Ivabradine for prevention of anthracycline-induced cardiotoxicity: a systematic review and meta-analysis

Abstract Background Anthracycline-based chemotherapy is highly effective against various malignancies but can lead to cancer therapy–related cardiac dysfunction, significantly impacting morbidity and mortality. Ivabradine, a heart rate–lowering agent that does not reduce contractility or blood pressure, has shown anti-inflammatory and antioxidant properties in preclinical models. However, its effectiveness in reducing anthracycline-induced cardiotoxicity is uncertain. Purpose We performed a systematic review and meta-analysis to determine whether ivabradine is cardioprotective in anthracycline-induced cardiac dysfunction, as assessed by global longitudinal strain (GLS) change, left ventricular ejection fraction (LVEF) change, and NT-proBNP change at 6 and 12 months of follow-up. Methods We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCT) comparing ivabradine to placebo or standard care in adult patients who were undergoing anthracycline chemotherapy. We found three trials (total n=210) with one trial in patients with lymphoma or sarcoma (n=107) and two trials in patients with breast cancer (n=103). We extracted data on GLS at 6 months (Fig. 1a) and 12 months (Fig. 1b), LVEF at 6 months (Fig. 2a), and NT-proBNP at 6 months (Fig. 2b). Data were computed as mean difference (MD) with 95% confidence intervals (CI) and analyzed using a random-effects model; heterogeneity was assessed by the I² statistic. Results Three RCTs (210 patients) were included. Ivabradine significantly preserved GLS at 6 months (Fig. 1a) compared to controls (MD −0.87; 95% CI −1.47 to −0.27; p=0.004), but by 12 months (Fig. 1b), GLS was similar between groups (MD −0.37; 95% CI −1.04 to 0.30; p=0.28). LVEF at 6 months (Fig. 2a) did not differ (MD 0.28; 95% CI −0.90 to 1.46; p=0.64), and NT-proBNP at 6 months (Fig. 2b) also showed no difference between ivabradine and control (MD −3.89; 95% CI −14.71 to 6.92; p=0.48). Ivabradine was generally well tolerated, with few transient visual side effects. Conclusion Ivabradine was found to have significant benefit in the preservation of GLS at 6 months in patients receiving anthracyclines, a potential marker of early cardioprotection. However, the benefit was not sustained at 12 months, and no clear differences were observed with LVEF or NT-proBNP. The findings point toward a possible short-term protective effect of ivabradine, but larger multicenter studies are required to determine optimal dosage regimens, establish suitable subgroups that would be most likely to benefit, and examine long-term cardioprotective effects in patients receiving anthracycline-based chemotherapy.GLS after 6 months (A) and 12 months (B) A: LVEF after 6m, B: NT-pro BNP after 6m

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