Effect of ivabradine on major adverse cardiovascular events and mortality in critically ill patients: a systematic review and meta-analyses of randomised controlled trials with trial sequential analyses

Aileen Chen; Nadia Elia; Jelena Dunaiceva; Alain Rudiger; Bernhard Walder; Bernardo Bollen Pinto

doi:10.1016/j.bja.2020.01.027

Effect of ivabradine on major adverse cardiovascular events and mortality in critically ill patients: a systematic review and meta-analyses of randomised controlled trials with trial sequential analyses

Br J Anaesth. 2020 Jun;124(6):726-738. doi: 10.1016/j.bja.2020.01.027. Epub 2020 Mar 6.

Authors

Aileen Chen¹, Nadia Elia², Jelena Dunaiceva³, Alain Rudiger⁴, Bernhard Walder¹, Bernardo Bollen Pinto⁵

Affiliations

¹ Division of Anaesthesiology, Department of Acute Medicine, Geneva University Hospitals, Switzerland; Perioperative Basic, Translational and Clinical Research Group, Division of Anaesthesiology, Geneva University Hospitals, Geneva, Switzerland.
² Division of Anaesthesiology, Department of Acute Medicine, Geneva University Hospitals, Switzerland; Institute of Global Health, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
³ Division of Anaesthesiology, Department of Acute Medicine, Geneva University Hospitals, Switzerland.
⁴ Medical Department, Hospital Limmettal, Schlieren, Switzerland.
⁵ Division of Anaesthesiology, Department of Acute Medicine, Geneva University Hospitals, Switzerland; Perioperative Basic, Translational and Clinical Research Group, Division of Anaesthesiology, Geneva University Hospitals, Geneva, Switzerland. Electronic address: bernardo.bollenpinto@hcuge.ch.

PMID: 32147100
DOI: 10.1016/j.bja.2020.01.027

Abstract

Background: Ivabradine lowers heart rate (HR) without affecting contractility or vascular tone. It is licensed for HR control in chronic heart diseases. We performed a systematic review and meta-analyses to examine whether ivabradine could decrease major adverse cardiovascular events (MACE) and mortality in critically ill patients.

Methods: We searched Medline, Embase, Cochrane Library, and Web of Science for RCTs. Trial quality was assessed using the Cochrane risk of bias tool. Random-effects meta-analyses were performed if at least three trials or 100 patients were available. Results are reported as weighted mean difference (WMD), odds ratio (OR), and 95% confidence intervals (CIs). Trial sequential analyses were performed to estimate the sample size needed to reach definitive conclusions of efficacy or futility.

Results: We included 13 RCTs (n=1497 patients). We found no evidence of an impact of ivabradine on MACE (three RCTs, 819 patients; OR=0.77; 95% CI, 0.53-1.11) or mortality (10 RCTs, 1356 patients; OR=1.07; 95% CI, 0.63-1.82), but sample sizes were not reached to allow definitive conclusions. Compared with placebo or standard care, ivabradine reduced HR (eight RCTs, 464 patients; WMD, -9.5 beats min^-1; 95% CI, -13.3 to -5.8). Risk of bradycardia was not different between ivabradine and control (five RCTs, 434 patients; OR=1.2; 95% CI, 0.60-2.38). Risk of bias was overall high or unclear.

Conclusions: Ivabradine reduces HR compared with placebo or standard care. The effect on MACE or mortality in acute care remains unclear. Further RCTs powered to detect changes in clinically relevant outcomes are warranted.

Clinical trial registration: Prospero CRD42018086109.

Keywords: atrial fibrillation; cardiovascular agents; critical care; critical illness; heart failure; ivabradine; myocardial infarction.

Publication types

Meta-Analysis
Systematic Review

MeSH terms

Cardiovascular Agents / therapeutic use*
Critical Illness
Heart Diseases / drug therapy*
Heart Diseases / mortality*
Heart Diseases / physiopathology
Humans
Ivabradine / therapeutic use*
Treatment Outcome

Substances

Cardiovascular Agents
Ivabradine