Hypertension Experts Push For New Trial Of Renal Denervation To Show Efficacy

Since Medtronic’s sham-controlled SYMPLICITY HTN-3 trial of its Symplicity renal denervation device failed to meet its primary efficacy endpoint, manufacturers developing renal denervation systems have been working with researchers and FDA to map the next steps in researching and developing this hypertension therapy.

Companies developing renal denervation systems to treat hypertension are working together with FDA and hypertension experts to map out the future of the technology in the aftermath of the disappointing SYMPLICITY HTN-3 results.

SYMPLICITY HTN-3, the first major sham-controlled trial of renal denervation in patients with uncontrolled hypertension, showed that treatment with Medtronic PLC’s Symplicity did not have a significantly greater effect on systolic blood pressure than a sham procedure in patients with systolic blood pressure over 160 mmHg despite taking at least three anti-hypertensive medications including a diuretic. (See (Also see "Renal Denervation Story Not Over Yet Despite SYMPLICITY HTN-3 Disappointment" - Medtech Insight, 2 Apr, 2014.).)

“Now we have to really focus on what went wrong here and how we can proceed, because just because one study fails doesn't mean the whole area should be invalid. That's just not the way science works,” former American Society for Hypertension president William White, from the University of Connecticut Health Center in Farmington, told “The Gray Sheet.” White has led research of many hypertension therapies, including renal denervation studies.

“The key thing right now is to have proof of concept that this works at all” – Dominic Sica, Virginia Commonwealth University

Although it was a major set-back for the development of renal denervation therapy, SYMPLICITY HTN-3 has not deterred the companies developing these systems from trying to find a hypertensive population that will benefit from their renal denervation system. Manufacturers, including Medtronic, St. Jude Medical Inc. (EnligTHN), Boston Scientific Corp. (Vessix), and Johnson & Johnson/Cordis Corp. (Renlane) have begun selling renal denervation catheter systems outside of the U.S., and have been working with CDRH and hypertension researchers to develop a trial design that will prove the benefits of their renal denervation device.

An important step in this collaboration was a June 26 meeting in North Bethesda, Maryland hosted by the American Society of Hypertension (ASH) and led by White, titled “ASH Workshop II on Device Therapy for Hypertension: Pathways for Moving Development Forward.” It was a follow-up of the first ASH workshop on renal denervation held in Bethesda in October 2013. “It was very valuable for us to focus on the next steps and the next pathway forward for renal denervation and the management of hypertension,” White said.

The meeting included representatives from FDA, ASH, CMS, NIH as well as other academic experts on hypertension. The meeting included presentations and discussions on preclinical models to evaluate renal nerve ablation, which patients should be treated in renal denervation studies, and the best trial designs for future renal denervation ablation studies. White said that ASH is a good partner for FDA in this endeavor because although its members care for patients with hypertension, most of them do not have a financial stake in the success of renal denervation overall since it will be interventional cardiologists actually performing the ablation procedures.

Proving It Works At All

Many participants at the June 26 meeting agreed that the manufacturers of renal denervation devices need to take a step-back from large trials like SYMPLICITY HTN-3, and design a smaller clinical trial that shows that a renal denervation device can actually produce a clinically meaningful reduction in blood pressure.

“Most of us who do research are of the mindset that a controlled clinical trial is necessary to make sure that it works ok and not just is safe,” White said. “All of us feel that the amount of basic research going on this area has been focused mainly on safety to the artery and not so much on efficacy.”

White believes a sham-controlled trial with about 160 patients is needed to establish the efficacy of renal ablation denervation. “And then, if your device lowers blood pressure than you can go to a bigger study where you determine exactly where you'd use this, what type of patients and so forth,” he said.

“If I were a doctor thinking about whether I would use a renal denervation catheter – if it doesn't lower it as well as a drug, I'm not going to be very impressed by it, because it's more invasive. [So] I'd at least like to see a clinically important reduction,” White said.

He estimates that an 8 mmHg average reduction from baseline in 24 hour ambulatory blood pressure – which would translate to about a 12-15 mmHg reduction in in-clinic blood pressure – that would be “a very robust effect” and show that the device is worthy of further study. “Because that effect is the same as one or two drugs,” he explained. “If it does that in a population who is at risk or not compliant [with medication], I would go ahead and say that this has enough of an effect that I'll pursue this in a population on drugs who is not controlled. I'd like to see a bigger response than that, but I realize that you've got a heterogenous group.”

Confounded By Drugs

White was among the researchers at the meeting in June who said that renal ablation denervation needs to be tested in a sham-controlled trial in which – unlike the patients in SYMPLICITY HTN-3 – the patients are not currently on any hypertensive medications.

“Given the unexpected results of Symplicity HTN-3 trial, new scientific and device development pathways need to be considered in the renal denervation arena” – FDA

Although the ultimate patient population that would be treated with renal denervation will probably have tried drugs first, medications may confound trial results and make it impossible to get a clear reading on how much impact renal denervation actually has on blood pressure, White told “The Gray Sheet.”

The variation in medication regimens among patients was “a very big problem in the SYMPLICITY HTN-3 study. There were lots of people going on and off medications back and forth and a lot of contamination [of the data]. How can you find out if the device is working when it’s added to five drugs. Maybe the drugs are blocking the ability for us to see the effect of the device. Maybe it did work better than we thought.”

Trying to differentiate the effects of different simultaneous blood pressure therapies is “a nightmare,” Dominic Sica of the Virginia Commonwealth University in Richmond said at the June 26 workshop, “The trouble is that they all affect sympathetic nerve traffic. Every one of them is in some way, up down or sideways…The key thing right now is to have proof of concept that this works at all.”

However, it’s hard to find a group of patients with very high blood pressure who are not taking anti-hypertensive medication already. So the best approach to finding patients for this new efficacy trial that White is proposing would be to find patients whose blood pressure is high despite taking medications, and then take them off the drugs for a while before and after treating them with renal denervation ablation.

This approach has been tried safely with other therapies in the past, he said. “We have a history in this country and also in Europe of having patients wash-out from their present medications and get to a stable hypertensive baseline. It might sound a little archaic but it's been done for 40 years and it’s been done safely, I don't believe it causes harm to do that.” Patients could always chose to go back on their medications after the renal denervation therapy and the number that do that would be an endpoint of the study, he said.

White said that some people working on renal denervation for the device manufacturers may have been skeptical of this approach, but “I think that as they've heard more from more people - not just me - they realize it's much more feasible and ethically appropriate [than moving directly into another large pivotal trial like SYMPLICITY HTN-3].”

At the end of the meeting, Bram Zuckerman, director of CDRH’s Division of Cardiovascular Devices, agreed on the need for clinical data that “can describe reasonably well that there's true effectiveness” before trying to sort out which patient population is best-suited to renal ablation denervation. “And to do that would really take the cooperation of everyone involved and I hope that we can do it, given the magnitude of the problem of hypertension and the world.”

White said he is going to publish a “proceedings paper” summarizing the discussions and presentations at the July 26 workshop and hopes to see that published this year. The proceedings paper from the 2013 ASH symposium on device therapy for hypertension was posted online July 15 by the Journal of the American Society of Hypertension.

In a prepared statement, an FDA spokeswoman said, “Given the unexpected results of Symplicity HTN-3 trial, new scientific and device development pathways need to be considered in the renal denervation arena. The recent American Society of Hypertension meeting in which FDA participated presented excellent suggestions for new options for studying this challenging field at the preclinical and clinical levels.”

The agency is “most interested in sponsors making appropriate use of the FDA’s pre-submission process to discuss preclinical issues and relevant clinical trial designs,” the spokeswoman noted. “This is a dynamic area where interactive scientific and regulatory discussion among industry, FDA, and investigators will lead to the best use of resources and optimal development of renal denervation science.”

[Editor’s note: Each week, “The Pink Sheet” DAILY includes a story contributed by "The Gray Sheet" highlighting a current issue affecting the medical device or diagnostics sectors.]