TRED-HF

Published

Halliday BP, et al. "Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial". The Lancet. 2019. 393(10166):61-73.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with dilated cardiomyopathy whose symptoms and cardiac function recover, does withdrawing medications increase the likelihood of relapsing dilated cardiomyopathy?

Bottom Line

Patients with dilated cardiomyopathy whose function recovers with treatment are at increased risk of relapse at 6 months if treatment is withdrawn.

Major Points

A significant proportion of patients with heart failure with reduced ejection fraction (HFrEF) have their symptoms resolve and ejection fraction recover with medical therapy. Compared to patients with persistently reduced EF patients with recovered EF have better outcomes. It is unclear whether this represents temporary remission or complete recovery of cardiac muscle dysfunction where medical therapy could be safely withdrawn. Evidence is lacking to guide the decision; a systematic review by Hopper et al featured 11 randomised trials and concluded that withdrawal of heart failure medications increased the risk of recurrence.

Published in 2019, TRED-HF pilot study randomized 51 patients with recovered dilated cardiomyopathy to withdrawal of medication or to continuation of medications. At the completion of the study a single arm crossover occurred where the control group who had not relapsed underwent the same medication withdrawal process. The primary outcome was relapse of heart failure, with a secondary outcome of composite MACE or unplanned hospital admission for heart failure. Most patients (80%) had idiopathic cardiomyopathy. At the completion of the 6 month randomization phase, 45.7% of patients in the treatment withdrawal group had a HF relapse event. There were none such events in the treatment continuation group. There were no deaths, major cardiovascular events or unplanned admissions for either group. After resuming heart failure medications all patients had no clinical evidence of HF or symptoms at follow up and 80% had recovered EF.

Though just a pilot study, the obvious difference in relapse between treatment withdrawal and continuation (45.7% vs. 0%) provides reasonable evidence against cessation of chronic heart failure medications among those with HFrEF and recovery of EF. This trial is somewhat limited by generalizability, given the large proportion of individuals with idiopathic or familial dilated cardiomyopathy. A large proportion of individuals with these types of cardiomyopathies likely have a genetic predisposition for HF. Whether individuals with other cardiomyopathies (e.g., alcoholic, ischemic) would fare as poorly with medication withdrawal is unknown.

Guidelines

As of June 2019, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter,open-label, pilot, randomized trial with single arm crossover phase
• N=51
  • Treatment withdrawal (n=25)
  • Treatment continuation (n=26)
• Setting: Recruitment from network of 7 UK hospitals, with assessment at a single center
• Enrollment: 2016-2017
• Mean follow-up: 6 months
• Analysis: Intention-to-treat
• Primary outcome: Relapse of dilated cardiomyopathy

Population

Inclusion Criteria

• Dilated cardiomyopathy with prior LVEF ≤40%
• No HF symptoms at present
• Current treatment with a loop diuretic, beta-blocker, ACE-i, ARB, or mineralocorticoid receptor antagonist
• LVEF ≥50% and LVEDV indexed to body surface area within the normal range on cardiac MRI
• Plasma NT-pro-BNP ≤250 ng/L

Exclusion Criteria

• Uncontrolled hypertension (BP >160/100 mmHg)
• Moderate or worse valve disease
• eGFR <30 mL/min/1.73m²
• Atrial, supraventricular, or ventricular arrhythmia requiring beta-blockade
• Pregnancy
• Angina
• Age <16 years

Baseline Characteristics

From treatment withdrawal group

• Demographics: Age 54 years, 54% female
• PMH: AF 32%, Hypertension 12%, Diabetes 0%, Smoker 0%
• Cause of DCM: Idiopathic 80%, familial 12%, environmental insult 8%, truncating variant TTN 28%
• LVEF at initial diagnosis: 28%
• Absolute improvement in LVEF: 29%
• Months since LVEF >50%: 28 (8 to 45)
• Medications at enrolment:
  • ACE-i or ARB: 100%
  • Beta-blocker: 84%
  • Mineralocorticoid antagonist: 48%
  • Loop diuretic: 12%
• Clinical characteristics at enrolment: HR 62 BPM, BP 123/72 mm Hg, NT proBNP 72 ng/L
• Cardiac MRI: LVEDVi 86ml/m², LVEF 62%
• Cardiopulmonary exercise test: Peak VO₂ 29mL/kg per min, Exercise time 571 seconds

Interventions

• Randomized to a group in an open-label fashion:
  • Treatment withdrawal: Supervised, stepwise reduction in pharmacological treatment over a maximum of 16 weeks, with review every 2 weeks and subsequent medication changes. Specific stepwise withdrawal is documented in Figure 1 on page 63 of the manuscript.
    • Clinic visit and NT-pro-BNP measurement every 4 weeks; interim review via phone if patient remained asymptomatic
  • Treatment continuation: Continued pharmacological therapy
    • Clinical review and NT-pro-BNP measurement after 8 weeks
• Follow up:
  • At 16 weeks, NT proBNP concentration
  • At 6 months, patients underwent cardiac MRI scan to evaluate LV volume and functions, NT proBNP measurement, and CPET, and completion of KCCQ and SAQ symptom questionnaires
• After the 6 month follow up visit patients crossed over, i.e., those in the treatment continuation group who had not met the primary endpoint underwent the same treatment withdrawal protocol as the treatment withdrawal group. The primary endpoint was calculated before the randomization phase.

Outcomes

Comparisons are treatment withdrawal vs. treatment continuation.

Primary Outcomes

Relapse of dilated cardiomyopathy in the randomization phase

Defined as reduction in LVEF >10% to less than 50%; increase in LVEDV >10% to higher than normal range; two-fold rise in baseline NT-pro-BNP and to more than 400 ng/L; or clinical evidence of heart failure

45.7% vs. 0% (P=0.0001)

Reason for meeting endpoint (n=20, each participant could have several of these events)

From clinical HF: N=1

From LVEF reduction: N=12

From LVEDV increase: N=11

From NT proBNP increase: N=9

Secondary Outcomes

Composite of cardiovascular mortality, major adverse cardiovascular events, and unplanned cardiovascular hospital admission

No events recorded in either group

Sustained atrial or ventricular arrhythmias

1 event in the treatment withdrawal group

Change from baseline to follow-up

LVEF: -10% vs. 0% (P=0.0001)

LVEDVi: 5 ml/m² vs. 1 ml/m² (P=0.14)

NT proBNP: 0.5 ng/L vs. 0.1 ng/L (P=0.11)

KCCQ score: -5.0 vs. 1.0 (P=0.04)

SAQ score: 0.2 vs -1.0 (P=0.15)

Exercise time: -13s vs. -1s (P=0.83)

Peak VO₂: -2 vs. 0 ml/kg/min (P=0.40)

Subgroup Analysis

Relapse of dilated cardiomyopathy in the single arm crossover group

36% (95% CI 20.6-57.8)

All patients who met the primary outcome commenced treatment

No patients had symptoms at next follow up

85% LVEF improve to greater than 50%

Prespecified Analysis

Predictors of primary endpoint

Advancing age (P=0.03)

No use of a mineralocorticoid receptor antagonist (P=0.004)

Prescription of >2 HF medications (P=0.004)

Increased NT proBNP concentration (P=0.02)

Decreased peak radial strain (P=0.02)

Adverse Events

3 events recorded in the withdrawal group: hospital admission for urosepsis, non cardiac chest pain and an elective admission for a pre existing condition

Criticisms

• Most (92%) had idiopathic or familial dilated cardiomyopathy. Unclear if generalizable to other types of recovered heart failure (e.g., ischemic).
• Open label.

Funding

British Heart Foundation, and additional support from the Alexander Jansons Foundation, the Cardiovascular Research Centre and the National Institute for Health Research Biomedical Research Unit at Royal Brompton Hospital and Imperial College London, the Imperial College Biomedical Research Centre, the Wellcome Trust and Rosetrees Trust.