Elsevier

The Lancet

Volume 391, Issue 10137, 9–15 June 2018, Pages 2335-2345
The Lancet

Articles
Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial

https://doi.org/10.1016/S0140-6736(18)31082-1Get rights and content

Summary

Background

Early studies suggest that radiofrequency-based renal denervation reduces blood pressure in patients with moderate hypertension. We investigated whether an alternative technology using endovascular ultrasound renal denervation reduces ambulatory blood pressure in patients with hypertension in the absence of antihypertensive medications.

Methods

RADIANCE-HTN SOLO was a multicentre, international, single-blind, randomised, sham-controlled trial done at 21 centres in the USA and 18 in Europe. Patients with combined systolic–diastolic hypertension aged 18–75 years were eligible if they had ambulatory blood pressure greater than or equal to 135/85 mm Hg and less than 170/105 mm Hg after a 4-week discontinuation of up to two antihypertensive medications and had suitable renal artery anatomy. Patients were randomised (1:1) to undergo renal denervation with the Paradise system (ReCor Medical, Palo Alto, CA, USA) or a sham procedure consisting of renal angiography only. The randomisation sequence was computer generated and stratified by centres with randomised blocks of four or six and permutation of treatments within each block. Patients and outcome assessors were blinded to randomisation. The primary effectiveness endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Patients were to remain off antihypertensive medications throughout the 2 months of follow-up unless specified blood pressure criteria were exceeded. Major adverse events included all-cause mortality, renal failure, an embolic event with end-organ damage, renal artery or other major vascular complications requiring intervention, or admission to hospital for hypertensive crisis within 30 days and new renal artery stenosis within 6 months. This study is registered with ClinicalTrials.gov, number NCT02649426.

Findings

Between March 28, 2016, and Dec 28, 2017, 803 patients were screened for eligibility and 146 were randomised to undergo renal denervation (n=74) or a sham procedure (n=72). The reduction in daytime ambulatory systolic blood pressure was greater with renal denervation (−8·5 mm Hg, SD 9·3) than with the sham procedure (−2·2 mm Hg, SD 10·0; baseline-adjusted difference between groups: −6·3 mm Hg, 95% CI −9·4 to −3·1, p=0·0001). No major adverse events were reported in either group.

Interpretation

Compared with a sham procedure, endovascular ultrasound renal denervation reduced ambulatory blood pressure at 2 months in patients with combined systolic–diastolic hypertension in the absence of medications.

Funding

ReCor Medical.

Introduction

Targeted endovascular catheter-based denervation of the renal efferent and afferent nerves with minimally invasive approaches has been investigated as a novel blood pressure lowering treatment for resistant hypertension.1 Although in initial randomised trials, catheter-directed radiofrequency ablation was associated with blood pressure reduction,2, 3 a subsequent sham-controlled study did not show improvement in blood pressure control.4

Several features of this sham-controlled trial might have limited its ability to show blood pressure reduction following renal denervation.5 These include uncertainty regarding the completeness of denervation, variable adherence to antihypertensive medications among patients during follow-up, and a population including patients with isolated systolic hypertension or substantial vascular stiffness that might be difficult to reverse.6, 7 Subsequently, trials have been designed with more attention to procedural technique and the inclusion of patients with less severe hypertension in order to examine the blood pressure lowering efficacy of catheter-based renal denervation in the absence of antihypertensive medications.6, 8 The results of one such study support the ability of renal denervation with a multielectrode radiofrequency ablation device to reduce blood pressure.9

Research in context

Evidence before this study

We searched PubMed up to April 15, 2018, without time or language restriction with the terms “renal denervation”, “hypertension”, “randomised”, “hypertension”, and various combinations of those words to identify systematic reviews, meta-analyses, and randomised controlled trials of blood pressure lowering efficacy of renal denervation. We identified 11 meta-analyses that included randomised and non-randomised controlled trials of patients with uncontrolled hypertension despite being treated with antihypertensive medications. The 2017 Cochrane Collaboration meta-analysis that included 12 eligible sham and non-sham controlled studies (1149 participants) showed moderate quality evidence that renal denervation did not change office or ambulatory blood pressure compared with standard or intensified antihypertensive therapy. This meta-analysis did not include trials assessing the effect of renal denervation in patients with hypertension in the absence of antihypertensive medications. Since the publication of these meta-analyses, interim analysis of the SPYRAL HTN-OFF MED randomised, sham-controlled trial reported reduction in 24-h ambulatory systolic blood pressure with radiofrequency-based renal denervation compared with a sham procedure at 3 months in the absence of antihypertensive medications.

Added value of this study

The RADIANCE-HTN SOLO trial was designed to show the effect of endovascular ultrasound renal denervation on ambulatory blood pressure compared with a sham procedure in patients with combined systolic–diastolic hypertension who were off antihypertensive medications. This study was powered for efficacy and our results showed a greater reduction in daytime and 24-h systolic ambulatory blood pressure at 2 months in patients who underwent renal denervation than in patients who underwent a sham procedure.

Implications of all the available evidence

The RADIANCE-HTN SOLO and SPYRAL HTN-OFF MED trials enrolled largely similar patient populations, and yielded consistent results, showing that catheter-based renal denervation, using ultrasound or radiofrequency, lowers blood pressure among patients with hypertension who are off antihypertensive medications. The results of both trials will inform the design of future studies in this population to provide additional safety and long-term efficacy data, which will be important to establish the role of renal denervation in the treatment of hypertension.

An alternative technology has been developed that delivers ultrasound energy to thermally ablate the renal sympathetic nerves (Paradise renal denervation system, ReCor Medical, Palo Alto, CA, USA). Placed percutaneously within the main renal arteries and centred by a low pressure, water-filled cooling balloon (appendix), this endovascular catheter achieves a circumferential ring of ablation10, 11 at a depth of 1–6 mm from the vessel lumen in animal models (data on file, ReCor Medical), which is the expected location of the efferent and afferent renal nerves in the adventitia.12 In patients with resistant hypertension, feasibility studies have shown reductions in blood pressure and a low incidence of adverse events, albeit without comparison with a sham procedure.13, 14

We designed the RADIANCE-HTN trial to compare the blood pressure lowering efficacy of this endovascular ultrasound renal denervation system with a sham procedure in two separate cohorts: patients with mild-to-moderate hypertension, who underwent randomisation while off antihypertensive medications (SOLO cohort), and patients with uncontrolled hypertension despite receiving three antihypertensive medications (TRIO cohort).15 Each cohort was independently powered to detect a difference between renal denervation and the sham procedure in terms of the primary endpoint, of change in daytime ambulatory systolic blood pressure at 2 months. In this Article, we report the primary results of the RADIANCE-HTN randomised trial in the SOLO cohort.

Section snippets

Study design and participants

RADIANCE-HTN SOLO is a multicentre, international, single-blind, randomised, sham-controlled trial. The design of the RADIANCE-HTN trials has been described previously.15 Participants were recruited into the SOLO cohort of the RADIANCE-HTN trial from 21 hospitals in the USA and 18 in Europe (France, Germany, the Netherlands, Belgium, and the UK; appendix). The study was approved by local ethics committees or institutional review boards and was done in accordance with the declaration of

Results

Between March 28, 2016, and Dec 28, 2017, 803 patients with a history of hypertension were enrolled into the SOLO cohort of the RADIANCE-HTN trial. After a 4-week period during which all antihypertensive medications were discontinued, 170 patients met both daytime ambulatory blood pressure and non-invasive imaging criteria and thus underwent subsequent renal angiography. Anatomical reasons for exclusion during non-invasive imaging or renal catheter angiography are shown in the appendix. 146

Discussion

Among patients with combined systolic–diastolic hypertension who were not taking or had been withdrawn from antihypertensive medications, endovascular ultrasound renal denervation achieved a greater reduction in daytime ambulatory systolic blood pressure at 2 months than did a sham procedure. This blood pressure lowering effect was consistent for daytime ambulatory diastolic and 24-h ambulatory systolic blood pressure, as well as office and home systolic and diastolic blood pressures. The blood

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    *

    Contributed equally

    The complete list of study investigators and study committee members is available in the appendix

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