Felix Mahfoud, MD, MA
Professor of Cardiology
University Heart Center Basel
University Hospital Basel
Basel, Switzerland
felix.mahfoud@usb.ch

Ajay J. Kirtane, MD
Professor of Medicine
Columbia University Medical Center
Director, Columbia Interventional Cardiovascular Care
Chief Academic Officer, Division of Cardiology
Columbia University Vagelos College of Physicians and Surgeons
New York, New York
akirtane@columbia.edu

Andrew Sharp, MD
Professor of Cardiology
University College Dublin and Mater Misericordiae University Hospital
Dublin, Ireland
profandrewsharpuk@gmail.com

What would you like to see in the next generation of trials?

Dr. Kirtane: I would love to see health care utilization and/or clinical outcomes among patients treated with renal denervation (RDN) technologies compared with a group of patients who didn’t receive RDN. I don’t think it is good enough to “just treat” without some improvement in these outcomes.

Dr. Sharp: I would like to see the following types of clinical trials: trials intentionally deploying RDN further upstream in young hypertensive patients; trials looking at the association of RDN with concomitant conditions, such as obstructive sleep apnea, heart failure with preserved ejection fraction (HFpEF), and advanced chronic kidney disease; and trials looking at surrogate markers of hypertensive end-organ damage, such as left ventricular hypertrophy (LVH).

Prof. Mahfoud: The next generation of trials should focus on long-term cardiovascular outcomes to establish the prognostic benefit of RDN beyond blood pressure (BP) reduction. We also need pragmatic, real-world studies to assess effectiveness in broader populations, including those with comorbidities or variable adherence to antihypertensive medication. These trials are currently ongoing (eg, SPYRAL AFFIRM). Trials integrating RDN with medication titration strategies could also provide interesting insights for hypertension (HTN) management.

How do you think data collection should be handled?

Dr. Sharp: There should be national registries established in each country where the device is clinically available, collecting office, home, and ambulatory BP data where available, along with comorbidity and drug details as a minimum. Thirty-day and 1-year safety data should also be included, including vascular and renal safety.

Dr. Kirtane: This could be done by a variety of methods—either high-quality and monitored data in the setting of a typical device trial, or even via a nested design within a registry.

Prof. Mahfoud: Data collection should be centralized, standardized, and ideally integrated into electronic health records for real-world capture. We need to ensure quality and reproducibility. Longitudinal follow-up through national registries would help capture safety, adherence, device performance, and outcomes over time.

What should be the endpoints of future trials?

Prof. Mahfoud: Future trials should incorporate both surrogate and hard endpoints. In addition to 24-hour and office BP reduction, we should focus on major adverse cardiovascular events, renal function trajectories, medication burden, and patient-reported outcomes such as quality of life and treatment satisfaction. Cost-effectiveness should also be included to inform reimbursement and health policy. It would also be interesting to explore the effect of RDN on time in target range, a measure of both BP variability and control.

Dr. Kirtane: These can vary, but elements like summed BP measurements over time (eg, area under the curve of BP) would be novel and useful. Home BP measurements using novel devices would also be of interest. Finally, reduction in health care utilization (eg, hospitalizations) would be great to see.

Dr. Sharp: It depends on what is the primary goal of the trial. For obstructive sleep apnea, a BP endpoint is the most logical one, but one could argue that number of apneic episodes is not impossible. For HFpEF, an endpoint that is more robust than a 6-minute walk test or New York Heart Association class would be valuable. It could be N-terminal pro–B-type natriuretic peptide given that patients with atrial fibrillation are likely to be excluded, where this value might be less robust. I think a harder endpoint, such as hospitalization, is not likely to be feasible in the short term given the number of patients required.

The most interesting outcome study that could be achieved, in my view, would be to randomize RDN added to patents with LVH and assess left ventricular mass by cardiac MRI at 1 year. If severe enough patients were recruited, we could do this trial with several hundred patients, and LVH is well established as a surrogate for hard outcomes in HTN. This might bridge the gap between BP endpoints and the 20,000 patients needed to attempt a hard outcomes study with RDN (a trial that in my view would be at significant risk of confounding).

What’s next in new applications beyond renal?

Prof. Mahfoud: We are starting to explore neuromodulation strategies targeting other vascular beds and nerve pathways. Pulmonary artery denervation in pulmonary HTN and hepatic denervation for metabolic disease are early examples. These approaches will need rigorous mechanistic studies and randomized trials to confirm both safety and clinical benefit.

Dr. Sharp: Two directions—(1) allied conditions as described previously that involve HTN and other disease and (2) multiorgan denervation. These require two different trial designs but both signal fascinating areas of development for device development in HTN.

Dr. Kirtane: To be honest, there is enough work to do with these technologies within the renals themselves before we start out “branching out” (pun intended) to other areas, such as hepatic/splenic arteries in search of new therapies for diabetes.

Disclosures
Prof. Mahfoud: Supported by Deutsche Forschungsgemeinschaft (SFB TRR219, Project-ID 322900939) and Deutsche Herzstiftung; received scientific support to Saarland University from Ablative Solutions, Medtronic, and ReCor Medical; until May 2024, received speaker honoraria/consulting fees from Ablative Solutions, AstraZeneca, Inari Medical, Medtronic, Merck, Novartis, Philip, and ReCor Medical.
Dr. Kirtane: Received institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Amgen, CathWorks, Concept Medical, Philips, ReCor Medical, Neurotronic, Biotronik, Chiesi, Bolt Medical, Magenta Medical, Supira, and Shockwave Medical; in addition to research grants, institutional funding includes fees paid to Columbia University and/or Cardiovascular Research Foundation for consulting and/or speaking engagements in which Dr. Kirtane controlled the content; equity options in Bolt Medical, Airiver; consulting fees from Sonivie; travel expenses/meals from Amgen, Medtronic, Biotronik, Boston Scientific, Abbott Vascular, CathWorks, Concept Medical, Novartis, Philips, Abiomed, ReCor Medical, Chiesi, Supira, and Shockwave.
Dr. Sharp: Consultant to Penumbra, Boston Scientific Corporation, Medtronic, Recor, and AngioDynamics.