Angiotensin receptor–neprilysin inhibition and combination use of guideline-directed medical therapies in acute heart failure

Both American and European heart failure (HF) guidelines currently recommend initiation and optimization of guideline-directed medical therapy (GDMT), which is composed of renin–angiotensin system (RAS) inhibitors, β-blocker, mineralocorticoid receptor antagonist (MRA), and sodium–glucose cotransporter 2 (SGLT2) inhibitor, during the hospitalization for acute HF (AHF).^1-3 In previous clinical trials, it was found that initiation of sacubitril/valsartan (Sac/Val) early in stabilized patients after an AHF episode requiring hospitalization resulted in a greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration than the use of standard RAS inhibitors over 8 weeks of therapy.⁴ However, since those trials and another AHF trial assessing intensive and rapid up-titration of GDMT included few patients being treated by SGLT2 inhibitors,^{4, 5} it is currently unclear whether the treatment effect of early Sac/Val initiation on NT-proBNP concentration differs according to the combination status of GDMT in this patient population.

In the recent Program Angiotensin–Neprilysin Inhibition in Admitted Patients with Worsening Heart Failure (PREMIER) study (NCT05164653),⁶ in-hospital initiation of Sac/Val, compared with the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB), also triggered a greater NT-proBNP concentration reduction over 8 weeks in Japanese patients admitted with AHF. In that study, background usage of individual GDMT other than RAS inhibitors was more frequent than in previous studies.⁴ We herein examined the NT-proBNP response according to the combination status of GDMT usage as a post hoc secondary analysis of the PREMIER study.⁶

The PREMIER study was an investigator-initiated, multicentre, prospective, randomized controlled, open-label, blinded-endpoint design that included haemodynamically stabilized Japanese inpatients after an AHF event, regardless of left ventricular ejection fraction (LVEF) status and acute de novo or decompensated chronic HF. The study participants on standard ACEI/ARB therapy were allocated within 7 days of an index hospitalization to receive either switched Sac/Val or continued ACEI/ARB therapy for 8 weeks. The study protocol was approved by the ethics committee of each site and individual informed consent was obtained before study entry.

Study participants were sub-classified according to the combined use of background GDMT, excluding the study drugs, at baseline (week 0). Patients who were on three background GDMT (β-blocker, MRA, and SGLT2 inhibitor) were categorized into quadruple (three GDMT and study drug) HF therapy recipients. In contrast, patients, who were on two or fewer background GDMT plus study drugs, were categorized into non-quadruple HF therapy recipients. The NT-proBNP concentration was analysed in a manner similar to the primary analysis,⁶ using a mixed-effects model for repeated measurements that included an interaction term between treatment and GDMT status, adjusted by baseline NT-proBNP levels and other variables with a large treatment-group difference (a standardized mean difference >0.200).

Among the full analysis set (n = 376; Sac/Val, n = 183; ACEI/ARB, n = 193),⁶ 188 patients (Sac/Val, n = 91; ACEI/ARB, n = 97) received quadruple HF therapy and 188 patients (Sac/Val, n = 92; ACEI/ARB, n = 96) received non-quadruple HF therapy. The background characteristics of the patients according to their GDMT status are shown in Table 1. Quadruple recipients were younger, had more de novo HF, and had a lower LVEF than non-quadruple recipients. In the quadruple recipients, percent reductions in the geometric means of NT-proBNP concentration at week 8, compared to the baseline value, were − 54% (95% confidence interval [CI], −61% to −45%) for the Sac/Val group and − 37% (95% CI, −47% to −25%) for the ACEI/ARB group; a group ratio with change (Sac/Val vs. ACEI/ARB) was 0.78 (95% CI, 0.62 to 0.98; p = 0.034). In the non-quadruple recipients, the reductions were −35% (95% CI, −45% to −22%) for the Sac/Val group and −26% (95% CI, −38% to −12%) for the ACEI/ARB group; the group ratio was 0.87 (95% CI, 0.69 to 1.09; p = 0.232) (Figure 1). This was similar in the exclusive analysis targeted at subgroup with background LVEF <40% (group ratio 0.62 [95% CI, 0.47 to 0.83; p = 0.001] for the quadruple recipients) (mean LVEF at randomization 27.7 ± 6.4%) and 0.77 (95% CI, 0.54 to 1.09; p = 0.140) for the non-quadruple recipients (mean LVEF at randomization 28.9 ± 6.0%) (Figure 1).

Table 1. Background characteristics of study patients according to guideline-directed medical therapy status at baseline

Variable	Quadruple GDMT recipients			Non-quadruple GDMT recipients
	Sac/Val (n = 91)	ACEI/ARB (n = 97)	SMD	Sac/Val (n = 92)	ACEI/ARB (n = 96)	SMD
Age, years	68.6 ± 13.3	71.4 ± 12.9	0.208	77.4 ± 10.3	75.9 ± 11.5	0.132
Male sex	66 (72.5)	75 (77.3)	0.111	57 (62.0)	58 (60.4)	0.032
Systolic blood pressure, mmHg	129.1 ± 17.6	126.7 ± 18.9	0.132	133.8 ± 21.3	128.1 ± 18.4	0.289
eGFR, ml/min/1.73 m2	55.6 ± 17.3	54.1 ± 13.6	0.101	51.0 ± 12.6	53.1 ± 15.4	0.151
De novo HF	54 (59.3)	63 (64.9)	0.116	48 (52.2)	44 (45.8)	0.127
LVEF at randomization, %	34.9 ± 13.4	35.2 ± 12.6	0.021	44.1 ± 16.1	44.7 ± 16.2	0.038
<40%	61 (67.0)	65 (67.0)	0.000	41 (44.6)	40 (41.7)	0.059
NT-proBNP at baselinea, pg/ml	1770 (1005–3475)	1730 (890–3118)	0.038	1695 (1030–2975)	2185 (1005–3660)	0.048
Use of other GDMTs at baseline
β-blocker (+), MRA (+), SGLT2i (+)	91 (100)	97 (100)	0.000	0	0
β-blocker (+), MRA (+), SGLT2i (–)	0	0		33 (35.9)	35 (36.5)	0.012
β-blocker (+), MRA (–), SGLT2i (+)	0	0		10 (10.9)	16 (16.7)	0.169
β-blocker (–), MRA (+), SGLT2i (+)	0	0		13 (14.1)	13 (13.5)	0.017
β-blocker (+), MRA (–), SGLT2i (–)	0	0		22 (23.9)	17 (17.7)	0.153
β-blocker (–), MRA (+), SGLT2i (–)	0	0		9 (9.8)	8 (8.3)	0.051
β-blocker (–), MRA (–), SGLT2i (+)	0	0		1 (1.1)	4 (4.2)	0.193
β-blocker (–), MRA (–), SGLT2i (–)	0	0		4 (4.3)	3 (3.1)	0.065

• Values are presented as mean ± standard deviation, n (%), or median (interquartile range).
• ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; GDMT, guideline-directed medical therapy; HF, heart failure; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; Sac/Val, sacubitril/valsartan; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SMD, standardized mean difference.
• ^a SMD for NT-proBNP was calculated on the log scale.

Figure 1

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Percent changes in the geometric means of N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration at week 8, compared to the baseline value, and their group ratios (sacubitril/valsartan [Sac/Val] vs. angiotensin-converting enzyme inhibitor/angiotensin receptor blocker [ACEI/ARB]), stratified by the quadruple and non-quadruple guideline-directed medical therapy recipients in the overall (left panel) and subgroup with background left ventricular ejection fraction (LVEF) <40% (right panel). Inter-treatment group comparisons were further adjusted by age and systolic blood pressure at baseline, whose standardized mean differences were greater than 0.200. CI, confidence interval.

A key finding of this secondary analysis of the PREMIER study was that the treatment effect of Sac/Val, relative to ACEI/ARB, on NT-proBNP reduction in patients admitted for AHF was potentially more evident in quadruple recipients, although there was no clear statistical heterogeneity between the GDMT subgroups (p_interaction = 0.505). In this context, the background LVEF was lower in quadruple therapy recipients than in non-quadruple therapy recipients. Studies have shown that the beneficial effect of Sac/Val therapy after AHF was generally evident in patients with a lower LVEF spectrum.^{4, 6} Hence, we assumed that our finding was due to the large proportion of participants with lower LVEF in the quadruple therapy recipients. However, in the exclusive analysis of patients with a background LVEF <40%, the NT-proBNP response to Sac/Val therapy was still evident in quadruple recipients. This may enhance the clinical significance of the early implementation of Sac/Val-based quadruple GDMTs after an AHF episode, especially in patients with a lower LVEF.

Our findings should be interpreted as indicative, considering several limitations but not as definitive proof of the evidence. This was a post hoc exploratory analysis from a randomized PREMIER study, which was not specifically designed to assess the difference in the treatment effect of Sac/Val according to the baseline combination status of GDMT. The relatively small number of subclassified patients reduced the statistical power to detect the differences. Additionally, this analysis was performed only to evaluate the original primary endpoint of the PREMIER study, and the implementation of GDMT along with other clinical confounding factors may have partially affected the impact of the study interventions on the endpoint. Finally, we did not consider the doses of individual GDMT and their changes, due to limited information after initiating the study drugs.

Collectively, our findings suggest that the Sac/Val-based full-combination use of GDMT, relative to ACEI/ARB-based use, was incremental in reducing NT-proBNP concentrations in haemodynamically stabilized patients after an AHF episode. Further studies are warranted to establish an optimized clinical strategy for contemporary GDMT implementation in patients with AHF.