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

Abstract

Background: 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.

Methods: 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.

Results: This study enrolled 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. 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]; P=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%]; P=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.

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

Registration: URL: https://clinicaltrials.gov/; Unique Identifier: NCT03650205.

Keywords: anthracycline; cardiac dysfunction; cardiotoxicity; ivabradine; prevention.

Figure 1. Study procedures and assessment timeline.

The timeline and key medical assessments conducted at baseline (0 months), during the chemotherapy treatment phase with high‐dose anthracycline (3 and 6 months), and during the 12‐month follow‐up after intervention are summarized. The schedule included medical consultations, biomarker dosages, transthoracic echocardiogram, ECG, Holter monitoring, and EQ‐5D‐3L assessments at each designated time point (0, 3, 6, and 12 months). ANT indicates anthracycline; BID, twice daily; EQ‐5D‐3L: EuroQol‐5 Dimension‐3 Level; and TTE, transthoracic echocardiogram.

Figure 2. Study flowchart.

Depiction of the participant allocation from the initial assessment to the completion of analysis within the study arms.

Figure 3. Global longitudinal strain of the left ventricle during the study.

GLS at 3, 6, and 12 months after randomization in comparison with baseline. GLS indicates global longitudinal strain. a. Pearson's chi‐square test.

Figure 4. Cardiac biomarkers during the study.

A, NT‐proBNP; (B) troponin T. P: Wilcoxon signed‐rank test (comparison within groups at the baseline value). NT‐proBNP indicates N‐terminal pro‐B‐type natriuretic peptide.

Figure 5. Ivabradine treatment to prevent anthracycline‐induced cardiotoxicity.

The diagram provides a schematic representation of the mechanism of action of ivabradine at the cellular level. Ivabradine treatment in patients with lymphoma or sarcoma treated with anthracycline did not prevent the decline in global longitudinal strain at 12 months. ANT indicates anthracycline; CAT, catalase; GLS, global longitudinal strain; GSH, glutathione; HR, heart rate; If, funny current; Iv, ivabradine; SA, sinoatrial; and SOD, superoxide dismutase.