|Pharmacotherapeutic group: Cardiac therapy, other cardiac preparations, ATC code: C01EB17.|
Mechanism of actionIvabradine is a pure heart rate lowering agent, acting by selective and specific inhibition of the cardiac pacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node and regulates heart rate. The cardiac effects are specific to the sinus node with no effect on intra-atrial, atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular repolarisation.Ivabradine can interact also with the retinal current Ih which closely resembles cardiac If. It participates in the temporal resolution of the visual system, by curtailing the retinal response to bright light stimuli. Under triggering circumstances (e.g. rapid changes in luminosity), partial inhibition of Ih by ivabradine underlies the luminous phenomena that may be occasionally experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field (see section 4.8).Pharmacodynamic effectsThe main pharmacodynamic property of ivabradine in humans is a specific dose dependent reduction in heart rate. Analysis of heart rate reduction with doses up to 20 mg twice daily indicates a trend towards a plateau effect which is consistent with a reduced risk of severe bradycardia below 40 bpm (see section 4.8).At usual recommended doses, heart rate reduction is approximately 10 bpm at rest and during exercise. This leads to a reduction in cardiac workload and myocardial oxygen consumption. Ivabradine does not influence intracardiac conduction, contractility (no negative inotropic effect) or ventricular repolarisation:- in clinical electrophysiology studies, ivabradine had no effect on atrioventricular or intraventricular conduction times or corrected QT intervals;- in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) between 30 and 45%), ivabradine did not have any deleterious influence on LVEF.
Clinical efficacy and safetyThe antianginal and anti-ischaemic efficacy of ivabradine was studied in five double-blind randomised trials (three versus placebo, and one each versus atenolol and amlodipine). These trials included a total of 4,111 patients with chronic stable angina pectoris, of whom 2,617 received ivabradine.Ivabradine 5 mg twice daily was shown to be effective on exercise test parameters within 3 to 4 weeks of treatment. Efficacy was confirmed with 7.5 mg twice daily. In particular, the additional benefit over 5 mg twice daily was established in a reference-controlled study versus atenolol: total exercise duration at trough was increased by about 1 minute after one month of treatment with 5 mg twice daily and further improved by almost 25 seconds after an additional 3-month period with forced titration to 7.5 mg twice daily. In this study, the antianginal and anti-ischaemic benefits of ivabradine were confirmed in patients aged 65 years or more. The efficacy of 5 and 7.5 mg twice daily was consistent across studies on exercise test parameters (total exercise duration, time to limiting angina, time to angina onset and time to 1 mm ST segment depression) and was associated with a decrease of about 70% in the rate of angina attacks. The twice-daily dosing regimen of ivabradine gave uniform efficacy over 24 hours.In a 889-patients randomised placebo-controlled study, ivabradine given on top of atenolol 50 mg o.d. showed additional efficacy on all ETT parameters at the trough of drug activity (12 hours after oral intake).In a 725-patients randomised placebo-controlled study, ivabradine did not show additional efficacy on top of amlodipine 10 mg o.d. at the trough of drug activity (12 hours after oral intake) while an additional efficacy was shown at peak (3-4 hours after oral intake).In a 1277-patients randomised placebo-controlled study, ivabradine demonstrated a statistically significant additional efficacy on response to treatment (defined as a decrease of at least 3 angina attacks per week and/or an increase in the time to 1 mm ST segment depression of at least 60 s during a treadmill ETT) on top of amlodipine 5 mg o.d. or nifedipine GITS 30 mg o.d. at the trough of drug activity (12 hours after oral ivabradine intake) over a 6-week treatment period (OR = 1.3, 95% CI [1.01.7]; p=0.012). Ivabradine did not show additional efficacy on secondary endpoints of ETT parameters at the trough of drug activity while an additional efficacy was shown at peak (3-4 hours after oral ivabradine intake).Ivabradine efficacy was fully maintained throughout the 3- or 4-month treatment periods in the efficacy trials. There was no evidence of pharmacological tolerance (loss of efficacy) developing during treatment nor of rebound phenomena after abrupt treatment discontinuation. The antianginal and anti-ischaemic effects of ivabradine were associated with dose-dependent reductions in heart rate and with a significant decrease in rate pressure product (heart rate x systolic blood pressure) at rest and during exercise. The effects on blood pressure and peripheral vascular resistance were minor and not clinically significant.A sustained reduction of heart rate was demonstrated in patients treated with ivabradine for at least one year (n = 713). No influence on glucose or lipid metabolism was observed.The antianginal and anti-ischaemic efficacy of ivabradine was preserved in diabetic patients (n = 457) with a similar safety profile as compared to the overall population.A large outcome study, BEAUTIFUL, was performed in 10917 patients with coronary artery disease and left ventricular dysfunction (LVEF<40%) on top of optimal background therapy with 86.9% of patients receiving beta-blockers. The main efficacy criterion was the composite of cardiovascular death, hospitalization for acute MI or hospitalization for new onset or worsening heart failure. The study showed no difference in the rate of the primary composite outcome in the ivabradine group by comparison to the placebo group (relative risk ivabradine:placebo 1.00, p=0.945). In a post-hoc subgroup of patients with symptomatic angina at randomisation (n=1507), no safety signal was identified regarding cardiovascular death, hospitalization for acute MI or heart failure (ivabradine 12.0% versus placebo 15.5%, p=0.05). A large outcome study, SIGNIFY, was performed in 19102 patients with coronary artery disease and without clinical heart failure (LVEF > 40%), on top of optimal background therapy. A therapeutic scheme higher than the approved posology was used (starting dose 7.5 mg b.i.d. (5 mg b.i.d, if age ≥ 75 years) and titration up to 10 mg b.i.d). The main efficacy criterion was the composite of cardiovascular death or non-fatal MI. The study showed no difference in the rate of the primary composite endpoint (PCE) in the ivabradine group by comparison to the placebo group (relative risk ivabradine/placebo 1.08, p=0.197). Bradycardia was reported by 17.9 % of patients in the ivabradine group (2.1% in the placebo group). Verapamil, diltiazem or strong CYP 3A4 inhibitors were received by 7.1% of patients during the study.A small statistically significant increase in the PCE was observed in a pre-specified subgroup of patients with angina patients in CCS class II or higher at baseline (n=12049) (annual rates 3.4% versus 2.9%, relative risk ivabradine/placebo 1.18, p=0.018), but not in the subgroup of the overall angina population in CCS class ≥ I (n=14286) (relative risk ivabradine/placebo 1.11, p=0.110).The higher than approved dose used in the study did not fully explain these findings.The SHIFT study was a large multicentre, international, randomised double-blind placebo controlled outcome trial conducted in 6505 adult patients with stable chronic CHF (for ≥ 4 weeks), NYHA class II to IV, with a reduced left ventricular ejection fraction (LVEF ≤ 35%) and a resting heart rate ≥ 70 bpm.Patients received standard care including beta-blockers (89 %), ACE inhibitors and/or angiotensin II antagonists (91 %), diuretics (83 %), and anti-aldosterone agents (60 %). In the ivabradine group, 67% of patients were treated with 7.5 mg twice a day. The median follow-up duration was 22.9 months. Treatment with ivabradine was associated with an average reduction in heart rate of 15 bpm from a baseline value of 80 bpm. The difference in heart rate between ivabradine and placebo arms was 10.8 bpm at 28 days, 9.1 bpm at 12 months and 8.3 bpm at 24 months.The study demonstrated a clinically and statistically significant relative risk reduction of 18% in the rate of the primary composite endpoint of cardiovascular mortality and hospitalisation for worsening heart failure (hazard ratio: 0.82, 95%CI [0.75;0.90] p<0.0001) apparent within 3 months of initiation of treatment. The absolute risk reduction was 4.2%. The results on the primary endpoint are mainly driven by the heart failure endpoints, hospitalisation for worsening heart failure (absolute risk reduced by 4.7 %) and deaths from heart failure (absolute risk reduced by 1.1 %). Treatment effect on the primary composite endpoint, its components and secondary endpoints
The reduction in the primary endpoint was observed consistently irrespective of gender, NYHA class, ischaemic or non-ischaemic heart failure aetiology and of background history of diabetes or hypertension.In the subgroup of patients with HR ≥ 75 bpm (n=4150), a greater reduction was observed in the primary composite endpoint of 24 % (hazard ratio: 0.76, 95%CI [0.68;0.85] p<0.0001) and for other secondary endpoints, including all cause death (hazard ratio: 0.83, 95%CI [0.72;0.96] p=0.0109) and CV death (hazard ratio: 0.83, 95%CI [0.71;0.97] p=0.0166). In this subgroup of patients, the safety profile of ivabradine is in line with the one of the overall population. A significant effect was observed on the primary composite endpoint in the overall group of patients receiving beta blocker therapy (hazard ratio: 0.85, 95%CI [0.76;0.94]). In the subgroup of patients with HR ≥ 75 bpm and on the recommended target dose of beta-blocker, no statistically significant benefit was observed on the primary composite endpoint (hazard ratio: 0.97, 95%CI [0.74;1.28]) and other secondary endpoints, including hospitalisation for worsening heart failure (hazard ratio: 0.79, 95% CI [0.56;1.10]) or death from heart failure (hazard ratio: 0.69, 95% CI [0.31;1.53]).There was a significant improvement in NYHA class at last recorded value, 887 (28%) of patients on ivabradine improved versus 776 (24%) of patients on placebo (p=0.001).
|Primary composite endpoint
||0.82 [0.75; 0.90]
|Components of the composite:
- CV death
- Hospitalisation for worsening HF
|| 449 (13.85)
|| 491 (15.04)
|| 0.91 [0.80; 1.03]
0.74 [0.66; 0.83]
|Other secondary endpoints:
- All cause death
- Death from HF
- Hospitalisation for any cause
- Hospitalisation for CV reason
|| 503 (15.52)
|| 552 (16.91)
|| 0.90 [0.80; 1.02]
0.85 [0.78; 0.92]
Paediatric populationA randomised, double blind, placebo controlled study was performed in 116 paediatric patients (17 aged [6-12[months, 36 aged [1-3[ years and 63 aged [3-18[ years) with CHF and dilated cardiomyopathy (DCM) on top of optimal background treatment. 74 received ivabradine (ratio 2:1). The starting dose was 0.02 mg/kg bid in age-subset [6-12[months, 0.05 mg/kg bid in [1-3[ years and [3-18[ years <40 kg, and 2.5 mg bid in [3-18[ years and ≥ 40 kg. The dose was adapted depending on the therapeutic response with maximum doses of 0.2 mg/kg bid, 0.3 mg/kg bid and 15 mg bid respectively. In this study, ivabradine was administered as oral liquid formulation or tablet twice daily. The absence of pharmacokinetic difference between the 2 formulations was shown in an open-label randomised two-period cross-over study in 24 adult healthy volunteers.A 20% heart rate reduction, without bradycardia, was achieved by 69.9% of patients in the ivabradine group versus 12.2% in the placebo group during the titration period of 2 to 8 weeks (Odds Ratio: E = 17.24, 95% CI [5.91 ; 50.30]). The mean ivabradine doses allowing to achieve a 20% HRR were 0.13 ± 0.04 mg/kg bid, 0.10 ± 0.04 mg/kg bid and 4.1 ± 2.2 mg bid in the age subsets [1-3[ years, [3-18[ years and <40 kg and [3-18[ years and ≥ 40 kg, respectively.Mean LVEF increased from 31.8% to 45.3% at M012 in ivabradine group versus 35.4% to 42.3% in the placebo group. There was an improvement in NYHA class in 37.7% of ivabradine patients versus 25.0% in the placebo group. These improvements were not statistically significant.The safety profile, over one year, was similar to the one described in adult CHF patients.The long-term effects of ivabradine on growth, puberty and general development as well as the long-term efficacy of therapy with ivabradine in childhood to reduce cardiovascular morbidity and mortality have not been studied.The European Medicines Agency has waived the obligation to submit the results of studies with Procoralan in all subsets of the paediatric population in the treatment of angina pectoris. The European Medicines Agency has waived the obligation to submit the results of studies with Procoralan in children aged 0 to less than 6 months in the treatment of chronic heart failure.