Cardiotoxic Effect of Modern Anthracycline Dosing on Left Ventricular Ejection Fraction: A Systematic Review and Meta‐Analysis of Placebo Arms From Randomized Controlled Trials

BACKGROUND: Anthracyclines are a key chemotherapeutic agent used against hematological and solid organ malignancies. However, their benefits in cancer survival are limited by cumulative, dose‐related cardiotoxicity. The impact of anthracyclines on left ventricular ejection fraction (LVEF), in the era of modern chemotherapy regimens, remains unclear. METHODS AND RESULTS: Three databases (CENTRAL, MEDLINE, and SCOPUS) were systematically searched for randomized trials evaluating cardioprotective agents against placebo, in preventing cardiotoxicity. Echocardiography or magnetic resonance measured LVEF pre‐ and post‐anthracycline‐based chemotherapy was abstracted from placebo trial arms. The key terms included “anthracycline,” “cardiotoxicity” and “randomized.” A doxorubicin equivalent anthracycline dose metric was calculated to compare different anthracyclines. A random‐effects model was used to pool mean difference in LVEF after anthracycline. Meta‐regressions were calculated to identify variation sources. We included 660 patients from 19 trials. The weighted mean baseline LVEF across studies was 62.6%, and follow‐up LVEF assessment was performed at 6 months. The pooled mean decline in LVEF among placebo arms was 5.4% (95% CI, 3.5%–7.3%) with a doxorubicin equivalent anthracycline dose of 385 mg/m(2). Meta‐regression analysis showed no significant difference in LVEF against doxorubicin equivalent anthracycline dose as continuous (P=0.29) or against published cut‐offs for cardiotoxicity (250 mg/m(2), P=0.21; 360 mg/m(2), P=0.40; and 400 mg/m(2), P=0.66). The differences in mean LVEF were not associated with sex, adjunct chemotherapy, or cancer type. CONCLUSIONS: The magnitude of LVEF impairment post‐anthracycline therapy appears less than previously described with modern dosing regimens. This may improve the accuracy of power calculation for future clinical trials assessing the role of cardioprotective therapy.