Table 1.
Effects of ivabradine therapy on clinical outcomes in patients with heart failure.
| Subjects | Dose of Ivabradine | Type of Study | Findings | Reference |
|---|---|---|---|---|
| Patients with HF (LVEF < 40%, HR > 70 bpm) (n = 37) | 2.5–7.5 mg, b.i.d. for >12 months | Retrospective cohort study | ↓ risk of hospitalization ↓ number of hospitalizations ↔ length of hospitalization ↔ death rate |
[16] |
| Moderate-to-severe HF patients with HR > 70 bpm (n = 3241) (SHIFT study) | Started at 5 mg b.i.d. and titrated to 7.5 mg b.i.d. or 2.5 mg b.i.d. | Randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial | ↓ event rates in patients with 0 or 3+ comorbidities ↓ HF hospitalization |
[17] |
| Hemodynamically stable acute HF patients (n = 63) | Started at 5 mg daily, followed by 10 mg daily for >90 days | Retrospective cohort | ↓ length of hospitalization ↓ rehospitalization ↓ high dose of β-blockers ↓ NYHA class |
[18] |
| Moderate-to-severe HF patients with HR > 77 bpm (n = 208) (SHIFT study) | Started at 5 mg b.i.d. and titrated to 7.5 mg b.i.d. or 2.5 mg b.i.d. for 31–35 months | Randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial | ↓ NYHA class ↑ Global self-assessment improvement ↑ Global assessment improvement (physician perspective) ↑ Health-related quality of life ↓ all-cause cardiovascular death ↓ all-cause hospitalization ↓ all-cause mortality |
[19] |
| Patients with chronic HF (n = 767) (RELIf-CHF study) | 5 mg b.i.d. and titrated to 7.5 mg or 2.5 mg b.i.d. for 12 months | Observational follow-up study | ↓ NYHA class ↓ decompensation ↓ HF hospitalizations ↑ general health ↑ QoL |
[20] |
| Moderate-to-severe HF patients with HR < 75 (n = 1188) and >75 bpm (n = 2052) (SHIFT study) | 5 mg b.i.d. titrated to 7.5 mg b.i.d. for a median follow-up of 22.5 months | Randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial | In HR > 75 bpm group: ↓ cardiovascular death ↓ death from HF ↓ hospitalization In HR < 75 bpm group: ↔ cardiovascular death ↔ death from HF ↔ hospitalization |
[21] |
| Hospitalized HF patients in the SHIFT study (n = 514) | Started at 5 mg b.i.d. and titrated to 7.5 mg b.i.d. or 2.5 mg b.i.d. for 3 months | Randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial | ↓ all-cause hospitalization at 1, 2, and 3 months ↔ hospitalization due to cardiovascular causes at all time-points ↔ death rate |
[22] |
| Acute HF patients with inflammatory rheumatic disease (n = 12) | 2.5 mg/d b.i.d. titrated to 5 mg/d b.i.d. for 2 weeks | Retrospective observational study | ↓ NYHA class | [23] |
| Moderate-to-severe HF patients with HR > 70 bpm plus angina pectoris (n = 1085) (SHIFT and SIGNIFY studies) | Started at 5 mg b.i.d. and titrated to 7.5 mg b.i.d. or 2.5 mg b.i.d. for 31-35 months | Randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial | SHIFT study: ↔ Composite primary end point ↔ Cardiovascular death ↔ First hospitalization due to worsening HF SIGNIFY study: ↔ Composite primary end point ↔ Cardiovascular death ↔ non-fatal MI |
[24] |
| Moderate-to-severe HF patients (HR > 70 bpm) with prior mineralocorticoid receptor antagonist (MRA) (n = 1981) (SHIFT study) | Started at 5 mg b.i.d. and titrated to 7.5 mg b.i.d. or 2.5 mg b.i.d. for 31–35 months | Randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial | Compared to the MRA group at baseline: ↔ Composite primary end point ↔ Cardiovascular death ↔ HF death |
[25] |
| Moderate-to-severe HF patients (HR > 70 bpm) with diabetes (n = 973) (SHIFT study) | Started at 5 mg b.i.d. and titrated to 7.5 mg b.i.d. or 2.5 mg b.i.d. for 31–35 months | Randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial | ↔ Outcomes of different treatments (ivabradine vs. placebo; insulin vs. non-insulin) In diabetic and non-diabetic patients: ↓ hospitalization for worsening HF ↓ cardiovascular hospitalization In non-diabetic patients: ↓ all-cause hospitalization |
[26] |
| Patients with HFpEF (n = 84) (EDIFY study) | Started at 5 mg b.i.d. and titrated to 7.5 mg b.i.d. or 2.5 mg b.i.d. for 8 months | Randomized, double-blind, placebo-controlled, multicenter clinical trial | ↔ 6MWT | [27] |
| Acute decompensated HFrEF patients (n = 292) | Not given. Follow-up for 1 year after discharge | Retrospective study | ↓ cardiovascular death ↓ all-cause mortality ↓ rehospitalization ↓ NYHA class |
[28] |
| Patients with systolic chronic HF (n = 98) | Started at 5 mg b.i.d. and titrated to 7.5 mg b.i.d. or 2.5 mg b.i.d. for 6 months | Open-label, blinded, parallel-group, interventional, prospective-cohort study | ↓ NYHA class | [29] |
| Moderate-to-severe HF patients (HR > 70 bpm) with left bundle branch block (n = 467) (SHIFT study) | Started at 5 mg b.i.d. and titrated to 7.5 mg b.i.d. or 2.5 mg b.i.d. for 31-35 months | Randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial | ↔ primary end point ↔ cardiovascular death ↔ HF hospitalization ↔ all-cause death |
[30] |
| Patients with chronic HF (n = 110) (APULIA study) | 5 mg b.i.d. for a month | Multicentric observational study | ↓ HR ↑ physical functioning ↑ physical role functioning ↑ emotional role functioning ↑ mental health scale |
[31] |
| Patients with cardiomyopathy (n = 33) | 5 mg b.i.d. for 3 months and 7.5 mg b.i.d. for 3 months | Observational study | ↓ NYHA class ↑ general health ↑ social activity ↑ physical health ↑ emotional health |
[32] |
| Hospitalized patients with acute decompensated systolic heart failure (n = 10) | Started at 5 mg b.i.d. and titrated to 7.5 mg b.i.d. or 2.5 mg b.i.d. until discharged | Observational, open-label, longitudinal, and retrospective study | ↓ NYHA class | [33] |
| Patients with HF (n = 10) | 5 mg b.i.d. and titrated to 7.5 mg b.i.d. for 6 months | Randomized, double-blind study | ↓ NYHA class ↑ QoL |
[34] |
| Patients with chronic HF (n = 1873) | 5 mg b.i.d. and titrated to 7.5 mg or 2.5 mg b.i.d. for 4 months | Observational and longitudinal study | ↓ NYHA class ↓ decompensation |
[35] |
| Children with dilated cardiomyopathy (n = 74) | 0.02 mg/kg b.i.d. (6–12 months old) or 0.05 mg/kg b.i.d. (1–18 years old) or 2.5 mg b.i.d. (>40 kg bw) and titrated for 12 months. | Randomized, double-blind, placebo-controlled, phase II/III clinical trial | ↑ PedQL ↔ NYHA class |
[36] |
b.i.d., twice daily; bw, body weight; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, heart rate; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; PedQL, pediatric quality of life inventory; QoL, quality of life; 6MWT, 6 min walking test; ↔, no difference; ↓, reduced; ↑, increased.