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3 Preclinical Model andHistopathology Translational Medicine andRenal Denervation
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35
(SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised,
sham-controlled trial. Lancet. 2020;27:30554–7.
18. Kandzari DE, Bohm M, Mahfoud F, etal. Effect of renal denervation on blood pressure in the presence of antihypertensive
drugs: 6-month efcacy and safety results from the SPYRAL
HTN-ON MED proof-of-concept randomised trial. Lancet.
2018;391:2346–55.
19. Azizi M, Schmieder RE, Mahfoud F et al. Six-month results of
treatment-blinded medication titration for hypertension control
following randomization to endovascular ultrasound renal denervation or a sham procedure in the RADIANCE-HTN SOLO trial.
Circulation. 2019.
20. Mulder J, Hokfelt T, Knuepfer MM, Kopp UC. Renal sensory and sympathetic nerves reinnervate the kidney in a similar
time- dependent fashion after renal denervation in rats. Am J Physiol
Regul Integr Comp Physiol. 2013;304:R675–82.
21. Nagasu H, Satoh M, Kuwabara A, etal. Renal denervation reduces
glomerular injury by suppressing NAD(P)H oxidase activity in
Dahl salt-sensitive rats. Nephrol Dial Transplant. 2010;25:2889–98.
22. Girchev R, Markova P, Vuchidolova V.Inuence of renal denervation on renal effects of acute nitric oxide and ETA/ETB receptor
inhibition in conscious normotensive rats. J Physiol Pharmacol.
2006;57:17–27.
23. Rippy MK, Zarins D, Barman NC, Wu A, Duncan KL, Zarins
CK. Catheter-based renal sympathetic denervation: chronic
preclinical evidence for renal artery safety. Clin Res Cardiol.
2011;100:1095–101.
24. Lerman LO, Schwartz RS, Grande JP, Sheedy PF, Romero
JC.Noninvasive evaluation of a novel swine model of renal artery
stenosis. J Am Soc Nephrol. 1999;10:1455–65.
25. Tellez A, Rousselle S, Palmieri T, etal. Renal artery nerve distribution and density in the porcine model: biologic implications for
the development of radiofrequency ablation therapies. Transl Res.
2013;162:381–9.
26. Atherton DS, Deep NL, Mendelsohn FO. Micro-anatomy of the
renal sympathetic nervous system: a human postmortem histologic
study. Clin Anat. 2012;25:628–33.
27. Sakakura K, Ladich E, Cheng Q, et al. Anatomic assessment of
sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol.
2014;64:635–43.
28. Sato Y, Kawakami R, Jinnouchi H etal. Comprehensive assessment
of human accessory renal artery peri-arterial renal sympathetic
nerve distribution. JACC;0.
29. Sakakura K, Ladich E, Edelman ER, et al. Methodological standardization for the pre-clinical evaluation of renal sympathetic
denervation. JACC Cardiovasc Interv. 2014;7:1184–93.
30. Virmani R, Avolio AP, Mergner WJ, etal. Effect of aging on aortic
morphology in populations with high and low prevalence of hypertension and atherosclerosis. Comparison between occidental and
Chinese communities. Am J Pathol. 1991;139:1119–29.
31. Whitney KM, Schwartz Sterman AJ, O'Connor J, Foley GL,
Garman RH. Light microscopic sciatic nerve changes in control
beagle dogs from toxicity studies. Toxicol Pathol. 2011;39:835–40.
32. Biberthaler P, Mussack T, Wiedemann E, et al. Evaluation of
S-100b as a specic marker for neuronal damage due to minor head
trauma. World J Surg. 2001;25:93–7.
33. Pace V, Perentes E, Germann PG. Pheochromocytomas and ganglioneuromas in the aging rats: morphological and immunohistochemical characterization. Toxicol Pathol. 2002;30:492–500.
34. Burgi K, Cavalleri MT, Alves AS, Britto LR, Antunes VR,
Michelini LC. Tyrosine hydroxylase immunoreactivity as indicator of sympathetic activity: simultaneous evaluation in different tissues of hypertensive rats. Am J Physiol Regul Integr Comp Physiol.
2011;300:R264–71.
35. Ammar S, Ladich E, Steigerwald K, Deisenhofer I, Joner
M. Pathophysiology of renal denervation procedures: from renal
nerve anatomy to procedural parameters. EuroIntervention. 2013;9
Suppl R:R89–95.
36. Wittkampf FH, Nakagawa H, Yamanashi WS, Imai S, Jackman
WM. Thermal latency in radiofrequency ablation. Circulation.
1996;93:1083–6.
37. Steigerwald K, Titova A, Malle C, etal. Morphological assessment
of renal arteries after radiofrequency catheter-based sympathetic
denervation in a porcine model. J Hypertens. 2012;30:2230–9.
38. Sakakura K, Tunev S, Yahagi K, et al. Comparison of histopathologic analysis following renal sympathetic denervation over multiple time points. Circ Cardiovasc Interv. 2015;8:e001813.
39. Kandzari DE, Böhm M, Mahfoud F, etal. Effect of renal denervation on blood pressure in the presence of antihypertensive
drugs: 6-month efcacy and safety results from the SPYRAL
HTN-ON MED proof-of-concept randomised trial. Lancet.
2018;391:2346–55.
40. Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based
renal denervation in patients with uncontrolled hypertension in
the absence of antihypertensive medications (SPYRAL HTN-OFF
MED): a randomised, sham-controlled, proof-of-concept trial.
Lancet. 2017;390:2160–70.
41. Mahfoud F, Mancia G, Schmieder R, et al. Renal denervation in high-risk patients with hypertension. J Am Coll Cardiol.
2020;75:2879–88.
42. Azizi M, Schmieder RE, Mahfoud F, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN
SOLO): a multicentre, international, single-blind, randomised,
sham- controlled trial. Lancet. 2018;391:2335–45.
43. Sakakura K, Roth A, Ladich E, et al. Controlled circumferential renal sympathetic denervation with preservation of the renal
arterial wall using intraluminal ultrasound: a next-generation
approach for treating sympathetic overactivity. EuroIntervention.
2015;10:1230–8.
44. Sato Y, Kawakami R, Jinnouchi H etal. Comprehensive assessment
of human accessory renal artery peri-arterial renal sympathetic
nerve distribution. JACC: Cardiovascular Interventions. 2020.
45. Sato Y, Kawakami R, Sakamoto A, et al. Paradise™ Ultrasound
renal denervation system for the treatment of hypertension. Future
Cardiol. 2021. https://doi.org/10.2217/fca- 2020- 0228
Appraisal ofRandomized
https://t.me/medicina_free
Sham- Controlled Trial Data onRenal
Denervation fortheManagement
ofHypertension
StefanC.Bertog, AungMyat, AlokSharma, KoljaSievert,
KerstinPiayda, IrisGrunwald, MarkusReinartz,
AnjaVogel, IloskaPamela, NataliaGaleru,
JudithAnnaLuisaStean, GerhardSell, JohannRaab,
ErhardStarck, AndreasZeiher, WolfgangStelter,
DagmaraHering, DeepakL.Bhatt, andHorstSievert
4
Introduction
What started the enthusiasm for renal denervation (RDN)?
Evidence from numerous animal studies outlined in previous
chapters demonstrated the potential efcacy and benets of
RDN. Most notably, studies in a pig model using a single
electrode radiofrequency (RF) catheter not only showed the
desired necrotic nerve bers and brosis but also suggested
that endovascular RF ablation was safe [1, 2]. The rst (nonrandomized) published study (Symplicity-1) included 45
patients with resistant hypertension (HTN) who underwent
endovascular RDN with the use of a single electrode RF
catheter and showed a 27/17 mmHg reduction in one-year
ofce blood pressure and 11 mm Hg reduction in systolic
ambulatory blood pressure (ABPM) (p< 0.05 compared to
S. C. Bertog (*)
Cardiovascular Center Frankfurt, Frankfurt, Germany
Minneapolis Veterans Affairs Medical Center,
Minneapolis, Minnesota, USA
A. Myat
Medpace UK, London, UK
A. Sharma
Minneapolis Veterans Affairs Medical Center,
Minneapolis, Minnesota, USA
K. Sievert · K. Piayda · I. Grunwald · M. Reinartz · A. Vogel ·
I. Pamela · N. Galeru · J. A. L. Steffan · G. Sell · J. Raab · E. Starck
· A. Zeiher · W. Stelter · H. Sievert
Cardiovascular Center Frankfurt, Frankfurt, Germany
D. Hering
College of Health Solutions, Arizona State University,
Phoenix, AZ, USA
Department of Hypertension and Diabetology, Medical University
of Gdansk, Gdańsk, Poland
D. L. Bhatt
Brigham and Women’s Hospital, Boston, MA, USA
baseline) [3]. Blood pressure response was dened as a
10mmHg or greater reduction in ofce systolic blood pressure. There was a 13% non-responder rate. Complications
included a guide catheter-induced renal artery dissection
requiring stenting and one access-related pseudoaneurysm.
The nding that ABPM response is less pronounced than
ofce blood pressure would continue to show in nearly all
subsequent non-sham controlled studies examining the efcacy of RDN.In 10 patients renal and overall norepinephrine
spillover (method described by Prof. Hering in a prior chapter) was measured and found to be reduced after RDN.In
addition, in two patients a reduction in muscle sympathetic
nerve activity (MSNA, method described by Prof. Hering in
a prior chapter) was shown supporting a reduction not just in
renal but also overall sympathetic nerve activity [4, 5].
Subsequently, the results of a registry including Symplicity-1
and other patients (n=87) were published showing the durability of the blood pressure lowering effect of RDN (ofce
blood pressure reduction of 33/14mmHg and 32/14mmHg
at 24 and 36 months, respectively, p <0.05 compared with
baseline) [6, 7]. It also suggested an increase in the responder
rate with time (to 93% at 36 months) [6]. One renal artery
stenosis possibly related to the treatment and one stenosis
remote from the treatment site (where some degree of preexistent stenosis was present prior to RDN) were reported at
follow-up.
These encouraging results were followed by Symplicity
HTN-2 [8]. This was the rst randomized trial assessing
RDN but without the use of a sham group. Patients (n=106)
with resistant HTN were randomized to RDN with the single
electrode (RF) Symplicity catheter in addition to medical
therapy versus medical therapy alone. Once again, at 6
months, a 32/12mmHg and 11/7mmHg reduction in ofce
blood pressure and ABPM was shown (p<0.05 compared to
control) in the denervation group and no signicant blood
© 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_4
37
38
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S. C. Bertog et al.
pressure reduction occurred in the medical therapy group.
The results were durable. At 12 months, the reduction in
ofce systolic blood pressure remained at 28 mm Hg
(p < 0.05 compared to control) [9]. There were no major
adverse events and it was reassuring that there was no signicant change in renal function or in the urine albumin to creatinine ratios at follow-up. After study completion, patients
were allowed to crossover and 46 patients decided to do so.
In these patients, there was a 24/8mmHg reduction in ofce
blood pressure at follow-up (p<0.05 compared to control)
[9]. Finally, at 3-year follow-up, the ofce blood pressure
reduction was maintained (33/14mmHg, p<0.001) [10]. It
was later demonstrated that patients who underwent RDN
displayed less of an exercise induced blood pressure increase
and better heart rate recovery after exercise while reducing
the baseline heart rate and preserving chronotropic competence [11].
In the SYMPATHY trial (n=139) with a design similar to
Symplicity HTN-2, there was no signicant blood pressure
reduction with RDN compared to the control group [12]. In
the open label multicenter Prague-15 study, 106 patients with
resistant HTN were randomized to RDN with the single electrode (RF) Symplicity catheter or intensication of antihypertensive therapy including the addition of spironolactone. At 6
months, a signicant reduction in similar magnitude in systolic ABPM occurred (~8mmHg) in both groups leading to
the conclusion that RDN had a blood pressure lowering effect
similar to the addition of spironolactone [13]. At 12 months in
the same study, there was a signicant difference in blood
pressure lowering favoring the addition of spironolactone over
RDN but this was not sustained at 24 months [14, 15]. In a
similar fashion, a smaller open label randomized trial using
the single electrode (RF) Symplicity catheter or adding spironolactone as the fourth agent suggested a more pronounced
blood pressure reduction with the addition of spironolactone
[16]. DENERHTN, an open label multicenter randomized
trial of patients (n=106) with resistant HTN performed in 15
centers in France, similar to Symplicity HTN-2, showed a signicant reduction in systolic ABPM in the RDN groupcompared to the control group albeit less pronounced (5.9mmHg)
[17]. In this trial, it was shown that night time systolic ABPM
and variability may be predictors of blood pressure response
after RDN [18]. Using the single electrode RF catheter smaller
single arm studies suggested a blood pressure reduction in
patients with milder forms of HTN but to a lesser degree.
There were obvious limitations to the above studies. Though
Symplicity HTN-2 was a randomized trial, patients and investigators were not blinded, thereby potentially allowing a
Hawthorne effect, placebo effect and observer bias to confound
results. More importantly, inclusion of patients was based on
the ofce systolic blood pressure and comparison at follow-up
was performed with the baseline (inclusion) blood pressure.
Therefore, regression to the mean may have led to an overestimation of the effect of RDN which may explain the less pronounced effect on ABPM (which also may be affected by
regression to the mean but, possibly, to a lesser extent). These
limitations have prompted the performance of the rst randomized sham controlled trial of RDN in addition to medical therapy versus medical therapy only using a single electrode RF
catheter (Symplicity HTN-3) [19, 20]. Patients who were randomized to the sham group underwent renal angiography only.
Maximum efforts were made to prevent patients from recognizing if they received treatment. It should be mentioned that it
has been shown that patients did not know what treatment they
had received. At 6 months, though the blood pressure was
lower in both groups, there was no signicant difference in
ofce systolic blood pressure reductions (14 mm Hg vs.
12mmHg reduction) or systolic ABPM reductions(6.8mmHg
vs. 4.8mmHg) in patients who underwent RDN versus sham.
Predictors of systolic ofce blood pressure response were baseline ofce systolic blood pressure≥180mmHg, aldosterone
antagonist use and non-use of vasodilators [21].
Although it remains unclear why prior studies had demonstrated a dramatic benet of RDN and Symplicity HTN-3
did not, a number of possibilities have been suggested. First,
an overination of the benets of Symplicity HTN-1 and 2
may have been related to prior limitations in trial design
including the aforementioned placebo effect, Hawthorne
effect, observer bias and regression to the mean. Second,
operators in Symplicity HTN-3 had limited experience with
single electrode RF ablation. In this context, it is important
to mention that only one denervation procedure was performed by 31% of operators and the mean number of denervation procedures per operator was 3.3 (nevertheless, there
was no difference in outcomes regardless of number of procedures performed). Third, incomplete denervation may
have been an important factor. For example, the mean number of ablations per artery in Symplicity HTN-3 was 3.9
which is signicantly less than the number of ablations in
routine clinical practice (however, not too different from the
average number of ablations performed in Symplicity HTN-1
[4 per artery]). Moreover, it has been shown in a post hoc
analysis of Symplicity HTN 3 that a greater reduction in
ofce blood pressureand systolic ABPM as well as heart rate
was seen with a higher number of ablations and energy delivery in a four quadrant pattern [21]. Fourth, patient selection
may have affected trial results. For example, subgroup analysis showed that there was a signicant difference in ofce
blood pressure reduction favoring RDN in patients who were
younger than 65 years. It could also be shown that patients
with combined (systolic-diastolic) HTN beneted more from
RDN than those with isolated systolic HTN [22]. It should be
mentioned that Symplicity HTN-3 was not the only negative
sham-controlled trial. In one other single center trial, patients
(n=69) were randomized to single RF catheter RDN versus
sham [23]. No signicant blood pressure reduction could be
demonstrated and there was also no effect on arterial stiffness, central blood pressure or heart rate variability [24]. In
another randomized sham controlled trial using the single
electrode Symplicity Flex catheter in patients with resistant
4 Appraisal ofRandomized Sham-Controlled Trial Data onRenal Denervation fortheManagement ofHypertension
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39
HTN no treatment effect could be seen with RDN [25].
Finally, in one randomized sham controlled trial in which
patients with mild resistant HTN (n=71) underwent RDN
with a single electrode RF catheter versus sham, no signicant blood pressure reduction could be shown in the intention to treat analysis but a small signicant difference in
ambulatory systolic blood pressure occurred in the per protocol analysis favoring RDN (−8.3mmHg vs. −3.5mmHg)
[26]. However, as in Symplicity HTN-2, a reduction of the
exercise induced blood pressure increase occurred after
RDN [27]. It was shown, using cardiac MRI, that stroke volume had decreased in those who underwent RDN [28].
Whatever the reason for the negative results may have
been, the disappointing array of results have led to the
design of newer generation devices that potentially facilitate
the procedure itself and lead to more complete denervation.
An important shortcoming of the rst generation single
electrode RF catheter was that signicant catheter manipu-
Table 4.1 Randomized sham controlled trials
Device Patients Inclusion BP
Symplicity
HTN-3
Desch etal. Single
ReSET Single
SPYRAL
HTN-OFF
MED
Single
electrode
Symplicity
Flex Catheter
electrode
Symplicity
Flex Catheter
electrode
Symplicity
Flex Catheter
SPYRAL
catheter
Resistant HTN Ofce systolic blood
Mild resistant
HTN
Therapy
resistant HTN
HTN, on no
meds during
study
pressureat least
160mmHg and
systolic ABPM at least
135mmHg
Daytime systolic
ABPM 135–
145mmHg or daytime
diastolic ABPM
90–94mmHg
Daytime systolic
ABPM>145mmHg
Ofce systolic blood
pressure150–
180mmHg and at least
90mmHg ofce
diastolic blood
pressure, in addition
systolic ABPM at least
140mmHg
lation was frequently necessary when attempting to achieve
circumferential denervation with no guarantee that this, in
fact, occurred. Data to suggest a closer proximity of renal
sympathetic nerve bers to the renal artery in extrarenal
segmental arteries, have also led to changes in the denervation strategy from denervation in the main renal artery only
to denervation of the main and extrarenal segmental
branches. Furthermore, given that the depth of renal sympathetic bers has been shown well beyond 3–4mm from the
adventitia, technology has been developed that allows
deeper reach limiting injury to the media and intima (such
as ultrasound energy with concomitant cooling of the intima/
media or alcohol injection, both technologies described in
later chapters in more detail). The focus of the following
will be the results of randomized sham-controlled trials
using these newer generation devices that are the reason that
RDN continues to be pursued in clinical practice and scientic trials (Table4.1). However, it should be mentioned that
Mean
age Number Blood pressure reduction Safety
58 535 Non-signicant versus sham
(at 6 months), in a subgroup
analysis there was signicant
benet in those who were <65
years of age, patients with
combined HTN benetted
more than those with isolated
systolic HTN, Note: at
long-term (36 months)
follow-up there was a
pronounced 16mmHg
systolic ABPM blood pressure
reduction with renal
denervation compared with
sham (0.3mmHg) p≤0.0001
65 71 At 6 months no difference in
the intention to treat analysis
but in the per protocol
analysis small (4.8mmHg)
benet in systolic ABPM
favoring RDN
54 69 At 6 months no difference No relevant
52 331 At 3 months, compared to
sham,4mmHg
greaterreduction in systolic
ABPM (p=0.0005),
3.1mmHg greater
reductionin diastolic ABPM
(p<0.0001) and
6.5mmHggreater reduction
in ofce systolic (p<0.0001)
and 4.4 mmHg greater
reduction inofce diastolic
bloodpressure (p<0.0001)
One new renal
artery stenosis in
the RDN group
No relevant
events
events
No relevant
events
(continued)
40
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Table 4.1 (continued)
Device Patients Inclusion BP
SPYRAL
HTN-ON
MED
REQUIRE Paradise
RADIANCE
SOLO
RADIANCE
TRIO
REDUCE
HTN:
REINFORCE
SPYRAL
catheter
ultrasound
catheter
Paradise
ultrasound
catheter
Paradise
ultrasound
catheter
Bipolar
radiofrequency
electrodes
mounted on
balloon catheter
Uncontrolled
HTN
Resistant HTN At least 150/90 daytime
HTN, on no
meds during
study
Resistant HTN At least 140/90mmHg
After
antihypertensive
medication
wash-out
Ofce systolic blood
pressure 150–
180mmHg, ofce
diastolic blood pressure
90mmHg or higher
and systolic ABPM
140–170mmHg
ABPM
At least 140/90mmHg
but <180/110mmHg
ofce blood pressure
daytime ABPM
Ofce systolic blood
pressure at least
150mmHg and
<181mmHg and
systolic ABPM at least
135mmHg
S. C. Bertog et al.
Mean
age Number Blood pressure reduction Safety
54 80 At 6 months, compared to
51 143 At 3 months, no difference in
54 146 At 2 months, compared
52 136 At 2 months, daytime systolic
58 51 At 6 months lower systolic
sham,systolic ABPM was
7mmHg lower (p=0.0059)
and diastolic ABPM
4.1mmHg lower
(p=0.0174) and ofce
systolic and diastolic blood
pressures were signicantly
lower by 6.6 mmHg and
4.2mmHg respectively
(p<0.05). At 36 months,
ABPM reduction
10/6mmHg more
pronounced with RDN
(p<0.05)
blood pressure compared to
sham, higher than expected
BP reduction in the sham
group
tosham, 4.1/1.8mmHg
lower ABPM (p=0.006 for
systolic blood pressure and
0.07 for diastolic blood
pressure), 6.5/4mmHg lower
ofce blood pressure
(p=0.007 for systolic and
0.005 for diastolic blood
pressure); At 12 months,
compared to sham,no
difference in daytime
ambulatory systolic blood
pressure, signicant 6 mmHg
reduction in ofce systolic
blood pressure and no
difference in home systolic
blood pressure, fewer
medications in the RDN
group
ABPM 4.5mmHg lower
than sham (p=0.022),
4.2mmHg greater24h
systolic ABPM reduction
(p=0.016)compared to
sham, also ofce systolic
blood pressure 7mmHg
lower in the RDN group
(p
<0.05), however no
signicant difference in
diastolic BP; at 6 months, no
difference in ABPM but
higher number of medications
in the sham group
ofce blood pressure but at
12 months no difference
No relevant
events
No relevant
events
One patient in the
RDN group
underwent renal
artery stenting
though there may
have been a
pre-existent lesion
One access
pseudoaneurysm
One renal artery
stenosis occurred
at follow-up in the
RDN group
4 Appraisal ofRandomized Sham-Controlled Trial Data onRenal Denervation fortheManagement ofHypertension
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41
the nal follow-up of SYMPLICITY HTN-3 did suggest a
signicant blood pressure reduction from renal denervation
even with the older generation (Symplicity Flex) catheter
that only became more apparent with longer-term follow-up
and potential attenuation of any placebo or Hawthorne
effects [29]. In fact, at 36 months, the change in ofce systolic blood pressure was −26mmHg in the renal denervation group and -6mmHg in the sham control group (adjusted
treatment difference 22 mm Hg, p ≤ 0.0001). The systolicABPM reduction at 26 months was 16 mmHg in the
denervation group versus 0.3mmHg in the sham control
group (p≤0.0001). In addition, blood pressures in the renal
denervation group were in the therapeutic range signicantly longer than in the sham group (18% vs. 9%
p≤0.0001). There was no evidence of late procedure related
adverse events. There was no difference in the composite
safety endpoint at 48 months (including all-cause death,
new onset end-stage renal disease, embolic events, vascular
complications, renal artery reintervention or hypertensive
crises). These ndings suggest that longer term follow- up
may be very important when examining the potential benets of renal denervation.
Randomized Sham-Controlled Trials Using
theSPYRAL Catheter (Medtronic,
Minneapolis, MN, USA)
Two large, randomized sham-controlled trials [30] using the
multielectrode SPYRAL catheter have been performed.
Denervation with the SPYRAL catheter is usually performed
in the main and extrarenal segmental branches (the technology and technique are described more in detail in a later
chapter). As previously mentioned, it has been shown that
more distal branch denervation may be more effective than
renal artery trunk denervation alone [31]. In SPYRAL HTNOFF MED, 331 patients on no medications with an ofce
systolic blood pressure of 150–180 mm Hg and diastolic
blood pressure of ≥90mmHg were randomized to RDN or
sham (renal angiography) [30, 32, 33]. All investigators who
were involved in follow-up care were blinded to the procedure. At 3 months, in those who underwent RDN there was a
3.9 mm Hg greater reduction in systolic ABPM and a
6.5mm Hg greater reduction in ofce systolic blood pressure compared to patients who underwent the sham procedure only (p < 0.05). Similarly, there was a 3.1 mm Hg
greater reduction in diastolic ABPM (p<0.05). There were
no relevant safety concerns. It is important to emphasize the
mean patient age (52 years) and the inclusion of only those
patients who had combined (systolic/diastolic) HTN. In a
post hoc analysis of SPYRAL HTN-OFF MED examining
BP waveforms obtained with a brachial cuff-based sphygmomanometer, there was an inverse relationship between
baseline augmentation index, augmentation pressure, backward wave amplitude, forward wave amplitude and estimated aortic pulse wave velocity and blood pressure response
to RDN [34]. These parameters may, therefore, be used to
help predict a blood pressure response to RDN.Furthermore,
it was shown that baseline heart rate predicted RDN response.
A reduction in mean ofce blood pressure and ABPM was
greater in patients with a baseline heart rate of ≥70/min and
the heart rate reduction after RDN was more pronounced
than in the sham group [35, 36]. In addition, patients with
higher baseline renin levels (≥0.65ng/ml/h) had a more pronounced blood pressure reduction after RDN than those with
lower baseline renin levels [37]. The renin and aldosterone
levels in patients who underwent RDN was lower than in the
sham group after RDN.
In SPYRAL HTN-ON MED, 80 patients with uncontrolled HTN (on 1-3 antihypertensive medications) were randomized to RDN versus sham (renal angiography) [38].
Similar to SPYRAL HTN-OFF MED, all investigators
involved in follow-up were blinded to the treatment. Once
again, compared to the sham group, at 6 months there was a
signicantly more pronounced reduction in ABPM in the
RDN group (7.4mmHg and 4.1 mm Hg systolic and diastolic, respectively, p<0.05 compared to sham). The change
in ofce blood pressure was also more pronounced in the
RDN group compared to sham(by6.8/3.5mmHg, p<0.05).
Mean patient age was 54 years and, once again, patients were
enrolled if they had combined HTN.At 3-year follow-up the
benet was maintained (10mm Hg and 5.9 mm Hg more
pronounced systolic and diastolic ABPM favoring the RDN
group, p < 0.05). There was also a signicant reduction in
diastolic ABPM (−5.90 mmHg, p = 0.0055 compared to
sham). The number of antihypertensive medications had not
changed between the groups (3.3 medications in the RDN
group vs. 3.1in the sham group) [39]. In a post hoc analysis,
a decrease in the morning diastolic blood pressure surge
slope (a measure of the sympathetically driven morning
blood pressure surge) could be seen [40]. It should be mentioned that the number of patients who underwent ABPM
follow-up at 24 and 36 months was limited (33 patients in the
RDN group and 17in the sham group at 24 months).
Randomized Sham Controlled Trials Using
theRecor Medical Paradise System (Recor
Medical, Palo Alto, CA, USA)
This system was rst available for treatment of resistant
HTN in 2012. The rst-in-man single-arm REDUCE study
(n=11) demonstrated a signicant reduction in ofce blood
pressure and ABPM in patients with resistant HTN [41].
Given a concern for renal artery stenosis related to the focal
circumferential energy emission, the recommended ow rate
42
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S. C. Bertog et al.
of the cooling solution was increased. Efcacy and safety
were subsequently studied in the REALISE (n = 20) and
ACHIEVE (n=96) studies [42, 43]. The latter demonstrated
a 7.5mmHg reduction in systolic ABPM at 12 month follow- up in patients with resistant HTN.No renal artery stenoses occurred. More recently, results of the RADIANCE [44]
trial have been published. This was a randomized, placebo/
sham- controlled trial with two study arms. In the rst, the
SOLO arm (n=146), patients with moderate HTN (on 0–2
medications) discontinued antihypertensive medications and
underwent RDN or sham procedure [45]. Renal denervation
was accompanied by a signicant 4.1 mm Hg reduction
(compared to sham procedure) of systolic ABPM at 2-month
follow- up (p<0.05). The change in diastolic ABPM did not
reach statistical signicance (1.8mmHg, p= 0.07). There
was also a signicant reduction in ofce systolic and diastolic blood pressure (by 6.5/4.1 greater than in the sham
group, p < 0.05). A favorable effect was maintained at 6
months only when adjusted for the number of antihyperten-
sive medications [46]. Though there was no signicant dif-
ference in ABPM at 12 months, patients were on signicantly
less antihypertensive medications in the treatment group
[47]. Further, in those patients who were initially assigned to
the sham group and ultimately crossed over to denervation,
there was a 10.8 mm Hg reduction in systolic ABPM 6
months following denervation [48]. In contradistinction to
SPYRAL HTN-OFF MED, a post hoc analysis did not demonstrate any signicant reduction in plasma renin or aldosterone levels after RDN and the renin level did not predict
response to RDN [49]. After trial completion, patients in the
sham group were allowed to undergo RDN and exhibited a
signicant blood pressure reduction (−11/7 mm Hg and
−11/8 mm Hg mean change in daytime ABPM 2 and 6
months from baseline) and, after unblinding, the blood pressure reduction was maintained at 12 months despite use of
fewer medications [47, 48]. In the TRIO arm (n = 136), in
patients with resistant HTN, the antihypertensive regimen
was changed to a single daily pill containing three antihypertensives (calcium channel blocker, angiotensin receptor
blocker and thiazide diuretic) [50]. In addition, patients were
randomly assigned to denervation or sham groups. In patients
who underwent RDN, at 2 months, there was a signicantly
more pronounced reduction in daytime systolic ABPM by
4.5mmHg compared to sham (p<0.05). In addition, there
was a signicantly more pronouncedreduction in 24h systolicABPM (by 4.2 mmHg, p=0.016) and ofce systolic
blood pressure (by7 mm Hg, p=0.037)favoring denervation but there was no signicant difference in diastolic blood
pressure. After 2 months, antihypertensive medications were
increased if blood pressure control was inadequate (home
blood pressure measurement >135/85mmHg) with addition
of spironolactone, bisoprolol, a centrally acting alpha-2
receptor agonist and an alpha-1 receptor blocker. At 6
months, the number of added antihypertensive medications
was higher (1.1) in the sham group compared to patients who
underwent RDN (0.7, p = 0.045). At 6-month follow-up,
there was no signicant difference in ABPM between the
groups (abstract presented at Transcatheter Therapeutics
[TCT] in Orlando 2021). Results of another randomized trial
(REQUIRE) [44, 48] enrolling 143 patients with resistant
HTN in an Asian population have recently been published
[51]. It did not show any signicant difference with RDN
using the Recor system compared to sham. Finally, the
RADIANCE II pivotal trialenrolled patients (n = 224)with
mild to moderate HTN with random assignment in a 2:1
fashion to device therapy versus sham [48].There was a 6.3
mmHg greater daytime systolic ABPM reduction (this was
the primary endpoint)in the RDN group compared to sham
(p<0.001). In addition, there were signicantly greater
reductions in all other blood pressure parameters (systolic
and diastolic ABPM, ofce systolic blood pressure) after
RDN compared with sham with the exception of diastolic
ofce blood pressure (which was numerically lower in the
RDN group but this did not reach statistical signicance
[p=0.07]) [52].
In the randomized RADIOSOUND trial, patients with
resistant HTN were assigned to either RDN using the
SPYRAL (radiofrequency) catheter in the main renal artery
only, denervation using the SPYRAL catheter in the main
renal artery, side branches and accessory renal arteries or
RDN using the Recor Medical Paradise (ultrasound) system
[53]. A total of 120 patients were enrolled. It demonstrated a
more pronounced daytime ABPM reduction in patients who
underwent ultrasound mediated denervation compared to RF
ablation in the main renal arteries only. However, there was
no signicant difference between the ultrasound group and
the group of patients who underwent RF ablation in the main
renal arteries, side branches and accessories when present.
Randomized Sham Controlled Trial Using
Bipolar Electrodes Mounted onaBalloon
One trial was published comparing RDN with a bipolar RF
electrode mounted on a balloon (Vessix Renal Denervation
System) [54]. In this trial, 51 patients were randomized to
RDN versus sham. Though there was a signicant ofce systolic blood pressure reduction at 6 months in favor of RDN,
there was no signicant difference in either ofce or ABPM
at 12-month follow-up.
4 Appraisal ofRandomized Sham-Controlled Trial Data onRenal Denervation fortheManagement ofHypertension
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43
Randomized Sham Controlled Trial Using
Perivascular Alcohol Infusion
withthePeregrine System
There are two ongoing trials examining this technology with
a trial design similar to that of the SPYRAL HTN-ON and
OFF med trials. This technology is further described in a
dedicated chapter for this device.It is important to mention
that at submission of this chapter, the results of TARGET BP
OFF MED were published. One hundred and six patients off
antihypertensive medications were randomized to alcohol
denervation versus sham (renal angiogram). At 8 weeks and
12 months, there was no difference in ABPM but the medication burden was lower in patients who underwent renal
denervation (1.5 versus 2.3 medications) [55].
Randomized Sham Controlled Trial Using
Externally Delivered Focused Ultrasound
forRDN
Only one sham controlled randomized trial using this concept has been published (WAVE-IV) and this did not demonstrate any antihypertensive efcacy [56].
Conclusion
Though not all studies examining renal denervation with rst
generation devices unequivocally show a blood pressure
reduction, more recent evidence using latest generation
devices consistently demonstrates a signicant blood pressure reduction with renal denervation compared to sham procedures. Moreover, long-term follow-up of the largest sham
controlled trial to date comparing the rst generation single
electrode RF catheter to sham now also showed a signicant
benet of renal denervation with regards to blood pressure
reduction emphasizing the importance of longer term follow up in studies examining renal denervation and suggesting a
potentially more pronounced long-term effect. Given a consistent presence of a small group of non-responders throughout aforementioned trials, it will be most important to further
examine the reasons for non-response and to study which
factors (anatomically, physiologically and clinically) best
predict which patients are most likely to benet.
References
1. Steigerwald K, Titova A, Malle C, etal. Morphological assessment
of renal arteries after radiofrequency catheter-based sympathetic
denervation in a porcine model. J Hypertens. 2012;30:2230–9.
2. Rippy MK, Zarins D, Barman NC, Wu A, Duncan KL, Zarins
CK. Catheter-based renal sympathetic denervation: chronic
preclinical evidence for renal artery safety. Clin Res Cardiol.
2011;100:1095–101.
3. Krum H, Schlaich M, Whitbourn R, etal. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety
and proof-of-principle cohort study. Lancet. 2009;373:1275–81.
4. Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD.Renal
sympathetic-nerve ablation for uncontrolled hypertension. N Engl
J Med. 2009;361:932–4.
5. Hering D, Lambert EA, Marusic P, et al. Substantial reduction in
single sympathetic nerve ring after renal denervation in patients
with resistant hypertension. Hypertension. 2013;61:457–64.
6. Krum H, Schlaich MP, Sobotka PA, etal. Percutaneous renal denervation in patients with treatment-resistant hypertension: nal 3-year
report of the Symplicity HTN-1 study. Lancet. 2014;383:622–9.
7. Symplicity HTNI. Catheter-based renal sympathetic denervation
for resistant hypertension: durability of blood pressure reduction
out to 24 months. Hypertension. 2011;57:911–7.
8. Symplicity HTNI, Esler MD, Krum H, et al. Renal sympathetic
denervation in patients with treatment-resistant hypertension (The
Symplicity HTN-2 Trial): a randomised controlled trial. Lancet.
2010;376:1903–9.
9. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year
results from the Symplicity HTN-2 randomized, controlled trial.
Circulation. 2012;126:2976–82.
10. Esler MD, Bohm M, Sievert H, etal. Catheter-based renal denervation for treatment of patients with treatment-resistant hypertension:
36 month results from the SYMPLICITY HTN-2 randomized clinical trial. Eur Heart J. 2014;35:1752–9.
11. Ukena C, Mahfoud F, Kindermann I, et al. Cardiorespiratory
response to exercise after renal sympathetic denervation in patients
with resistant hypertension. J Am Coll Cardiol. 2011;58:1176–82.
12. de Jager RL, de Beus E, Beeftink MM, etal. Impact of medication
adherence on the effect of renal denervation: the SYMPATHY trial.
Hypertension. 2017;69:678–84.
13. Rosa J, Widimsky P, Tousek P, etal. Randomized comparison of
renal denervation versus intensied pharmacotherapy including
spironolactone in true-resistant hypertension: six-month results
from the Prague-15 study. Hypertension. 2015;65:407–13.
14. Rosa J, Widimsky P, Waldauf P, etal. Role of adding spironolactone and renal denervation in true resistant hypertension: oneyear outcomes of randomized PRAGUE-15 study. Hypertension.
2016;67:397–403.
15. Rosa J, Widimsky P, Waldauf P, etal. Renal denervation in comparison with intensied pharmacotherapy in true resistant hypertension: 2-year outcomes of randomized PRAGUE-15 study. J
Hypertens. 2017;35:1093–9.
16. Oliveras A, Armario P, Clara A, etal. Spironolactone versus sympathetic renal denervation to treat true resistant hypertension: results
from the DENERVHTA study - a randomized controlled trial. J
Hypertens. 2016;34:1863–71.
17. Azizi M, Sapoval M, Gosse P, etal. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre,
open-label, randomised controlled trial. Lancet. 2015;385:1957–65.
18. Gosse P, Cremer A, Pereira H, etal. Twenty-four-hour blood pressure monitoring to predict and assess impact of renal denervation: the DENERHTN study (renal denervation for hypertension).
Hypertension. 2017;69:494–500.
19. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial
of renal denervation for resistant hypertension. N Engl J Med.
2014;370:1393–401.
20. Kandzari DE, Bhatt DL, Sobotka PA, et al. Catheter-based renal
denervation for resistant hypertension: rationale and design of the
SYMPLICITY HTN-3 Trial. Clin Cardiol. 2012;35:528–35.
44
https://t.me/medicina_free
S. C. Bertog et al.
21. Kandzari DE, Bhatt DL, Brar S, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J.
2015;36:219–27.
22. Mahfoud F, Bakris G, Bhatt DL, etal. Reduced blood pressurelowering effect of catheter-based renal denervation in patients with
isolated systolic hypertension: data from SYMPLICITY HTN-3 and
the Global SYMPLICITY Registry. Eur Heart J. 2017;38:93–100.
23. Mathiassen ON, Vase H, Bech JN, et al. Renal denervation in
treatment-resistant essential hypertension. A randomized, SHAMcontrolled, double-blinded 24-h blood pressure-based trial. J
Hypertens. 2016;34:1639–47.
24. Peters CD, Mathiassen ON, Vase H, etal. The effect of renal denervation on arterial stiffness, central blood pressure and heart rate
variability in treatment resistant essential hypertension: a substudy
of a randomized sham-controlled double-blinded trial (the ReSET
trial). Blood Press. 2017;26:366–80.
25. Engholm M, Bertelsen JB, Mathiassen ON, etal. Effects of renal
denervation on coronary ow reserve and forearm dilation capacity in patients with treatment-resistant hypertension. A randomized, double-blinded, sham-controlled clinical trial. Int J Cardiol.
2018;250:29–34.
26. Desch S, Okon T, Heinemann D, etal. Randomized sham- controlled
trial of renal sympathetic denervation in mild resistant hypertension. Hypertension. 2015;65:1202–8.
27. Fengler K, Heinemann D, Okon T, et al. Renal denervation
improves exercise blood pressure: insights from a randomized,
sham-controlled trial. Clin Res Cardiol. 2016;105:592–600.
28. Lurz P, Kresoja KP, Rommel KP, etal. Changes in stroke volume
after renal denervation: insight from cardiac magnetic resonance
imaging. Hypertension. 2020;75:707–13.
29. Bhatt DL, Vaduganathan M, Kandzari DE, et al. Long-term outcomes after catheter-based renal artery denervation for resistant
hypertension: nal follow-up of the randomised SYMPLICITY
HTN-3 trial. Lancet. 2022.
30. Bohm M, Townsend RR, Kario K, et al. Rationale and design
of two randomized sham-controlled trials of catheter-based
renal denervation in subjects with uncontrolled hypertension in
the absence (SPYRAL HTN-OFF MED Pivotal) and presence
(SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design. Clin Res Cardiol.
2020;109:289–302.
31. Pekarskiy SE, Baev AE, Mordovin VF, et al. Denervation of the
distal renal arterial branches vs. conventional main renal artery
treatment: a randomized controlled trial for treatment of resistant
hypertension. J Hypertens. 2017;35:369–75.
32. Bohm M, Kario K, Kandzari DE, etal. Efcacy of catheter-based
renal denervation in the absence of antihypertensive medications
(SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised,
sham-controlled trial. Lancet. 2020;395:1444–51.
33. Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based
renal denervation in patients with uncontrolled hypertension in
the absence of antihypertensive medications (SPYRAL HTN-OFF
MED): a randomised, sham-controlled, proof-of-concept trial.
Lancet. 2017;390:2160–70.
34. Weber T, Wassertheurer S, Mayer CC, et al. Twenty-four-hour
pulsatile hemodynamics predict brachial blood pressure response
to renal denervation in the SPYRAL HTN-OFF MED trial.
Hypertension. 2022;79:1506–14.
35. Bohm M, Tsious K, Kandzari DE, etal. Effect of heart rate on the
outcome of renal denervation in patients with uncontrolled hypertension. J Am Coll Cardiol. 2021;78:1028–38.
36. Bohm M, Mahfoud F, Townsend RR, etal. Ambulatory heart rate
reduction after catheter-based renal denervation in hypertensive
patients not receiving anti-hypertensive medications: data from
SPYRAL HTN-OFF MED, a randomized, sham-controlled, proofof- concept trial. Eur Heart J. 2019;40:743–51.
37. Mahfoud F, Townsend RR, Kandzari DE, etal. Changes in plasma
renin activity after renal artery sympathetic denervation. J Am Coll
Cardiol. 2021;77:2909–19.
38. Kandzari DE, Bohm M, Mahfoud F, etal. Effect of renal denervation on blood pressure in the presence of antihypertensive
drugs: 6-month efcacy and safety results from the SPYRAL
HTN-ON MED proof-of-concept randomised trial. Lancet.
2018;391:2346–55.
39. Mahfoud F, Kandzari DE, Kario K, etal. Long-term efcacy and
safety of renal denervation in the presence of antihypertensive
drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled
trial. Lancet. 2022;399:1401–10.
40. Kario K, Weber MA, Bohm M, etal. Effect of renal denervation in
attenuating the stress of morning surge in blood pressure: post-hoc
analysis from the SPYRAL HTN-ON MED trial. Clin Res Cardiol.
2021;110:725–31.
41. Mabin T, Sapoval M, Cabane V, Stemmett J, Iyer M.First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention. 2012;8:57–61.
42. Daemen J, Mahfoud F, Kuck KH, et al. Safety and efcacy of
endovascular ultrasound renal denervation in resistant hypertension: 12-month results from the ACHIEVE study. J Hypertens.
2019;37:1906–12.
43. Montalescot G, Cluzel P, Girerd X, Pathek A. REALISE trial:
renal denervation by ultrasound transcatheter emission: six month
results. J Am Coll Cardiol. 2014;64.
44. Mauri L, Kario K, Basile J, etal. A multinational clinical approach
to assessing the effectiveness of catheter-based ultrasound renal
denervation: the RADIANCE-HTN and REQUIRE clinical study
designs. Am Heart J. 2018;195:115–29.
45. Azizi M, Schmieder RE, Mahfoud F, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN
SOLO): a multicentre, international, single-blind, randomised,
sham- controlled trial. Lancet. 2018;391:2335–45.
46. Azizi M, Schmieder RE, Mahfoud F, etal. Six-month results of
treatment-blinded medication titration for hypertension control
following randomization to endovascular ultrasound renal denervation or a sham procedure in the RADIANCE-HTN SOLO trial.
Circulation. 2019.
47. Azizi M, Daemen J, Lobo MD, et al. 12-month results from the
unblinded phase of the RADIANCE-HTN SOLO trial of ultrasound
renal denervation. JACC Cardiovasc Interv. 2020;13:2922–33.
48. Mahfoud F, Bloch MJ, Azizi M, et al. Changes in blood pressure after crossover to ultrasound renal denervation in patients
initially treated with sham in the RADIANCE-HTN SOLO trial.
EuroIntervention. 2021;17:e1024–e32.
49. Fisher NDL, Kirtane AJ, Daemen J, etal. Plasma renin and aldosterone concentrations related to endovascular ultrasound renal
denervation in the RADIANCE-HTN SOLO trial. J Hypertens.
2022;40:221–8.
50. Azizi M, Sanghvi K, Saxena M, etal. Ultrasound renal denervation
for hypertension resistant to a triple medication pill (RADIANCEHTN TRIO): a randomised, multicentre, single-blind, shamcontrolled trial. Lancet. 2021;397:2476–86.
51. Kario K, Yokoi Y, Okamura K, etal. Catheter-based ultrasound renal
denervation in patients with resistant hypertension: the randomized,
controlled REQUIRE trial. Hypertens Res. 2022;45:221–31.
52. Endovascular Ultrasound Renal Denervation to Treat Hypertension
JAMA. 2023;329(8):651. https://doi.org/10.1001/jama.2023.0713
53. Fengler K, Rommel KP, Lapusca R, etal. Renal denervation in isolated systolic hypertension using different catheter techniques and
technologies. Hypertension. 2019;74:341–8.
54. Weber MA, Kirtane AJ, Weir MR, etal. The reduce HTN: reinforce:
randomized, Sham-controlled trial of bipolar radiofrequency renal
denervation for the treatment of hypertension. JACC Cardiovasc
Interv. 2020;13:461–70.
4 Appraisal ofRandomized Sham-Controlled Trial Data onRenal Denervation fortheManagement ofHypertension
https://t.me/medicina_free
45
55. Pathak A, Rudolph UM, Saxena M, etal. Alcohol mediated renal
denervation in patients with hypertension in the absence of antihypertensive medications. Eurointervention. 2023, July 10th ahead
of print.
56. Schmieder RE, Ott C, Toennes SW, et al. Phase II randomized
sham-controlled study of renal denervation for individuals with
uncontrolled hypertension- WAVE IV.J Hypertens. 2018;36:680–9.
Dr. Bhatt discloses the following relationships—Advisory Board:
AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera,
Cereno Scientic, Elsevier Practice Update Cardiology, High Enroll,
Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck,
MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado
Biosciences, Stasys; Board of Directors: AngioWave (stock options),
Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.
LINQ (stock options), High Enroll (stock), Society of Cardiovascular
Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart
Association Quality Oversight Committee; Consultant: Broadview
Ventures; Data Monitoring Committees: Acesion Pharma, Assistance
Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial,
funded by St. Jude Medical, now Abbott), Boston Scientic (Chair,
PEITHO trial), Cleveland Clinic (including for the ExCEED trial,
funded by Edwards), Contego Medical (Chair, PERFORMANCE 2),
Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of
Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the
ABILITY-DM trial, funded by Concept Medical), Novartis, Population
Health Research Institute; Rutgers University (for the NIH-funded
MINT Trial); Honoraria: American College of Cardiology (Senior
Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC
Accreditation Oversight Committee), Arnold and Porter law rm (work
related to Sano/Bristol-Myers Squibb clopidogrel litigation), Baim
Institute for Clinical Research (formerly Harvard Clinical Research
Institute; RE-DUAL PCI clinical trial steering committee funded by
Boehringer Ingelheim; AEGIS-II executive committee funded by CSL
Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter),
Canadian Medical and Surgical Knowledge Translation Research
Group (clinical trial steering committees), Cowen and Company, Duke
Clinical Research Institute (clinical trial steering committees, including
for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP
Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the
American College of Cardiology (Guest Editor; Associate Editor), K2P
(Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/
ReachMD (CME steering committees), MJH Life Sciences, Oakstone
CME (Course Director, Comprehensive Review of Interventional
Cardiology), Piper Sandler, Population Health Research Institute (for
the COMPASS operations committee, publications committee, steering
committee, and USA national co-leader, funded by Bayer), Slack
Publications (Chief Medical Editor, Cardiology Today’s Intervention),
Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD
(CME steering committees), Wiley (steering committee); Other:
Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry
Steering Committee (Chair), VA CART Research and Publications
Committee (Chair); Patent: Sotagliozin (named on a patent for sotagliozin assigned to Brigham and Women’s Hospital who assigned to
Lexicon; neither I nor Brigham and Women’s Hospital receive any
income from this patent); Research Funding: Abbott, Acesion Pharma,
Ammune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer,
Beren, Boehringer Ingelheim, Boston Scientic, Bristol-Myers Squibb,
Cardax, CellProthera, Cereno Scientic, Chiesi, CinCor, CSL Behring,
Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals,
Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia,
Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic,
Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk,
Owkin, Pzer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid
Hoffman Foundation, Roche, Sano, Stasys, Synaptic, The Medicines
Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s
Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston
Scientic, CSI, Endotronix, St. Jude Medical (now Abbott), Philips,
SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College
of Cardiology; Unfunded Research: FlowCo, Takeda.
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