Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website https://cr.elmerpub.com

Original Article

Volume 000, Number 000, June 2025, pages 000-000

Effect of Angiotensin Receptor-Neprilysin Inhibitor in Patients With Heart Failure: A Real-World Study

Figure 1. Consort diagram for the present analysis. ARNI: angiotensin receptor-neprilysin inhibitor; HF: heart failure; HFrEF: heart failure with reduced ejection fraction.

Figure 2. Changes in SBP and DBP at baseline and after 6 months (M) in each patient. DBP: diastolic blood pressure; HFrEF: heart failure with reduced ejection fraction; SBP: systolic blood pressure.

Figure 3. Associations between changes in SBP or DBP from baseline to 6 months after ARNI treatment (ΔSBP or ΔDBP) and SBP (a) or DBP (b) at baseline. ARNI: angiotensin receptor-neprilysin inhibitor; DBP: diastolic blood pressure; SBP: systolic blood pressure.

Figure 4. Associations between changes in NT-proBNP from baseline to 6 months after ARNI treatment (ΔNT-proBNP) and NT-proBNP (a) or echocardiographic parameters (b-f) at baseline. Echocardiographic parameters related to cardiac function (LVEF (b), CO (c)), and cardiac dilation (LVDd (d), LVDs (e), and LVMI (f)) at baseline were used. ARNI: angiotensin receptor-neprilysin inhibitor; CO: cardiac output; LVDd: left ventricular end-diastolic dimension; LVDs: left ventricular end-systolic dimension; LVEF: left ventricular ejection fraction; LVMI: left ventricular mass index; NT-proBNP: N-terminal pro-brain natriuretic peptide.

Figure 5. Associations between changes in NT-proBNP from baseline to 6 months after ARNI treatment (ΔNT-proBNP) and indicators of left ventricular diastolic dysfunction and high left atrial pressure (E/e' (a), E/A (b), LAVI (c), and TRPG (d)) at baseline. E/A: ratio of early to late diastolic transmitral flow velocity; E/e': ratio of early transmitral Doppler velocity to early diastolic annular velocity; LAVI: left atrial volume index; NT-proBNP: N-terminal pro-brain natriuretic peptide; TRPG: tricuspid regurgitation pressure gradient.

Figure 6. Changes in NT-proBNP and LVEF at baseline and after 6 months (M) in each patient. LVEF: left ventricular ejection fraction; NT-proBNP: N-terminal pro-brain natriuretic peptide.

Figure 7. Associations between changes in NT-proBNP from baseline to 6 months after ARNI treatment (ΔNT-proBNP) or NT-proBNP levels at baseline and ΔSBP/ΔDBP or SBP/DBP at baseline. ARNI: angiotensin receptor-neprilysin inhibitor; DBP: diastolic blood pressure; NT-proBNP: N-terminal pro-brain natriuretic peptide; SBP: systolic blood pressure.

Figure 8. Associations between doses of ARNI and changes in ΔLVEF (a) and ΔNT-proBNP (b). ARNI: angiotensin receptor-neprilysin inhibitor; LVEF: left ventricular ejection fraction; NT-proBNP: N-terminal pro-brain natriuretic peptide.

**Table 1.** Characteristics of the Patients at Baseline (N = 46)
	Overall (N = 46)	HFrEF (N = 17)	Non-HFrEF (N = 29)	P value
Continuous variables are expressed as mean ± SD. ACEi: angiotensin-converting enzyme inhibitor; AF: atrial fibrillation; ARB: angiotensin II receptor blocker; BMI: body mass index; BW: body weight; CKD: chronic kidney disease; Cr: creatinine; CRT: cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy-defibrillator; DBP: diastolic blood pressure; DL: dyslipidemia; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; HF: heart failure; HFrEF: heart failure with reduced ejection fraction; HR: heart rate; HTN: hypertension; HU: hyperuricemia; IHD: ischemic heart disease; MRA: mineralocorticoid receptor antagonist; NT-proBNP: N-terminal pro-brain natriuretic peptide; NYHA: New York Heart Association; SAS: sleep apnea syndrome; SBP: systolic blood pressure; SGLT2i: sodium-glucose cotransporter-2 inhibitor.
Age (years)	67 ± 13	65 ± 12	68 ± 14	0.53
Males (%)	31 (67)	11 (65)	20 (69)	0.77
BW (kg)	66.7 ± 15.7	62.6 ± 15.6	69.2 ± 15.5	0.17
BMI (kg/m²)	25.5 ± 4.7	24.5 ± 4.6	26.2 ± 4.7	0.24
SBP (mm Hg)	131 ± 25	127 ± 27	133 ± 24	0.42
DBP (mm Hg)	78 ± 16	79 ± 19	77 ± 13	0.61
HR (bpm)	73 ± 13	74 ± 11	73 ± 14	0.75
NYHA (%)				< 0.01
I	18 (39.1)	2 (11.8)	16 (55.2)
II	17 (37.0)	9 (52.9)	8 (27.6)
III	10 (21.7)	5 (29.4)	5 (17.2)
VI	1 (2.2)	1 (5.88)	0 (0)
Cr (mg/dL)	0.99 (0.8 - 1.42)	0.97 (0.73 - 1.64)	1 (0.83 - 1.35)	0.88
eGFR (mL/min/1.73 m²)	52.7 ± 20	52.2 ± 22.0	52.9 ± 19.1	0.91
NT-proBNP (pg/mL)	550 (173 - 1,406)	1,583 (775 - 3,431)	385 (132 - 681)	< 0.01
Inpatient visit for acute HF	9 (20)	6 (35)	3 (10)	0.04
Prior HF hospitalization (%)	23 (50)	13 (76)	10 (34)	< 0.01
HTN (%)	30 (65.2)	13 (70.6)	18 (62.1)	0.56
DM (%)	15 (32.6)	7 (41.2)	8 (27.6)	0.34
DL (%)	29 (63.0)	10 (58.8)	19 (65.5)	0.65
HU (%)	20 (43.5)	8 (47.1)	12 (41.4)	0.71
SAS (%)	6 (13.0)	0 (0)	6 (20.7)	0.04
CKD (%)	26 (56.5)	9 (52.9)	17 (58.6)	0.71
AF (%)	11 (21.6)	4 (23.5)	6 (20.7)	0.82
IHD (%)	15 (32.6)	8 (47.1)	7 (24.1)	0.11
HF therapy
β-blocker (%)	39 (84.8)	15 (88.2)	26 (82.8)	0.62
ACEi (%)	13 (28.3)	7 (41.2)	6 (20.7)	0.14
ARBs (%)	30 (71.4)	9 (52.9)	21 (72.4)	0.18
MRA (%)	24 (52.2)	10 (58.8)	14 (48.3)	0.49
SGLT2i (%)	13 (28.3)	5 (29.4)	8 (27.6)	0.89
Loop diuretic (%)	23 (50.0)	12 (70.6)	11 (37.9)	0.03
Tolvaptan (%)	4 (8.7)	4 (23.5)	0 (0)	< 0.01
CRT/CRT-D (%)	5 (9.8)	4 (23.5)	1 (3.45)	0.03

Table 1. Characteristics of the Patients at Baseline (N = 46)

Overall (N = 46)

HFrEF (N = 17)

Non-HFrEF (N = 29)

P value

Continuous variables are expressed as mean ± SD. ACEi: angiotensin-converting enzyme inhibitor; AF: atrial fibrillation; ARB: angiotensin II receptor blocker; BMI: body mass index; BW: body weight; CKD: chronic kidney disease; Cr: creatinine; CRT: cardiac resynchronization therapy; CRT-D: cardiac resynchronization therapy-defibrillator; DBP: diastolic blood pressure; DL: dyslipidemia; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; HF: heart failure; HFrEF: heart failure with reduced ejection fraction; HR: heart rate; HTN: hypertension; HU: hyperuricemia; IHD: ischemic heart disease; MRA: mineralocorticoid receptor antagonist; NT-proBNP: N-terminal pro-brain natriuretic peptide; NYHA: New York Heart Association; SAS: sleep apnea syndrome; SBP: systolic blood pressure; SGLT2i: sodium-glucose cotransporter-2 inhibitor.

Age (years)

67 ± 13

65 ± 12

68 ± 14

0.53

Males (%)

31 (67)

11 (65)

20 (69)

0.77

BW (kg)

66.7 ± 15.7

62.6 ± 15.6

69.2 ± 15.5

0.17

BMI (kg/m²)

25.5 ± 4.7

24.5 ± 4.6

26.2 ± 4.7

0.24

SBP (mm Hg)

131 ± 25

127 ± 27

133 ± 24

0.42

DBP (mm Hg)

78 ± 16

79 ± 19

77 ± 13

0.61

HR (bpm)

73 ± 13

74 ± 11

73 ± 14

0.75

NYHA (%)

< 0.01

18 (39.1)

2 (11.8)

16 (55.2)

17 (37.0)

9 (52.9)

8 (27.6)

III

10 (21.7)

5 (29.4)

5 (17.2)

1 (2.2)

1 (5.88)

0 (0)

Cr (mg/dL)

0.99 (0.8 - 1.42)

0.97 (0.73 - 1.64)

1 (0.83 - 1.35)

0.88

eGFR (mL/min/1.73 m²)

52.7 ± 20

52.2 ± 22.0

52.9 ± 19.1

0.91

NT-proBNP (pg/mL)

550 (173 - 1,406)

1,583 (775 - 3,431)

385 (132 - 681)

< 0.01

Inpatient visit for acute HF

9 (20)

6 (35)

3 (10)

0.04

Prior HF hospitalization (%)

23 (50)

13 (76)

10 (34)

< 0.01

HTN (%)

30 (65.2)

13 (70.6)

18 (62.1)

0.56

DM (%)

15 (32.6)

7 (41.2)

8 (27.6)

0.34

DL (%)

29 (63.0)

10 (58.8)

19 (65.5)

0.65

HU (%)

20 (43.5)

8 (47.1)

12 (41.4)

0.71

SAS (%)

6 (13.0)

0 (0)

6 (20.7)

0.04

CKD (%)

26 (56.5)

9 (52.9)

17 (58.6)

0.71

AF (%)

11 (21.6)

4 (23.5)

6 (20.7)

0.82

IHD (%)

15 (32.6)

8 (47.1)

7 (24.1)

0.11

HF therapy

β-blocker (%)

39 (84.8)

15 (88.2)

26 (82.8)

0.62

ACEi (%)

13 (28.3)

7 (41.2)

6 (20.7)

0.14

ARBs (%)

30 (71.4)

9 (52.9)

21 (72.4)

0.18

MRA (%)

24 (52.2)

10 (58.8)

14 (48.3)

0.49

SGLT2i (%)

13 (28.3)

5 (29.4)

8 (27.6)

0.89

Loop diuretic (%)

23 (50.0)

12 (70.6)

11 (37.9)

0.03

Tolvaptan (%)

4 (8.7)

4 (23.5)

0 (0)

< 0.01

CRT/CRT-D (%)

5 (9.8)

4 (23.5)

1 (3.45)

0.03

**Table 2.** Change in BW, BP, Biochemical Parameters, and Cardiothoracic Ratio Between Baseline and 6 Months After ARNI Treatment
	Overall	HFrEF	Non-HFrEF
Continuous variables are expressed as mean ± SD. ARNI: angiotensin receptor-neprilysin inhibitor; BW: body weight; Cr: creatinine; CTR: cardiothoracic ratio; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; HFrEF: heart failure with reduced ejection fraction; NT-proBNP: N-terminal pro-brain natriuretic peptide; SBP: systolic blood pressure; SD: standard deviation; UA: uric acid.
BW (kg)	66.7 ± 15.7	64.9 ± 14.7	46	0.01	62.6 ± 15.6	60.6 ± 14.7	17	0.02	69.2 ± 15.5	67.4 ± 14.3	29	0.1
SBP (mm Hg)	131 ± 25	126 ± 23	46	0.1	127 ± 27	120 ± 23	17	0.3	133 ± 24	129 ± 22	29	0.21
DBP (mm Hg)	78 ± 16	72 ± 15	46	0.03	79 ± 19	73 ± 20	17	0.23	77 ± 13	71 ± 11	29	0.07
NT-proBNP (pg/mL)	600.5 (163.3 - 1,671)	461.5 (142.8 - 1,056)	40	< 0.01	1,583 (653 - 4,059)	678 (386 - 2,388)	14	< 0.01	365 (120 - 714)	199 (118 - 806)	26	0.28
Cr (mg/dL)	0.99 (0.8 - 1.42)	1.07 (0.85 -1.43)	46	0.2	0.97 (0.73 - 1.64)	1.08 (0.81 - 1.59)	17	> 0.99	1.00 (0.83 - 1.35)	1.00 (0.85 - 1.34)	29	0.43
eGFR (mL/min/1.73 m²)	52.7 ± 20	51.8 ± 21.7	46	0.53	52.2 ± 22	50.9 ± 22.9	17	0.56	52.9 ± 19.1	52.3 ± 21.5	29	0.73
UA (mg/dL)	5.91 ± 1.37	5.72 ± 1.44	45	0.29	5.73 ± 1.38	5.5 ± 1.54	16	0.5	6.0 ± 1.39	5.84 ± 1.4	29	0.42
CTR (%)	52.4 ± 5.28	51.2 ± 4.3	46	< 0.01	55.6 ± 5.19	53.1 ± 4.51	17	> 0.01	50.5 ± 4.39	50 ± 3.8	29	0.32

Table 2. Change in BW, BP, Biochemical Parameters, and Cardiothoracic Ratio Between Baseline and 6 Months After ARNI Treatment

Overall

HFrEF

Non-HFrEF

Baseline

6 M

Baseline

6 M

Baseline

6 M

Continuous variables are expressed as mean ± SD. ARNI: angiotensin receptor-neprilysin inhibitor; BW: body weight; Cr: creatinine; CTR: cardiothoracic ratio; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; HFrEF: heart failure with reduced ejection fraction; NT-proBNP: N-terminal pro-brain natriuretic peptide; SBP: systolic blood pressure; SD: standard deviation; UA: uric acid.

BW (kg)

66.7 ± 15.7

64.9 ± 14.7

0.01

62.6 ± 15.6

60.6 ± 14.7

0.02

69.2 ± 15.5

67.4 ± 14.3

0.1

SBP (mm Hg)

131 ± 25

126 ± 23

0.1

127 ± 27

120 ± 23

0.3

133 ± 24

129 ± 22

0.21

DBP (mm Hg)

78 ± 16

72 ± 15

0.03

79 ± 19

73 ± 20

0.23

77 ± 13

71 ± 11

0.07

NT-proBNP (pg/mL)

600.5 (163.3 - 1,671)

461.5 (142.8 - 1,056)

< 0.01

1,583 (653 - 4,059)

678 (386 - 2,388)

< 0.01

365 (120 - 714)

199 (118 - 806)

0.28

Cr (mg/dL)

0.99 (0.8 - 1.42)

1.07 (0.85 -1.43)

0.2

0.97 (0.73 - 1.64)

1.08 (0.81 - 1.59)

> 0.99

1.00 (0.83 - 1.35)

1.00 (0.85 - 1.34)

0.43

eGFR (mL/min/1.73 m²)

52.7 ± 20

51.8 ± 21.7

0.53

52.2 ± 22

50.9 ± 22.9

0.56

52.9 ± 19.1

52.3 ± 21.5

0.73

UA (mg/dL)

5.91 ± 1.37

5.72 ± 1.44

0.29

5.73 ± 1.38

5.5 ± 1.54

0.5

6.0 ± 1.39

5.84 ± 1.4

0.42

CTR (%)

52.4 ± 5.28

51.2 ± 4.3

< 0.01

55.6 ± 5.19

53.1 ± 4.51

> 0.01

50.5 ± 4.39

50 ± 3.8

0.32

**Table 3.** Change in Echocardiographic Parameter Between Baseline and 6 Months After ARNI Treatment
	Overall	HFrEF	Non-HFrEF
Continuous variables are expressed as mean ± SD. ARNI: angiotensin receptor-neprilysin inhibitor; CO: cardiac output; E/A: ratio of early to late diastolic transmitral flow velocity; E/e': ratio of early transmitral Doppler velocity/early diastolic annular velocity; HFrEF: heart failure with reduced ejection fraction; LAVI: left atrial volume index; LVDd: left ventricular end-diastolic dimension; LVDs: left ventricular end-systolic dimension; LVEF: left ventricular ejection fraction; LVMI: left ventricular mass index; SD: standard deviation; TRPG: tricuspid regurgitation pressure gradient.
LVEF (%)	45 ± 16	52 ± 15	46	< 0.01	29 ± 8	41 ± 13	17	< 0.01	55 ± 11	58 ± 12	29	0.03
LVDd (mm)	53.2 (46.5 - 56.3)	49.3 (44.8 - 54.1)	46	< 0.01	54.0 (51.1 - 58.4)	49.3 (45.8 - 56.9)	17	< 0.01	52.1 (44.4 - 54.9)	49.3 (44 - 53.5)	29	0.14
LVDs (mm)	41.8 (33.4 - 48.6)	36.4 (29.4 - 42.3)	46	< 0.01	48.9 (43.9 - 50.7)	38.3 (32.6 - 47.9)	17	< 0.01	37.4 (28.6 - 42.2)	35.3 (26.2 - 38.6)	29	0.02
CO (L/min)	4.14 ± 1.86	3.87 ± 1.88	45	0.4	3.87 ± 2.14	3.63 ± 1.59	17	0.67	4.31 ± 1.7	4.01 ± 2.05	28	0.49
LVMI (mL/m²)	116.9 (96.25 - 139.8)	109.4 (90.97 - 131.3)	46	0.07	134.1 (106.4 - 146.1)	109.3 (92.3-142.0)	17	0.01	110 (91.1 - 130.6)	109.5 (89.5 - 129.4)	29	0.73
E/A	0.9 (0.7 - 1.2)	0.8 (0.6 - 1.1)	40	0.29	1.0 (0.95 - 2.2)	0.8 (0.5 - 2.2)	13	0.33	0.84 (0.7 - 1)	0.8 (0.68 - 1.1)	27	0.87
E/e' (mean)	10.6 (8.66 - 14.7)	10.6 (8.18 - 13.3)	42	0.37	13.5 (9.55 - 19.6)	10.5 (8.36 - 13.7)	16	0.21	9.74 (8.63 - 12.03)	10.7 (7.51 - 12.7)	26	> 0.99
LAVI (mL/m²)	40.9 (28.0 - 60.4)	38.6 (26.8 - 51.4)	40	0.08	47.9 (30.7 - 69.5)	37 (19 - 59.2)	15	0.01	38.1 (27.1 - 52.2)	40 (30 - 50.5)	25	0.91
TRPG (mm Hg)	23.5 (17.2 - 34.1)	20.6 (16.1 - 27.1)	37	0.08	30 (20 - 42.2)	18.7 (16 - 23.6)	15	< 0.01	22.45 (16 - 29.25)	22.15 (17.48 - 29.6)	22	0.69

Table 3. Change in Echocardiographic Parameter Between Baseline and 6 Months After ARNI Treatment

Overall

HFrEF

Non-HFrEF

Baseline

6 M

Baseline

6 M

Baseline

6 M

Continuous variables are expressed as mean ± SD. ARNI: angiotensin receptor-neprilysin inhibitor; CO: cardiac output; E/A: ratio of early to late diastolic transmitral flow velocity; E/e': ratio of early transmitral Doppler velocity/early diastolic annular velocity; HFrEF: heart failure with reduced ejection fraction; LAVI: left atrial volume index; LVDd: left ventricular end-diastolic dimension; LVDs: left ventricular end-systolic dimension; LVEF: left ventricular ejection fraction; LVMI: left ventricular mass index; SD: standard deviation; TRPG: tricuspid regurgitation pressure gradient.

LVEF (%)

45 ± 16

52 ± 15

< 0.01

29 ± 8

41 ± 13

< 0.01

55 ± 11

58 ± 12

0.03

LVDd (mm)

53.2 (46.5 - 56.3)

49.3 (44.8 - 54.1)

< 0.01

54.0 (51.1 - 58.4)

49.3 (45.8 - 56.9)

< 0.01

52.1 (44.4 - 54.9)

49.3 (44 - 53.5)

0.14

LVDs (mm)

41.8 (33.4 - 48.6)

36.4 (29.4 - 42.3)

< 0.01

48.9 (43.9 - 50.7)

38.3 (32.6 - 47.9)

< 0.01

37.4 (28.6 - 42.2)

35.3 (26.2 - 38.6)

0.02

CO (L/min)

4.14 ± 1.86

3.87 ± 1.88

0.4

3.87 ± 2.14

3.63 ± 1.59

0.67

4.31 ± 1.7

4.01 ± 2.05

0.49

LVMI (mL/m²)

116.9 (96.25 - 139.8)

109.4 (90.97 - 131.3)

0.07

134.1 (106.4 - 146.1)

109.3 (92.3-142.0)

0.01

110 (91.1 - 130.6)

109.5 (89.5 - 129.4)

0.73

E/A

0.9 (0.7 - 1.2)

0.8 (0.6 - 1.1)

0.29

1.0 (0.95 - 2.2)

0.8 (0.5 - 2.2)

0.33

0.84 (0.7 - 1)

0.8 (0.68 - 1.1)

0.87

E/e' (mean)

10.6 (8.66 - 14.7)

10.6 (8.18 - 13.3)

0.37

13.5 (9.55 - 19.6)

10.5 (8.36 - 13.7)

0.21

9.74 (8.63 - 12.03)

10.7 (7.51 - 12.7)

> 0.99

LAVI (mL/m²)

40.9 (28.0 - 60.4)

38.6 (26.8 - 51.4)

0.08

47.9 (30.7 - 69.5)

37 (19 - 59.2)

0.01

38.1 (27.1 - 52.2)

40 (30 - 50.5)

0.91

TRPG (mm Hg)

23.5 (17.2 - 34.1)

20.6 (16.1 - 27.1)

0.08

30 (20 - 42.2)

18.7 (16 - 23.6)

< 0.01

22.45 (16 - 29.25)

22.15 (17.48 - 29.6)

0.69