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Abstract

Background:

Sacubitril/valsartan (SV) is recommended for patients with heart failure (HF). In addition, a combination of 4 HF medications, including SV, is recommended in patients with HF with reduced ejection fraction (HFrEF). However, evidence on the characteristics of patients who could continue SV and its initiation methods is limited.

Objective:

To investigate the factors associated with SV continuation and methods of combining HF medications.

Methods:

This retrospective cohort study included HF patients who initiated with SV at our institution. The endpoint was SV continuation for 6 months after its initiation. Multivariate analysis was used to extract factors associated with SV continuation. The relationship between the methods of combining HF medications (renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, or sodium-glucose cotransporter 2 inhibitors), including the number of HF medications, their combination patterns, and the timing of their initiation, and SV continuation was examined in patients with HFrEF.

Results:

Of 186 eligible patients, 68.8% had HFrEF, and 79.0% continued SV for 6 months. Significant factors associated with SV continuation were albumin ≥ 3.5 g/dL (odds ratio, 4.81; 95% confidence interval, 2.19-10.59), body mass index (BMI) ≥ 18.5 kg/m² (4.17; 1.10-15.85), and systolic blood pressure (SBP) ≥ 110 mmHg (2.66; 1.12-6.28). In patients with HFrEF, the proportion of HF medications not initiated simultaneously with SV was significantly higher in the continuation group than in the discontinuation group (67.3% vs 33.3%, P = 0.002). The number of HF medications and their combination patterns were not significantly associated with SV continuation.

Conclusion and Relevance:

Albumin, BMI, and SBP are useful indicators for selecting patients who are likely to continue SV. In addition, initiating only SV without simultaneously initiating other HF medications in patients with HFrEF may lead to SV continuation.

Keywords

sacubitril/valsartan heart failure factor continuation combination drug therapy treatment initiation pharmacotherapy HFrEF treatment

Introduction

The number of patients with heart failure (HF) is increasing annually worldwide.¹ In Japan, the 1-year rehospitalization rate due to worsening HF is 25%, and the 1-year all-cause mortality rate is 23%, with poor prognosis.² HF is classified into 3 categories based on the left ventricular ejection fraction (LVEF): HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). HF treatment guidelines indicate the treatment for each category.^3-5 For patients with HFrEF, a combination of 4 HF medications is recommended: angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB)/angiotensin receptor neprilysin inhibitor (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter 2 inhibitors (SGLT2i).^3-5 For patients with HFmrEF and HFpEF, treatment of comorbidities, such as hypertension, atrial fibrillation, and diabetes, and administration of diuretics for congestion is the standard treatment.^3-5 This includes using medications, such as ACEi/ARB/ARNI, beta-blockers, MRA, SGLT2i, anticoagulants, antiarrhythmics, and hypoglycemic agents.^3,4 Furthermore, patients whose LVEF is improved to > 40%, referred to as patients HF with improved ejection fraction, are recommended to continue HF treatment even after their LVEF has increased.⁴

Sacubitril/valsartan (SV), an ARNI, reduce rehospitalization and cardiovascular death rates compared with enalapril, an ACEi, in patients with HFrEF.⁶ Whereas, in patients with LVEF ≥ 45%, SV has not been shown to be more effective than ARB.⁷ In another study of patients with symptomatic HF, SV reportedly reduced HF hospitalization and cardiovascular death in patients with HFmrEF compared with renin-angiotensin system inhibitors (RASi).⁸ Therefore, SV is recommended in patients with HFrEF, HFmrEF, and those with LVEF closer to the lower normal limits.^3,4

In a previous study, the SV prescription rate 1 year after discharge was 13% in patients first admitted for HF.⁹ In addition, 12.7% of patients using ACEi or ARB switched to SV within approximately 1.5 years.¹⁰ Furthermore, approximately 25% of patients started on SV discontinued within 1 year.^10,11 Thus, despite the recommendations for SV in the guidelines, the initiation and continuation rates of SV are extremely low. This may be influenced by various factors, such as patient characteristics and adverse effects.

In outpatients with HFrEF, factors associated with SV discontinuation were unemployment, low scores on the Kansas City Cardiomyopathy Questionnaire, chronic kidney disease (CKD), and arrhythmias.¹⁰ In patients admitted for HF, factors associated with SV continuation were LVEF ≤ 40% and a history of HF hospitalization.¹² SV continuation may be affected by physical characteristics, such as body mass index (BMI), blood pressure, and laboratory data. However, evidence on the physical characteristics of patients who could continue SV and initiation methods is limited.

In patients with HFrEF, the combination of 4 HF medications is recommended,^3-5 and early initiation and titration of these medications have been shown to improve prognosis.¹³ Furthermore, according to a meta-analysis, the combination of 4 HF medications (SV, beta-blockers, MRA, and SGLT2i) prolongs survival compared with the combination of ACEi/ARB and beta-blockers.¹⁴ These findings suggest that patients using the 4 HF medications at SV initiation may have more stable HF symptoms due to their additive effects compared with those who are not. However, the relationship between the number of HF medications, their combination patterns, and the timing of their initiation and SV continuation are unclear. Therefore, clarifying the optimal method of combining the 4 HF medications may lead to SV continuation.

To select patients who could continue SV, we aimed to investigate the factors associated with SV continuation in patients with HF. We also investigated the relationship between methods of combining HF medications and SV continuation in patients with HFrEF.

Methods

Study Design and Patients

We performed a retrospective cohort study of HF patients who initiated with SV at the Department of Cardiology, Showa University Fujigaoka Hospital, from August 1, 2020, to December 31, 2022. The inclusion criteria were as follows: (1) HF diagnosis or confirmation based on the criteria in the guidelines,³ (2) HF in all LVEF categories, (3) SV initiation twice daily or switching from SV once daily for hypertension treatment¹⁵ to SV twice daily for HF treatment, and (4) SV initiation for HF treatment either in inpatient or outpatient settings. The exclusion criteria were as follows: death during hospitalization, participation in a clinical trial at SV initiation, unknown primary endpoints because treatment could not be continued at our institution, and age < 18 years. After the exclusion of 36 patients, 186 patients were included in this study (Supplementary Figure 1).

This study was approved by the Ethics Committee of Showa University, Japan (Approval No. 22-255-B), which waived the requirement for informed consent due to the retrospective nature of the study. Patients were informed that they could opt out of having their data used for research purposes on the Showa University Fujigaoka Hospital’s website.

Treatment of HF

The cardiologist prescribed HF medications following treatment guidelines.³ SV was initiated twice daily for HF patients, either inpatient or outpatient settings. When switching from ACEi to SV, SV was administered at least 36 hours after the last dose of ACEi. Subsequently, SV was titrated up to 400 mg/day, as tolerated by the patient. The physician made the decision to discontinue SV based on the patient’s condition.

Data Collection

Data on patient characteristics, physical findings, laboratory data, and medications were collected from the medical records at SV initiation. Patient characteristics included age, sex, BMI, past admission for HF, LVEF, past smoking and drinking, primary causes of HF, and comorbidities. Physical findings included systolic and diastolic blood pressure. Laboratory data included hemoglobin, blood urea nitrogen, serum creatinine, estimated glomerular filtration rate (eGFR), albumin, sodium, potassium, and brain natriuretic peptide (BNP) levels. Data at the closest point to SV initiation were collected if physical findings and laboratory data at SV initiation were unavailable.

The following medications used before and at SV initiation were investigated: RASi (ACEi/ARB/ARNI), beta-blockers, MRA, SGLT2i, loop diuretics, tolvaptan, thiazide diuretics, antiarrhythmic agents, antiplatelet agents, anticoagulants, statins, hypoglycemic agents, calcium channel blockers, and potassium adsorbents. Medications before SV initiation were defined as those prescribed in ambulatory care just before SV initiation.

We also collected information on the setting of SV initiation (inpatient or outpatient), duration of SV use in the discontinuation group, and reasons for SV discontinuation from the medical records. The dose at SV initiation, discontinuation, and 6 months after SV initiation were also collected.

In patients with HFrEF, information on the number of HF medications (RASi, beta-blockers, MRA, and SGLT2i) 6 months after SV initiation was collected for the continuation and discontinuation groups.

Endpoint

The endpoint was SV continuation for 6 months after its initiation. Patients who discontinued SV even once within 6 months after SV initiation were assigned to the discontinuation group.

Statistical Analysis

Sample size

We estimated that a sample size of 131 patients would be required to detect an odds ratio of 2.0, with 80% statistical power at a significance level of 0.05 in an equivalence test of the hypothesis, assuming the SV continuation rate to be 85%.^12,16-19 The sample size calculated using the actual SV continuation rate of 79% was 102 patients. Therefore, the sample size in this study was sufficient to arrive at a valid conclusion.²⁰

Stratification

For convenience in clinical use, the continuous variables were dichotomized and treated as categorical variables. Patients were divided into 2 groups based on the cutoff values according to the World Health Organization’s definition for age (65 years), BMI (18.5 kg/m²), and hemoglobin (13 and 12 g/dL in males and females, respectively). There is no report of an appropriate cutoff value for systolic blood pressure (SBP); therefore, the cutoff value was explored and set at 110 mmHg. Patients were divided into 2 groups based on eGFR (cutoff: 60 mL/min/1.73 m²) according to the CKD guidelines,²¹ albumin levels (cutoff: 3.5 g/dL) according to the criteria for hypoalbuminemia,²² and BNP levels (cutoff: 200 pg/mL) as an indicator of the need for HF treatment.²³ Other laboratory data were divided into 2 groups according to the upper or lower limits of the reference range values for clinical laboratory tests established by the Japanese Association of Clinical Laboratory Standards.²⁴

Factors affecting SV continuation

Patient characteristics, physical findings, laboratory data, medications, the dose of SV initiation, and the setting of SV initiation were compared between the SV continuation and discontinuation groups. Univariate analysis was performed using the χ² test or Fisher’s exact test. Significant variables extracted by univariate analysis were entered into the multivariate analysis. Ischemic heart disease and antiplatelet agents (r: 0.698), the setting of SV initiation and albumin levels (r: -0.545), and albumin and BNP levels (r: –0.491) were correlated; thus, ischemic heart disease and albumin were entered into the multivariate analysis. Ischemic heart disease was selected because it is a common cause of HF. Albumin was selected because its odds ratio for SV continuation was higher than that in the setting of SV initiation and BNP. SBP was not correlated with hypertension (r: 0.121); however, both factors reflect blood pressure; thus, SBP, which was used to determine SV initiation, was selected. Finally, age < 65 years, BMI ≥ 18.5 kg/m², SBP ≥ 110 mmHg, albumin ≥ 3.5 g/dL, and ischemic heart disease were entered into the multivariate analysis. Multivariate analysis was performed using logistic regression analysis. Independent and significant factors associated with SV continuation were extracted using a stepwise method. P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 28 (IBM, Tokyo, Japan).

Relationship between methods of combining HF medications and SV continuation in patients with HFrEF

In patients with HFrEF (LVEF < 40%), the relationship between the methods of combining HF medications (RASi, beta-blockers, MRA, and SGLT2i) and SV continuation was investigated in the following 4 ways.

The relationship between the number of HF medications before and at SV initiation and SV continuation was investigated using the χ² test or Fisher’s exact test. “Heart failure medications before SV initiation” were defined as those prescribed in ambulatory care just before SV initiation. When SV was initiated in an outpatient setting, the HF medications before SV initiation were defined as those prescribed in the last ambulatory care visit. When SV was initiated in an inpatient setting, the HF medications before SV initiation were defined as those prescribed in the ambulatory care visit immediately preceding the admission.

The combination patterns of HF medications in the SV continuation and discontinuation groups were compared using the χ² test or Fisher’s exact test.

The relationship between initiating any of HF medications other than SV (beta-blockers, MRA, and SGLT2i) at the same time as SV initiation and SV continuation was investigated using the χ² test. “At the same time as SV initiation” was defined as the same day as SV initiation when SV was initiated in an outpatient setting or the period from admission to SV initiation when SV was initiated in an inpatient setting.

In the inpatient group, the period from admission to SV initiation between the SV continuation and discontinuation groups was compared using the Mann-Whitney U test.

Results

Patient Characteristics

Patient characteristics are shown in Tables 1 and 2. The patients’ median age was 74 (interquartile range; 61-81) years, 137 (73.7%) were male, and 128 (68.8%) had HFrEF. Ten patients (5.4%) had previously used SV for hypertension,¹⁵ and 81 patients (43.5%) initiated with SV during hospitalization. The initiation dose of SV was 100 mg/day in 164 patients (88.2%, Supplementary Table 1). No factor was missing in more than 10% of patients.

Table 1.

Patient Characteristics and Medications Before SV Initiation (n = 186).

Variables	n (%) or median (interquartile range)
Age (years)	74	(61-81)
Male	137	(73.7)
BMI (kg/m²)	23.3	(21.1-26.1)
Past admission for heart failure	41	(22.0)
LVEF
< 40%, HFrEF	128	(68.8)
≥ 40%, HFmrEF/HFpEF	58	(31.2)
Past smoking	106	(57.0)
Past drinking	68	(36.8)
Primary cases of heart failure
Ischemic heart disease	70	(37.6)
Hypertensive heart disease	22	(11.8)
Valvular heart disease	47	(25.3)
Cardiomyopathy	78	(41.9)
Comorbidities
Hypertension	126	(67.7)
Diabetes	77	(41.4)
Chronic kidney disease	52	(28.0)
Atrial fibrillation	56	(30.1)
Old myocardial infarction	57	(30.6)
Medications before SV initiation^a
RASi	123	(66.1)
SV^b	10	(5.4)
Beta-blockers	116	(62.4)
MRA	77	(41.4)
SGLT2i	45	(24.2)
Loop diuretics	83	(44.6)
Tolvaptan	21	(11.3)
Thiazide diuretics	6	(3.2)
Antiarrhythmic agents	14	(7.5)
Antiplatelet agents	49	(26.3)
Anticoagulants	58	(31.2)
Statins	81	(43.5)
Hypoglycemic agents	35	(18.8)
Calcium channel blockers	54	(29.0)
Potassium adsorbents	8	(4.3)

No factor was missing in more than 10% of patients.

The medications before SV initiation were defined as those prescribed in ambulatory care just before SV initiation. When SV was initiated in an outpatient setting, the medications before SV initiation were defined as those prescribed in the last ambulatory care visit. When SV was initiated in an inpatient setting, the medications before SV initiation were defined as those prescribed in the ambulatory care visit immediately preceding the admission.

Used SV previously for hypertension.

Abbreviations: BMI, body mass index; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonists; RASi, renin-angiotensin system inhibitors; SGLT2i, sodium-glucose cotransporter 2 inhibitors; SV, sacubitril/valsartan.

Table 2.

Patient Findings and Medications at SV Initiation (n = 186).

Variables	n (%) or median (interquartile range)
Setting of SV initiation
Inpatient	81	(43.5)
Outpatient	105	(56.5)
Physical findings at SV initiation
Systolic BP (mmHg)	124	(112-138)
Diastolic BP (mmHg)	70	(61-80)
Laboratory data at SV initiation
Hemoglobin (g/dL)	13.1	(11.4-14.5)
BUN (mg/dL)	21.8	(16.7-27.3)
SCr (mg/dL)	1.05	(0.84-1.38)
eGFR (mL/min/1.73 m²)	51.8	(38.2-64.9)
Albumin (g/dL)	3.8	(3.3-4.2)
Sodium (mEq/L)	140	(138-142)
Potassium (mEq/L)	4.2	(3.9-4.5)
BNP (pg/mL)	282	(114-592)
Medications at SV initiation
Beta-blockers	161	(86.6)
MRA	125	(67.2)
SGLT2i	89	(47.8)
Loop diuretics	126	(67.7)
Tolvaptan	35	(18.8)
Thiazide diuretics	2	(1.1)
Antiarrhythmic agents	15	(8.1)
Antiplatelets agents	60	(32.3)
Anticoagulants	73	(39.2)
Statins	99	(53.2)
Hypoglycemic agents	27	(14.5)
Calcium channel blockers	37	(19.9)
Potassium adsorbents	6	(3.2)

No factor was missing in more than 10% of patients.

Abbreviations: BNP, brain natriuretic peptide; BP, blood pressure; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; MRA, mineralocorticoid receptor antagonists; SCr, serum creatinine; SGLT2i, sodium-glucose cotransporter 2 inhibitors; SV, sacubitril/valsartan.

Endpoint

SV was continued for ≥ 6 months in 147 patients (79.0%). In contrast, 39 patients (21.0%) discontinued SV within 6 months. The most common reason for SV discontinuation was hypotension (74.4%, Supplementary Table 2). In the discontinuation group, the median duration of SV use was 26 days (Supplementary Table 2). Furthermore, in the continuation group, only 33.3% of the patients achieved the SV target dose at 6 months after SV initiation (Supplementary Table 1). The rate of patients receiving SV 100 mg/day at discontinuation was 79.5% (Supplementary Table 1).

In patients with HFrEF, the rate of using the 4 HF medications 6 months after SV initiation was 44.2 and 40.0% in the continuation and discontinuation groups, respectively (Supplementary Figure 2).

Factors Affecting SV Continuation

In the univariate analysis, the proportions of patients with age < 65 years, BMI ≥ 18.5 kg/m², hypertension, SV initiation in the outpatient setting, SBP ≥ 110 mmHg, albumin ≥ 3.5 g/dL, and BNP < 200 pg/mL were significantly higher in the continuation group than in the discontinuation group (Table 3). In contrast, the proportions of patients with ischemic heart disease and taking antiplatelet agents were significantly lower in the continuation group than in the discontinuation group (Table 3).

Table 3.

Relationship Between Patient Characteristics and SV Continuation (n = 186).

Variables		Continuation		Discontinuation		P value
		n = 147		n = 39
		n (%)		n (%)
Age	< 65 (years)	55	(37.4)	7	(17.9)	0.022
Male		109	(74.1)	28	(71.8)	0.767
BMI	≥ 18.5 (kg/m²)	138	(96.5)	32	(84.2)	0.012
Past admission for heart failure		32	(21.8)	9	(23.1)	0.861
HFrEF		104	(70.7)	24	(61.5)	0.270
Past smoking		86	(58.5)	20	(51.3)	0.418
Past drinking		53	(36.1)	15	(39.5)	0.697
Primary causes of heart failure
Ischemic heart disease		49	(33.3)	21	(53.8)	0.019
Hypertensive heart disease		20	(13.6)	2	(5.1)	0.174
Valvular heart disease		37	(25.2)	10	(25.6)	0.952
Cardiomyopathy		64	(43.5)	14	(35.9)	0.390
Comorbidities
Hypertension		105	(71.4)	21	(53.8)	0.037
Diabetes		59	(40.1)	18	(46.2)	0.498
Chronic kidney disease		45	(30.6)	7	(17.9)	0.117
Atrial fibrillation		41	(27.9)	15	(38.5)	0.201
Old myocardial infarction		42	(28.6)	15	(38.5)	0.234
Medications before SV initiation^a
RASi		100	(68.0)	23	(59.0)	0.288
SV^b		8	(5.4)	2	(5.1)	1.000
Beta-blockers		94	(63.9)	22	(56.4)	0.388
MRA		65	(44.2)	12	(30.8)	0.130
SGLT2i		33	(22.4)	12	(30.8)	0.281
Loop diuretics		67	(45.6)	16	(41.0)	0.611
Tolvaptan		14	(9.5)	7	(17.9)	0.157
Thiazide diuretics		4	(2.7)	2	(5.1)	0.607
Antiarrhythmic agents		12	(8.2)	2	(5.1)	0.738
Antiplatelet agents		39	(26.5)	10	(25.6)	0.911
Anticoagulants		47	(32.0)	11	(28.2)	0.652
Statins		64	(43.5)	17	(43.6)	0.995
Hypoglycemic agents		26	(17.7)	9	(23.1)	0.444
Calcium channel blockers		42	(28.6)	12	(30.8)	0.788
Potassium adsorbents		6	(4.1)	2	(5.1)	0.674
Setting of SV initiation
Inpatient		57	(38.8)	24	(61.5)	0.011
Outpatient		90	(61.2)	15	(38.5)
Physical findings at SV initiation
Systolic BP	≥ 110 mmHg	122	(83.0)	25	(64.1)	0.010
Laboratory data at SV initiation
Hemoglobin	M ≥ 13, F ≥ 12 (g/dL)	92	(63.0)	18	(46.2)	0.057
BUN	≤ 20 (mg/dL)	59	(41.0)	12	(30.8)	0.246
SCr	M ≤ 1.07, F ≤ 0.79 (mg/dL)	69	(46.9)	20	(51.3)	0.629
eGFR	≥ 60 (mL/min/1.73 m²)	48	(32.7)	11	(28.2)	0.596
Albumin	≥ 3.5 (g/dL)	115	(79.3)	17	(43.6)	<0.001
Sodium	≥ 138 (mEq/L)	118	(80.3)	34	(87.2)	0.321
Potassium	≤ 4.8 (mEq/L)	136	(92.5)	33	(84.6)	0.206
BNP	< 200 (pg/mL)	66	(45.5)	7	(18.9)	0.003
Medications at SV initiation
Beta-blockers		129	(87.8)	32	(82.1)	0.353
MRA		97	(66.0)	28	(71.8)	0.492
SGLT2i		66	(44.9)	23	(59.0)	0.118
Loop diuretics		97	(66.0)	29	(74.4)	0.320
Tolvaptan		25	(17.0)	10	(25.6)	0.220
Thiazide diuretics		1	(0.7)	1	(2.6)	0.376
Antiarrhythmic agents		12	(8.2)	3	(7.7)	1.000
Antiplatelets agents		42	(28.6)	18	(46.2)	0.037
Anticoagulants		57	(38.8)	16	(41.0)	0.798
Statins		77	(52.4)	22	(56.4)	0.654
Hypoglycemic agents		20	(13.6)	7	(17.9)	0.494
Calcium channel blockers		32	(21.8)	5	(12.8)	0.213
Potassium adsorbents		5	(3.4)	1	(2.6)	1.000

Used SV previously for hypertension.

Abbreviations: BMI, body mass index; BNP, brain natriuretic peptide; BP, blood pressure; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonists; RASi, renin-angiotensin system inhibitors; SCr, serum creatinine; SGLT2i, sodium-glucose cotransporter 2 inhibitors; SV, sacubitril/valsartan.

In the multivariate analysis, albumin ≥ 3.5 g/dL, BMI ≥ 18.5 kg/m², and SBP ≥ 110 mmHg were independent significant factors associated with SV continuation (Table 4).

Table 4.

Factors Associated With SV Continuation in Patients With Heart Failure (n = 186).

Variable		β	OR	95% CI	P value
Albumin at SV initiation	≥ 3.5 g/dL vs < 3.5 g/dL	1.572	4.814	2.188-10.589	< 0.001
BMI	≥ 18.5 kg/m² vs < 18.5 kg/m²	1.428	4.168	1.096-15.852	0.036
Systolic BP at SV initiation	≥ 110 mmHg vs < 110 mmHg	0.976	2.655	1.123-6.278	0.026

Age, BMI, ischemic heart disease, systolic BP at SV initiation, and albumin at SV initiation were entered into the multivariate analysis.

Abbreviations: β, beta coefficient; BMI, body mass index; BP, blood pressure; CI, confidence interval; OR, odds ratio; SV, sacubitril/valsartan.

Relationship Between Methods of Combining HF Medications and SV Continuation in Patients With HFrEF

The number of the 4 HF medications before or at SV initiation was not significantly different between the SV continuation and discontinuation groups (Figure 1).

Figure 1.

Relationship between the number of heart failure medications initiated before and at SV initiation and SV continuation in patients with HFrEF. The heart failure medications included RASi, beta-blockers, MRA, and SGLT2i. “Heart failure medications before SV initiation” were defined as those prescribed in ambulatory care just before SV initiation. When SV was initiated in an outpatient setting, the heart failure medications before SV initiation were defined as those prescribed in the last ambulatory care visit. When SV was initiated in an inpatient setting, the heart failure medications before SV initiation were defined as those prescribed in the ambulatory care visit immediately preceding the admission.

The combination patterns of the 4 HF medications at SV initiation were not significantly different between the SV continuation and discontinuation groups (Supplementary Table 3).

The proportion of patients who had not initiated any of HF medications other than SV (beta-blockers, MRA, and SGLT2i) at the same time as SV initiation was significantly higher in the SV continuation group than in the discontinuation group (67.3% vs 33.3%, P = 0.002, Figure 2).

Figure 2.

Relationship between initiation of any of heart failure medications other than SV at the same time as SV initiation and SV continuation in patients with HFrEF. The heart failure medications other than SV included beta-blockers, MRA, and SGLT2i. “At the same time as SV initiation” was defined as the same day as SV initiation when SV was initiated in an outpatient setting or the period from admission to SV initiation when SV was initiated in an inpatient setting.

In patients who initiated SV during hospitalization (n = 60), the period from admission to SV initiation was not significantly different between the SV continuation and discontinuation groups (median [interquartile range], continuation group vs discontinuation group, 5 [3-6] vs 6 [3-10], P = 0.184).

Discussion

Albumin ≥ 3.5 g/dL, BMI ≥ 18.5 kg/m², and SBP ≥ 110 mmHg were factors associated with SV continuation in patients with HF. In addition, in patients with HFrEF, SV initiation as a single agent without initiating HF medications other than SV (beta-blockers, MRA, and SGLT2i) at the same time was associated with SV continuation. To the best of our knowledge, this is the first study to identify the physical factors associated with SV continuation in patients with HF and an effective combination of HF medications. These factors could be useful indicators for selecting patients who are likely to continue SV. Furthermore, it may lead to suggestions for effective methods of combining HF medications at SV initiation.

We found that lower albumin levels were associated with SV discontinuation. Patients with lower albumin levels might have discontinued SV because of their poor general condition.²⁵ Alternatively, SV may have been discontinued due to progressive fluid retention and inability to maintain circulation.²⁵ Therefore, we considered that patients with preserved albumin levels could continue SV because of their good general condition and stable circulation.

Patients who discontinued SV reportedly have a lower BMI than those who continued SV.^16,17 There are 2 possible reasons that BMI was associated with SV continuation. The first is the effect of SV blood concentration. A systematic review of patients with cachexia, including those with BMI < 20 kg/m², reported that patients with a lower BMI had a smaller volume of drug distribution than those with a higher BMI.²⁶ This suggests that, at the same dose, the blood concentration of SV in slimmer patients would likely be higher than that in normal- or overweight patients. Therefore, patients with low BMI may show stronger pharmacological effects of SV due to increased blood concentration, resulting in a higher rate of adverse effects. The second possible reason is the influence of SV tolerability. Patients with high BMI may have a better tolerance for the adverse effects of SV, such as hypotension, renal dysfunction, and hyperkalemia. A higher BMI has been reported as a determinant of achieving the SV target dose.¹⁶ Therefore, patients with high BMI were possibly more tolerant of the adverse effects and could continue SV.

The relationship between low blood pressure at SV initiation and SV discontinuation has been reported,^17,18,27 and similar results were found in this study. A previous study has shown that, in patients with HF, SBP at 2 to 4 weeks after SV initiation was 6 to 10 mmHg lower than that at SV initiation.¹⁸ Therefore, patients with blood pressure ≥110 mmHg at SV initiation may have been able to continue SV because of the low risk of symptomatic hypotension. In this study, we found a cutoff value of 110 mmHg for SBP at SV initiation, which may be a critical indicator for determining SV initiation.

In patients with HFrEF, initiating HF medications (beta-blockers, MRA, or SGLT2i) simultaneously with SV initiation may have increased the risk of adverse effects leading to SV discontinuation. There are 2 possible reasons for this increased risk. First, there is the additive effect of HF medications. Adverse effects of beta-blockers include hypotension and bradycardia, those of MRA include hyperkalemia and renal dysfunction, and those of SGLT2i include hypotension and renal dysfunction.⁵ Therefore, initiating HF medications simultaneously with SV initiation may have led to a stronger effect on hypotension, renal dysfunction, and hyperkalemia due to the additive effects of the medications. Second, inpatients may have had unstable blood pressure and HF. During periods of unstable blood pressure and HF, initiating SV and HF medications other than SV at the same time may have increased the risk of adverse effects. Therefore, to reduce the risk of discontinuation due to adverse effects, it may be better to initiate SV as a single agent. Particularly for inpatients, it is preferable to initiate SV as a single agent after blood pressure and HF have stabilized. In addition, a few patients discontinued any HF medications at SV initiation (6 patients in the continuation group and 3 in the discontinuation group); thus, discontinuing HF medications at SV initiation is not necessary.

In the STRONG-HF study, patients in the high-intensity care group were prescribed several HF medications at discharge, and a few patients were not receiving HF medications after 6 weeks (1.0%-5.0%).¹³ This suggests that several HF medications could be initiated at discharge. However, the inclusion criteria for our study differed from those for the STRONG-HF study, so that, this study included patients with unstable blood pressure and HF. This may have contributed to the finding that SV initiation as a single agent leads to SV continuation.

In patients with HFrEF, the use of 4 HF medications is recommended.^3-5 It has been reported that early initiation and up-titration of HF medications improved the prognosis of patients with HF.¹³ Therefore, we hypothesized that the number of 4 HF medications at SV initiation would lead to SV continuation, but no relationship was observed. This could be because this was a retrospective study with uncontrollable confounding factors.

Limitations

This study had 4 limitations. First, the external validity of the factors could not be verified as this was a single-center study. Second, data on the severity of HF in outpatients based on the New York Heart Association were unavailable; thus, the relationship between HF severity and SV continuation could not be investigated. To complement this limitation, the setting of SV initiation was included in the analysis. Third, owing to the retrospective nature of the study, standardizing the period between before and at SV initiation and the frequency of clinic visits after SV initiation was impossible. Fourth, no information was collected on the duration of use and doses of HF medications other than SV, SV adherence during the 6 months after SV initiation, and past preferences.

Conclusion and Relevance

Albumin ≥ 3.5 g/dL, BMI ≥ 18.5 kg/m², and SBP ≥ 110 mmHg were factors associated with SV continuation in patients with HF. These factors can be useful indicators for selecting patients who are more likely to continue SV. In addition, in patients with HFrEF, SV initiation as a single agent without initiating beta-blockers, MRA, or SGLT2i at the same time as SV initiation may lead to SV continuation. This result can serve as suggestions for methods of combining HF medications at SV initiation. Furthermore, this information will be useful for healthcare professionals when initiating SV.

Supplemental Material

sj-docx-1-aop-10.1177_10600280241277354 – Supplemental material for Factors Associated With Sacubitril/Valsartan Continuation and the Methods of Combining Heart Failure Medications in Patients With Heart Failure

Supplemental material, sj-docx-1-aop-10.1177_10600280241277354 for Factors Associated With Sacubitril/Valsartan Continuation and the Methods of Combining Heart Failure Medications in Patients With Heart Failure by Erika Iwasaki, Noriko Kohyama, Mayumi Inamoto, Michiru Nagao, Tomiko Sunaga, Hiroshi Suzuki, Mio Ebato and Mari Kogo in Annals of Pharmacotherapy

Footnotes

Acknowledgements

The authors are grateful to Yusuke Kato for his efforts in collecting the data.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Erika Iwasaki

Noriko Kohyama

Tomiko Sunaga

Supplemental Material

Supplemental material for this article is available online.

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