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Meta-Analysis
. 2020 Nov 4;11(11):CD013004.
doi: 10.1002/14651858.CD013004.pub2.

Ivabradine as adjuvant treatment for chronic heart failure

Carina Benstoem  1 , Christina Kalvelage  1 , Thomas Breuer  1 , Nicole Heussen  2   3 , Gernot Marx  1 , Christian Stoppe  1 , Vincent Brandenburg  4
Affiliations
Meta-Analysis

Ivabradine as adjuvant treatment for chronic heart failure

Carina Benstoem et al. Cochrane Database Syst Rev. .

Abstract

Background: Chronic heart failure is one of the most common medical conditions, affecting more than 23 million people worldwide. Despite established guideline-based, multidrug pharmacotherapy, chronic heart failure is still the cause of frequent hospitalisation, and about 50% die within five years of diagnosis.

Objectives: To assess the effectiveness and safety of ivabradine in individuals with chronic heart failure.

Search methods: We searched CENTRAL, MEDLINE, Embase, and CPCI-S Web of Science in March 2020. We also searched ClinicalTrials.gov and the WHO ICTRP. We checked reference lists of included studies. We did not apply any time or language restrictions.

Selection criteria: We included randomised controlled trials in which adult participants diagnosed with chronic heart failure were randomly assigned to receive either ivabradine or placebo/usual care/no treatment. We distinguished between type of heart failure (heart failure with a reduced ejection fraction or heart failure with a preserved ejection fraction) as well as between duration of ivabradine treatment (short term (< 6 months) or long term (≥ 6 months)).

Data collection and analysis: Two review authors independently assessed trials for inclusion, extracted data, and checked data for accuracy. We calculated risk ratios (RR) using a random-effects model. We completed a comprehensive 'Risk of bias' assessment for all studies. We contacted authors for missing data. Our primary endpoints were: mortality from cardiovascular causes; quality of life; time to first hospitalisation for heart failure during follow-up; and number of days spent in hospital due to heart failure during follow-up. Our secondary endpoints were: rate of serious adverse events; exercise capacity; and economic costs (narrative report). We assessed the certainty of the evidence applying the GRADE methodology.

Main results: We included 19 studies (76 reports) involving a total of 19,628 participants (mean age 60.76 years, 69% male). However, few studies contributed data to meta-analyses due to inconsistency in trial design (type of heart failure) and outcome reporting and measurement. In general, risk of bias varied from low to high across the included studies, with insufficient detail provided to inform judgement in several cases. We were able to perform two meta-analyses focusing on participants with heart failure with a reduced ejection fraction (HFrEF) and long-term ivabradine treatment. There was evidence of no difference between ivabradine and placebo/usual care/no treatment for mortality from cardiovascular causes (RR 0.99, 95% confidence interval (CI) 0.88 to 1.11; 3 studies; 17,676 participants; I2 = 33%; moderate-certainty evidence). Furthermore, we found evidence of no difference in rate of serious adverse events amongst HFrEF participants randomised to receive long-term ivabradine compared with those randomised to placebo, usual care, or no treatment (RR 0.96, 95% CI 0.92 to 1.00; 2 studies; 17,399 participants; I2 = 12%; moderate-certainty evidence). We were not able to perform meta-analysis for all other outcomes, and have low confidence in the findings based on the individual studies.

Authors' conclusions: We found evidence of no difference in cardiovascular mortality and serious adverse events between long-term treatment with ivabradine and placebo/usual care/no treatment in participants with heart failure with HFrEF. Nevertheless, due to indirectness (male predominance), the certainty of the available evidence is rated as moderate.

PubMed Disclaimer

Conflict of interest statement

CB: none known.

CK: none known.

TB: none known.

NH: none known.

GM: none known.

CS: none known.

VB: none known.

Figures

1
1
Study flow diagram for selection of randomised controlled trials.
2
2
Study flow diagram for selection of economic evaluations.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Usual care with ivabradine compared to placebo, usual care, or no treatment in participants with HFrEF (long‐term treatment (≥ 6 months) with ivabradine), Outcome 1: Mortality from cardiovascular causes (follow‐up range 19 months to 23 months)
1.2
1.2. Analysis
Comparison 1: Usual care with ivabradine compared to placebo, usual care, or no treatment in participants with HFrEF (long‐term treatment (≥ 6 months) with ivabradine), Outcome 2: Rate of serious adverse events
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    1. Tumasyan LR, Adamyan KG. Comparative efficacy of carvedilol and ivabradine in severe chronic heart failure of ischemic origin with baseline heart rate below and above 70 beat per minute. European Heart Journal 2009;30:427.
Vatinian 2015 {published data only}
    1. Vatinian S, Gurgenyan S, Nikoghosyan K. Efficacy of addition of ivabradine to bisoprolol in patients with essential hypertension, coronary artery disease and reduced left ventricular systolic function. European Heart Journal 2015;36:672-3.
Volterrani 2011 {published data only}
    1. Volterrani M, Cice G, Caminiti G, Vitale C, D'Isa S, Perrone FP, et al. Effect of Carvedilol, Ivabradine or their combination on exercise capacity in patients with Heart Failure (the CARVIVA HF trial). International Journal of Cardiology 2011;151(2):218-24. - PubMed
Xu 2011 {published data only}
    1. Xu Y. Effects of ivabradine in combination with metoprolol on left ventricle remodeling after Q-wave myocardial infarction with early moderate left ventricle systolic dysfunction. International Journal of Cardiology 2011;152(Suppl 1):55-6.
Yao 2014 {published data only}
    1. Yao X, Andrii B. Effects of heart rate control with ivabradine plus beta-blocker on exercise tolerance in patients after Q-wave myocardial infarction with early left ventricular systolic dysfunction. JACC 2014;64(16):C204.

References to ongoing studies

ACTRN12612000710820 {published data only}
    1. ACTRN12612000710820. Novel interventions in heart failure with preserved ejection fraction using ivabradine. www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612000710820 (data registered 3 July 2012).
ChiCTR‐IIR‐17013377 {published data only}
    1. ChiCTR‐IIR‐17013377. Efffect of ivabradine in heart failure with preserved ejection fraction: a multicenter and randomized controlled clinical trial. www.chictr.org.cn/showprojen.aspx?proj=22845 (date of registration 14 November 2017).
EUCTR2012‐002742‐20‐CZ {published data only}
    1. EUCTR2012‐002742‐20‐CZ. Effect of ivabradine versus placebo on cardiac function and on capacity to perform exercise in patients suffering from diastolic heart failure. www.clinicaltrialsregister.eu/ctr-search/trial/2012-002742-20/GB (first entered 18 March 2013).
EUCTR2014‐003286‐21‐IE {published data only}
    1. EUCTR2014‐003286‐21‐IE. A multicentre, interventional, parallel group, randomised, open-label, exploratory study to assess the earlier introduction of Ivabradine in the Management of Systolic Dysfunction Heart Failure. The QUALIVA study. www.clinicaltrialsregister.eu/ctr-search/trial/2014-003286-21/IE (first entered 28 November 2014).
NCT02188082 {published data only}
    1. NCT02188082. Clinical trial of systolic heart failure treatment of ivabradine hemisulfate sustained-release tablets (FIRST). clinicaltrials.gov/ct2/show/NCT02188082 (first posted 11 July 2014).
NCT03701880 {published data only}
    1. NCT03701880. Early use of ivabradine in heart failure. clinicaltrials.gov/ct2/show/NCT03701880 (first posted 10 October 2018).

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