Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial

Abstract

Background: Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown.

Methods: We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311.

Findings: Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5-67·2]; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% [95% CI 20·6-57·8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure.

Interpretation: Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely.

Funding: British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust.

Figure 1

Flowchart of TRED-HF study design ACE=angiotensin converting enzyme. ARB=angiotensin receptor blocker. CMR=cardiovascular magnetic resonance. CPET=cardiopulmonary exercise test. KCCQ=Kansas City Cardiomyopathy Questionnaire. MRA=mineralocorticoid receptor antagonist. NT-pro-BNP=N-terminal pro-B-type natriuretic peptide. SAQ=symptom assessment questionnaire.

Figure 2

Trial profile One patient in the treatment withdrawal group who withdrew from the study was excluded from secondary analyses (table 3, table 4) because of absence of follow-up data. Therefore, 50 patients completed follow-up in the randomised phase. 49 patients completed follow-up after starting treatment withdrawal in the randomised and crossover phases (one patient did not cross over from the continued treatment group to begin treatment withdrawal). AF=atrial fibrillation. CPET=cardiopulmonary exercise test. DCM=dilated cardiomyopathy. ITT=intention-to-treat. LVEDVi=left ventricular end-diastolic volume indexed to body surface area. LVEF=left ventricular ejection fraction. NSVT=non-sustained ventricular tachycardia. NT-pro-BNP=N-terminal pro-B-type natriuretic peptide. PICs=participant identification centres.

Figure 3

Kaplan-Meier curve of time to primary endpoint in randomised phase, according to treatment group One patient dropped out at 7 days.

Figure 4

Venn diagram showing components contributing to primary endpoint definition Numbers of patients with each combination of endpoints included. LVEDVi=left ventricular end-diastolic volume indexed to body surface area. LVEF=left ventricular ejection fraction. NT-pro-BNP=N-terminal pro-B-type natriuretic peptide. *Refers to one patient who developed peripheral oedema.

Figure 5

Change in secondary endpoint variables between baseline and follow-up in the randomised phase of the study, based on treatment group Each circle represents one patient. bpm=beats per min. DCM=dilated cardiomyopathy. LVEDVi=left ventricular end-diastolic volume indexed to body surface area. LVEF=left ventricular ejection fraction. NT-pro-BNP=N-terminal pro-B-type natriuretic peptide.