Biomarker-Guided Cardioprotection for Patients Treated With Anthracyclines: A Randomized Clinical Trial

Abstract

Importance: There are gaps in the understanding of the clinical actionability of cardiovascular biomarkers for risk stratification during cardiotoxic chemotherapy.

Objectives: To gain insights into an N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided approach for cardioprotection in patients with breast cancer or lymphoma treated with anthracyclines and quantify the feasibility, tolerability, and exploratory efficacy of an NT-proBNP-guided strategy compared with usual care.

Design, setting, and participants: The NT-proBNP guide, a multicenter, randomized (stratified 1:1 by cancer type) clinical trial, included 100 participants with breast cancer or lymphoma initiating anthracyclines from March 18, 2021, to October 20, 2023, who were followed up for 12 months.

Interventions: Study participants in the NT-proBNP-guided arm had biomarker concentrations measured prior to anthracycline initiation (baseline), at each cycle, and at 3, 6, 9, and 12 months. An elevated NT-proBNP concentration triggered the initiation or titration of neurohormonal therapy. Participants in the usual care arm received routine care without prospective monitoring of NT-proBNP concentrations.

Main outcomes and measures: The primary outcomes were feasibility and safety of the NT-proBNP-guided approach. Feasibility was defined by recruitment, retention, and medication compliance rates. Safety outcomes were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0, at each visit. Exploratory outcomes included differences in blinded, centrally quantified echocardiographic measures and NT-proBNP concentrations between the 2 arms. Analysis was performed on an intention-to-treat approach.

Results: Across 100 participants (mean [SD] age, 52.2 [14.4] years; 86 women [86.0%]), 74 (74.0%) had breast cancer and 26 (26.0%) had lymphoma. At 12 months, the retention rate was 92.7% (89 of 96). In the NT-proBNP-guided arm, 27 participants had NT-proBNP elevations, with a median time from baseline to first elevation of 14 days (IQR, 0-76 days), and a median time between the first NT-proBNP elevation and neurohormonal therapy prescription of 1 day (IQR, 0.5-9 days). There were no significant differences in targeted adverse events between the NT-proBNP-guided (23 events) and usual care (16 events) arms (P = .13). At 3 months, left ventricular ejection fraction (LVEF) was modestly higher in the NT-proBNP-guided arm compared with usual care (mean difference, 2.0% [95% CI, 0.5%-3.5%]; P = .007). NT-proBNP concentrations increased in both arms over the study duration, but elevations were slightly attenuated in the NT-proBNP-guided arm.

Conclusions and relevance: This randomized clinical trial of an NT-proBNP-guided approach to neurohormonal therapy in patients with cancer treated with anthracyclines demonstrates the feasibility, safety, and potential modest, early improvement in LVEF of a biomarker-guided approach. These findings provide support for further study of an NT-proBNP-guided approach to cardioprotection for patients undergoing cancer treatment.

Trial registration: ClinicalTrials.gov Identifier: NCT04737265.

Figure 1.. Flow Diagram

Flow diagram of the N-terminal pro–B-type natriuretic peptide (NT-proBNP)-guide trial. AE indicates adverse event; PRO-CTCAE, patient-reported outcomes version of the Common Terminology Criteria for Adverse Events.

Figure 2.. N-Terminal Pro–B-Type Natriuretic Peptide (NT-proBNP) Elevations and Neurohormonal Therapy Use

NT-proBNP elevations, left ventricular ejection fraction, and neurohormonal therapy use are noted according to each participant and study visit in the NT-proBNP–guided arm. “M” denotes current neurohormonal therapy use. Red rectangles denote NT-proBNP concentration above the upper limit of normal. Each row presents an individual participant. “C” denotes anthracycline infusion cycles. There were 11 participants with baseline elevations of NT-proBNP concentrations. In total, 27 participants experienced at least 1 NT-proBNP concentration elevation. Of these, 4 did not have any initiation or titration of medications at any time point. EF indicates ejection fraction; NA, not available.

Figure 3.. N-Terminal Pro–B-Type Natriuretic Peptide (NT-proBNP) Concentrations and Left Ventricular Ejection Fraction (LVEF) Trajectories By Treatment Arm

A, Trajectories of change in NT-proBNP concentrations in the NT-proBNP–guided arm and usual care arm. Error bars are estimated means with 95% CIs at 2 weeks and 3, 6, 9, and 12 months after baseline, obtained from generalized estimating equations. NT-proBNP was log₂ transformed, where each 1-unit increase indicates a doubling. B, Estimated mean changes in LVEF in the NT-proBNP–guided arm and usual care arm. Solid dots with error bars are estimated mean (95% CI) obtained from generalized estimating equations.