Journal of RESEARCH ARTICLE

Geriatric Cardiology J Geriatr Cardiol 2023; 20(12): 855–866

Efficacy and safety of sacubitril/valsartan after six months in

patients with heart failure with reduced ejection fraction and
asymptomatic hypotension

An-Hu WU, Zong-Wei LIN, Zhuo-Hao YANG, Hui ZHANG, Jia-Yi HU, Yi WANG, Rui TANG,
Xin-Yu ZHANG, Xiao-Ping JI✉, Hui-Xia LU✉
National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascu-
lar Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Ch-
inese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
✉ Correspondence to: jixiaoping@sdu.edu.cn (JI XP); luhuixia@sdu.edu.cn (LU HX)
https://doi.org/10.26599/1671-5411.2023.12.005

ABSTRACT

BACKGROUND It is not clear whether sacubitril/valsartan is beneficial for patients with heart failure (HF) with reduced ejec-
tion fraction (HFrEF) and low systolic blood pressure (SBP). This study aimed to investigate the efficacy and tolerability of sacu-
bitril/valsartan in HFrEF patients with SBP < 100 mmHg.

METHODS & RESULTS An observational study was conducted on 117 patients, 40.2% of whom had SBP < 100 mmHg wit-
hout symptomatic hypotension, and 59.8% of whom had SBP ≥ 100 mmHg in an optimized HF follow-up management system.
At the 6-month follow-up, 52.4% of patients with SBP < 100 mmHg and 70.0% of those with SBP ≥ 100 mmHg successfully rea-
ched the target dosages of sacubitril/valsartan. A reduction in the concentration of N-terminal pro-B-type natriuretic peptide was
similar between patients with SBP < 100 mmHg and SBP ≥ 100 mmHg (1627.5 pg/mL and 1340.1 pg/mL, respectively; P = 0.75).
The effect of sacubitril/valsartan on left ventricular ejection fraction was observed in both SBP categories, with a 10.8% increase in
patients with SBP < 100 mmHg (P < 0.001) and a 14.0% increase in patients with SBP ≥ 100 mmHg (P < 0.001). The effects of sac-
ubitril/valsartan on SBP were statistically significant and inverse across both SBP categories (P = 0.001), with an increase of 7.5
mmHg in patients with SBP < 100 mmHg and a decrease of 11.5 mmHg in patients with SBP ≥ 100 mmHg. No statistically signi-
ficant differences were observed between the two groups in terms of the occurrence of symptomatic hypotension, deteriorating re-
nal function, hyperkalemia, angioedema, or stroke.

CONCLUSIONS Within an optimized HF follow-up management system, sacubitril/valsartan exhibited excellent tolerability
and prompted left ventricular reverse remodeling in patients with HFrEF who presented asymptomatic hypotension.

T here are 10% to 20% of patients with heart
failure (HF) with reduced ejection fraction
(HFrEF) experience low systolic blood pre-
ssure (SBP).[1] In patients with HFrEF, it can indicate
severely impaired left ventricular systolic function,[1]
an independent predictor of outcome,[2–6] and a signif-
icant contributor to medication intolerance and a fail-
ure to titrate to target doses of evidence-based medical
therapy.[7–10] The management of patients with HFrEF
with low SBP continues to be a major challenge for cli-
nical practice.
In the Prospective Comparison of angiotensin recep-
tor-neprilysin inhibitor (ARNI) with an angiotensin-con-
verting enzyme inhibitor (ACEI) to Determine Impact
on Global Mortality and Morbidity in Heart Failure
(PARADIGM-HF) trial, sacubitril/valsartan reduced the
primary composite outcome of HF hospitalization or
cardiovascular mortality by 20%, as compared with en-
alapril.[11] According to this study, updated evidence-
based guidelines for the treatment of HF provided cla-
ss I, level of evidence B recommendation to replace re-
nin-angiotensin system blockers with sacubitril/vals-
artan in patients with chronic symptomatic HFrEF de-
spite optimal treatment.[12] In addition to blocking the
renin-angiotensin system, sacubitril/valsartan also en-
hances the activity of vasoactive substances such as na-

© 2023 JGC All rights reserved; www.jgc301.com

 JOURNAL OF GERIATRIC CARDIOLOGY
triuretic peptides and bradykinin, leading to a lower bl-
ood pressure (BP) than an ACEI or angiotensin II rece-
ptor blocker (ARB), which may raise concerns among
physicians regarding its routine use in patients with
low BP. A post-hoc analysis of the PARADIGM-HF stu-
dy compared the effects of sacubitril/valsartan in HFr-
EF patients across different BP groups, demonstrating
that lower SBP during the run-in period and after rand-
omization did not attenuate the benefit of sacubitril/
valsartan compared with enalapril.[6] Nevertheless, this
study excluded patients with symptomatic hypotension,
SBP less than 100 mmHg at screening, or 95 mmHg at
randomization. Therefore, there is a lack of evidence on
the efficacy and safety of initiating sacubitril/valsartan
in patients with HFrEF and SBP < 100 mmHg, alth-
ough the European Society of Cardiology guidelines re-
commend that a HF specialist should be sought rather
than stopping or decreasing drugs with class I indicati-
on in HFrEF in patients with persisting low BP or symp-
toms of orthostatic hypotension.[13]
We have developed a follow-up management syst-
em tailored to Chinese patients with chronic HF (CHF),
which has demonstrated its ability to enhance the pr-
oportion of patients achieving the target dose of sac-
ubitril/valsartan and improve the recovery of ventricu-
lar remodeling and cardiac function.[14] We have also
proposed strategies for titrating sacubitril/valsartan in
HFrEF patients with concomitant hypotension, based on
existing research evidence and our clinical practice ex-
perience.[15] The primary objective of this study was to as-
sess the efficacy and safety of sacubitril/valsartan over a
six-month period among patients with HFrEF experien-
cing asymptomatic hypotension and enrolled in this op-
timized HF follow-up management system.
METHODS
Study Population
We conducted a retrospective observational study
and the study population consisted of both outpatients
and inpatients of the cardiology department with a di-
agnosis of HFrEF treated with sacubitril/valsartan for
more than six months in Qilu Hospital of Shandong
University, China between October 2017 and March
2022. The patients comprising our study cohort were
participants in our CHF patient follow-up management
system, which was elaborated upon in the subsequent
856
RESEARCH ARTICLE
sections. The data in this study were acquired from the
electronic medical record system of Qilu Hospital of
Shandong University, China. The inclusion criteria we-
re: (1) age ≥ 18 years; (2) symptomatic HF defined as
NYHA (the New York Heart Association) class II–IV;
(3) left ventricular ejection fraction (LVEF) < 40% by
echocardiography; and (4) SBP < 100 mmHg without
severe hypotension symptoms in the early stages of pr-
escription, and SBP ≥ 100 mmHg. The exclusion criter-
ia were: (1) lost to follow-up after initiation of sacubi-
tril/valsartan; (2) LVEF > 40% by echocardiography;
and (3) SBP < 100 mmHg with severe hypotension sy-
mptoms in the early stages of prescription.
Patients were monitored regularly in outpatient set-
tings over the course of a six-month follow-up period. A
total of 300 patients were preliminarily screened, 117
patients of whom met the eligibility criteria for analy-
sis, including 47 patients with SBP < 100 mmHg and 70
patients with SBP ≥ 100 mmHg (Figure 1). This study
was conducted in accordance with the principles of the
Declaration of Helsinki. The Research Ethics Commi-
ttee of Qilu Hospital of Shandong University, China
(KYLL-202205-036-1) approved this study protocol. Wr-
itten informed consent was obtained from all participat-
ing individuals prior to their involvement in study-re-
lated activities.
CHF Follow-up Management System
All trial participants were enrolled in the CHF foll-
ow-up management system throughout their hospital-
ization and post-discharge periods. This study empl-
oyed a well-monitored protocol for initiating the admi-
nistration of sacubitril/valsartan at varying doses to all
patients with HFrEF who did not exhibit signs of hypo-
tension. In the absence of pronounced hypotensive sy-
mptoms, such as severe dizziness, exhaustion, or acute
weakness, after the initial administration, the dosage of
sacubitril/valsartan would be incrementally escalated
toward the target dose or the maximum acceptable do-
se. The specific implementation measures have been
elaborated upon in a prior research investigation.[14]
Definition
Asymptomatic hypotension is defined as SBP < 100
mmHg without symptoms of hypotension, such as diz-
ziness. Severe symptomatic hypotension refers to SBP
< 100 mmHg, accompanied by unbearable hypotension
symptoms such as dizziness, fatigue, weakness, etc. The
http://www.jgc301.com; jgc@jgc301.com
 RESEARCH ARTICLE
Figure 1 Flowchart of patient selection. ARNI: angiotensin receptor-neprilysin inhibitor; HFrEF: heart failure with reduced ejection
fraction; SBP: systolic blood pressure.
gentle titration strategy is frequently employed in our
follow-up system for patients with lower BP. This ap-
proach involves gradually adjusting the dose of sa-
cubitril/valsartan in small increments (6.25 mg bid or
12.5 mg bid or 25 mg bid or 50 mg bid) every 1–2 weeks,
taking into consideration factors such as BP, heart rate,
renal function, and electrolyte levels. It is typically adv-
ised for patients to acquire sacubitril/valsartan tablets
with a dosage strength of 50 mg per tablet, and therea-
fter divide them into smaller portions of 1/8, 1/4, or 1/2
using a pharmaceutical cutting device. The target dose
of sacubitril/valsartan is 200 mg twice a day.
Study Outcomes
The primary efficacy outcome was the change of N-
terminal pro-B-type natriuretic peptide (NT-proBNP)
levels in six months after starting sacubitril/valsartan.
Key safety outcomes included the incidence of symp-
tomatic hypotension, worsening renal function, hyper-
kalemia, angioedema, and stroke. The secondary out-
comes included the changes in left ventricular end-di-
astolic diameter (LVEDD), left atrium diameter (LAD),
NYHA functional classification, SBP, and diastolic BP
(DBP), as well as the dose changes of sacubitril/valsar-
tan and beta-blockers also in six months after the initia-
tion of sacubitril/valsartan.
Statistical Analysis
The present analysis divided patients into two baseli-
ne SBP groups: (1) low SBP, defined as SBP < 100 mmHg;
http://www.jgc301.com; jgc@jgc301.com
JOURNAL OF GERIATRIC CARDIOLOGY
and (2) SBP ≥ 100 mmHg. Continuous variables are pr-
esented as mean ± SD or medians (interquartile range).
Categorical variables are presented as counts (percent-
ages). Continuous variables were compared with the in-
dependent Student’s t-test, the pairwise t-test, or Wil-
coxon matched-pairs signed-ranks test as appropriate.
Categorical variables were compared with the binomial
test, the Pearson’s chi-squared test, or Fisher’s exact te-
st. The analyses were performed with SPSS 25.0 (SPSS
Inc., IBM, Armonk, NY, USA). Two-sided P-value < 0.05
were considered statistically significant.
RESULTS
Patient Disposition and Baseline Characteristics
Among the 117 patients included in this study, 47 pa-
tients (40.2%) had SBP < 100 mmHg and 70 patients
(59.8%) had SBP ≥ 100 mmHg. The mean baseline SBP
values were 90.6 ± 5.1 mmHg and 121.6 ± 15.9 mmHg in
each group, respectively. As shown in Table 1, patients
with low SBP were more often women. They were also
more likely to have atrial fibrillation, as well as lower
serum creatinine and DBP levels. Conversely, patients
with SBP ≥ 100 mmHg were more likely to have a his-
tory of type 2 diabetes mellitus. Low SBP patients were
less likely to be treated with either an ACEI or an ARB
for HF therapy. In addition, patients with low SBP were
more likely to be prescribed digitalis glycosides comp-
857
 JOURNAL OF GERIATRIC CARDIOLOGY RESEARCH ARTICLE

Table 1 Baseline characteristics of study populations.

SBP < 100 mmHg SBP ≥ 100 mmHg
Characteristics (n = 47) (n = 70) P-value

Age, yrs 45.3 ± 14.5 50.2 ± 15.4 0.084

Male 26 (55.3%) 55 (78.6%) 0.008
Heart failure etiology
Ischaemic 8 (17.0%) 16 (22.9%) 0.443
Non-ischaemic 39 (83.0%) 54 (77.1%)
Dilated cardiomyopathy 24 (51.1%) 30 (42.9%)
Peripartum cardiomyopathy 6 (12.8%) 3 (4.3%)
Others 9 (19.1%) 21 (30.0%)
SBP, mmHg 90.6 ± 5.1 121.6 ± 15.9 < 0.001
Diastolic blood pressure, mmHg 59.9 ± 7.3 75.5 ± 13.5 < 0.001
* *
N-terminal pro-B-type natriuretic peptide, pg/mL 1452.0 (600.6–3172.0) 1690.0 (384.2–3582.5) 0.917
Serum creatinine, μmol/L 79.5 ± 19.3 95.1 ± 24.5 0.003
2
Estimated glomerular filtration rate, mL/min per 1.73 m 90.7 ± 21.5 84.1 ± 26.9 0.243
Potassium, mmol/L 4.3 ± 0.3 4.4 ± 0.4 0.139
Comorbidities
Atrial fibrillation 8 (17.0%) 2 (2.9%) 0.019
Diabetes mellitus 3 (6.4%) 16 (22.9%) 0.035
Chronic kidney disease 5 (10.6%) 9 (12.9%) 0.717
Dyslipidemia 2 (4.3%) 6 (8.6%) 0.472
Treatments
Angiotensin-converting enzyme inhibitor/Angiotensin II 7 (14.9%) 27 (38.6%) 0.006
receptor blocker
Beta-blockers 46 (97.9%) 69 (98.6%) 0.775
Mineralocorticoid receptor antagonist 45 (95.7%) 66 (94.3%) 0.726
SGLT2 inhibitors 15 (31.9%) 20 (29.0%) 0.699
Diuretics 29 (61.7%) 42 (60.0%) 0.853
Digoxin 15 (31.9%) 10 (14.3%) 0.023
Ivabradine 13 (27.7%) 19 (27.1%) 0.951
NYHA functional class 0.457
II 25 (53.2%) 30 (42.9%)
III 17 (36.2%) 28 (40.0%)
IV 5 (10.6%) 12 (17.1%)
Echocardiography
Left ventricular ejection fraction, % 26.0 (21.0–37.0)* 29.5 (20.8–35.0)* 0.747
Left ventricular end-diastolic diameter, mm 63.6 ± 11.0 64.9 ± 8.4 0.523
* *
Left atrium diameter, mm 42.0 (39.0–50.0) 45.5 (41.0–51.0) 0.093
*
Data are presented as means ± SD or n (%). Presented as median (interquartile range). NYHA: the New York Heart Association; SBP:
systolic blood pressure.

ared with those with higher SBP. There were no signific- Impact of SBP on Outcomes
ant differences between the SBP categories in terms of During the follow-up period, changes in echocardio-
NT-proBNP, echocardiographic parameters (LVEF, LV- graphic parameters under sacubitril/valsartan treatm-
EDD, and LAD) and NYHA functional classification. ent in the study population were summarized (Table 2,

858 http://www.jgc301.com; jgc@jgc301.com

 RESEARCH ARTICLE JOURNAL OF GERIATRIC CARDIOLOGY

Figure 2, supplemental material, Table 1S). There was P = 0.02) in patients with SBP ≥ 100 mmHg. In both SBP
an increase in LVEF by sacubitril/valsartan in both SBP categories, the reductions in heart rate (10.5 beats/min
categories (Pinteraction = 0.12), with an increase of 10.8% vs. 16.5 beats/min, P = 0.15) and estimated glomerul-
(95% CI: 7.7%–14.0%) in patients with SBP < 100 mmHg ar filtration rate (eGFR) (7.5 mL/min per 1.73 m2 vs. 7.6
(P < 0.001) and an increase of 14.0% (95% CI: 11.0%– mL/min per 1.73 m2, P = 0.69) were comparable. Among
17.0%) in patients with SBP ≥ 100 mmHg (P < 0.001). As those with SBP < 100 mmHg, serum potassium incr-
compared with patients with SBP ≥ 100 mmHg, LAD eased by 0.1 mmol/L (95% CI: 0.0–0.3), whereas it decr-
reduction was similar (3.1 mm vs. 3.5 mm, P = 0.63), wh- eased by 0.1 mmol/L (95% CI: -0.3–0.1) among those wi-
ereas LVEDD reduction was lower (3.3 mm vs. 6.5 mm, th SBP ≥ 100 mmHg (Table 2, supplemental material,
P = 0.03) in patients with SBP < 100 mmHg. Table 2S).
There was a similar decrease in NT-proBNP concen-
Dosage Patterns of Sacubitril/Valsartan and Beta-
tration in patients with SBP < 100 mmHg (1627.5 pg/mL
blockers
vs. 1340.1 pg/mL, P = 0.75) in comparison with those
with SBP ≥ 100 mmHg. With sacubitril/valsartan addi- In the group with SBP < 100 mmHg, a higher propor-
tion, both SBP categories exhibited an improvement in tions of patients initiated sacubitril/valsartan with dos-
NYHA functional classification, with the proportion of es below 50 mg twice daily (44.7% vs. 30.0%) and with
NYHA I–II functional classification increasing from doses in the range of 50–100 mg twice daily (48.9% vs.
53.2% at baseline to 92.9% at six months for patients wi- 47.1%), when compared to the group with SBP ≥ 100
th SBP < 100 mmHg and 42.9% to 92.8% for patients wi- mmHg. During the follow-up period, more patients wi-
th SBP ≥ 100 mmHg (Figure 2 & Figure 3, supplemental th SBP ≥ 100 mmHg received more than 50% of the tar-
material, Table 2S & Table 3S). geted dose of sacubitril/valsartan than those with lower
SBP (90% vs. 76.2%, P = 0.049). A target dose of sacubi-
Trend of SBP over Time and Other Outcomes tril/valsartan was achieved by 52.4% of patients with
From baseline to month six, there was a significant in- SBP < 100 mmHg and 70.0% of patients with SBP ≥ 100
verse effect of sacubitril/valsartan on SBP across both mmHg (P = 0.061). The median time to receive targeted
SBP categories (Pinteraction = 0.001), with an increase of doses of sacubitril/valsartan was three months for pa-
7.5 mmHg (95% CI: 3.4–11.6) in patients with SBP < 100 tients with SBP ≥ 100 mmHg and six months for patie-
mmHg (P = 0.001) and a reduction of 11.5 mmHg (95% nts with SBP < 100 mmHg. The proportion of patients
CI: 7.0–16.0) in patients with SBP ≥ 100 mmHg (P < 0.001). who received 50% and 100% of targeted dose of beta-
When compared with patients with SBP < 100 mmHg, blockers was consistent across both SBP categories (78.6%
the reduction in DBP was greater (7 mmHg vs. 2 mmHg, vs. 77.1%, P = 0.860, and 50.0% vs. 55.7%, P = 0.557) (Fig-
Table 2 Treatment effects of sacubitril/valsartan on selected vital signs and laboratory values across two SBP categories from bas-
eline to month six.
SBP < 100 mmHg (n = 47) SBP ≥ 100 mmHg (n = 70)
P-value
Difference (95% CI) P-value Difference (95% CI) P-value
Left ventricular ejection fraction, % 10.8 (7.7–14.0) < 0.001 14.0 (11–17.0) < 0.001 0.12
Left ventricular end-diastolic diameter, mm -3.3 (-5.6–-1.1) 0.004 -6.5 (-8.5–-4.5) < 0.001 0.03
Left atrium diameter, mm -3.1 (-5.4–-0.9) 0.008 -3.5 (-5.5–-2.0) < 0.001 0.63
N-terminal pro-B-type natriuretic peptide, pg/mL -1627.5 (-2638.4–-763.6) < 0.001 -1340.1 (-1988.0–-855.1) < 0.001 0.75
SBP, mmHg 7.5 (3.4–11.6) 0.001 -11.5 (-16.0–-7.0) < 0.001 < 0.001
Diastolic blood pressure, mmHg -2.0 (-5.0–1.5) 0.134 -7.0 (-10.5–-4.0) < 0.001 0.02
Heart rate, beats/min -10.5 (-18.0–-4.0) 0.025 -16.5 (-20.0–-13.5) < 0.001 0.15
Estimated glomerular filtration rate, mL/min per 7.5 (-0.3–15.3) 0.059 7.6 (1.8–14.1) 0.015 0.69
1.73 m2
Serium potassium, mmol/L 0.1 (-0.0–0.3) 0.095 -0.1 (-0.3–0.1) 0.203 0.04

SBP: systolic blood pressure.

http://www.jgc301.com; jgc@jgc301.com 859

 JOURNAL OF GERIATRIC CARDIOLOGY
Figure 2 The changes in vital signs and laboratory values following treatment with sacubitril/valsartan for six months in the two SBP
categories. LVEDD: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; NT-proBNP: N-terminal pro-B-type
natriuretic peptide; SBP: systolic blood pressure.
ure 3, supplemental material, Table 4S–Table 6S, sup-
plemental material, Figure 1S).
Other Medications Used to Treat HF
Throughout the titration procedure, there was a re-
duction in the administration of diuretics and digoxin
in both experimental groups, although the utilization
of SGLT2 inhibitors exhibited an increase in both gro-
ups. Notably, in the group with SBP < 90 mmHg, there
was a more significant reduction in the administration
of spironolactone (supplemental material, Table 7S &
Table 8S).
Subgroup Analysis in SBP < 100 mmHg
We also conducted a subgroup analysis between SBP
< 90 mmHg and 90 mmHg ≤ SBP < 100 mmHg, the in-
creases in LVEF, SBP, eGFR, serum potassium, as well
as the reductions in LVEDD, LAD, NT-proBNP and he-
art rate did not differ between the two categories of SBP
(Table 3).
860
RESEARCH ARTICLE
Safety Analysis
A total of three patients (6.4%) with SBP < 100 mmHg
and four patients (5.7%) with SBP ≥ 100 mmHg discon-
tinued sacubitril/valsartan permanently due to sympto-
matic hypotension during six months of treatment wi-
th sacubitril/valsartan. Among patients with SBP < 100
mmHg, three patients suffered from renal dysfunction
(eGFR < 30 mL/min per 1.73 m2). Meanwhile, two pat-
ients (2.9%) in the higher SBP categories reported stro-
ke, and no hyperkalemia and angioedema were obser-
ved in our study population in either SBP category (Ta-
ble 4).
DISCUSSION
Because recent randomized trials investigating ARNI
in patients with HFrEF did not include patients with SBP
< 95 mmHg or 100 mmHg at screening or randomiza-
tion, respectively; this study was the first to validate the
role of sacubitril/valsartan in improving ventricular re-
http://www.jgc301.com; jgc@jgc301.com
 RESEARCH ARTICLE JOURNAL OF GERIATRIC CARDIOLOGY

Figure 3 The dose titration of sacubitril/valsartan (A), beta-blockers (B), and the change in NYHA functional classification (C) acr-
oss the two SBP categories from baseline to six months after initiation. bid: twice daily; NYHA: the New York Heart Association; SBP:
systolic blood pressure; TD: targeted dose.

Table 3 Subgroup analysis in patients with heart failure with reduced ejection fraction and SBP < 100 mmHg.
SBP < 90 mmHg (n = 19) 90 mmHg ≤ SBP < 100 mmHg (n = 28)
P-value
Difference (95% CI) P-value Difference (95% CI) P-value
Left ventricular ejection fraction, % 9.7 (3.7–15.7) 0.004 11.6 (7.9–15.3) < 0.001 0.54
Left ventricular end-diastolic diameter, mm -1.6 (-5.0–1.9) 0.346 -4.6 (-7.7–-1.6) 0.004 0.17
Left atrium diameter, mm -1.5 (-4.2–1.1) 0.232 -4.2 (-7.7–-0.7) 0.020 0.24
N-terminal pro-B-type natriuretic peptide, pg/mL -1509.9 (-2332.5–-687.3) 0.002 -787.0 (-4083.6–-431.8) 0.002 0.72
SBP, mmHg 6.9 (0.1–13.7) 0.048 8.0 (2.4–13.5) 0.007 0.80
Heart rate, beats/min -10 (-0.5–25.0) 0.073 -12 (2.0–20.5) 0.023 0.88
Estimated glomerular filtration rate, mL/min per 5.5 (-9.2–20.2) 0.423 9.1 (-0.8–18.9) 0.067 0.65
1.73 m2
Serium potassium, mmol/L 0.2 (-0.1–0.4) 0.150 0.1 (-0.1–0.3) 0.377 0.72

SBP: systolic blood pressure.

http://www.jgc301.com; jgc@jgc301.com 861

 JOURNAL OF GERIATRIC CARDIOLOGY
Table 4
Adverse effects SBP < 100 mmHg (n = 47)
Permanent discontinuation due to hypotension
Hyperkalemia
Renal impairment
Angioedema
Stroke
verse remodeling in HFrEF patients with SBP < 100
mmHg without an increase in adverse effects, includ-
ing symptomatic hypotension, worsening renal funct-
ion, hyperkalemia, angioedema, and stroke.[11,16,17]
According to our study, 52.4% of HFrEF patients wi-
th SBP < 100 mmHg were able to achieve the target do-
ses of sacubitril/valsartan after six months of treatm-
ent. It should be noted that the proportions of targeted
sacubitril/valsartan and beta-blockers were compara-
ble between the two categories of SBP, except that pa-
tients with SBP ≥ 100 mmHg received an increased pr-
oportion of the 1/2 target dose of sacubitril/valsartan.
However, the proportion of patients in our study who
received sacubitril/valsartan target doses was higher
than in other published studies. For example, in patie-
nts enrolled in the CHAMP-HF (Change the Manage-
ment of Patients With Heart Failure) registry, among th-
ose with SBP < 110 mmHg (n = 674), 17.5% of patients
with beta-blockers, 6.2% of patients with ACEI/ARB,
and 1.8% of patients with ARNI were receiving target
doses. Among those with SBP ≥ 110 mmHg (n = 2421),
19.0% of patients with beta-blockers, 12.1% of patients
with ACEI/ARB, and 2.0% of patients with ARNI were
receiving target doses.[18] Similarly, in the CHECK-HF
(Chronisch Hartfalen European Society of Cardiology-
richtlijn Cardiologische praktijk Kwaliteitsproject Ha-
rtFalen) registry, patients with SBP < 95 mmHg less of-
ten received the guideline-recommended target dose of
beta-blockers and renin-angiotensin system inhibitors,
and more often of mineralocorticoid receptor antagonist
compared with ≥ 130 mmHg.[19] It is not surprising that
the indicators associated with ventricular remodeling
have also markedly improved with such high on-target
rates. NT-proBNP and LAD reductions, as well as an in-
crease in the LVEF from baseline, were consistent in pa-
tients with SBP < 100 mmHg compared with SBP ≥ 100
mmHg, although sacubitril/valsartan was more effect-
ive in reducing LVEDD in patients with a baseline SBP ≥
100 mmHg. Additionally, both SBP categories showed a
significant improvement in NYHA functional classifi-
cation.
862
RESEARCH ARTICLE
Safety analysis.
SBP ≥ 100 mmHg (n = 70) P-value
3 (6.4%) 4 (5.7%) 1.000
0 0 –
3 (6.4%) 0 0.062
0 0 –
0 2 (2.9%) 0.515
We achieved such high proportions of sacubitril/va-
lsartan targeted doses for three main reasons. Firstly, a
low-dose up-titration regimen was implemented during
the titration process. In accordance with the latest
guidelines, sacubitril/valsartan is recommended to be
administered twice daily to patients with HFrEF at a
dose of 100 mg. However, multiple clinical studies have
demonstrated that initiating sacubitril/valsartan at a
lower dose can not only improve cardiac function and
ventricular remodeling, but also decrease the risk of hy-
potension among patients with low basal BP or those
who were ACEI/ARB.[20–22] Secondly, the titration rate
was very gentle. The median time to target dose of sacu-
bitril/valsartan was three months in patients with SBP ≥
100 mmHg and six months in patients with SBP < 100
mmHg, which was significantly longer than the time
suggested by guidelines for patients with HFrEF with-
out hypotension. A post-hoc analysis of the TITRATI-
ON (Safety and Tolerability of Initiating LCZ696 in Hea-
rt Failure Patients) trial identified that 80% of patients
with low screening SBP levels achieved and tolerated
target dose of sacubitril/valsartan by gradually increas-
ing the dose.[8] In light of these findings, clinicians should
not hesitate to consider starting sacubitril/valsartan the-
rapy for patients with HFrEF despite the presence of a
low SBP, since sacubitril/valsartan has been proven to
improve morbidity and mortality in patients with HF-
rEF. Thirdly, the follow-up management and self-monit-
oring programs for HF patients were crucial and essen-
tial. Studies have shown that high-dose sacubitril/va-
lsartan can not only improve clinical status, exercise per-
formance, and cardiac function, but also result in a lower
mortality or hospitalization rate for HFrEF patients as
compared to low-dose therapy.[23,24] As a consequence,
our HF team developed a rigorous follow-up plan that
focused on titrating sacubitril/valsartan to achieve the
target dose for HF patients.
In our study, it was observed that the administration
of sacubitril/valsartan led to a notable reversal of ven-
tricular remodeling in HFrEF patients with concomit-
http://www.jgc301.com; jgc@jgc301.com
 RESEARCH ARTICLE
ant hypotension. However, it cannot be overlooked that
the population included in our study consisted of pa-
tients who were initially able to tolerate sacubitril/val-
sartan and were closely monitored for a minimum of six
months in our follow-up management system, which
may introduce a certain degree of selection bias. The
rationale behind this design was two-fold. Firstly, wit-
hin our team’s established follow-up management sys-
tem, the majority of HFrEF patients without hypotens-
ion symptoms were considered for initiation of sacu-
bitril/valsartan at an appropriate dosage, and through
vigilant monitoring, it was observed that most patients
were able to tolerate the medication well. However, a
small subset of patients experienced severe early-onset
hypotension symptoms, such as debilitating dizziness
and fatigue, leading to the discontinuation of sacubit-
ril/valsartan. Furthermore, the primary objective of this
study was to evaluate the effectiveness and safety of sac-
ubitril/valsartan in two distinct groups of patients with
HFrEF: those with SBP < 100 mmHg and those with SBP
≥ 100 mmHg, who had demonstrated initial tolerance to
the medication within our follow-up management sys-
tem. Consequently, the sample population of the study
exhibits a considerable degree of distinctiveness, there-
by minimizing the presence of selection bias. However,
it is worth noting that all of our findings were derived fr-
om individuals enrolled in our follow-up system who ex-
hibited high compliance. The purpose of our research is
to serve as a valuable source of inspiration and informa-
tion for the medical community, shedding light on the
effectiveness and safety of sacubitril/valsartan in specif-
ic subgroups of HFrEF patients.
Furthermore, sacubitril/valsartan exhibited an inve-
rse effect on SBP across both SBP categories, with a 7.5
mmHg of increase in patients with SBP < 100 mmHg
and a 11.5 mmHg of reduction in patients with SBP ≥ 100
mmHg. As a matter of fact, this conclusion was consist-
ent with a post-hoc analysis of the PARADIGM-HF trial,
which found that SBP increased in patients with the low-
est baseline SBP (< 110 mmHg) and decreased in pati-
ents with higher baseline SBP after starting sacubitril/
valsartan for four months, the same result over the whole
period of follow-up.[6] In a real-world study, after fifteen
months of sacubitril/valsartan treatment for patients
with HFrEF and SBP < 100 mmHg, the SBP increased
from 92.7 mmHg at baseline to 102.9 mmHg.[25] Thus,
sacubitril/valsartan may counteract its antihyperten-
sive side effects by improving cardiac function in pat-
http://www.jgc301.com; jgc@jgc301.com
JOURNAL OF GERIATRIC CARDIOLOGY
ients with HFrEF and hypotension, similar to the resu-
lts of the Carvedilol Prospective Randomized Cumulat-
ive Survival (COPERNICUS) study, in which patients
with a pretreatment SBP of 85 mmHg to 95 mmHg did
not experience a decline in their SBP prior to the initi-
ation of carvedilol, but instead experienced an increase
after 10.4 months.[26] The phenomenon of SBP regress-
ion to the mean following the administration of sacubi-
tril/valsartan has garnered significant academic interest.
The increase in SBP observed among patients with ini-
tially lower SBP levels may be associated with improve-
ment in ejection fraction and stroke volume. Conversely,
the decrease in SBP among individuals with elevated ba-
seline SBP is associated with a decline in the equilibrium
between preload and afterload.
Our study found that only three patients (6.4%) dis-
continued sacubitril/valsartan permanently due to sy-
mptomatic hypotension during titration in patients with
HFrEF and SBP < 100 mmHg. In fact, in the PARADI-
GM-HF study, the risk of hypotension after randomiza-
tion was 13.4% with ARNI; however, only 2.7% of pati-
ents had an SBP < 90 mmHg associated with symptoms.
Investigators either reduced or temporarily stopped
ARNI treatment (54.1%), simply waited for spontaneous
improvement (34.3%), or changed concomitant treat-
ments (12.8%). Permanent discontinuation of the treat-
ment was observed in only 2.2% of cases.[27] Even in pa-
tients with acutely decompensated HF, the Compa-
rison of Sacubitril/Valsartan Versus Enalapril on Eff-
ect on NT-proBNP in Patients Stabilized From an Acute
Heart Failure Episode (PIONEER-HF) trial and the Co-
mparison of Pre- and Post-discharge Initiation of LCZ
696 Therapy in HFrEF Patients After an Acute Decom-
pensation Event (TRANSITION) trial provide insightful
evidence regarding the BP tolerance of ARNI. It has be-
en found in the PIONEER-HF trial that the proportion
of patients experiencing symptomatic hypotension was
not significantly higher when treated with ARNI than
when treated with enalapril (15% vs. 12.7%) in this con-
text of increased risk for adverse effects.[28] The TRA-
NSITION trial demonstrated that the introduction of
ARNI was feasible even before discharge following wo-
rsening HF, and that symptomatic hypotension was in-
frequent and not significantly different between pre-
discharge and post-discharge initiation (12.7% vs. 9.5%).[29]
Overall, the lower the pretreatment SBP, the higher the
likelihood that patients with HFrEF would experience
adverse events, be intolerant of high doses of beta-block-
863
 JOURNAL OF GERIATRIC CARDIOLOGY
ers or sacubitril/valsartan, or require permanent with-
drawal from treatment. These risks were primarily asso-
ciated with the severity of the underlying illness rather
than treatment with life-saving drugs for HFrEF. Ho-
wever, if physicians are willing to initiate both drugs,
rather than being intimidated by their poor tolerance,
HFrEF patients with hypotension will benefit greatly
from treatment with beta-blockers and sacubitril/va-
lsartan.
A total of nineteen patients with SBP < 90 mmHg
were enrolled in our study. In the subgroup analysis, it
was found that sacubitril/valsartan was equally effect-
ive and safe when used in people with SBP < 90 mmHg
and 90 mmHg ≤ SBP < 100 mmHg. SBP < 90 mmHg
was listed as a contraindication in the 2021 European
Society of Cardiology[13] and 2022 American College of
Cardiology/American Heart Association/Heart Failure
Society of America Guidelines for the Management of
Heart Failure;[12] However, in the real world, sacubitril/
valsartan, the class I life-saving medication used in HF-
rEF, should not be initiated solely based on SBP. Cau-
tela, et al.[1] developed a five-step pharmacological ma-
nagement algorithm for ambulatory HFrEF patients wi-
th low BP. This algorithm was adopted as a reference du-
ring the titration process, which may be the reason we we-
re able to achieve such a high proportion of sacubitril/
valsartan doses. A consensus document from the Heart
Failure Association of the European Society of Cardi-
ology identified three patient profiles that may be relev-
ant for the implementation of treatment in patients with
HFrEF who have low BP.[30] The use of guideline-direc-
ted medical therapy tailored to the condition and pr-
ofile of each patient may be a better, more comprehens-
ive approach than titrating each drug class before mov-
ing on to the next.[31] Therefore, HFrEF with low SBP will
enter a new era of personalized treatment.
LIMITATIONS
This study has some limitations that must be acknow-
ledged. In the first place, it is a retrospective observati-
onal study conducted within a single institution. Secon-
dly, it should be noted that this study exclusively focu-
sed on patients with HFrEF who initially demonstrated
tolerability to sacubitril/valsartan and were monitored
for a minimum of six months within our CHF follow-up
management system. It should be acknowledged that
864
RESEARCH ARTICLE
promoting our follow-up management system and at-
taining such high patient compliance may take some
time and present some obstacles. Nevertheless, it is ap-
parent that patients experience substantial benefits fr-
om the implementation of this specific management ap-
proach. Hence, it is anticipated that our research will pr-
ovide valuable insights and serve as a point of referen-
ce for further investigations in this area. Thirdly, it has
a relatively small study population, which may affect
the statistical performance. In addition, the limited fo-
llow-up time did not provide sufficient opportunity for
the assessment of clinical outcomes.
CONCLUSIONS
It is a major challenge to treat patients with HFrEF
and low SBP as there was a lack of evidence of guidel-
ine-directed medical therapy. It is concluded from this st-
udy that sacubitril/valsartan initiation significantly im-
proved left ventricular reverse remodeling in patients
with HFrEF and low SBP within an optimized HF foll-
ow-up management system. In comparison with higher
baseline SBP, the incidence of adverse effects did not dif-
fer significantly. The results of our study demonstrate th-
at sacubitril/valsartan has the potential to counteract
its antihypertensive side effects by improving cardiac
function in patients with HFrEF and asymptomatic hy-
potension, low SBP should not preclude clinicians from
considering sacubitril/valsartan initiation in patients
with special needs. It is anticipated that our improved
follow-up management strategy may serve as a catalyst
for expanding the utilization of sacubitril/valsartan am-
ong a broader population of HFrEF patients who also ex-
perience concurrent hypotension.
ACKNOWLEDGMENTS
This study was supported by the National Natural Sc-
ience Foundation of China (No.81873516 & No.821704-
63), the National Key Research and Development Pr-
ogram of China (2021YFF0501404 & 2021YFF0501403 &
2017YFC1308303), the Natural Science Foundation of
Shandong Province (ZR2019PH030 & ZR2019BH052),
and the China International Medical Foundation (Z-
2019-42-1908-2). All authors had no conflicts of interest to
disclose. The authors would like to thank the patients,
their families, and all investigators involved in this st-
udy.
http://www.jgc301.com; jgc@jgc301.com
 RESEARCH ARTICLE
REFERENCES
[1] Cautela J, Tartiere JM, Cohen-Solal A, et al. Management
of low blood pressure in ambulatory heart failure with re-
duced ejection fraction patients. Eur J Heart Fail 2020; 22:
1357−1365.
[2] O’Connor C, Fiuzat M, Mulder H, et al. Clinical factors
related to morbidity and mortality in high-risk heart failu-
re patients: the GUIDE-IT predictive model and risk score.
Eur J Heart Fail 2019; 21: 770−778.
[3] Arundel C, Lam PH, Gill GS, et al. Systolic blood press-
ure and outcomes in patients with heart failure with red-
uced ejection fraction. J Am Coll Cardiol 2019; 73: 3054−
3063.
[4] Agostoni P, Paolillo S, Mapelli M, et al. Multiparametric
prognostic scores in chronic heart failure with reduced ej-
ection fraction: a long-term comparison. Eur J Heart Fail
2018; 20: 700−710.
[5] Chioncel O, Lainscak M, Seferovic PM, et al. Epidemiol-
ogy and one-year outcomes in patients with chronic heart
failure and preserved, mid-range and reduced ejection fr-
action: an analysis of the ESC Heart Failure Long-Term
Registry. Eur J Heart Fail 2017; 19: 1574−1585.
[6] Böhm M, Young R, Jhund PS, et al. Systolic blood press-
ure, cardiovascular outcomes and efficacy and safety of sa-
cubitril/valsartan (LCZ696) in patients with chronic heart
failure and reduced ejection fraction: results from PARA-
DIGM-HF. Eur Heart J 2017; 38: 1132−1143.
[7] Greene SJ, Fonarow GC, DeVore AD, et al. Titration of me-
dical therapy for heart failure with reduced ejection frac-
tion. J Am Coll Cardiol 2019; 73: 2365−2383.
[8] Senni M, McMurray JJV, Wachter R, et al. Impact of sy-
stolic blood pressure on the safety and tolerability of initi-
ating and up-titrating sacubitril/valsartan in patients with
heart failure and reduced ejection fraction: insights from
the TITRATION study. Eur J Heart Fail 2018; 20: 491−500.
[9] Greene SJ, Butler J, Albert NM, et al. Medical therapy for
heart failure with reduced ejection fraction: the CHAMP-
HF registry. J Am Coll Cardiol 2018; 72: 351−366.
[10] Desai AS, Solomon S, Claggett B, et al. Factors associated
with noncompletion during the run-in period before ran-
domization and influence on the estimated benefit of LC-
Z696 in the PARADIGM-HF trial. Circ Heart Fail 2016; 9:
e002735.
[11] McMurray JJ, Packer M, Desai AS, et al. Angiotensin-ne-
prilysin inhibition versus enalapril in heart failure. N Engl
J Med 2014; 371: 993−1004.
[12] Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/
ACC/HFSA guideline for the management of heart failu-
re: a report of the American College of Cardiology/Ame-
rican Heart Association Joint Committee on Clinical Pra-
ctice Guidelines. Circulation 2022; 145: e895−e1032.
[13] McDonagh TA, Metra M, Adamo M, et al. 2021 ESC gu-
idelines for the diagnosis and treatment of acute and ch-
ronic heart failure. Eur Heart J 2021; 42: 3599−3726.
[14] Wang C, Lin Z, Miao D, et al. Dose titration of sacubitril/
valsartan for heart failure with reduced ejection fraction:
a real-world study. ESC Heart Fail 2023; 10: 1961−1971.
[15] Wu AH, Lin ZW, Ji XP, et al. [Titration strategy of sacub-
itril/valsartan in patients with heart failure with reduced
ejection fraction and hypotension]. Zhonghua Xin Xue Gu-
an Bing Za Zhi 2023; 51: 1098−1103. [In Chinese].
http://www.jgc301.com; jgc@jgc301.com
JOURNAL OF GERIATRIC CARDIOLOGY
[16] Jering KS, Claggett B, Pfeffer MA, et al. Prospective ARNI
vs. ACE inhibitor trial to DetermIne Superiority in reduc-
ing heart failure Events after Myocardial Infarction (PAR-
ADISE-MI): design and baseline characteristics. Eur J He-
art Fail 2021; 23: 1040–1048.
[17] Angiotensin-neprilysin inhibition in acute decompensat-
ed heart failure. N Engl J Med 2019; 380: 1090.
[18] Peri-Okonny PA, Mi X, Khariton Y, et al. Target doses of
heart failure medical therapy and blood pressure: insigh-
ts from the CHAMP-HF registry. JACC Heart Fail 2019; 7:
350−358.
[19] Veenis JF, Brunner-La Rocca HP, Linssen GCM, et al. Tre-
atment differences in chronic heart failure patients with re-
duced ejection fraction according to blood pressure. Circ
Heart Fail 2020; 13: e006667.
[20] Pandey AC, Jer D, Kuo RS, et al. Novel doses of sacubit-
ril/valsartan in patients unable to tolerate traditional the-
rapy: effects on N-terminal pro B-type natriuretic peptide
levels. Clin Cardiol 2021; 44: 85−90.
[21] Kim H, Oh J, Lee S, et al. Clinical evidence of initiating a
very low dose of sacubitril/valsartan: a prospective obse-
rvational analysis. Sci Rep 2021; 11: 16335.
[22] Hu J, Wu Y, Zhou X, et al. Beneficial effects of sacubit-
ril/valsartan at low doses in an Asian real-world heart fa-
ilure population. J Cardiovasc Pharmacol 2020; 76: 445−
451.
[23] Kido K, Bianco C, Caccamo M, et al. Evaluating sacubit-
ril/valsartan dose dependence on clinical outcomes in pat-
ients with heart failure with reduced ejection fraction. Ann
Pharmacother 2021; 55: 1069−1075.
[24] Corrado E, Dattilo G, Coppola G, et al. Low- vs high-dose
ARNI effects on clinical status, exercise performance and
cardiac function in real-life HFrEF patients. Eur J Clin Ph-
armacol 2022; 78: 19−25.
[25] Chang HY, Feng AN, Fong MC, et al. Sacubitril/valsart-
an in heart failure with reduced ejection fraction patients:
real world experience on advanced chronic kidney disea-
se, hypotension, and dose escalation. J Cardiol 2019; 74:
372−380.
[26] Rouleau JL, Roecker EB, Tendera M, et al. Influence of pr-
etreatment systolic blood pressure on the effect of carved-
ilol in patients with severe chronic heart failure: the Carv-
edilol Prospective Randomized Cumulative Survival (CO-
PERNICUS) study. J Am Coll Cardiol 2004; 43: 1423−1429.
[27] Vardeny O, Claggett B, Kachadourian J, et al. Incidence,
predictors, and outcomes associated with hypotensive ep-
isodes among heart failure patients receiving sacubitril/
valsartan or enalapril: the PARADIGM-HF (Prospective
Comparison of Angiotensin Receptor Neprilysin Inhibitor
With Angiotensin-Converting Enzyme Inhibitor to Deter-
mine Impact on Global Mortality and Morbidity in Heart
Failure) trial. Circ Heart Fail 2018; 11: e004745.
[28] Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotens-
in-neprilysin inhibition in acute decompensated heart fa-
ilure. N Engl J Med 2019; 380: 539−548.
[29] Wachter R, Senni M, Belohlavek J, et al. Initiation of sacu-
bitril/valsartan in haemodynamically stabilised heart fail-
ure patients in hospital or early after discharge: primary
results of the randomised TRANSITION study. Eur J He-
art Fail 2019; 21: 998−1007.
[30] Rosano GMC, Moura B, Metra M, et al. Patient profiling
865
 JOURNAL OF GERIATRIC CARDIOLOGY RESEARCH ARTICLE

in heart failure for tailoring medical therapy. A consens- [31] Ameri P, Bertero E, Maack C, et al. Medical treatment of
us document of the Heart Failure Association of the Eur- heart failure with reduced ejection fraction: the dawn of a
opean Society of Cardiology. Eur J Heart Fail 2021; 23: 872− new era of personalized treatment?. Eur Heart J Cardiov-
881. asc Pharmacother 2021; 7: 539−546.

Please cite this article as: WU AH, LIN ZW, YANG ZH, ZHANG H, HU JY, WANG Y, TANG R, ZHANG XY, JI XP, LU HX. Efficacy
and safety of sacubitril/valsartan after six months in patients with heart failure with reduced ejection fraction and asymptomatic hyp-
otension. J Geriatr Cardiol 2023; 20(12): 855−866. DOI: 10.26599/1671-5411.2023.12.005

866 http://www.jgc301.com; jgc@jgc301.com