Cardiovascular Journal of Africa: Vol 30 No 5 (October 2019)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 5, September/October 2019 AFRICA 249
Renal denervation: bleak past, brighter future
Brian Rayner
Heradien et al. present a timely review of the history and
future directions of renal denervation (RD) for the control
of hypertension and the prevention of cardiovascular disease
(CVD) page 290.1 In their review they outline the importance
of sympathetic overactivity (or autonomic imbalance) in the
pathogenesis of hypertension and in CVD in particular; the role
of renal sympathetic overactivity; methods of interrupting renal
sympathetic fibres; advances in catheters and techniques; results
of initial and recent trials; prevention of cardiac arrhythmias;
and future directions. This editorial will provide a perspective on
the clinical role of RD.
The publication of SYMPLICITY HTN-1, followed shortly
thereafter by SYMPLICITY HTN-2, sent shock waves through
the hypertension community.2,3 Both studies showed profound and
long-lasting office blood pressure (BP) reduction (approximately
30/15 mmHg) after RD in patients with resistant hypertension
(RH). SYMPLICITY HTN-1 was a proof-of-concept study,
while SYMPLICITY HTN-2 was a randomised, unblinded study
of RD versus no procedure. There was great excitement and there
appeared little doubt that the procedure was highly effective.
However, the Federal Drug Administration (FDA) requested
a single-blind, randomised trial with sham procedure using
ambulatory BP monitoring as an endpoint before registration,
so SYMPLICITY HTN-3 was conceived and executed.
Unfortunately, the study showed no significant benefit of RD
over sham procedure on ambulatory or office BP.4 This was a
great lesson to everyone, and also reinforced the concept that
randomised, prospective, blinded studies are the only way to
prove efficacy of any intervention to avoid bias and confounding
factors. Many now believed that RD had no future in the
treatment of hypertension. However, in all three studies, no
safety concerns were demonstrated.
As a result, the South African hypertension practice guideline
in 2014 (and other hypertension guidelines) did not recommend
RD for the treatment of hypertension,5,6 and it looked as though
RD had fallen off the radar and had a bleak future. Furthermore,
the PRAGUE-15 study showed that RD, in the setting of true
RH with confirmed adherence, was not superior to intensified
pharmacological treatment, and the addition of spironolactone
(if tolerated) seemed to be more effective in BP reduction.7
The results of SYMPLICITY HTN-3 led to a great deal of
introspection by investigators involved in RD studies. However,
there were several problems with SYMPLICITY HTN-3 that
may have explained the negative result. First, it was underpowered
because of the impressive results of SYMPLICITY HTN-1 and
-2. Second, many operators were extremely inexperienced, only
performing one procedure. Third, full bilateral denervation was
not achieved in a high percentage of cases, and non-adherence at
baseline and adherence in the study reduced differences between
sham and active treatment. 8
Recommendations were mandated for the next generation
of sham, randomised, controlled trials. Four-quadrant ablation
of both kidneys circumferentially had to be achieved using
only experienced interventionalists from experienced centres.8
This was assisted by the development of a radiofrequency
multi-electrode catheter (Spyral, Medtronic, Ireland), designed
to enable reliable circumferential four-quadrant ablation.
Adherence had to be confirmed by either witnessed intake of
medication (if applicable) and/or urine analysis of medication
adherence in each patient. BP assessment had to be performed
by 24-hour ambulatory BP to avoid bias and super-added white
coating. Studying patients in the absence of any medication was
also suggested to assess the ‘true’ BP reduction of RD.
The recent publication of three pivotal studies greatly
renewed interest in RD. Two studies were performed in patients
off medication (SPYRAL HTN-OFF and RADIANCE-
HTN SOLO) and one on medication (SPYRAL HTN-ON).9-11
The prospective, randomised, double-blind, sham-controlled
SPYRAL HTN-OFF study included patients with hypertension
with an office systolic BP between 150 and 180 mmHg, office
diastolic BP > 90 mmHg, and ambulatory SBP of 140–170
mmHg with no concomitant antihypertensive therapy.
In the first interim analysis at three months of 80 patients
treated, a significant reduction in office systolic BP of –7.7
mmHg (p = 0.0155) and diastolic BP of –4.9 mmHg (p = 0.0077),
ambulatory systolic BP of –5.0 mmHg (p = 0.04) and 24-hour
diastolic BP of –4.4 mmHg ( p = 0.0024) was documented,
compared with sham treatment. RADIANCE HTN-SOLO was a
similar study except that a balloon-based catheter (Paradise, Recor,
CA, USA) ablated renal sympathetic nerves circumferentially
using ultrasound energy. A similar magnitude of BP reduction to
SPYRAL HTN-OFF was achieved compared to sham treatment.
The SPYRAL HTN-ON, a prospective, randomised, double-
blind, sham-controlled study, used the same BP criteria as for
the SPYRAL-OFF study, but included moderate, uncontrolled
Keywords: renal denervation, hypertension
Cardiovasc J Afr 2019; 30: 249–250
DOI: 10.5830/CVJA-2019-056
Senior Scholar and Emeritus Professor, Division of
Nephrology and Hypertension, Kidney and Hypertension
Research Unit, University of Cape Town, Cape Town, South
Africa
Brian Rayner, MB ChB, FCP, MMed, PhD,
Editorial