Ultrasound renal denervation shows “consistent” results in twin studies

ReCor Medical has announced that primary endpoint results from the RADIANCE II pivotal trial were published in the Journal of the American Medical Association (JAMA). Study results showed that the Paradise ultrasound renal denervation (uRDN) system successfully reduced blood pressure compared to sham.

IN ADDITION, POOLED ANALYSIS results from the combined primary efficacy endpoint and safety data from RADIANCE SOLO, RADIANCE TRIO, and RADIANCE II were concurrently published in JAMA

Cardiology. Results of the pooled analysis showed a consistent blood pressure lowering effect across a broad range of hypertension, including mild to moderate and resistant hypertension.

RADIANCE II is a randomised, sham-controlled US Food and Drug Administration (FDA) investigational device exemption (IDE) pivotal trial of the Paradise uRDN system in the treatment of patients with uncontrolled hypertension. Conducted as an international multicentre study at more than 60 study centres in eight countries, 224 patients with uncontrolled hypertension were randomised 2:1 to uRDN or a sham.

Patients were to remain off antihypertensive medications throughout the two months of followup unless specified blood pressure criteria were exceeded. At the twomonth primary efficacy endpoint, patients treated with the Paradise uRDN system had a mean reduction in daytime ambulatory systolic blood pressure of -7.9mmHg, compared to a reduction of -1.8mmHg in the sham arm, corresponding to a statistically significant and clinically relevant treatment option.

Furthermore, they state that interventionalists require expertise in renal interventions and specific training in renal denervation procedures. “Centres performing these procedures require the skills and resources to deal with potential complications,” Barbato et al state.

Presently both the Symplicity Spyral and Paradise system carry a CE mark, and Medtronic and ReCor both filed premarket approval applications to the US Food and Drug Administration (FDA) in late 2022 for their respective devices.

“To date, there are at least 18 societal and/or expert consensus documents published, and the increasing number of citations seems to parallel the mounting evidence for renal denervation therapy,” David Kandzari (Piedmont Heart Institute and Cardiovascular Services, Atlanta, USA), a member of the writing committee for the ESC/EAPCI consensus statement and prinicipal investigator in the SPYRAL HTN-ON MED trial, told Cardiovascular News. “In all, these documents are important for providing clinicians with guidance regarding the evidence basis for renal denervation safety and effectiveness, patient selection, and procedural technique. Many of the documents also underscore the need for shared-decision making and accounting for patient preference.

“The ESC/EAPCI document offers the most contemporary evidence and informed clinical considerations for renal denervation, including recommendations for not only patient selection but also for institutions related to renal denervation programme development, patient selection, and operator proficiency.” between-group difference of -6.3mmHg (p<0.0001). The study also achieved its primary safety composite outcome with no major adverse events observed.

Concurrently published in JAMA Cardiology, the RADIANCE pooled analysis includes data from more than 500 patients randomised in the three studies from ReCor’s RADIANCE global programme: RADIANCEHTN TRIO, which studied patients with resistant hypertension, and RADIANCE-HTN SOLO and RADIANCE II, which studied patients with mild-moderate hypertension.

The combined dataset showed an overall reduction in daytime ambulatory systolic blood pressure in the uRDN group of -8.5mmHg with a difference between treatment and sham at two months of -5.9mmHg (p<0.0001), favouring uRDN. Blood pressure results were similarly positive in the 24-hour, night-time, home, and office measures. A favourable safety profile was consistently observed following uRDN treatment across the studies.

“The results of the RADIANCE clinical trials are meaningful in that they solidify the role of the Paradise uRDN system as an adjunctive therapy for hypertension treatment, in addition to medications and lifestyle modification. Having three consistent sham-controlled clinical trials demonstrating that the Paradise uRDN system can safely lower blood pressure across a range of patients is a very high bar to have met,” said co-principal investigator Ajay Kirtane (New York-Presbyterian Hospital, New York, USA).

Co-principal investigator Michel Azizi (Université Paris Cité, Hôpital Européen Georges Pompidou, Paris, France) added: “The pooled analysis of RADIANCE SOLO, TRIO, and RADIANCE II shows a remarkable consistency of effect in patients with mild to moderate hypertension and those with resistant hypertension. These results are in line with the new 2023 consensus statement of the European Society of Cardiology (ESC) Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI).

The publication of these results in JAMA and JAMA Cardiology will bring the evidence of the performance of uRDN in the treatment of hypertension to a broad audience of physicians.”

The publication of a consensus statement from the European Society of Cardiology (ESC) Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) is among the final steps in the evaluation of renal denervation as a device-based treatment for hypertension. This is according to Felix Mahfoud (Saarland University Hospital, Homburg, Germany), a member of the expert committee behind the paper, and one of the foremost investigators of the technique. He discusses patient selection and future indications for the therapy with Cardiovascular News

What is the background to the ESC/EAPCI consensus statement on renal denervation?

This consensus document was deemed necessary because a significant amount of new sham-controlled trial evidence has become available. In the 2018 guidelines of the ESC and the European Society of Hypertension (ESH), devicebased hypertension treatment was graded with a class 3 recommendation, not to be used routinely in clinical practice. There was a sentence added to the statement that until further evidence regarding the safety and efficacy becomes available, these devices should not be used outside of clinical trials. We felt it was important to re-evaluate the evidence that has aggregated after the publication of the guidelines, and by now we have five sham-controlled clinical trials that have indeed proven the efficacy and safety of renal denervation in the presence and absence of antihypertensive drugs.

Renal denervation: A recent history

What have the recent trials shown?

We know it works in patients with and without antihypertensive medication, but this is a very broad potential patient population. We felt it is also important to provide guidance on where denervation may be used in clinical practice and felt this should be reserved as a treatment option for patients with so-called “resistant” hypertension, meaning despite treatment with three antihypertensive drugs, they still have uncontrolled blood pressure values, as confirmed by office and ambulatory blood pressure.

Despite having evidence that this works in a very broad population, we nailed it down, first and foremost, to patients with resistant hypertension. There is another potential indication for renal denervation and that is in patients where drugs are not tolerated, those not willing or able to take antihypertensive drugs, and those with a preference to be treated with a device-based approach.

How significant a development is this?

It is not the intent of the consensus statement to change people’s perception. The perception needs to be adapted according to the published trial evidence. This is really more to inform clinical practice. What we did is reach consensus on different statements. The challenge is who to treat within clinical practice, and this is the overall objective of such consensus statements. Which patients in which centres? How should the centres be trained? What are the potential complications of the procedure that interventionalists need to be informed about?

Are there “ideal” patients for renal denervation?

What we have to accept is that this is a treatment possibility for patients with uncontrolled blood pressure. It is not replacing drugs, it is not replacing lifestyle modification—this is another approach available in our armamentarium to lower blood pressure. But, it is not exclusive. It is not renal denervation or nothing. Most patients we treat have undergone lifestyle modification, but it was unsuccessful. They have been treated with several drugs, are still uncontrolled and have high blood pressure and have high cardiovascular risk. In these patients it is another treatment that may bring blood pressure down.

How excited are you by this treatment?

We started the scientific evaluation of this approach 15 years ago. It is among the very few device-based treatments that has beaten sham control. This is something we have to keep in mind. There has been a very rigorous evaluation of the procedure, which is not available for other techniques that we use every day. This is something we have to acknowledge, [and] that we have a lot of clinical data, a lot of robust methodologically defined and properly designed studies conducted around the world and they have proven that this technology lowers blood pressure. You cannot question whether or not it works—it works—that is a statement. Now it is our responsibility to offer this to certain, but not all, patients at risk.

2019

I am excited, of course, because it is about science, but this is probably among the last steps in the evaluation of this technology. We are working on a US Food and Drug Administration (FDA) submission so hopefully this will become available in the USA soon. I think overall we are in good shape moving forward with this technology. We are now looking into new indications such as heart failure, atrial fibrillation and ventricular tachycardia. We have registry data confirming that in those populations it is safe, and now we are heading off to new shores and among those are heart failure, certainly and arrhythmias are also very interesting.

Where are the gaps in our knowledge?

Identification of responders is the unmet need. It is something that we are investigating in clinical studies to get further insights, and has never been available, even for antihypertensive drugs. I am not sure if we will succeed in this with renal denervation, but we are still trying. The second question is whether or not this blood pressure lowering translates into improvements in outcomes. We know that blood pressure as LDL [low-density lipoprotein] cholesterol closely associates with cardiovascular morbidity and mortality, and when you lower blood pressure or LDL cholesterol, it is believed that it lowers morbidity and mortality too, so I am pretty confident that this will translate into improved outcomes—but it has not yet been shown.

Medical) gains CE mark

2014 Results of SYMPLICITY HTN-3 bring renal denervation train “to a grinding halt”

2017 SPYRAL HTN-OFF MED, first seen at ESC 2017, provides “proof of principle” that renal denervation works

2018

Positive data from SPYRAL HTN-ON MED and RADIANCE SOLO trials, shared at EuroPCR 2018 “reignite interest in the field”

Six-month onmedication RADIANCEHTN SOLO trial results find patients treated with ReCor ultrasound system were prescribed fewer medications than those treated with a sham procedure

2020

At virtual ACC meeting, three-month SPYRAL HTN-OFF MED trial data show renal denervation bests sham treatment to lower blood pressure in untreated hypertension

2021 EuroPCR 2021 hears registry data indicating that renal denervation with the Symplicity system saw significant and sustained blood pressure reductions in a real-world population through three years

2022

Late-breaking trial data presented at EuroPCR 2022 underscore the potential of renal denervation as an adjunctive therapy to treat hypertension, experts say

2023 ESC and EAPCI publish renal denervation consensus statement, indicating that renal denervation represents another treatment option in patients with uncontrolled resistant hypertension