Changes in blood pressure after crossover to ultrasound renal denervation in patients initially treated with sham in the RADIANCE-HTN SOLO trial

Background

Catheter-based renal denervation (RDN) has been developed to modulate sympathetic renal
activity with a single percutaneous intervention[1]. The technique can be used complementarily to
pharmacological treatment if shown to be effective, safe and durable. The main advantage of RDN
is to possibly overcome the low adherence to chronic pharmacological therapy, a known
phenomenon in the treatment of arterial hypertension[2, 3].

The RADIANCE-HTN SOLO trial[4] compared ultrasound RDN using the Paradise® system
with a sham procedure (randomised 1:1) in patients with arterial hypertension after discontinuing
pharmacological treatment (4 weeks before until 2 months after the intervention). The primary
endpoint of the trial was daytime ambulatory systolic blood pressure (dASBP) at 2 months post
intervention.

In the RADIANCE-HTN SOLO trial, treatment with RDN lead to a reduction of dASBP of
-6.3mmHg (CI95%: -9.4 to -3.1mmHg, p-value < 0.0001), without major adverse events recorded.
All patients were unblinded as determined by the study protocol after the primary analysis.

Aim of the study

The crossover study now published by Mahfoud et al.[5] is a pre-specified post-hoc analysis
of the RADIANCE-HTN SOLO trial assessing the effects of RDN in patients initially treated with
sham procedure that remain with uncontrolled hypertension after the unblinding period.

Methods

From 72 patients submitted to a sham procedure in the RADIANCE-HTN SOLO trial, 33
patients (47.8%) had uncontrolled hypertension after completion of the trial and accepted to
undergo ultrasound RDN with the Paradise® system. The mean time from randomisation in the
trial and crossover to RDN was 22±6 months.

In contrast to the primary part of the trial, patients were maintained in the usual medication
at the time of crossover, and post-procedure pharmacological treatment did not follow a prespecified
protocol.

The primary analysis of the study was the comparison of dASBP at two and six months after
RDN, in relation to baseline values.

Secondary analysis were average 24h ambulatory, night-time ambulatory, and office blood
pressure (BP). The proportion of patients with controlled dASBP (<135/85 mmHg) and controlled
office BP (<140/90) were also compared.

The investigators assessed medication burden by the total number of antihypertensive
medications and the sum of defined daily dose (DDD) of each individual antihypertensive
medication.

Results

The mean time between pre-crossover ambulatory blood pressure measurement and
crossover RDN was 22±15 days.

The mean age was 54 years and 39% were female. The average number of antihypertensive
medications at time of crossover was 1.2 ± 0.8.

The average decrease in daytime systolic ambulatory pressure was 11.2 ± 13.7mmHg at 2
months and 10.8 ± 17.3 at 6 months.

Decreases in average 24h BP, daytime and night-time ABSP were concordant with the
primary analysis and also statistically significant.

The proportion of patients with controlled dASBP was 54.5

Messages

The RADIANCE-HTN programe has provided evidence on the effectiveness and safety of
ultrasound renal denervation in patients with uncontrolled hypertension. The main merits of the
RADIANCE-HTN SOLO trial were the performance of a sham procedure in the control arm and the
absence of concomitant medication in the peri-procedure period[4].

The post-hoc study by Mahfoud et al. provided further evidence on the biological effect of
ultrasound renal denervation by studying sham-treated patients that were offered RDN after
unblinding.

The study observed a significant decrease on dASBP at 2 months that was maintained at 6
months, which is in accordance with the effect observed in the primary trial.
As a post-hoc analysis, the study has the limitations of a non-randomised design and openlabel
intervention. However, each patient served as his own control since results are compared to
pre-intervention levels. Moreover, concomitant medication was not significantly altered during
follow-up.

The average decrease in mean dASBP was slightly higher than what had been observed in
the primary clinical trial, a difference that can partly be explained by the study limitations.
Nevertheless, other effects such as synergism with pharmacological treatment cannot be
excluded.

The authors must be congratulated on their efforts to provide long term follow-up of patients
included in the randomised clinical trial. Unblinding of patients in sham-controlled trials is
important for the enrollment of patients. The authors were able to use the unblinding procedure to
provide more insight on the effects of RDN.

Future direction

The field of RDN is being able to provide evidence on the effectiveness and safety of the
procedure regarding the endpoint of BP reduction. From a theoretical standpoint, it remains an
interesting approach to the treatment of a chronic disease which is the single most important risk
factor for cardiovascular adverse events.

The inclusion of more patients in clinical trials of RDN, as well as longer follow-up, are a
major challenge for the field. Also, technical improvements might enhance the effectiveness of
therapy in the near future. The development of a reliable marker of sympathetic modulation after
the procedure would also be a significant step forward.