HER-SAFE study design: an open-label, randomised controlled trial to investigate the safety of withdrawal of pharmacological treatment for recovered HER2-targeted therapy-related cardiac dysfunction

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Recovered HER2-targeted therapy-related cardiac dysfunction in breast cancer survivors (n=90). Intervention: Phased withdrawal of pharmacological heart failure treatments (ACE inhibitor/ARB and/or beta-blocker) vs. Continuation of current pharmacological heart failure treatments (ACE inhibitor/ARB and/or beta-blocker). Primary outcome: Incidence of recurrent cancer therapy-related cardiac dysfunction (CTRCD) or clinical heart failure over 12 months.

Benjamin Dowsing; Hakim‐Moulay Dehbi; Robin Chung; Joanna Pedra; Orla Worn; Jessica Artico; Peter Schmid; Rebecca Roylance; Peter Kellman; James Moon; Tom Crake; Mark Westwood; Arjun K. Ghosh; María Sol Andrés; Muhummad Sohaib Nazir; Alexander R. Lyon; Daniel Chen; Charlotte Manisty

doi:10.1136/bmjopen-2024-091917

February 1, 2025BMJ OpenOpen Access

HER-SAFE study design: an open-label, randomised controlled trial to investigate the safety of withdrawal of pharmacological treatment for recovered HER2-targeted therapy-related cardiac dysfunction

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Key result

Trial tests whether withdrawing heart failure therapy is non-inferior to continuation in recovered HER2 CTRCD.

n=90

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Why the study?

Whether heart failure therapy must be continued in patients with recovered HER2-targeted therapy-related cardiac dysfunction after completing cancer treatment is unclear.

Is phased withdrawal of pharmacological heart failure therapy non-inferior to treatment continuation with respect to the incidence of recurrent cardiac dysfunction or clinical heart failure over 12 months in non-high cardiovascular risk breast cancer survivors with recovered HER2-targeted therapy-related cardiac dysfunction?

Key Points

To determine whether heart failure therapy can be safely withdrawn in non-high cardiovascular risk breast cancer survivors who have recovered from HER2-targeted therapy-related cardiac dysfunction.
Multicenter, open-label randomized controlled trial (NCT05880160) planning to recruit 90 non-high cardiovascular risk breast cancer survivors with recovered HER2 cardiac dysfunction.
Participants are randomized to withdrawal versus continuation of heart failure therapy and followed for 12 months.
Assessments include serial cardiovascular magnetic resonance with automated artificial intelligence analysis at baseline, 6, and 12 months, biomarker panels across six time points, and quality-of-life questionnaires.
Protocol design paper outlining the primary non-inferiority endpoint: the 12-month incidence of guideline-defined cardiac dysfunction or clinical heart failure.
Secondary endpoints include changes in cardiac blood biomarkers, CMR-derived strain, myocardial tissue mapping, and medication disutility scores.
Study enrolment began in 2023 with more than 71 participants enrolled at manuscript preparation; full trial completion is expected following recruitment closure in March 2025.

Study Design

Type

RCT (n=90)

Blinding

Open-label

Randomization

Minimisation using a biased coin probability method (70%) and marginal balance distance method

Multicenter

Yes

Structured PICO

Is phased withdrawal of pharmacological heart failure therapy non-inferior to treatment continuation with respect to the incidence of recurrent cardiac dysfunction or clinical heart failure over 12 months in non-high cardiovascular risk breast cancer survivors with recovered HER2-targeted therapy-related cardiac dysfunction?

P

Population

Planned enrolment of 90 adult non-high CV risk breast cancer survivors in the UK with recovered HER2-targeted therapy-related cardiac dysfunction (LVEF >50% for 6 months, NT-proBNP <125 ng/L) on ongoing heart failure therapy, followed for 12 months.

I

Intervention

Phased withdrawal of pharmacological heart failure treatments (ACE inhibitors, angiotensin receptor blockers, and/or beta-blockers) according to a prespecified algorithm: drug doses reduced by 50% in a stepwise manner every 2 weeks over a maximum of 16 weeks until taking 25% or less of the maximum recommended dose, at which point the medication is stopped before moving to the next medication.

C

Comparator

Continuation of current pharmacological heart failure treatments (ACE inhibitors, angiotensin receptor blockers, and/or beta-blockers).

O

Outcome

Incidence of recurrent cancer therapy-related cardiac dysfunction (CTRCD) or clinical heart failure over 12 months following randomisation, defined by the ICOS 2021 consensus statement as at least one of: (1) asymptomatic LVEF reduction by ≥10 percentage points to an LVEF <50%; (2) asymptomatic LVEF reduction by ≥5 percentage points to an LVEF <50% plus new relative decline in GLS by >15% from baseline and/or new rise in cardiac biomarkers (>2-fold increase in NT-proBNP to >400 ng/L, or high-sensitivity troponin >99th percentile); or (3) clinical heart failure with at least one of fall in LVEF ≥5%, increase in cardiac biomarkers, relative fall >15% in GLS, or new arrhythmia (excluding ectopy), assessed using central Core Lab CMR with blinded analysts.composite

This study protocol outlines the first multicentre randomised controlled trial to evaluate whether heart failure medications can be safely withdrawn in non-high-risk breast cancer survivors with recovered HER2-targeted therapy-related cardiac dysfunction.

Limitations

Unblinded (open-label) study design.
Cohort restricted to non-high cardiovascular risk patients, so results will not be generalisable to higher risk populations.
Planned as a pilot study of early outcomes over 12 months; not powered to address changes in secondary outcomes.
Unblinded study design
Cohort restricted to non-high cardiovascular risk patients, limiting generalisability to higher risk populations
Planned as a pilot study of early outcomes and not powered to address changes in secondary outcomes

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Implication

First RCT to test phased HF therapy withdrawal in recovered HER2 CTRCD; leaves open whether noninferior to continuation over 12 months.

Abstract

INTRODUCTION: A quarter of breast cancers show human epidermal growth factor-2 (HER2) overexpression, where targeted therapy dramatically improves survival. However, cancer therapy-related cardiac dysfunction (CTRCD) occurs in up to 15% of patients. With the interruption of HER2 therapy, if necessary, and the initiation of heart failure therapy (HFT), HER2 CTRCD recovers in over 80% of cases. The need to continue HFT in 'recovered' HER2 CTRCD following completion of HER2 therapy is unclear and there are potential significant impacts on patient's quality of life (QoL). The Randomised Controlled Trial for the Safety of Withdrawal of Pharmacological Treatment for Recovered HER2 Targeted Therapy Related Cardiac Dysfunction (HER-SAFE) aims to evaluate whether HFT can be safely withdrawn in non-high cardiovascular (CV) risk patients with 'recovered' HER2 CTRCD. METHODS AND ANALYSIS: This is a multicentre, open-label randomised controlled trial investigating whether withdrawal of HFT is non-inferior to continuation in non-high CV risk, breast cancer survivors with recovered HER2 CTRCD after cancer treatment completion. The primary endpoint is the incidence of guideline-defined cardiac dysfunction or clinical heart failure. Secondary endpoints include changes in cardiac blood biomarkers, cardiovascular magnetic resonance (CMR)-derived strain and tissue mapping and heart failure symptom questionnaires. The study will recruit 90 participants who will undergo serial clinical assessment over 12 months with advanced cardiovascular imaging (CMR scans with automated analysis at baseline, 6 and 12 months), cardiac biomarker measurement (six time points over 12 months), plus complete heart failure QoL and medication disutility questionnaires. This is the first multicentre study to address this significant clinical issue. ETHICS AND DISSEMINATION: This study was approved by the research ethics committee (London-London Bridge, 23/LO/0152). The results will be disseminated in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT05880160.

Discussion

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Cite This Study

Dowsing et al. (2025) conducted an RCT in Recovered HER2-targeted therapy-related cardiac dysfunction in breast cancer survivors (n=90). Phased withdrawal of pharmacological heart failure treatments (ACE inhibitor/ARB and/or beta-blocker) vs. Continuation of current pharmacological heart failure treatments (ACE inhibitor/ARB and/or beta-blocker) was evaluated on Incidence of recurrent cancer therapy-related cardiac dysfunction (CTRCD) or clinical heart failure over 12 months. Phased withdrawal of heart failure therapy is being evaluated for non-inferiority versus continuation over 12 months in 90 breast cancer survivors with recovered HER2 CTRCD.

synapsesocial.com/papers/6a86e045cbc6304817bef15f https://doi.org/10.1136/bmjopen-2024-091917

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HER-SAFE study design: an open-label, randomised controlled trial to investigate the safety of withdrawal of pharmacological treatment for recovered HER2-targeted therapy-related cardiac dysfunction

Figures

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

HER-SAFE study design: an open-label, randomised controlled trial to investigate the safety of withdrawal of pharmacological treatment for recovered HER2-targeted therapy-related cardiac dysfunction

Figures

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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