The role of cardio-protective agents in breast cancer patients to prevent anthracycline induced cardiotoxicity: a systematic review and network meta-analysis

Background Anthracycline (ANT)-based chemotherapy for breast malignancies have significantly improved cancer outcomes. However, the cardiotoxicity induced by ANTs in the breast cancer population has increased major adverse cardiac events. While randomised controlled trials (RCTs) have explored different primary preventative agents to confer cardio-protection pre chemotherapy, comparisons between agents has been limited. It is unclear which drug is the most efficacious in preserving Left Ventricular Ejection Fraction (LVEF) amongst this population. Purpose To perform a network meta-analysis of RCTs comparing the impact on LVEF of various prophylactic cardio-protective agents, when prescribed to breast cancer patients prior to ANT-based chemotherapy. Methods Two independent authors performed a literature search as per the PRISMA guidelines using four databases (CENTRAL, Cochrane Reviews, MEDLINE, SCOPUS), to find RCTS evaluating cardio protective agents. The trial population was limited to patients with breast cancer without prior ANT exposure. Trials were only included if the cardio-protective agents were commenced prior to ANT dosing. The assessed outcome was a mean change in LVEF pre and post ANT dosing, compared to placebo prevention. Extracted data included age, ANT dose, and LVEF pre and post chemotherapy. The Cochrane Risk of Bias tool was used to appraise included RCTs. Results From 2807 search results, we identified twelve RCTs which evaluated 1126 patients. Seven studies assessed beta-blockers alone and two assessed combination ACE inhibitors and beta blockers. Individual studies assessing ACE inhibitors, spironolactone or rosuvastatin alone were also included. All patients were female with an average age of 50.5 and average ANT dose of 412 mg/m2. Our network meta-analysis showed beta-blockers showed significant protection with higher LVEF than placebo by 2.38% [0.52, 4.25]. ACE inhibitors showed a similar magnitude of LVEF preservation 2.59% [−0.20, 5.38] but not statistically significant due to wider CI because of lower sample size (n=250). Spironolactone showed a statistically significant preservation in LVEF by 12.80% [3.44, 22.16], however this was based on a single study (n=83), with marked measurement bias and deviations from intended intervention. All included trials had an intermediate or high risk of bias, with marked heterogeneity in ANT dosing and LVEF monitoring. Conclusion Beta-blockers minimise LVEF decline when administered prior to anthracycline chemotherapy, compared against alternate agents. Data may be underpowered to demonstrate the benefit of ACE inhibitor and combination beta blocker/ACE inhibitor prescription. The quality of RCT data to date is limited by a high risk of bias and significant heterogeneity between RCA reporting. This analysis is likely to inform clinical practice, and allow clinicians to prescribe primary cardio-protection in patients at high risk of cardiotoxicity. Funding Acknowledgement Type of funding source: None