CONGRESS COVERAGE: Renal Sympathetic Denervation for Resistant Hypertension: Symplicity HTN-3 and the Power of Placebo
Authors: Tziomalos Konstantinos , Athyros Vasilios G. , Doumas Michael 
Published: June 2014

DEAR EDITOR

The results of the Symplicity HTN-3 trial have been presented
a few days ago in the 2014 Scientific Meeting of the
American College of Cardiology and simultaneously published
in the New England Journal of Medicine [1]. The
Symplicity HTN-3 trial was the first placebo-controlled (via
sham procedure) study evaluating the effects of renal sympathetic
denervation (RSD) in patients with resistant hypertension.
The study met its primary safety endpoint but failed to
achieve its primary and secondary efficacy endpoints generating
major disappointment in the scientific community and
raised significant concerns about the future of this novel interventional
approach for the management of patients with
resistant hypertension.

The Symplicity HTN-3 trial was a multicenter, prospective,
randomized, single-blind, sham-controlled study conducted
in the United States of America. The study was performed
in patients with uncontrolled resistant hypertension,
i.e. office systolic blood pressure >160 mmHg despite the
use of at least three antihypertensive drugs (one of which
was a diuretic) in maximally tolerated doses. Moreover,
home blood pressure monitoring for two weeks and 24h ambulatory
blood pressure monitoring ensured the diagnosis of
true resistant hypertension, excluding patients with pseudoresistance
due to the white-coat effect. From a total of 1,441
patients screened for eligibility, 535 patients fulfilled the
inclusion/criteria and were randomly assigned to either RSD
or a sham procedure (placebo) in a 2 to 1 ratio and were then
followed-up for 6 months.

The primary safety endpoint was a composite of hard and
surrogate events (all-cause mortality, end-stage renal failure,
embolic episodes leading to target organ damage, renovascular
complications and new-onset renal artery stenosis, and
hypertensive crises) less of approximately 10%, based on prior information. The office blood pressure reduction at 6
months with a superiority margin of 5 mmHg for renal nerve
ablation was the primary efficacy endpoint and the ambulatory
blood pressure reduction at the same time point was the
secondary efficacy endpoint.

The study achieved its primary safety endpoint, since no
significant differences in adverse events were observed between
RSD and sham procedure. In total, there were 5 significant
adverse events in the active treatment group compared
with one significant adverse event in the placebo
group, and the difference was not significant (p=0.67).
Moreover, no significant deterioration of renal function
was observed with RSD, even in patients with chronic
kidney disease (estimated glomerular filtration rate < 60
ml/min/1.73m2). The reassuring renal safety profile confirms
the short-term safety of RSD that was observed in previous
studies [2-5], but does not totally exclude potential long-term
detrimental effects on renal function [6, 7].

The major disappointment however comes from the efficacy
endpoints. The study failed to achieve both its primary
and secondary efficacy endpoints. In particular, the mean
reduction in office blood pressure was 14.1 mmHg with active
therapy and 11.7 mmHg with placebo at 6 months, and
was highly significant for both groups compared to baseline
(p<0.001). However, the between-group difference in systolic
blood pressure reduction was small (2.4 mmHg) and
was not significant (p=0.26) in terms of the pre-defined superiority
of 5 mmHg. Similarly, the mean reduction in ambulatory
blood pressure at 6 months was 6.8 mmHg with active
therapy and 4.8 mmHg with placebo compared to baseline,
and the small between-group difference (2.0 mmHg) was not
significant (p=0.98) for a superiority margin of 2 mmHg.

Several points need to be highlighted and evaluated in the
context of previous knowledge in order to avoid misleading
conclusion.

Firstly, the magnitude of office blood pressure reduction
was almost half than in previous studies (14.1 mmHg versus
25-30 mmHg) [2, 3, 5, 8-11]. The inferior efficacy of RSD in
the Symplicity-3 might be attributed to differences in study populations and several other factors. It has to be noted however
that all previous studies were uncontrolled. It has been
estimated that the anticipated blood pressure reduction with
RSD is approximately 15 mmHg, when all other factors are
taken in consideration [12].

Secondly, the ambulatory blood pressure reduction was
significantly lower than the office blood pressure reduction
(6.8 mmHg versus 14.1 mmHg), and this also was not an
unexpected finding. A marked disparity between office and
ambulatory blood pressure reduction with RSD has been
observed in all previous RSD studies [13], and this disparity
is significantly higher than with antihypertensive drug therapy
[14].

Thirdly, the main factor contributing to the negative findings
of the study was the impressive blood pressure reduction
with the sham procedure (11.7 mmHg). However, this
was also not an unexpected finding and it should have been
anticipated based on previous data. Indeed, two studies performed
in patients with resistant hypertension and similar
baseline characteristics, revealed a strong placebo effect: the
Rheos pivotal trial and the darusentan study [15, 16]. The
powerful placebo effect almost “killed” both carotid baroreceptor
activation and endothelin receptor antagonism for the
treatment of resistant hypertension [17, 18].

Finally, potential disadvantages in study design cannot be
entirely excluded. The study design was very meticulous and
of the highest quality, and included sham procedure and ambulatory
blood pressure monitoring overcoming previous
concerns [19, 20]. However, one factor might have significantly
influenced the findings of the study: the absence of
familiarity with this novel procedure. The study was conducted
in 88 sites all over the United States and more than
100 interventional cardiologists performed the procedure, for
a mean of 3 to 4 procedures for each interventionalist. This
raises the concern of a learning curve, especially because
RSD was performed with the single-tip Symplicity catheter,
which needs a lot of manipulations.

Overall, the negative findings of the Symplicity-3 trial
“turned-off” the initial enthusiasm about RSD in many physicians,
both hypertension specialists and primary care doctors.
However, a sober and dispassionate approach seems
more rational, avoiding overwhelming enthusiasm and excessive
pessimism. Carefully designed clinical trials along
with intensive research about response predictors are eagerly
awaited in order to identify patient subgroups that will benefit
from RSD.