51 / 70
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 5, September/October 2019
AFRICA
293
of hypertension therapy, socio-economic factors limiting
drug access, social support, depression and anxiety, regimen
complexity and side effects. Taken in context with the significant
drop in BP in the sham group, it is reasonable to suspect that
unpredictable variable adherence to antihypertensive medication
may have impacted on the results of SYMPLICITY HTN-3.
This concern led to the design of ‘off-medication’ trial designs
following SYMPLICITY HTN-3. These are discussed below.
Hawthorne effect:
This effect describes the adjusted behaviour
of trial participants to seemingly please/impress study
investigators.
34
Examples of such behaviour include patients
taking their medication more diligently, reducing their salt intake
and exercising more regularly. It is difficult, if not impossible, to
reduce this type of behaviour.
Regression to the mean (RTM):
RTM is defined as the tendency
for an extreme measurement on one occasion to become less
extreme when measured again. This may explain why, unlike
previous SYMPLICITY trials, SYMPLICITY HTN-3 showed
only a –4.1-mmHg between-group SBP treatment difference.
To reduce this niggly statistical phenomenon, statisticians
recommended that, rather than a Student’s
t
-test, analysis of
covariance (ANCOVA) might be a more appropriate test to use
in future RDN trials.
35
Finally, it is essential to note that the potential biases
introduced by both the Hawthorne effect and regression to the
mean can be addressed by randomisation.
Operator experience and catheter design:
In SYMPLICITY
HTN-3, 112 operators performed an average of 3.3 procedures
per operator.
20
Less than five procedures were performed per
site, and more than 50% of the operators performed two or
fewer procedures in the trial. Several technical challenges may
face the inexperienced operator: difficult intubation with poor
guide catheter back-up, accessory polar renal arteries (smaller
than the main vessel) that could not be treated, the ‘hostile’
groin, e.g. morbid obesity and inability to visualise anatomically
whether a successful four-quadrant ablation was performed,
using a two-dimensional fluoroscopic image. Operators were
also instructed to avoid distal renal arteries, but Sakakura
et al.
subsequently discovered that in human cadavers, the renal nerves
run closer to the arterial lumen distal to the renal bifurcation
than proximally (2.6 mm vs 3.4 mm).
36
These sites, although
being typical ‘sweet spot targets’ for denervation, were therefore
missed in most cases. Animal studies have shown that RDN
success is very much dependent on distal denervation.
37,38
The Flex catheter (Medtronic Inc) is a single-point denervation
system that uses a proprietary algorithmof retraction, flexion and
rotation to focus radiofrequency energy points in recommended
anatomical sites of the renal artery. It was challenging to
perform enough four-quadrant ablations with the old system
but the newer Symplicity Spyral catheter, which is an over-
the-wire system, is a safer, more intuitive system that not only
associates with more four-quadrant ablations but also enables
the operator to safely perform distal ablations without the
danger of perforation or dissection. The newer system typically
requires less fluoroscopy time with less ionising radiation and
lower doses of iodine contrast agent, resulting in better renal
function outcomes post-procedurally.
A new generation of sham, controlled RCTs
Recently reported positive results from three new randomised
sham, controlled trials might have rekindled interest in RD. All
three trials were designed to compensate for the confounding
factors identified in SYMPLICITY HTN-3. Although smaller
in scope than SYMPLICITY HTN-3, the sham controlled
SPYRAL HTN OFF-MED trial tested the hypothesis that RD
would reduce BP in the absence of antihypertensive drugs.
39
Patients with milder HT were asked to discontinue their BP
medication for at least one month before and during the
trial duration. Similar to SYMPLICITY HTN-3, patients were
randomised to RD or sham RD. Compliance was checked
with urine drug levels throughout the trial. RD was performed
by experienced proceduralists, who also denervated the distal
renal arteries with a second-generation quadripolar catheter
(Symplicity Spyral).
Results were reported at three months and albeit much
less than previous trials, showed that RD reduced office and
ambulatory BP in hypertensive drug-naïve patients, confirming
the proof of concept. Likewise, the sham, controlled SPYRAL
HTNON-MED trial showed similar, if not greater improvements
in both office and 24-hour blood pressure six months post-RD
in a similar population treated with one to three antihypertensive
agents.
40
Finally, the sham, controlled RADIANCE HTN SOLO trial
employed a design quite similar to SPYRAL HTN OFF-MED
but using an ultrasound-based catheter denervation system
(Otsuka/ReCor Paradise).
41
Interestingly this catheter was
not advanced into the distal renal arteries but only into the
main vessel. The results after two months showed significant
reductions in office and ambulatory BP comparable to the
SPYRAL HTN trials.
Together, these trials blew new life into endovascular RD
and provided the much-needed hope that RD does indeed
lower BP in selected patients when the right technique is used
by experienced renal denervationists. Now the world waits with
bated breath for the final RD trial that will use the knowledge
learned from hard lessons, and hopefully either bury or enthrone
RD in its rightful place in HT management.
Types of patients likely to benefit from RD
Three types of patients will likely benefit from RD. The first
and most prevalent group are those who are non-adherent to
their antihypertensive therapies (AHT). Almost one-third of
all hypertensive patients never start with their prescription of
antihypertensive drugs when first diagnosed.
42
The variable
plasma half-life of AHT also explains why some AHT lack
true 24-hour cover and why uncontrolled hypertensive patients
experience most of their events during the early morning hours
when drug levels reach their nadir. The ‘always-on effect’ of RD
may help to reduce these pharmacological shortcomings.
The second group that may also benefit are those patients
with clinical signs of IST, for example a resting heart rate
of
≥
75 bpm in beta-blocker-naïve subjects, patients with
non-dipping or during 24-hour ABPM.
7,43
The dipping of
blood pressure at night is mediated by reduction of daytime
sympathetic tone and increase in nocturnal vagal tone. Finally,
the group that will probably benefit most are patients with the
metabolic syndrome.
44