Current Problems in Cardiology 49 (2024) 102376

Contents lists available at ScienceDirect

Current Problems in Cardiology

journal homepage: www.elsevier.com/locate/cpcardiol

Invited Review Article

Beta-blocker therapy in heart failure with preserved ejection

fraction (B-HFpEF): A systematic review and meta-analysis
Rasha Kaddoura, RPh, MSc (Pharm), PharmD a, *, Vichithranie Madurasinghe, MSc b,
Ammar Chapra, MD c, Dina Abushanab, RPh, BSc, MSc d, Daoud Al-Badriyeh, PhD e,
Ashfaq Patel, MD c
a
Pharmacy Department, Heart Hospital, Hamad Medical Corporation, Doha, Qatar
b
Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
c
Department of Cardiology, Heart Hospital, Hamad Medical Corporation, Doha, Qatar
d
Drug Information Center, Hamad Medical Corporation, Doha, Qatar
e
College of Pharmacy, QU Health, Qatar University, Doha, Qatar

A R T I C L E I N F O A B S T R A C T

Keywords: Introduction: While beta-blockers are considered the cornerstone of treatment for heart failure
Adrenergic beta-antagonists with reduced ejection fraction, the same may not apply to patients with heart failure with pre­
Bisoprolol served ejection fraction (HFpEF). To date, the benefit of beta-blockers remains uncertain, and
Carvedilol
there is no current consensus on their effectiveness. This study sought to evaluate the efficacy of
Diastolic dysfunction
HFpEF
beta-blockers on mortality and rehospitalization among patients with HFpEF.
Metoprolol Methods: A systematic review and meta-analysis of randomized or observational cohort studies
Nebivolol examined the efficacy of beta-blocker therapy in comparison with placebo, control, or standard
medical care in patients with HFpEF, defined as left ventricular ejection fraction ≥50 %. The main
endpoints were mortality (i.e., all-cause and cardiovascular), rehospitalization (i.e., all-cause and
for heart failure) and a composite of the two.
Results: Out of the 13,189 records initially identified, 16 full-text records met the inclusion criteria
and were analyzed recruiting a total of 27,188 patients. The mean age range was 62–84 years old,
predominantly female, with HFpEF in which 63.4 % of patients received a beta-blocker and 36.6
% did not. The pooled analysis of included cohort studies, of variable follow-up durations, showed
a significant reduction in all-cause mortality by 19 % (odds ratio (OR) 0.81; 95 % confidence
interval (CI): 0.65–0.99, p = 0.044) whereas rehospitalization for heart failure (OR 1.13; 95 % CI:
0.91–1.41, p = 0.27) or its composite with all-cause mortality (OR 1.01; 95 % CI: 0.78–1.32, p =
0.92) were similar between the beta-blocker and control groups.
Conclusion: This meta-analysis showed that beta-blocker therapy has the potential to reduce all-
cause mortality in patients with HFpEF based on observational studies. Nevertheless, it did
not affect rehospitalization for heart failure or its composite with all-cause mortality. Large scale
randomized trials are needed to clarify this uncertainty.

* Corresponding author.
E-mail addresses: [email protected], [email protected] (R. Kaddoura).

https://doi.org/10.1016/j.cpcardiol.2024.102376

Available online 5 January 2024

0146-2806/© 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
R. Kaddoura et al. Current Problems in Cardiology 49 (2024) 102376

Introduction

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by symptoms of congestion and/or
exercise intolerance, with left ventricular ejection fraction (LVEF) within the normal limits (i.e., LVEF ≥50 %).1 However, these normal
limits have previously been categorized using different cut-offs, such as LVEF >40 %, >45 %, and ≥50 %.2 Currently, the American and
European heart failure guidelines define HFpEF as a condition with LVEF ≥50 %, accompanied by signs and symptoms of heart failure,
along with evidence of elevated left ventricular filling pressures, e.g., increased natriuretic peptide levels and hemodynamic mea­
surements.2,3 HFpEF imposes a financial burden and affects the allocation of healthcare system resources,4 and has been linked to
increased morbidity and mortality rates.2,5 The reported mortality rates for HFpEF are 29 % within one year and 65 % within five
years.6 At 49 months, 61 % of HFpEF patients experienced recurrent hospitalizations due to any cause.7 The current management
strategy for HFpEF pivots on symptom relief with the use of loop diuretics, treating any underlying etiologies, if identified at all, such as
amyloidosis, and managing concurrent comorbid conditions such as atrial fibrillation, hypertension, and chronic kidney disease.2,3
The pathogenesis of HFpEF is multifactorial and has been associated with sympathetic overactivation, which can result in a
shortened left ventricular diastolic filling time, development of tachyarrhythmias, and hypertension. To counteract these detrimental
neurohormonal effects of the sympathetic nervous system, beta-blockers were proposed.8 In addition, the demographic of patients
affected by HFpEF are commonly elderly who are at increased risk of having preexisting cardiac comorbidities such as coronary artery
disease and atrial fibrillation for which beta-blocker therapy is already one of the therapeutic choices. Nonetheless, there is a concern
that beta-blockers, by slowing the heart rate, could potentially aggravate chronotropic incompetence leading to further intensification
of their symptoms.9 Although the SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors
With Heart Failure) trial demonstrated a significant reduction in the composite outcome of all-cause mortality or cardiovascular
hospital admission with nebivolol, it is important to highlight that only 15 % of the patients had LVEF >50 %. Therefore, the trial may
not have had sufficient statistical power for a conclusive analysis of HFpEF subgroups.10
Despite the fact that beta-blockers are considered the cornerstone of treatment for heart failure with reduced ejection fraction,2,3
their benefit in HFpEF remains uncertain, and there is no current consensus on their effectiveness in HFpEF. Studies investigating the
efficacy and safety of beta-blockers in unselected HFpEF patients are becoming abundant. Given this uncertainty, we conducted a
comprehensive systematic review and meta-analysis, encompassing all the relevant studies present in the literature, to evaluate the
efficacy of beta-blockers on mortality and rehospitalizations among patients with HFpEF.8

Methods

This systematic review and meta-analysis was conducted in accordance with the Cochrane Handbook for Systematic Reviews,11 and
reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement12 and the
Meta-analysis Of Observational Studies in Epidemiology (MOOSE) checklist.13 The review protocol was registered in the International
Prospective Register of Systematic Reviews (PROSPERO 2023 CRD42023427519).

Eligibility criteria

Inclusion criteria involved randomized or observational cohort studies that recruited adult patients with HFpEF, defined as LVEF
≥50 %, and examined the efficacy of beta-blocker therapy in comparison with placebo, control, or standard medical care. The follow-
up duration of an eligible study needed to be at least six months. Studies which focused on beta-blockers in the context of acute
coronary events or those that only recruited a special patient population such as those with a history of myocardial infarction, atrial
fibrillation, or ventricular arrhythmias were excluded. Studies that conducted a head-to-head comparison between two beta-blocker
agents were also excluded. Finally, abstracts, conference proceedings, study protocols, unpublished studies, case reports, or case series
were not included.

Search strategy

A comprehensive systematic electronic literature search using EMBASE and MEDLINE (via Ovid® interface) was performed from
inception to May 19, 2023. Medical Subject Headings (MeSH), Emtree and broad keywords were combined with Boolean terms “OR”
and “AND”. The terms and their synonyms included: “heart failure”, “heart failure with preserved ejection fraction”, “diastolic”,
“preserved”, “beta-blockers”, “adrenergic beta-antagonists”, “beta adrenergic receptor blocking agent”, individual beta-blocker agents
(acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, penbutolol,
pindolol, propranolol, sotalol, and timolol), “clinical trial”, “clinical trial registry”, “observational study”, “randomized trial” and
“trials”. The list of references of the included studies and relevant reviews were also manually searched to identify additional studies.
The complete search strategy is detailed in Table S1.

Study selection and data extraction

The titles and abstracts of the search records were examined. Excluded were studies that did not meet the inclusion criteria, were of
irrelevant topic, duplicate publications, or involved non-adult participants. The full text of all potentially relevant abstracts was ob­
tained and reviewed in duplicate to ascertain the final eligibility. The data of the included studies were extracted and compiled into

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tables, which included study objective(s), design, study characteristics, eligibility criteria, interventions, comparators, patient char­
acteristics, outcome measures, results, limitations, and conclusions. The main outcomes of interest were mortality (i.e., all-cause and
cardiovascular), rehospitalization (i.e., all-cause and for heart failure) and a composite of the two outcomes. The planned secondary
outcome measures comprised improvement in the New York Heart Association (NYHA) functional class, natriuretic peptide levels, and
echocardiographic parameters of cardiac structure (e.g., left atrial diameter) and functions (diastolic and systolic). Examples for left
ventricular systolic function parameters included LVEF and for diastolic function such as E/A and E/E′ ratios. The definition of each
individual outcome measure was based on the original study from which it was derived. The analysis of outcome measures at specific
time points (i.e., short- and longer-term follow-up) was conducted according to the availability of data.

Fig. 1. PRISMA flow diagram.

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Quality assessment

The methodological quality was assessed using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) risk of bias
tool for observational studies,14 and the revised Cochrane Risk of Bias 2 (RoB2) tool for randomized trials at the individual study level
for each outcome by two authors.15 The ROBINS-I tool evaluates seven domains and categorizes the level of bias as low, moderate,
serious, critical risk, or no information.14 The RoB2 tool comprises five domains, the bias is judged as low risk, some concerns, or high
risk for each domain as well as the overall study.15 Any disagreements between authors were resolved through reaching a consensus.

Data synthesis and statistical analysis

Data were combined in a systematic review, forest plots and a meta-analysis. The meta-analysis was conducted using an aggregate
approach. Two studies were the minimum number to perform a quantitative data synthesis for an outcome.16 Random-effects model
was used due to the anticipated heterogeneity between studies. For each outcome, the odds ratio (OR) with 95 % confidence interval
(CI) was computed. Statistical heterogeneity was examined by the Cochran’s Q statistic and reported as the inconsistency factor (I2)
value for every outcome. The I2 values greater than 50 % represented high heterogeneity.17 Sensitivity analyses were conducted by
including or excluding studies in a meta-analysis based on the follow-up duration to check if the overall OR and conclusions are
affected. Some studies could not be added to the computing of pooled OR of outcomes because the needed raw event data was not
available. In these studies, outcomes were reported as an already calculated hazard ratio (HR) or risk ratio (RR) measure. To test the
effect of excluding such studies from the pooled OR of outcomes, the sensitivity analyses also included, for the mortality outcome as an
example, a scenario where all computed mortality OR of individual studies, which are included in the base case analysis of the
mortality outcome, were pooled together with the reported HR and RR measures of the mortality from the studies that were not
included at base case pooling of OR of mortality, which also used the standard errors and corresponding variance. A priori subgroup
analyses to explore the impact of age (> or ≤75 years), body mass index (BMI) (> or ≤30 kg/m2), and LVEF (> or ≤60 %) have been
performed through the reported outcomes. Reporting or publication bias was visually inspected by funnel plots, but Egger’s test was
not mathematically valid due to the small study numbers that were pooled (i.e., <10 studies). A significance level of alpha <0.05 was
used. All analyses were performed by statistical program R software (RStudio 2023.06.0 + 421)

Results

Search results

Of 13,189 records identified by the systematic literature search, 579 were duplicate publications. After excluding irrelevant records
(e.g., reviews, conference proceedings, etc.) based on screening the study titles and/or abstracts, 523 records were retrieved in full text.
Of these, 16 records met the inclusion criteria,18-33 which included one randomized trial18 and 15 observational cohort studies (Fig. 1
and Tables S2, S3).19-33

Characteristics of included studies

Study characteristics
The included studies recruited patients between 2001 and 2022. Most of the studies were conducted in Europe (France, Germany,
Spain, Sweden, United Kingdom) and the United States. The studies enrolled 27,188 patients, out of whom 17,232 (63.4 %) were
treated with a beta-blocker and 9,956 (36.6 %) without it. The study volume ranged from 40 to 14,434 patients (Tables S3 and S4).

Patient characteristics
The range of mean age was 62–84 years old and females accounted for 16–78 % of patients with a body mass index of 21–37 kg/m2.
The comorbidities included hypertension (29–95 %), diabetes (12–88 %), atrial fibrillation (5–64 %), and a history of myocardial
infarction (10–60 %). One study only included hypertensive patients (100 %).23 Upon presentation, patients were usually symptomatic
(NYHA III: 16–44 %) (Table S5), with elevated natriuretic peptide levels, and mild renal impairment (Table S6). Beta-blockers were
either compared with a placebo or usual care. The only randomized study used metoprolol succinate18 and one cohort study tested
bisoprolol.31 The remaining cohort studies examined either two,22,25,29,33 three,24,32 or any beta-blocker(s)19,20,21,23,26,27,28,30 (Table
S3). Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) (excluding Bitar et al.19), mineralocorticoid
receptor antagonists (MRA), and diuretics were used in 32–76 %, 4–32 %, and 9–98 %, respectively. Angiotensin receptor-neprilysin
inhibitors (ARNI) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) use was not reported in any study (Table S7). Echocar­
diographic measurements included mean LVEF 55–69 %, left atrium diameter 35–41 mm, left ventricular end-diastolic diameter
40–48 mm, and E/A velocities 0.70–0.90 (Tables S8).

Outcomes

Most of the included studies reported all-cause mortality at various follow-up periods (i.e., six months to six years). Other reported
clinical outcomes included rehospitalization and composite of mortality or rehospitalization. The only randomized study did not report
clinical outcomes18 (Table S9).

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Mortality
Ten studies reported all-cause mortality,19-22,26-31 either at six months,20 within three years,19,21,22,27,28 or at five or more
years26,29,30,31 of follow-up. Four studies reported all-cause mortality as hazard ratio27,31 or relative risk.22,29 The pooled outcome of
the remaining six studies showed significant reduction in all-cause mortality by 19 % (OR 0.81; 95 % CI: 0.65–0.99, p = 0.044) without
significant heterogeneity (I2 = 38.1 %, 95 % CI: 0–75.4 %) (Fig. 2, Panel A) or publication bias (Fig. 2, Panel B). When the two studies
of the shortest follow-up duration were removed, 20,21 the reduction in mortality was not significant (OR 0.77; 95 % CI: 0.59–1.02, p =
0.068; I2 = 54.0 %, 95 % CI: 0–84.8 %) (Fig. S1). Similarly, when pooling the outcomes at six-month follow-up of the two studies that
were removed,20,21 there was no difference in all-cause mortality between the groups (OR 0.86; 95 % CI: 0.56–1.32, p = 0.49; I2 = 0 %)
(Fig. S2).

Rehospitalization
Five studies reported rehospitalization for heart failure,20,21,26,27,30 either at six months,20 within two years,21,27 or at five or more
years26,30 of follow-up. One study reported rehospitalization for heart failure as hazard ratio.27 The pooled outcome of the remaining
four studies did not show significant reduction in this outcome (OR 1.13; 95 % CI: 0.91–1.41, p = 0.27; I2 = 54.1 %, 95 % CI: 0–84.8 %)
(Fig. 3, Panel A) with potential publication bias (Fig. 3, Panel B). When the study of six-month follow-up was removed, 20 there was
also no significant reduction in rehospitalization for heart failure (OR 1.07; 95 % CI: 0.89–1.29, p = 0.47; I2 = 1 %, 95 % CI: 0–89.7 %)
(Fig. S3). Similar non-significant results were obtained when removing or separately pooling the outcomes of the studies with shortest
follow-up20,21 (Figs. S4 and S5, respectively).

Mortality or rehospitalization for heart failure

Three studies reported the composite of all-cause mortality or rehospitalization for heart failure,21,26,30 without a difference in
pooled events between the groups (OR 1.01; 95 % CI: 0.78–1.32, p = 0.92; I2 = 63.0 %, 95 % CI: 0–89.4 %) (Fig. 4, Panel A) or
publication bias (Fig. 4, Panel B). Removing the studies with the shortest (Fig. S6) or the longest follow-up (Fig. S7) did not change the
findings.

Sensitivity and subgroup analyses

When including all relevant studies in the estimation of an overall mortality outcome, based on available OR in individual studies
and, when this is not available, based on reported HR and RR of mortality, with their variance, the pooled outcome was consistent with
the base case pooled OR of mortality, with an overall OR of 0.75 (95 % CI: 0.62–0.88) (Fig. S8). When using the natural logarithm of the
pooled OR, HR, and RR (e.g., logOR), the pooled outcome was − 0.34 (95 % I: − 0.48–0.19), which is undefined and indicates that OR of

Fig. 2. All-cause mortality of any duration (A) Forest plot, (B) Funnel plot.

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Fig. 3. Rehospitalization for heart failure of any duration (A) Forest plot, (B) Funnel plot.

Fig. 4. Mortality or rehospitalization for heart failure of any duration (A) Forest plot, (B) Funnel plot.

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mortality is between 0 and 1, also consistent with the base case OR of mortality (Fig. S9). The impact of age (> or ≤75 years), BMI (> or
≤30 kg/m2), and LVEF (> or ≤60 %) cutoffs has been examined through the reported outcomes. The benefit has only been shown
among patients older than 75 years old with mortality reduction by 21 % (OR 0.79; 95 % CI: 0.66–0.93, p = 0.007) without significant
heterogeneity (I2 = 26.0 %, 95 % CI: 0–92.3 %) (Fig. 5). Other nonsignificant findings are demonstrated in Figs. S10–S16.

Risk of bias

The overall risk of bias assessment was moderate for all-cause mortality, cardiovascular mortality, and rehospitalization for heart
failure. The risk of bias was mainly due to confounding (Tables S10–S14).

Discussion

In this systematic review and meta-analysis of 16 studies recruiting over 27,000 patients with HFpEF (i.e., LVEF ≥50 %), the pooled
analysis of included cohort studies, of variable follow-up durations, showed 19 % reduction in all-cause mortality risk. Sensitivity
analyses confirmed mortality benefit. In comparison with younger age (<75 years), older patients had significant mortality reduction
by 21 %. Rehospitalization for heart failure or its composite with all-cause mortality were similar between the beta-blocker and control
groups.
To the best of our knowledge, this is the first meta-analysis to include studies that recruited patients with HFpEF defined as LVEF of
50 % or more as per the recent guidelines.2,3 The currently published meta-analyses included studies with various study designs and
LVEF cut-off inclusion criteria i.e., either ≥40 %, ≥45 %, or ≥50 %.8,9,34-43 Fukuta et al. pooled data from five randomized controlled
trials (RCT; n = 538),9 only one of them included patients with LVEF ≥50 %, which is also included in the present meta-analysis.18
Their meta-analysis did not demonstrate significant improvement in the surrogate markers including change in NYHA functional class,
natriuretic peptide levels, or exercise capacity in comparison with control with observed heterogeneity across the studies.9 Other three
meta-analyses included both randomized and observational studies of various LVEF cut-off in their inclusion criteria.8,34,35 They
included two or three RCT and 11 to 15 observational trials. The RCT included patients with LVEF ≥40 % with specified patient
population, i.e., either elderly,44 Japanese,45 or patients with prior myocardial infarction.46 The observational studies included pa­
tients with LVEF ranged from >40 % to >50 %. Of the studies that included patients with LVEF ≥50 %, four studies were included
in20,22,28,30 and five were excluded from the present meta-analysis.47-51 The latter studies were excluded either because there was not a
comparison between the beta-blocker and control groups,51 or a specified objective to assess beta-blocker therapy but rather there was
an assessment of the efficacy of other drug therapy with an analysis of beta-blockers as a subgroup without adequate details about the
patients who received beta-blockers.47-50 The overall conclusion of the three meta-analyses was that beta-blockers significantly
reduced all-cause mortality (relative risk (RR) 0.79–0.91) but not rehospitalization or the composite of mortality or rehospitaliza­
tion.8,34,35 Significant reduction by 25 % in all-cause mortality was observed in the subgroup of patients with LVEF ≥50 %.8,35
However, mortality benefit was not observed in patients older than 75 years.8
A patient-level meta-analysis of 11 RCT explored the efficacy of beta-blockers in heart failure patients stratified by LVEF and heart
rhythm at baseline. Of the included 14,262 patients in sinus rhythm, 244 (1.7 %) patients with LVEF ≥50 % (i.e., a median of 58 %). Of
3,034 patients in atrial fibrillation, 73 (2.4 %) patients had LVEF ≥50 %. In patients with sinus rhythm, not atrial fibrillation, beta-
blocker therapy was associated with lower all-cause and cardiovascular mortality than placebo across all LVEF strata except the
LVEF ≥50 % stratum. Baseline LVEF was inversely correlated with all-cause mortality (i.e., increased by 16 % (95 % CI: 19–26 %) for
each 5 % decline in LVEF).36 Other meta-analyses assessed the efficacy of heart failure drug classes, including beta-blocker class, in
patients with HFpEF phenotype.37-43 However, they did not consider the LVEF ≥50 % cut-off for HFpEF definition. Zheng et al. did not
find mortality (all-cause and cardiovascular) benefit with all drug classes except beta-blockers that significantly reduced all-cause (RR

Fig. 5. All-cause mortality in patients older than 75 years.

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0.78; 95 %CI: 0.65–0.94) and cardiovascular (RR 0.75; 95 %CI: 0.60–0.94) mortality but not rehospitalization for heart failure in
comparison with placebo in HFpEF patient with LVEF ≥40 %. However, subgroup analysis according to LVEF cut-off of ≥50 % or ≥60
% did not yield any mortality benefit.38 In a meta-analysis of RCT by Faisal et al., among the four heart failure drug classes (beta-­
blockers, ACEI, ARB, MRA), only beta-blockers significantly reduced all-cause (RR 0.79, 95 % CI: 0.66–0.96) and cardiovascular (RR
0.67, 95 % CI: 0.46–0.98) mortality but not rehospitalization for cardiac causes.41
In two network meta-analyses of RCT that recruited HFpEF patients with LVEF >40 %, none of the drug classes (beta-blockers,
ACEI, ARB, ARNI, MRA, SGLT2i) was associated with a significant reduction in all-cause or cardiovascular mortality. Whereas three
drug classes (ARNI, MRA, SGLT2i) were associated with significant reduction in rehospitalization for heart failure.42,43 Bonus et al. in
their network meta-analysis included only one RCT that investigated beta-blocker therapy in HFpEF patients with LVEF ≥45 %. Thus,
no conclusion about beta-blockers effect could be drawn.37 Finally, Martin et al. conducted a Cochrane review that investigated the
effect of beta-blockers, ACEI, ARB, ARNI, and MRA in patients with HFpEF defined as LVEF >40 %. 39,40 Ten studies (n = 3087)
investigated beta-blocker therapy, of them three studies did not report LVEF measurements,52,53,54 one study enrolled patients with
LVEF ≥50 %,18 and another study recruited patients with chronic mitral valve regurgitation.55 Beta-blockers from four studies (n =
1105) reduced cardiovascular mortality (risk ratio 0.78, 95 % CI: 0.62–0.99) with low evidence certainty. However, the authors
concluded that their use is not supported by adequate evidence in the absence of other compelling indication.40
In prior studies, LVEF >35 % was the cut-off value to define HFpEF, which was subsequently invalidated by the introduction of
heart failure with mildly reduced ejection fraction (HFmrEF) phenotype.34,38 A systematic review of 62 studies that comprehensively
examined HFpEF profile (i.e., LVEF >40 %), demonstrated that there are substantial differences in LVEF cut-off values, clinical
profiles, epidemiological indices, treatment, and outcomes across registries, observational studies, and clinical trials. Thus, precise
definition and inclusion criteria for a more homogenous population may improve the profiling of patients with HFpEF.56 In addition,
including patients with variable LVEF cut-offs (i.e., >40 %, ≥45 %, and ≥50 %) is a principal limitation since patients with HFmrEF (i.
e., LVEF 40–49 %) are considered to possess clinical characteristics and prognosis that are comparable to those with reduced ejection
fraction.57
The benefit of beta-blockers in HFpEF in terms of all-cause mortality but not rehospitalization is thought to be related to the fact
that HFpEF patients are usually elderly with multiple cardiac and/or non-cardiac comorbidities, particularly diabetes mellitus and
chronic obstructive pulmonary disease. The fact that beta-blockers may worsen insulin resistance and bronchial constriction may
possibly explain the increase in rehospitalization rates due to non-cardiac causes.34,35 According to published literature, the exact
mechanism for the efficacy of beta-blockers in HFpEF is unclear.34,35,58 Sympathetic nerve activity overactivation, left ventricle
diastolic dysfunction, and increased electric conductivity and myocardial contractility are believed to be among the contributing
factors to the pathophysiology of HFpEF. The neurohormonal effects of sympathetic nerve activity, left ventricular hypertrophy,
myocardial fibrosis, and left ventricular diastolic dysfunction worsening could be counteracted by beta-blockers.8,58 In addition,
beta-blockers may potentially improve ventricular diastolic function and remodeling, which in part, is due to its effect in improving
endothelial function by exerting anti-oxidative and anti-inflammatory effects.35,58 In addition, beta-blockers are the recommended
treatment for common coexisting conditions (e.g., coronary artery disease, atrial fibrillation) in many HFpEF patients, particularly the
elderly.8,9,34,35,58
Although the present meta-analysis found that beta-blocker therapy significantly reduced all-cause mortality in HFpEF, these
findings should be interpreted with caution due to the perceived limitations. Firstly, the benefit was derived from observational studies
which are inherently subjected to selection bias and confounding factors which threaten findings validity; therefore, a random-effects
model was considered in the analysis. Furthermore, since there was a lack of randomization in these studies, no conclusions can be
drawn regarding causality. These findings should therefore be considered as hypothesis generating. Additionally, there may be errors
attributed to the completeness of chart review. Considering this meta-analysis is an aggregate study-level analysis, inter-study het­
erogeneity cannot be totally ruled out. Moreover, our study did not examine all non-clinical outcomes such as measures of quality of
life (QOL) since they were not consistently reported in all studies. Considering the importance of any therapy on symptomatic relief
and improvement in QOL, for beta blockers in HFpEF patients, this too needs to be further clarified. However, to the best of our
knowledge, the available data lacks abundance and has variations in tool used for QOL assessment. Thus, data could not be meta-
analyzed. Similarly, the impact of beta-blockers on ejection fraction, diastolic function, symptoms, exercise tolerance and hemody­
namic consequences on exercise was not assessed in this meta-analysis due to inadequate reporting. Furthermore, the setting of the
studies included both community and hospital settings. The lack of consistent reporting of ethnicities in these studies did not permit us
to draw conclusions about potential effects of ethnic differences on beta-blocker efficacy in HFpEF patients. Finally, with regards to the
medical treatment, there were certain inconsistencies noted in the reporting of guideline-directed heart failure medications. The beta
blocker agents used, their dosages and duration of therapy substantially varied between the studies, or the respective information was
not detailed in many of the cohort studies. Furthermore, only a small proportion of patients received the target doses and thus, the
optimal agent, dose, or duration could not be inferred. There was also insufficient data about the indications, adherence, or dose
titration of the beta-blockers.
Given that HFpEF is a heterogenous entity, the use of beta blockers will probably be beneficial in selected subgroups which have yet
to be identified. Thus, the selective use of beta-blockers in HFpEF should be further studied in robustly designed randomized trials.
Thus, a one-size-fits-all approach to using beta-blockers in HFpEF is not optimal. There is paucity of randomized trials that examine the
efficacy of beta-blockers in patients with HFpEF, defined as LVEF 50 % or more. In this meta-analysis, only one pilot study was
identified.18 Therefore, further well-designed, and adequately powered randomized trials are needed to confirm the efficacy of
beta-blocker therapy in HFpEF patients. A design for a non-registered trial, at ClinicalTrials.gov, was published in 2010 with a plan to
randomize 1,200 patients to metoprolol succinate or control to examine the impact of therapy on composite of cardiovascular death or

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hospitalization for heart failure. However, there was no update about the progress of this study.59 There are three registered ran­
domized trials that are examining the use of beta-blockers in patients with HFpEF (NCT04434664, NCT04767061, NCT05553314).
None of the registered trials has been powered to find a difference in clinical outcomes such as hospitalization for heart failure or
cardiovascular mortality. The first study (BLOCK HFpEF, NCT04434664, n = 50) is comparing between metoprolol succinate and
amlodipine in a cross over design in hypertensive patients to examine the change in home systolic blood pressure (i.e., primary
outcome). The second study (NCT04767061, n = 16) is investigating the effect of beta-blocker on physical functions such as change in
exercise capacity, physical activity, and lower extremity function. Finally, a randomized, double-blind, placebo-controlled trial
(NCT05553314, n = 100) is testing carvedilol on the change of natriuretic peptide after six months of treatment in hypertensive
patients.

Conclusion

This meta-analysis showed beta-blocker therapy has the potential to reduce all-cause mortality in patients with HFpEF based on
observational studies, while it did not affect rehospitalization for heart failure or its composite with all-cause mortality. Large scale
randomized trials are needed to clarify this uncertainty.

Ethics approval and consent to participate

Not applicable.

Funding

Open Access funding provided by the Qatar National Library.

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgment

Thanks to all the peer reviewers and editors for their time in the first place and for their valuable opinions and suggestions which
helped refine and improve the manuscript.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cpcardiol.2024.102376.

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