Ivabradine in Combination with Metoprolol Improves Symptoms and Quality of Life in Patients with Stable Angina Pectoris: A post hoc Analysis from the ADDITIONS Trial.

OBJECTIVES: Elevated heart rate can increase myocardial oxygen demand and reduce myocardial perfusion, provoking myocardial ischemia and angina symptoms. We evaluated adding ivabradine to the therapy of patients on metoprolol. METHODS: ADDITIONS (prActical Daily efficacy anD safety of Procoralan® In combinaTION with betablockerS) was a multicenter, 4-month, noninterventional, prospective, open-label trial that involved stable-angina patients. Along with metoprolol, patients received ivabradine (5 or 7.5 mg, b.i.d.). We investigated the effect of ivabradine on heart rate, angina attacks, nitrate consumption, quality of life (QoL) and tolerability as well as the influence of baseline heart rate. RESULTS: Heart rate fell by 19.7 ± 11.2 bpm, with an 8-fold decrease in weekly angina attacks (1.7 ± 2.2 to 0.2 ± 0.7) and nitrate consumption (2.4 ± 3.4 to 0.3 ± 0.9). Patient numbers in Canadian Cardiovascular Society class I more than doubled (i.e. from 29 to 65%) and QoL improved (the EQ-5D index and visual analog scale scores rose from 0.68 ± 0.27 to 0.84 ± 0.20 and 58.1 ± 18.4 to 72.2 ± 15.5 mm, respectively). The effect of ivabradine was greater in patients with a baseline heart rate ≥70 bpm (mean reduction in heart rate -21.2 ± 10.4 bpm, with a relative reduction in angina attacks and short-acting nitrate consumption of 87.1 and 87.2%, respectively). CONCLUSIONS: Ivabradine combined with metoprolol safely and effectively reduces heart rate, angina attacks and nitrate use, and improves QoL in stable-angina patients.

Effectiveness of Ivabradine Treatment in Different Subpopulations with Stable Angina in Clinical Practice: A Pooled Analysis of Observational Studies.

OBJECTIVES: The efficacy of ivabradine has been demonstrated in different subpopulations of stable angina patients in randomized clinical trials. This study explored its effectiveness in subpopulations seen in clinical practice as they often differ from those of randomized trials. METHODS: Data were pooled from three German observational studies with similar inclusion criteria (stable angina and heart rate ≥60 bpm). All patients received 2.5, 5, or 7.5 mg b.i.d. of ivabradine for 4 months, with or without concomitant beta-blocker. Antianginal effectiveness was analyzed in subpopulations defined by gender, age, heart rate, angina severity, use of concomitant beta-blocker, previous percutaneous coronary intervention procedure, and comorbidities (including previous myocardial infarction and diabetes). RESULTS: Treatment data were available on 8,555 patients, where therapy with ivabradine was associated with a significant reduction in the frequency of angina attacks and consumption of short-acting nitrates of 87%. Effectiveness was maintained in all investigated subpopulations, with a reduction in antianginal parameters of 82-90%. Clinical status (Canadian Cardiovascular Society class) and quality of life were also improved. Ivabradine was well tolerated in all subgroups. CONCLUSIONS: Ivabradine is effective and safe in all subpopulations of angina patients seen in clinical practice, independent of age, comorbidities, and use of beta-blocker.

HCN4 provides a 'depolarization reserve' and is not required for heart rate acceleration in mice.

Cardiac pacemaking involves a variety of ion channels, but their relative importance is controversial and remains to be determined. Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, which underlie the I(f) current of sinoatrial cells, are thought to be key players in cardiac automaticity. In addition, the increase in heart rate following beta-adrenergic stimulation has been attributed to the cAMP-mediated enhancement of HCN channel activity. We have now studied mice in which the predominant sinoatrial HCN channel isoform HCN4 was deleted in a temporally controlled manner. Here, we show that deletion of HCN4 in adult mice eliminates most of sinoatrial I(f) and results in a cardiac arrhythmia characterized by recurrent sinus pauses. However, the mutants show no impairment in heart rate acceleration during sympathetic stimulation. Our results reveal that unexpectedly the channel does not play a role for the increase of the heart rate; however, HCN4 is necessary for maintaining a stable cardiac rhythm, especially during the transition from stimulated to basal cardiac states.

Effectiveness and Impact on Adherence of a New Fixed-Dose Combination of Ivabradine and Metoprolol in a Wide Range of Stable Angina Patients in Real-Life Practice.

INTRODUCTION: The antianginal effectiveness of ivabradine administration in addition to beta-blockers has been shown in patients with stable angina. The first fixed-dose combination (FDC) of ivabradine and metoprolol is now available and its evaluation in various stable angina patient populations relevant to clinical practice would be useful. METHODS: In this 4-month, prospective, multicenter, observational study, the effectiveness and tolerability of the metoprolol/ivabradine FDC was assessed in patient subgroups specified according to age, coronary artery disease (CAD) duration, Canadian Cardiovascular Society (CCS) class, co-morbidities, and previous myocardial infarction (MI) or revascularization. Heart rate (HR), angina attack frequency, short-acting nitrate (SAN) consumption, functional status, and medication adherence were documented at baseline and after 4 months of follow-up. RESULTS: A total of 747 stable angina patients were included and divided into subgroups. At 4 months, a significant decrease in HR, angina attack frequency, and SAN consumption per week was consistently observed across all patient subgroups. The proportion of CCS class I patients increased significantly from baseline to month 4. In all patient subgroups, at 4 months, a significant increase was observed in the proportion of patients with self-reported complete adherence. Complete adherence at the final visit was found to decrease with an increasing number of medications. Physicians evaluated the effectiveness and tolerability of the FDC as 'very good' and 'good' for more than 96% of patients in all analyzed patient subgroups. CONCLUSIONS: Treatment with metoprolol/ivabradine FDC significantly improved angina symptoms and adherence, with an excellent tolerability profile, in stable angina patient subgroups relevant to real-life clinical practice, regardless of age, CAD duration, CCS class, comorbidities, previous MI, or history of revascularization. TRIAL REGISTRATION: ISRCTN51906157. FUNDING: This study was sponsored by Servier Deutschland GmbH. Editorial assistance and the Rapid Service Fee were funded by Servier, France. Plain language summary available for this article.

Treatment of Stable Angina with a New Fixed-Dose Combination of Ivabradine and Metoprolol: Effectiveness and Tolerability in Routine Clinical Practice.

INTRODUCTION: In this prospective, multicenter, observational cohort study, the effectiveness and tolerability of the first fixed-dose combination (FDC) formulation of the selective heart rate reducing agent ivabradine and the beta-blocker metoprolol was evaluated in stable angina pectoris (AP) patients in a clinical practice setting. METHODS: Stable AP outpatients received a FDC of ivabradine and metoprolol (b.i.d.) for 4 months, in addition to cardiovascular standard therapy. Resting heart rate (HR), number of angina attacks, short-acting nitrate consumption, severity of symptoms (assessed by patient judgment and documented by CCS score) and tolerability were documented. Medication adherence was assessed by a modified four-item Morisky questionnaire. Descriptive statistics were performed on all data. RESULTS: A total of 747 stable AP patients (mean age, 66.4 years, 62% male, 50% and 31% with previous PCI and myocardial infarction, respectively) were included. Apart from ivabradine and beta-blockers as free combination, most frequently used concomitant standard medications at baseline were aspirin (68%), statins (71%), ACEI/AT1-blockers (76%), diuretics (35%), and calcium antagonists (15%). Highly prevalent comorbidities were hypertension (86%), hyperlipidemia (65%), and diabetes (35%). After 4 months, switch to treatment with the FDC was associated with a significant reduction in mean HR by 10 bpm. Proportion of patients with ≥ 1 angina attacks/week decreased from 38 to 7%. Patients in CCS class 1 increased (25 to 63%), while they decreased in CCS class 3 (19 to 5%). Medication adherence was also significantly improved (p < 0.001 for all changes from baseline). Mostly mild adverse events were documented in 5.4% of patients. CONCLUSIONS: In these stable AP patients in a real-life setting, treatment with a FDC of ivabradine and metoprolol was associated with reduced HR and angina symptoms, while exercise capacity (CCS score) was improved. These effects may be mainly mediated by the increased medication adherence of patients observed with use of the FDC formulation. FUNDING: Servier TRIAL REGISTRATION NUMBER: ISRCTN51906157.

Effectiveness and Tolerability of Ivabradine with or Without Concomitant Beta-Blocker Therapy in Patients with Chronic Stable Angina in Routine Clinical Practice.

INTRODUCTION: In the prospective, open-label, non-interventional, multicenter RESPONSIfVE study, the effectiveness, response rates and tolerability of ivabradine with or without beta blocker (BB) were evaluated in patients with chronic stable angina pectoris (AP) in daily clinical practice. METHODS: In patients with AP, ivabradine was given twice daily in flexible doses for 4 months. Resting heart rate (HR), number of angina attacks, short-acting nitrate use, severity of symptoms [by Canadian Cardiovascular Society (CCS) score] and tolerability with or without existing BB therapy were documented and analyzed using descriptive statistical methods. RESULTS: In total, 1250 patients with AP (mean age 66.0 ± 10.9 years, 59.6% male, 31.9% previous myocardial infarction) and an indication for ivabradine were included. Sixty-five percent of all patients received BB. Further concomitant standard medication included aspirin (74.2%), statins (69.3%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (84.2%), diuretics (40.0%), long-acting nitrates (15.7%), and calcium antagonists (21.4%). After 4 months of ivabradine treatment (mean daily dose 11.0 ± 2.7 mg), mean HR was reduced from 82.4 ± 11.8 beats per minute (bpm) to 67.1 ± 8.4 bpm. The average number of angina attacks/week decreased from 1.2 ± 1.9 to 0.1 ± 0.6 and the average use of short-acting nitrates/week from 1.5 ± 2.8 units to 0.2 ± 1.0 units. CCS classification of patients improved from 76% classified in CCS grades II or III and 24% in CCS grade I to 66% classified in CCS grade I and only 35% remaining in CCS grades II or III at study end. Response rate to ivabradine (defined as HR <70 bpm or HR reduction ≥10 bpm) reached 87%. HR reduction, symptomatic improvement and response rates were comparable in patients with or without BB. Adverse drug reactions were reported for 2.2% of patients. CONCLUSION: In this prospective study over a four-month period in clinical practice, ivabradine effectively reduced HR, angina attacks, and nitrate consumption in patients with AP with or without concomitant BB therapy. Ivabradine improved CCS scores and achieved a high treatment response rate with good general tolerability. FUNDING: Servier. TRIAL REGISTRATION: Controlled-trials.com identifier, ISRCTN73861224.

Advances in the management of heart failure: the role of ivabradine.

A high resting heart rate (≥70-75 b.p.m.) is a risk factor for patients with heart failure (HF) with reduced ejection fraction (EF), probably in the sense of accelerated atherosclerosis, with an increased morbidity and mortality. Beta-blockers not only reduce heart rate but also have negative inotropic and blood pressure-lowering effects, and therefore, in many patients, they cannot be given in the recommended dose. Ivabradine specifically inhibits the pacemaker current (funny current, If) of the sinoatrial node cells, resulting in therapeutic heart rate lowering without any negative inotropic and blood pressure-lowering effect. According to the European Society of Cardiology guidelines, ivabradine should be considered to reduce the risk of HF hospitalization and cardiovascular death in symptomatic patients with a reduced left ventricular EF ≤35% and sinus rhythm ≥70 b.p.m. despite treatment with an evidence-based dose of beta-blocker or a dose below the recommended dose (recommendation class "IIa" = weight of evidence/opinion is in favor of usefulness/efficacy: "should be considered"; level of evidence "B" = data derived from a single randomized clinical trial or large nonrandomized studies). Using a heart rate cutoff of ≥ 75 b.p.m., as licensed by the European Medicines Agency, treatment with ivabradine 5-7.5 mg b.i.d. reduces cardiovascular mortality by 17%, HF mortality by 39% and HF hospitalization rate by 30%. A high resting heart rate is not only a risk factor in HF with reduced EF but also at least a risk marker in HF with preserved EF, in acute HF and also in special forms of HF. In this review, we discuss the proven role of ivabradine in the validated indication "HF with reduced EF" together with interesting preliminary findings, and the potential role of ivabradine in further, specific forms of HF.

Ivabradine in combination with Beta-blockers in patients with chronic stable angina after percutaneous coronary intervention.

INTRODUCTION: The anti-anginal efficacy of ivabradine is well established. We describe a post hoc analysis in the ADDITIONS database to investigate effectiveness and tolerability of ivabradine in combination with beta-blocker in patients with angina who have had a percutaneous coronary intervention (PCI). METHODS: ADDITIONS was a non-interventional, multicenter prospective study including 2,330 patients with stable angina. In addition to beta-blocker, patients were treated with ivabradine in approved dosages for 4 months. We divided the population according to whether they had previously had a PCI or not, and explored the effect of ivabradine on heart rate, number of weekly angina attacks, frequency of nitrate consumption, as well as quality of life (QoL) and tolerability. RESULTS: Data were available for 2,319 patients, of whom 51.4% had previously had a PCI. There was no difference in the effect of ivabradine on mean heart rate between patients with a previous PCI [64.4 ± 7.6 beats per minute (bpm)] than those without (66.8 ± 8.5 bpm) at 4 months (both P < 0.0001). Similarly, the number of angina attacks decreased from 1.9 ± 2.4 to 0.5 ± 1.5 per week in patients with a previous PCI and 1.5 ± 2.0 to 0.3 ± 1.0 per week in patients without a previous PCI (both P < 0.0001). The frequency of nitrate consumption fell from 2.7 ± 3.7 to 1.0 ± 1.9 per week and 1.8 ± 2.8 to 0.6 ± 1.5 per week (both P < 0.0001) in patients with and without a previous PCI, respectively. There was no difference in the improvements in Canadian Cardiovascular Society class of angina, QoL, and physicians' assessment of effectiveness and tolerability between patients with a previous PCI and those without. CONCLUSION: Ivabradine is an effective and well-tolerated anti-anginal treatment in patients with stable angina after PCI. Ivabradine reduced the frequency of weekly angina attacks and nitrate consumption, led to an improvement in Canadian Cardiovascular Society class and a substantial improvement in the QoL of stable angina patients.

Ivabradine treatment in a chronic heart failure patient cohort: symptom reduction and improvement in quality of life in clinical practice.

INTRODUCTION: In the prospective, open-label multicenter INTENSIFY study, the effectiveness and tolerability of ivabradine as well as its impact on quality of life (QOL) in chronic systolic heart failure (CHF) patients were evaluated over a 4-month period. METHODS: In CHF patients with an indication for treatment with ivabradine, resting heart rate (HR), heart failure symptoms [New York Heart Association (NYHA) class, signs of decompensation], left ventricular ejection fraction, brain natriuretic peptide (BNP) values, QOL, and concomitant medication with focus on beta-blocker therapy were documented at baseline, after 4 weeks, and after 4 months. The results were analyzed using descriptive statistical methods. RESULTS: Thousand nine hundred and fifty-six patients with CHF were included. Their mean age was 67 ± 11.7 years and 56.9% were male. 77.8% were receiving beta-blockers. Other concomitant medications included angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (83%), diuretics (61%), aldosterone antagonists (18%), and cardiac glycosides (8%). At baseline, the mean HR of patients was 85 ± 11.8 bpm, 51.1% and 37.2% of patients were classified as NYHA II and III, respectively, and 22.7% showed signs of decompensation. BNP concentrations were tracked in a subgroup, and values exceeding 400 pg/mL were noted in 53.9% of patients. The mean value of the European quality of life-5 dimensions (EQ-5D) QOL index was 0.64 ± 0.28. After 4 months of treatment with ivabradine, HR was reduced to 67 ± 8.9 bpm. Furthermore, the proportion of patients presenting with signs of decompensation decreased to 5.4% and the proportion of patients with BNP levels >400 pg/mL dropped to 26.7%, accompanied by a shift in NYHA classification towards lower grading (24.0% and 60.5% in NYHA I and II, respectively). EQ-5D index improved to 0.79 ± 0.21. CONCLUSION: Over 4 months of treatment, ivabradine effectively reduced HR and symptoms in CHF patients in this study reflecting daily clinical practice. These benefits were accompanied by improved QOL and good general tolerability.

Ivabradine in combination with beta-blocker reduces symptoms and improves quality of life in elderly patients with stable angina pectoris: age-related results from the ADDITIONS study.

BACKGROUND: Clinical trials have proven the anti-anginal and anti-ischemic efficacy of the pacemaker current inhibitor ivabradine in combination with beta-blockers in patients with stable angina pectoris (AP). This retrospective subgroup analysis of the ADDITIONS study evaluated the effectiveness and tolerability of ivabradine combined with beta-blockers, and its effects on angina symptoms and quality of life in elderly patients ≥ 75 years in everyday practice. METHODS: In the non-interventional, multicenter, prospective, open-label ADDITIONS study 2330 patients with stable AP of different age groups were treated with a flexible dose of ivabradine twice daily in addition to beta-blockers for 4 months. Heart rate (HR), number of angina attacks, nitrate consumption, tolerance, and quality of life (QoL) were evaluated. A subgroup analysis was performed, focusing on 479 patients (21%) ≥ 75 years. RESULTS: In these 479 patients ≥ 75 years ivabradine (mean dose 11.61 ± 3.18 mg per day) after 4 months of treatment reduced HR by 19.2 ± 11.6 bpm to 65.4 ± 8.3 bpm. The average number of angina attacks per week was decreased by 1.6 ± 1.8 to 0.4 ± 1.3 and the average consumption of short-acting nitrates per week was reduced by 2.2 ± 3.2 to 0.6 ± 1.8 units (both p < 0.0001). There was a marked shift in Canadian Cardiovascular Society (CCS) grade distribution with most patients (57%) now classified as CCS grade I, and 42% as CCS grades II and III. This was accompanied by an improvement in EQ-5D QoL index to 0.75 ± 0.22 (p < 0.0001). Tolerability of ivabradine treatment was rated by the physicians as "very good/good" for 72%/28% of elderly patients. CONCLUSIONS: In daily clinical practice, addition of ivabradine to beta-blockers was effective in reducing HR, angina attacks and nitrate consumption in elderly patients (≥ 75 years) with stable angina pectoris. In addition, a marked improvement of CCS symptom scores and QoL was demonstrated. Treatment was generally well tolerated.

Bradycardic and proarrhythmic properties of sinus node inhibitors.

Sinus node inhibitors reduce the heart rate presumably by blocking the pacemaker current If in the cardiac conduction system. This pacemaker current is carried by four hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. We tested the potential subtype-specificity of the sinus node inhibitors cilobradine, ivabradine, and zatebradine using cloned HCN channels. All three substances blocked the slow inward current through human HCN1, HCN2, HCN3, and HCN4 channels. There was no subtype-specificity for the steady-state block, with mean IC50 values of 0.99, 2.25, and 1.96 microM for cilobradine, ivabradine, and zatebradine, respectively. Native If, recorded from mouse sinoatrial node cells, was slightly more efficiently blocked by cilobradine (IC50 value of 0.62 microM) than were the HCN currents. The block of I(f) in sinoatrial node cells resulted in slower and dysrhythmic spontaneous action potentials. The in vivo action of these blockers was analyzed using telemetric ECG recordings in mice. Each compound reduced the heart rate dose-dependently from 600 to 200 bpm with ED50 values of 1.2, 4.7, and 1.8 mg/kg for cilobradine, ivabradine, and zatebradine, respectively. beta-Adrenergic stimulation or forced physical activity only partly reversed this bradycardia. In addition to bradycardia, all three drugs induced increasing arrhythmia at concentrations greater than 5 mg/kg for cilobradine, greater than 10 mg/kg for zatebradine, or greater than 15 mg/kg for ivabradine. This dysrhythmic heart rate is characterized by periodic fluctuations of the duration between the T and P wave, resembling a form of sick sinus syndrome in humans. Hence, all available sinus node inhibitors possess an as-yet-unrecognized proarrhythmic potential.

Functional expression of the human HCN3 channel.

Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels underlie the inward pacemaker current, termed I(f)/I(h), in a variety of tissues. Many details are known for the HCN subtypes 1, 2, and 4. We now successfully cloned the cDNA for HCN3 from human brain and compared the electrophysiological properties of hHCN3 to the other three HCN subtypes. Overexpression of human HCN3 channels in HEK293 cells resulted in a functional channel protein. Similar to hHCN2 channels, hHCN3 channels are activated with a rather slow time constant of 1244 +/- 526 ms at -100 mV, which is a greater time constant than that of HCN1 but a smaller one than that of HCN4 channels. The membrane potential for half-maximal activation V((1/2)) was -77 +/- 5.4 mV, and the reversal potential E(rev) was -20.5 +/- 4 mV, resulting in a permeability ratio P(Na)/P(K) of 0.3. Like all other HCNs, hHCN3 was inhibited rapidly and reversibly by extracellular cesium and slowly and irreversibly by extracellular applied ZD7288. Surprisingly, the human HCN3 channel was not modulated by intracellular cAMP, a hallmark of the other known HCN channels. Sequence comparison revealed >80% homology of the transmembrane segments, the pore region, and the cyclic nucleotide binding domain of hHCN3 with the other HCN channels. The missing response to cAMP distinguishes human HCN3 from both the well cAMP responding HCN subtypes 2 and 4 and the weak responding subtype 1.