<figure><img src="image_1.png" /></figure>

HAL
open science

# What We Know and Don't Know About Renal Denervation to Lower Blood Pressure

Katherine H Chau, Michel Azizi, Ajay J Kirtane

► To cite this version:

Katherine H Chau, Michel Azizi, Ajay J Kirtane. What We Know and Don't Know About Renal Denervation to Lower Blood Pressure. JAMA Cardiology, 2022, 7 (5), pp.471. 10.1001/jamacardio.2022.0169 . hal-04052434

HAL Id: hal-04052434

https://hal.science/hal-04052434

Submitted on 11 Apr 2023

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
VIEWPOINT

**Katherine H. Chau, MD, MS**
Division of Cardiology, Columbia University Irving Medical Center/ New York-Presbyterian Hospital, New York.

**Michel Azizi, MD, PhD**
Université de Paris, Hypertension
Department and DMU CARTE, AP-HP Hôpital Européen Georges-Pompidou, INSERM, CIC1418, Paris, France.

**Ajay J. Kirtane, MD, SM**
Division of Cardiology, Columbia University Irving Medical Center/ New York-Presbyterian Hospital, New York; Cardiovascular Research Foundation, New York, New York; and Associate Editor, *JAMA Cardiology*.

**Corresponding Author:** Ajay J. Kirtane, MD, SM, Herbert and Sandi Feinberg Interventional Cardiology and Heart Valve Center, Department of Cardiology, Columbia University Irving Medical Center/New York-Presbyterian Hospital, 161 Fort Washington Ave, Herbert Irving Pavilion, 6th Floor, New York, NY 10032 (ak189@cumc.columbia.edu).

# What We Know and Don't Know About Renal Denervation to Lower Blood Pressure

**Hypertension (HTN)** is a highly prevalent cause of cardiovascular morbidity and mortality, with overall rates of blood pressure (BP) control remaining poor¹ despite numerous treatment options. The reasons for this treatment gap are multifactorial and include limited durability of lifestyle modifications, variable adherence to medications, medication adverse effects, and limited access to adequate health care resources and follow-up.

For patients with HTN that is poorly controlled with medical therapy, device-based therapies that aim to lower BP are under investigation with the goal of achieving better rates of HTN control. Rather than replacing other established therapies, device-based therapies for HTN could act as adjuncts to lifestyle modification and pharmacologic interventions. Among device-based approaches to HTN, renal denervation (RDN) is an emerging technology that has shown promise in lowering BP.

Activation of the sympathetic nerves of the kidney can decrease renal blood flow and excretion of salt and water, and increase renin levels, leading to increased activation of the renin-angiotensin-aldosterone system. The sympathetic nerves lie within the periadventitial space surrounding the renal arteries and can be accessed through an endovascular approach. Current RDN systems consist of intra-arterial catheters that are used to ablate renal nerves by either radiofrequency, ultrasound, or ethanol injection. Ablation of renal nerve fibers decreases sympathetic nerve activity, resulting in both local and systemic effects that result in lowered BP.

## Efficacy of RDN

The first report of catheter-based RDN was a case study that demonstrated a dramatic lowering of BP as well as multiple markers of renin-angiotensin activity in a patient with severe HTN despite multiple medications.² Several positive clinical studies rapidly followed this report, leading to an almost unbridled enthusiasm for RDN that was ultimately muted by the completion of a blinded, 535-patient, randomized clinical trial that failed to show superiority of radiofrequency-based RDN of the main renal arteries compared with a sham procedure at 6 months, with both treatment groups demonstrating substantial reductions in BP.³

Subsequent trials investigating newer-generation devices with optimized RDN techniques (and, importantly, enrolling study participants with stabilized adjunctive pharmacologic regimens) have been completed. Within these trials, the efficacy of RDN in lowering BP over a sham procedure has been demonstrated in patients with both uncontrolled as well as resistant HTN without any appreciable adverse safety events.⁴ The reductions in BP with RDN in these trials have been more modest than in the initial reports, with reductions in

systolic BP of approximately 8 mm Hg from baseline (approximately 5 mm Hg compared with a sham procedure). Notably, in the Paradise Renal Denervation: A Global Evaluation in Clinical Hypertension (RADIANCE-HTN) SOLO trial, when medications were added back to both treatment groups to achieve better rates of control, the BP-lowering effect of RDN was maintained at longer follow-up with less medications needed to achieve similar blood pressures in the RDN group compared with sham.⁵

A theoretical advantage of RDN is that it is a therapy that is "always on," with effects discernible throughout the 24-hour circadian cycle. Thus, RDN could be less dependent upon both within-day variability as well as day-to-day adherence, potentially differentiating its mechanism of action from conventional pharmacologic and nonpharmacologic interventions. For example, in the sham-controlled RADIANCE-HTN SOLO trial, after adjustment for baseline BP and number of medications, randomization to RDN was associated with reductions in daytime, nighttime, and 24-hour BP.⁶ Visit-to-visit variability in BP was also lower with RDN compared with sham at 12 months. Further, in 6-month follow-up of the RADIANCE-HTN TRIO trial of patients with hypertension resistant to combination therapy with a thiazide diuretic, angiotensin-receptor blocker, and a calcium channel blocker, the addition of an aldosterone antagonist during the medication titration phase of the trial to achieve BP control occurred less frequently among patients randomly assigned to RDN vs sham (40% vs 61%), despite reductions in systolic BP of 12 mm Hg from baseline in both groups.⁷

## Further Questions

RDN has been shown in clinical trials to be effective at lowering BP, but not all treated patients respond to RDN and—especially without an intraprocedural marker of efficacious ablation—it is difficult to predict a priori who will respond to the therapy. Although reductions in BP with RDN among responders do appear consistent and not driven by outliers (Figure), approximately one-third of patients can be classified as nonresponders with a decrease in systolic BP of less than 5 mm Hg after RDN. Upfront identification of patients who may have an inadequate BP response could therefore potentially spare them having to undergo a procedure. Whether performing more complete denervation procedures or even considering the potential for intraprocedural mapping to guide RDN procedures will be able to lower the rates of nonresponsiveness is speculative at present.

Several additional questions remain, including longer-term safety of the procedure and the durability of the BP-lowering effect. Data from a large registry of
<figure><img src="image_3.png" /><figcaption>Figure. Individual Changes in Ambulatory Systolic Blood Pressure Response to Renal Denervation vs Sham in the RADIANCE-HTN TRIO Trial</figcaption></figure>

Waterfall plots depicting individual changes in daytime ambulatory systolic blood pressure at 2 months compared between renal denervation (A) and sham (B) in the Paradise Renal Denervation: A Global Evaluation in Clinical Hypertension (RADIANCE-HTN) TRIO trial. Between-group differences: 5 mm Hg decrease, *P* = .005; 10 mm Hg decrease, *P* = .01.

patients treated in Europe have been favorable in both regards,⁸ but to date, randomized clinical trials of RDN have consisted of modest sample sizes with relatively short durations of follow-up. Ultimately, whether the reduction in BP effected by RDN translates into a reduction in either BP-related events (eg, unplanned hospitalizations) or downstream adverse cardiovascular events is a critically important question that, as yet, remains unanswered. Additional study of the mechanistic effects of RDN provides the opportunity for further investigation of autonomic influences on BP control, thereby establishing a biological premise for RDN rather than simply an interventional rationale to execute the procedure.

## Who Could Be Potential Candidates for RDN?

Despite the most recent evidence that demonstrates that RDN can lower BP, lifestyle modification and multiple medications are read-

ily available, do not require an invasive procedure, and should be considered the standard of care. These principles reinforce the need for careful screening and assessment of patients both for secondary causes of HTN as well as for initiation of other BP treatments upstream to consideration of a referral for RDN. Indeed, as observed in the RADIANCE-HTN TRIO trial, many screened patients with demonstrable resistant HTN had BP that subsequently became controlled after switching to single-pill combination therapy, obviating the eligibility for randomization to RDN in the trial. This finding alone emphasizes the utility and importance of combination pharmacology when treating HTN (without RDN). As such, future potential candidates for RDN will likely be patients with uncontrolled hypertension despite being on multiple medications (including combination therapy), or patients who are truly unable to tolerate or adhere to medications.

## ARTICLE INFORMATION

**Published Online:** March 30, 2022.
doi:10.1001/jamacardio.2022.0169

**Conflict of Interest Disclosures:** Dr Azizi reported receiving research grants from the French Ministry of Health, Quantum Genomics, and the European Horizon 2020 program; grant support and nonfinancial support from ReCor Medical and Idorsia; and personal fees from CVRx, AstraZeneca, and Alnylam pharmaceuticals. Dr Kirtane reported receiving institutional funding to Columbia University and/or Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Amgen, CSI, Philips, ReCor Medical, Neurotronic, Biotronik, Chiesi, Bolt Medical, Magenta Medical, Canon, and SoniVie (in addition to research grants, institutional funding included fees paid to Columbia University and/or Cardiovascular Research Foundation for consulting and/or speaking engagements in which Dr Kirtane controlled the content); consulting fees from IMDS; and travel expenses/meals from Medtronic, Boston Scientific, Abbott Vascular, CSI, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. No other disclosures were reported.

## REFERENCES

1. Muntner P, Hardy ST, Fine LJ, et al. Trends in blood pressure control among US adults with hypertension, 1999-2000 to 2017-2018. JAMA. 2020;324(12):1190-1200. doi:10.1001/jama.2020.14545

2. Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal sympathetic-nerve ablation for uncontrolled hypertension. *N Engl J Med*. 2009;361(9):932-934. doi:10.1056/NEJMco904179

3. Bhatt DL, Kandzari DE, O'Neill WW, et al; SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. *N Engl J Med*. 2014;370(15):1393-1401. doi:10.1056/NEJMoa1402670

4. Kandzari DE, Townsend RR, Bakris G, et al. Renal denervation in hypertension patients. *Catheter Cardiovasc Interv*. 2021;98(3):416-426. doi:10.1002/ccd.29884

5. Azizi M, Daemen J, Lobo MD, et al; RADIANCE-HTN Investigators. 12-Month results from the unblinded phase of the RADIANCE-HTN

SOLO trial of ultrasound renal denervation. JACC Cardiovasc Interv. 2020;13(24):2922-2933. doi:10.1016/j.jcin.2020.09.054

6. Azizi M, Schmieder RE, Mahfoud F, et al; RADIANCE-HTN Investigators. Six-month results of treatment-blinded medication titration for hypertension control following randomization to endovascular ultrasound renal denervation or a sham procedure in the RADIANCE-HTN SOLO trial. *Circulation*. Published online March 17, 2019. doi:10.1161/CIRCULATIONAHA.119.040451

7. Kirtane A. RADIANCE-HTN: 6-month outcomes of a randomized trial of renal denervation vs a sham procedure for resistant hypertension—impact of treatment-blinded medication titration. Paper presented at: Transcatheter Cardiovascular Therapeutics Conference; November 4, 2021; Orlando, FL.

8. Mahfoud F, Böhm M, Schmieder R, et al. Effects of renal denervation on kidney function and long-term outcomes. *Eur Heart J*. 2019;40(42):3474-3482. doi:10.1093/eurheartj/ehz118