Anthracycline users with breast cancer or lymphoma had a higher risk of congestive heart failure (CHF) persisting during long-term follow-up in a population-based case-control study, found researchers.
And the cumulative incidence of new-onset CHF was higher for cancer patients treated with anthracyclines compared with healthy controls at every time point, they found.
These were:
• one year: 1.81% vs 0.09%
• five years: 2.91% vs 0.79%
• 10 years: 5.36% vs 1.74%
• 15 years: 7.42% vs 3.18%
• 20 years: 10.75% vs 4.98%
Importantly, cancer patients receiving anthracyclines were at elevated risk of CHF compared with controls (adjusted HR 3.25, 95% CI 2.11-5.00), whereas patients with cancer not receiving anthracyclines did not have such risk reach significance (HR 1.78, 95% CI 0.83-3.81), said Dr Hector Villarraga of Mayo Clinic in Minnesota, and colleagues.
“Our long-term follow-up data suggest that some cancer patients treated with anthracyclines remained at increased risk of CHF decades after their cancer diagnosis,” wrote the authors in JAMA Network Open.
Therefore, they should have “regular clinical follow-up to screen for and modify coexisting cardiovascular risk factors (e.g. diabetes, hypertension, hyperlipidaemia, body mass index, tobacco exposure and sedentary lifestyle) and assess for early signs and symptoms of CHF”, they recommended.
Medpage Today reports that anthracycline therapy includes doxorubicin (Adriamycin) and epirubicin (Ellence) and has established links to cardiovascular adverse events like left ventricular (LV) dysfunction, heart failure, myocarditis, pericarditis, atrial fibrillation, ventricular tachycardia and ventricular fibrillation.
Villarraga’s group reported that the exact anthracycline dose – including the low range <180 mg/m2 or the high range >250 mg/m2 – did not appear to significantly change the user’s risk of CHF.
Besides anthracycline use, age was the other independent predictor of CHF identified (HR 2.77 per 10 years, 95% CI 1.99-3.86).
Interestingly, radiation therapy to the chest and mediastinum had a protective, inverse relationship with CHF (adjusted HR 0.32, 95% CI 0.13-0.74).
There was no difference in the risk of developing CHF among participants treated before versus after the year 2000 or users of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), or statins.
“It is clear from this study … that there is an increased risk of both short- and long-term clinical CHF after anthracycline exposure in patients with breast cancer or lymphoma regardless of cumulative dose.
“These data continue to move forward the field of cardio-oncology, but they also emphasise the need for improved understanding of the pathophysiology of this disease process to facilitate better use of surveillance and treatment strategies,” said Dr Michael Fradley, medical director of the Cardio-Oncology Programme at the University of Pennsylvania, in an accompanying editorial.
American guidelines give an IIa recommendation for ARB, ACE inhibitor, and beta blocker treatment for asymptomatic patients with cancer therapy-related cardiomyopathy. Initiation of these drugs for the primary prevention of drug-induced cardiomyopathy gets a more tepid IIb recommendation.
Meanwhile, evaluation of cardiac function has IIa endorsements for people with cardiovascular risk factors or known cardiac disease being considered for or already receiving potentially cardiotoxic anticancer therapies.
For their retrospective study, Villarraga and colleagues relied on the Rochester Epidemiology Project, which makes integrated health records from two healthcare systems in Olmsted County, Minnesota, available for researchers.
Study participants were 812 residents of Olmsted County diagnosed with breast cancer or lymphoma from January 1985 to December 2010, who were matched 1:1.5 with healthy controls from the same community.
The overall cohort averaged 52.6 years of age, with 78% being women and 93% classified as white.
The investigators had their analyses adjusted for between-group differences in baseline age, sex, diabetes, hypertension, hyperlipidaemia, coronary artery disease, obesity and smoking history.
Follow-up comprised a combination of electronic data extraction and manual record review, and reached a median 8.6 years in the case group versus 12.5 years in the control group.
Overall, patients with cancer, anthracycline users or not, had higher risks of CHF compared with the control cohort (adjusted HR 2.86, 95% CI 1.90-4.32).
Fradley highlighted the lack of imaging assessment of LV function in the study. “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,” he noted.
“This highlights our deficiency in understanding the pathophysiology of anthracycline-associated cardiac dysfunction; its potential impact on the myocardium is not only limited to a decline in contractility. It is essential we better understand the mechanism of anthracycline-associated cardiac dysfunction, for better surveillance and management recommendations.”
The study authors also acknowledged the lack of racial and ethnic diversity in the study population, which might limit its generalisability.
“Further prospective studies are required to balance the potential benefits of anthracycline vs the cardiovascular risks and to develop surveillance models and susceptibility indexes,” they added.
A preliminary version of the project had been presented at the American College of Cardiology annual meeting in 2018.
Study details
Association of Anthracycline With Heart Failure in Patients Treated for Breast Cancer or Lymphoma, 1985-2010
Carolyn Larsen, Mariana Garcia Arango, Harika Dasari, et al.
Published in JAMA Network Open on 3 February 2023
Key Points
Question What is the long-term incidence of heart failure (HF) in patients with cancer treated with anthracyclines in a population-based sample?
Findings In this case-control study among 2196 individuals, including 812 participants with cancer and 1384 control participants, the cumulative incidence of HF in participants with cancer treated with anthracycline was 7.4% over 15 years, more than two times higher than in matched controls, and was not significant for a subgroup of participants with cancer not treated with anthracycline compared with controls. The shift in risk was observed during the first year of follow-up and persisted over the follow-up period.
Meaning These findings suggest that anthracycline treatment in patients with cancer was associated with more than twice the risk of HF compared with controls.
Abstract
Importance
Anthracyclines 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.
Objective
To 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 Participants
This 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.
Exposures
Cancer treatment and CHF risk factors.
Main Outcomes and Measures
The 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, hyperlipidaemia, coronary artery disease, obesity, and smoking history.
Results
A 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 Relevance
In 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.
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