Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalised with heart failure and reduced left ventricular ejection fraction (ETHIC-AHF): A randomised study

doi:10.1016/j.ijcard.2016.04.136

International Journal of Cardiology

Volume 217, 15 August 2016, Pages 7-11

https://doi.org/10.1016/j.ijcard.2016.04.136 Get rights and content

Abstract

Objectives

To analyse the effect of the early coadministration of ivabradine and beta-blockers (intervention group) versus beta-blockers alone (control group) in patients hospitalised with heart failure and reduced left ventricular ejection fraction (HFrEF).

Methods

A comparative, randomised study was performed to compare the treatment strategies of beta-blockers alone versus ivabradine and beta-blockers starting 24 hours after hospital admission, for acute HF in patients with an left ventricular ejection fraction (EF) < 40%, sinus rhythm, and a heart rate (HR) > 70 bpm.

Results

A total of 71 patients were examined, 33 in the intervention group and 38 in the control group. No differences were observed with respect to their baseline characteristics or standard treatment at discharge. HR at 28 days (64.3 ± 7.5 vs. 70.3 ± 9.3 bpm, p = 0.01) and at 4 months (60.6 ± 7.5 vs. 67.8 ± 8 bpm, p = 0.004) after discharge were significantly lower in the intervention group. Significant differences were found with respect to the EF and brain natriuretic peptide levels at 4 months. No differences in clinical events (rehospitalisation/death) were reported at 4 months. No severe side effects attributable to the early administration of ivabradine were observed.

Conclusions

The early coadministration of ivabradine and beta-blockers during hospital admission for acute HFrEF is feasible and safe, and it produces a significant decrease in HR at 28 days and at 4 months after hospital discharge. It also seemed to improve systolic function and functional and clinical parameters of HF patients at short-term.

Section snippets

Introduction and objectives

Heart failure (HF) is a clinical syndrome with enormous relevance, given its constantly growing prevalence and its associated significant morbidity and mortality [1], [2]. Within this group, approximately half of the patients have reduced left ventricular ejection fraction (HFrEF) [1]. It is known that heart rate (HR) is a parameter with prognostic value for patients presenting with HFrEF, and sinus rhythm. Both basal HR and the reduction of this value have a prognostic ability in patients with

Material and methods

This prospective, comparative, randomized, non-blinded study was designed with a strategy of simple randomisation. We compared the therapeutic strategy currently recommended by the clinical practice guidelines of the European Society of Cardiology [6], which consists of the use of beta-blockers in increasing doses and the administration of ivabradine to patients in sinus rhythm, who, after reaching the optimal or the maximum tolerated dose ob beta-blockers, exhibited HR values above 70 bpm

Results

The flowchart of the study is shown in Fig. 1. From the 156 patients admitted during the 18-month study period (from November 2013 to April 2015) with acute heart failure and left ventricular ejection fraction < 40%, without contraindications to take beta-blockers, and who were not candidates for any non-pharmacological treatment, a total of 72 patients were evaluated. One patient retired the informed consent during admission and was excluded. Thus, 71 patients were included in the study, 38 in

Discussion

Introducing and up-titrating drugs early during the vulnerable phase post-hospitalisation could be important to reduce mortality and early rehospitalisations. Our results demonstrate the safety of the early combined use of ivabradine and beta-blockers in patients admitted to the hospital with acute HF (both chronically decompensated as well as de novo), and that a higher, statistically significant, percentage of patients achieved the target HR value in comparison with the standard strategy of

Limitations

This was a monocentric study with a limited number of patients; however, the sample size was adequate for the study of the primary endpoint (reduction of the HR at 28 days after initiating the treatment). However, as mentioned above, although no differences in morbidity and mortality were found between both groups, an improvement in surrogated markers such as left ventricular ejection fraction and BNP levels in the intervention arm could be observed.

Conclusions

The strategy of the early coadministration of ivabradine and beta-blockers during a decompensation episode of HFrEF is feasible and safe. It significantly and markedly reduced HR at 28 days and at 4 months following hospital discharge. Moreover, at 4 months, this therapeutic strategy was associated with a significant improvement of functional and biochemical parameters which can be related to the prognosis, such as left ventricular ejection fraction, BNP levels, and severity of symptoms of HF. A

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

References (14)

M. Bohm et al.
Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial
Lancet
(2010)
J.S. Borer et al.
Efficacy and safety of ivabradine in patients with severe chronic systolic heart failure (from the SHIFT study)
Am. J. Cardiol.
(2014)
K. Swedberg et al.
Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?
J. Am. Coll. Cardiol.
(2012)
K. Swedberg et al.
Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study
Lancet
(2010)
M. Anguita et al.
Prevalence of heart failure in the Spanish general population aged over 45 years. PRICE Study
Rev. Esp. Cardiol.
(2008)
K. Macintyre et al.
Evidence of improving prognosis in heart failure. Trends in case fatality in 66547 patients hospitalised between 1986 and 1995
Circulation
(2016)
M. Bohm et al.
Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study
Clin. Res. Cardiol.
(2013)

There are more references available in the full text version of this article.

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Our analysis included 50% of the required sample size. Ten trials reported data on HR.30–32 34 36 38–42 The median average HR was 75 beats min−1 (range of averages, 62–95 beats min−1) in the ivabradine group and 85 beats min−1 (range, 63–104 beats min−1) in the control group (10 RCTs, n=1045; WMD=–6.6; 95% CI, –9.6 to –3.6; P<0.001).
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Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalised with heart failure and reduced left ventricular ejection fraction (ETHIC-AHF): A randomised study

Abstract

Objectives

Methods

Results

Conclusions

Section snippets

Introduction and objectives

Material and methods

Results

Discussion

Limitations

Conclusions

Conflict of interest

Lancet

Am. J. Cardiol.

J. Am. Coll. Cardiol.

Lancet

Prevalence of heart failure in the Spanish general population aged over 45 years. PRICE Study

Rev. Esp. Cardiol.

Evidence of improving prognosis in heart failure. Trends in case fatality in 66547 patients hospitalised between 1986 and 1995

Circulation

Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study

Clin. Res. Cardiol.