TRED-HF

From Wiki Journal Club
Jump to: navigation, search
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. 2018. ePub 2018-11-09:1-13.
PubMedFull text

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cardiomyopathy whose function recovers with treatment are at increased risk of relapse at 6 months if treatment is withdrawn.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. [1] [2] Compared to patients with persistently reduced EF patients with recovered EF have better outcomes. [3] 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represents temporary remission or complete recovery of cardiac muscle dysfunction where medical therapy could be safely withdrawn.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. [4]

The TRED HF study randomised 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.

The withdrawal protocol involved ceased low or reducing doses of medication with loop diuretics first, followed by mineralocorticoid receptor antagonists, beta blockers and finally ACE inhibitors and ARBs. The withdrawal group were contacted by phone every 2 weeks and clinic visits and BNP measurement every 4 weeks. Patients in both groups were followed up at 16 weeks and 6 months which included repeat cMRI to assess LVEF and LVEDV, BNP measurement and clinical review.

At the completion of the study 40% of patients in the withdrawal group had relapse requiring recommencement of HF medications. Similar results occurred in the control group who underwent withdrawal in the crossover phase. Most patients met multiple criteria for relapse though only one patient had clinical evidence of heart failure. 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.

This study suggest that patients with recovered dilated cardiomyopathy should not cease heart failure medications, and that doing so results in increased relapse. This is a common and important clinical question in this population who are typically younger and with less comorbidity, compared to patients with HFrEF secondary to ischaemia or hypertension who often have other indications for these medications.

Guidelines

No current American or European guidelines on this topic

Design

  • Multicenter,open-label, pilot, randomized trial with single arm crossover phase
  • N=51
    • Treatment withdrawal (n=25)
    • Continued treatment (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

  • Previous diagnosis of dilated cardiomyopathy with LVEF ≤40%
  • Absence of current symptoms of heart failure
  • Current treatment with a loop diuretic, beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or mineralocorticoid receptor antagonist
  • Current LVEF ≥50% and LVEDV indexed to body surface area within the normal range on cardiovascular magnetic resonance
  • Plasma NT-pro-BNP ≤250 ng/L

Exclusion Criteria

  • Uncontrolled hypertension defined by a clinic blood pressure >160/100 mmHg
  • Valvular disease of moderate or greater severity
  • 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: Median 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%
    • MRA 48%
    • Loop diuretic 12%
  • Clinical characteristics at enrolment: Heart rate 62 bpm, Blood pressure 123/72mm Hg, NT-pro-BNP 72ng/L
  • CMR variables at enrolment: LVEDVi 86ml/m2, LVEF 82%
  • CPET at enrolment: Peak VO2 29mL/kg per min, Exercise time 571 seconds

Interventions

  • Randomized to:
    • Medication withdrawal: supervised, step-wise reduction in pharmacological treatment over a maximum of 16 weeks, with review every 2 weeks and subsequent medication changes
      • Clinic visit and NT-pro-BNP measurement every 4 weeks; interim review via phone if patient remained asymptomatic
    • Medication continuation: continued pharmacological therapy
      • Clinical review and NT-pro-BNP measurement after 8 weeks
  • Withdrawal protocol
    • Loop diuretics were reduced first, followed by MRA, beta-blockers and then finally ACE inhibitor or ARB
    • If patients were taking ≤40mg of Frusemide, ≤50mg Spironolactone, or 25% or less of the maximum dose of ACE inhibitor, ARB or beta blocker they were ceased
    • if patients were taking larger doses they were reduced by 50% every 2 weeks
  • Follow up:
    • At 16 weeks, all patients underwent clinical review and measurement of NT-pro-BNP concentration
    • At 6 months, patients underwent CMR scan to evaluate LV volume and functions, NT-pro-BNP measurement, and CPET, and completion of KCCQ and SAQ symptom questionnaires
  • After the 6 month follow up visit patients in the Medication continuation group who had not met the primary endpoint underwent the same treatment withdrawal protocol as the Medication withdrawal group

Outcomes

Comparisons are treatment withdrawal group vs. control group

Primary Outcomes

Relapse of dilated cardiomyopathy
45.7% vs. 0% (P=0.0001)
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

Secondary Outcomes

Composite of cardiovascular mortality, major adverse cardiovascular events, and unplanned cardiovascular hospital admission
No events recored in either group
Sustained atrial or ventricular arrhythmias
1 event in the treatment withdrawal group
Change from baseline to follow up (LVEF)
LVEF: -10% vs. 0% (P=0.0001)
Change from baseline to follow up (LVEDVi)
5 ml/m2 vs. 1 ml/m2 (P=0.1361)
Change from baseline to follow up ( plasma NT-pro-BNP)
0.5 ng/L vs. 0.1 ng/L (P= 0.1069)
Change from baseline to follow up (KCCQ score)
-5.0 vs. 1.0 (P=0.0354)
Change from baseline to follow up (SAQ score)
0.2 vs -1.0 (P=0.1483)
Change from baseline to follow up (Exercise time)
-13 s vs. -1s (P=0.8344)
Change from baseline to follow up (Peak VO2)
-2 vs. 0 ml/kg per min (P=0.4020)

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 recommenced 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=0.0309)
  • prescription of MRA (P=0.0042)
  • prescription of more than two heart failure medications (P=0.0040)
  • increased NT-pro-BNP concentration (P=0.0161)
  • decreased peak radial strain (P=0.0177)

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

  • The study enrolled only recovered dilated cardiomyopathy cannot be generalised to other causes of recovered heart failure.
  • Patients and clinicians were not blinded to treatment allocation which may have favoured detection of heart failure in the withdrawal group, thought only 1 patient met the primary endpoint for clinical signs of heart failure
  • The study does not describe how many patients had ceased all, some or no medications or the compliance with medication withdrawal in each group.
  • The small size (N=51) lacks power to determine accurately which features may predict relapse of withdrawal of medications.

Funding

The trial received funding from the 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.

Further Reading

  1. Punnoose LR et al. Heart failure with recovered ejection fraction: a distinct clinical entity. J. Card. Fail. 2011. 17:527-32.
  2. Merlo M et al. Prevalence and prognostic significance of left ventricular reverse remodeling in dilated cardiomyopathy receiving tailored medical treatment. J. Am. Coll. Cardiol. 2011. 57:1468-76.
  3. Basuray A et al. Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes. Circulation 2014. 129:2380-7.
  4. Hopper I et al. Can medications be safely withdrawn in patients with stable chronic heart failure? systematic review and meta-analysis. J. Card. Fail. 2014. 20:522-32.