David E. Kandzari, MD; Stephen G. Worthley, MB BS, PhD

Disclosures

July 02, 2014

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Is Renal Denervation Getting Too Much Attention?

David E. Kandzari, MD: Hello. I am Dr. David Kandzari, interventional cardiologist and Chief Scientific Officer from the Piedmont Heart Institute in Atlanta, Georgia. Welcome to the EuroPCR Congress in Paris, France. Joining me today is my longstanding friend and colleague, Dr. Stephen Worthley, Helpman Professor of Cardiology at the University of Adelaide in Australia. Welcome, Stephen.

Stephen G. Worthley, MB BS, PhD: Thanks, Dave. It's great to be here.

Dr. Kandzari: Stephen, our topic is renal denervation and the buzz here at EuroPCR. By way of disclosures, you presented some key data as the principle investigator of the EnligHTN program[1,2] in Australia with the St. Jude Renal Denervation Program. I have been part of the SYMPLICITY program in the United States, and we presented some data today on the HTN-3 trial.[3] We will talk about that in more detail. Many people have been struck by the attention to renal denervation at these sessions here in Paris and whether that is appropriate given the focus on the commercialization of renal denervation therapies and the number of presentations that have been dedicated to these. Is this all appropriate, or is it a bit too much?

Dr. Worthley: That is a good question. The negative SYMPLICITY HTN-3 trial[4,5] was presented at the American College of Cardiology meeting in March, but this has been the first global meeting since then for the community interested in renal denervation. So, it's not a surprise that it has been a significant focus of EuroPCR. The proceduralists involved are very keen to get together, as a group, to understand and contextualize the results of HTN-3. I look forward to asking you more about the teasing out of the data and what information we can get from it beyond what was presented in March. We also need to look at the longer-term datasets that were presented and try to understand what they mean with respect to each other.

SYMPLICITY HTN-3 is a very important study. In no way does the significant amount of time spent on renal denervation at this meeting diminish or trivialize those results. SYMPLICITY HTN-3 has a significant impact for our patients and for us. It will help us with the design of future studies that genuinely will help us understand in which patients (if any) there is a role for renal denervation.

Dr. Kandzari: I agree. It isn't that people have dismissed the negative efficacy results of SYMPLICITY HTN-3 and are acting as though they didn't exist. This is the first global opportunity for investigators to get together and think about what the next steps are today, tomorrow, and beyond. Before we talk about the data that you shared today on the new catheter system for renal denervation and the data I presented from the SYMPLICITY HTN-3 subgroup analyses, what have been some of the more important takeaways about renal denervation at this meeting so far?

More Safety Data

Dr. Worthley: We have some extra information at longer time points and in larger numbers and an expansion of the potential safety concerns about renal denervation with a number of different technologies. For example, with the Global SYMPLICITY Registry (GSR), we have heard several presentations by Felix Mahfoud.[6,7,8] With more than 1000 patients now, the data are giving us comfort about safety. Some important subsets are being looked at in terms of efficacy signals. Higher pretreatment systolic blood pressure continues to emerge as a predictor for reduction in blood pressure with treatment. There are some other interesting ones coming out like the data about the number of lesions that were presented by Dr. Mahfoud yesterday.

We have also seen from some more rigorous but small first-in-human studies some longer-term outputs with both ultrasound-based and radiofrequency technologies. They have all been fairly consistent with approximately 25 mm Hg office-measured blood pressure reduction and approximately 8-10 mm Hg ambulatory systolic blood pressure reduction.

Dr. Kandzari: Most of those trials were single-arm unblinded trials, right?

Dr. Worthley: Absolutely. With some larger numbers and longer time points, we have seen affirmation of previously reported results. Right now, our goal is to contextualize those results in light of SYMPLICITY HTN-3 and understand how we move forward from here.

Dr. Kandzari: You brought up a good point about the consistency across all of these technologies in the safety of the therapy. We have almost taken safety for granted, and it is obviously still important to monitor safety, but safety has been consistent across all of these therapies for renal denervation. The GSR is the best example of that in such a broad, real-world experience.

New Predictors of Response

Dr. Kandzari: There was a hotline topic session today, a late-breaking session for key renal denervation studies. We saw data from the GSR[7] about predictors of response, patients with more comorbid conditions, and the increasing blood pressure at baseline being some predictors of a greater reduction after renal denervation therapy. We also heard a presentation[9] from the Boston Scientific Vessix™ Program showing longer-term data with that technology and the durability of sustained reductions in blood pressure. It's a limited-number, single-arm, unblinded experience, but it still showed incremental reductions in systolic and diastolic blood pressure over time.

You shared some new, more complete data with the 6-month primary endpoint from the St. Jude EnligHTN Program.[10] Can you tell us about that?

Dr. Worthley: The EnligHTN Program and system has had an iterative improvement with its next-generation system, so that it now delivers energy simultaneously from all 4 electrodes at once. It is a multielectrode catheter, and this has markedly shortened the procedural times. Potentially, the less time we spend in the renal artery, the better. Rather than spending 24 minutes to deliver the ablative therapy, it is now 4 minutes.

Given some algorithm changes, it was important to ensure that it was still as safe and efficacious as the first-generation system. In the first-in-human trial of 39 patients, we saw no device- or procedure-related serious events, neither periprocedurally nor through 6 months of follow-up. We saw a 25-mm Hg systolic office blood pressure reduction at the 6-month time point, which is essentially identical to that seen with the first EnligHTN system.

Dr. Kandzari: So, it is a more procedurally efficacious catheter with the same magnitude of reduction in blood pressure. What are the next steps for that program?

Dr. Worthley: That's the key. This was an important program because this multielectrode technology for the EnligHTN catheter is going to be taken forward as an appropriate comparator for renal denervation. Not just the multielectrode system but many others, such as the Vessix, will be looked at carefully by investigators and industry to determine the right design, using the lessons from SYMPLICITY HTN-3.

Subgroup Analyses From SYMPLICITY HTN-3

Dr. Kandzari: One of the lessons is to revisit the preclinical science, isn't it? The enthusiasm for this technology took off so fast that we exceeded the science behind it. We still have debate among pathologists about the distribution of the renal efferent and afferent nerves. Is it better to ablate more distally than proximally? There is still a great deal of science to be learned.

From SYMPLICITY HTN-3, we presented the subgroup analyses today.[3] SYMPLICITY HTN-3 was the largest randomized trial. It was a sham-controlled blinded trial in the sense that the assessors did not know the treatment status. The patients did not know their treatment status. This was very different from all of the other predicate unblinded trials, and SYMPLICITY HTN-3 did not meet its primary efficacy endpoint. It did meet the safety endpoint, but the fact that these results were discordant from all of the predicate trials, including the data that you shared today, motivated us to perform additional analyses. We specifically looked at the patient population. We examined medication changes and the relationship of procedural technique to blood pressure outcome. In a trial that did not meet its primary endpoint, the identification of variables that differentially predicted the blood pressure outcome between the control group and the renal denervation group implied that there might be confounders in the trial.

For example, we found that a high baseline blood pressure, baseline aldosterone antagonist use, and the number of ablations predicted a reduction in systolic blood pressure in the renal denervation group. Vasodilator therapy predicted an increase in the blood pressure. There were different predictors in the control group, one of them being African American ethnicity. We detailed this with greater clarity with respect to vasodilator and aldosterone antagonist use; the differences in the African American population were exceptionally interesting to us. This is a group in whom vasodilator therapy was most common. In African American patients who underwent renal denervation, their blood pressure reduction at 6 months was almost identical in magnitude to non-African American patients. It was the sham-control group of African American patients who had this unexpected 18-mm Hg drop in their blood pressure. Why that occurred is still a point of focus for us.

The other issue that you mentioned is technique, which is fascinating. We identified that an increasing number of ablations was associated with a consistent and progressive reduction in systolic blood pressure. We found this consistently with office blood pressure, ambulatory blood pressure, and -- to a lesser extent -- with other measures of sympathetic drive (such as heart rate) and pulse pressure. We looked further into the "circumferentiality" of the renal denervation procedure. Were the ablations performed in all 4 quadrants of the renal artery? Here we found that, of interest, in this study (at least by the methods that we used to capture these data), three quarters of the patients did not have circumferential or more complete 4-quadrant ablation in at least 1 renal artery. When we examined the achievement of 4-quadrant ablation, there was a graduated reduction in blood pressure such that patients who had 4-quadrant ablations in 1 renal artery had a greater reduction in blood pressure than those who had none at all, and 4-quadrant ablation in 2 renal arteries was even better. That pattern held true for ambulatory blood pressure as well as for home blood pressure and office systolic blood pressure.

It clearly highlights the procedural or technical aspect of renal denervation, but these are exploratory analyses. Many people are going to run away with the idea of this as being a technical factor -- and the singular reason that the trial failed. That is clearly not the case. To date, no single factor is responsible for the negative efficacy results of SYMPLICITY HTN-3.

Dr. Worthley: I agree. This information is all hypothesis-generating for the future. I am keen to ask you about some of your insights about the number of lesions. When we look at the multielectrode systems that are being used now, they effectively are giving a minimum of 8 -- and many times more -- lesions per renal artery as a standard, whereas the average was slightly more than 4 lesions per renal artery in SYMPLICITY HTN-3. Did your subanalyses have any insights about number of lesions?

Dr. Kandzari: We looked at the number of notches that are sometimes identified after renal denervation, and that did not correlate with a reduction in blood pressure. It was simply the number of ablations, which increases with increasing renal artery length. We have also looked to some extent at distal vs proximal ablation, and we have not found any consistency there. We haven't found a correlation with impedance either. It is the sheer number of ablations that seems to be the factor that correlates with blood pressure reduction.

Designing the Next Clinical Trial

Dr. Kandzari: Let's move just in our last few minutes to 2 issues about clinical practice and clinical trials. It would be an entire discussion to design the next study, but do we move forward now exclusively with randomized sham-controlled trials, or are there still opportunities for other designs?

Dr. Worthley: Well-performed, appropriate, placebo-controlled comparator (and we can have a lot of discussion about exactly what that arm is) studies are essential for us in this field to prove beyond a shadow of a doubt that renal denervation is as efficacious as we saw in some of the first-in-human studies. With the appropriate modulation after the results of SYMPLICITY HTN-3, we are beholden to do those trials, and all of the major companies that are still involved and interested in doing this, and the investigators, are very keen to see that.

Dr. Kandzari: It's fair to say too that we are not going to see another trial like SYMPLICITY HTN-3 again.

Dr. Worthley: No.

Dr. Kandzari: We have learned some very important lessons about the enrollment phase, about stabilization of medical therapy. What I didn't share is that 40% of the patients had medication changes between randomization and 6 months, so a lot of changing of medications took place in a study with a protocol that mandated a stable regimen. We have learned a lot of lessons from the subgroups and medication analyses as well. We are not going to see a SYMPLICITY HTN-3-like trial again, but we will probably see randomized and sham-controlled trials, at least to some extent.

Dr. Worthley: Having a sham-controlled trial is going to be important, given the negative results for SYMPLICITY HTN-3. No investigator would be so naive or complacent to think that some other technology is going to be superior. There will need to be modifications to the technology. The other question is which patient population should be studied. Should we perhaps be studying a group of patients who are intolerant of medications, or medication-naive patients, trying to show noninferiority vs other medications? The greatest dataset that we have at the moment is in resistant hypertensive patients who are on 3 or more medications including a diuretic, and whose office blood pressures are higher than 160 mm Hg with ambulatory blood pressure of at least 135 mm Hg.

Should We Continue With Renal Denervation?

Dr. Kandzari: We are moving into new frontiers when we talk about moderate hypertension or medication-naive patients. We are adding another element of uncertainty.

In clinical practice, in many places such as Europe, renal denervation is still commercially available, although we have seen a decline since the results of SYMPLICITY HTN-3. Is it still appropriate in your practice or others to do renal denervation as routine clinical practice?

Dr. Worthley: In routine clinical practice, in the absence of careful rigorous data collection programs, I would caution against doing it at the moment. However, everyone still very much wants to understand more about this technology. We are in the early days of understanding it. Is it appropriate to be performing it? I still think it is, but it should be within a rigorous data collection program; ideally, a trial. That could be an observational, single-arm registry trial in markets where it is approved, but performing it in expanded patient sets and outside of those data collection platforms is not right at the moment.

Dr. Kandzari: It is the responsibility of the many centers where this is still being performed today to continue to collect information on these patients. It raises a lot of issues, and we are reminded by our colleague Murray Esler that many patients are awaiting this therapy, acknowledging the uncertainties of the results as well. Many of us are still working to design the clinical trials that will finally get the solutions we are looking for.

Dr. Worthley: This is the not the death of renal denervation. It's an exciting time for device-based hypertension. There is still a huge unmet need. We can argue exactly what is true resistance, but no one would pretend that it's not somewhere between 5% and 10% of the hypertensive population. Indeed, when we are talking about a billion people worldwide, there are a lot of people who are still not being treated properly.

Dr. Kandzari: We need to resolve this renal denervation and treatment-resistant hypertension issue as we move in parallel for heart failure, pulmonary vein isolation, atrial fibrillation, and other more pleiotropic effects of a hypersympathetic drive in renal denervation.

Dr. Worthley: It's interesting. We have appropriately seen real attenuation generation systems. We are not going to see the radial approach. We are now focused back at the clinical endpoint. We need to prove that the current technologies actually can do what we believe they can do.

Dr. Kandzari: That's a terrific point and a great one to end on. Stephen, thanks for your perspectives.

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