Seth Bilazarian, MD

Disclosures

April 21, 2014

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Hopes Dashed by SYMPLICITY HTN-3

Hi. This is Seth Bilazarian from theheart.org on Medscape, reporting from the American College of Cardiology (ACC) meeting in Washington, DC.

I want to make a few comments on the SYMPLICITY HTN-3 trial.[1,2] Briefly, SYMPLICITY is the name of a series of trials sponsored by the Medtronic company that are evaluating the efficacy and safety of therapy with a renal denervation catheter for a variety of problems, but most importantly for hypertension.

In the area of disclosure, I was a SYMPLICITY investigator. I was not compensated for my work and I am not an employee of the hospital where I performed the procedures, but for purposes of disclosure, I was quite an enthusiast about the potential for this technology, and I was quite disappointed [with the results].

The SYMPLICITY HTN-3 trial had 535 patients, with 2:1 randomization. Patients were blinded to the therapy. They were brought into the catheterization laboratory wearing blindfolds, and headphones with music playing. After having a sheath placed in the groin and an angiogram of the renal artery, patients were randomized to undergo either an actual procedure or a sham procedure in which we would pretend to do something, and then they would leave the room.

Patients were blinded for 6 months afterward, and at the end of 6 months they were unblinded, so the blinding was very effective during the study. The 2:1 randomization was designed to show effective blood pressure lowering. Previous studies in which there wasn't randomization or sham procedures with blinding showed as much as a 30-mm Hg blood pressure reduction over the course of 12 years, which persisted for many years.

That was the great hope going into this, but the results of the SYMPLICITY HTN-3 trial[1] presented at the ACC Scientific Session showed only about a 2.4-mm Hg greater reduction in office blood pressure at 6 months compared with the sham arm. There was actually a 14-mm Hg blood pressure reduction from baseline to 6 months in the treatment group, but there was also a 12-mm Hg reduction in the sham arm.

These patients, just to be clear, had very significant hypertension. To be in the trial, patients had to have a systolic blood pressure higher than 160 mm Hg and had to be on 3 drugs, all at maximal doses, and 1 of them had to be a diuretic. They could be on more drugs, and many of my patients were on more than 3 drugs. These patients went through this procedure, and the average blood pressure at the end of the trial for all 535 patients in both arms was still higher than 160 mm Hg, so this is a very serious group of patients who are not yet well treated.

Renal Denervation in the Real World

Today, a second trial in the SYMPLICITY family of studies was presented: the Global SYMPLICITY Registry (GSR).[3] This included the first 1000 patients treated commercially outside of the United States where this device is available.

The GSR showed that for a variety of patients, renal denervation lowered blood pressure, as previously shown in nonrandomized trials. In the subset of patients with systolic blood pressures of 160 mm Hg (matching up with what was seen in the SYMPLICITY HTN-3 trial), they showed a 20-mm Hg blood pressure reduction in the registry vs 14 mm Hg in the randomized trial, which is not very different.

Why was this the case? There has been a lot of discussion about it, and many potential explanations have been offered. One is that patients seem to have a very robust decline in their blood pressure in the medical treatment group that is stable and not expected to change. This is a concern for me.

As an investigator, what actually happened to patients' drug therapy over time is not reported, either in the manuscript or anywhere else that I can find. What happens from a practical standpoint for a community-based physician is that patients walking around with blood pressures of 170-180 mm Hg go to emergency rooms or see their primary care physicians, and their blood pressure medications are altered. That was said not to be the case, but it is not specifically reported, so was there a change?

For anyone who participates in clinical trials, the oversight of a clinical trial is such that the patients are very rigorously followed, and there is pill-counting and recommendations for strict compliance, all of which is very different from what happens with "optimal medical therapy" in real-world practice.

Furthermore, this was a renal denervation strategy with a particular device, so it could be that this particular device isn't the best device for renal denervation.

A third practical question, which is unanswered, is whether we really achieved renal denervation. The animal and preclinical trials looked at how much energy was needed to create an injury that went from the renal artery lumen down to the renal nerves. Perhaps in this middle-aged group of patients with hypertension on a western diet, there is greater thickening of the renal vessel, which could actually cause problems in delivering the energy required to achieve effective renal denervation.

Uncontrolled Hypertension in the Balance

Those are some of the questions that have come up that may explain why we didn't see the robust results we were hoping for. Although I don't have to make the decision, if I were a senior executive at one of the companies involved, a decision to go forward would be very difficult in terms of investing corporate resources on the development of these devices.

As a clinician, however, we really need help, because there are 535 patients still walking around with systolic blood pressures higher than 160 mm Hg despite this therapy and being on 3 maximal-dose drugs. Many patients in our practices aren't optimally controlled. Many patients can't take optimal medical therapy because of adherence or intolerance of therapy issues, so a variety of patients would greatly benefit from another strategy.

There is no question that there will be great enthusiasm for a therapy that could deliver the promise of a 30-mm Hg blood pressure reduction that was safe, effective, and durable. Another question is whether it is even correct to compare such a strategy with optimal medical therapy. Wouldn't it be valuable to show that this technique alone is equally good in terms of long-term clinical results compared with multiple drug therapy?

These questions are yet to be answered, and we may never get the answers because industry may choose not to invest in these programs going forward. Other questions, such as the potential for renal denervation as a therapy for such problems as left ventricular hypertrophy, congestive heart failure, or obstructive sleep apnea, have gone by the wayside at this point.

From my standpoint, I would enthusiastically want to participate as an investigator and talk to my patients, candidly disclosing the results of this trial, about enrolling in a new trial of renal denervation. There is great need for therapies that are effective for this patient population. The risks associated with blood pressure in this range (over 160 mm Hg) are well known, and strategies to treat these patients are greatly needed.

So, there are a lot of unanswered questions, as well as a great disappointment, both for the clinical practicing community as well as for patients. There has been a deflation in the device community about this innovation that has at least stalled progress and presents a hurdle going forward.

That is my quick update on renal denervation. Until next time, thank you, from the ACC in Washington.

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