Heart Failure Risk Lingers Long After Chemotherapy, Regardless of Dose

Anthracycline users with breast cancer or lymphoma had an upfront risk of congestive heart failure (CHF) that persisted during long-term follow-up in a population-based case-control study.

The cumulative incidence of new-onset CHF was significantly higher for cancer patients treated with anthracyclines compared with healthy controls at every time point — namely:

• 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%

• 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), reported Hector Villarraga, MD, of Mayo Clinic in Rochester, Minnesota, and colleagues.

“Our long-term follow-up data suggest that some patients with cancer treated with anthracyclines remained at increased risk of CHF decades after their cancer diagnosis. Therefore, these individuals are expected to require regular clinical follow-up to screen for and modify coexisting cardiovascular risk factors (e.g., diabetes, hypertension, hyperlipidemia, body mass index, tobacco exposure, and sedentary lifestyle) and assess for early signs and symptoms of CHF,” the authors wrote in JAMA Network Open.

Anthracycline therapy includes doxorubicin (Adriamycin) and epirubicin (Ellence) and has established links to cardiovascular adverse events such as 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 emphasize the need for improved understanding of the pathophysiology of this disease process to facilitate better use of surveillance and treatment strategies,” commented Michael Fradley, MD, medical director of the Cardio-Oncology Program at the University of Pennsylvania in Philadelphia, in an accompanying editorial.

American guidelines give a 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 through 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, hyperlipidemia, 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 that we better understand the mechanism of anthracycline-associated cardiac dysfunction to offer better surveillance and management recommendations,” the editorialist wrote.

The study authors also acknowledged the lack of racial and ethnic diversity in the study population, which may limit the study’s generalizability.

“Further prospective studies are required to balance the potential benefits of anthracycline vs the cardiovascular risks and to develop surveillance models and susceptibility indexes,” the team added.

A preliminary version of the project had been presented at the American College of Cardiology annual meeting in 2018.