Table 2.
Effects of ivabradine on cardiac function in human studies.
| Subjects | Dose of Ivabradine | Type of Study | Findings | Reference |
|---|---|---|---|---|
| Hospitalized patients with severe CHF (n = 10) | Infusion at 0.1 mg/kg for 90 min, followed by 0.05–0.075 mg/kg for 90 min | Single-center open-label phase II clinical trial | At 4 h: ↓ HR, ↑ SV ↑ LV systolic work |
[40] |
| Hemodynamically stable acute HF patients (n = 63) | Started at 5 mg daily, followed by 10 mg daily for > 90 days | Retrospective cohort | ↓ HR, ↑ LVEF ↔ SBP, ↔ DBP |
[18] |
| 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 | ↑ LVEF | [35] |
| Acute decompensated HFrEF patients (n = 292) | Not given. Follow-up for 1 year after discharge | Retrospective study | ↓ HR ↔ SBP, ↔ LVEF |
[28] |
| 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: ↓ HR In HR < 75 bpm group: ↔ HR |
[21] |
| Moderate-to-severe HF patients with HR > 70 bpm (n = 298) (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 8 months | Randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial | ↓ office HR ↓ 24-HR ↓ HR awake ↓ HR asleep |
[42] |
| Patients with chronic HF (n = 30) | 5 mg b.i.d. for 4 months | Cross-sectional | ↓ LVEDV, ↓ LVESV ↑ LVEF, ↑ SV, ↑ Ees ↓ VAC |
[41] |
| 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 | ↓ HR ↑ LVEF |
[23] |
| 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 | ↓ LVESVI, ↓ LVESV, ↓ LVEDVI, ↓ LVEDV, ↑ LVEF |
[19] |
| 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 | ↓ HR ↔ E/e′, ↔ E, ↔ Ea, ↔ Ees, ↔ Ea/Ees ↔ Total mitral flow duration ↔ Mitral flow integral time velocity ↔ Lateral e′, ↔ Septal e′ ↔ Mean of lateral and septal e′ ↔ LVEDV, ↔ SV, ↔ LAVI |
[27] |
| Male patients with chronic HF (n = 22) | 5 mg b.i.d. and titrated to 7.5 mg for 6 months | Longitudinal study | ↓ HR ↔ SBP, ↔ DBP, ↔ LVEF |
[43] |
| 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 | ↓ HR | [29] |
| Patients with systolic HF (n = 43) | 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 | Longitudinal study | ↓ HR ↔ SBP, DBP ↔ LVEDV, LVESV, LVEF, ↔ E/A, ↓ E/E′ ↓ LA Vmax, ↓ LA Vp ↔ LA Vmin ↔ LA passive emptying volume and fraction ↓ LA active emptying volume and fraction ↓ PA lateral, septum, and tricuspid ↓ PA lateral–PA tricuspid ↔ PA lateral–PA septum ↓ PA septum–PA tricuspid ↓ interatrial conduction delay ↔ left intra-atrial conduction delay ↓ right intra-atrial conduction delay |
[44] |
| Moderate-to-severe HF patients (HR > 70 bpm) (n = 143) (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 8 months | Randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial | ↓ HR, ↔ LVESP, ↑ SV ↔ Pulse pressure, ↔ MAP ↑ Total arterial compliance ↓ Ea, ↔ TPR, ↔ CO, ↔ Ees ↑ LVEF, ↔ LVESV ↔ LVEDV, ↔ Ea/Ees |
[45] |
| 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 | ↓ HR, ↑ LVEF | [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 | ↓ HR, ↓ SBP ↔ DBP, ↔ MBP |
[33] |
| Moderate-to-severe HF patients (HR > 70 bpm) with left bundle branch block (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 8 months | Randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial | ↓ LVESVI, ↓ LVEDVI ↓ LVESV, ↓ LVEDV ↑ LVEF |
[46] |
| 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, double-dummy study |
↑ VO2 | [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 | ↑ LVEF | [35] |
| 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 | ↓ HR, ↑ LVEF | [20] |
| Patients with stable symptomatic chronic HF (n = 52) |
5 mg b.i.d. and titrated to 7.5 mg 2.5 mg b.i.d. for 12 months | Observational follow-up study | ↓ LVEDV, ↓ LVESV, ↑ LVEF, ↓ DT ↔ TAPSE, ↔ PASP, ↔ RV FAC, ↔ E peak, ↔ A peak, ↔ myocardial performance index ↑ systolic velocity ↑ Early diastolic velocity ↓ Late diastolic velocity ↔ RV IVV, ↔ RV IVA ↑ RV GLS, ↑ RV LS ↑ RV LSRS, ↑ RV LSRE ↑ RV LSRA |
[47] |
| 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 | ↓ HR, ↑ LVEF | [36] |
b.i.d., twice daily; bw, body weight; CHF, congestive heart failure; CO, cardiac output; DBP, diastolic blood pressure; DT, deceleration time; E, early diastolic mitral inflow velocity; E′, early diastolic mitral annular velocity; Ea, arterial elastance; E/A, early-to-late diastolic mitral inflow velocity; E/e′, ratio of peak early diastolic mitral flow velocity to the mean of annular lateral and septal velocities; Ees, left ventricular end-systolic elastance; FAC, fractional area change; GLS, global longitudinal strain; HF, heart failure; HR, heart rate; IVA, myocardial acceleration during isovolumic contraction; IVV, peak myocardial velocity during isovolumic contraction; LA, left atrium; LAVI, left atrial volume index; LS, longitudinal strain; LSRA, longitudinal strain rate diastolic late filling; LSRE, longitudinal strain rate diastolic early filling; LSRS, systolic longitudinal strain rate; LV, left ventricle; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESP, left ventricular end-systolic pressure; LVESV, left ventricular end-systolic volume; LVESVI, left ventricular end-systolic volume index; MAP, mean arterial pressure; MBP, mean blood pressure; PA, the interval from the onset of P wave to appearance of the late diastolic wave in Doppler imaging; PASP, pulmonary artery systolic pressure; RV, right ventricle; SBP, systolic blood pressure; SV, stroke volume; TAPSE, tricuspid annular plane systolic excursion; TPR, total peripheral resistance; Vmax, maximum volume at the end-systolic phase; Vmin, minimum volume at the end-diastolic phase; VAC, ventricular-arterial coupling; VO2, peak oxygen consumption; Vp, volume before P wave; ↔, no difference; ↓, reduced; ↑, increased.