Anthracyclines are highly effective chemotherapeutic agents, but this is often limited by cardiotoxicity, which can lead to long-term cardiac complications. Nebivolol, a third-generation beta-blocker with vasodilatory properties, has been proposed as a potential cardioprotective agent in this setting. Its ability to induce nitric oxide release has demonstrated promising effects, including antioxidant activity, cardiac neo-angiogenesis, and protection of mitochondrial and endothelial function. This trial aimed to evaluate whether Nebivolol could mitigate the cardiotoxic effects of anthracyclines (PMID: 22727976).

The CONTROL trial, a randomized, parallel, placebo-controlled, double-blinded superiority study, assessed Nebivolol’s cardioprotective role in 80 patients with breast cancer (BC) or diffuse large B-cell lymphoma (DLBCL) scheduled for first-line anthracycline-based chemotherapy. Despite the hypothesis, the trial findings revealed that Nebivolol did not prevent left ventricular ejection fraction (LVEF) reduction at 12-month follow-up compared to placebo and showed no benefit across secondary endpoints. The risk of cancer therapy-related cardiac dysfunction (CTRCD) observed was consistent with existing literature and was not influenced by preventive Nebivolol use. Importantly, in patients without prior cardiac disease and with normal baseline LVEF, the reduction in LVEF at 12 months was modest despite undergoing anthracycline treatment.
These neutral results stand in contrast to earlier evidence that suggested a statistically significant benefit of neurohormonal antagonists in preventing anthracycline-induced LVEF reduction (PMID: 33083790).
The authors acknowledged several limitations in the study. The relatively small sample size could limit statistical power, though the findings are strengthened by cardiac magnetic resonance (CMR)-based LVEF assessment and consistency across endpoints, with no indication of treatment effects. Additionally, the single-center design may limit the generalizability of results. Lastly, the inclusion criteria resulted in a predominance of female participants (70%). While this may limit generalizability to male patients, it also differentiates this study as one of the first cardiovascular randomized trials with a mainly female population, which addresses a critical gap in research representation.

The CONTROL trial demonstrates that Nebivolol does not significantly prevent LVEF decrease or reduce the risk of CTRCD in patients undergoing anthracycline-based chemotherapy. These results highlight the importance of additional research to identify effective strategies for cardioprotection. Future studies should prioritize larger, multicenter trials, incorporate advanced imaging techniques, and develop biomarkers to enable earlier detection of cardiotoxicity. Additionally, better underlying mechanisms of anthracycline-induced cardiotoxicity could lead to the development of more targeted and effective interventions for cardioprotection in patients undergoing cancer treatment.