Efficacy and safety of sacubitril/valsartan after six months in patients with heart failure with reduced ejection fraction and asymptomatic hypotension

Abstract

BACKGROUND

It is not clear whether sacubitril/valsartan is beneficial for patients with heart failure (HF) with reduced ejection fraction (HFrEF) and low systolic blood pressure (SBP). This study aimed to investigate the efficacy and tolerability of sacubitril/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 without 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 reached 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 sacubitril/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 significant differences were observed between the two groups in terms of the occurrence of symptomatic hypotension, deteriorating renal 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.

There are 10% to 20% of patients with heart failure (HF) with reduced ejection fraction (HFrEF) experience low systolic blood pressure (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 significant contributor to medication intolerance and a failure 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 clinical practice.

In the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting 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 enalapril.^[11] According to this study, updated evidence-based guidelines for the treatment of HF provided class I, level of evidence B recommendation to replace renin-angiotensin system blockers with sacubitril/valsartan in patients with chronic symptomatic HFrEF despite optimal treatment.^[12] In addition to blocking the renin-angiotensin system, sacubitril/valsartan also enhances the activity of vasoactive substances such as natriuretic peptides and bradykinin, leading to a lower blood pressure (BP) than an ACEI or angiotensin II receptor 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 study compared the effects of sacubitril/valsartan in HFrEF patients across different BP groups, demonstrating that lower SBP during the run-in period and after randomization 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, although the European Society of Cardiology guidelines recommend that a HF specialist should be sought rather than stopping or decreasing drugs with class I indication in HFrEF in patients with persisting low BP or symptoms of orthostatic hypotension.^[13]

We have developed a follow-up management system tailored to Chinese patients with chronic HF (CHF), which has demonstrated its ability to enhance the proportion of patients achieving the target dose of sacubitril/valsartan and improve the recovery of ventricular 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 experience.^[15] The primary objective of this study was to assess the efficacy and safety of sacubitril/valsartan over a six-month period among patients with HFrEF experiencing asymptomatic hypotension and enrolled in this optimized 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 diagnosis 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 sections. The data in this study were acquired from the electronic medical record system of Qilu Hospital of Shandong University, China. The inclusion criteria were: (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 prescription, and SBP ≥ 100 mmHg. The exclusion criteria were: (1) lost to follow-up after initiation of sacubitril/valsartan; (2) LVEF > 40% by echocardiography; and (3) SBP < 100 mmHg with severe hypotension symptoms in the early stages of prescription.

Patients were monitored regularly in outpatient settings 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 analysis, 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 Committee of Qilu Hospital of Shandong University, China (KYLL-202205-036-1) approved this study protocol. Written informed consent was obtained from all participating individuals prior to their involvement in study-related activities.

Figure 1.

Flowchart of patient selection.

ARNI: angiotensin receptor-neprilysin inhibitor; HFrEF: heart failure with reduced ejection fraction; SBP: systolic blood pressure.

CHF Follow-up Management System

All trial participants were enrolled in the CHF follow-up management system throughout their hospitalization and post-discharge periods. This study employed a well-monitored protocol for initiating the administration of sacubitril/valsartan at varying doses to all patients with HFrEF who did not exhibit signs of hypotension. In the absence of pronounced hypotensive symptoms, 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 dose. 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 dizziness. Severe symptomatic hypotension refers to SBP < 100 mmHg, accompanied by unbearable hypotension symptoms such as dizziness, fatigue, weakness, etc. The gentle titration strategy is frequently employed in our follow-up system for patients with lower BP. This approach involves gradually adjusting the dose of sacubitril/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 advised for patients to acquire sacubitril/valsartan tablets with a dosage strength of 50 mg per tablet, and thereafter 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 symptomatic hypotension, worsening renal function, hyperkalemia, angioedema, and stroke. The secondary outcomes included the changes in left ventricular end-diastolic diameter (LVEDD), left atrium diameter (LAD), NYHA functional classification, SBP, and diastolic BP (DBP), as well as the dose changes of sacubitril/valsartan and beta-blockers also in six months after the initiation of sacubitril/valsartan.

Statistical Analysis

The present analysis divided patients into two baseline SBP groups: (1) low SBP, defined as SBP < 100 mmHg; and (2) SBP ≥ 100 mmHg. Continuous variables are presented as mean ± SD or medians (interquartile range). Categorical variables are presented as counts (percentages). Continuous variables were compared with the independent Student’s t-test, the pairwise t-test, or Wilcoxon 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 test. 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 patients (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 history 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 compared with those with higher SBP. There were no significant differences between the SBP categories in terms of NT-proBNP, echocardiographic parameters (LVEF, LVEDD, and LAD) and NYHA functional classification.

Table 1. Baseline characteristics of study populations.

Characteristics	SBP < 100 mmHg (n = 47)	SBP ≥ 100 mmHg (n = 70)	P-value
Data are presented as means ± SD or n (%). *Presented as median (interquartile range). NYHA: the New York Heart Association; SBP: systolic blood pressure.
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
Estimated glomerular filtration rate, mL/min per 1.73 m2	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 receptor blocker	7 (14.9%)	27 (38.6%)	0.006
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

Impact of SBP on Outcomes

During the follow-up period, changes in echocardiographic parameters under sacubitril/valsartan treatment in the study population were summarized (Table 2, Figure 2, supplemental material, Table 1S). There was an increase in LVEF by sacubitril/valsartan in both SBP categories (P_interaction = 0.12), with an increase of 10.8% (95% CI: 7.7%–14.0%) in patients with SBP < 100 mmHg (P < 0.001) and an increase of 14.0% (95% CI: 11.0%–17.0%) in patients with SBP ≥ 100 mmHg (P < 0.001). As compared with patients with SBP ≥ 100 mmHg, LAD reduction was similar (3.1 mm vs. 3.5 mm, P = 0.63), whereas LVEDD reduction was lower (3.3 mm vs. 6.5 mm, P = 0.03) in patients with SBP < 100 mmHg.

Table 2. Treatment effects of sacubitril/valsartan on selected vital signs and laboratory values across two SBP categories from baseline 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
SBP: systolic blood pressure.
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 1.73 m2	7.5 (-0.3–15.3)	0.059		7.6 (1.8–14.1)	0.015	0.69
Serium potassium, mmol/L	0.1 (-0.0–0.3)	0.095		-0.1 (-0.3–0.1)	0.203	0.04

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.

There was a similar decrease in NT-proBNP concentration in patients with SBP < 100 mmHg (1627.5 pg/mL vs. 1340.1 pg/mL, P = 0.75) in comparison with those with SBP ≥ 100 mmHg. With sacubitril/valsartan addition, both SBP categories exhibited an improvement in NYHA functional classification, with the proportion of NYHA I–II functional classification increasing from 53.2% at baseline to 92.9% at six months for patients with SBP < 100 mmHg and 42.9% to 92.8% for patients with SBP ≥ 100 mmHg (Figure 2 & Figure 3, supplemental material, Table 2S & Table 3S).

Figure 3.

The dose titration of sacubitril/valsartan (A), beta-blockers (B), and the change in NYHA functional classification (C) across 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.

Trend of SBP over Time and Other Outcomes

From baseline to month six, there was a significant inverse effect of sacubitril/valsartan on SBP across both SBP categories (P_interaction = 0.001), with an increase of 7.5 mmHg (95% CI: 3.4–11.6) in patients with SBP < 100 mmHg (P = 0.001) and a reduction of 11.5 mmHg (95% CI: 7.0–16.0) in patients with SBP ≥ 100 mmHg (P < 0.001). When compared with patients with SBP < 100 mmHg, the reduction in DBP was greater (7 mmHg vs. 2 mmHg, P = 0.02) in patients with SBP ≥ 100 mmHg. In both SBP categories, the reductions in heart rate (10.5 beats/min vs. 16.5 beats/min, P = 0.15) and estimated glomerular filtration rate (eGFR) (7.5 mL/min per 1.73 m² vs. 7.6 mL/min per 1.73 m², P = 0.69) were comparable. Among those with SBP < 100 mmHg, serum potassium increased by 0.1 mmol/L (95% CI: 0.0–0.3), whereas it decreased by 0.1 mmol/L (95% CI: -0.3–0.1) among those with SBP ≥ 100 mmHg (Table 2, supplemental material, Table 2S).

Dosage Patterns of Sacubitril/Valsartan and Beta-blockers

In the group with SBP < 100 mmHg, a higher proportions of patients initiated sacubitril/valsartan with doses below 50 mg twice daily (44.7% vs. 30.0%) and with doses in the range of 50–100 mg twice daily (48.9% vs. 47.1%), when compared to the group with SBP ≥ 100 mmHg. During the follow-up period, more patients with SBP ≥ 100 mmHg received more than 50% of the targeted dose of sacubitril/valsartan than those with lower SBP (90% vs. 76.2%, P = 0.049). A target dose of sacubitril/valsartan was achieved by 52.4% of patients with SBP < 100 mmHg and 70.0% of patients with SBP ≥ 100 mmHg (P = 0.061). The median time to receive targeted doses of sacubitril/valsartan was three months for patients with SBP ≥ 100 mmHg and six months for patients with SBP < 100 mmHg. The proportion of patients who received 50% and 100% of targeted dose of beta-blockers was consistent across both SBP categories (78.6% vs. 77.1%, P = 0.860, and 50.0% vs. 55.7%, P = 0.557) (Figure 3, supplemental material, Table 4S–Table 6S, supplemental material, Figure 1S).

Other Medications Used to Treat HF

Throughout the titration procedure, there was a reduction in the administration of diuretics and digoxin in both experimental groups, although the utilization of SGLT2 inhibitors exhibited an increase in both groups. 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 increases in LVEF, SBP, eGFR, serum potassium, as well as the reductions in LVEDD, LAD, NT-proBNP and heart rate did not differ between the two categories of SBP (Table 3).

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
SBP: systolic blood pressure.
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 1.73 m2	5.5 (-9.2–20.2)	0.423		9.1 (-0.8–18.9)	0.067	0.65
Serium potassium, mmol/L	0.2 (-0.1–0.4)	0.150		0.1 (-0.1–0.3)	0.377	0.72

Safety Analysis

A total of three patients (6.4%) with SBP < 100 mmHg and four patients (5.7%) with SBP ≥ 100 mmHg discontinued sacubitril/valsartan permanently due to symptomatic hypotension during six months of treatment with sacubitril/valsartan. Among patients with SBP < 100 mmHg, three patients suffered from renal dysfunction (eGFR < 30 mL/min per 1.73 m²). Meanwhile, two patients (2.9%) in the higher SBP categories reported stroke, and no hyperkalemia and angioedema were observed in our study population in either SBP category (Table 4).

Table 4. Safety analysis.

Adverse effects	SBP < 100 mmHg (n = 47)	SBP ≥ 100 mmHg (n = 70)	P-value
Permanent discontinuation due to hypotension	3 (6.4%)	4 (5.7%)	1.000
Hyperkalemia	0	0	–
Renal impairment	3 (6.4%)	0	0.062
Angioedema	0	0	–
Stroke	0	2 (2.9%)	0.515

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 randomization, respectively; this study was the first to validate the role of sacubitril/valsartan in improving ventricular reverse remodeling in HFrEF patients with SBP < 100 mmHg without an increase in adverse effects, including symptomatic hypotension, worsening renal function, hyperkalemia, angioedema, and stroke.^[11,16,17]

According to our study, 52.4% of HFrEF patients with SBP < 100 mmHg were able to achieve the target doses of sacubitril/valsartan after six months of treatment. It should be noted that the proportions of targeted sacubitril/valsartan and beta-blockers were comparable between the two categories of SBP, except that patients with SBP ≥ 100 mmHg received an increased proportion 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 patients enrolled in the CHAMP-HF (Change the Management of Patients With Heart Failure) registry, among those 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 HartFalen) registry, patients with SBP < 95 mmHg less often 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 increase in the LVEF from baseline, were consistent in patients with SBP < 100 mmHg compared with SBP ≥ 100 mmHg, although sacubitril/valsartan was more effective in reducing LVEDD in patients with a baseline SBP ≥ 100 mmHg. Additionally, both SBP categories showed a significant improvement in NYHA functional classification.

We achieved such high proportions of sacubitril/valsartan 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 hypotension 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 sacubitril/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 without hypotension. A post-hoc analysis of the TITRATION (Safety and Tolerability of Initiating LCZ696 in Heart Failure Patients) trial identified that 80% of patients with low screening SBP levels achieved and tolerated target dose of sacubitril/valsartan by gradually increasing the dose.^[8] In light of these findings, clinicians should not hesitate to consider starting sacubitril/valsartan therapy 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 HFrEF. Thirdly, the follow-up management and self-monitoring programs for HF patients were crucial and essential. Studies have shown that high-dose sacubitril/valsartan can not only improve clinical status, exercise performance, 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 ventricular remodeling in HFrEF patients with concomitant hypotension. However, it cannot be overlooked that the population included in our study consisted of patients who were initially able to tolerate sacubitril/valsartan 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, within our team’s established follow-up management system, the majority of HFrEF patients without hypotension symptoms were considered for initiation of sacubitril/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 sacubitril/valsartan. Furthermore, the primary objective of this study was to evaluate the effectiveness and safety of sacubitril/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 system. Consequently, the sample population of the study exhibits a considerable degree of distinctiveness, thereby minimizing the presence of selection bias. However, it is worth noting that all of our findings were derived from individuals enrolled in our follow-up system who exhibited high compliance. The purpose of our research is to serve as a valuable source of inspiration and information for the medical community, shedding light on the effectiveness and safety of sacubitril/valsartan in specific subgroups of HFrEF patients.

Furthermore, sacubitril/valsartan exhibited an inverse 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 consistent with a post-hoc analysis of the PARADIGM-HF trial, which found that SBP increased in patients with the lowest baseline SBP (< 110 mmHg) and decreased in patients 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 antihypertensive side effects by improving cardiac function in patients with HFrEF and hypotension, similar to the results of the Carvedilol Prospective Randomized Cumulative 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 initiation of carvedilol, but instead experienced an increase after 10.4 months.^[26] The phenomenon of SBP regression to the mean following the administration of sacubitril/valsartan has garnered significant academic interest. The increase in SBP observed among patients with initially lower SBP levels may be associated with improvement in ejection fraction and stroke volume. Conversely, the decrease in SBP among individuals with elevated baseline SBP is associated with a decline in the equilibrium between preload and afterload.

Our study found that only three patients (6.4%) discontinued sacubitril/valsartan permanently due to symptomatic hypotension during titration in patients with HFrEF and SBP < 100 mmHg. In fact, in the PARADIGM-HF study, the risk of hypotension after randomization was 13.4% with ARNI; however, only 2.7% of patients 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 treatments (12.8%). Permanent discontinuation of the treatment was observed in only 2.2% of cases.^[27] Even in patients with acutely decompensated HF, the Comparison of Sacubitril/​Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode (PIONEER-HF) trial and the Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event (TRANSITION) trial provide insightful evidence regarding the BP tolerance of ARNI. It has been 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 context of increased risk for adverse effects.^[28] The TRANSITION trial demonstrated that the introduction of ARNI was feasible even before discharge following worsening HF, and that symptomatic hypotension was infrequent 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-blockers or sacubitril/valsartan, or require permanent withdrawal from treatment. These risks were primarily associated with the severity of the underlying illness rather than treatment with life-saving drugs for HFrEF. However, 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/valsartan.

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 effective 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 HFrEF, should not be initiated solely based on SBP. Cautela, et al.^[1] developed a five-step pharmacological management algorithm for ambulatory HFrEF patients with low BP. This algorithm was adopted as a reference during the titration process, which may be the reason we were able to achieve such a high proportion of sacubitril/valsartan doses. A consensus document from the Heart Failure Association of the European Society of Cardiology identified three patient profiles that may be relevant for the implementation of treatment in patients with HFrEF who have low BP.^[30] The use of guideline-directed medical therapy tailored to the condition and profile of each patient may be a better, more comprehensive approach than titrating each drug class before moving 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 acknowledged. In the first place, it is a retrospective observational study conducted within a single institution. Secondly, it should be noted that this study exclusively focused 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 promoting our follow-up management system and attaining such high patient compliance may take some time and present some obstacles. Nevertheless, it is apparent that patients experience substantial benefits from the implementation of this specific management approach. Hence, it is anticipated that our research will provide valuable insights and serve as a point of reference for further investigations in this area. Thirdly, it has a relatively small study population, which may affect the statistical performance. In addition, the limited follow-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 guideline-directed medical therapy. It is concluded from this study that sacubitril/valsartan initiation significantly improved left ventricular reverse remodeling in patients with HFrEF and low SBP within an optimized HF follow-up management system. In comparison with higher baseline SBP, the incidence of adverse effects did not differ significantly. The results of our study demonstrate that sacubitril/valsartan has the potential to counteract its antihypertensive side effects by improving cardiac function in patients with HFrEF and asymptomatic hypotension, 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 among a broader population of HFrEF patients who also experience concurrent hypotension.

SUPPLEMENTARY DATA

Supplementary data to this article can be found online.