European Journal of Heart Failure (2014)

doi:10.1002/ejhf.76

Independence of the blood pressure lowering

effect and efficacy of the angiotensin receptor
neprilysin inhibitor, LCZ696, in patients with
heart failure with preserved ejection fraction:
an analysis of the PARAMOUNT trial
Pardeep S. Jhund1,2, Brian Claggett1, Milton Packer3, Michael R Zile 4, Adriaan A.
Voors5, Burkert Pieske6, Martin Lefkowitz7, Victor Shi7, Toni Bransford7, John J. V.
McMurray2, and Scott D Solomon1*
1 Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA; 2 BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences,
University of Glasgow, Glasgow, UK; 3 Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA; 4 Ralph H. Johnson Veterans Affairs
Medical Center and Medical University of South Carolina, Charleston, SC, USA; 5 Department of Cardiology, University Medical Centre, Groningen, University of Groningen,
Groningen, the Netherlands; 6 Department of Cardiology, Medical University Graz, Graz, Austria; and 7 Novartis Pharmaceuticals, East Hanover, NJ, USA

Received 23 October 2013; revised 3 January 2014; accepted 17 January 2014

Aims The first in class angiotensin receptor neprilysin inhibitor, LCZ696 has been shown to reduce levels of N-terminal
pro-brain natriuretic peptide (NT-proBNP), reduce left atrial size and improve New York Heart Association (NYHA)
class in patients with heart failure with preserved ejection fraction (HFpEF). We examined whether the effects of
LCZ696 were independent of systolic blood pressure (SBP) lowering.
.....................................................................................................................................................................
Methods In the Prospective comparison of ARNi (angiotensin receptor neprilysin inhibitor) with ARB (angiotensin receptor
and results blocker) on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial 301 patients were
randomly assigned to LCZ696 or valsartan. We examined the relationship between SBP lowering and LCZ696 on
NT-proBNP level, left atrial size, NYHA class and estimated glomerular filtration rate (eGFR). By 12 weeks blood
pressure was reduced by 9 mmHg (SD 15)/5 mmHg (SD 11) in patients receiving LCZ696 in comparison with 3 mmHg
(SD 17)/2 mmHg (SD 12) in those receiving valsartan. The change in NT-proBNP was poorly correlated with change
in SBP (LCZ696, r = 0.17, P = 0.06; valsartan, r = 0.05, P = 0.58) After adjustment for change in SBP, the ratio of
change in NT-proBNP at 12 weeks for LCZ696 vs. valsartan was 0.76 (95% CI 0.63–0.93, P = 0.008), and similar to
the ratio not adjusting for SBP (0.76, 95% CI 0.63–0.92, P = 0.006); P for interaction was 0.38). Similarly, reduction
in left atrial volume index at 36 weeks, improvement in NYHA class and eGFR were all independent of the change
in SBP.
.....................................................................................................................................................................
Conclusion In patients with HFpEF, the effect of the angiotensin receptor neprilysin inhibitor LCZ696 on NT-proBNP, left atrial
volume, functional class, and eGFR was independent of reduction in SBP.
..........................................................................................................
Keywords Blood pressure • Heart failure • Neprilysin inhibitor • NT-proBNP • Preserved ejection fraction

*Corresponding author: Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115, USA. Tel: +1 857 3071954, Fax: +1 857 3071944, E-mail:
ssolomon@rics.bwh.harvard.edu

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
2 P.S. Jhund et al.

region. The primary endpoint was change from baseline in NT-proBNP

Introduction

..................................................................................................................................................................................
at 12 weeks with secondary endpoints of changes in echocardiographic
The diagnosis of heart failure with preserved ejection fraction measures, blood pressure and NYHA class. The study conforms with
(HFpEF) is associated with considerable morbidity and mortality the principles outlined in the Declaration of Helsinki and all subjects
but no treatments have been shown to improve morbidity or gave written informed consent.
mortality in these patients.1 – 5 The majority of patients with The NT-proBNP level was measured at screening, randomization,
week 4, week 12, and week 36 or at end of study or at early termination
HFpEF have a history of hypertension, and the consequent adverse
visits. Assessment of NT-proBNP for efficacy was measured at a
structural and functional changes of the heart, arteries and kidneys
central laboratory (Quest Diagnostics, Valencia, CA, USA) with the
are thought to play a central role in the development of heart
Elecsys NT-proBNP immunoassay (Roche Diagnostics, Indianapolis, IN,
failure (HF) in these patients. While treatment of hypertension has USA). Echocardiography was performed at screening, randomization,
been considered a central strategy in the treatment of HFpEF, the week 12, and week 36 or at end of study or early termination visits.
effects of blood pressure lowering on the cardiac, vascular, and Analyses were conducted at a core laboratory (Brigham and Women’s
renal abnormalities in this syndrome are uncertain, as are its effects Hospital, Boston, MA, USA). Measurements were made in triplicate
on symptoms and outcomes.6,7 in accordance with the recommendations of the American Society of
In the recent Prospective comparison of ARNi (angiotensin Echocardiography.9 The NYHA status was recorded at each visit and
receptor neprilysin inhibitor) with ARB (angiotensin receptor eGFR was calculated by the MDRD formula.
blocker) on Management Of heart failUre with preserved ejectioN Blood pressure was measured at each visit in the sitting position.
At each visit three readings were taken and the mean calculated.
fracTion (PARAMOUNT) trial,8 301 patients were randomized to
Pulse pressure and mean arterial pressure were calculated from these
treatment either with the angiotensin receptor blocker valsartan
mean values. Change in systolic blood pressure (SBP) and diastolic
or the ARNi LCZ696. LCZ696 comprises the molecular moieties
blood pressure was calculated as the difference between baseline and
of the neprilysin (neutral endopeptidase 24.11) inhibitor prodrug 12 week and 36 week follow-up mean sitting blood pressure. Change
AHU377 and the ARB valsartan in one compound. Neprilysin also in pulse pressure and mean arterial pressure was calculated by the
breaks down polypeptide vasoconstrictors such as angiotensin II, same method. The percentage change in SBP was also calculated as the
therefore to offset the loss of this effect, background ARB admin- difference between baseline and 12 week and 36 week blood pressure
istration is required. Patients were randomly assigned (1:1) to divided by baseline blood pressure.
treatment with either LCZ696 200 mg b.i.d. or valsartan (Dio-
van) 160 mg bid after stopping their usual angiotensin-converting
Statistical analysis
enzyme-inhibitor (ACE-I) or ARB for 24 h. LCZ696 200 mg b.i.d.
gives similar plasma valsartan exposure as the Diovan prepara- The correlation between change in SBP and continuous variables was
assessed using Pearson or Spearman correlation as appropriate. The
tion of valsartan 160 mg b.i.d. Compared with valsartan, LCZ696
endpoint of change in NT-proBNP was analysed using multiple linear
reduced N-terminal pro-B-type natriuretic peptide (NT-proBNP)
regression with randomized treatment and randomization stratification
at 12 weeks (the primary endpoint), and reduced left atrial vol- (previous use of an ACE inhibitor or ARB, and region) as fixed
ume and New York Heart Association (NYHA) class at 36 weeks. It factors and the baseline log-transformed NT-proBNP as a covariate.
remains unknown whether the effects of LCZ696 in these patients To assess whether the effect of treatment was independent of change
were related to the blood pressure lowering effect of the drug. We in SBP, change in SBP at 12 weeks was entered into the model and
therefore used data from the PARAMOUNT trial to explore the an interaction term between treatment and continuous change in SBP
hypothesis (in a small post hoc study) that greater blood pressure was tested. The primary 12 week analysis was pre-specified as a last
lowering by LCZ696 was not responsible for its cardiac and renal observation carried forward analysis and included all patients randomly
effects by assessing whether these changes were independent of assigned to treatment groups who had a baseline and at least one post-
the blood pressure lowering observed. baseline assessment. For this reason SBP was not carried forward in
any analyses where SBP was missing to minimise any error introduced
through the introduction of a last observation carried value in the
explanatory variable as well as the outcome variables that already
Methods included a last value carried forward. The same procedures were
The design and results of the PARAMOUNT trial (registered at Clin- used to assess diastolic blood pressure, mean arterial pressure and
icalTrials.gov, NCT00887588) have been previously published.8 The pulse pressure as measures of blood pressure change. Logarithmic
study was a randomized, double-blind, parallel-group, active controlled transformation was used for NT-proBNP as the distribution was
trial. Men and women aged 40 years or older with a left ventricular skewed. To examine the effect of LCZ696 on measures of left atrial
ejection fraction (LVEF) ≥45% and with a documented history of heart size, analyses were performed on differences between baseline and
failure with associated signs or symptoms were eligible for randomiza- 36 week measures of left atrial size as specified in the PARAMOUNT
tion. Patients were required to have a NT-proBNP level of ≥400 pg/mL trial. Again, multiple linear regression using the same fixed factors,
at screening, be on diuretic therapy, and have a systolic blood pres- change in SBP covariates and interaction term, as above, were entered
sure ≤140 mmHg, or ≤160 mmHg if on three or more blood pressure into the model with baseline left atrial measures (diameter and volume
drugs at randomization, have an estimated glomerular filtration rate index). Change in NYHA class at 36 weeks by treatment was tested
(eGFR) of at least 30 mL/min per 1.73 m2 at screening [calculated by the using the Cochran–Mantel–Haenszel test with the randomization
six-variable Modification of Diet in Renal Disease (MDRD) formula], stratification variables, and change in SBP as stratification levels. To
and a potassium concentration of no more than 5.2 mmol/L. Treat- test the interaction between treatment and change in SBP with respect
ment assignment was stratified by previous use of ACE-I or ARB and to change in NYHA class an ordered logistic regression model was

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
LCZ696 and blood pressure in HFpEF 3

fitted. The same procedures were used to assess diastolic blood results were consistent (see the Supporting Information, Tables

........................................................................................................................................................................
pressure, mean arterial pressure and pulse pressure as measures of S1 and S2).
blood pressure change as well as percentage change in SBP. We also We found that SBP variability was not different between the
explored the effect of treatment on SBP variability and whether the LCZ696 and valsartan groups at 12 weeks (P = 0.70) or at 36 weeks
effect of treatment on outcomes was modified by SBP variability. In
(P = 0.56). There was no interaction between SBP pressure vari-
an exploratory analysis we examined whether the effect of treatment
ability and the effect of treatment on NT-proBNP at 12 weeks,
was mediated by change in SBP through a mediation model.10 As the
(P = 0.56), change in NYHA class by 36 weeks (p = 0.74), left atrial
sample size is small in the present study this was performed as an
exploratory analysis only. All analyses were carried out using STATA diameter (P = 0.06), left atrial volume index (p = 0.83), or eGFR
version 12 (Stata Corp, College Station, TX, USA). A P-value of <0.05 (P = 0.08).
was considered significant. In an exploratory mediation model we found no significant
mediation of the effect of treatment with LCZ696 on changes
in NT-proBNP through blood pressure (estimated mediation 2%;
Results 95%CI −14% to 24%, P = 0.89).
Of the 301 patients randomized in the study, 274 patients (137
in each treatment group) had a valid SBP reading at baseline and Discussion
at 12 weeks. The mean change in SBP at 12 weeks in the LCZ696
group was −9 mmHg (SD 15) and −3 mmHg (SD 17) in the valsar- In this study, we found that the efficacy of the novel angiotensin
tan group (P = 0.002). The SBP measurements at 36 weeks were receptor neprilysin inhibitor LCZ696 in reducing levels of NT-
available in 126 patients in the LCZ696 group and 124 patients proBNP at 12 weeks was independent of the blood pressure
in the valsartan group, with a mean SBP change of −7 mmHg (SD lowering effect of the drug, as were improvements in left atrial
17) and −1 mmHg (SD 18), respectively (P = 0.002). Higher SBP size, NYHA class and eGFR at 36 weeks. These findings suggest
at baseline was associated with higher LVEF (r = 0.14, P = 0.04), that LCZ696 has potentially beneficial effects in patients HFpEF
lower E′ (r = −0.224, P = 0.002), higher E/E′ ratio (r = 0.2, = 0.01) over and above its ability to lower systolic blood pressure.
and female sex (45%, 64%, and 63% female in tertiles 1, 2, and 3, A number of observations from the PARAMOUNT trial further
respectively, P = 0.006). support our finding that the effect of LCZ696 is independent of
The distribution and baseline characteristics of patients accord- blood pressure lowering. That reduction in NT-proBNP preceded
ing to tertile of change in SBP at 12 weeks are shown in Table 1. reduction in left atrial size suggests that the reduction in NT-
There were no significant interactions between treatment group, proBNP is unlikely to be secondary to a reduction in left atrial size
baseline characteristics and change in SBP. as a result of less atrial stretch owing primarily to lower blood
There was poor correlation between change in SBP and change pressure. However, this simple temporal association is not proof
in NT-proBNP at 12 weeks in the LCZ696 (r = 0.17, P = 0.06) of causality. The improvement in eGFR in the LCZ696 group also
and valsartan (r = 0.05, P = 0.58) group (Figure 1). At 12 weeks cannot be readily explained through a blood pressure lowering
NT-proBNP fell significantly in the LCZ696 group vs. the valsartan mechanism. LCZ696 inhibits neprilysin which breaks down atrial
group (ratio for change 0.76, 95% CI 0.63–0.92, P = 0.006). When natriuretic peptide (ANP). As ANP increases efferent glomerular
stratified by tertile of change in SBP by 12 weeks, a similar ratio arteriolar tone, potentiation of ANP might be one mechanism by
of change in NT-proBNP in the LCZ696 vs. valsartan groups which LCZ696 maintains eGFR.11,12 This has been demonstrated
was observed (Figure 2). After adjusting for change in SBP over in pharmacodynamic studies of omapatrilat,13 a combined ACE-I
12 weeks the ratio for change in NT-proBNP at 12 weeks in and neprilysin inhibitor, and lower rates of renal dysfunction
the LCZ696 group vs. the valsartan group was (0.76, 95% CI have been reported in clinical trials of the drug.14,15 These find-
0.63–0.93, P = 0.008), similar to that for the unadjusted change ings indicate that dual inhibitors of the renin–angiotensin and
in NT-proBNP (0.76, 95%CI 0.63–0.92, P = 0.006). There was no neprilysin systems have complex modes of action that cannot be
interaction between randomized treatment and change in SBP on simply ascribed to changes in one physiological parameter such
the outcome of NT-proBNP level at 12 weeks (P = 0.38). Similarly, as blood pressure. Finally, in the Aldosterone Receptor Blockade
the correlation between change in SBP and change in NT-proBNP in Diastolic Heart Failure (Aldo-DHF) trial,16 a greater fall in SBP
at 36 weeks was poor (LCZ696: r = 0.015, P = 0.90; valsartan: was observed in the spironolactone group compared with the
r = −0.09, P = 0.36). placebo group but, similarly, improvement in diastolic function (as
The correlation between change in SBP and change in left atrial measured by the E/E′ ratio) was greater in the spironolactone
diameter, left atrial volume, and eGFR at 36 weeks was similarly group even after adjustment for blood pressure. The mechanisms
poor (P = 0.73, P = 0.76, and P = 0.04, respectively). In models of action of spironolactone and LCZ696 in HFpEF are likely to
assessing the influence of change in SBP on the effect of treatment be different, but the consistency of a blood pressure independent
on changes in these measures, we also found no interaction effect supports the argument that blood pressure lowering does
(Table 2). While NYHA class improved more in the LCZ696 group not necessarily underpin benefit in HFpEF.
there was also no interaction between change in SBP and treatment The concept that managing hypertension has a crucial role in
on change in NYHA class (Figure 3). treating HFpEF derives from the observation that hypertension
Analyses were repeated using diastolic blood pressure, mean causes adverse structural and functional changes in the heart,
arterial pressure, pulse pressure and percentage change in SBP, the which are thought to be at least in part responsible for the

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
4 P.S. Jhund et al.

Table 1 Baseline characteristics according to tertile of change systolic blood pressure at 12 weeks and treatment with
LCZ 696 and valsartan

Tertile 1, Tertile 2 Tertile 3, P for P for interaction

n = 100 N = 90 n = 84 trend (treatment × change
(−48 to (−11 to (1–61 in systolic
−12 mmHg) 0 mmHg) mmHg) blood pressure)
...........................................................................................................................................
Age (years) 70.3 (9.3) 71.2 (9.0) 72.0 (9.1) 0.20 0.88
Women 63 (63%) 42 (46.7%) 52 (61.9%) 0.31 0.08
NYHA Class
NYHA Class I 2 (2.2%)
NYHA Class II 81 (81%) 72 (80%) 67 (79.6)
NYHA Class III 19 (19%) 16 (17.8%) 17 (20.2%) 0.80 0.68
Previous history
Previous admission to hospital for heart failure 40 (40%) 31 (34.4%) 38 (45.2%) 0.74 0.93
History of atrial fibrillation 43 (43%) 39 (43.3%) 32 (38.1%) 0.57 0.06
Atrial fibrillation at screening ECG 30 (30%) 25 (27.8%) 23 (27.4%) 0.99 0.61
History of hypertension 92 (92%) 84 (93.3%) 80 (95.2%) 0.56 0.83
History of diabetes 36 (36%) 35 (38.9%) 26 (31.0%) 0.26 0.92
History of myocardial infarction 26 (26%) 18 (20%) 15 (25.4%) 0.09 0.56
Left ventricular ejection fraction (%) 58.9 (8.2) 57.1 (6.7) 58.5 (8.6) 0.66 0.97
Left ventricular ejection fraction ≥45% and <50% 13 (14.3) 11 (13.4%) 8 (10%) 0.23 0.53
NT-proBNP (pg/mL) 836 (567–1340) 947 (515–1454) 755 (439–1129) 0.26 0.76
Heart rate (bpm) 68.8 (13.0) 70.0 (12.9) 67.8 (13.0) 0.70 0.72
Body mass index (kg/m2 ) 30.7 (5.9) 30.2 (5.1) 28.7 (5.8) 0.02 0.88
Mean sitting systolic BP (mmHg) 141.4 (13.0) 135.2 (12.5) 129.3 (14.9)
Mean sitting diastolic BP (mmHg) 80.0 (10.3) 77.9 (8.5) 74.6 (10.5) <0.001 0.27
Pulse pressure (mmHg) 60.5 (14.2) 57.2 (13.4) 54.8 (16.4) 0.001 0.37
eGFR (mL/min per 1.73 m2 ) 67.5 (20.1) 64.5 (19.0) 65.3 (21.9) 0.44 0.11
eGFR <60 mL/min per 1.73 m2 36 (36) 38 (43.2%) 36 (43.9%) 0.66 0.80
Baseline echocardiographic measures
E′ (cm/s) 7.4 (2.5) 7.4 (2.9) 7.5 (2.8) 0.92 0.17
E/A 1.2 (0.6) 1.1 (0.6) 1.1 (0.7) 0.20 0.80
E/E′ 13.2 (6.2) 12.2 (5.8) 12.3 (3.9) 0.38 0.67
Left atrial diameter (cm) 3.6 (0.5) 3.8 (0.5) 3.7 (0.5) 0.70 0.97
Left atrial volume (mL) 64.5 (26.2) 66.4 (28.7) 64.2 (23.3) 0.23 0.05
Left atrial volume index (mL/m2 ) 35.8 (13.4) 35.7 (13.8) 35.7 (12.9) 0.96 0.07
Left ventricular end diastolic volume (mL) 105.0 (23.2) 115.1 (29.8) 118.7 (32.4) 0.004 0.32
Left ventricular end systolic volume (mL) 43.4 (14.6) 50.1 (17.8) 50.3 (21.8) 0.02 0.50
Left ventricular mass (g) 143.0 (41.5) 145.4 (36.9) 149.9 (43.8) 0.27 0.14
Left ventricular mass index (g/m2 ) 75.7 (19.1) 75.8 (20.9) 81.8 (23.3) 0.08 0.72
Relative wall thickness (%) 0.4 (0.1) 0.4 (0.1) 0.4 (0.1) 0.68 0.75
Tricuspid regurgitant velocity (m/s) 2.5 (0.4) 2.5 (0.3) 2.7 (0.5) 0.46 0.12
Baseline treatments
Randomized to LCZ696 58 (58%) 47 (52%) 32 (38%)
ACE inhibitors 53 (53%) 54 (60.0%) 40 (47.6%) 0.80 0.12
ARBs 44 (44%) 33 (36.7%) 36 (43.9%) 0.41 0.24
ACE inhibitors or ARBs 96 (96%) 85 (94.4%) 76 (90.5%) 0.03 0.32
Diuretics 100 (100%) 90 (100%) 84 (100%)
Beta blockers 79 (79%) 70 (77.8%) 69 (82.1%) 0.66 0.65
Aldosterone antagonists 27 (27%) 12 (13.3%) 15 (17.9%) 0.36 0.97

NYHA, New York Heart Association; ECG, electrocardiogram; NT-proBNP, N-terminal pro-brain natriuretic peptide; BP, blood pressure; eGFR, estimated glomerular filtration
rate; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
LCZ696 and blood pressure in HFpEF 5

syndrome of HFpEF.17,18 Lowering SBP may reverse these changes

...................................................................................
leading to improvement in the signs and symptoms of HFpEF
and lower levels of NT-proBNP. In HFpEF, both structural cardiac
remodelling and higher levels of NT-proBNP are associated with
worse outcomes.19,20 Therapies known to alter outcomes in HFrEF
have all been associated with modest blood pressure lowering
when tested in HFpEF populations. In the largest HFpEF trial
to date, the Irbesartan in Heart Failure with Preserved Systolic
Function (I-PRESERVE) study, SBP fell by a mean of 3.8 mmHg in
the 2067 patients randomized to the ARB irbesartan.3 Despite
this, irbesartan did not alter morbidity or mortality in the trial
(neither did it reduce levels of NT-proBNP). However, this does
not exclude a potential blood pressure effect of these drugs. For
example, in contrast, in the VALsartan In Diastolic Dysfunction Figure 1 Correlation between change in systolic blood pres-
(VALIDD) trial,21 a blood pressure dependent effect of valsartan on sure at 12 weeks and change in N-terminal pro-brain natriuretic
echocardiographic parameters of diastolic function were observed. peptide (NT-proBNP) at 12 weeks according to randomized
However, in contrast, patients in the PARAMOUNT trial had a treatment, LCZ696 (open circles, dashed line), valsartan (closed
lower blood pressure (by design) and parameters such as E′ were circles, solid line).
not affected by treatment with LCZ696, perhaps because it was not
possible for the treatments to lower blood pressure much further.
However, a treatment effect was still observed and it is possible natriuretic peptides. Treatment with LCZ696 would be expected
that the effect of drugs such as valsartan and LCZ696 may be blood to raise BNP acutely, though improvement in haemodynamics over
pressure dependent at higher blood pressure but independent of time would likely reduce the production of natriuretic peptides.
the blood pressure lowering effect in individuals where the blood NT-proBNP, which is not affected by neprilysin, remains a good
pressure is already well controlled. marker of severity of heart failure even in the setting of neprilysin
If blood pressure is not the mechanism by which these poten- inhibition. A number of other natriuretic peptides, including ANP
tial benefits were observed then other pathways must be con- and C-type natriuretic peptide, are also broken down by neprilysin
sidered. The most obvious candidate is the effect of LCZ696 on and therefore might have been potentiated by neprilysin inhibition,

Figure 2 Ratio of change in N-terminal pro-brain natriuretic peptide (NT-proBNP) at 12 weeks for LCZ696 vs. valsartan by tertile of change
in systolic blood pressure (SBP) and after adjustment for systolic blood pressure.

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
6 P.S. Jhund et al.

Table 2 Change in left atrial diameter, left atrial volume and estimated glomerular filtration rate (eGFR) according
to treatment and change in systolic blood pressure at 36 weeks

Tertile 1, n = 89 Tertile 2, n = 83 Overall Tertile 3, n = 78

(−50 to −12 mmHg) (−11 to −2 mmHg) .........................................
(3–62 mmHg)
Change Change Change
P LCZ696 vs. valsartan P for
(95%CI) (95%CI) (95%CI)
(adjusted for change interaction
in SBP at 36 weeks)
...........................................................................................................................................
Left atrial diameter
LCZ696 −0.15(−0.25 to −0.06) −0.12(−0.23 to −0.01) −0.19(−0.32 to −0.05) 0.03 0.91
Valsartan −0.04(−0.14 to −0.06) −0.07(−0.16 to −0.02) −0.11(−0.22 to −0.01)
Left atrial indexed volume
LCZ696 −2.65 (−4.71 to −0.59) −1.77 (−4.87 to −1.34) −3.74 (−7.18 to −0.29) 0.01 0.61
Valsartan −0.28(−3.54 to −2.98) 0.22 (−2.69 to −3.14) 0.80(−2.53 to 4.13)
eGFR
LCZ696 −3.83(−6.99 to −0.67) −1.28(−6.26 to −3.70) 1.86(−3.02 to −6.74) 0.002 0.69
Valsartan −9.09(−12.78 to −5.41) −3.03(−7.16 to −1.11) −4.28(−7.34 to −1.23)

NYHA = New York Heart Association. SBP, systolic blood pressure.

Figure 3 Proportion of patients with improved, unchanged or worsened New York Heart Association (NYHA) class at 36 weeks by LCZ696
vs. valsartan by tertile of change in systolic blood pressure.

as suggested above. This might explain why improvement in left are incompletely understood,8 but abnormal pressure–volume
...................................

atrial measures and eGFR occurred independently of blood pres-
sure, through direct effects on the myocardium and kidney.22 We
did not measure other natriuretic peptides and cannot confirm this
hypothesis but further studies to explore this potential mechanism
are warranted.
Although we have demonstrated that the effect of LCZ696 on
left atrial size, NT-proBNP, NYHA class, and eGFR are indepen-
dent of change in blood pressure, we did observe a greater degree
of blood pressure reduction with LCZ696 compared with valsar-
tan. This finding may still be beneficial in other aspects of the
pathophysiology of HFpEF. Haemodynamic abnormalities in HFpEF
responses to exercise and abnormal ventricular–arterial coupling
are thought to be important and are intimately linked to blood
pressure.8 The ability of a drug to significantly lower blood pressure
may help to normalize such haemodynamic responses in HFpEF.
Although the effect of LCZ696 on NYHA class was independent of
blood pressure in this analysis, we cannot exclude a blood pressure
dependent effect of LCZ696 on this parameter of physical capacity
that might become evident in a larger trial with longer follow-up. It
is also important to recognize that blood pressure was extremely
well controlled in PARAMOUNT patients at the time of random-
ization; we cannot rule out the possibility that in patients with

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology
LCZ696 and blood pressure in HFpEF 7

uncontrolled blood pressure, the blood pressure lowering effect of 4. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson

.......................................................................................................................................................................
EL, Olofsson B, Ostergren J. Effects of candesartan in patients with chronic heart
LCZ696 might contribute to the potential benefit, as was suggested
failure and preserved left-ventricular ejection fraction:the CHARM-Preserved
in the subgroup of patients in the PARAMOUNT trial with a SBP Trial. Lancet 2003;362:777–781.
of >140 mmHg. We did, however, observe a wide range of blood 5. Cleland JGF, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. The
perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur
pressure changes in contrast to the limited initial range of SBP. Heart J 2006;27:2338–2345.
Several limitations of our analysis should be noted. Our analysis 6. Aurigemma GP, Gaasch WH. Diastolic heart failure. N Engl J Med
is a post hoc study of a trial with a relatively small sample size 2004;351:1097–1105.
7. Borlaug B, Paulus WJ. Heart failure with preserved ejection frac-
and relatively well controlled blood pressure. We cannot rule tion:pathophysiology, diagnosis, and treatment. Eur Heart J 2011;32:670–679.
out the possibility that in a larger sample with wider variation 8. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V,
in blood pressure an interaction with change in blood pressure Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJV. The
angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved
will be found. We did not have detailed physiological measures ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet
of renal perfusion and measures of other natriuretic peptides 2012;380:1387–1395.
to provide further information about the possible mechanism by 9. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard
MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton
which LCZ696 produced its effect. The outcomes studied are MSJ, Stewart WJ. Recommendations for chamber quantification:a report from
surrogate endpoints and it may be that in larger trials testing the the American Society of Echocardiography’s Guidelines and Standards Com-
effect of LCZ696 on morbidity and mortality a blood pressure mittee and the Chamber Quantification Writing Group, developed in con-
junction with the European Association of Echocardiograph. J Am Soc Echo
dependent effect on outcomes may be seen. 2005;18:1440–1463.
In summary, the novel ARNi, LCZ696, produces favourable 10. Morgan-Lopez AA, MacKinnon DP. Demonstration and evaluation of a
changes in NT-proBNP, NYHA class, eGFR and left atrial dimen- method for assessing mediated moderation. Behav Res Methods 2006;38:
77–87.
sions in patients with HFpEF. These potential benefits, which will be 11. Marin-Grez M, Fleming JT, Steinhausen M. Atrial natriuretic peptide causes pre-
tested in an outcomes trial, appear to be independent of reductions glomerular vasodilatation and post-glomerular vasoconstriction in rat kidney.
in systolic blood pressure. Nature 1986;324:473–476.
12. Dunn BR, Ichikawa I, Pfeffer JM, Troy JL, Brenner BM. Renal and systemic
hemodynamic effects of synthetic atrial natriuretic peptide in the anesthetized
rat. Circ Res 1986;59:237–246.
Funding 13. Regamey F, Maillard M, Nussberger J, Brunner HR, Burnier M. Renal
hemodynamic and natriuretic effects of concomitant angiotensin-converting
None. enzyme and neutral endopeptidase inhibition in men. Hypertension 2002;40:
266–272.
Conflict of interest: S.D.S., M.Z., B.P., A.V., M.P., and J.J.V.M. have 14. Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau JL, Swedberg K.
Comparison of omapatrilat and enalapril in patients with chronic heart failure:the
received research support and have consulted for Novartis. V.S., T.B., Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events
and M.L. are employees of Novartis. P.S.J. has no conflict of interest to (OVERTURE). Circulation 2002;106:920–926.
declare. 15. Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier F, Kerut EK, Porter CB,
Proulx G, Qian C, Block AJ. Comparison of vasopeptidase inhibitor, omapatrilat,
and lisinopril on exercise tolerance and morbidity in patients with heart failure:
IMPRESS randomised trial. Lancet 2000;356:615–620.
Supplementary Information 16. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke
W, Duvinage A, Stahrenberg R, Durstewitz K, Löffler M, Düngen H-D, Tschöpe
Additional Supporting Information may be found in the online C, Herrmann-Lingen C, Halle M, Hasenfuss G, Gelbrich G, Pieske B. Effect of
spironolactone on diastolic function and exercise capacity in patients with heart
version of this article:
failure with preserved ejection fraction: the Aldo-DHF randomized controlled
Table S1. Change in log NT-proBNP at 12 weeks and change in left trial. JAMA 2013;309:781–791.
atrial diameter and index volume and eGFR at 36 weeks according 17. Zile MR, Gaasch WH, Carroll JD, Feldman MD, Aurigemma GP, Schaer GL, Ghali
JK, Liebson PR. Heart failure with a normal ejection fraction:is measurement
to change in mean arterial pressure, diastolic blood pressure, pulse
of diastolic function necessary to make the diagnosis of diastolic heart failure?
pressure and percentage change in systolic blood pressure. Circulation 2001;104:779–782.
Table S2. Change in NYHA class at 36 weeks according to tertile 18. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure – abnormalities in
active relaxation and passive stiffness of the left ventricle. N Engl J Med
of change in mean arterial pressure, diastolic blood pressure, pulse
2004;350:1953–1959.
pressure and percentage change in systolic blood pressure. 19. Kirk V, Bay M, Parner J, Krogsgaard K, Herzog TM, Boesgaard S, Hassager
C, Nielsen OW, Aldershvile J, Nielsen H. N-terminal proBNP and mortality
in hospitalised patients with heart failure and preserved vs. reduced systolic
function:data from the prospective Copenhagen Hospital Heart Failure Study
References (CHHF). Eur J Heart Fail 2004;6:335–341.
20. Zile MR, Gottdiener JS, Hetzel SJ, McMurray JJ, Komajda M, McKelvie R, Baicu
1. Aronow WS, Ahn C, Kronzon I. Effect of propranolol versus no propranolol on
CF, Massie BM, Carson PE. Prevalence and significance of alterations in cardiac
total mortality plus nonfatal myocardial infarction in older patients with prior
structure and function in patients with heart failure and a preserved ejection
myocardial infarction, congestive heart failure, and left ventricular ejection frac-
fraction. Circulation 2011;124:2491–2501.
tion ≥40% treated with diuretics plus angiotensin-converting enzyme inhibitors.
21. Solomon SD, Janardhanan R, Verma A, Bourgoun M, Daley WL, Purkayastha
Am J Cardiol 1997;80:207–209.
D, Lacourcière Y, Hippler SE, Fields H, Naqvi TZ, Mulvagh SL, Arnold JM,
2. Setaro JF, Zaret BL, Schulman DS, Black HR, Soufer R. Usefulness of ver-
Thomas JD, Zile MR, Aurigemma GP;Valsartan In Diastolic Dysfunction (VALIDD)
apamil for congestive heart failure associated with abnormal left ventricular
Investigators. Effect of angiotensin receptor blockade and antihypertensive drugs
diastolic filling and normal left ventricular systolic performance. American J Cardiol
on diastolic function in patients with hypertension and diastolic dysfunction: a
1990;66:981–986.
randomised trial. Lancet 2007;369:2079–2087.
3. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson
22. Nunez DJ, Dickson MC, Brown MJ. Natriuretic peptide receptor mRNAs in the
S, Donovan M, Iverson E, Staiger C, Ptaszynska A. Irbesartan in patients with
rat and human heart. J Clin Invest. 1992;90:1966–1971.
heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456–2467.

© 2014 The Authors

European Journal of Heart Failure © 2014 European Society of Cardiology