Introduction

Achieving target doses of angiotensin receptor-neprilysin inhibitor (ARNI) in patients with heart failure with reduced ejection fraction (HFrEF) is often challenging due to the risk of hypotension. In clinical practice, suboptimal doses of ARNI despite stable BP may lead to inadequate treatment response. Nevertheless, in patients with low BP, increasing the ARNI dose may lead to adverse events, compromising the clinical outcomes.

Aim

To ascertain the dose-dependent impact of ARNI as per the on-treatment blood pressure (BP) profile.

Patient Profile

• Patient with HFrEF (N=1,097) receiving ARNI for ≥6 months.
• All subjects were participants of the STrain for Risk Assessment and Therapeutic Strategies in patients with Heart Failure treated with Angiotensin Receptor-Neprilysin Inhibitor (STRATS-HF-ARNI) registry.

Methods

Study Design

Treatment Strategy

Outcomes

Results

• The median age of the study population was 66 years, and 69% of them were men.
• The average systolic blood pressure (SBP) was 117 (106-127) mmHg and average ARNI dose was 150 (100–231) mg/day, respectively. The median baseline left ventricular ejection fraction (LVEF) for the study population was 30 (25–35) %. 
• According to a multi-variable analysis, patients with a low-BP profile (mean SBP < 110 mmHg) had a higher tendency for low-dose ARNI, as compared to those with a high-BP profile [odds ratio (OR): 1.94, 95% confidence interval (CI) 1.45–2.60, p < 0.001). 
• The low-dose ARNI treatment was significantly asso­ciated with increasing age (OR: 1.15 per 10-year increase, 95% CI 1.03–1.28, p = 0.012).
• As per a multivariable analysis, low on-treatment BP was independently associated with low-dose ARNI treatment (OR: 2.07, 95% CI 1.54–2.77, p < 0.001). 
• Echocardiographic improvement was evident at 1 year of treatment in both dose groups, though the intermediate-to-high-dose group exhibited more pronounced changes. 
• An LVEF improvement ≥40% at follow-up was seen in 43.4% patients in the intermediate-to-high-dose group vs. 41.8% patients in the low-dose group (p for difference = 0.701). 
• Improvement in the myocardial function was seen in both the groups, the same being more distinct in the intermediate-to-high-dose group. 
• The risk of mortality over a median follow-up period of 3.1 years was higher in patients treated with low-dose ARNI vs. those treated with intermediate-to-high-dose ARNI. These trends remained consistent in both high-BP and low-BP profiles.
• As per a multivariable analysis low-dose ARNI, age, chronic kidney disease, use of beta-blockers, baseline LVEF, and E/e′ (E to e’ velocity) had an independent association with all-cause mortality. 
• The low-dose group had a higher risk of all-cause death [adjusted hazard ratio (aHR): 2.34, 95% CI 1.53–3.57, p < 0.001), CV death (aHR: 2.95, 95% CI 1.70–5.13, p < 0.001), and composite outcomes (aHR: 1.41, 95% CI 1.02–1.95, p = 0.039 for death + HF hospitalization; and aHR: 1.43, 95% CI 1.00–2.04, p = 0.050 for CV death + HF hospitaliza­tion), as compared to the intermediate-to high-dose group. 
• Lower dose of ARNI exhibited a significant association with higher risk of all-cause death (HR per 50 mg decrease: 1.20, 95% CI 1.07–1.35, p = 0.002), CV death (HR: 1.20, 95% CI 1.03–1.40, p = 0.019), and composite outcomes (HR: 1.11, 95% CI 1.03–1.20, p = 0.006 for death + HF hospitalization; and HR: 1.10, 95% CI 1.02–1.20, p = 0.018 for CV death + HF hospitalization).

Conclusions

• Amongst patients with HFrEF treated with ARNI, a low dose of ARNI led to insufficient improvement in myocardial function and worse clinical outcomes, compared to higher dose treatment. 
• These trends were observed in patients with an appropriate on-treatment BP under ARNI, and in those presenting with a sustained low-BP profile.

PLoS One. 2025 Jul 28;20(7):e0328971. Doi: 10.1371/journal.pone.0328971.