Redo renal denervation using a multi-electrode radiofrequency system in patients with persistent therapy-resistant hypertension
Redo renal denervation using a multi-electrode radiofrequency system in patients with persistent therapy-resistant hypertension
J. Daemen 0
L. Feyz 0
L. Van Zandvoort 0
N. M. Van Mieghem 0
0 Department of Interventional Cardiology, Erasmus Medical Center , Rotterdam , The Netherlands
Objectives Renal sympathetic denervation has been studied as a potential therapeutic option for patients with therapyresistant hypertension; however, a significant proportion of patients do not show a significant reduction in blood pressure and are classified as non-responders. The objective of the present study was to assess whether a redo renal denervation procedure increases response rates. Methods We present a case series of three consecutive renal denervation non-responders treated with the multi-electrode radiofrequency St. Jude EnligHTN catheter after an average of 22 months. Patients were followed for 6 months. Results Mean age was 66 years and two patients were male. Patients were previously treated using either ReCor's Paradise system, the Vessix V2 system or the Covidien OneShot system. Mean office blood pressure one year after the initial procedure was 187/102 mm Hg with a mean 24 h ambulatory blood pressure of 166/102 mm Hg. All patients underwent a successful redo procedure using the EnligHTN system because of persistent therapy-resistant hypertension. At 6 months a significant drop in both office and ambulatory blood pressure of -27/-6 mm Hg and -15/-13 mm Hg, respectively, was observed. No significant renal artery stenosis was observed at 6 months. Conclusions In patients with therapy-resistant hypertension who do not respond to an initial renal denervation procedure, a redo procedure using the St. Jude EnligHTN system may help to significantly improve blood pressure control.
Sympathetic denervation; Hypertension; Catheter ablation
Controlling blood pressure in hypertensive patients
remains a challenge and treatment targets are frequently not
achieved despite multiple antihypertensive drugs . Renal
sympathetic denervation (RDN) has been studied as a
potential therapy to decrease blood pressure in patients with
therapy-resistant hypertension [2?4]. Several catheter-based
RDN techniques exist and proof of adequate denervation
and efficacy is mounting [5, 6]. However, the individual
magnitude of the treatment effect varies extensively, with
a significant proportion of patients not responding to the
therapy in terms of blood pressure reduction ?
irrespective of the technology used. A substantial number of both
patient and procedural characteristics have been
hypothesised to account for this so-called non-responsiveness [7,
8]. While characteristics such as older age and a
noncompliant arterial system as well as inadequate renal nerve
destruction on treatment with first generation devices are
clear, theoretical causes of this non-responsiveness,
scientific evidence is still scarce. Previous work has already
demonstrated that a higher degree of renal nerve disruption
leads to greater inhibition of the sympathetic nerve system
. Building further on this hypothesis, performing a redo
procedure could theoretically make sense in a proportion
of the patients who do not respond to the initial RDN
procedure. Apart from one case report on a successful redo
procedure using the Symplicity Flex system, and one study
on the effect of cryoablation as a second line option in
RDN non-responders, no data on the additional effect of
a redo RDN procedure on blood pressure reduction are
available [10, 11]. We present a series of three consecutive
RDN non-responders who underwent a second procedure
using the next generation multi-electrode St. Jude Medical
Patient selection and definitions
Three consecutive patients who did not show a relevant
reduction in both office and ambulatory blood pressure after
renal sympathetic denervation because of therapy-resistant
hypertension are presented. All procedures were carried out
at the Erasmus Medical Center, Rotterdam, the Netherlands,
between December 2012 and March 2013. Initial
denervation was performed with the Paradise system (ReCor
Medical, Palo Alto, CA), the OneShot system (Covidien,
Campbell, CA) and the Vessix V2 system (Boston
Scientific, Natick, MA), respectively . In order to qualify as
non-responders, patients had to fulfil the following criteria:
mean systolic 24 h ambulatory blood pressure >150 mm Hg
despite treatment with >3 antihypertensive drugs or failure
to show a reduction of >10 mm Hg in mean systolic 24 h
ambulatory blood pressure at 12 months after the initial
Office blood pressure recordings were collected in
accordance with the Standard Joint National Committee
VII Guidelines and ESC/ESH Guidelines .
Twentyfour hour ambulatory blood pressure was obtained using an
Ambulatory Blood Pressure System (Spacelabs Healthcare,
Inc., Issaquah, WA, USA).
Redo procedures were performed at 22.3 ? 4.6 months
after the initial procedure. At the time of the redo
procedure all patients were free of adverse events related to the
index procedure, showed no signs of renal artery
stenosis ? diagnosed using either computed tomography (CT) or
magnetic resonance (MR) angiography ? and had preserved
Redo denervation procedure
All patients were preloaded with 300 mg aspirin, if na?ve,
and advised to continue with aspirin for at least 1 month.
All procedures were performed under conscious sedation
using 1 to 3 mg of midazolam and 50 to 100 ?g of fentanyl.
After local anaesthesia, common femoral artery access was
obtained by echo-guided puncture and a 6 Fr sheath was
introduced. Under fluoroscopic guidance the short 6 Fr sheath
was exchanged for an 8 Fr RDN or IMA tipped guiding
sheath, which is recommended for the easier use of the
St. Jude EnligHTN system. Pre-procedurally, 100 IU
heparin/kg were administered to achieve an active clotting time
>250 s. After engaging the renal arteries by using a no-touch
technique with the help of a standard high-torque Balance
Heavyweight (BHW) coronary guidewire, selective renal
artery angiograms were made and an appropriate basket
size was chosen (small basket 4.0?5.5 mm diameter/large
basket 5.5?8.0 mm diameter). The BHW guidewire was
exchanged for the EnligHTN ablation catheter and its tip
positioned proximally to the bifurcation of the main renal artery.
The basket catheter, containing four bipolar
platinum-iridium electrodes, was then opened and the impedance of each
electrode on the basket was monitored. After a total of four
ablations were performed successfully the basket was
collapsed and retracted proximally while another four ablations
were performed in the same artery. A total of eight
ablations were performed in each vessel, except for one artery
in one patient in which the basket could not be engaged due
to the very steep take-off of the right renal artery.
All patients were discharged home the following day. All
patients were followed according to a dedicated follow-up
protocol including office visits at 1, 3 and 6 months, office
blood pressure measurement at each time point and
ambulatory blood measurements at 3 and 6 months. Additionally,
a 12-lead ECG, blood and urine collections and a 6-month
assessment of renal artery patency using either CT or MR
angiography were done in all patients.
Patient demographics and baseline characteristics are
depicted in Table 1. Procedural characteristics in Table 2 and
clinical follow-up parameters in Table 3.
Patient 1 was a 76-year-old obese female with persistent
headaches, known atrial fibrillation and hypertension since
the age of 36. Due to repeated episodes of
life-threatening gastrointestinal bleeding coumadin was stopped and
replaced by aspirin. Secondary causes of hypertension
were excluded. With a mean office blood pressure of
207/93 mm Hg (24 h ambulatory blood pressure monitoring
155/75 mm Hg) despite the use of three antihypertensive
drugs, she underwent a first RDN using the ReCor
Paradise system. After an uneventful recovery her blood
pressure remained uncontrolled and she suffered from an
ischaemic stroke. One year after the initial treatment,
office blood pressures remained 193/93 mm Hg and given
her clearly hypertension-related comorbidities, a second
procedure combining a redo RDN procedure and a
percutaneous left atrial appendage closure was performed.
Due to the very steep take-off of her right renal artery
only a left-sided ablation could be performed successfully.
After a successful recovery, office blood pressures
significantly dropped to 131/75 mm Hg (ambulatory 129/73 at
3 months, 157/79 mm Hg at 6 months and 110/64 mm Hg
at 12 months). The headaches resolved and renal
function increased from 56 ml/min at baseline to 61 ml/min at
Patient 2 was a 59-year-old Caucasian male with
persistent headaches and a 40-year history of hypertension
for which he received six antihypertensive drugs. Renal
function was preserved. With a mean office blood
pressure of 165/100 mm Hg and a 24 h ambulatory blood
pressure of 161/109 mm Hg he underwent a successful bilateral
RDN procedure using the Vessix V2 RDN system after
secondary causes of hypertension were excluded. One year
after the initial procedure his clinical condition remained
stable with no improvement in blood pressure control. Both
office and ambulatory blood pressure remained unchanged
(office mean 173/115 mm Hg, ambulatory 161/107 mm Hg)
despite a stable medication regimen. Given his persistent
headaches and persistent refractory hypertension, a redo
denervation was scheduled. After intensive follow-up at
1, 3 and 6 months, ambulatory blood pressures started to
decrease slightly to 159/110 at 3 months and 152/103 at
6 months, while office blood pressure remained stable.
Patient 3 was a 60-year-old Caucasian male with a
history of insulin-dependent diabetes, hypercholesterolaemia
and hypertension of more than 10 years. The patient was
a heavy smoker (over 20 pack-years). Despite two
percutaneous coronary interventions, the patient suffered from
stable angina CCS Class II and severe fatigue. Both renal
and cardiac functions were preserved. The patient was on
six antihypertensive drugs and was referred for RDN with
an office and ambulatory blood pressure of 184/103 mm Hg
and 162/98 mm Hg, respectively. One year after a
successful bilateral RDN using the Covidien OneShot system,
blood pressures remained unchanged and angina worsened
to class III. Given his extensive number of comorbidities,
persistent grade III hypertension with a mean office blood
pressure of 195/98 mm Hg (ambulatory 164/98 mm Hg),
a redo procedure was scheduled in combination with
a further coronary angiogram. After a successful bilateral
RDN using the EnligHTN system, the coronary angiogram
showed severe three-vessel disease. The patient was
discussed by the heart team and accepted for coronary artery
bypass surgery which was performed soon thereafter. The
patient recovered quickly and uneventfully. Along with
a significant reduction in both office and ambulatory blood
pressure to 165/99 mm Hg and 146/86 mm Hg his
symptoms of fatigue resolved and angina reduced to class I. The
number of antihypertensive drugs was reduced to two at
In the present case series, we report the outcome of three
consecutive patients with persistent grade III hypertension
despite an initial technically successful RDN procedure one
year previously, while still being on optimal medical
therapy. A second RDN procedure using the St. Jude EnligHTN
system proved to be safe in all patients with no
procedurerelated adverse events up to 6 months. Drops in ambulatory
systolic blood pressure ranged from 9 mm Hg in patient 2,
to 20 mm Hg in patient 3.
Uncontrolled hypertension is independently associated
with the incidence of stroke, coronary and peripheral artery
disease, heart failure, sudden death and renal insufficiency
[14, 15]. Conversely, only a small proportion of
hypertensive patients have elevated blood pressure alone; the
majority also suffer from additional cardiovascular risk
factors. Furthermore, the presence of hypertension and other
cardiovascular risk factors may potentiate one another,
resulting in an exponentially elevated risk for future adverse
events . The latter is reflected by the patients presented
in this case series, in which persistently uncontrolled blood
pressure might have contributed to their comorbidities and
adverse events. Despite extensive follow-up at a tertiary
referral centre, where secondary causes of hypertension were
excluded in all patients and drug regimens were improved,
blood pressure levels remained unacceptably high. This
illustrates the need for more effective antihypertensive
therapies in patients with drug-resistant hypertension. Over the
past years, a wide variety of invasive and non-invasive
treatment options with the intention to reduce sympathetic
nervous system activity and thereby improve blood pressure
control, have been evaluated [16, 17]. Of these,
percutaneous RDN is currently the most widely studied option
with studies reporting 24 h ambulatory systolic blood
pressure reduction in the range of 2 to 16 mm Hg [4, 18, 19].
However, individual treatment response varied extensively
from unchanged hypertension and thus non-responsiveness,
to frank hypotension and the need to taper pharmacological
antihypertensive treatment. The frequency of non-responder
rates reportedly varies between 15 and 30% where the
definition of a lack in decrease in office systolic blood pressure
>10 mm Hg was used [9, 20, 21].
Despite the growing body of evidence supporting the
potential additional value of renal sympathetic denervation
in patients with therapy-resistant hypertension, responders
have not been clearly identified yet. The hypothesis of the
present study was to test if a second denervation using the
multi-electrode EnligHTN system could lead to a higher
degree of sympathetic nerve damage and subsequently lead
to a higher level of blood pressure reduction as a surrogate
endpoint. Two previous studies have evaluated the
effectiveness of a second denervation procedure. A case report by
Lambert et al. reported on a 79-year-old hypertensive
patient who experienced a drop of 40 mm Hg in systolic
officebased blood systolic blood pressure 6 months after an
initial procedure using the Medtronic Symplicity system .
With the blood pressure back to baseline levels at 1-year
after the procedure the decision was made to perform a redo
procedure using the same device. Three months later, office
systolic blood pressure levels were again 40 mm Hg lower.
This case suggests that the redo denervation procedure had
a positive effect, but also illustrates the high variability of
office blood pressure thus precluding any firm conclusions.
A second study evaluated the safety and effectiveness of
cryoablation in ten RDN non-responders . The study
reported an impressive reduction in both mean systolic
office blood pressures as well as ambulatory blood pressure
of 61 mm Hg and 52 mm Hg, respectively, at 12 months.
In the Symplicity HTN-I study, a mean reduction in renal
norepinephrine spillover of 47% was reported. However, the
95% confidence interval ranged from 28 to 65% . The
hypothesis that this first generation device was potentially
not as technically efficacious as initially hypothesised was
soon confirmed by interesting post-mortem work by Vink
et al. . In a patient who died 12 days after an RDN
procedure, the authors demonstrated a dome-shaped
distribution field with limited penetration leaving a large part of
the nerves in periadventitial areas unaffected. The authors
concluded that it was unlikely that RDN using the first
generation Symplicity device would result in complete
interruption of the continuity of all adventitial nerve bundles
around the renal arteries. As a consequence, several new
devices quickly appeared on the market with data showing
substantially higher degrees of periadventitial nerve
damage along with higher drops in norepinephrine levels [5, 6].
Remarkably, non-responder rates did not clearly improve,
suggesting that specific patient-related factors might also
account for part of the non-response. The fact that the redo
procedure was effective in all three patients in the present
study creates a new dilemma since all of them were treated
with second-generation devices. On the other hand, it
suggests that a redo procedure could be an option for all
nonresponders ? at least for now.
To the best of our knowledge this is the first report of
the potential performance of a redo RDN procedure using
the EnligHTN RDN system in three patients with persistent
refractory hypertension. Despite their rather distinct
baseline characteristics and risk profile, the redo procedure
significantly helped in improving blood pressure control and
physical condition in two patients and modestly reduced
blood pressure in one patient. Given the lack of validated
alternative treatment options in these high-risk patients, we
believe that a redo RDN using the EnligHTN system can be
a safe and effective option to improve blood pressure and
potentially reduce future adverse cardiovascular events.
The present study was limited by the small number of
patients with extensive comorbidities. Two of the three
patients received additional treatment in combination with the
redo denervation procedure. However, it is unlikely that the
left atrial appendage closure and/or coronary artery bypass
surgery led to the significant blood pressure reductions
observed in both patients with a 20-year history of
hypertension. Finally, we cannot confirm that the redo procedure
might have had a similar effect if devices other than the
EnligHTN system had been used.
Redo RDN using the EnligHTN system may be a safe and
effective option to improve blood pressure control in
patients with persistent therapy-resistant hypertension after
the initial RDN procedure.
Conflict of interest J. Daemen receives institutional research support
from Boston Scientific, St. Jude Medical, Medtronic, ReCor Medical.
N.M. Van Mieghem receives institutional research support from ReCor
Medical. L. Feyz and L. Van Zandvoort declare that they have no
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