Ivabradine Treatment to Prevent Anthracycline-Induced Cardiotoxicity: A Randomized Clinical Trial
Authors: Rizk Stephanie Itala , Costa Isabela Bispo Santos da Silva , Cruz Cecilia Beatriz Bittencourt Viana , Pileggi Brunna , Andrade Fernanda Thereza de Almeida , Gonzalez Thalita Barbosa , Bittar Cristina Salvadori , Fukushima Julia Tizue , Quintao Vinicius Caldeira , Osawa Eduardo Atsushi , Alves Juliana Barbosa Sobral , Fonseca Silvia Moulin Ribeiro , Garcia Diego Ribeiro , Pereira Juliana , Buccheri Valeria , Ávila Juliana , Kawahara Lucas Tokio , Barros Cecilia Chie Sakaguchi , Ikeoka Lucas Takeshi , Nakada Letícia Naomi , Fellini Mariella , Rocha Vanderson Geraldo , Rego Eduardo Magalhães , Hoff Paulo Marcelo Gehm , Kalil Filho Roberto , Landoni Giovanni , Hajjar Ludhmila Abrahão 
Published: November 2024

Background

Cancer therapy-related cardiac dysfunction frequently occurs in patients receiving anthracycline. Ivabradine reduces the heart rate without affecting contractility and has shown anti-inflammatory, antioxidant, and antiapoptotic effects in experimental models of cardiotoxicity. This study aims to evaluate the effect of ivabradine on cancer therapy-related cardiac dysfunction incidence in patients with lymphoma or sarcoma treated with anthracycline.

Methods

This study was a prospective, randomized, and triple-blind trial. Patients starting anthracycline therapy were given either ivabradine 5 mg twice daily or placebo until 30 days after completing treatment. The primary outcome was a ≥10% relative reduction in global longitudinal strain at 12 months. The secondary outcomes included 12-month clinical outcomes, a ≥10% decrease in the left ventricular ejection fraction to <55%, diastolic dysfunction, and troponin T and NT-proBNP levels.

Results

This study was conducted with 107 patients (51 in the ivabradine group and 56 in the placebo group). The median dose of anthracycline was 300 mg/m2(250--300 mg/m2) in both groups. A ≥10% relative reduction in global longitudinal strain at 12 months was reached in 57% of the ivabradine group and in 50% of the placebo group (OR 1.32, 95% CI: -0.612.83, p=.477). Fewer patients in the ivabradine group than in the placebo group had troponin T levels ≥14 ng/L [16 (39.0%) vs. 23 (62.2%), p=0.041] at 6 months. There were no differences in the other secondary outcomes.

Conclusions

A fixed 10 mg/day dose of ivabradine does not protect cancer patients against anthracycline cardiotoxicity.

Clinical trials registration

NCT03650205https://clinicaltrials.gov/study/NCT03650205?cond=NCT03650205&rank=1

Clinical perspectives

This study found that ivabradine at a fixed dose of 10 mg/day does not effectively prevent cardiotoxicity in cancer patients undergoing anthracycline (ANT) therapy, contrary to previous expectations.

These findings suggest that ivabradine may not be sufficient as a cardioprotective agent in ANT therapy, emphasizing the need to explore additional or alternative strategies to manage cardiotoxicity in cancer patients.

The study highlights a potentially complex interaction between ANT and cardiac tissue, indicating a need for further research to fully understand and address this risk.