You know, I think among anybody in the United States, though, having the longest experience with renal denervation, now for me for more than 15 years, it's a real welcomed opportunity to be part of a very creative program, thanks to you all who have contributed to this, to think about this in a collaborative, multidisciplinary fashion. It's not so often that we get together as cardiovascular practitioners, interventionalists, internal medicine physicians, and others to discuss what may be of potential great global public health impact as well with renal denervation. So as Michael introduced, too, even modest reductions in blood pressure translate to clinically relevant events, and although, as Michael introduced, perhaps the higher blood pressure, the greater the fall, this is not regression to the mean, but the Wilder effect that those individuals, like many other illnesses, who have the greatest severity of illness, derive the greatest relative and absolute benefits. But from a patient perspective, though, even with a single antihypertensive medication, from large studies totaling over 350,000 patients in total, although the absolute placebo subtracted benefit with a single antihypertensive, maybe 5 millimeters of mercury in the office setting, modest reductions translate into clinically relevant events, but from a patient perspective, this is very challenging to sustain. For a longer-term follow-up, there's an erosion of blood pressure control due to an inability to sustain for many individuals adherence to lifestyle interventions and medication adherence, which we'll discuss, and this is no more evident than in the famed SPRINT trial, which has changed our guidelines, which has reminded us of the benefits of intensive blood pressure lowering for reductions in all-cause and cardiovascular mortality, and in this study, which has changed guidelines for more intensive blood pressure treatment goals, as Debbie introduced, nevertheless, over long-term follow-up, disappointingly, there is this loss of blood pressure control, this erosion of blood pressure control, and therefore, the entire clinical benefit is forfeited. As a pioneering technology with radiofrequency denervation, the SPIRAL program remains to date the most robust and with the greatest duration of follow-up, examining radiofrequency renal denervation therapy in not simply sham control of randomized clinical trials, but in broad, real-world clinical practice, now totaling over thousands of patients, and in off-med and on-med situations, demonstrating the biologic proof of principle, but also how this therapy may be enveloped into clinical practice among patients with persistent uncontrolled hypertension despite the prescription of antihypertensive medications. And in the early pilot studies, the off- and on-med pilot studies, treatment with radiofrequency renal denervation in these studies demonstrated statistically significant, clinically meaningful reductions in both office and ambulatory blood pressure and by both systolic and diastolic measures. And moreover, we demonstrated for the first time this always-on effect with renal denervation therapy, which has been a constant throughout all of the radiofrequency renal denervation trial program studies, specifically demonstrating that over the 24-hour period, there is this persistent, constant reduction in blood pressure at all time periods that is not observed in the sham control group as evidenced in the right-hand panels. And moreover, this is particularly distinct from the limitations of pharmacotherapies, not simply drug adherence, but with regard to pharmacokinetic profiles and dosing regimens, and it's of special relevance to those individuals whose blood pressure phenotype conveys an especially high risk for adverse events such as nocturnal or early morning hypertension. Recall the recent publication this past month in The Lancet of the Spanish Registry of nearly 60,000 patients in which the greatest predictor of cardiovascular mortality by ABPM is nocturnal hypertension. In the SPIRAL OnMed's pivotal study from a regulatory perspective, combining the pilot off-med study through a Bayesian analysis with an expansion cohort, treatment with renal denervation, again, is associated with significant reductions in both ambulatory and office blood pressure and, again, by both the systolic and diastolic criteria. More recently, we've presented as a late-breaking trial at the American Heart Association the SPIRAL OnMed study that did demonstrate absolute reductions on par with previous studies and a significant reduction in office systolic blood pressure in the context of medications with uncontrolled hypertension, but no significant difference with regard to the primary end point of 24-hour ambulatory blood pressure, not because of an absence of a reduction in blood pressure in the renal denervation group, but unexpectedly a larger-than-expected reduction in blood pressure in the ambulatory—excuse me, in the sham control group. And this is largely driven by an escalation in medications prior to ascertainment of the primary end point, and despite protocol mandate to keep medications the same, nevertheless, in the sham control group, there was an escalation in drug dose, drug number, and drug classes in the sham control group that was not observed in the renal denervation group. As an example, in comparison to the OnMed's pilot study in which the changes in medications were of low frequency but, more importantly, similar between the two groups, in comparison to the expansion cohort, there was a greater number of individuals in the sham group who escalated their medication burden, and conversely, in the renal denervation group, there was a greater proportion of individuals who decreased their blood pressure medications. Their blood pressure lowered following renal denervation, they're monitoring their blood pressure at home, and they consequently decreased their medications. These data are confirmed by drug adherence testing through blood and urine toxicology studies, and altogether then, there was a tenfold increase in the net change in medications that would favor blood pressure lowering in patients in the sham control group. But nevertheless, through a win-ratio analysis in the study, renal denervation therapy one, there's a one-and-a-half-fold likelihood that with renal denervation therapy, still, patients can either experience a meaningful reduction in blood pressure or a reduction in medications. And altogether, this therapy has consistently demonstrated proven safety. There are no major unanticipated adverse device-related events, no occurrences of renal artery stenosis. Indeed, in over 10,000 patient years of follow-up and a composite of 50 trials of renal denervation therapy, the occurrence of renal stenosis is less than that which we expected from the natural history of a light population. So in summary, altogether, there are consistent, significant, meaningful reductions across the renal denervation program with radiofrequency renal denervation therapy, but given the longevity of follow-up in this program, we have the advantage of looking at long-term durability of this procedure. We've demonstrated it with the Spiral Simplicity HTN-3 study and shown here in the Spiral OnMed study. Through three years of follow-up, the reductions are sustained, if not amplified, favoring renal denervation therapy in the context of a similar medication burden in the renal denervation group and, if anything, a higher medication burden in the sham control group. And again, even through three years of follow-up, we see this persistence of this always-on effect. We now see some effect in the sham control group due to escalation of medications, but indeed, through three years of follow-up, nearly 85% of the patients treated with renal denervation therapy, and then again, in the context of medications, achieved a blood pressure of less than 140 millimeters systolic, compared with about half that in the patients in the sham control group. And moreover, in the Global Simplicity Registry, which is a multinational registry enrolling now more than 3,000 patients treated with this therapy, there are sustained reductions and durable reductions through long-term follow-up, both by office and ABPM criteria that are not explicable by an escalation in medications. And this opportunity provides the translation of having a greater time spent in target range or therapeutic range after renal denervation therapy with a linear reduction in major adverse events that are inclusive of cardiovascular death, myocardial infarction, and stroke as well. But this issue with regard to studies that are dependent as device-based therapies for hypertension on patients either abstaining from medications per protocol or alternatively maintaining the same number and dose of medications, which is, as exemplified, very difficult to do, raises the issue of patient adherence and patient preference with adherence being a surrogate. Indeed, it's expected that one in three individuals with hypertension-prescribed medications are partially or incompletely adherent to their medications, and this is evidenced in the SPIRAL-HT and OnMed study in which, with patients' awareness of the purpose of testing for drug adherence, still 40 percent of patients at any time point were either completely or partially non-adherent to the prescribed medication regimen. From the 2018 FDA panel meeting that we helped, that we participated in, it was concluded that patient preference and quality of life assessments would be invaluable to helping understand the risk-benefit profile for patients in the shared decision-making process. An individual's desire for an alternative therapy, such as device-based therapies for hypertension with renal denervation, are conditioned by a desire to lower blood pressure and appreciation of the benefits of blood pressure lowering, but it's also colored by personal experience with blood pressure effects and symptoms of uncontrolled hypertension, perhaps medication side effects, firsthand experience with the impact of adverse cardiovascular events, such as stroke or heart failure associated with hypertension, but also through physician endorsement in a shared decision-making process. And whether it's the SEI, National Kidney Foundation, consensus document, the European Society of Hypertension document, or even more recently, that from the European Society of Cardiology, shared decision-making emphasizes an important process in deciding for the recommendation or not of renal denervation therapy. What's quite remarkable, however, is the disparity, though, with regard to patient preference and physicians' perceptions of referral for renal denervation therapy. Patients prefer a therapy, such as renal denervation, independent of the severity of their hypertension or their medication burden, but in comparison, healthcare providers are only more likely to refer patients for renal denervation therapy for the extremes of hypertension, that is, having a high medication burden and or, alternatively, a very severe level of blood pressure. But indeed, in large, unselected patient populations surveyed, rather than increasing or escalating the medication burden, roughly one-third of individuals would prefer a therapy such as renal denervation therapy. But finally, the most rigorous of patient preference studies is to perform what's termed a discrete choice experiment, and in doing so, we surveyed 400 patients with uncontrolled hypertension, not part of renal denervation trials, and posed to them scenarios of drug or device therapies with attributes and attribute levels, attributes including the duration of a benefit, the extent of a benefit, and the level of benefit, safety issues as well. And in doing so, independent of drug or device therapies, patients, thankfully, prioritized blood pressure lowering as the major decision-maker for their preference for a particular therapy for hypertension, and it's followed thereafter by the durability of effect, and although patients might prefer not to undergo an invasive procedure, that decision is far outweighed by the opportunity to reduce their blood pressure. In fact, in modeling of such, assuming a roughly 10-millimeter reduction in office systolic blood pressure, which we have observed in renal denervation trials, a duration of effect of one year, and we've now demonstrated this at least through three years, and in fact, more recent evidence has published through 10 years of durability after renal denervation therapy and with no drug side effects, and even exaggerating the risks of complications of renal denervation therapy to levels in a sensitivity analysis that we've never even observed in clinical trials. Nearly three-quarters of individuals may prefer a therapy such as renal denervation. So in summary, renal denervation therapy with radiofrequency energy demonstrates sustained reductions in both ambulatory and systolic blood pressure in the presence and absence of medications, a consistent always-on effect with durability at least through three years of follow-up, and remarkable safety across a variety of patients treated. Trials are forthcoming as we hopefully near this year a panel meeting for FDA review of this technology and the ultrasound technology for approval in commercial practice, but still studies are ongoing to further understand quality of life and examine the benefit in selected patients such as those with diabetes or chronic kidney disease or isolated systolic hypertension. Thank you.

renal denervation therapy

uncontrolled hypertension

collaborative discussions

blood pressure reduction

ongoing studies