Ivabradine and/or Sacubitril/Valsartan in the Treatment of Heart Failure with Reduced Ejection Fraction

Treatment of Heart Failure

Ivabradine is indicated for the treatment of heart failure in symptomatic patients with left ventricular ejection fraction (LVEF) ≤ 35%, sinus rhythm, and heart rate (HR) ≥ 70/min even with the use of a beta-blocker, renin-angiotensin-aldosterone system (RAAS) inhibitor, or mineralocorticoid receptor antagonist.

The combination of sacubitril/valsartan is recommended for patients with HFrEF who remain symptomatic despite the treatment with an angiotensin-converting enzyme inhibitor (ACEi).

Study Methodology and Course, Population Monitored

A total of 464 symptomatic patients with HFrEF (75.6% men; average age 59.0 years; average LVEF 28.7%) were included in a retrospective study from a multicenter Taiwanese database.

Inclusion criteria were as follows:

• age ≥ 20 years
• use of ivabradine and/or sacubitril/valsartan between 2016 and 2018
• standard heart failure treatment with a RAAS inhibitor and beta-blocker
• sinus rhythm and resting HR ≥ 70/min before starting ivabradine

According to heart failure therapy, patients were divided into 3 groups:

• 1: Simultaneous treatment with ivabradine and sacubitril/valsartan (n = 154)
• 2A: Sequential treatment - ivabradine introduced first, followed by sacubitril/valsartan (n = 203)
• 2B: Sequential treatment - sacubitril/valsartan introduced first, followed by ivabradine (n = 107)

Patients were assessed for systolic blood pressure (SBP), HR, LVEF, and the incidence of cardiovascular (CV) death and rehospitalizations.

The initial dose of sacubitril/valsartan and ivabradine was 116.6 vs. 115 mg (p = 0.820) and 8.7 vs. 8.7 mg (p = 0.890) in groups 1 and 2 respectively. After an average follow-up period of 27.4 months, the dose was 176.8 vs. 190.1 mg (p = 0.185) and 9.4 vs. 9.0 mg (p = 0.103).

Results

During the observation period, the incidence of cardiovascular (CV) death and/or first acute rehospitalization for heart failure was 22.85/100 patients/year. A lower risk was observed in group 1 patients (16.92/100 vs. 25.70/100 patients/year in group 2; hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.46–0.90; p = 0.01). Patients in group 2A had a similar incidence compared to group 2B (26.64/100 vs. 23.57/100 patients/year; p = 0.44).

No significant changes in SBP were observed during the follow-up: 122.1 to 122.0 mmHg in group 1 (p = 0.945) and 119.1 to 119.0 mmHg in group 2 (p = 0.919). HR decreased from 88.3 to 81.0/min in group 1 and from 88.0 to 77.6/min in group 2 (p < 0.001). LVEF improved from an average of 28.5 to 41.3% (∆12.8%) in group 1 and from 28.7 to 38.0% (∆9.3%) in group 2 (p = 0.007).

Initially, SBP was significantly lower and HR higher in group 2A compared to group 2B. After starting combination therapy in this group, the trend reversed (∆SBP 4.6 vs. -4.8 mmHg; ∆HR -9.1 vs. 2.6/min; p < 0.001) and EF improved by 0.7 and 3.6% (p = 0.002). A more significant HR reduction was observed in group 2B after starting combination therapy (-11.3 vs. -2.2/min in group 2A; p < 0.001). However, a greater improvement in LVEF was noted in group 2A after adding sacubitril/valsartan (8.3 vs. 5.0% in group 2B after adding ivabradine; p = 0.012). Overall, SBP and HR were comparable in groups 2A and 2B at the end of the follow-up.

Conclusion

In patients with HFrEF, simultaneous treatment with ivabradine and sacubitril/valsartan is more advantageous than sequential therapy in terms of reverse left ventricular remodeling due to their synergistic effect. Ivabradine treatment was associated with a more significant improvement in hemodynamic stability, while sacubitril/valsartan usage improved left ventricular ejection fraction.

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Source: Lee Y.-H., Lin P.-L., Chiou W.-R, et al. Combination of ivabradine and sacubitril/valsartan in patients with heart failure and reduced ejection fraction. ESC Heart Fail 2021; 8 (2): 1204–1215, doi: 10.1002/ehf2.13182.