麻豆传媒

GAITHERSBURG, Md. -- Industry seems to have learned from early mistakes with renal denervation, as development for device-based hypertension treatment appears to be headed in line with expectations of an FDA advisory panel.

While just a few years ago renal denervation was thought to be dead, modestly positive results with new catheters in trials like SPYRAL HTN-OFF MED and RADIANCE-HTN SOLO have led to a new spate of big pivotal trials getting underway.

The FDA advisory committee meeting with manufacturers and other stakeholders wasn't aimed at a vote on the safety and effectiveness of these procedures just yet, rather it focused on potential indications, effectiveness endpoints, safety, and other considerations for renal denervation and other therapies.

It all appeared to confirm what manufacturers are already doing for their development programs:

• Medtronic: the Symplicity Spyral renal denervation catheter is the subject of the ongoing SPYRAL PIVOTAL - SPYRAL HTN-OFF MED trial (sham controlled, with a primary endpoint of 24-hour ambulatory blood pressure [BP] at 3 months)
• ReCor Medical: the Paradise renal denervation catheter is being studied in the RADIANCE-II pivotal study (sham controlled, with a primary endpoint of change in daytime ambulatory BP at 2 months)
• ROX Medical: the CONTROL HTN-2 trial (sham controlled, primary endpoint of change in mean 24-hour ambulatory BP at 6 months) is looking at the Coupler, a device that is supposed to reduce BP by creating an arteriovenous anastomosis in the iliac region
• Vascular Dynamics: the CALM-2 pivotal study (sham controlled, primary endpoint of change in mean 24-hour systolic ambulatory BP at 180 days) is studying an endovascular baroreceptor amplification device, the MobiusHD, which stretches and squares off the carotid sinus

"We don't anticipate any changes, and look forward to continued discussions with FDA to ensure alignment in our approach," a Medtronic spokesperson told 麻豆传媒 after the panel.

Trial, Registry Design

The unanimous use of ambulatory BP in all these studies appeared reassuring to the advisory panel as a whole. "If manufacturers come with office BP measurements, they'll get raked off the coals probably," joked committee chair Richard Lange, MD, of Texas Tech University Health Sciences Center El Paso.

Moreover, the consensus was that a minimum 5-7 mm Hg reduction in systolic BP would be reasonable to say that a device has a clinically-significant benefit. If there is no substantial BP lowering, it would also be acceptable to say that the device helped by allowing the patient to go off at least one medication, the group said.

Any benefit should last out to 12 months if not more, the advisors noted, although some argued that there should be at least another year of observation after the initial 12 months that renal denervation is still gaining effect.

In addition, most panelists said that sham should be included when possible, even if certain factors could unblind the treatment group, such as stenoses occurring close to the arteriovenous anastomosis or a neck twitch from baroreceptor amplification.

Crossovers, on the other hand, are generally not a good idea, because the confounders and other problems introduced might outweigh any enriched exposure to the intervention, according to the group. "It makes no sense to me because we're looking at long-term issues here," said Jeffrey Brinker, MD, of the Johns Hopkins Hospital in Baltimore.

As for safety in renal denervation, most said they were satisfied with duplex ultrasound to screen for renal artery stenosis. A protocol to screen at 6 months should be sufficient, though some suggested later follow-up for a subset of patients.

A renal denervation registry that captures renal function would be a good idea, according to Jamie Dwyer, Jr., MD, of Vanderbilt University Medical Center in Nashville, Tennessee.

Indeed, the position of the American College of Cardiology (ACC) is that post-market evaluation will be key to evaluating the safety of renal denervation, said William Borden, MD, of George Washington University in Washington, D.C., who spoke as its representative during the public hearing session of the meeting.

To that end, in 2020, the PVI Registry from the ACC's National Cardiovascular Data Registry will begin capturing clinical indications for renal denervation, whether patients are part of a trial, and other details. This "could be an avenue to study these devices in the longer term and in a real world setting," Borden said.

Who Should Get these Devices?

Most members of the panel said they would be comfortable starting with antihypertensive-resistant patients before expanding studies to a wider pool of the drug naïve.

They also expressed discomfort with studies on narrow, homogeneous populations being used to support broad-based indications.

"We know in the device world the sample size is as small as you can make it, so stratification between men and women and by age is never possible," noted David Naftel, PhD, of the University of Alabama School of Medicine in Birmingham.

"We've moved into a totally different world here. The patient population is so diverse that [with] age, gender, socioeconomic [class], race, obesity, we're almost in the drug side of the world where we don't usually live. I can't see us doing any kind of study with a small sample size that doesn't address age, gender, race," he continued. "We're moving into a very big area that's going to be incredibly difficult and very necessary."

How young is too young for renal denervation was the subject of some debate.

"God gave us renal nerves for a reason, and we're taking them out. In terms of subject population, it would be unwise to do really young people and people who have a long natural life expectancy," said John Hirshfeld, Jr., MD, of Philadelphia's Hospital of the University of Pennsylvania. He defined "really young" as age 40 and under.

But the epidemic of hypertension in children should not be ignored, argued one pediatric nephrologist. "My patients are clear antecedents of adult disease," said Frederick Kaskel, MD, of Children's Hospital at Montefiore in New York City.

He noted that many are going into adulthood with left ventricular hypertrophy and minor renal impairment because of their elevated BP. "I'm not saying to go study children with these devices. But when they become adults they [should] be eligible to be looked at."

Ultimately, it's the patient's decision, so it's important to consider patient preference in a "formal way" as impacted by cultural and socioeconomic factors, said Joaquin Cigarroa, MD, of Oregon Health & Science University in Portland.

"Just like we talked about making sure that enrolled patients are hopefully more representative of our demographics, this is critically important as well to informing us as clinicians of their preferences," he emphasized.

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