TRED-HF: Tread With Caution While Withdrawing Heart Failure Medication in Recovered Dilated Cardiomyopathy Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy: an open-label, pilot, randomised trial

The results of the TRED-HF trial published in The Lancet showed that withdrawal of heart failure medications among patients with dilated cardiomyopathy (DCM) who had recovered their LV function resulted in the relapse of HF. According to Halliday and his colleagues, until robust predictors of relapse are defined, treatment should continue indefinitely.

In this trial, Halliday et al. aimed to assess the safety and efficacy of withdrawal of heart failure medications among patients with dilated cardiomyopathy (DCM) who had recovered their left ventricular ejection fraction (LVEF). Prior to the trial, the safety of withdrawing treatment in this situation was unknown.

In this open-label, pilot, randomized trial, 51 eligible patients were randomized in a 1:1 ratio to either withdrawal of HF medications (n = 25) or continuation of medications (n = 26). After 6 months, patients in the medication continuation arm crossed over to medication discontinuation. The duration of follow-up was 6 months. 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.

The investigators reported that 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.

The primary outcome, relapse of HF, for drug discontinuation vs. continuation, was 44% vs. 0%, p = 0.0001. In the control (continuation) arm, following 6-month cross-over, relapse occurred in 36% of patients. All patients with relapse were asymptomatic, and 85% of relapsed patients still had an LVEF >50%. The results of this trial indicated that the withdrawal of HF medications among patients with DCM who had recovered their LV function resulted in the relapse of HF, and should probably be avoided unless necessary and until predictors of relapse can be better outlined. The investigators acknowledged certain limitations including small sample size, unblinded design, and single-center study.

In an accompanying editorial, Jane Wilcox and Clyde W Yancy from Northwestern University, Feinberg School of Medicine stated, “The results of TRED-HF are not definitive as this was a highly selected, open-label pilot study with small numbers of patients with dilated cardiomyopathy; all of these aspects were necessary to ensure safety and restrict exposure to an uncertain intervention. Further studies to identify ventricular recovery are warranted, but we should tread lightly. In addition to the clinical findings from this study—the effects of advanced age, higher NT-pro-BNP concentration, the need for a multidrug heart failure regimen, and reduced global radial strain—future explorations should include a broader profile of omics (eg, proteomics, genomics, and metabolomics) and rigorously standardised measures of cardiac mechanics. For those in whom recovery has occurred, avoidance of morbidity and costs associated with lifelong medical treatment can and should matter. For those in remission, identifying the minimal exposure to evidence-based medical treatment required for stability should be a similar pursuit.” Speaking of the impact on clinical practice, they said that going forward, in response to a patient’s question: “Now that my heart failure has improved, am I able to stop my heart failure drugs?”, the answer should be, “No, not at this time.” In those patients fortunate enough to have an improvement in ventricular function and amelioration of the clinical syndrome of heart failure, we should continue effective treatments indefinitely.”