Table 1.
Summary of the principal results of the main publications of ivabradine in coronary artery disease
| Publication | Study summary |
|---|---|
| CAD: monotherapy | |
| Borer et al., 2003 [19] (n = 360) | Randomised, double-blind, placebo-controlled, multicentre study in patients with stable CAD and chronic stable angina (n = 360). Duration: 2 weeks double-blind + 2–3 months open-label. Efficacy: TST and TLA. At 2 weeks, TST increased by 32.0, 44.1 and 46.2 s with ivabradine 2.5, 5 and 10 mg bid vs 9.0 s with placebo (p = 0.016 for 5 and 10 mg bid dose vs placebo). TLA increased by 22.5, 27.2 and 40.8 s with ivabradine 2.5, 5 and 10 mg bid vs 12.7 s with placebo (p = 0.049 for 10 mg bid dose vs placebo). Resting HR and exercise HR decreased significantly with ivabradine 2.5, 5 and 10 mg bid (all p < 0.05 vs placebo) |
| INITIATIVE [23] (n = 939) | Randomised, double-blind, active-controlled, parallel-group, multicentre study in patients with CAD and stable angina. Duration: 16 weeks. Efficacy: TED during ETT. Change in TED at trough: +86.8 and +91.7 s with ivabradine 7.5 and 10 mg bid vs +78.8 s with atenolol 50–100 mg/day (mean difference 10.3 and 15.7 s; p < 0.001 for non-inferiority). Change in the number of angina attacks per week at 16 weeks: −2.2 and −2.3 for ivabradine 7.5 and 10 mg bid vs −2.7 for atenolol. Change in resting HR: −14.3 and −14.31 bpm for ivabradine 7.5 and 10 mg bid vs −15.6 bpm for atenolol |
| Ruzyllo et al., 2007 [45] (n = 1195) | Randomised, double-blind, parallel-group, multicentre study in patients with chronic stable angina. Duration: 3 months. Efficacy: TED during ETT. Change in TED at trough: +27.6 and +21.7 s with ivabradine 7.5 and 10 mg bid vs +31.2 s with amlodipine 10 mg od (mean difference 1.8 and 6.6 s; p < 0.001 for non-inferiority). Change in the number of angina attacks per week: −3.0 and −3.2 for ivabradine 7.5 and 10 mg bid vs −3.0 for amlodipine |
| CAD: combination therapy | |
| ASSOCIATE [48] (n = 889) | Randomised, double-blind, placebo-controlled, multicentre study in patients with chronic stable angina. Duration: 4 months. Ivabradine 5–7.5 mg bid + atenolol 50 mg od vs placebo + atenolol 50 mg od. Efficacy: TED during ETT. Change in TED at trough: +24.3 s vs +7.7 s (p < 0.001). Change in TLA: +26.0 s vs +9.4 s (p < 0.001). Change in TAO: +49.1 s vs +22.7 s (p < 0.001). Change in TST: +45.7 s vs +15.4 s (p < 0.001) |
| Amosova et al., 2011 [49] (n = 29) | Randomised, parallel-group, single-blind study in patients with MI and moderate left ventricular systolic dysfunction. Duration: 2 months. Ivabradine 5–7.5 mg bid + bisoprolol 5 mg od versus bisoprolol 5–10 mg od. Change in mean resting HR: from 76.6 to 59.3 bpm (p < 0.001 vs baseline) vs from 75.9 to 60.5 bpm (p = 0.002 vs baseline). Change in 6-min walking test distance: from 388 to 446 m (p < 0.001 vs baseline) vs from 386 to 400 m (p = NS) |
| ADDITIONS [50] (n = 2330) | Multicentre, open-label, observational study in patients with stable angina pectoris. Duration: 4 months. Ivabradine 2.5–7.5 mg bid + β-blocker. Change in resting HR: from 85.0 to 65.6 bpm (p < 0.0001 vs baseline). Change in the number of angina attacks per week: −1.4 (p < 0.0001 vs baseline). Change in the consumption of nitrates: −1.9 U (p < 0.0001 vs baseline) |
| REDUCTION [58] (n = 4,954) | Multicentre, open-label, observational study in patients with stable angina pectoris. Duration: 4 months. Ivabradine 2.5–7.5 mg bid + β-blocker. Change in resting HR: −12.4 bpm (p < 0.0001 vs baseline). Change in the number of angina attacks per week: from 2.8 to 0.5 (p < 0.0001 vs baseline). Change in the consumption of nitrates: from 3.7 to 0.7 U (p < 0.0001 vs baseline) |
| López-Bescós et al., 2007 [24] (n = 386) | Randomised, double-blind, parallel-group, multicentre study in patients with chronic stable angina on concomitant therapy (excluding β-blockers). Duration: 12 months. Ivabradine 5 or 7.5 mg bid. Change in resting HR: −9.7 and −12.3 bpm. Change in the number of angina attacks per week: −1.9 and −1.2. Change in the consumption of nitrates: −1.2 and −1.7 U |
| Skalidis et al., 2011 [46] (n = 21) | Prospective study in patients with stable CAD. Duration: 1 week. Ivabradine 5 mg bid plus current medication. HR: from 78 to 65 bpm (p < 0.01). Hyperaemia CFV: from 53.5 to 57.9 cm/s (p < 0.01). Resting CFV: from 19.7 to 17.0 cm/s (p < 0.01). Coronary flow reserve: from 2.78 to 3.51 (p < 0.01) |
| CAD: special populations | |
| Elderly [56] (n = 382) | Multicentre, open-label, observational study in elderly patients (>80 years old) with stable angina pectoris. Duration: 4 months. Ivabradine 2.5–7.5 mg bid + β-blocker. Change in resting HR: −12.0 bpm (p < 0.0001 vs baseline). Change in the number of angina attacks per week: from 3.0 to 0.8 (p < 0.0001 vs baseline). Change in the consumption of nitrates: from 4.2 to 1.2 U (p < 0.0001 vs baseline) |
| Subpopulations [21] (n = 2,425) | Pooled analysis of five randomised, double-blind, parallel-group studies in patients with angina pectoris. Duration: 3–4 months. Ivabradine 5–10 mg bid. Change in resting HR: −14.5 % (11.3 bpm) in all patients; reduction of 12.4–16.3 % in subpopulations (no difference between groups). Change in the number of angina attacks per week: −59.4 % in all patients; reduction of 51 % to 70 % in subpopulations (no difference between groups). Change in the consumption of nitrates: −53.7 % in all patients; reduction of 0.4 to 3.4 U/week in subpopulations |
| Diabetes [57] (n = 2,907) | Pooled analysis of eight multicentre, randomised, double-blind studies in patients with stable angina. Duration: 2 weeks to 1 year. Ivabradine 2.5–20 mg bid. Change in resting HR: −11.3 bpm in patients without diabetes mellitus vs −11.6 bpm in patients with diabetes mellitus. Change in the number of angina attacks per week: −2.2 in patients without diabetes mellitus vs −2.0 in patients with diabetes mellitus |
| CAD: with left ventricular dysfunction (BEAUTIFUL) | |
| Main results [59] (n = 10,917) | Randomised, double-blind, placebo-controlled, multicentre study in patients with CAD and LVEF of <40 % also receiving conventional CV therapy. Duration: 19 months (median). Ivabradine 5–7.5 mg bid vs placebo. Efficacy: composite endpoint of CV death, admission to hospital for acute MI and admission to hospital for new-onset or worsening HF. Primary endpoint: 15.4 % vs 15.3 % of patients (p = 0.94). Pre-specified analysis in patients with heart rate ≥70 bpm (n = 5,392): hospitalization for MI, 36 % RRR (p = 0.001); coronary revascularization, 30 % RRR (p = 0.016) |
| Angina subgroup [61] (n = 1,507) | Post hoc analysis of the BEAUTIFUL trial in patients with stable angina. Duration: 18 months (median). Ivabradine 5–7.5 mg bid vs placebo. Efficacy: composite endpoint of CV death, admission to hospital for acute MI and admission to hospital for new-onset or worsening HF. Primary endpoint: 24 % RRR (p = 0.05). Hospitalization for MI: 42 % RRR (p = 0.021). In patients with heart rate ≥70 bpm: hospitalization for MI, 73 % RRR (p = 0.002); coronary revascularization, 59 % RRR |
| ECHO substudy [62] (n = 590) | Echocardiographic substudy of BEAUTIFUL. Duration: 3–12 months. Ivabradine 5–7.5 mg bid vs placebo. Efficacy: LVEDVI. Change in LVEDVI: −1.48 vs +1.85 mL/m2 (p = 0.018). Change in LVEF: 2.00 vs 0.01 % (p = 0.009) |
| Holter substudy [22] (n = 840) | Holter substudy of the BEAUTIFUL trial. Duration: 6 months. Ivabradine 5–7.5 mg bid vs placebo. Efficacy: 24-h HR reduction. HR reduction: 6.3 vs 0.4 bpm (p < 0.001). In ivabradine group, waking vs sleeping HR reduction was 6.8 vs 5.2 bpm. Incidence of severe bradycardic episodes (<30 bpm) during waking or sleep was ≤1 % in both groups. More ivabradine patients than placebo patients had HR <40 or <50 bpm, but there was no between-group difference in episode severity |
bid twice daily, bpm beats per minute, CAD coronary artery disease, CFV coronary flow velocity, CV cardiovascular, ETT exercise tolerance test, HF heart failure, HR heart rate, LVEDVI left ventricular end-diastolic volume index, LVEF left ventricular ejection fraction, MI myocardial infarction, NS not significant, od once daily, RRR relative risk reduction, TAO time to angina onset, TED total exercise duration, TLA time to limiting angina, TST time to 1-mm ST-segment depression