Beta-blockers withdrawal in patients with heart failure with preserved ejection fraction and chronotropic incompetence: Effect on functional capacity rationale and study design of a prospective, randomized, controlled trial (The Preserve-HR trial).

Abstract Background The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is complex and multifactorial. Chronotropic incompetence (ChI) has emerged as a crucial pathophysiological mechanism. Beta‐blockers, drugs with negative chronotropic effects, are commonly used in HFpEF, although current evidence does not support its routine use in these patients. Hypothesis We postulate beta‐blockers may have deleterious effects in HFpEF and ChI. This work aims to evaluate the short‐term effect of beta‐blockers withdrawal on functional capacity assessed by the maximal oxygen uptake (peakVO2) in patients with HFpEF and ChI. Methods This is a prospective, crossover, randomized (1:1) and multicenter study. After randomization, the clinical and cardiac rhythm will be continuously registered for 30 days. PeakVO2 is assessed by cardiopulmonary exercise testing (CPET) at 15 and 30 days in both groups. Secondary endpoints include quality of life, cognitive, and safety assessment. Patients with stable HFpEF, functional class New York Heart Association (NYHA) II‐III, chronic treatment with beta‐blockers, and ChI will be enrolled. A sample size estimation [alfa: 0.05, power: 90%, a 20% loss rate, and delta change of mean peakVO2: +1.2 mL/kg/min (SD ± 2.0)] of 52 patients is necessary to test our hypothesis. Results Patients started enrolling in October 2018. As January 14th, 2020, 28 patients have been enrolled. It is projected to enroll the last patient at the end of July 2020. Conclusions Optimizing therapy that improves functional capacity remains an unmeet priority in HFpEF. Deprescribing beta‐blockers in patients with HFpEF and ChI seems a plausible intervention to improve functional capacity. This trial is an attempt towards precision medicine in this complex syndrome. Trial registration http://clinicaltrials.gov: NCT03871803.

Results: Patients started enrolling in October 2018. As January 14th, 2020, 28 patients have been enrolled. It is projected to enroll the last patient at the end of July 2020.
Conclusions: Optimizing therapy that improves functional capacity remains an unmeet priority in HFpEF. Deprescribing beta-blockers in patients with HFpEF and ChI seems a plausible intervention to improve functional capacity. This trial is an attempt towards precision medicine in this complex syndrome.

| INTRODUCTION
Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that is the predominant form of HF in western countries. [1][2][3][4] Chronotropic incompetence (ChI), defined as the inability to increase heart rate during exercise adequately, is commonly present (ranging from 20 to 75%) in HFpEF patients. [5][6][7][8][9][10][11] Furthermore, ChI has been proposed as a pathophysiologic mechanism associated with poorer outcomes and decreased functional capacity in a subgroup of patients with HFpEF. 8,12,13 Data from current registries show a high proportion (ranging from 50% to 80%) of beta-blockers prescription in HFpEF patients regardless of the heart rhythm. 3,14 Nevertheless, there is no well-established evidence endorsing the effect of beta-blockers. For instance, recent studies suggested that patients with an ejection fraction of 50% or greater did not see any benefits from receiving beta-blockers. [15][16][17] Even more, the evidence is missing stratifying patients with HFpEF across ChI status.
When ChI is present, beta-blockers may have negative effects on functional capacity and other surrogates of the disease severity by exacerbating the ChI. Thus, we hypothesize that deprescribing betablockers in this particular scenario will translate into an improvement in short-term maximal functional capacity. The purpose of this randomized controlled study is to evaluate the short-term effects of beta-blockers withdrawal on the functional capacity, cognitive function, and quality of life (QoL) in patients with HFpEF and documented ChI.
The primary endpoint of the study is absolute and relative changes in peak oxygen uptake (peakVO2) at 15-day after the inter-

| Study design
This study is designed as a multicenter, prospective, controlled, randomized, two-arms, cross-over, efficacy trial. The population includes patients with the diagnosis of stable HFpEF according to criteria of the European Society of Cardiology 18 and New York Heart Association functional (NYHA) class II-III/IV. A computer-generated randomization sequence previously designed will be used to allocate participants (in a 1:1 ratio) to receive: (a) withdrawal of beta-blocker followed by beta-blocker reintroduction in two periods of 15 days; or (b) continuation of beta-blocker followed by beta-blocker withdrawal in two periods of 15 days. A summary of the study design is described in Figure 1. The study will be conducted in two centers in Spain. Discounting the time due to staggered entry, the total duration of a patient's follow-up will be 6 months. All patients will provide signed informed consent before randomization. The research ethics committee approves the protocol of our center following the principles of the Declaration of Helsinki and national regulations.

| Study population sampling
Candidate patients will be selected from the outpatient HF-clinics of the Hospital Clínico Universitario of Valencia-Spain and Hospital Clínico Universitario de Santiago-Spain. Treatment will be following current guidelines 18 Table 1. Inclusion criteria require the presence of ChI after performing the cardiopulmonary exercise testing (CPET). The chronotropic index is equal to (heart rate at peak exercise−resting heart rate)/([220age] − resting heart rate). 19 ChI is defined as a chronotropic index <0.62.

| Treatment intervention and visits
Following screening (visit 0) and randomization (visit 1) visits, the procedures across treatment arms are:   At visit 5, the responsible cardiologist will assess all the examination test and individually decide the convenience of beta-blockers reintroduction or withdrawal in both arms. A cardiologist of the HF-unit will clinically evaluate all patients at 60-day after randomization (visit 6). Additional visits will be permitted according to the patient's clinical status and will be registered.

| Study procedures
A scheme of procedures along the visits is presented in Figure 1.

| Cognitive assessment by MMSE and MoCa
MMSE and MoCa tests will be used to assess the cognitive abilities and evaluate the impact of the intervention on cognitive function. 22 Each subject will undergo three tests (at baseline, 15 days, and 30 days). Overall scores will be analyzed.

| Health-related QoL
MLHF questionnaire 23 will be used to assess the impact of the intervention on QoL. Each subject will undergo three tests (at baseline, 15 days, and 30 days).

| Continuous ECG recording
The heart rhythm and rate are continuously recorded during 30 days by remote monitoring systems integrated into clothing (Nuubo Suite License).

| Serum biomarkers
Three blood samples (at baseline, 15 days, and 30 days) are collected under standardized conditions for biomarkers' profiling. Prognostic biomarkers in HF will be analyzed, 24 NT-proBNP and CA125 will be measured by electrochemiluminescence immunoassay.

| Sample size calculation
The null hypothesis of the study is that the mean peakVO2 absolute differences from baseline to 15 days after the withdrawal of betablockers will be similar. The sample size determination for this study assumes two-sided testing at the 0.05 significance alpha level.
Because this is a randomized clinical trial, we assume no differences in peakVO2 at baseline among the two arms. Based on a prior study of our group in HFpEF, we assume eligible patients will have a mean (SD) peakVO2 of 10 ± 2.8 mL/kg/min. 8  Assuming an allocation ratio of 1:1, a total of 42 patients (21 patients per group) would provide 90% of power at a significance alpha level < 0.05. Assuming 20% of withdrawals or losses to followup, a total of 26 patients per arm (52 patients) will be enrolled. The software used for sample size calculation was "xsampsi" from Stata 14.1.

| Statistical plan
Continuous variables will be presented as mean ± SD or median (interquartile range-IQR) as appropriately; categorical variables as percentages. All statistical comparisons will be made under the intention-to-treat principle. A repeated-measures analysis of variance (ANOVA) will be used for the comparisons of continuous outcomes among the two-intervention groups. The interaction group*timepoints will be tested to unveil any effect of time (15 and 30 days) on the magnitude of the intervention. Only in the event of imbalance in baseline characteristics, repeated-measures analysis of covariance (ANCOVA) will be used. A two-sided P-value of <0.05 will be considered to be statistically significant for all analyses. All analyses will be performed with Stata 14.1.

| RESULTS: CURRENT STATUS
The ethics committee approved the protocol of our center, following the principles of the Declaration of Helsinki and national regulations.
We expect to finish the inclusion at the end of July 2020. are not yet entirely clarified. 30,31 Among cardiac mechanisms, ChI has been proposed as a pathophysiologic mechanism associated with poorer exercise capacity in a subgroup of patients with HFpEF. [6][7][8] Along this same line, recent evidence has shown that ChI is frequently present (ranging from 20% to 75%) in HFpEF patients. [5][6][7][8][9][10][11] From epidemiological perspective, patients with HFpEF are usually older, predominantly females and with high prevalence of other cardiovascular comorbid conditions such as atrial fibrillation, hypertension, and renal dysfunction 1-4 which in the end contribute to reduced exercise tolerance, and may explain the high proportion (ranging from 50% to 60%) of beta-blockers prescription in HFpEF patients. 3,4,14 Nevertheless, emerging evidence suggests that pharmacological heart rate lowering is not beneficial in patients with preserved ejection fraction. [15][16][17] In this regard, the proposed pathophysiological mechanism of pharmacological heart rate lowering in HFpEF patients is the prolongation of the filling of the cardiac chambers, which increases filling pressures, left ventricular diastolic wall stress and central arterial pressures. 12 To date, there is no convincing evidence to support the beneficial effects of beta-blockers prescription in HFpEF patients. [32][33][34][35][36] A recent meta-analysis suggests a clinically beneficial effect of beta-blockers in patients with HF and left ventricular ejection fraction ≥40%; however, the evidence to those with left ventricular ejection fraction >50% is limited. 37 Recently, a recent secondary study from TOPCAT showed that for patients with an EF of 50% or greater, beta-blocker use was associated with an increased risk of HF hospitalizations but not CVD mortality. 15 However, no prior randomized clinical trial has explored the effects of beta-blocker withdrawal on functional capacity in HFpEF patients with documented ChI.

| Biological plausibility
Currently, no study has evaluated the acute hemodynamic effects of beta-blockers in HFpEF. 17 However, clinical experience with these agents provides some insights. In this sense, some authors have suggested that prolonged diastolic filling related to heart rate lowering increases ventricular pressures in HFpEF patients. 17,38 Interestingly, beta-blocker cessation would translate into a reduction in enddiastolic pressures, as has been recently suggested with a decrease in natriuretic peptides following beta-blockers withdrawal. 38 Another potential beneficial effects of beta-blockers withdrawal on HFpEF patients with ChI stand out: (a) increase in heart rate response during exercise which may be considered as a compensatory mechanism for maintaining cardiac output in patients with significant diastolic dysfunction; and (b) amelioration of delayed memory retrieval in cognitively impaired patients, 39 and (c) attenuation arterial central pressures at rest and during exercise. 12

| Feasibility and future implications
HFpEF is a heterogeneous syndrome in which no pharmacological therapy has shown promising results. Identifying those HFpEF patients with ChI could help us to characterize the different phenotypes of this syndrome and optimize medical treatment. In this regard, beta-blockers withdrawal could represent a treatment option in those patients with documented ChI. This strategy is an attempt to move forward into precision medicine in HFpEF by identifying the ChI phenotype and treating it accordingly.

| CONCLUSION
To date, there is no evidence about the benefit of beta-blockers in HFpEF patients, even less in those with documented ChI. In this randomized controlled trial, we aim to evaluate the effects of beta-blocker withdrawal on short-term functional capacity in stable HFpEF patients.