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Renal Denervation Lowers Blood
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Pressure inSham Controlled Studies:
Meta-Analysis
VasiliosPapademetriou, FotisTatakis, PanagiotisTsious,
andKonstantinosTsious
5
Introduction
Uncontrolled hypertension is considered as one of the most
important cardiovascular risk factors [1–4]. Despite the existence of a great variety of antihypertensive regimens, treatment and control of hypertension remains low globally [5,
6]. Poor compliance, medication intolerance and socioeco-
nomic reasons are some of the factors that undoubtedly contribute to an inadequate control of hypertension.
The key role of the sympathetic nervous system in modulating the pathophysiology of arterial hypertension has long
been recognized and for many years research has focused in
confronting its consequences [7, 8]. It is widely known that
radical surgical sympathectomy applied years ago, was very
successful in controlling severe or malignant hypertension,
resulting in marked improvement or even cure of patients
with advanced or terminal end organ damage due to uncontrolled hypertension. Surgical renal denervation was tried in
a limited number of patients with mixed results [9–13].
Recently, catheter based techniques using mainly
radiofrequency or thermal energy brought to light the concept of renal denervation (RDN) as a viable therapeutic
option in cardiovascular medicine. During the last decade,
several single arm studies have shown signicant reduction in blood pressure among patients with uncontrolled
hypertension [14–16]. Although the early proof of concept studies showed a surprisingly great blood pressure
reduction with renal denervation, the largest sham-con-
V. Papademetriou
Georgetown University and VA Medical Center,
Washington, DC, USA
F. Tatakis · P. Tsious
First Cardiology Clinic, Hippokration Hospital, National and
Kapodistrian University, Athens, Greece
K. Tsious (*)
Georgetown University and VA Medical Center,
Washington, DC, USA
First Cardiology Clinic, Hippokration Hospital, National and
Kapodistrian University, Athens, Greece
trolled study (SYMPLICITY HTN-3) failed to conrm
similar ndings [17].
The negative results of Simplicity HTN-3 have been attributed to several parameters that include: poor drug adherence,
inhomogeneity of patient population, carry over diuretic effect
and other factors to name a few [18–22]. However, it has also
been discussed that incomplete renal denervation due to the
catheter design, operator inexperience and learning curve have
signicantly inuenced the outcomes observed through the
abovementioned trial [18–24]. Since then, both basic and clinical research took place and results have been taken into consideration in the careful design of modern devices and
procedures used in the renal denervation era. Thus, in this
chapter we present a systematic review and meta-analysis,
which examine results of sham- controlled studies using especially modern technologies and procedures.
Meta-Analysis inRenal Denervation Era
The meta-analysis included six sham-controlled studies that
used radiofrequency or ultrasound-based devices to achieve
successful renal denervation. Of the aforementioned studies,
three used the single tip catheter (Flex, Medtronic) and
placed lesions in the main renal artery (rst generation studies) [17, 25, 26]. The other three studies, utilized either the
multi-electrode Spyral catheter (Medtronic) and placed
lesions at the distal segment of the renal artery and into the
branches, or focused ultrasound (ReCor) that can deliver
thermal energy deeper into the adventitia of the main renal
artery, resulting in a greater sympathetic ber interruption
(second generation studies) [27–30].
Results
Overall, six randomized, sham-controlled studies were
incorporated in the present meta-analysis [17, 25–30]. Of
those three trials used the rst generation radiofrequency
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_5
47
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V. Papademetriou et al.
renal denervation device and technique and the other three
used second generation devices and techniques. Thus, this
meta-analysis rst analyzed all sham controlled studies
together and then subgrouped studies into rst and second
generation devices.
In total, 981 patients with hypertension were randomized
in all six trials to undergo renal denervation (n= 585) or
sham-procedure (n = 396). Baseline demographics, blood
pressure measurements, other factors and clinical characteristics of the participants are presented in Table5.1 at the end
of the present chapter.
Ambulatory Blood Pressure Monitoring
The primary end-point of these studies was change in systolic ABP.In total, compared to sham control (Fig.5.1), renal
denervation resulted in −3.62 mmHg (95% CI: −5.28 to
−1.96; I2=0%) greater reduction of 24-h systolic ambula-
tory blood pressure (ABP). In addition, renal denervation
resulted in a mean reduction of 24-h diastolic ABP by
−1.92mmHg (95% CI: −3.65 to −0.20; I2=46%) in com-
parison with the sham procedure (Fig.5.2).
Daytime andNighttime Ambulatory Blood
Pressure Monitoring
Furthermore, renal denervation decreased daytime systolic
ambulatory blood pressure by −5.51mmHg (95% CI: −7.79 to
−3.23; I2=0%) (Fig.5.3) and nighttime systolic ambulatory
blood pressure by a non-signicant −3.06 mmHg (95% CI:
−8.69 to 2.56; I2=73%), both compared to sham (Fig.5.4).
Further analysis revealed that renal denervation has signicantly reduced daytime diastolic ambulatory blood pressure level by −1.90 mmHg (95% CI: −3.48 to −0.32;
I2=4%), but failed to bring about a signicant decrease in
the nighttime diastolic ambulatory blood pressure
(−0.80mmHg; 95% CI: −3.61 to 2.02; I2=57%) in comparison with sham procedure.
Thus, although renal denervation was associated with a signicant decrease in both systolic and diastolic daytime ambulatory blood pressure, it did not consistently cause a substantial
reduction in nighttime ambulatory blood pressure levels.
Oce Blood Pressure
Results reveal that renal denervation induced a signicant
reduction in ofce systolic blood pressure level by
−5.47mmHg (95% CI −8.10 to −2.84; I2=0%), compared
to sham procedure (Fig.5.5). Diastolic ofce blood pressure
also decreased by −4.25mmHg (95% CI −6.16 to −2.33;
I2=0%), compared to sham procedure (Fig.5.6).
First andSecond Generation ofRenal
Denervation Devices andTechniques
A separate analysis of ambulatory blood pressure results
based on use of rst or second generation devices of renal
denervation is presented in Figs.5.7 and 5.8.
As shown in Figs.5.7 and 5.8, studies that used rst generation devices [17, 25, 26] failed to show any signicant
decrease in systolic (−2.23 mmHg; 95% CI: −4.70 to 0.24)
or diastolic (−0.18; 95% CI: −2.34 to 1.98) ambulatory
blood pressure. In contrast studies that used second generation devices [27–29] resulted in a signicant decrease of
both systolic and diastolic ambulatory blood pressure by
−4.76mmHg (95% CI: −7.00 to −2.52) and −2.94 mmHg
(95% CI: −5.01 to −0.87), respectively.
Blood Pressure Lowering Eect
ofSham-Procedure
The meta-analysis also evaluated the effect of shamprocedure on 24-h systolic and diastolic ambulatory
blood pressure levels among the second-generation trials. Thus, it was reported that sham procedure resulted in
a non- significant change in 24-h systolic ambulatory
blood pressure levels (MD: −1.15, 95% CI: −2.67–0.36,
I2= 0%), while it brought about a significant reduction
in 24-h diastolic ambulatory blood pressure by
1.52mmHg (95% CI: −2.53- −0.51, I2=0%). Moreover,
studies demonstrated a significant decrease in systolic
office blood pressure by 3.05mm Hg (95% CI: −5.30-
−0.81, I2=0%) and a non-significant reduction in dia-
stolic office blood pressure by 0.65mm Hg (95% CI:
−2.03 to 0.73, I2=0%).
5 Renal Denervation Lowers Blood Pressure inSham Controlled Studies: Meta-Analysis
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RADIANCE-HTN SOLO
[28]
Untreated Hypertension
SPYRAL HTN-ON MED
[27]
on drugs
49
SPYRAL HTN-OFF MED
[26]
Resistant Hypertension Untreated Hypertension Uncontrolled Hypertension
SYMPLICITY HTN-3
[15] ReSET [16] Desch etal [17]
SymplicitySpyral and G3 SymplicitySpyral and G3 Paradise System
Symplicity Flex
Catheter
Hypertension
Catheter
73/69.6 97/97 100/100 26.3/23.8* 34/35* 81/72
NR 71±10/70±11 67±11/68±12 72.3±10.9/75.5±11.5 75.5±11.4/76.2±10.2 72±12.1/72.6±12.3**
159.1±13.2/88±14 152±12/91±9 140.2±4.6/78.2±7.4 153.4±9/99.1±7.7 151.9±7.1/96.9±6.9 142.6±8.1/87.3±5
159.5±15.3/90.9±14.4 153±13/89±11 140.4±5.6/80.6±7.1 151.6±7.4/98.7±8.2 151.1±6.8/97.6±8.3 143.8±10.4
) 34.2±6.5/33.9±6.4 28.2±5/28.8±3.9 31.9±4.4/31.2±4.6 29.8±5.1/30.2±5.1 31.4±6.4/32.5±4.6 29.9±5.9/29±5
2
NR 161.4±6.4/101.5±7.5 163.1±7.2/102.3±8 153.6±15.7/99.1±9.4
NR 159±12/96±9 144.4±4.8/80.6±7.8 NR 156.4±8.1/101±7.1 150.3±7.8/93.1±4.8
NR 159±14/93±12 143±4.7/82.9±7.3 NR 157.4±8.4/102.7±9.3 150±9.8/93.5±5.5
NR 136±17/79±11 130.5±9.7/69.7±8 NR 144.9±11/90.5±10.6 130.3±11.9/78.2±8
72.8±15.7/74±18.7 NR 79±20/84±20 80.9±16.7/88.3±20.5 81.9±15.3/82±19.7 84.7±16.2/83.2±16.1
NR 141±18/80±10 132.3±11.7/73.2±8.4 NR 141±8.5/89.5±8.9 132.5±13.7/80±8.1
5.1±1.4/5.2±1.4 4.1±1.2/4.1±1.1 4.4±1.3/4.3±1.3 0/0 2.2±0.9/2.3±0.8 0/0
Study
N (RDN) 535 (364) 69 (36) 71 (35) 80 (38) 80 (38) 146 (74)
Table 5.1 Baseline characteristics of study participants in the 6 sham-controlled studies included in this meta-analysis (Stavropoulos etal. 2020)
Condition Resistant Hypertension Resistant
Energy source Radiofrequency Radiofrequency Radiofrequency Radiofrequency Radiofrequency Ultrasound
Device Symplicity Flex Catheter Symplicity Flex
Follow-up (months) 6 3 6 3 6 2
Age RDN/sham (years) 57.9±10.4/56.2±11.2 54.3±7.8/57.1±9.6 64.5±7.6/57.4±8.6 55.8±10.1/52.8±11.5 53.9±8.7/53±10.7 54.4±10.2/53.8±10
Female RDN/sham (%) 40.9/35.7 25/23 23/31 31.6/26.2 13/19 38/46
Caucasians RDN/sham
(%)
Smokers RDN/sham (%) 9.9/12.3 19/15 17/11 10.5/23.8 21/26 NR
BMI RDN/sham (kg/m
Heart Rate RDN/sham
(beats/min)
RDN 24h ABPM
(mmHg)
sham 24h ABPM
(mmHg)
RDN OBP (mmHg) 179.7±16.1/96.5±16.6 160±20/95±15 NR 162±7.6/99.9±6.8 164.6±7.1/99.6±6.9 154.5±12.4/99.7
sham OBP (mmHg) 180.2±16.8/98.9±15.8 166±19/90±17
RDN HBP (mmHg) 169±15.9/89.6±15.9 NR NR NR NR 147.5±8.8/94.8±6.9
sham HBP (mmHg) 169.1±16.3/92.9±16.4 NR NR NR NR 147.7±12.3/94.6±7
RDN daytime ABPM
(mmHg)
sham daytime ABPM
(mmHg)
RDN nighttime ABPM
2
(mmHg)
sham nighttime ABPM
(mmHg)
eGFR RDN/sham (ml/
)
ISH RDN/sham (%) NR NR 66/56 0/0 0/0 0/0
Diabetes RDN/sham (%) 47/40.9 25/31 54/36 2.6/7.1 13/19 3/7
min/1.73m
Antihypertensive agents
RDN/sham (n)
*Not reported in more than 40% of study participants
**Values prior to the washout-not baseline
50
RDN Sham Mean Difference
Mean Difference
Favours RDN Favours Sham
RDN
Sham
Mean Difference
Mean Difference
Favours RDN Favours Sham
1
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V. Papademetriou et al.
Study or Subgroup Mean
Azizi 2018
Bhatt 2014
Desch 2015
Kandzari 2018
Mathiassen 2016
Townsend 2017
Total (95% CI)
Heterogeneity: Tau
Test for overall effect: Z = 4.29 (P < 0.0001)
-6.75
2
= 0.00; Chi2 = 4.00, df = 5 (P = 0.55); I2 = 0%
SD Total Mean SD To talWeight IV, Random, 95% CI
-7
-7
-9
-3.7
-5.3
15.11 329
10.97
16.4
9.82
74
8.6
32
11
36
35
36
542 376 100.0% -3.62 [-5.28, -1.96]
-3.1
-4.79
-3.5
-1.6
-2.6
-0.7
9.7
17.25
9.81
10.7
12.8
9.95
72
162
35
36
35
36
31.0%
28.2%
11.0%
10.9%
13.2%
-3.90 [-6.88, -0.92]
-1.96 [-5.08, 1.16]
-3.50 [-8.50, 1.50]
-7.40 [-12.41, -2.36]
-1.10 [-7.99, 5.79]
5.8%
-4.60 [-9.17, -0.03]
IV, Random, 95% CI
-10
-5
0
5
10
Fig. 5.1 Effect of renal denervation on 24-h systolic ambulatory blood pressure monitoring compared to sham-procedure (Reproduced from
Stavropoulos etal. 2020, [30])
Total Mean SD Total
Study or Subgroup Mean
Azizi 2018
Desch 2015
Kandzari 2018
Mathiassen 2016
Townsend 2017
-4.4
-2.8
-1.7
-4.8 5.95
SD
5.8
74 72
-3
6.1
5.63
32
-2.1
5.34
-6
7.4
36
-1.9
8.2
8.6
35 35
-2.6
7.5
34
-0.5
5.97
Weight IV, Random, 95% CI
28.5%
35
21.8%
36
15.1%
14.1%
20.5%
36
IV, Random, 95% CI
-1.40 [-3.33, 0.53]
-0.70 [-3.33, 1.93
-4.10 [-7.71, -0.49
0.90 [-2.88, 4.68]
-4.30 [-7.09, -1.51]
]
]
Total (95% CI)
2
Heterogeneity. Tau
Test for overall effect: Z = 2.19 (P = 0.03)
= 1.74; Chi2 = 7.42, df = 4(P = 0.12); I2 = 46%
211
214 100.0% -1.92 [-3.65, -0.20]
-10 10-5 50
Fig. 5.2 Effect of renal denervation on 24-h diastolic ambulatory blood pressure monitoring compared to sham-procedure (Reproduced from
Stavropoulos etal. 2020, [30])
RDN Sham
Study or Subgroup Mean
Azizi 2018
Desch 2015
Kandzari 2018
Mathiassen 2016
Total (95% CI)
2
Heterogeneity: Tau
= 0.00; Chi2 = 1.12, df = 3 (P = 0.77); I2 = 0%
SD TotalMeanSDTotal Weight
74
9.3
-8.5
11.3
18.9
32
36
35
-8.5
-8.8
-6.1
11.11
177
Test for overall effect: Z = 4.73 (P < 0.00001)
-2.2
-3.7
-3.2
-4.3
10
10.11
11.4
15.17233
Mean Difference
IV, Random, 95% CI
53.1%
35
20.0%
36
19.0%
100.0% -5.51 [-7.79, -3.23]
176
-6.30 [-9.43, -3.17]
-4.80 [-9.90, 0.30]
-5.60 [-10.84, -0.36]
7.9%
-1.80 [-9.91, 6.31]
Mean Difference
IV, Random, 95% CI
-1
0 0-5 50
Favours RDN Favours sham
Fig. 5.3 Effect of renal denervation on daytime systolic ambulatory blood pressure monitoring compared to sham-procedure (Reproduced from
Stavropoulos etal. 2020, [30])
RDN Sham
Mean Difference
Mean Difference
Favours RDN Favours Sham
RDN
Sham
Favours RDN Favours sham
RDN Sham
Mean Difference
Mean Difference
Favours RDN Favours Sham
5 Renal Denervation Lowers Blood Pressure inSham Controlled Studies: Meta-Analysis
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51
Study or Subgroup Mean
Azizi 2018
Desch 2015
Kandzari 2018
Mathiassen 2016
Total (95% CI)
Heterogeneity: Tau
Test for overall effect: Z = 1.07 (P = 0.29)
-4.8 11 .7 74 -3.1 11.5 71
-1.9
-9.8
-1.4
2
= 23.35; Chi2 =10.96, df = 3 (P = 0.01); I2=73%
SD To tal Mean SD To talWeight
14.29
13.9
18.2
178
32
37
35
-3.8
2.1
-1.1
13.5
14.4
3512.98
38
33
177 100.0%
IV, Random, 95% CI
30.4%
23.8%
24.7%
21.1%
-1.70 [-5.48, 2.08]
-1.90 [-4.66, 8.46]
-11.90 [-18.10, -5.70]
-0.30 [-8.08, 7.48]
-3.06 [-8.69, 2.56]
IV, Random, 95% CI
-10 10-5 50
Fig. 5.4 Effect of renal denervation on nighttime systolic ambulatory blood pressure monitoring compared to sham-procedure (Reproduced from
Stavropoulos etal. 2020, [30])
Study or Subgroup Mean
Azizi 2018
Bhatt 2014
Kandzari 2018
Townsend 2017
Total (95% CI)
Heterogeneity: Tau
Test for overall effect: Z = 4.08 (P < 0.0001)
-10.8
-14.13
2
= .00; Chi2 = 2.54, df = 3 (P = 0.47); I2 = 0%
SD Total Mean SD To talWeight
-9.4
-9.7
13.6
23.93
12.5
13.66
74
353
38
37
502
-3.9
-11.74
-2.6
-2.5
17.4 72 26.9%
171
25.94
12.9
13.56
32.4%
40
21.8%
41
18.9%
324 100.0%
Mean Difference
IV, Random, 95% CI
-6.90 [-11.97,-1.83]
-2.39 [-7.01, 2.23]
-6.80 [-12.44, -1.16]
-7.20 [-13.25, -1.15]
-5.47 [-8.10, -2.84]
Mean Difference
IV, Random, 95% CI
-10
-5
0
10
5
Fig. 5.5 Effect of renal denervation on systolic ofce blood pressure compared to sham-procedure (Reproduced from Stavropoulos etal. 2020,
[30])
Study or Subgroup Mean
Azizi 2018
Kandzari 2018
Townsend 2017
Total (95% CI)
2
Heterogeneity. Tau
= 0.00; Chi2 = 0.35, df = 2 (P = 0.84); I2 = 0%
Test for overall effect: Z = 4.35 (P = 0.0001)
SD To talMean SD To talWeight IV, Random, 95% CI
-5.5 8.474-1.21072
-5.2
-5.3
7.6
8.07
33
37
-1.7
-0.3
8.17
407.9
149 15341100.0%
IV, Random, 95% CI
40.8%
31.0%
28.2%
-3.50 [-6.94, -0.06)
-5.00 [-8.61, -1.39]
-4.30 [-7.30,-1.30]
-4.25 [-6.16, 2.33]
-10
-5
0
10
5
Fig. 5.6 Effect of renal denervation on diastolic ofce blood pressure compared to sham-procedure (Reproduced from Stavropoulos etal. 2020,
[30])
52
RDN
Sham
Mean Difference
Mean Difference
Test for subgroup differences : Chi2 = 2.22, df =1 (P = 0.14), I2 = 55.0%
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V. Papademetriou et al.
Study or Subgroup Mean
1.1.1 Second generation trials
Azizi 2018
Kandzari 2018
Townsend 2017
Subtotal (95% CI)
2
Heterogeneity: Tau
Test for overall effect: Z = 4.17 (P = 0.0001)
1.1.2 First generation trials
Bhatt 2014
Desch 2015
Mathiassen 2016
Subtotal (95% CI)
Heterogeneity: Tau
Test for overall effect: Z = 1.77 (P = 0.08)
Total (95% CI)
Heterogeneity: Tau
Test for overall effect: Z = 4.27 (P < 0.0001)
= 0.00; Chi2 = 1.39, df =2 (P = 0.50); I2 = 0%
2
= 0.00; Chi2 = 0.38, df = 2 (P = 0.83); I2 = 0%
2
= 0.00; Chi2 = 3.99, df = 5 (P = 0.55); I2 = 0%
SD Total Mean SD To tal
-7
8.6
74
-9
11
9.82
16.4
36
34
144
329
32
35
396
-5.3
-6.75
-7
-3.7
15.11
10.97
Weight IV, Random, 95% CI
-3.1 9.7 72 31.1%
11.0%
36
10.7
-1.6
9.95-0.7
-4.76 17.25 162 28.3%
9.81
-3.5
12.8-2.6
12.8%
36
54.9%
144
11.0%
35
5.8%
35
45.1%
232
376540 100.0% -3.62 [-5.28, -1.96]
IV, Random, 95% CI
-3.90 [-6.88, -0.92]
-7.40 [-12.41, -2.39]
-4.60 [-9.23, 0.03]
-4.76 [-7.00, -2.52]
-1.96 [-5.08, 1.16]
-3.50 [-8.50, 1.50]
-1.10 [-7.99, 5.79]
-2.23 [-4.70, 024]
-10
-5
Favours RDN Favours Sham
0
10
5
Fig. 5.7 Effect of rst and second generation renal denervation devices, and overall effect on 24-h systolic ambulatory blood pressure monitoring
(Reproduced from Stavropoulos etal. 2020, [30])
Fig. 5.8 Effect of rst and second generation renal denervation devices, and overall effect on 24-h diastolic ambulatory blood pressure monitoring
(Reproduced from Stavropoulos etal. 2020, [30])
Renal Function
Overall renal denervation did not affect renal function.
There was a non-signicant decrease in estimated glomerular ltration rate by 0.24ml/min/1.73m2 (95% CI: −1.95
to 1.47; I2=0%), as compared to sham procedure (Fig.5.9).
Of note trials using novel renal denervation devices and
techniques, such as SPYRAL HTN-ON MED, the SPYRAL
HTN-OFF MED and the RADIANCE-HTN SOLO trials, did
not alter signicantly the observed results concerning the renal
function (mean difference= −0.02; 95% CI: −2.64 to 2.62;
I2=0%), as shown in Fig.5.10. All studies reported the effect
of renal denervation or sham procedure on renal function
according to the Modication of Diet in Renal Disease
(MDRD) formula. In conclusion, there was no difference in
renal function comparing renal denervation to sham procedure
(mean difference=0.00; 95% CI: −0.02 to 0.02; I2=0%), as
shown in Fig.5.11.
RDN Sham
Mean Difference
Mean Difference
Favours RDN Favours Sham
RDN Sham
Mean Difference
Mean Difference
Favours RDN Favours Sham
5 Renal Denervation Lowers Blood Pressure inSham Controlled Studies: Meta-Analysis
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53
Study or Subgroup Mean
Azizi 2018
Bhatt 2014
Kandzari 2018
Townsend 2017
Total (95% CI)
Heterogeneity: Tau2 = 0.00; Chi2 = 0.53, df = 3 (P = 0.91); I2 = 0%
Test for overall effect: Z = 0.27 (P = 0.78)
-2.12
-1.34
SD Total Mean SD To tal
1.3
13.1
73
364
12.91
8.19
38
2.19
11.13
37
512 321 100.0% -0.24 [-1.95, 1.47]
2.4
-17.2
-1.87
1.11
11.7
12.14
11.5
13.42
Weight IV, Random, 95% CI
69
171
40
41
IV, Random, 95% CI
17.5%-1.10 [-5.18, 2.98]
57.6%
15.0%
9.8%
-4.40 [-2.65,1.85]
0.53 [-3.88,4.94]
1.08 [-4.37,6.53]
-10
-5
0
5
10
Fig. 5.9 Effect of renal denervation on renal function, as assessed by the estimated glomerular ltration rate compared to sham-procedure
(Reproduced from Stavropoulos etal. 2020, [30])
Study or Subgroup Mean
Azizi 2018
Kandzari 2018
Townsend 2017
Total (95% CI)
Heterogeneity: Tau
Test for overall effect: Z = 0.01 (P = 0.99)
-1.34
2
= 0.00; Chi2 = 0.49, df = 2 (P = 0.78); I
SD To tal Mean SD To tal
1.3 13.1 73 2.4 11.7 69
-1-87
38
8.19
13.42
1.11
11.13
2.19 41
37
148 150 100.0% -0.02 [-2.64, 2.61]
4011-5
2
Weight IV, Random, 95% CI
41.4%
35.4%
23.2%
= 0%
IV, Random, 95% CI
-1.10 [-5.18, 2.98]
0.53 [-3.88, 4.94]
-1.08 [-4.37, 6.53
]
-10
-5
0
5
10
Fig. 5.10 Effect of renal denervation on renal function, as assessed by the estimated glomerular ltration rate compared to sham-procedure,
across the second generation renal denervation studies (Reproduced from Stavropoulos etal. 2020, [30])
Fig. 5.11 Effect of renal denervation on serum creatinine levels, compared to sham-procedure (Reproduced from Stavropoulos etal. 2020, [30])
Major Adverse Events
occurred several weeks after the implementation of the shamprocedure, thus, they were not attributed to the procedure.
No major adverse events were reported (all-cause death,
major cardiovascular events, peri-procedural complications,
signicant renal impairment or hypotensive/hypertensive
crisis) in the active arm of any of the sham controlled trials
(SPYRAL HTN-ON MED, the SPYRAL HTN-OFF MED
and the RADIANCE-HTN SOLO) [27–29].
One case of stroke and one case of unstable angina requiring percutaneous coronary intervention were reported in the
sham group in the ReSET trial [25]; despite both events
In the SYMPLICITY HTN-3 trial, which is the largest sham
controlled study [17], no signicant difference was reported
between the two treatment groups, regarding the incidence of
the primary safety endpoint (a composite of major adverse
events, dened as death from any cause, end- stage renal disease, an embolic event resulting in end-organ damage, renalartery or other vascular complications, or hypertensive crisis
within 30 days or new renal-artery stenosis of more than 70%
within 6 months) and the major adverse cardiovascular events.
54
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V. Papademetriou et al.
Discussion
Results of this meta-analysis demonstrate that renal denervation results in a statistically signicant and clinically meaningful decrease in ambulatory and ofce blood pressure and
it is free of severe or clinically important side effects. The
procedure, therefore, meets the FDA requirements of being
“safe and effective” for the treatment of uncontrolled
hypertension. Data indicate that the procedure is safe and
effective not only in patients with treated, uncontrolled
hypertension, but also in treatment naïve patients as shown in
the landmark SPYRAL HTN-OFF MED Pivotal trial [31].
Data were extracted from six sham-controlled randomized studies that enrolled a total of 981patients with uncontrolled hypertension [30]. The most important nding of this
meta-analysis is the demonstrated efcacy of the second
generation RDN devices, and the lack of efcacy of the rst
generation devices. Studies utilizing second generation
devices revealed a decrease in ambulatory blood pressure of
−4.8 (95% CI: −7 to −2.5)/−2.9 (95% CI: −5 to −0.9)mmHg,
whereas the change in ambulatory or ofce blood pressure
with the rst generation devices/studies did not achieve statistical signicance. Thus, it is reasonable to assume that the
rst generation studies achieved quantitatively “less” renal
denervation as compared to second generation devices/studies. This can be explained from the following reasons: (a) the
rst generation studies used a single-tip radiofrequency catheter with which it is difcult to achieve circumferential
denervation, (b) fewer lesion were placed in the main renal
artery, and (c) lesions were placed randomly in the main
renal artery in areas where only some of the sympathetic
bers were reachable [30]. On the other hand, the second
generation devices/studies utilized multi-electrode catheters
and placed lesions in the distal segments of the renal arteries
and into the branches, where bers are closer to the lumen,
and easier to reach. Focus ultrasound may succeed in better
denervation, as it can penetrate deeper than radiofrequency
energy [30, 32].
In contrast to actual renal denervation, the sham- procedure
was not associated with any signicant decrease in blood
pressure in any of the second-generation renal denervation
studies, whereas the results from SYMPLICITY HTN-3
revealed a substantial and statistically signicant shameffect. This can be explained by the better screening at baseline and conscious attempt to avoid the un-intended BP
exacerbation effect. Moreover, results indicate that procedures are safe in both the rst- and second-generation studies
without any major procedural events and no evidence of
deterioration in renal function.
Another important nding conrmed in this analysis is
the relatively small difference between the change in ofce
and ambulatory systolic blood pressure achieved with renal
denervation (5.5 vs. 4.6mmHg). Previous uncontrolled sin-
gle arm studies indicated a much larger difference in the
magnitude of 20–25mmHg. Smaller difference is more realistic and more in line with numerous older drug treatment
hypertension trials [33]. In this meta-analysis we found a
non-signicant decrease in nighttime systolic blood pressure. This could be attributed to existing high heterogeneity.
Other recent studies documented signicant decrease in
nighttime systolic blood pressure. A secondary analysis of
RADIANCE HTN-SOLO trial in which participants could
be started on antihypertensive therapy after entry into the
resulted in a signicantly greater reduction in nighttime systolic ambulatory blood pressure compared to sham procedure [34]. Furthermore, the SPYRAL HTN-ON MED trial
revealed that renal denervation resulted in a signicant
decrease in nighttime systolic blood pressure as compared to
sham (–11.90mmHg, 95% CI: −18.2 to −5.6mmHg) [28,
30, 35].
Nevertheless, this analysis has also important limitations:
The small total number of included randomized controlled
trials (n=6), the relatively limited sample size (n=981), the
short follow-up period (up to 6 months) and the absence of
cross-over trials, may be considered as the main limitations.
Nonetheless, results of this analysis represent the rst
solid evidence that renal denervation works and it is safe.
This data provide license for research to continue and more
and larger studies to be carried out. Renal denervation is
alive and well and further studies will re-enforce its importance in the treatment and control of hypertension.
Conclusion
Overall, data from this meta-analysis demonstrate in a convincing way that renal denervation works. Data were derived
from rigorously designed and meticulously conducted sham
control trials. Sufces to say that these are the rst studies to
have ever shown and prove in a scientic way that RDN
decreases BP in patients with uncontrolled hypertension.
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Endpoints forClinical Effects ofRenal
https://t.me/medicina_free
Denervation: What Is theBest
Surrogate?
KevinA.Friede, MaratFudim, andPaulA.Sobotka
6
Introduction
In the past several years, renal denervation (RDN) has proven
to be an effective treatment for resistant hypertension (HTN).
As accumulating evidence suggests that RDN also benets
other conditions including heart failure (HF), atrial brillation, and insulin resistance, it is likely that RDN may, in the
near future, be frequently employed for several common
indications.
Unfortunately, the procedure does not always result in
lower blood pressures (BPs) and many patients continue to
need antihypertensive medications. There are several
potential explanations for this persistent elevation of BP
after RDN; notably, incomplete ablation of the renal nerves
or a cause other than increased sympathetic nerve activity
(SNA) as the cause of resistant HTN in an individual
patient. Mapping of the renal nerves may enable selective
ablation of sympatho-stimulatory bers while avoiding
ablation of sympatho- inhibitory bers, which would
decrease the rate of futile ablation and lower the risk of
ablation-related complications.
Because it is not sufcient to simply measure BP to
ascertain successful RDN, it is apparent that surrogate
measures of increased sympathetic activity are needed.
Identifying the contribution of renal SNA to the underlying hypertensive pathophysiology is critical, as it allows
K. A. Friede
Division of Cardiology, Duke University, Durham, NC, USA
Center for Applied Genomics & Precision Medicine, Duke
University, Durham, NC, USA
e-mail: kevin.friede@duke.edu
M. Fudim
Division of Cardiology, Duke University, Durham, NC, USA
Duke Clinical Research Institute, Durham, NC, USA
e-mail: marat.fudim@duke.edu
P. A. Sobotka (*)
Sensible Biotechnologies, Oxford, England
for better selection of patients in whom RDN is likely to
have clinical benet and provides for documentation of
technical (procedural) success. In addition, techniques for
measuring SNA allow for evaluation of patients in whom
there is late loss of clinical benet, to determine whether
nerve regrowth plays a role and whether repeat RDN might
be of benet.
In this chapter, we will discuss direct and indirect methods for assessing SNA in humans; how these methods can be
used as screening tools for selecting patients for RDN; how
they could be used to gauge technical success; and how each
method might be used in specic disease processes.
Anatomy andPhysiology oftheRenal Nerves
The autonomic nervous system works through complex integrated processes in the kidneys to maintain the body’s uid
volume, electrolyte composition, and vascular tone [1].
Communication between the kidneys and the central nervous
system (CNS) travels in a reex loop between afferent, efferent sympathetic, and efferent parasympathetic bers [2–6],
integrating input from several end-organ sensors and baroreceptors [7–9]. Of note, the kidney has its own intrinsic autoregulatory nervous system that operates without CNS input;
this is termed the reno-reex mechanism [10].
Renal sympathetic nerves originate at spinal segments
T11 to L3 and contain inputs from the thoracic and lumbar
splanchnic nerves, aortic plexus, and posterior vagal trunk
[6, 11]. The renal sympathetic nerves travel through the
adventitia of the renal arteries [12–14]; it is for this reason
that ablation of these nerves is possible via percutaneous
access to the renal arteries [15].
Of note, recent evidence suggests the composition and
physiology of renal afferent nerves may be more complex
than was initially believed. This may explain the heterogeneity of observed clinical trial results, and, in particular, the inter-individual variability in response on a
spectrum from good response to non-response and even
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_6
57
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