Article Text

Original research
Effects of adding ivabradine to usual care in patients with angina pectoris: a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis
  1. Mathias Maagaard1,
  2. Emil Eik Nielsen2,
  3. Naqash Javaid Sethi1,
  4. Liang Ning3,4,
  5. Si-hong Yang4,
  6. Christian Gluud5 and
  7. Janus Christian Jakobsen1,6
  1. 1Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Copenhagen, Denmark
  2. 2Department of Internal Medicine, Holbæk Hospital, Holbæk, Denmark
  3. 3Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences Guanganmen Hospital, Xicheng District, China
  4. 4Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
  5. 5The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Copenhagen, Denmark
  6. 6Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
  1. Correspondence to Dr Mathias Maagaard; mathias.maagaard{at}


Objective To determine the impact of ivabradine on outcomes important to patients with angina pectoris caused by coronary artery disease.

Methods We conducted a systematic review. We included randomised clinical trials comparing ivabradine versus placebo or no intervention for patients with angina pectoris due to coronary artery disease published prior to June 2020. We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, Cochrane methodology, Trial Sequential Analysis, Grading of Recommendations Assessment, Development, and Evaluation, and our eight-step procedure. Primary outcomes were all-cause mortality, serious adverse events and quality of life.

Results We included 47 randomised clinical trials enrolling 35 797 participants. All trials and outcomes were at high risk of bias. Ivabradine compared with control did not have effects when assessing all-cause mortality (risk ratio [RR] 1.04; 95% CI 0.96 to 1.13), quality of life (standardised mean differences −0.05; 95% CI −0.11 to 0.01), cardiovascular mortality (RR 1.07; 95% CI 0.97 to 1.18) and myocardial infarction (RR 1.03; 95% CI 0.91 to 1.16). Ivabradine seemed to increase the risk of serious adverse events after removal of outliers (RR 1.07; 95% CI 1.03 to 1.11) as well as the following adverse events classified as serious: bradycardia, prolonged QT interval, photopsia, atrial fibrillation and hypertension. Ivabradine also increased the risk of non-serious adverse events (RR 1.13; 95% CI 1.11 to 1.16). Ivabradine might have a statistically significant effect when assessing angina frequency (mean difference (MD) 2.06; 95% CI 0.82 to 3.30) and stability (MD 1.48; 95% CI 0.07 to 2.89), but the effect sizes seemed minimal and possibly without any relevance to patients, and we identified several methodological limitations, questioning the validity of these results.

Conclusion Our findings do not support that ivabradine offers significant benefits on patient important outcomes, but rather seems to increase the risk of serious adverse events such as atrial fibrillation and non-serious adverse events. Based on current evidence, guidelines need reassessment and the use of ivabradine for angina pectoris should be reconsidered.

PROSPERO registration number CRD42018112082.

  • coronary artery disease
  • pharmacology
  • quality of care and outcomes

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  • Contributors MM: conceived the systematic review, conducted literature search, data extraction, data analysis, data interpretation and wrote the article. EEN, LN and S-hY: conducted literature search, data extraction and amended the article. NJS: conducted data extraction and amended the article. CG: helped conceive the systematic review, provided invaluable comments and amended the article. JCJ: conceived the systematic review, aided in data interpretation and amended the article.

  • Funding Funding by the Copenhagen Trial Unit by wages paid to JCJ and CG. The funding is through the Danish Finance Act.

  • Disclaimer The funding source had no influence on the systematic review.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data are available as supplementary files. Data can also be requested from the corresponding author.

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