Statins to prevent early cardiac dysfunction in cancer patients at increased cardiotoxicity risk receiving anthracyclines

Abstract

Background and aims: Anthracyclines can cause cancer therapy-related cardiac dysfunction (CTRCD). We aimed to assess whether statins prevent decline in left ventricular ejection fraction (LVEF) in anthracycline-treated patients at increased risk for CTRCD.

Methods: In this multicenter double-blinded, placebo-controlled trial, patients with cancer at increased risk of anthracycline-related CTRCD (per ASCO guidelines) were randomly assigned to atorvastatin 40 mg or placebo once-daily. Cardiovascular magnetic resonance (CMR) imaging was performed before and within 4 weeks after anthracyclines. Blood biomarkers were measured at every cycle. The primary outcome was post-anthracycline LVEF, adjusted for baseline. CTRCD was defined as a fall in LVEF by >10% to <53%. Secondary endpoints included left ventricular (LV) volumes, CTRCD, CMR tissue characterization, high sensitivity troponin I (hsTnI), and B-type natriuretic peptide (BNP).

Results: We randomized 112 patients (56.9 ± 13.6 years, 87 female, and 73 with breast cancer): 54 to atorvastatin and 58 to placebo. Post-anthracycline CMR was performed 22 (13-27) days from last anthracycline dose. Post-anthracycline LVEF did not differ between the atorvastatin and placebo groups (57.3 ± 5.8% and 55.9 ± 7.4%, respectively) when adjusted for baseline LVEF (P = 0.34). There were no significant between-group differences in post-anthracycline LV end-diastolic (P = 0.20) or end-systolic volume (P = 0.12), CMR myocardial edema and/or fibrosis (P = 0.06-0.47), or peak hsTnI (P ≥ 0.99) and BNP (P = 0.23). CTRCD incidence was similar (4% versus 4%, P ≥ 0.99). There was no difference in adverse events.

Conclusions: In patients at increased risk of CTRCD, primary prevention with atorvastatin during anthracycline therapy did not ameliorate early LVEF decline, LV remodeling, CTRCD, change in serum cardiac biomarkers, or CMR myocardial tissue changes.

Trial registration: NCT03186404.

Keywords: Anthracycline; Cardiotoxicity; Magnetic resonance imaging; Primary prevention; Statins.

Graphical Abstract

Summary of study enrollment, assessments, and outcomes. Randomized patients had cardiovascular magnetic resonance imaging (CMR) pre- and 72 (63–122) days post-anthracycline initiation / 22 (13–27) days post last dose of anthracycline. The stethoscopes and blood tubes reflect repeated clinical and biomarker assessment after every anthracycline cycle.

Figure 1

Consort diagram.

Figure 2

Pre- and post-anthracycline measures of LVEF, GLS, and GCS in the atorvastatin and placebo groups. Individual lines represent individual patients. The solid line and bars represent the mean and 95% CI pre- and post-anthracycline.

Figure 3

Trajectory of high sensitivity troponin I, B-type natriuretic peptides, C-reactive proteins measured pre- and post-anthracycline, and each anthracycline cycle are summarized. The group-specific trajectories were estimated using GEE with cycles as a categorical variable, and the corresponding 95% CIs were estimated based on robust sandwich estimators. Given the variability in the number of cycles between patients and fewer patients receiving more than five cycles, we lumped all observations at Cycle 5 and all subsequent cycles into one single category. In addition, we included the estimates and the CI at the end of anthracycline treatment without connecting the trajectories to signal that not all patients received five cycles of anthracycline. Note that patient-specific data points in all cycles are shown in Supplementary material online, Fig. S2.

Figure 4

Post hoc analysis of the comparison of the effect of statins on post-anthracycline LVEF in clinically relevant subgroups. Regardless of the subgroup the effect remained similar to the main effect. Any CVD risk factors included diabetes, hypertension, or smoking (current or prior history). Please note that the total number of patients add to 108 given the 4 dropouts.