The REMOVE study is a prospective, multicenter, open-label, randomized clinical trial. The study is designed to evaluate the effect of withdrawing neurohormonal blockade drug therapy for HF, including beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs) compared with continuing this therapy in patients with CRT who recovered LVEF function and normal volumes (figure 1). Sodium-glucose cotransporter type 2 inhibitors are not included within this OMT, as they were introduced after the trials justifying CRT use and provide benefits across the entire LVEF spectrum. After signing the informed consent for participation, patients meeting all the inclusion criteria and none of the exclusion criteria (table 1 of the supplementary data), will be randomized at a 1:1 ratio to either OMT withdrawal (intervention group) or continuation (control group). Randomization will be controlled by groups: age (<60 years vs 60-75 years vs >75 years), sex, atrial fibrillation, time since CRT (<2 years vs ≥2 years), and time since LVEF normalization (<2 years vs ≥2 years). Assignment to each group will be carried out using an online computer program generated by the Plataforma de Informática Biomédica y Bioinformática (IMIB, Biomedical Informatics and Bioinformatics Platform; Pascual Parrilla, Spain). The study is registered in ClinicalTrials.gov (NCT05151861) and has been approved by the ethics committee of the coordinating center (CEIm Hospital Clínico Universitario Virgen de la Arrixaca) and the Spanish Agency for Medicines and Medical Devices (AEMPS). The conduct of this study will adhere to the principles of Good Clinical Practice, the Declaration of Helsinki, and current legislation regarding clinical trials. All patients will sign informed consent before inclusion in the study.

Figure 1.

Central illustration. Graphic summary of the study. AF, atrial fibrillation; NT-proBNP, N-terminal pro-B-type natriuretic peptide fraction; NYHA, New York Heart Association; SR, sinus rhythm.

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The study population will include outpatients of both sexes, aged ≥18 years with a CRT device implanted at least 1 year previously to treat LBBB and LVEF ≤40% due to a nonischemic cause. Patients will qualify for enrollment if they meetall the inclusion criteria and none of the exclusion criteria (table 1 of the supplementary data). The main inclusion criteria are as follows: current LVEF ≥50% and normal volume measurements in 2 consecutive echocardiography studies at least 3 months apart, with the most recent one within the last 6 months; New York Heart Association (NYHA) class I-II; no HF hospital admissions within the past year; N-terminal pro-B-type natriuretic peptide (NT-proBNP) fraction <450 pg/mL (<900 pg/mL if atrial fibrillation is present) in the last 6 months; OMT with beta-blockers, ACEIs/ARBs/ARNIs with or without MRAs; and a properly functioning CRT device with pacing >95%. The key exclusion criteria are as follows: significant, nonrevascularized coronary artery disease; history of sustained ventricular tachycardia or aborted sudden death or appropriate implantable cardioverter defibrillator shock; uncontrolled hypertension; beta-blocker requirement for other indications, such as arrhythmia control; severe valve disease; diabetes or hypertension with microalbuminuria or proteinuria; and renal insufficiency with estimated glomerular filtration rate <30 mL/min/1.73 m2 (Chronic Kidney Disease Epidemiology Collaboration formula).

Patients will be randomized 1:1 to withdrawal (intervention group) or continuation (control group) of medical treatment. As this is an open-label study, both the research team and the patients will be aware of the study group assigned; only the cardiologist performing the echocardiography studies will be blinded to the assigned group. The study design, medical visits, and procedures are summarized in figure 2 and table 1.

Figure 2.

Study design and follow-up protocol. ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; ARNIs. angiotensin receptor neprilysin inhibitors; BBs, beta-blockers; MRAs, mineralocorticoid receptor antagonists.

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Extension and simple crossover phase

After the week 48 visit (final visit), a phase involving extension of follow-up or a simple crossover will be initiated (figure 3). Immediately after completion of each patient's assessment, they will be offered the option to participate for an additional year in the trial's extension phase, according to 2 possibilities:

• A.

  Patients from the intervention group: once the safety hypothesis of treatment withdrawal has been confirmed, these patients will continue without treatment and undergo clinical examination, laboratory testing, and echocardiography study at 6 and 12 months under the same criteria for drug reintroduction as in the main phase of the study.

• B.

  Patients from the control group: if they continue to meet the inclusion criteria and show no exclusion criteria, control patients will be offered the opportunity to switch to the intervention group. The follow-up and data collection protocols will be the same as those established for the main study phase and will last for 1 year.

Figure 3.

Follow-up protocol for the study extension phase. ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; ARNIs, angiotensin receptor neprilysin inhibitors; BBs, beta blockers; MRAs, mineralocorticoid receptor antagonists.

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If any components of the primary endpoint occur within the intervention group, the drugs withdrawn will be fully restarted. The research team will individually reassess management in patients who have other events (eg, sustained arrhythmia), except in the case of hypertension. In these cases, the use of dihydropyridine calcium channel blockers or thiazides, as well as lifestyle measures, will be prioritized. Treatment initiation for hypertensive patients with values >140/90mmHg will follow current recommendations,8 starting with ACEIs/ARBs as the first-line therapy, followed by MRAs, and finally, beta-blockers.

The research team will monitor the progress of the study once per month. Any events during follow-up will be reported and analyzed by the team, which will collaborate with the cardiologist responsible for each center to determine subsequent decisions and the suitability of continuing with the study. The decision to continue in the extension or crossover phase will be made on a patient-by-patient basis, following the same clinical safety criteria used in the main phase of the study, provided there are no major events and patients experiencing a recurrence of cardiomyopathy show a positive response to medication resumption.

The primary endpoint is recurrence of cardiomyopathy at any point of the study after medication withdrawal, defined by at least 1 of the following criteria: a) a reduction in LVEF >10% (provided the overall LVEF is <50%) compared with baseline echocardiography findings; b) a decrease in LVEF >10% accompanied by an increase in left ventricular end-systolic volume indexed by body surface area >15% relative to baseline values and exceeding the normal range (31 mL/m2 in men and 27 mL/m2 in women), or c) unplanned hospital admission, emergency room visit, or day hospital visit due to decompensated HF requiring intravenous diuretics, as determined by the research team.

The secondary endpoints include the following: a) a composite of total mortality, cardiovascular mortality, unscheduled hospital admission, emergency room visit, or day hospital visit due to HF, and sustained atrial or ventricular arrhythmia (>30 s); b) changes in LVEF values, indexed ventricular volumes, indexed left atrial volume by body surface area, and global longitudinal left ventricular strain with respect to baseline values; c) quantitative changes in NT-proBNP values; and d) changes in quality of life, according to the results of the KCCQ and MLHFQ scales.

Based on calculations performed in the TRED-HF6 study, with 80% power and a significance level of 5%, a sample size of 30 patients per group allows for detection of differences between the groups (assuming no relapses in the control group), if the incidence of the primary event in the treatment withdrawal group is 23%.

Demographic data and other baseline characteristics of the trial participants will be reported using descriptive statistical indices for the total sample and each of the study groups. Continuous variables will be described using measures of central tendency (mean) and dispersion (standard deviation), whereas categorical values will be summarized using tables of absolute and relative frequency. Baseline characteristics of the 2 participating groups will be compared. Categorical variables will be compared using the chi-square test, and continuous variables with the Student t-test. A P-value <.05 will be considered significant. Analysis of both primary and secondary variables will be conducted on an intention-to-treat basis.

For the analysis of the primary endpoint variable, relapse percentages with 95% confidence intervals will be calculated for both groups. Differences between the groups will be estimated using a proportions test. A logistic regression model will be used to adjust for age and sex. Secondary endpoint variables, such as mortality and hospital readmissions, will be analyzed using Kaplan-Meir survival curves and log-rank tests. Age and sex adjustments will be made using Cox proportional hazards modeling. Additional continuous indicators, such as echocardiography findings and NT-proBNP values will be analyzed using paired t-tests and multiple regression models, adjusting for age and sex.

In HF patients with decreased LVEF, the use of pharmacological treatments that block neurohormonal activation offers substantial benefits by notably reducing morbidity, mortality, and hospital readmissions.1,3 Within this patient population, there is a specific subset with ventricular dysfunction and LBBB who can benefit from CRT, an option that provides prognostic advantages beyond those achieved with OMT. Clinical guidelines recommend CRT for patients with LVEF ≤35% who remain symptomatic despite receiving OMT for a minimum of 3 months.3 The accumulated evidence indicates that individuals with nonischemic dilated cardiomyopathy and LBBB exhibit a heightened response in terms of remodeling and enhanced ejection fraction,9 and therefore, better clinical outcomes after CRT.10 While medications act at the neurohormonal level, CRT primarily addresses the electromechanical contraction delays and subsequent myocardial stress caused by intraventricular and interventricular asynchrony.11

Following CRT, the degree of improvement in cardiac remodeling varies. In certain cases, patients achieve normalization of LVEF, earning them the name super-responders. The prevalence of this favorable response varies widely, ranging from 10% to 29%, and is highly dependent on the definition used, which is based on both echocardiographic and clinical parameters.4,12,13 Super-responders embody the most favorable outcome, characterized by LVEF ≥50% and a considerable reduction in ventricular volumes (≥30% decrease in end-systolic volumes) following CRT.4 This response has led to the hypothesis that the primary cause of ventricular dysfunction in these patients is the conduction disorder, as correction with the device can restore normal cardiac structure and function. In essence, what maximum tolerated doses of OMT failed to achieve can be accomplished with CRT. This differential response suggests a reversible cardiomyopathy secondary to the electromechanical disorder corrected by CRT.5 Several studies have shown that super-responders have a favorable prognosis, marked by low overall and cardiovascular mortality rates, as well as fewer HF readmissions.14,15 Generally, these patients also have a low incidence of ventricular arrhythmias and appropriate shocks due to improved cardiac remodeling and reduced wall stress.16,17 However, this notion has been questioned,18 possibly because it is derived from studies including patients with pre-existing ventricular arrhythmia and an unfavorable substrate, such as significant myocardial fibrosis, which is more prevalent in ischemic dilated cardiomyopathy.

It has been suggested that the observed improvement in remodeling after CRT is due to the combined effect of CRT itself and the subsequent enhancement of OMT, as higher doses can be administered. Thus, patients receiving higher post-CRT OMT doses have a better prognosis at follow-up.19,20 However, this does not necessarily imply causation; it may simply identify patients with less advanced disease showing a better intrinsic response to CRT. Moreover, it remains unclear whether dosage changes alone can explain such a marked remodeling improvement. Studies indicate only a modest 16% difference in the maximum treatment dose between super-responders and nonsuper-responders.21 In addition, these investigations analyzed the role of OMT in the total population of resynchronized patients, with a wide range of LVEF values post-CRT. Hence, the findings may not provide sufficient evidence to allow definitive conclusions.

While there is no denying that OMT has a role in post-CRT patients with persistent ventricular dysfunction, its significance in patients with normalized function remains unclear. It is unknown whether OMT withdrawal in such cases offers benefits either in preserving LVEF or in decreasing events during follow-up. A study investigating OMT withdrawal in patients with recovered LVEF6 reported short-term recurrence of cardiomyopathy in nearly half the sample. However, the study did not include patients with CRT. Thus, the initial LVEF recovery was due to OMT and not CRT, and the results obtained would be expected. To date, only 1 recent study7 has analyzed OMT withdrawal in a specific patient population experiencing LVEF normalization following CRT. The authors concluded that discontinuation of this therapy was safe in most patients after a 2-year follow-up. Notably, the study randomized patients to various withdrawal strategies: withdrawal of beta-blockers only, of renin-angiotensin-aldosterone system blockers only, or complete medication withdrawal. This last group, the focus of our study, comprised 20 patients, and only a minority successfully sustained total withdrawal at completion of follow-up due to emerging cardiologic comorbidities, such as hypertension and supraventricular arrhythmia. Therefore, the available scientific evidence on complete OMT withdrawal in CRT super-responders is quite limited.

The limitations of this study include enrollment of a small number of patients and an initial follow-up period of 1 year, with the possibility of extending to 2 years, which, nevertheless, might not suffice to detect long-term recurrence of cardiomyopathy. In addition, the open-label study design might lead to biases, although these could be minimized by masking echocardiography measurements related to the primary endpoint. Lastly, the intervention group will undergo a larger number of follow-up visits for safety purposes. This might affect the results by enhancing the detection of events in these patients. Nonetheless, the definition established for the primary event decreases the likelihood that irrelevant findings will influence the study outcomes.