Long-term impact of angiotensin receptor-neprilysin inhibitor based on short-term treatment response in heart failure

Abstract

Aims: The long-term effect of angiotensin receptor-neprilysin inhibitor (ARNI) remains uncertain in patients who have experienced improvements in left ventricular (LV) systolic function or significant LV reverse remodelling following a certain period of treatment. It is also unclear how ARNI performs in patients who have not shown these improvements. This study aimed to assess the impact of prolonged ARNI use compared with angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with and without significant treatment response after 1 year of heart failure (HF) treatment.

Methods and results: The present study enrolled patients with HF with reduced ejection fraction (HFrEF) who were treated with either ARNI or ACEIs/ARBs within 1 year of undergoing index echocardiography. After 1 year of treatment, patients were reclassified into the following groups: (i) patients with HF with improved ejection fraction and persistent HFrEF and (ii) patients with and without LV reverse remodelling based on the follow-up echocardiography. The effect of ARNI versus that of ACEIs/ARBs in each group was assessed from the time of categorizing into new groups using the composite event of all-cause mortality and HF hospitalization. A total of 671 patients with HFrEF (age, 66.4 ± 14.1 years; males, 66.8%) were included, and 133 (19.8%) composite events of death and rehospitalization for HF were observed during the follow-up (median follow-up, 44 [interquartile range, 34-51] months). ARNI had a significantly lower event rate than ACEIs/ARBs in patients with HF with improved ejection fraction (7.0% vs. 30.4%, P = 0.020) and those with persistent HFrEF (17.6% vs. 49.7%, P < 0.001). Irrespective of whether patients exhibited LV reverse remodelling (15.8% vs. 31.1%, P = 0.001) or not (15.0% vs. 54.9%, P < 0.001), ARNIs were associated with a significantly lower event rate than ACEIs/ARBs.

Conclusions: Regardless of significant treatment response measured by either LVEF or LV reverse remodelling after 1 year of treatment, the extended utilization of ARNI demonstrated a more favourable prognosis than that of ACEIs/ARBs in patients with HFrEF.

Keywords: Angiotensin receptor-neprilysin inhibitor; Heart failure with improved ejection fraction; Heart failure with reduced ejection fraction; Reverse remodelling.

Figure 1

Kaplan–Meier curve analysis for composite events of all‐cause mortality and hospitalization for HFrEF after 1 year of treatment in patients using ARNI and those using ACEIs/ARBs (composite event rate: ARNI, 15.5% vs. ACEIs/ARBs, 37.0%, P < 0.001). ACEIs, angiotensin‐converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitors; HFrEF, heart failure with reduced ejection fraction.

Figure 2

Prolonged use of ARNI can be superior to ACEIs/ARBs in patients with HFrEF for those who did or did not exhibit significant LVEF improvement following 1 year of treatment. (A) Patients with persistent reduced EF following 1 year of treatment (ARNI vs. ACEIs/ARBs, 17.6% vs. 49.7%, P < 0.001) and (B) patients with HFimpEF following 1 year of treatment (ARNI vs. ACEIs/ARBs, 7.0% vs. 30.4%, P = 0.020). ACEIs, angiotensin‐converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitors; EF, ejection fraction; HFrEF, heart failure with reduced ejection fraction; HFimpEF, heart failure with improved ejection fraction; LVEF, left ventricular ejection fraction.

Figure 3

Prolonged use of ARNI can be superior to ACEIs/ARBs in patients with HFrEF for those who did or did not exhibit significant improvement of LV reverse remodelling following 1 year of treatment. (A) Patients without LV reverse remodelling following 1 year of treatment (ARNI vs. ACEIs/ARBs; 15.0% vs. 54.9%, P < 0.001) and (B) Patients with LV reverse remodelling after 1 year of treatment (ARNI vs. ACEIs/ARBs, 15.8% vs. 31.1%, P = 0.001). ACEIs, angiotensin‐converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitors; HFrEF, heart failure with reduced ejection fraction; LV, left ventricle.

Figure 4

Subgroup analysis of hazard ratios for composite events after adjusting for age, sex, hypertension, diabetes mellitus, beta‐blocker, left ventricular end‐systolic volume, and left ventricular end‐diastolic volume. EF, ejection fraction.