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CLINICAL RESEARCH
European Heart Journal (2017) 38, 3308–3317
doi:10.1093/eurheartj/ehx525
Hypertension
Roland E. Schmieder1*, Frank Wagner2, Michael Mayr3, Christian Delles4,
Christian Ott1, Christian Keicher2, Maja Hrabak-Paar3,5, Tobias Heye3,
Solveig Aichner3, Yasser Khder6, Denise Yates7, Diego Albrecht6,
Thomas Langenickel6, Patrick Freyhardt2, Rolf Janka8, and Jens Bremerich3
1
Department of Nephrology and Hypertension, University Hospital Erlangen, Ulmenweg 18, 91054 Erlangen, Germany; 2Charité Research Organisation, Berlin, Charité Research
Organisation GmbH, Charitéplatz 1, 10117 Berlin (Mitte), Germany; 3Outpatient Department, University Hospital Basel, Basel, Switzerland; 4Institute of Cardiovascular and Medical
Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK; 5University Hospital Center Zagreb, University of
Zagreb School of Medicine, Ki spati ceva 12 (Rebro), 10 000 Zagreb, Croatia; 6Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland; 7Novartis Institutes for BioMedical
Research, Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA; and 8Department of Radiology, University Hospital Erlangen, Maximiliansplatz 1, 91054 Erlangen, Germany
Received 7 March 2017; revised 17 July 2017; editorial decision 15 August 2017; accepted 18 August 2017; online publish-ahead-of-print 27 September 2017
See page 3318 for the editorial comment on this article (doi: 10.1093/eurheartj/ehx560)
Aims
Progressive aortic stiffening eventually leads to left ventricular (LV) hypertrophy and heart failure if left untreated.
Anti-hypertensive agents have been shown to reverse this to some extent. The effects of sacubitril/valsartan
(LCZ696), a dual-action angiotensin receptor blocker (ARB), and neprilysin inhibitor, on arterial stiffness and LV
remodelling have not been investigated.
……………………………………………………………………………………………………………………………………………………………………………
Methods
This was a randomized, multi-centre, double-blind, double-dummy, active-controlled, parallel group, study to comand results
pare the effects on cardiovascular remodelling of sacubitril/valsartan with those of olmesartan in patients with
hypertension and elevated pulse pressure. Magnetic resonance imaging scans were used to assess LV mass and local
aortic distensibility, at baseline and at 12 and 52 weeks after initiation of treatment. Central pulse and systolic pressure were determined using a SphymoCorV XCEL device at each time point. A total of 114 patients were included,
with 57 in each treatment group. The mean age was 59.8 years, and 67.5% were male. Demographic characteristics
did not vary between the two sets of patients. Left ventricular mass index decreased to a greater extent in the
sacubitril/valsartan group compared to the olmesartan group from baseline to 12 weeks (-6.36 vs. -2.32 g/m2;
P = 0.039) and from baseline to 52 weeks (-6.83 vs. -3.55 g/m2; P = 0.029). These differences remained significant
after adjustment for systolic blood pressure (SBP) at follow-up (P = 0.036 and 0.019 at 12 and 52 weeks, respectively) and similar signals (though formally non-significant) were observed after adjusting for changes in SBP
(P = 0.0612 and P = 0.0529, respectively). There were no significant differences in local distensibility changes from
baseline to 12 or 52 weeks between the two groups; however, there was a larger reduction in central pulse pressure for the sacubitril/valsartan group compared to the olmesartan group (P = 0.010).
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……………………………………………………………………………………………………………………………………………………………………………
Conclusion
Since LV mass change correlates with cardiovascular prognosis, the greater reductions in LV mass indicate valuable advantages of sacubitril/valsartan compared to olmesartan. The finding that LV mass index decrease might be to some extent
independent of SBP suggests that the effect of the dual-acting agent may go beyond those due to its BP-lowering ability.
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Keywords
Hypertension
•
Arterial stiffness
•
Heart failure
•
Left ventricular hypertrophy
•
Angiotensin
•
Neprilysin
* Corresponding author. Tel: þ49 9131 85-36245, Fax: þ49 9131 85-36215, Email: [email protected]; [email protected]
C The Author 2017. For permissions, please email: [email protected].
Published on behalf of the European Society of Cardiology. All rights reserved. V
Downloaded from https://academic.oup.com/eurheartj/article-abstract/38/44/3308/4259266 by Eli M Oboler Library Serials user on 03 January 2019
The effect of sacubitril/valsartan compared to
olmesartan on cardiovascular remodelling in
subjects with essential hypertension: the
results of a randomized, double-blind,
active-controlled study
3309
The effect of sacubitril/valsartan compared to olmesartan
Introduction
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Downloaded from https://academic.oup.com/eurheartj/article-abstract/38/44/3308/4259266 by Eli M Oboler Library Serials user on 03 January 2019
Cardiovascular (CV) remodelling is a gradual process that progresses
with age and is accelerated in the presence of hypertension.1 There
are a number of contributory factors, including decreasing elastin
content of the artery wall, increased collagen deposition, endothelial
dysfunction, and alterations in smooth muscle tone.2 The loss of artery elasticity results in increased systolic blood pressure (SBP) with
little change in diastolic blood pressure (DBP), leading to increased
pulse pressure (PP). This process results in increased cardiac afterload, leading to left ventricular (LV) remodelling followed by LV
hypertrophy. Both arterial stiffening and increased LV mass have
been associated with increased CV risk in community-based cohorts3–7 and patients with essential hypertension,8–10 and are therefore important treatment targets.
Treatment-induced decreases in BP have been shown to indirectly reduce arterial stiffness and LV mass by lowering stress applied
to the blood vessel wall and the heart, respectively, diminishing the
extent of CV remodelling.11 On the other hand, certain antihypertensive agents have demonstrated efficacy that goes beyond BP reduction.12–14 Drugs that inhibit the renin–angiotensin system (RAS)
have been shown to be particularly effective.14 Such agents disrupt
angiotensin-II-mediated signalling pathways, decreasing extracellular
matrix remodelling, endothelial dysfunction, and inflammation.11,15
In addition, similar changes to the more peripheral arteries result in
decreased pulse wave reflection, leading to a lesser augmentation of
central PP at the aorta.11 Both angiotensin-converting enzyme
(ACE) inhibitors and angiotensin receptor blockers (ARBs) have
been shown to reduce vascular and LV remodelling, and cause reduction of LV hypertrophy, in patients with hypertension or CV disease.13,14,16–19
A further target for BP reduction is the endopeptidase, neprilysin.
Inhibition of this species increases bioavailability of natriuretic peptides, promoting vasodilation and reducing ventricular remodelling.20
However, agents that inhibit neprilysin also increase the formation of
vasoconstrictory species, such as angiotensin II and endothelin.21,22
Evaluation of the neprilysin inhibitor, candoxatril, demonstrated disappointing antihypertensive effects, leading to discontinuation of its
development.23 Dual inhibition of neprilysin and ACE with the agent
omapatrilat provided SBP and PP lowering along with decreased stiffness, which was superior to that achieved with the ACE-inhibitor,
enalapril, alone.24 However, the unacceptable rate of angioedema
thwarted its approval. Sacubitril/valsartan, a more recently developed
drug, disrupts angiotensin II signalling through blockade of the AT1
receptor, and inhibits neprilysin through the non-peptidic AHU377
moiety.20,25 In patients with heart failure with a reduced ejection fraction, the agent was found to significantly reduce the risk of the composite end point of CV death or heart failure hospitalization, CV
death and death from any cause in comparison to enalapril.26
Sacubitril/valsartan is presently approved in more than 60 countries
worldwide and is indicated to reduce the risk of CV death and hospitalization for patients with chronic heart failure with a reduced ejection fraction. To further understand the effects of sacubitril/valsartan
on the LV and large arteries the present study evaluated the effects
of sacubitril/valsartan compared to the ARB, olmesartan, on CV
remodelling in patients with hypertension.
..
.. Methods
..
..
.. Study design
.. This was a multi-centre randomized, multi-centre, double-blind, double..
.. dummy, active-controlled, parallel group study to compare the effects
.. on CV remodelling of sacubitril/valsartan with those of olmesartan
..
.. in patients with hypertension and elevated PP (Clinicaltrials.gov,
.. NCT01870739). The study comprised a screening period followed by a
.. 4-week washout period, where eligible patients stopped using any anti..
.. hypertensive medication (Figure 1). During these 4 weeks, patients
.. received both a placebo to sacubitril/valsartan and a placebo to olmesar..
.. tan in order to evaluate treatment compliance. The patients subsequently
.. underwent a cardiac and aortic magnetic resonance imaging (MRI) scan
.. (3.0 Tesla), had SphygmoCorV XCEL measurements taken, and provided
..
.. blood samples. The CV-MRI images were sent to an academic imaging
.. core laboratory for quality control. Upon verification that the scans were
..
.. evaluable, patients were randomized 1: 1 to sacubitril/valsartan or olme.. sartan by using consecutive ascending randomization numbers in the
.. treatment blocks allocated to each study site. The randomization was
..
.. stratified by the presence or absence of statin and oral antidiabetic ther.. apy. The randomization list was produced using an automated random
..
.. number generator.
..
During the first 2 weeks of the drug treatment period, patients
.. received
sacubitril/valsartan 200 mg q.d. (tablet) plus a placebo to olme..
.. sartan (capsule), or olmesartan 20 mg q.d. (capsule) plus a placebo to
.. sacubitril/valsartan (tablet). The dosages were then force-titrated to
..
.. maintenance doses of sacubitril/valsartan 400 mg q.d. or olmesartan
.. 40 mg q.d., which were taken for the subsequent 10 weeks. After this
.. time, amlodipine could be added to the therapy (add-on period) if
..
.. deemed necessary for achieving adequate BP control. No dose adjust.. ments of sacubitril/valsartan or olmesartan, or interruptions, were
..
.. permitted.
..
Patient compliance was evaluated by the counting of pills by a physician
..
at
selected
time-points. In addition, patients were provided with individual
..
.. diary cards to record administration of the study medication on a daily
.. basis. These cards were checked regularly by site staff.
..
..
The study was approved by the local ethics committee at each trial
.. centre, and was conducted in accordance with the Declaration of
..
.. Helsinki and its amendments. All included patients provided written in.. formed consent.
..
..
..
..
.. Patients
.. Included individuals were >_18 years of age and had essential hypertension
.. Stage 1 and 2 [mean seated [ms] SBP >_140 mmHg and <180 mmHg)8
..
.. and elevated brachial PP (>_50 mmHg).27 Patients were excluded if they
.. had any contraindications to MRI; had any contraindications to olmesar..
.. tan or amlodipine; had severe hypertension (msSBP >_180 mmHg,
.. msDBP >_110 mmHg); were pregnant; had a history of angioedema; had a
.. history or evidence of a secondary form of hypertension; had experi..
.. enced a transient ischaemic attack, stroke, myocardial infarction (MI), or
.. peripheral artery disease requiring intervention in the 12 months prior to
..
.. screening; had undergone percutaneous coronary intervention; had type
.. 1 diabetes mellitus; or had type 2 diabetes mellitus that was not well
.. controlled with oral medication, or was being treated with insulin.
..
.. Certain concomitant medications were prohibited, including any anti.. hypertensive agents (ARBs, ACE-inhibitors, b-blockers, diuretics) or anti..
.. arrhythmic drugs. Patients who were being treated with a statin were
.. required to have been taking the same statin at the same dose for at least
.. 4 weeks prior to screening.
3310
R.E. Schmieder et al.
Measurements
Data were entered into an electronic case report form. All patients had
their office BP and heart rate measured in standard fashion8 and underwent a 12-lead electrocardiogram (ECG) at rest. At the visit immediately
prior to initiation of the study drug, a CV-MRI scan was performed in
order to determine aortic distensibility and LV mass. In addition the
Sphygmocor device was used to perform pulse wave analysis and pulse
wave velocity (PWV). The pulse wave assessments and MRI scans were
performed at baseline and after 12 and 52 weeks of treatment.
.. in systole (Amax) and diastole (Amin) at three different locations: in the
..
.. ascending (ascending aorta) and descending (proximal descending aorta)
.. aorta at the level of the right pulmonary artery and 10 cm lower (distal
.. descending aorta). Distensibility was calculated as follows:
..
..
Amax-Amin
.. Distensibility ½10-3 mmHg-1 ¼
1000:
..
Amin ðpulse pressureÞ
..
..
..
..
.. Pulse wave analysis and velocity
.. The SphygmoCorV XCEL device (AtCor Medical, Sydney Australia) was
..
.. used to provide a central arterial pressure waveform from which central
.. PP, augmentation pressure (AP; added pressure due to wave reflection),
.. and augmentation pressure index (AI; % of central PP due to wave reflec..
.. tion) were derived. The carotid–femoral PWV, was also measured.
.. Measurements were taken in supine position and BP measurements for
..
.. calibration of the Sphygmocor were taken immediately prior to the pulse
.. wave recording.
..
..
.. Statistics
.. The study primary end point was that change from baseline in local
..
.. distensibility as measured by MRI in ascending, proximal descending, and
.. distal descending aorta after 52 weeks of treatment. Secondary and ex..
.. ploratory end points included but not limited to: vascular parameters
.. such as local aortic strain, aortic PWV, central blood pressure, augmenta.. tion index, as well as LV mass and LV mass index.
..
..
Sample size estimation was based on an observed standard deviation
.. (SD) for change from baseline to 52 weeks using MRI of 1.08793,
..
.. 5.63031, and 1.51536 10-3 mmHg-1 in ascending, proximal descending,
.. and distal descending aorta in an internal study (unpublished data). A 50
..
sufficient to allow detecting a treatment
.. patients per arm was considered
.. difference of 0. 6785 10-3 mmHg-1 between the two study groups in
.. proximal descending aorta (approximately half of the observed SD). This
..
.. difference was considered as clinically relevant. The number of random.. ized patients was believed appropriate to ensure that 100 patients com.. plete 52 weeks of treatment.
..
..
For baseline characteristics, the continuous variables were provided as
.. means with SD, while categorical data were presented as absolute values
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Magnetic resonance imaging acquisition
Electrocardiogram-gated MRI was performed at each site on a 3.0 Tesla
whole body scanner equipped with cardiac phased array coils (Magnetom
Trio, Magnetom Skyra, Magnetom Prisma; Siemens Healthineers,
Germany). After scout imaging and acquisition of a stack of axial Single
Shot Turbo Spin Echo (HASTE) images of the whole chest cine balanced
steady state free precession images were acquired in the short axis (contiuguous gapless, whole heart), as well as in vertical and horizontal long
axes views (3 midventricular slices in each orientation) with the following
sequence parameters: Slice thickness 8 mm, FOV 340 273 mm; In plane
resolution 1.5 1.5 mm2; Flip angle 50 ; Lines per phase 13; retrospective
ECG gating, 25 calculated phases; bandwith 970 Hz per pixel; repetition
time 3 ms; echo time 1.5 ms. Subsequently retrospectively ECG gated axial
spoiled gradient recalled echo were acquired at the level of the right pulmonary artery and 10 cm below with the following sequence parameters:
Slice thickness 6 mm; matrix 256 256; FOV 340 292 mm2; Spatial
resolution 1.1 1.1 mm2; Calculated phases 50; temporal resolution
20 ms; Lines per phase 7; bandwith 401 Hz per pixel; repetition time 7 ms;
echo time 4 ms.
Magnetic resonance imaging analysis
Cine MRI was transferred to a post-processing server (SyngoVia; Siemens
Healthineers, Germany) for evaluation of LV mass. Inner and outer contours of the LV myocardium were segmented on short axis images, position of aortic and mitral valves on horizonatal and vertical long axes.
Mass and mass index were calculated as reported previously.28 For aortic
distensibility, the cross-sectional lumen area of the aorta was segmented
Downloaded from https://academic.oup.com/eurheartj/article-abstract/38/44/3308/4259266 by Eli M Oboler Library Serials user on 03 January 2019
Figure 1 Trial design.
3311
The effect of sacubitril/valsartan compared to olmesartan
and percentages. Statistically significant differences between baseline
characteristics were determined using a student’s t-test or a v2 test, as appropriate. The primary and secondary end points were analysed using a
linear model, with treatment as the fixed effect and the corresponding
baseline as a covariate. Least squares regression analysis was used to estimate the mean and 95% confidence interval (CI) for change from baseline
of each variable between the sacubitril/valsartan and olmesartan patients.
All analysis was performed using the SAS software.
Table 1
Sacubitril/ Olmesartan P-value
N 5 57
valsartan
N 5 57
…………………………………………………………………………………….
At baseline
Age (years, mean ± SD)
60.5 ± 7.8
59.2 ± 13.1
0.53
Gender (male N(%))
BMI (kg/m2, mean ± SD)
37 (64.9)
28.1 ± 4.5
40 (70.2)
28.6 ± 3.9
0.55
0.52
SBP (mmHg, mean ± SD)
155.3 ± 9.0
155.0 ± 9.1
0.88
154
136–179
156
139–178
92.7 ± 8.8
91.7 ± 8.7
93
68–107
92
69–110
Median (mmHg)
Min–max (mmHg)
Study patients
DBP (mmHg, mean ± SD)
A total of 115 patients were enrolled in the study, one of whom was
discontinued after randomization. This left 114 patients who received
the study medication to which they were assigned. The mean age of
the population was 59.8 ± 10.7 years and 67.5% were male, with
no significant differences between the two drug groups (Table 1).
The mean SBP was 155.1 ± 9.0 mmHg, and the mean DBP was
92.2 ± 8.7 mmHg, with highly similar values in the two groups. Heart
rate (mean: 70.2 ± 10.3 bpm) and PP (mean: 62.9 ± 9.3 mmHg) also
did not differ between the sets of patients. Left ventricular …
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