Aims Although the beneficial effect of sacubitril/valsartan (SAC/VAL) compared to enalapril was consistent across ischaemic (ICM) and non-ischaemic cardiomyopathy (NICM) groups, the PARADIGM-HF study did not analyze the effect of ventricular remodelling on patients with different etiologies, which may affect clinical treatment outcomes. This study aimed to compare left ventricular ejection fraction (LVEF) following SAC/VAL treatment and its association with clinical outcomes. Methods and results A total of 1,576 patients were analyzed. Patients were grouped by LVEF changes following SAC/VAL treatment for 8-month period. LVEF improvement ≥15% was defined as “significant improvement”, and <5% or worse was classified as “lack of improvement”. The primary outcome was a composite of cardiovascular death and unplanned hospitalization for heart failure. Patients with NICM had lower baseline LVEF but improvement was significantly greater comparing to those with ICM (baseline 28.0 ± 7.7% vs. 30.1 ± 7.1%, p < 0.001, LVEF increase of 11.1 ± 12.6% vs. 6.7 ± 10.2%, p < 0.001). The effect of functional improvement of SAC/VAL on NICM patients showed bimodal distribution. Primary endpoints were inversely associated with LVEF changes in NICM patients: adjusted hazard ratio was 0.42 (95% confidence interval [CI] 0.31-0.58, p < 0.001) for NICM patients with significant improvement, and was 1.73 (95% CI 1.38-2.16, p < 0.001) for NICM patients but lack of improvement. Primary endpoints of ICM patients did not demonstrate an association with LVEF changes. Conclusion Patients with NICM had higher degree of LVEF improvement than those with ICM following SAC/VAL treatment, and significant improvement of LVEF in NICM patients indicates favorable outcome.

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Aims Ivabradine and sacubitril/valsartan are second-line therapies for patients with heart failure and reduced ejection fraction (HFrEF) based on guideline recommendations. We aimed to evaluate the synergistic effects of these two medications. Methods and results Patients' data were extracted from a multicentre database between 2016 and 2018. Patients were classified into (1) Simultaneous group: simultaneous prescription of ivabradine and sacubitril/valsartan within 6 weeks; (2A) Sequential group, ivabradine-first: ivabradine was prescribed first, followed by sacubitril/valsartan; and (2B) Sequential group, sacubitril/valsartan-first: sacubitril/valsartan was prescribed first, followed by ivabradine. A total of 464 patients with HFrEF were enrolled. Cardiovascular death and/or unplanned re-hospitalizations for HF were less frequent (28.6% vs. 44.8%, P = 0.01), and the improvement of left ventricular ejection fraction (LVEF) was significantly greater in patients from the Simultaneous group than those from the Sequential group (ΔLVEF 12.8 ± 12.9% vs. 9.3 ± 12.6%, P = 0.007). Among Sequential subgroups, the ivabradine-first treatment decreased heart rate and increased systolic blood pressure (SBP) compared with sacubitril/valsartan-first treatment (Δheart rate À9.1 ± 12.9 b.p.m. vs. 2.6 ± 16.0 b.p.m., P < 0.001; ΔSBP 4.6 ± 16.5 mmHg vs. À4.8 ± 17.2 mmHg, P < 0.001), whereas sacubitril/valsartan-first treatment showed a higher degree of LVEF improvement (ΔLVEF 3.6 ± 7.8% vs. 0.7 ± 7.7%, P = 0.002) than ivabradine-first treatment. At the end of follow-up, SBP, LVEF, and left ventricular volume were comparable between two Sequential subgroups. Conclusions Among patients with HFrEF, simultaneous rather than sequential treatment with sacubitril/valsartan and ivabradine was a better strategy to reduce adverse events and achieve left ventricular reverse remodelling. Ivabradine treatment had a more significant benefit on improving haemodynamic stability, whereas sacubitril/valsartan treatment showed a more significant effect on improving LVEF.