TRED Lightly: Should Guideline-Directed Medical Therapy be Continued Indefinitely in Everyone?

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Author: Brent N. Reed, PharmD, BCCP, FCCP

Clinicians are occasionally faced with the question as to whether medications indicated as guideline-directed medical therapy (GDMT) can be withdrawn in patients with heart failure with reduced ejection fraction (HFrEF) who experience a recovery in left ventricular ejection fraction (LVEF). Although some improvement in LVEF occurs in about half of patients, full recovery has been observed in up to 10% of patients with heterogeneous etiologies of HFrEF.^1,2 The dilemma as to whether to continue GDMT can be especially challenging if the ongoing benefits of therapy are unclear but continuing it is costly or has a detrimental impact on quality of life.

Attempts to characterize patients with heart failure with recovered ejection fraction (HFrecEF) suggest that they tend to be younger and less likely to have ischemic disease or other common comorbidities (e.g., chronic kidney disease).^1,3 Additionally, patients with potentially reversible etiologies of heart failure (HF), such as peripartum cardiomyopathy, appear to be especially predisposed to EF recovery.⁴ Although prior studies have helped to define the HFrecEF population, only recently did evidence emerge to help guide clinicians on how to manage GDMT in these patients. Published in The Lancet earlier this year, the TRED-HF trial suggested that clinicians should proceed with caution, as the risk of relapse following GDMT withdrawal may be higher than initially expected.²

In brief, TRED-HF was an open-label randomized trial of patients with recovered dilated cardiomyopathy (n=51), defined as an improvement in LVEF from < 40% to > 50%, normalization of left ventricular end-diastolic volume (LVEDV), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) < 250 ng/L, and absence of HF signs or symptoms. Of note, the threshold of LVEF recovery used in TRED-HF differs from the definition used in the American College of Cardiology / American Heart Association guidelines (see Table 1 for details).⁵ Eligible patients were randomized to phased withdrawal of GDMT or continuation, and those in the continuation arm were eligible for crossover into the withdrawal arm at 6 months (Figure 1). Of the 25 patients randomized to GDMT withdrawal, 11 (44%) experienced relapse, defined as reduction in LVEF of > 10% to < 50%, an increase in LVEDV of > 10% and higher than normal, doubling of NT-proBNP to > 500 ng/mL, or signs or symptoms of HF. Of the 26 patients initially randomized to the continuation arm, phased withdrawal was attempted in 25 patients, and 9 patients (36%) eventually met the threshold for HF relapse.

Table 1. Heart Failure Definitions Used in 2013 ACC/AHA Guidelines⁵

Classification	Ejection Fraction
Heart failure with reduced ejection fraction (HFrEF)	< 40%
Heart failure with preserved ejection fraction (HFpEF)	> 50%
HFpEF, borderline*	41-49%
HFpEF, improved†	> 40%

Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association

*Sometimes referred to as heart failure with mid-range ejection fraction (HFmrEF)

†Sometimes referred to as heart failure with recovered ejection fraction (HFrecEF). Of note, TRED-HF used a recovery threshold of > 50%.²

Patients who relapsed in TRED-HF were more likely to be older (increased risk per every 10 years of age) and taking fewer HF medications (specifically mineralocorticoid antagonists), and were more likely to have higher baseline NT-pro-BNP concentrations or evidence of global radial strain. Importantly, most patients met the threshold for relapse based on structural changes or biomarker elevations rather than the emergence of clinical HF. No patients in either group died or required hospitalization for HF.

Although TRED-HF suggests that GDMT withdrawal in a heterogeneous population of patients with HFrecEF is risky, several important questions remain. For example, the study was small and underpowered, and groups with potentially reversible causes of HFrEF (e.g., peripartum or viral cardiomyopathy) were underrepresented. Additionally, although the risk of relapse was high, little is known about the long-term impact (e.g., quality of life, patient preferences) on patients in whom GDMT was successfully withdrawn. For those patients, being free of medications may have outweighed the risk of disease relapse. Consequently, clinicians may still be faced with the dilemma that TRED-HF attempted to resolve. For those scenarios, three key questions may help frame a shared decision-making process.

1. What is the etiology of HF and the expected risk of relapse?

Patients with ischemic cardiomyopathy were not included in TRED-HF, as the progressive nature of atherosclerotic cardiovascular disease makes the risk of relapse high. Additionally, patients may derive other benefits from GDMT (e.g., reduced risk of recurrent events). Although TRED-HF suggests that patients with nonischemic, dilated cardiomyopathy are also at high risk for relapse, the average age of patients in the study was 55 and most had idiopathic disease. Only eight patients (15.6%) had potentially reversible etiologies of HF, and only two had peripartum cardiomyopathy. As a result, it is still unclear whether the results of TRED-HF can be applied to these important patient subgroups.

2. Is the patient experiencing a problem with drug therapy?

Continuation of GDMT is predicated on the idea that the benefits of doing so outweigh the risks. For patients who do not have problematic adverse effects or concerns regarding the cost or convenience of GDMT, the risk of relapse likely outweighs the benefits of withdrawing therapy. However, for those patients where these factors are a major concern (e.g., younger patients, women who would like to become pregnant), the risk may be worth an attempt at GDMT withdrawal. Although TRED-HF narrows the population deemed to be at low risk of relapse, several important subgroups were underrepresented. Additionally, the trial evaluated complete GDMT withdrawal rather than the select discontinuation of specific agents that may be causing problems for patients. The nuances of determining which therapies may be considered for withdrawal should be individualized to each patient, and a full discussion of these considerations is beyond the scope of this post.

3. Can a patient who wants to attempt withdrawal be closely monitored?

One key finding in TRED-HF is that relapse can be detected early based on structural or biomarker changes, i.e., prior to the development of clinical HF. The study also suggests that patients who are likely to relapse will do so quickly, as most cases of relapse occurred during the study period, with nearly half of those occurring within 16 weeks of starting the withdrawal protocol. Considering these two findings together, TRED-HF provides a template for attempting GDMT withdrawal if a patient wishes to do so. All patients underwent a comprehensive clinical assessment at baseline, which included laboratories, cardiovascular magnetic resonance (CMR) imaging, and cardiopulmonary exercise testing (CPET); clinical reviews were then performed every 4 weeks thereafter, with interim phone calls made as frequently as every 2 weeks. As an alternative to the protocol used in TRED-HF, surveillance echocardiography and NT-pro-BNP measurements could be made at an even higher frequency in order to permit early detection of HF relapse.

Bottom line: TRED-HF suggests that GDMT withdrawal should be avoided in the majority of patients with HFrecHF. However, the study’s results should not be extrapolated to all patients with LVEF recovery, such as younger patients and/or those with potentially reversible etiologies of HFrEF. In these latter groups, TRED-HF provides a template for monitoring GDMT withdrawal in a way that detects relapse prior to the development of clinical HF.

Brent N. Reed, PharmD, BCCP, FAHA