Incidence of heart failure in patients with acute myeloid leukemia who received daunorubicin versus idarubicin: An analysis of the trinetx database

Abstract Background The 7+3 regimen, which combines 7 days of cytarabine with 3 days of an anthracycline, continues to be a cornerstone of induction chemotherapy for acute myeloid leukemia (AML). A known concern with anthracyclines is their dose-dependent cardiotoxicity, which can manifest as new-onset congestive heart failure (CHF). Among the most commonly employed anthracyclines in the United States are daunorubicin and idarubicin. While prior studies have suggested no significant difference in the incidence of CHF between these two agents, the clinical importance of anthracycline-induced cardiotoxicity necessitates further investigation, particularly using real-world data to capture a broader patient population and clinical variability. Methods We conducted a multi-center retrospective cohort study using TriNetX, a global health research network with over 100 million de-identified patient records from 89 healthcare organizations. Our study included adults (≥18 years) newly diagnosed with AML who received either daunorubicin or idarubicin as part of their 7+3 induction. Patients with a history of prior chemotherapy or pre-existing heart failure were systematically excluded to minimize confounding. The primary outcome was heart failure (HF) incidence up to 10 years post-treatment. Secondary outcomes included subtype-specific HF (HFrEF, HFpEF), all-cause mortality, and rates of second-line therapy. Propensity score matching was performed to mitigate confounding, accounting for age, sex, and comorbidities (hyperlipidemia, hypertensive diseases, nicotine dependence, tobacco use, diabetes mellitus, obesity, atherosclerotic heart disease). Outcomes were analyzed using Kaplan-Meier estimates, risk ratios (RR), odds ratios (OR), hazard ratios (HR), and 95% confidence intervals (CI). Results Of 2,040 patients meeting inclusion criteria (1,005 daunorubicin, 1,035 idarubicin), 887 patients remained in each cohort after propensity score matching. Mean age was 53.8 years across cohorts; 55% of daunorubicin and 56% of idarubicin patients were male. Primary analysis showed daunorubicin recipients had a significantly higher risk of developing heart failure compared to idarubicin (RR 1.42; 95% CI, 1.08–1.85; p=0.01). Over 10 years, the probability of remaining HF-free was lower for daunorubicin (72.08%) versus idarubicin (81.15%) (HR 1.44; 95% CI, 1.08–1.91; p=0.03). Subgroup analysis revealed daunorubicin was specifically associated with an increased risk of HFrEF (RR 1.97; 95% CI, 1.29–3.00; p<0.01). In contrast, no statistically significant difference was observed for HFpEF between the two groups (RR 1.34; 95% CI, 0.86–2.10; p=0.19). There were also no statistically significant differences identified between the groups regarding all-cause mortality (HR 0.99; 95% CI, 0.83–1.15, p=0.96), median time to relapse (209 vs. 224 days; p=0.12), or likelihood of requiring second-line therapy (RR 1.07; 95% CI, 0.97–1.18; p=0.15). Conclusions This large-scale, multi-center retrospective analysis using TriNetX demonstrates that daunorubicin was associated with a significantly higher incidence of heart failure, particularly HFrEF, compared to idarubicin. This contrasts with prior studies suggesting no differential risk. A plausible explanation for this observation could be that idarubicin is structurally less cardiotoxic than daunorubicin, specifically due to the replacement of its C-methoxyl group in the D ring with a hydrogen moiety, which is believed to be less cardiotoxic. These findings highlight the critical need for further prospective research on anthracycline-specific cardiotoxicity, with significant implications for optimizing AML induction therapy selection. While acknowledging retrospective study limitations (e.g., selection bias, inability to differentiate specific doses), our results suggest a potentially practice-informing distinction between these two widely used anthracyclines in AML treatment.