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

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.