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Objective: The introduction of the Hospital Readmission Reduction Program (HRRP) has led to renewed interest in developing strategies to reduce 30 day readmissions among patients with heart failure (HF). In this study, a model was developed to investigate whether the addition of ivabradine to a standard-of-care (SoC) treatment regimen for patients with HF would reduce HRRP penalties incurred by a hypothetical hospital with excess 30 day readmissions., Research Design: A model using a Monte Carlo simulation framework was developed. Model inputs included national hospital characteristics, hospital-specific characteristics, and the ivabradine treatment effect as quantified by a post hoc analysis of the Systolic Heart failure treatment with the I f inhibitor ivabradine Trial (SHIFT)., Results: The model computed an 83% reduction in HF readmission penalty payments in a hypothetical hospital with a readmission rate of 22.95% (excess readmission ratio = 1.056 over the national average readmission rate of 21.73%), translating into net savings of $44,016. A sensitivity analysis indicated that the readmission penalty is affected by the specific characteristics of the hospital, including the readmission rate, size of the ivabradine-eligible population, and ivabradine utilization., Conclusions: The results of this study indicate that the addition of ivabradine to an SoC treatment regimen for patients with HF may lead to a reduction in the penalties incurred by hospitals under the HRRP. This highlights the role ivabradine can play as part of a wider effort to optimize the care of patients with HF.

Objectives: In the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), slowing of the heart rate with ivabradine reduced cardiovascular death or heart failure hospitalizations among patients with systolic chronic heart failure (CHF). Subsequently, in the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) slowing of the heart rate in patients without CHF provided no benefit for cardiovascular death or nonfatal myocardial infarction (primary composite end point), with secondary analyses suggesting possible harm in the angina subgroup. Therefore, we examined the impact of ivabradine in the patients with CHF plus angina in SHIFT., Methods: SHIFT enrolled adults with stable, symptomatic CHF, a left ventricular ejection fraction ≤35% and a sinus rhythm with a resting heart rate ≥70 bpm. Outcomes were the SHIFT and SIGNIFY primary composite end points and their components., Results: Of 6,505 patients in SHIFT, 2,220 (34%) reported angina at randomization. Ivabradine numerically, but not significantly, reduced the SIGNIFY primary composite end point by 8, 11 and 11% in the SHIFT angina subgroup, nonangina subgroup and overall population, respectively. Ivabradine also reduced the SHIFT primary composite end point in all 3 subgroups., Conclusions: In SHIFT, ivabradine showed consistent reduction of cardiovascular outcomes in patients with CHF; similar results were seen in the subgroup of SHIFT patients with angina., (© 2016 S. Karger AG, Basel.)

Heart rate (HR) is a risk factor in patients with chronic systolic heart failure (HF) that, when reduced, provides outcome benefits. It is also a target for angina pectoris prevention and a risk marker in chronic coronary artery disease without HF. HR can be reduced by drugs; however, among those used clinically, only ivabradine reduces HR directly in the sinoatrial nodal cells without other known effects on the cardiovascular system. This review provides current information regarding the safety and efficacy of HR reduction with ivabradine in clinical studies involving >36,000 patients with chronic stable coronary artery disease and >6,500 patients with systolic HF. The largest trials, Morbidity-Mortality Evaluation of the I f Inhibitor Ivabradine in Patients With Coronary Disease and Left Ventricular Dysfunction and Study Assessing the Morbidity-Mortality Benefits of the I f Inhibitor Ivabradine in Patients With Coronary Artery Disease, showed no effect on outcomes. The Systolic Heart Failure Treatment With the I f Inhibitor Ivabradine Trial, a randomized controlled trial in >6,500 patients with HF, revealed marked and significant HR-mediated reduction in cardiovascular mortality or HF hospitalizations while improving quality of life and left ventricular mechanical function after treatment with ivabradine. The adverse effects of ivabradine predominantly included bradycardia and atrial fibrillation (both uncommon) and ocular flashing scotomata (phosphenes) but otherwise were similar to placebo. In conclusion, ivabradine improves outcomes in patients with systolic HF; rates of overall adverse events are similar to placebo., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: During the post-discharge phase following a heart failure hospitalization (HFH), patients are at high risk of early readmission despite standard of care therapy. We examined the impact of chronic exposure to ivabradine on early readmissions in patients hospitalized for heart failure during the course of the SHIFT study (Systolic Heart Failure treatment with the If inhibitor ivabradine Trial)., Methods and Results: A total of 1186 of the 6505 randomized patients experienced at least one HFH during the study, and had a more severe profile than those without HFH. Of these 1186 patients, 334 patients (28%) were rehospitalized within 3 months for any reason, mostly for cardiovascular causes (86%), including HFH (61%). Ivabradine was associated with fewer all-cause hospitalizations at 1 month [incidence rate ratio (IRR) 0.70, 95% confidence interval (CI) 0.50-1.00, P < 0.05], 2 months (IRR 0.75, 95% CI 0.58-0.98, P = 0.03), and 3 months (IRR 0.79, 95% CI 0.63-0.99, P = 0.04). A trend for a reduction in cardiovascular and HF hospitalizations was also observed in ivabradine-treated patients., Conclusion: We demonstrate in this post-hoc analysis that chronic exposure to ivabradine reduces the incidence of all-cause hospitalizations during the vulnerable phase after a HFH. Further studies are needed to investigate if in-hospital or early post-discharge initiation of ivabradine could be useful to improve early outcomes in patients hospitalized for HF., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background: Heart failure (HF) costs $21 billion annually in direct health care costs, 80% of which is directly attributable to hospitalizations. The SHIFT clinical study demonstrated that ivabradine plus standard of care (SoC) reduced HF-related and all-cause hospitalizations compared with SoC alone., Objective: To estimate the budget impact of ivabradine from a U.S. commercial payer perspective., Methods: A budget impact model estimated the per-member-per month (PMPM) impact of introducing ivabradine to existing formularies by comparing a reference scenario (SoC) and a new drug scenario (ivabradine + SoC) in hypothetical 1 million-member commercial and Medicare Advantage plans. In both scenarios, U.S. claims data were used for the reference cumulative annual rates of hospitalizations (HF, non-HF cardiovascular [CV], and non-CV), and hospitalization rates were adjusted using SHIFT data. The model controlled for mortality risk using SHIFT and U.S. life table data, and hospitalization costs were obtained from U.S. claims data: HF-related = $37,507; non-HF CV = $28,951; and non-CV = $17,904. The annualized wholesale acquisition cost of ivabradine was $4,500, with baseline use for this new drug at 2%, increasing 2% per year., Results: Based on the approved U.S. indication, approximately 2,000 commercially insured patients from a 1 million-member commercial plan were eligible to receive ivabradine. Ivabradine resulted in a PMPM cost savings of $0.01 and $0.04 in years 1 and 3 of the core model, respectively. After including the acquisition price for ivabradine, the model showed a decrease in total costs in the commercial ($991,256 and $474,499, respectively) and Medicare populations ($13,849,262 and $4,280,291, respectively) in year 1. This decrease was driven by ivabradine's reduction in hospitalization rates. For the core model, the estimated pharmacy-only PMPM in year 1 was $0.01 for the commercial population and $0.24 for the Medicare Advantage population., Conclusions: Adding ivabradine to SoC led to lower average annual treatment costs. The negative PMPM budget impact indicates that ivabradine is an affordable option for U.S. payers., Disclosures: This study was funded by Amgen. Patel is employed by Amgen; Kielhorn was employed by Amgen at the time of the study but is no longer affiliated with Amgen. Borer, Böhm, Ford, and Komajda have received scientific support, consultative fees, and/or speakers honoraria from Servier and Amgen in connection with SHIFT, the trial underlying this analysis. Borer also has received consultative fees from Celladon, Pfizer, ARMGO, Cardiorentis, Novartis, and Takeda USA. Kansal, Dorman, Krotneva, and Zheng are employees of Evidera, which was hired to assist with this study. Tavazzi has received research grants and consultation fees from Servier in connection with this study and has had advisory board memberships with Boston Scientific, Servier, Cardiorentis, Medtronic, St. Jude Medical, and CVie Therapeutics. Study concept and design were contributed by Dorman and Keilhorn, along with the other authors. Tavazzi, Komajda, Ford, BÖhm, and Borer oversaw collection of the data. Tavazzi, Komajda, Ford, BÖhm, and Borer (along with Karl Swedberg) formed the Executive Committee of SHIFT, the trial underlying this analysis. The manuscript was written by Kansal, along with the other authors, and revised by Borer and Patel, with assistance from the other authors.

Despite dramatic advances in therapy for heart failure (HF) during the past 3 decades, hospitalization and mortality rates remain relatively high. In recent decades, it has become apparent that HF is divisible into two equally lethal but pathophysiologically different sub-classes, the first comprising patients with LV systolic dysfunction [heart failure with reduced ejection fraction (HFrEF)] and the other, approximately equal in size, involving patients with "preserved" systolic function [heart failure with preserved ejection fraction (HFpEF)]. Evidence-based event reducing therapy currently is available only for HFrEF. With the completion of seminal trials of beta blockers, now part of standard therapy for HFrEF, it was apparent that heart rate slowing is an underlying basis of clinical effectiveness of HFrEF therapy. With the discovery of the "f current" that modulates the slope of spontaneous diastolic depolarization of the sino-atrial node, a non-beta blockade approach to heart rate slowing became available. Ivabradine, the first FDA-approved f-current blocker for HFrEF, markedly reduces hospitalizations for worsening heart failure, while also progressively reducing mortality as pre-therapy heart rate increases, and also promotes beneficial left ventricular remodeling, improves health-related quality of life and is effective despite a wide range of comorbidities. The drug is well tolerated and adverse effects are relatively few. Ivabradine represents an important addition to the armamentarium for mitigation of HFrEF., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: In heart failure, non-adherence increases events; in turn, the effect of hospitalization on adherence is incompletely understood. We explored the relationship of non-adherence to outcomes, hospitalizations with non-adherence, and the influence of non-adherence on treatment effects of heart rate lowering with ivabradine., Methods and Results: In the randomized, controlled Systolic Heart failure treatment with the If-inhibitor ivabradine Trial (SHIFT), we studied the effect of non-adherence (n = 1287) compared with adherence (n = 5204) on cardiovascular outcomes. After adjustment, non-adherence was associated with the primary composite endpoint of cardiovascular death and heart failure hospitalization (hazard ratio 3.47, 95% confidence interval 2.91-4.13, P < 0.0001). No interaction with the treatment groups of placebo or ivabradine (P for interaction 0.54) occurred. Similar results for cardiovascular death and heart failure hospitalization, as well as for cardiovascular hospitalization, heart failure death, and total death were observed. The effect of ivabradine was maintained in patients being adherent or becoming non-adherent during the trial (P for interaction = 0.54). Patients with a previous hospitalization were more likely to become non-adherent thereafter., Conclusions: Non-adherence identifies a group at particularly high cardiovascular event risk independent of treatment allocation. Non-adherent patients in the ivabradine group maintain a treatment benefit. Patients with previous hospitalizations are more likely to become non-adherent and represent a group of particularly high-risk patients in whom special attention to stimulate adherence may be valuable., Trial Registration: ISRCTN70429960., (© 2016 The Authors European Journal of Heart Failure © 2016 European Society of Cardiology.)

Incidence of chronic heart failure (HF) increases with age and cardiovascular (CV) morbidity. Co-morbidities increase hospitalization and mortality in HF, and non-CV co-morbidities may lead to preventable hospitalizations. We studied the impact of co-morbidities on mortality and morbidity in Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial, and investigated whether the impact of ivabradine was affected by co-morbidities. We analyzed the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trialpopulation, with moderate-to-severe HF and left ventricular dysfunction (in sinus rhythm with heart rate at rest ≥70 beats/min), according to co-morbidity: chronic obstructive pulmonary disease, diabetes mellitus, anemia, stroke, impaired renal function, myocardial infarction, hypertension, and peripheral artery disease. Co-morbidity load was classed as 0, 1, 2, 3, 4+ or 1 to 2 co-morbidities, or 3+ co-morbidities. Co-morbidities were evenly distributed between the placebo and ivabradine groups. Patients with more co-morbidities were likely to be older, women, had more advanced HF, were less likely to be on β blockers, with an even distribution on ivabradine 2.5, 5, or 7.5 mg bid and placebo at all co-morbidity loads. Number of co-morbidities was related to outcomes. Cardiovascular death or HF hospitalization events significantly increased (p <0.0001) with co-morbidity load, with the most events in patients with >3 co-morbidities for both, ivabradine and placebo. There was no interaction between co-morbidity load and the treatment effects of ivabradine. Hospitalization rate was lower at all co-morbidity loads for ivabradine. In conclusion, cardiac and noncardiac co-morbidities significantly affect CV outcomes, particularly if there are >3 co-morbidities. The effect of heart rate reduction with ivabradine is maintained at all co-morbidity loads., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: To evaluate clinical profiles and outcomes in patients with systolic heart failure (HF) with or without diabetes, and the efficacy and safety of ivabradine (heart rate-lowering agent) with respect to diabetic status., Methods and Results: This is a post hoc analysis on patients in SHIFT, a randomized controlled trial in adults in sinus rhythm with systolic HF, left ventricular ejection fraction ≤35%, and resting heart rate ≥70 b.p.m. Patients were randomized to ivabradine (titrated to 7.5 mg bid) or placebo. Diabetic status was established by medical history at baseline. The primary composite endpoint (PCE) was cardiovascular death or hospitalisation for worsening HF. Of 6505 patients, 30% had diabetes, 32% of whom used insulin. The PCE was more frequent in patients with diabetes [adjusted hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.07-1.31; p = 0.001], as was hospitalization for worsening HF (adjusted HR 1.28, 95% CI 1.13-1.44; P < 0.001), and was increased in patients treated with insulin (adjusted HR 1.43, 95% CI 1.23-1.66; P < 0.01 vs. non-diabetics). Ivabradine significantly reduced the PCE in patients with and without diabetes (adjusted HR 0.80, 95% CI 0.68-0.94 and HR 0.84, 95% CI, 0.75-0.95, respectively; interaction P was non-significant) vs. placebo. Adverse events were significantly more frequent in patients with diabetes (78%) than without (74%) (P < 0.001). Regardless of diabetic status, the incidence of serious adverse events was not significantly different between ivabradine and placebo., Conclusions: Comorbid diabetes in chronic HF worsens the prognosis of systolic HF patients. Irrespective of diabetic status, ivabradine is effective and safe in these patients., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Aims: Analysis of 24-h Holter recordings was a pre-specified substudy of SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) for exploring the heart rhythm safety of ivabradine and to determine effects of ivabradine on 24-h, daytime, and night-time heart rate (HR) compared with resting office HR., Methods and Results: The 24-h Holter monitoring was performed at baseline and 8 months after randomization to ivabradine (n = 298) or matching placebo (n = 304) titrated maximally to 7.5 mg b.i.d. in patients with baseline HR ≥70 b.p.m. Patients received guideline-based optimized heart failure therapy including ACE inhibitors and/or ARBs in 93% and beta-blockers at maximally tolerated doses in 93%. After 8 months, HR over 24 h decreased by 9.5 ± 10.0 b.p.m. with ivabradine, from 75.4 ± 10.3 b.p.m. (P < 0.0001), and by 1.2 ± 8.9 b.p.m. with placebo, from 74.8 ± 9.7 b.p.m. (P < 0.0001 for difference vs. ivabradine). HR reduction with ivabradine was similar in resting office and in 24-h, awake, and asleep recordings, with beneficial effects on HR variability and no meaningful increases in supraventricular or ventricular arrhythmias. At 8 months, 21.3% on ivabradine vs. 8.5% on placebo had ≥1 episode of HR <40 b.p.m. (P < 0.0001). No episode of HR <30 b.p.m. was recorded; 3 (1.2%) patients had RR intervals >2.5 s on ivabradine vs. 4 (1.6%) patients on placebo. No RR intervals >3 s were identified in patients taking ivabradine., Conclusion: Ivabradine safely and significantly lowers HR and improves HR variability in patients with systolic heart failure, without inducing significant bradycardia, ventricular arrhythmias, or supraventricular arrhythmias., (© 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.)

Resting heart rate is central to cardiac output and is influenced by changes occurring in numerous diseases. It predicts longevity and cardiovascular diseases, and current evidence suggests that it is also an important marker of outcome in cardiovascular disease, including heart failure. Beta-blockers improve outcomes in heart failure; however, they have effects outside reducing heart rate. Ivabradine has demonstrated efficacy in reducing rehospitalizations and mortality in heart failure and in improving exercise tolerance and reducing angina attacks in patients with coronary artery disease, whereas selective heart rate reduction may also prove to be beneficial in therapeutic areas outside those in which ivabradine has already demonstrated clinical efficacy. This review provides an update on the associations between heart rate and cardiovascular outcomes in various conditions, the experimental effects of heart rate reduction with ivabradine, and the potential new indications in cardiovascular disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Ivabradine, a specific heart rate lowering agent, was shown in the SHIFT study to reduce time to first hospitalization for worsening heart failure (HF) in chronic systolic HF patients and also to reduce recurrent/total hospitalizations over the study interval. We assessed the effects of adding ivabradine in patients with systolic HF on the number needed to treat (NNT) to reduce recurrent hospitalizations., Methods: The SHIFT trial included 6505 patients with symptomatic HF (NYHA II-IV), left ventricular ejection fraction ≤35% and heart rate ≥70 bpm in sinus rhythm. Patients were randomized to either ivabradine or placebo in addition to guidelines-based drug therapy. The times to first hospitalization were analyzed using a univariate Cox proportional-hazards model; the associated NNT was calculated using Kaplan-Meier estimates of the time-to-event curves at 1 year in each treatment arm. Recurrent hospitalizations were analyzed using a negative binomial and the estimated annual event rates used to calculate the associated patient-time NNTs respectively., Results: The estimated NNT (number needed to initiate treatment with ivabradine to prevent one first HF hospitalization within 1 year) was 27 (estimated hazard ratio: 0.75, P < 0.0001). For recurrent HF hospitalizations, one event would be prevented on average per 14 patient-years for any year of follow-up over the course of SHIFT (estimated rate ratio: 0.71, P < 0.0001). A key limitation of this analysis is that it did not account for a relationship between recurrent HF hospitalizations and subsequent mortality., Conclusion: In chronic systolic HF the effect of ivabradine on reducing recurrent HF hospitalizations results in a lower NNT compared to the effect on the time for first hospitalization. The effect of ivabradine on recurrent hospitalizations, in addition to first events, may be a more appropriate measure when considering the impact of a treatment with ivabradine on healthcare resource utilization.

Objectives: We explored the prescription of β-blockers with ivabradine in patients with systolic heart failure, focusing on the most frequently coprescribed β-blocker, carvedilol., Methods: We analyzed outcomes in SHIFT patients with systolic heart failure who were prescribed β-blockers (carvedilol, bisoprolol, metoprolol, or nebivolol) with ivabradine or placebo. Analysis was by intention to treat in patients prescribed a β-blocker at the time of the event., Results: Data were available for 2,596 patients receiving carvedilol, 1,483 bisoprolol, 1,424 metoprolol, and 197 nebivolol. Mean treatment duration was 19 months. There was no difference in the effect of ivabradine on the primary composite endpoint of cardiovascular death or heart failure hospitalization between the various β-blockers [hazard ratios (HR) for risk reduction, 0.75-0.89; p for interaction=0.86]. Patients prescribed carvedilol with ivabradine had lower rates of primary composite endpoint (HR 0.80, 95% CI: 0.68-0.94), heart failure hospitalization (HR 0.73, 95% CI: 0.61-0.88), and cardiovascular hospitalization (HR 0.80, 95% CI: 0.69-0.92) versus carvedilol with placebo. The dosage of carvedilol had no detectable effect and there were no unexpected safety issues., Conclusions: Whatever β-blocker was coprescribed with ivabradine, there were improvements in cardiovascular outcomes in patients with systolic heart failure, especially with the most prescribed β-blocker--carvedilol., (© 2015 S. Karger AG, Basel.)

Aims: Low systolic blood pressure (SBP) is associated with poor outcomes in heart failure and complicates management. In a post hoc analysis, we investigated the efficacy and safety of ivabradine in the SHIFT population divided by tertiles of baseline SBP., Methods and Results: The analysis comprised 2110 patients with SBP <115 mmHg, 1968 with 115≤ SBP <130 mmHg, and 2427 with SBP ≥130 mmHg. Patients with low SBP were younger, had lower ejection fraction, and were less likely to be at target beta-blocker dose than patients in the other SBP groups. Ivabradine was associated with a similar relative risk reduction of the composite outcome in the three SBP groups [SBP <115 mmHg, hazard ratio (HR) = 0.84, 95% confidence interval (CI) 0.72-0.98; 115≤ SBP <130 mmHg, HR = 0.86, 95% CI 0.72 to 1.03; SBP ≥130 mmHg, HR = 0.77, 95% CI 0.66 to 0.92; P interaction = 0.68]. Similar results were found for cardiovascular mortality (P interaction = 0.91), hospitalization because of heart failure (P interaction = 0.79), all-cause mortality (P interaction = 0.90), and heart failure mortality (P interaction = 0.18). There was no evidence for a difference in safety profile according to SBP group., Conclusion: The efficacy and safety of ivabradine is independent of SBP. This may have implications for the management of HF patients with low SBP and elevated heart rate., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Aims: We studied the relationship between heart rate and renal function and the effects of heart rate reduction with ivabradine in heart failure patients with and without renal dysfunction., Methods and Results: From the 6505 patients who were randomized in SHIFT, baseline creatinine and at least one follow-up measurement were available in 6160 patients. Median follow-up was 22.9 months. Worsening renal function (WRF) was defined as a creatinine increase of ≥0.3 mg/dL and ≥25% from the baseline value. WRF developed in 1029 (17%) patients and was directly related to baseline heart rate, with an incremental risk of 5% for every 5 b.p.m. heart rate increment (P=0.003). WRF was associated with an increased risk of the primary composite endpoint of hospitalization for worsening heart failure or cardiovascular death [hazard ratio (HR) 1.38, P<0.001] and of all-cause mortality (HR 1.42, P<0.001). Ivabradine use was associated with a reduction of the primary composite endpoint in patients both with (HR 0.82, P=0.023) and without renal dysfunction (HR 0.81, P<0.001) at baseline (P for interaction=0.89), and tolerability of ivabradine was comparable in the two groups. No differences were found in changes in renal function over time between ivabradine- and placebo-treated patients., Conclusion: In chronic stable systolic heart failure patients, heart rate is directly and independently associated with the risk of WRF, but reduction in heart rate by ivabradine had a neutral effect on renal function during 2 years of follow-up. The beneficial cardiovascular effects and safety of ivabradine were similar in patients with and without renal dysfunction., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

A post hoc analysis of Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) explored the efficacy and safety of ivabradine in severe heart failure (HF) as denoted by left ventricular ejection fraction (LVEF) ≤20% and/or New York Heart Association (NYHA) class IV. The SHIFT population (LVEF ≤35%, heart rate ≥70 beats/min, and sinus rhythm) comprised 712 patients with severe (defined previously) and 5,973 with less severe (NYHA classes II or III and LVEF >20%) HF, all randomized to ivabradine or placebo on a background of guideline-defined standard care. The rate of primary composite end point of cardiovascular death or HF hospitalization with placebo was higher in severe (42%) than less severe (27%) HF (p <0.001). Treatment with ivabradine in severe HF was associated with relative risk reductions indistinguishable from those of less severe disease for the primary end point (16% reduction), all-cause death (22%), cardiovascular death (22%), HF death (37%), and HF hospitalization (17%; all p values for interaction: NS). NYHA class improved in 38% (n = 129) ivabradine-treated patients with severe HF versus 29% (n = 104) placebo-treated patients (p = 0.009). In the 272 patients with severe HF and baseline heart rate ≥75 beats/min (the indication approved by the European Medicines Agency), ivabradine reduced the primary end point by 25% (p = 0.045), HF hospitalization by 30% (p = 0.042), and cardiovascular death by 32% (p = 0.034). Ivabradine's safety profile in severe HF was indistinguishable from less severe. In conclusion, our analysis confirms that heart rate reduction with ivabradine can be safely used in severe HF and may improve clinical outcomes independently of disease severity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: To test whether the efficacy and safety of the selective heart rate-reducing agent ivabradine changes according to age in chronic heart failure (HF) patients., Methods and Results: The ivabradine and placebo arms of SHIFT, which enrolled 6505 chronic HF patients, were combined and age distribution was divided by quartiles to give four groups (<53 years, n = 1522; 53 to <60 years, n = 1521; 60 to <69 years, n = 1750; and ≥69 years, n = 1712). The effects of ivabradine on cardiovascular outcomes, changes in heart rate, and adverse events, particularly bradycardia, were evaluated according to age group. A subgroup (602 patients) underwent 24 h ambulatory ECG Holter monitoring. The relative risk of the primary endpoint (cardiovascular death or hospitalization for worsening HF) was reduced by ivabradine in all age groups, ranging from 38% [hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.50-0.78, P < 0.001] in the youngest patients <53 years to 16% (HR 0.84, 95% CI 0.71-0.99, P = 0.035) in the oldest patients ≥69 years. Ivabradine up-titration reduced heart rate similarly in all age groups, by 11 b.p.m. As anticipated, bradycardia and phosphenes occurred more frequently with ivabradine, at a similar rate whatever the age. In the Holter substudy, there were no episodes of severe bradycardia and no clinically relevant pauses with ivabradine in any age group., Conclusions: Age does not limit the appropriate use of ivabradine in patients with chronic HF and systolic dysfunction. The safety and efficacy of ivabradine are comparable across all age groups.

Aims: To test the effect of ivabradine on the outcomes in a broad population with left-ventricular (LV) systolic dysfunction with coronary artery disease (CAD) and/or heart failure (HF)., Methods and Results: Individual trial data from BEAUTIFUL and SHIFT were pooled to evaluate the effect of ivabradine on the outcomes in patients with LV dysfunction and heart rate ≥ 70 b.p.m. The pooled population (n = 11 897; baseline age 62.3 ± 10.4 years, heart rate 79.6 ± 9.2 b.p.m., and LV ejection fraction 30.3 ± 5.6%) was well treated according to current recommendations (87% beta-blockers, 90% renin-angiotensin system inhibitors). Median follow-up was 21 months. Treatment with ivabradine was associated with a 13% relative risk reduction for the composite of cardiovascular mortality or HF hospitalization (P < 0.001 vs. placebo); this was driven by HF hospitalizations (19%, P < 0.001). There were also significant relative risk reductions for the composite of cardiovascular mortality, HF hospitalizations, or myocardial infarction (MI) hospitalization (15%, P < 0.001); cardiovascular mortality and non-fatal MI (10%, P = 0.023); and MI hospitalization (23%, P = 0.009). Similar results were found in patients with differing clinical profiles. Ivabradine was well tolerated., Conclusion: Ivabradine may be important for the improvement of clinical outcomes in patients with LV systolic dysfunction and heart rate ≥ 70 b.p.m., whatever the primary clinical presentation (CAD or HF) or clinical status (NYHA class).

Smoking is a major modifiable risk factor for cardiovascular (CV) disease. Varenicline is a pharmacological aid for smoking cessation. To explore the CV safety of varenicline, we investigated the incidence of CV events in varenicline-treated subjects across all phase 2-4 randomized placebo-controlled clinical trials of ≥12-week treatment duration conducted in smokers aged ≥18 years and sponsored by the drug manufacturer. This manuscript reports a subject-level meta-analysis of time to major adverse cardiovascular events (MACE; defined as CV-related death, nonfatal myocardial infarction, nonfatal stroke) and time to MACE+ (defined as MACE plus worsening or any procedure for peripheral vascular disease, hospitalization for angina, or performance of coronary revascularization). All events were adjudicated by an independent adjudication committee, blind to treatment assignment. Events were assessed during treatment and up to 30 days after the last treatment dose. The primary analytical method was a stratified logrank time-to-event analysis; secondary analyses were meta-analyses of incidence rate ratios and rate differences. Overall, 7002 subjects were included (varenicline: 4190; placebo: 2812) from 15 studies. MACE were reported by 13 varenicline subjects (0.31%) and 6 placebo subjects (0.21%) [hazard ratio, 1.95; 95% confidence interval (CI): 0.79-4.82; P = 0.15; risk difference, 0.006 events per subject-year; 95% CI: -0.003, 0.015, P = 0.19]. MACE+ were reported by 26 varenicline subjects (0.62%) and 12 placebo subjects (0.43%) (hazard ratio, 1.74; 95% CI: 0.91-3.34, P = 0.10; risk difference, 0.010; 95% CI: -0.002, 0.022, P = 0.11). This subject-level meta-analysis of MACE or MACE+ up to 30 days posttreatment in placebo-controlled clinical trials of varenicline found a trend toward increased incidence of these events in varenicline-treated patients that did not reach statistical significance. The overall number of events was low and the absolute risk of CV events with varenicline was small.

Aims: We explored the effect of treatment with ivabradine, a pure heart rate-slowing agent, on recurrent hospitalizations for worsening heart failure (HF) in the SHIFT trial., Methods and Results: SHIFT was a double-blind clinical trial in which 6505 patients with moderate-to-severe HF and left ventricular systolic dysfunction, all of whom had been hospitalized for HF during the preceding year, were randomized to ivabradine or to placebo on a background of guideline-recommended HF therapy (including maximized β-blockade). In total, 1186 patients experienced at least one additional HF hospitalization during the study, 472 suffered at least two, and 218 suffered at least 3. Patients with additional HF hospitalizations had more severe disease than those without. Ivabradine was associated with fewer total HF hospitalizations [902 vs. 1211 events with placebo; incidence rate ratio, 0.75, 95% confidence interval (CI), 0.65-0.87, P = 0.0002] during the 22.9-month median follow-up. Ivabradine-treated patients evidenced lower risk for a second or third additional HF hospitalization [hazard ratio (HR): 0.66, 95% CI, 0.55-0.79, P < 0.001 and HR: 0.71, 95% CI, 0.54-0.93, P = 0.012, respectively]. Similar observations were made for all-cause and cardiovascular hospitalizations., Conclusion: Treatment with ivabradine, on a background of guidelines-based HF therapy, is associated with a substantial reduction in the likelihood of recurrent hospitalizations for worsening HF. This benefit can be expected to improve the quality of life and to substantially reduce health-care costs.

Aims: The SHIFT echocardiographic substudy evaluated the effects of ivabradine on left ventricular (LV) remodelling in heart failure (HF)., Methods and Results: Eligible patients had chronic HF and systolic dysfunction [LV ejection fraction (LVEF) ≤35%], were in sinus rhythm, and had resting heart rate ≥70 bpm. Patients were randomly allocated to ivabradine or placebo, superimposed on background therapy for HF. Complete echocardiographic data at baseline and 8 months were available for 411 patients (ivabradine 208, placebo 203). Treatment with ivabradine reduced LVESVI (primary substudy endpoint) vs. placebo [-7.0 ± 16.3 vs. -0.9 ± 17.1 mL/m(2); difference (SE), -5.8 (1.6), 95% CI -8.8 to -2.7, P< 0.001]. The reduction in LVESVI was independent of beta-blocker use, HF aetiology, and baseline LVEF. Ivabradine also improved LV end-diastolic volume index (-7.9 ± 18.9 vs. -1.8 ± 19.0 mL/m(2), P= 0.002) and LVEF (+2.4 ± 7.7 vs. -0.1 ± 8.0%, P< 0.001). The incidence of the SHIFT primary composite outcome (cardiovascular mortality or hospitalization for worsening HF) was higher in patients with LVESVI above the median (59 mL/m2) at baseline (HR 1.62, 95% CI 1.03-2.56, P= 0.04). Patients with the largest relative reductions in LVESVI had the lowest event rates., Conclusion: Ivabradine reverses cardiac remodelling in patients with HF and LV systolic dysfunction.

Aims: Heart failure (HF) has a major impact on health-related quality of life (HQoL). The aim was to evaluate whether heart rate (HR) reduction with ivabradine can translate into increased HQoL in parallel to a reduction of primary outcomes in SHIFT., Methods and Results: In symptomatic patients with systolic HF treated with recommended background therapy, HQoL was assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) containing the following dimensions: overall summary score (OSS) and clinical summary score (CSS), analysed at baseline, and 4, 12, and 24 months, and last post-baseline visit. A total of 1944 patients (968 ivabradine, 976 placebo) were evaluated. At 12 months, incidence of clinical events (cardiovascular death or hospital admission for HF) was inversely associated with KCCQ scores. Ivabradine reduced HR by 10.1 bpm (placebo-corrected, P < 0.001) and improved KCCQ by 1.8 for CSS and 2.4 for OSS (placebo-corrected, P = 0.02 and P < 0.01, respectively); these changes were associated with the change in HR for both CSS (P < 0.001) and OSS (P < 0.001). The relationship was found in both allocation groups though the changes were more pronounced in the ivabradine group. Health-related quality of life at follow-up was better preserved in the ivabradine group compared with placebo; poorest outcomes were seen in the placebo group with lowest KCCQ scores (<50)., Conclusion: In patients with systolic HF, low HQoL is associated with an increased rate of cardiovascular death or hospital admission for HF. Reduction in HR with ivabradine is associated with improved HQoL. The magnitude of HR reduction is related to the extent of improvement in HQoL.

Background: Raised resting heart rate is a marker of cardiovascular risk. We postulated that heart rate is also a risk factor for cardiovascular events in heart failure. In the SHIFT trial, patients with chronic heart failure were treated with the selective heart-rate-lowering agent ivabradine. We aimed to test our hypothesis by investigating the association between heart rate and events in this patient population., Methods: We analysed cardiovascular outcomes in the placebo (n=3264) and ivabradine groups (n=3241) of this randomised trial, divided by quintiles of baseline heart rate in the placebo group. The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes. Analysis adjusted to change in heart rate was used to study heart-rate reduction as mechanism for risk reduction by ivabradine directly., Findings: In the placebo group, patients with the highest heart rates (>or=87 beats per min [bpm], n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to <72 bpm, n=461, 92 events; hazard ratio [HR] 2.34, 95% CI 1.84-2.98, p<0.0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17.4%, 95% CI 15.3-19.6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0.95, 0.85-1.06, p=0.352)., Interpretation: Our analysis confirms that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure., Funding: Servier, France., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Chronic heart failure is associated with high mortality and morbidity. Raised resting heart rate is a risk factor for adverse outcomes. We aimed to assess the effect of heart-rate reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure., Methods: Patients were eligible for participation in this randomised, double-blind, placebo-controlled, parallel-group study if they had symptomatic heart failure and a left-ventricular ejection fraction of 35% or lower, were in sinus rhythm with heart rate 70 beats per min or higher, had been admitted to hospital for heart failure within the previous year, and were on stable background treatment including a β blocker if tolerated. Patients were randomly assigned by computer-generated allocation schedule to ivabradine titrated to a maximum of 7.5 mg twice daily or matching placebo. Patients and investigators were masked to treatment allocation. The primary endpoint was the composite of cardiovascular death or hospital admission for worsening heart failure. Analysis was by intention to treat. This trial is registered, number ISRCTN70429960., Findings: 6558 patients were randomly assigned to treatment groups (3268 ivabradine, 3290 placebo). Data were available for analysis for 3241 patients in the ivabradine group and 3264 patients allocated placebo. Median follow-up was 22.9 (IQR 18-28) months. 793 (24%) patients in the ivabradine group and 937 (29%) of those taking placebo had a primary endpoint event (HR 0.82, 95% CI 0.75-0.90, p<0.0001). The effects were driven mainly by hospital admissions for worsening heart failure (672 [21%] placebo vs 514 [16%] ivabradine; HR 0.74, 0.66-0.83; p<0.0001) and deaths due to heart failure (151 [5%] vs 113 [3%]; HR 0.74, 0.58-0.94, p=0.014). Fewer serious adverse events occurred in the ivabradine group (3388 events) than in the placebo group (3847; p=0.025). 150 (5%) of ivabradine patients had symptomatic bradycardia compared with 32 (1%) of the placebo group (p<0.0001). Visual side-effects (phosphenes) were reported by 89 (3%) of patients on ivabradine and 17 (1%) on placebo (p<0.0001)., Interpretation: Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of this disorder., Funding: Servier, France., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Aims: Elevated heart rate is a significant marker for mortality and morbidity in cardiovascular disease including heart failure. Despite background treatment with a beta-blocker, many patients with heart failure and low ejection fraction maintain a heart rate above 70 b.p.m. Ivabradine reduces heart rate directly through inhibition of the I(f) ionic current. Methods SHIFT is a randomized, double-blind study designed to compare ivabradine with placebo on outcomes in patients with symptomatic chronic heart failure (NYHA class II-IV), left-ventricular ejection fraction < or =35%, and a prior hospitalization for worsening heart failure within the previous 12 months. Randomized treatment is given on top of guidelines-based therapy for chronic heart failure, including a beta-blocker at optimized dose. Resting heart rate at baseline must be > or =70 b.p.m. The primary endpoint is the composite of the time to first event of cardiovascular death or hospitalization for worsening heart failure. Secondary endpoints include all-cause, cardiovascular and heart failure mortality, and hospitalization. The randomized treatment period lasts approximately 12-48 months. The study will include approximately 6500 patients and will continue until > or =1600 primary endpoints have occurred. The first patient was randomized in October 2006, and the study is expected to end in 2010., Conclusion: The SHIFT study will assess if a heart rate reduction by direct sinus node inhibition can reduce cardiovascular outcomes in patients with chronic heart failure and left-ventricular systolic dysfunction.

Ivabradine is a specific heart rate-lowering antianginal agent that was evaluated in a clinical development program involving approximately 3,000 patients with stable coronary artery disease, most with angina pectoris. We analyzed the pharmacokinetics, efficacy (evaluated by exercise tolerance testing), safety, and effects on glucose metabolism of ivabradine in patients with diabetes mellitus (DM) in this program. Most analyses included data from 535 patients with DM, approximately 18% of the overall patient sample. Patients with DM were older, more likely to be women, and more likely to have more severe angina pectoris than patients without DM. The pharmacokinetics of ivabradine did not differ in patients with DM versus those without DM. A reduction in the heart rate at rest with ivabradine was similar in those with (15.2%) and without (15.7%) DM. At baseline, the exercise capacity tended to be lower in the patients with DM, but the improvements in most exercise tolerance measures with ivabradine treatment were similar in patients with and without DM. No special safety concerns were associated with ivabradine in those with DM. The rates of sinus bradycardia and visual disturbances, known to be related to the action of ivabradine, showed no relative increase in the patients with DM. Ivabradine treatment was not associated with adverse effects on glucose metabolism. In conclusion, ivabradine was effective in preventing angina in patients with DM and was not associated with particular safety concerns or adverse effects on glucose metabolism. Ivabradine represents an attractive alternative to beta blockers in patients with stable angina pectoris and DM.

Objectives: The antianginal and anti-ischemic efficacy of ivabradine has been demonstrated in large-scale trials. Pooling trial data allowed for subpopulation analyses of ivabradine's antianginal efficacy., Methods: Data on the frequency of angina attacks, short-acting nitrate consumption, and heart rate were pooled from 5 randomized trials in patients with stable angina pectoris receiving 5, 7.5, or 10 mg of ivabradine b.i.d. for 3 or 4 months. The subpopulations were defined according to age, sex, disease characteristics, and comorbidities (severity of angina, history of myocardial infarction, cerebrovascular disease, revascularization status, diabetes, asthma/chronic obstructive pulmonary disease, or peripheral vascular disease)., Results: Efficacy data were available for 2,425 patients (full analysis set), in whom ivabradine reduced the frequency of diary-based angina attacks by 59.4% and nitrate consumption by 53.7%. All subpopulations experienced 51-70% reductions in the frequency of angina attacks, with similar reductions for the other parameters studied. Ivabradine's efficacy was maintained in the presence of different comorbidities. In the safety set, ivabradine reduced heart rate by 14.5%. Ivabradine had a good safety and tolerability profile in all the subpopulations assessed., Conclusions: The antianginal efficacy of ivabradine was consistent across all the subpopulations analyzed, independent of the severity of angina and the presence of a comorbidity., (Copyright 2009 S. Karger AG, Basel.)

Ivabradine is a heart rate-lowering agent devoid of other direct cardiovascular effects that has been approved for treatment of patients with stable angina pectoris. The heart rate-lowering action of ivabradine, and its relation to clinical effects, was characterized during its development program in clinical and preclinical studies. Ivabradine selectively inhibits If in sinoatrial node cells, reducing diastolic depolarization rate and heart rate. At therapeutic concentrations, ivabradine has no action on other cardiac or vascular ion channels or receptors. Heart rate reduction with ivabradine is dose dependent and tends to a maximum or plateau level at high doses. With repeated oral dosing, the heart rate-lowering effect of ivabradine is near maximal in 2 weeks, maximal within 4 weeks, and is maintained without development of pharmacological tolerance during long-term treatment. On cessation of treatment, heart rate returns rapidly and progressively to pretreatment levels without rebound tachycardia or untoward cardiovascular events. In patients with stable angina, the reduction in heart rate is greatest in patients with the highest pretreatment heart rate, a property that should minimize the potential for ivabradine to produce excessive bradycardia. Heart rate lowering with ivabradine is associated with increases in indices of heart rate variability and causes no more than minimal changes in blood pressure. The characteristics of the heart rate-lowering action of ivabradine make it suitable for a range of patients including those for whom other antianginal agents may be contraindicated or not acceptably tolerated. They also suggest that management of treatment should be relatively simple in most patients.

Heart rate slowing has been accepted for decades as a primary therapeutic approach to prevention (and even to treatment) of angina pectoris. Pure heart rate slowing has not been achieved with previously available rate-slowing pharmacological agents (beta adrenergic blockers, certain calcium channel blockers), all of which have other pharmacological effects that may be beneficial but also may underlie adverse drug effects. Modulation of heart rate is a function of variation in the I(f) current, a sodium-potassium mediated membrane phenomenon that is active physiologically only in the heart's sinoatrial node. Though the current first was described more than 25 years ago, a practical pharmacological method for its inhibition only recently has been developed, tested and approved for use in Europe. The effective drug, ivabradine, has demonstrated anti-anginal, anti-ischemic efficacy and now is being tested for its effect on survival in patients with coronary artery disease and impaired left ventricular function, as well as for heart failure. The data supporting the use of the drug for angina prevention, and the potential for additional applications, are reviewed in this article.

Heart rate slowing is generally accepted as effective for angina prevention but this approach has not been rigorously evaluated as no pure heart rate slowing treatment has been available. With the identification of the I(f) current, the primary modulator of heart rate, and use of this as a target for drug development, the role of isolated heart rate slowing can be elucidated. More than 4,000 patients now have been studied in angina prevention trials with ivabradine, a prototype I(f) current inhibitor devoid of other cardiovascular effects. These studies demonstrate the efficacy of isolated heart rate slowing for angina prevention. Indeed, in one direct comparison with atenolol involving 939 patients, ivabradine not only was non inferior to the Beta-blocker but nominally appeared to be more efficient in angina prevention. Moreover, since ivabradine is devoid of most of the adverse effects of beta-blockers (and of calcium channel blockers), it is a suitable alternative when these established drugs are not adequately tolerated. Additional studies now must assess other potential actions in patients with coronary disease.

Heart rate is determined primarily by spontaneously repeating net inward current carried by sodium ions and potassium ions through hyperpolarization-activated cyclic-nucleotide-gated channels. Within the heart, these channels are found most abundantly in sinoatrial cardiomyocytes. The channels open in response to membrane hyperpolarization, modulated by local cAMP concentrations. They permit activation of the I(f) current, which can be blocked specifically by molecules characterized by linked benzazepinone and benzocyclobutane rings, and which are devoid of effects on cardiac conduction, inotropy or peripheral vascular tone. The resulting heart-rate reduction has been effective in angina prevention in clinical trials involving 4,000 patients, using the prototype I(f) inhibitor, ivabradine. No serious adverse events have been attributed to the treatment; the most prominent side-effect is dose-related, always reversible and often transient visual symptoms that seldom result in voluntary drug discontinuation.

Background: Heart rate reduction should benefit patients with chronic stable angina by improving myocardial perfusion and reducing myocardial oxygen demand. This study evaluated the antianginal and antiischemic effects of ivabradine, a new heart rate-lowering agent that acts specifically on the sinoatrial node., Methods and Results: In a double-blind, placebo-controlled trial, 360 patients with a > or =3-month history of chronic stable angina were randomly assigned to receive ivabradine (2.5, 5, or 10 mg BID) or placebo for 2 weeks, followed by an open-label 2- or 3-month extension on ivabradine (10 mg BID) and a 1-week randomized withdrawal to ivabradine (10 mg BID) or placebo. Primary efficacy criteria were changes in time to 1-mm ST-segment depression and time to limiting angina during bicycle exercise (exercise tolerance tests), performed at trough of drug activity. In the per-protocol population (n=257), time to 1-mm ST-segment depression increased in the 5 and 10 mg BID groups (P<0.005); time to limiting angina increased in the 10 mg BID group (P<0.05). Deterioration in all exercise tolerance test parameters occurred in patients who received placebo during randomized withdrawal (all P<0.02) but not in those still receiving ivabradine. No rebound phenomena were observed on treatment cessation., Conclusions: Ivabradine produces dose-dependent improvements in exercise tolerance and time to development of ischemia during exercise. These results suggest that ivabradine, representing a novel class of antianginal drugs, is effective and safe during 3 months of use; longer-term safety requires additional assessment.