Association of Anthracycline With Heart Failure in Patients Treated for Breast Cancer or Lymphoma, 1985-2010

Abstract

ImportanceAnthracyclines increase the risk for congestive heart failure (CHF); however, long-term cumulative incidence and risk factors for CHF after anthracycline therapy are not well defined in population-based studies.ObjectiveTo compare the long-term cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracycline therapy compared with healthy controls from the same community.Design, Setting, and ParticipantsThis retrospective population-based case-control study included data from the Rochester Epidemiology Project. Participants included residents of Olmsted County, Minnesota, diagnosed with breast cancer or lymphoma from January 1985 through December 2010 matched for age, sex, and comorbidities with healthy controls, with a final ratio of 1 case to 1.5 controls. Statistical analysis was performed between July 2017 and February 2022.ExposuresCancer treatment and CHF risk factors.Main Outcomes and MeasuresThe main outcome was new-onset CHF, as defined by the modified Framingham criteria. Cox proportional hazards regression was used to estimate hazard ratios (HRs) to compare the risk of CHF in participants with cancer vs controls, adjusted for age, sex, diabetes, hypertension, hyperlipidemia, coronary artery disease, obesity, and smoking history.ResultsA total of 2196 individuals were included, with 812 patients with cancer and 1384 participants without cancer. The mean (SD) age was 52.62 (14.56) years and 1704 participants (78%) were female. Median (IQR) follow-up was 8.6 (5.2-13.4) years in the case group vs 12.5 (8.7-17.5) years in the control group. Overall, patients with cancer had higher risk of CHF compared with the control cohort even after adjusting for age, sex, diabetes, hypertension, coronary artery disease, hyperlipidemia, obesity, and smoking status (HR, 2.86 [95% CI, 1.90-4.32]; P < .001). After adjusting for the same variables, CHF risk was greater for patients with cancer receiving anthracycline (HR, 3.25 [95% CI, 2.11-5.00]; P < .001) and was attenuated and lost statistical significance for patients with cancer not receiving anthracyclines (HR, 1.78 [95% CI, 0.83-3.81]; P = .14). Higher cumulative incidence for patients treated with anthracyclines vs comparator cohort was observed at 1 year (1.81% vs 0.09%), 5 years (2.91% vs 0.79%), 10 years (5.36% vs 1.74%), 15 years (7.42% vs 3.18%), and 20 years (10.75% vs 4.98%) (P < .001). There were no significant differences in risk of CHF for patients receiving anthracycline at a dose of less than 180 mg/m2 compared with those at a dose of 180 to 250 mg/m2 (HR, 0.54 [95% CI, 0.19-1.51]) or at a dose of more than 250 mg/m2 (HR, 1.23 [95% CI, 0.52-2.91]). At diagnosis, age was an independent risk factor associated with CHF (HR per 10 years, 2.77 [95% CI, 1.99-3.86]; P < .001).Conclusions and RelevanceIn this retrospective population-based case-control study, anthracyclines were associated with an increased risk of CHF early during follow-up, and the increased risk persisted over time. The cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracyclines at 15 years was more than 2-fold that of the control group.

Heart Failure in Patients With Cancer Treated With Anthracyclines—Revisiting the Foundation of Cardio-Oncology

“…Interestingly, there was also no significant difference in risk based on the cumulative dose of anthracycline. While several other studies evaluating the incidence of CHF in patients with cancer exposed to anthracyclines have published similar results, the study by Larsen et al is unique and distinctly adds to our understanding of the epidemiology of anthracycline-associated CHF, given the long-term follow-up and the inclusion of both patients with breast cancer and lymphoma. Moreover, Larsen et al define CHF using the modified Framingham criteria and performed manual record review to confirm the CHF diagnosis, which contributes to the reliability of the conclusions.…”

“…Larsen et al 1 found no association between anthracycline dose and CHF diagnosis, although previous studies have suggested left ventricular (LV) dysfunction is associated with higher cumulative anthracycline exposure. 5 It is important to note that there was no imaging assessment of LV function in the study by Larsen et al 1 Moreover, the use of traditional cardioprotective medications, including β-blockers, statins, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers, was not associated with a reduction in CHF. CHF symptoms can occur in the setting of both a normal and reduced LV ejection fraction, and the Rochester Epidemiology Project population represents a combination of both disease phenotypes.…”

“…Further surveillance should be considered if the cumulative dose is 250 mg/m 2 or greater of doxorubicin or equivalent (class IIa recommendation). In the study by Larsen and colleagues, 1 CHF was adjudicated using the modified Framingham criteria, which relies predominantly on symptoms and physical examination findings, as opposed to diagnostic testing.…”

“…Anthracyclines are a class of cancer therapeutics used to treat a variety of solid and hematologic malignant neoplasms and are associated with the development of CTRCD and CHF, particularly in a dose-dependent fashion; however, there remains significant uncertainty regarding its short- and long-term incidence. The study by Larsen and colleagues used a large population-based cohort from Olmsted County, Minnesota, as part of the Rochester Epidemiology Project, to better assess the cumulative incidence of CHF in patients with cancer, specifically breast cancer or lymphoma (predominantly non-Hodgkin). Compared with participants without cancer, those who had been treated for cancer had a higher risk of CHF even after adjusting for baseline characteristics, including age, sex, diabetes, hypertension, coronary artery disease, hyperlipidemia, obesity, and tobacco use (HR, 3.25; [95% CI, 2.11-5.00], P < .001), which persisted regardless of cancer type; however, this increased risk was primarily associated with anthracycline exposure.…”

Error in Affiliations

“…In the Original Investigation titled “Association of Anthracycline With Heart Failure in Patients Treated for Breast Cancer or Lymphoma, 1985-2010,” 1 published February 3, 2023, there was an error in Dr Goetz’s affiliation, which should have been Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota. This article has been corrected.…”