Summary of the clinical data on ivabradine in patients with stable angina with or without left ventricular systolic dysfunction or heart failure
| Effects of ivabradine on symptoms/myocardial ischaemia in patients with stable angina | |
| Publication | Study summary |
| Stable angina – monotherapy | |
| Borer et al
24 (n=360) | Randomised, double-blind, placebo-controlled, multicentre study in patients with chronic SA (n=360). Duration: 2 wks double-blind+2–3 months open-label. Efficacy: TST and TLA. At 2 wks, TST increased by 32.0 and 44.1 s with ivabradine 2.5 mg and 5 mg twice daily versus 9.0 s with placebo (P=0.016 for 5 mg twice daily dose vs placebo). TLA increased by 22.5 s and 27.2 s with ivabradine 2.5 and 5 mg twice daily versus 12.7 s with placebo. Resting HR and exercise HR decreased significantly with ivabradine 2.5 mg and 5 mg twice daily (both P<0.05 vs placebo). |
| INITIATIVE, 200528 (n=939) | Randomised, double-blind, parallel-group, multicentre study in patients with SA. Duration: 16 wks. Efficacy: TED during ETT. Change in TED at trough: +86.8 s with ivabradine 7.5 mg twice daily versus +78.8 s with atenolol 50–100 mg/day (mean difference 10.3 s; P<0.001 for non-inferiority). Change in the number of angina attacks/wk at 16 wks: −2.2 for ivabradine 7.5 mg twice daily versus −2.7 mg for atenolol. Change in resting HR: −14.3 bpm for ivabradine 7.5 mg twice daily versus −15.6 bpm for atenolol. |
| Ruzyllo et al
32 (n=1195) | Randomised, double-blind, parallel-group, multicentre study in patients with chronic SA. Duration: 3 months. Efficacy: TED during ETT. Change in TED at trough: +27.6 s with ivabradine 7.5 mg twice daily versus +31.2 s with amlodipine 10 mg od (mean difference 1.8 s; P<0.001 for non-inferiority). Change in the number of angina attacks/wk: −3.0 for ivabradine 7.5 mg twice daily versus −3.0 for amlodipine. |
| Skalidis et al
33 (n=21) | Prospective, open single-centre study in patients with stable CAD of one or two vessels, who were eligible for PCI. Duration: 1 wk. Efficacy: ivabradine 5 mg twice daily improved hyperaemic coronary flow velocity and reserve in patients with stable CAD. Resting-APV (17.0±5.5 vs 19.7±7.6, P=0.003) and augmentation of hyperaemia-APV (57.9±17.8 vs 53.5±21.4, P=0.009) led to improvement in CFR (3.51±0.81 vs 2.78±0.61, P<0.001). |
| Tagliamonte et al
34 (n=59) | Prospective, randomised, double-blind trial in patients with stable CAD. Duration: 1 month. Efficacy: coronary flow velocity reserve increased significantly with ivabradine 2.5–7.5 mg twice daily (3.52±0.64 vs 2.67±0.55, P<0.001) and bisoprolol 2.5–10 mg od (3.35±0.70 vs 2.72±0.55, P<0.001), but it was significantly greater with ivabradine. HR decreased similarly (63±7 vs 61±6 bpm; P=NS). |
| Gloekler et al
11 (n=46) | Prospective, randomised, placebo-controlled, monocentre, proof-of-concept trial in 46 patients with chronic stable CAD, 23 of whom received placebo and 23 ivabradine for 6 months. HR changed by +0.2 bpm with placebo and −8.1 bpm with ivabradine (P=0.0089). With placebo, collateral flow index decreased from 0.140 at baseline to 0.109 at follow-up (P=0.12), while it increased from 0.107 to 0.152 with ivabradine (P=0.0461). |
| Maranta et al
35 (n=15) | An open-label, proof-of-concept study in 15 patients with exercise-inducible ischaemia. Stress echocardiography was done at baseline after washout and repeated after 2 wks of ivabradine 7.5 mg twice daily at the same workload. Ivabradine reduced both acute LV dysfunction and stunning in CAD patients with exercise-induced ischaemia. |
| REDUCTION 200936 (n=4954) | Multicentre, open-label, observational study in patients with SA pectoris. Duration: 4 months. Ivabradine 2.5–7.5 mg twice daily+BB. Change in resting HR: −12.4 bpm (P<0.0001 vs baseline). Change in the number of angina attacks/wk: 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). |
| Stable angina – in combination | |
| ASSOCIATE, 200937 (n=889) | Randomised, double-blind, placebo-controlled, multicentre study in patients with chronic SA. Duration: 4 months. Ivabradine 5–7.5 mg twice daily+atenolol 50 mg od versus placebo+atenolol 50 mg od. Efficacy: TED during ETT. Change in TED at trough: +24.3 s versus +7.7 s (P<0.001). Change in TLA: +26.0 s versus +9.4 s (P<0.001). Change in TAO:+49.1 s versus +22.7 s (P<0.001). Change in TST: +45.7 s versus +15.4 s (P<0.001). |
| ADDITIONS 201238 (n=2330) | Multicentre, open-label, observational study in patients with SA. Duration: 4 months. Ivabradine 2.5–7.5 mg twice daily+BB. Change in resting HR: from 85.0 bpm to 65.6 bpm (P<0.0001 vs baseline). Change in the number of angina attacks/wk: −1.4 (P<0.0001 vs baseline). Change in the consumption of nitrates: −1.9 U (P<0.0001 vs baseline). |
| López-Bescós et al
29 (n=386) | Randomised, double-blind, parallel-group, multicentre study in patients with chronic SA on concomitant therapy (excluding BBs). Duration: 12 months. Ivabradine 5 mg or 7.5 mg twice daily. Change in resting HR: −9.7 and −12.3 bpm. Change in the number of angina attacks/wk: −1.9 and −1.2. Change in the consumption of nitrates: −1.2 U and −1.7 U. |
| Pooled analysis by Werdan39 (n=8555) | Pooled data from three observational clinical studies in 8555 patients with SA received 2.5 mg, 5 mg or 7.5 mg twice daily of ivabradine for 4 months. Therapy with ivabradine was associated with a significant reduction in the frequency of angina attacks and consumption of short-acting nitrates of 87%. Ivabradine is effective and safe in all subpopulations of angina patients seen in clinical practice, independent of age, comorbidities and use of BBs. |
| Panhellenic study, 201540 (n=2403) | Observational, prospective, open-label study in 2403 patients with chronic SA receiving ivabradine 5–7.5 mg twice daily for 4 months in combination with BBs. Ivabradine reduced resting HR from 81.5±9.7 bpm to 63.9±6.0 bpm (P<−0.001), mean number of anginal attacks decreased from 2.0±2.0 times/wk to 0.2±0.6 times/wk (P<0.001) and nitroglycerin consumption decreased from 1.4±2.0 times/wk to 0.1±0.4 times/wk (P<0.001). The percentage of patients with CCS angina class I increased from approximately 38% (baseline) to 84% (study completion; P<0.001). The mean EQ-5D visual analogue scale index increased by 16.1 points (P<0.001), and compliance with treatment was high throughout the trial (96%). |
| Stable angina – special populations | |
| Elderly – REDUCTION, 201142 (n=382) | Multicentre, open-label, observational study in elderly patients (≥80 years old) with SA. Duration: 4 months. Ivabradine 2.5–7.5 mg twice daily+BBs. Change in resting HR: −12.0 bpm (P<0.0001 vs baseline). Change in the number of angina attacks/wk: from 3.0 to 0.8 (P<0.0001 vs baseline). Change in the consumption of short-acting nitrates: from 4.2 U to 1.2 U (P<0.0001 vs baseline). |
| Elderly – ADDITIONS, 201443 (n=479) | Retrospective analysis of observational, multicentre, prospective, open-label ADDITIONS study investigating ivabradine twice daily+BB in SA patients ≥75 years. Duration: 4 months. Efficacy: HR fell by 19.2±11.6 bpm to 65.4±8.3 bpm. Frequency of angina attacks diminished by 1.6±1.8/wk to 0.4±1.3/wk and consumption of short-acting nitrates fell by 2.2±3.2 units/wk to 0.6±1.8 units/wk (both P<0.0001). Severity of angina, according to CCS grade, decreased and QOL improved (P<0.0001). |
| Pooled analysis from RCTs, 200926 (n=2425) | Pooled analysis of five randomised, double-blind, parallel-group studies in patients with SA. Duration: 3–4 months. Ivabradine ≥5 mg twice daily. 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/wk: −59.4% in all patients; reduction of 51%–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/wk in subpopulations. |
| Diabetes, 201044 (n=2907) | Pooled analysis of eight multicentre, randomised, double-blind studies in patients with SA. Duration: 2 wks–1 year. Change in resting HR: −11.3 bpm in patients without diabetes mellitus versus −11.6 bpm in patients with diabetes mellitus. Change in the number of angina attacks/wk: −2.2 in patients without diabetes mellitus versus −2.0 in patients with diabetes mellitus. |
| Postrevascularisation – post hoc analysis from ADDITIONS, 201545 (n=1193) | Observational, multicentre prospective study in patients with SA on BBs treated with ivabradine at standard doses. Duration: 4 months. In post-PCI patients, ivabradine decreased HR from 83.1 to 64.4 bpm (P<0.0001). Number of angina attacks decreased from 1.9/wk to 0.5/wk. Frequency of nitroglycerin fell from 2.7 times/wk to 1.0 times/wk. |
| Postrevascularisation – post hoc analysis of the Panhellenic study, 201746 (n=926) | Post hoc analysis of postrevascularisation patients in a prospective, observational study of 2403 patients with SA with CAD taking optimised BB therapy. Duration: 4 months. Treatment with ivabradine reduced angina attacks from 2.2/wk to 0.3/wk (P<0.001) and nitroglycerin consumption from 1.5 times/wk to 0.1 times/wk (P<0.001). QOL improved versus baseline (P<0.001). |
| Postrevascularisation – RIVENDEL study, 201747 (n=70) | Prospective, randomised controlled, open-label study examining the addition of ivabradine (up to 7.5 mg twice daily) to standard medical therapy in CAD patients >30 days after PCI. Duration: 8 wks. Addition of ivabradine to standard therapy reduced HR from 68.0 bpm to 62.2 bpm (P<0.001), improved flow-mediated dilation from 8.7 to 15.0 (P<0.001) and enhanced nitroglycerin-mediated dilation from 12.7 to 17.7 (P<0.001). |
| Effects of ivabradine on outcomes in patients with stable CAD | |
| SIGNIFY, 201448 (n=19 102) | Randomised, double-blind, placebo-controlled trial of ivabradine, added to standard therapy, in patients with stable CAD without clinical HF and HR ≥70 bpm. Ivabradine up to 10 mg twice daily versus placebo. Duration: 27.8 months (median). Efficacy: no difference in the incidence of the primary endpoint (a composite of death from CV causes or non-fatal MI) between the ivabradine and placebo groups (6.8% and 6.4%, respectively; HR: 1.08; 95% CI 0.96 to 1.20; P=0.20). |
| Effects of ivabradine in patients with LVSD with and without HF | |
| Amosova et al
49 (n=29) | Randomised, parallel-group, single-blind study in patients with SA and moderate LVSD. Duration: 2 months. Ivabradine 5–7.5 mg twice daily+bisoprolol 5 mg od versus bisoprolol 5–10 mg od. Change in mean resting HR: from 76.6 bpm to 59.3 bpm (P<0.001 vs baseline) versus from 75.9 bpm to 60.5 bpm (P=0.002 vs baseline). Change in 6 min walking test distance: from 388 m to 446 m (P<0.001 vs baseline) versus from 386 m to 400 m (P=NS). Angina attacks were reduced from 3.3±1.1 to 1.7±0.6 in the ivabradine group and from 3.2±1.0 to 2.5±0.9 in the bisoprolol-alone group (intergroup P=0.041). |
| Angina subgroup analysis from BEAUTIFUL, 200950 (n=1507) | Post hoc analysis in patients with SA and LVEF <40% from a randomised, double-blind, placebo-controlled, multicentre study. Duration: 19 months (median). Ivabradine 5–7.5 mg twice daily versus 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). Hospitalisation for MI: 42% RRR (P=0.021). In patients with HR ≥70 bpm: hospitalisation for MI: 73% RRR (P=0.002); coronary revascularisation: 59% RRR. |
| Angina subgroup analysis from SHIFT, 201756 (n=2220) | Post hoc analysis in patients with SA and chronic HF (LVEF ≤35%) from a randomised, double-blind, placebo-controlled, multicentre study in adults in sinus rhythm with stable. Duration: 22.9 months (median). Ivabradine up to 7.5 mg twice daily versus placebo. Efficacy: composite endpoint of CV death or non-fatal MI reduced by 8% versus placebo (P=NS) compared with 11% and 11% in patients without angina and in the overall population, respectively. |
Modified from reference: Deedwania.12
ADDITIONS, prActical Daily efficacy and safety of procoralan In combinaTION with beta blockerS; APV, time-averaged peak flow velocity; ASSOCIATE, evaluation of the Antianginal efficacy and Safety of the aSsociation Of the I f Current Inhibitor ivAbradine with a beTa-blockEr; BB, beta-blocker; bid, twice daily; bpm, beats per minute; BEAUTIFUL, morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left-ventricULar dysfunction; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; CFR, coronary flow reserve; CV, cardiovascular; EQ-5D, EuroQol five dimensions questionnaire; ETT, exercise tolerance test; HF, heart failure; HR, heart rate;INITIATIVE; INternatIonal TrIal of the AnTi-anginal effects of IVabradinE; LV, left ventricular; LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction; MI, myocardial infarction; NS, not significant; od, once daily; PCI, percutaneous coronary intervention; QOL, quality of life; REDUCTION, Reduction of ischemic events by reduction of heart rate in the treatment of stable angina with ivabradine; RIVENDEL, Heart Rate reduction by IVabradine for improvement of ENDothELial function in patients with coronary artery disease; RRR, relative risk reduction; SA, stable angina; SIGNIFY, Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease; SHIFT, Systolic Heart failure treatment with the I f inhibitor ivabradine Trial; TAO, time to angina onset; TED, total exercise duration; TLA, time to limiting angina; TST, time to 1 mm ST-segment depression; wk, week.