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

Abstract

SummaryBackgroundPatients 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.MethodsWe 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 After 6 months, patients in the continued treatment group had treatment withdrawn by the same method.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.FindingsBetween 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.InterpretationMany patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely.FundingBritish Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust.

Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19

“…61 In the TRED-HF trial, among asymptomatic patients with heart failure with recovered left ventricular ejection fraction, the phased withdrawal of medical therapy (including RAAS inhibitors) resulted in rapid relapse of dilated cardiomyopathy. 62 In addition, RAAS inhibitors are a cornerstone of therapy after myocardial infarction: maintenance of therapy in the days to weeks after the index event has been shown to reduce early mortality. 63 Among patients with unstable clinical status, myocardial injury associated with Covid-19 may pose even higher early risks after withdrawal of RAAS inhibitors.…”

Indications for β‐Blocker Prescriptions in Heart Failure with Preserved Ejection Fraction

“…We included only repeated hospitalizations that occurred beyond 90 days of an eligible hospitalization since repeated hospitalizations in close proximity of another hospitalization are likely to occur at the same hospital (with care from the same clinicians). We excluded hospitalizations for individuals with a history of LVEF of less than 40% (n = 10), for whom neurohormonal antagonists, including BBs, are beneficial …”

“…We excluded hospitalizations for individuals with a history of LVEF of less than 40% (n = 10), for whom neurohormonal antagonists, including BBs, are beneficial. 16 This study included data from three sources-REGARDS baseline assessment, REGARDS-Myocardial Infarction (MI) ancillary study adjudication database, and hospitalization-based medical records. Sociodemographics and geriatric conditions (functional limitation, cognitive impairment, hypoalbuminemia, and history of falls) came from the REGARDS baseline assessment.…”

COVID and the Renin-Angiotensin System: Are Hypertension or Its Treatments Deleterious?

“…It is not clear whether continuation or discontinuation of ARB or ACEi is a good option in COVID-19 infection, as there is a lack of clinical data to support an increased risk of contracting a severe form of COVID-19. In addition, we do not even know whether renin angiotensin system inhibitor therapy is beneficial or harmful for virally mediated lesions, and switching to other drugs may worsen the patient's condition, especially for heart failure patients with reduced ejection fraction (42). Clinical trials are ongoing to analyze the beneficial effect of LOSARTAN in COVID-19 (NCT04311177 and NCT04312009), and a trial will start soon to analyze the consequences of discontinuation or continuation of ACEi/ARB (NCT04338009).…”