Randomized, Placebo-Controlled, Triple-Blind Clinical Trial of Ivabradine for the Prevention of Cardiac Dysfunction During Anthracycline-Based Cancer Therapy.

in Journal of the American Heart Association by Stephanie Itala Rizk, Isabela Bispo Santos da Silva Costa, Cecília Beatriz Bittencourt Viana Cruz, Brunna Pileggi, Fernanda Thereza de Almeida Andrade, Thalita Barbosa Gonzalez, Cristina Salvadori Bittar, Julia Tizue Fukushima, Vinicius Caldeira Quintao, Eduardo Atsushi Osawa, Juliana Barbosa Sobral Alves, Silvia Moulin Ribeiro Fonseca, Diego Ribeiro Garcia, Juliana Pereira, Valeria Buccheri, Juliana Avila, Lucas Tokio Kawahara, Cecilia Chie Sakaguchi Barros, Lucas Takeshi Ikeoka, Letícia Naomi Nakada, Mariella Fellini, Vanderson Geraldo Rocha, Eduardo Magalhães Rego, Paulo Marcelo Gehm Hoff, Roberto Kalil Filho, Giovanni Landoni, Ludhmila Abrahão Hajjar

TLDR

  • Ivabradine, a medication that slows down heart rate, did not show effectiveness in preventing anthracycline-related heart problems in patients with cancer.
  • The study found that ivabradine reduced the risk of high troponin T levels at 6 months, but this effect was not sustained at the 12-month follow-up.

Abstract

Cancer therapy-related cardiac dysfunction frequently occurs in patients receiving anthracycline. Ivabradine reduces heart rate without affecting contractility and showed anti-inflammatory, antioxidant, and antiapoptotic effects in experimental cardiotoxicity models. This study aims to evaluate the effect of ivabradine on cancer therapy-related cardiac dysfunction in patients with lymphoma or sarcoma treated with anthracycline. In a randomized, triple-blind trial, patients starting anthracycline therapy received either ivabradine 5 mg twice daily or placebo until 30 days after completing treatment. The primary outcome was the incidence of cardiotoxicity measured as a ≥10% relative reduction in global longitudinal strain at 12 months from baseline. Secondary outcomes included 12-month clinical outcomes, a ≥10% decrease in the left ventricular ejection fraction to <55%, diastolic dysfunction, and troponin T and N-terminal pro-B-type natriuretic peptide levels. This study enrolled 107 patients (51 in the ivabradine group and 56 in the placebo group). The median dose of anthracycline was 300 mg/m(250-300 mg/m) in both groups. Cardiotoxicity measured as a ≥10% relative reduction in global longitudinal strain at 12 months was reached in 57% versus 50% in the ivabradine and placebo groups (odds ratio, 1.32 [95% CI, 0.61-2.83];=0.477). Fewer patients in the ivabradine group than in the placebo group had troponin T levels ≥14 ng/L (16 [39.0%] versus 23 [62.2%];=0.041) at 6 months, with this difference not maintained at the 12-month follow-up. In addition, there were no differences in the other secondary outcomes. A fixed 10 mg/day dose of ivabradine does not protect patients with cancer against anthracycline cardiotoxicity. URL: https://clinicaltrials.gov/; Unique Identifier: NCT03650205.

Overview

  • The study aimed to evaluate the effect of ivabradine on cancer therapy-related cardiac dysfunction in patients with lymphoma or sarcoma treated with anthracycline.
  • A total of 107 patients were randomly assigned to receive either ivabradine 5 mg twice daily or placebo until 30 days after completing anthracycline treatment.
  • The primary outcome was the incidence of cardiotoxicity measured as a ≥10% relative reduction in global longitudinal strain at 12 months from baseline.

Comparative Analysis & Findings

  • The incidence of cardiotoxicity measured as a ≥10% relative reduction in global longitudinal strain at 12 months was reached in 57% versus 50% in the ivabradine and placebo groups, respectively (odds ratio, 1.32 [95% CI, 0.61-2.83];=0.477).
  • Fewer patients in the ivabradine group than in the placebo group had troponin T levels ≥14 ng/L at 6 months (16 [39.0%] versus 23 [62.2%];=0.041), but this difference was not maintained at the 12-month follow-up.
  • There were no differences in the other secondary outcomes, including 12-month clinical outcomes, diastolic dysfunction, and troponin T and N-terminal pro-B-type natriuretic peptide levels.

Implications and Future Directions

  • This study suggests that a fixed 10 mg/day dose of ivabradine does not protect patients with cancer against anthracycline cardiotoxicity.
  • Future studies may explore the potential benefit of ivabradine in combination with other cardioprotective agents or at higher doses to prevent anthracycline-related cardiac dysfunction.
  • Additionally, studies with larger sample sizes and longer follow-up periods may help to better understand the effects of ivabradine on clinically relevant cardiac outcomes in patients with cancer.
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