The Evidence Is Building for ACE Inhibitors in Anthracycline-Associated Cardiotoxicity

July 13, 2021 by Elisa Becze BA, ELS, Editor

Cardiac toxicities are associated with many types of cancer therapies, with both length of and time since treatment increasing a patient’s risk for the adverse event. Anthracycline chemotherapies are among the oldest agents still used for a variety of cancer diagnoses, and as cancer survivorship continues to grow, more patients are presenting with late-onset cardiac complications.

In an article (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline) in the June 2021 issue of the Clinical Journal of Oncology Nursing (CJON), Kobza outlined the evidence for angiotensin-converting enzyme (ACE) inhibitors and other cardioprotective agents in slowing the progression of cardiotoxicity from anthracyclines, including nursing considerations and implications for practice.

Anthracycline’s Cardiac Complications

“Anthracycline cardiac toxicities present in a wide range of clinical conditions, including cardiac ischemia, arrhythmias, pericarditis, and, most commonly, left ventricular dysfunction (LVD),” Kobza explained (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline). LVD is a greater than 10% reduction in left ventricular ejection fraction (LVEF): 50%–70% is normal, 41%–49% is considered borderline, and 40% or lower may indicate heart failure.

Patients may present with asymptomatic or symptomatic LVD at nearly any point after starting treatment:

Acute: within 150 days
Early: 151–365 days
Late: more than one year later

Early LVD is most commonly irreversible, leading to cardiomyopathy and congestive heart failure, Kobza said (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline). Researchers initially thought the incidence was dose dependent, but subsequent studies showed it occurred at both low and high anthracycline doses.

Because LVEF decline is often asymptomatic and undetectable on echocardiogram, researchers concluded that it occurs late in the progression of LVD. Whether asymptomatic or symptomatic, onset of heart failure requires interruption or discontinuation of therapy, Kobza reported (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline).

Managing Anthracycline-Induced LVEF

The American Society for Clinical Oncology (https://www.asco.org/) (ASCO), European Society for Medical Oncology (https://www.esmo.org/) (ESMO), and National Comprehensive Cancer Network (https://www.nccn.org/) each includes recommendations for care in its clinical practice guidelines. Most of the recommendations revolve around screening and prevention (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline) to avoid LVEF altogether, Kobza said, but ASCO’s and ESMO’s guidelines include considerations for cardioprotective agents as well.

Based on data that demonstrate ACE inhibitors can slow the progression of LVD and prevent remodeling of smooth muscle and cardiac myocytes as well as recommendations for their use as first-line therapy for asymptomatic LVD in nononcologic adult patients, researchers have suggested using ACE inhibitor prophylaxis for anthracycline-induced LVD as well. However, to date no large-scale clinical trials (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline) have studied their use in adults with oncology diagnoses, Kobza said.

Clinical Practice Guidelines for Anthracycline-Induced Cardiotoxicity

American Society of Clinical Oncology

Identify risk factors pretreatment.
Monitor for cardiotoxicity using LVEF.
Preferred cardiac imaging: echocardiography
Timing of cardiac monitoring in asymptomatic patients: determined by provider based on clinical judgment and patient circumstances
Recommend dexrazoxane, continuous infusion, or liposomal formulation of anthracycline.
Recommend referral to cardiologist or cardio-oncologist.

European Society for Medical Oncology

Identify risk factors pretreatment.
Monitor for cardiotoxicity using LVEF.
Monitor subclinical cardiotoxicity using cardiac biomarkers (troponin I, B-type natriuretic peptide).
Preferred cardiac imaging: echocardiography
Timing of cardiac monitoring in asymptomatic patients receiving adjuvant anthracycline or HER2 agent: every 3 months during therapy, then 12 and 18 months after initiation of therapy
Recommend use of beta blockers or ACE inhibitors.
Recommend referral to cardiologist or cardio-oncologist.

National Comprehensive Cancer Network

Identify risk factors pretreatment.
Monitor for cardiotoxicity using LVEF.
Preferred cardiac imaging: echocardiography
Timing of cardiac monitoring in asymptomatic patients: consider in high-risk patients within one year of last anthracycline dose.
Recommend referral to cardiologist or cardio-oncologist.

Note. From Kobza (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline).

What the Evidence Says

After conducting a literature review of the currently available evidence for ACE inhibitors for anthracycline-induced cardiotoxicity, Kobza reported the results (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline) from five articles:

A prospective, parallel-group, randomized controlled study to investigate doxorubicin-induced LVD concluded that ACE inhibitors and beta blockers did not significantly prevent a decline in LVEF.
A prospective, observational, single-center study to assess whether treatment with perindopril would prevent epirubicin-induced LVD concluded that the treatment preserved LVEF in the intervention group.
A randomized, single-blind, placebo-controlled, single-center study to assess the effectiveness of enalapril in preventing doxorubicin-induced LVD found that LVEF was significantly lower in patients who did not receive the intervention but recorded no significant change in LVEF for those who did.
A meta-analysis of 14 studies, 3 of which involved ACE inhibitors alone (all used enalapril), examining the effect of cardioprotective agents on anthracycline-induced LVD concluded that enalapril prevented a drop in LVEF from baseline when compared to controls.
Another meta-analysis of 22 studies evaluating the effects of several cardioprotective agents on anthracycline-induced LVD, 3 of which examined ACE inhibitors, found that the agents offered greater LVEF preservation compared to placebo or controls.

Kobza also reported (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline) on the strengths and limitations for all five studies. Refer to the full CJON article (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline) for the complete overview.

Implications for Nursing Care and Practice

Clinical nurses should advocate (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline) for screening and early monitoring in patients with risk factors for or signs and symptoms of heart failure, and advanced practice providers should closely monitor patients receiving cardiotoxic therapies, Kobza said. Risk factors include tobacco use, obesity, diabetes, hypertension, and hyperlipidemia. Clinical signs and symptoms include tachycardia, dyspnea (on exertion or at rest), pulmonary edema, peripheral edema, orthopnea, chest pain, palpitations, elevated jugular venous pressure, or S3 gallop.

Patient education should involve risk-reduction counseling on heart-healthy diets, physical activity ideas, healthy weight resources, tobacco use or exposure, and medication adherence.

For more information about cardioprotection with ACE inhibitors for anthracycline-induced LVD and the opportunity to earn 0.75 nursing continuing professional development contact hours, free for ONS members, refer to Kobza’s full article (https://cjon.ons.org/cjon/25/3/cardiac-toxicity-using-angiotensin-converting-enzyme-inhibitors-prevent-anthracycline).

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