient's ABPM has been placed after witness pill intake. The next morning, he or she is also taking that higher medication burden.
When they come into the clinic for the office blood pressure assessment, we ask them not to take it. We're seeing two things happening there. We're seeing the trough of their medications, even if they're higher, and they are higher, you're going to see some sham effect. Secondly, maybe they're not taking those medicines before they come into the clinic anyhow, you might see a diluted effect as well.
Can I just jump in?
Yeah
Really quickly there? One of the things, if you were in the session today with the drug trials, you'll notice that they even specifically noted on their endpoint that they always try to measure at the drug trough. That's more similar to what we saw in the office. The other simple way I try to think about this is with the protocol here is, it's totally fine when you're taking your meds. It only makes a difference when there's an unbalanced increase of meds between the two arms. The timing, and we can refer back to that timing thing at another time. The timing essentially means that the office is taking into account changes of meds once, but the ABPM is kind of taking it into account twice.
Did you look at patients that had stable medication regimens?
Yeah, great question. Two things. One is that, when a third of the study population has changes in their medicines, and you try to exclude those who didn't make medication changes, there's two challenges with that. One, some might call it like a per protocol analysis. The answer is that we don't see still differences, and the reasons are very important why. One, is that you've already markedly reduced your sample size by about 33%, so your statistical power is gone to null. Secondly, if you think about taking out the patients who made medication changes, and remember, medication changes can go both ways. If your blood pressure's high, you can go up, but if it's looking really good with renal denervation, you stop taking them, right?
If you exclude those patients with medication changes, you're almost converging towards the null, towards the middle, because the people who had high blood pressure and who are taking more medicines that would show greater difference with renal denervation are taken out of that equation. The people with renal denervation who had a really good blood pressure and were starting to take fewer medicines are also taken out. You're getting more of a narrow comparison. It's largely underpowered anyhow.
Yeah, you take out the highest blood pressure shams and the lowest blood pressure RDNs. You're kind of left with an unequal comparison.
Yeah.
Yeah. The other thing I'll note on that is we did anticipate that there could be a situation where you have these unequal medication changes, and that's why the win ratio analysis was pre-specified, and it deals with that type of situation. To David's point that he explained earlier, win ratio will allow you, with the full sample size, to account for both medication changes and changes in blood pressure.
Thanks.
Go to Larry.
Larry Biegelsen, Wells Fargo. Thanks for taking the question. One for Dr. Kandzari, one for Jason. Dr. Kandzari, subgroups. Were there any important differences in subgroups? I'm interested in U.S. versus OUS, 65 above and below, dippers, non-dippers, blacks and non-blacks. We didn't see that, I don't think, in the presentation. Jason, can you talk about the financial goals that you had, the $500 million in 2026 calendar year, $2 billion-$3 billion in 2030? I'm curious why you didn't reiterate that today. You sound confident in the totality of the data. I get that, but I think one could infer if you were really confident in it still, you would reiterate the financial goals you put out a year ago.
Sure
Why not? Thanks.
With regard to subgroups, Larry, we really have just received this data, and we're putting it together. We haven't performed all the subgroup analyses and predictors of treatment effect. One group, though, that does stand out in terms of a negative predictor is the black ethnicity cohort, but I think it's explainable by the considerable medication changes that you saw in the sham control group as well.
Okay. With respect to the market, as I said earlier, our view of the potential of this market, Larry, hasn't changed. We still see this as a multibillion-dollar opportunity. Hypertension, as I said, is billion people desperately in need of solutions, this is a big opportunity. I think that the easiest way for us to think about it is 1% penetration is greater than $1 billion of opportunity. The exact ramp to get to that full market potential, I think is going to depend on a few variables that we're going to have to see how that plays out. That's like timing of approvals, exact labeling, and reimbursement. I think I'll dive into reimbursement just as an example of changes, right?
Last year, we thought that we would be a candidate for MCIT was repealed, we were going down the path of something different. Now CMS has proposed TCET, we don't exactly know what that is yet. That's an example of one of those variables where we just don't know how it's going to play out yet, we're going to have to see, that'll help determine the ramp.
Let's go to Josh.
Thanks a lot. Josh Jennings from Cowen. First, I just wanted to ask about clinical endpoints, there are clinical endpoints in the secondary outcome measures that are listed on clinicaltrials.gov, I think new stroke, new MI, mortality. Do they become more important with these results, either for the clinical community or on the reimbursement side? Will we see those results? I think the clinical trial design is out to 36 months looking at these clinical endpoints.
Yeah. Just as an aside, we're going to follow these patients through 3 years, and a subgroup even through 5 years of follow-up. One of the issues that's always a challenge in renal denervation trials is also the confounding when there's crossover from the sham control group, and there's a large number of patients altogether from the study treated that you don't have a good adequate comparator. Just as a broader statement with regard to clinical outcomes, as you know well, there were no major adverse events or differences between the 2 groups. If anything, one new stroke in the sham control group, but not in the renal denervation group. Very consistent with the previous studies. We'll pool the totality of data for long-term follow-up with clinical outcomes as well.
I also am always reminding myself too, though, that there's no reason that the blood pressure reduction with renal denervation therapy shouldn't translate into clinical benefit, just as a calcium channel blocker, an ACE inhibitor could do so. We also have some insight to this from, as I was sharing, the time and therapeutic range data from Global SYMPLICITY Registry. We don't hold the drugs that I routinely prescribe, as I will tomorrow morning in clinic, we don't hold them to a mortality reduction as well. It's a blood pressure reduction upon which they're approved and upon which they're used as well. As the breadth of evidence, as the evidence base continues to accrue, I think we'll have better opportunity to look into the true heart events, though.
On the payer side, just with your discussions around clinical outcomes and just they were baked in the trial design. That's just why I'm asking. My follow-up is just with the submission and just the labeling of OFF-MED as the pilot, ON-MED as in the expansion, is there anything we should read in this or should we just be thinking are the regulators going to be more heavily weighting the OFF-MED results versus ON-MED results? Thanks a lot.
Generally, Josh, I think that for all of the stakeholders, whether you're talking the regulators or the payers, they're going to value the totality of the evidence. I don't think that there's necessarily a method where they score one more than the other. I think they're going to look at the totality of the evidence, which is very strong. Go to Robbie.
Thanks. Robbie Marcus, JPMorgan. You talked about a couple different pathways you're ready for in reimbursement in the U.S., and you talked about needing guidelines in Europe, most likely. How are you thinking about what some of those different pathways might be in the U.S.? Do you expect an FDA panel, and how long are you expecting for reimbursement to come through after approval? Should we be thinking one to two years, or is this something that might take longer?
Okay. Sorry, I'm going to try to get all of your questions down so I don't-
The different-
There's different pathways, which I was really speaking to CMS, and then there's panel, which is approval related.
Timelines.
How long for reimbursement.
Yep.
Is that what you're saying? Okay. I'm going to try to put the reimbursement questions together. Why don't I take the approval one first. The panel is up to the FDA, but we'll be preparing as if we will need a panel. We would likely find out sometime, I would guess, in the first quarter of next year, whether we need a panel or not. That would be my guess on that, but that's up to them. In terms of reimbursement, the different pathways I was speaking of with CMS is you could go for a national cover, or we could go for a national coverage decision, and those typically come with evidence development. We could go to each of the Medicare MACs one by one by one, which there's seven of them.
You just go locally to the different Medicare MACs, or there's this new TCET regulation or legislation that's been proposed, but there's no details. We're guessing that CMS is going to provide more details at the beginning of this next calendar year. That's our best guess. We have requested time with CMS to discuss this further and try to narrow in on what might be the best scenario for us given this new TCET one. In terms of the timing for reimbursement, generally, I would think that for Medicare, for all of these pathways, usually about one year to get reimbursement, typically. Don't know on TCET. For private payers, there will be some that will be early. There will some that will be really late. Like I said, they're going to be really heterogeneous.
If I could sneak one more in. Dr. Kandzari, I didn't see the chart in the presentation about the waterfall of how different patients reacted or responded to therapy. Do you know what % responded or didn't respond, and how do you think that'll impact physician utilization?
Yeah. This is not your question, but sorry, just to go back before we lose momentum on this. I just wanted to say, although the guidelines documents in Europe, for example, aren't, as you said, scheduled for 2024, we have a document from the European Society of Cardiology that's a consensus document that is currently underway in publication that has far moved from reserving this for research to identifying which patients in clinical practice should be used. Responder analyses are hard for me to answer, in part because it depends on when you look and what your cutoff criteria are. No significant differences here, though, with regard to responders from all of our previous trials, depending on how you wish to identify it. Indeed, it would make sense because the absolute reductions for office blood pressure and ambulatory blood pressure are completely consistent with the previous studies.
In terms of identifying, quote, "non-responders," there's no consensus on how that is defined. For people who don't necessarily have a blood pressure reduction that's predefined, this is a space of ongoing study for us, to be sure. Right now, the greatest predictor of blood pressure response, independent of the RDN technology, is having a higher blood pressure at baseline. There are some other biomarkers and things that are suggested for us that we're looking into, but I think this is an area still of ongoing science for us.
Yeah. I just want to note too that, certainly we would like to better understand responders and have 100% response rate, but there are other medical devices and drugs that don't have-- Most drugs don't have a 100% response rate. It's always been curious to me how we really focus in on that for renal denervation, where we don't for the blood pressure medications or others. In fact, excuse me, for blood pressure medications, I do know that the response rate is exactly zero when you don't take your drugs.
Let's go to Ryan.
Thanks. Ryan Zimmerman, BTIG. I saw on the presentation, a trial entitled AFFIRM. I'm just wondering, Jason, if that is a post-market study that you're preparing for, or if there is going to be prerequisites given the data today for post-market studies from payers in order to seek reimbursement. How you're thinking about that currently.
Yeah. Again, several questions there. AFFIRM is a study that is ongoing right now. It's already enrolling. In fact, the PI is sitting next to me, so he can speak to it as well. Primarily, one of the big purposes of AFFIRM is to look at some of those patient subsets that were excluded from the on-and-off med trials. We're looking at isolated systolic hypertension, chronic kidney disease, and diabetics. Those are all in there. That was agreed upon with the FDA. There's a performance goal. In terms of whether there will be any other post-market requirements, and that would be from the FDA, from a regulatory standpoint, that's to be determined through the next many months as they review our submission and we go back and forth on that. I can't comment on that. It's too early to tell.
You had from-
No, that was it.
That was it? Okay. I got it. Good.
Go to Travis.
Hi. Travis Steed, Bank of America. Thanks for hosting the event tonight. I did want to, on the FDA, maybe you covered this earlier and I missed it, I'm just curious if you expect the label to be a broad label or limited to a certain patient population. When you think about tonight's results, do you think it impacts the amount of investment that you need to spend to develop this market? I think you were already spending close to $100 million, if I'm correct, on Ardian. Does that accelerate and step up from here now that you move into commercial phase? Kind of stay consistent?
Okay. Walk me through the all three of them again?
Sorry. Yeah. Sorry. FDA label was the first one.
Label. Okay.
Investment. Does tonight's results change the amount of investment?
Oh, do we need more because of the results?
Exactly.
Just generally, are we going to invest more anyway?
Exactly. Yeah.
Yeah. Okay.
From here.
Great. Okay, label. We've proposed a broad label, which is what we've said before. Nothing has changed because of that, we feel our data supports that. That'll ultimately be up to the FDA, and that's kind of some of the final stuff that happens during the process. Again, that'll be up to the FDA, but we've proposed a broad label. In terms of investment, I don't think that we need more investment because of what we saw in the results today. Most of the physicians that we've talked to, and if you were in the room, the panel was pretty okay with the results, and it made sense to them. We saw this good effect of Ardian, and then we had this drug impact in the sham part of things. Most of the physicians I've talked to so far have all been pretty favorable.
I would say there's no additional investment needed because of this trial. Certainly not. In terms of additional investment to prepare for market, certainly. That's something that we're doing now, where like I said earlier, we're going to have a separate field therapy development force. All of those things are additional investments. Most of that added investment is going towards prepping for commercialization.
All right. That's helpful. Then on the pipeline, since you did put it on the slide, just curious on timing, and do you need new trials to do that, and how you think it impacts the market opportunity and like, for example, like the other energy sources that you mentioned, like how do you think that impacts the procedure or the opportunity?
Yeah. I think generally, I'm not going to talk about specific timelines of the product pipeline, but what I will say is our plan is to have a pretty steady cadence of introductions over time.
Go to Cecilia.
Great. Thanks. Cecilia Furlong from Morgan Stanley. I wanted to go back just, you kind of touched on it a bit, but focus on OBP versus ambulatory and really the more clinically relevant. As you think about just the results today, do you see at least initially a change in how physicians are thinking about kind of the initial patient population that they're looking at to commence utilization of HTN in post-approval?
To begin with, just as we introduced and as you suggested, office blood pressure is the dominant metric for decision making. We don't routinely perform ambulatory blood pressure in the clinical setting, at least certainly in the U.S. and in most other geographies. As I've also introduced, office blood pressure is the sole criterion that sets the targets for therapeutic goals by societies, and consensus documents, and it's been the primary endpoint of many other major trials just outside the space of renal denervation. I think that will still be the main criterion that doctors are going to be using in terms of informing their decisions or to recommendations in the shared decision-making process for renal denervation for their patients.
In fact, in the AFFIRM trial, for instance, we're looking now at not ambulatory per se, but office criteria as one of the many, but the principal metric that we're following in these patients given its clinical relevance today. I'm sorry, there was a second part to that?
It was really just one, and you kind of addressed it. Would you see a change in how physicians, based off of this clinical data, think about just the target patient population that they initially start to utilize this in?
No, I think that as consistent with, like Jason shared, 12 documents that have come back and come forward in the past two years from societies and consensus documents both in the U.S. and abroad, from Asia to Europe to the United States, proposing considerations for patient selection. They're really still all about patients with uncontrolled hypertension, in the presence or absence of medicines. Also focusing more, I think the focus will be not only on hypertension alone, recognizing that 60% of the patients in the United States with hypertension do not meet their societal or guideline-recommended target goals. I think renal denervation brings to the space greater awareness of hypertension. It usually has fallen to the side when patients come in complaining of other knee pain or other symptoms. Now blood pressure will come more to the forefront because of this new therapeutic opportunity.
Secondly, I think that doctors will still just simply rely on the office blood pressure, but they'll look not just for that but on the cardiovascular risk of the patient. A patient with uncontrolled hypertension, but who also poses high cardiovascular risk for death, stroke, myocardial infarction, or poses high risk for what's called hypertension-mediated end organ disease, kidney failure, heart failure, stroke, among others.
Generally, if you look at those consensus statements on where RDN should be used, they kind of fall into 3 categories: resistant, uncontrolled hypertension with high cardiovascular risk factors, other risk factors like David just talked about, or the third category is intolerant to medications or significant patient preference to try something other than medications. That's pretty consistent across those consensus statements.
Okay. If I could just follow up really quickly. You talked about to a large percentage of the patients in the clinical trials came through the outreach. Patients are much more motivated, maybe in the ones that were enrolled versus your typical patient population. Can you speak to just how you think about how those results translate into what we saw? As you're targeting patients, just your outreach efforts, how you build that momentum in the market. Pipeline question as well as you think about the further opportunity to enhance this procedure, feedback has been one area that I've heard a few times. Just your thoughts on being able to augment the procedure via feedback and potential timelines. Thank you.
Just as a qualifying statement, the direct-to-the-patient advertising, so to speak, of the clinical trial, it's by all means not to the exclusion of the primary practitioner. We go to them as well. We've done a shotgun approach. I'll just say the beauty of renal denervation, too, just as an aside, is as an interventional cardiologist, unlike carotid stenting or other procedures that have been divisive among disciplines, this has been a uniform approach across multiple disciplines from the very beginning. Hypertensionists, endocrinologists, nephrologists, internal medicine doctors, non-invasive cardiologists, among others. When you see people as part of these clinical trials or a part of these programs, it's truly a multidisciplinary approach at the global leading cause of death and disability.
Secondly, that said, however, there is clearly a patient population that is considerable, that is seeking an alternative to existing therapies of drugs and lifestyle interventions for the treatment of their hypertension. On the one hand, as a clinical trialist, it certainly facilitates it because you have more people coming to look for a therapeutic alternative. Sometimes they're told in the treatment-resistant patients, they have no therapeutic options, and this is a great opportunity for them. The other, though, is that we have, and in fact, just a few moments ago, I received from the editor that they're going to publish this as soon as they can. We've done a patient preference study as part of our program. Others have performed patient preference studies in Asia and in Europe.
When asked if your blood pressure is still uncontrolled and you require an additional medicine to improve your blood pressure, or would you rather have a single-base catheter procedure, a catheter-based procedure, at least 30% of those individuals would prefer such a therapy, such as renal denervation. In the most rigorous, called discrete choice experiments that we've performed, depending on the scenarios of blood pressure reduction and durability that we offer, anywhere from 30%-70% of patients would prefer a therapy such as renal denervation. What's interesting about those studies is that the biggest driver for them for selecting renal denervation is to, A, have an improvement in blood pressure. Sometimes it's not even nearly what we've observed, like 10 millimeters mercury in the trial. That trumps even safety of the procedure for these patients as well. Fortunately, it's very safe too.
They also, secondly, look for durability, and we've demonstrated that now at least through three years of follow-up.
Okay. Then we'll wrap up with Chris.
Thanks for taking the questions. David Rescoe with Truist Securities. Just to follow up on some of the comments you made about the longer-term development aspects of the product. I'm just wondering if any of these things in the pipeline are more related to things that need to be done ahead of the launch or these more longer-term opportunities, thus essentially the product in its current state is what you would go to market with.
The product in its current state is great, and that's what we're going to market with these thereafter.
Thank you.
Agree. No, it doesn't matter.
Yeah, I should answer it. You should answer that question.
Very user-friendly.
Finish with Chris.
Thanks, Ryan. Chris Pasquale, Nephron. Along those lines-
There was significant heterogeneity in terms of the number of lesions or number of energy ablations delivered per patient. Was that strictly based on anatomy, or was it up to the physician to sort of tell when they're done?
Great question, Chris. It's exclusively based on anatomy. Specifically, per protocol, we target the distal branch arteries of the renal artery architecture, as well as the main renal artery. We even are able to treat what we call accessory renal arteries. Some people have two major arteries to their kidney rather than just one. That occurred in a quarter of the 26% specifically of the study population. It really just depends on how many branches an individual has and how many renal arteries an individual has. It's purely anatomically based.
Maybe just to wrap things up. Doctor, if this was available tomorrow and reimbursement was not a consideration, who would you use this technology on in your practice?
It would be very much the patients, for example, that we're currently enrolling in the AFFIRM trial. The AFFIRM study is a 1,000-patient study that, as Jason introduced, is examining renal denervation therapy in a much less selected, broader patient population, representative of those we encounter in clinical practice, like in today's trial, but also a broader group with other coexisting illnesses that would've been excluded from the trial. Put simply, in patients who are on medications and still have uncontrolled hypertension, on patients less common but certainly existent and routine in practice, people who have so many intolerances that they can't take a number of medicines or just very few but have persistently elevated hypertension. Especially focusing, as I shared earlier, on patients who have uncontrolled hypertension and still poor or high cardiovascular risk or risk for end-organ failure like renal disease as well.
Quite a broad population, in other words. Yeah.
Okay. I want to thank everyone for attending tonight. I want to thank Dr. Kandzari for participating, thank all the Medtronic people that helped and assisted in preparing for tonight's program. Thanks a lot. If you have additional questions, you can reach out to me or a member of my team. That concludes the program. Thanks.