Despite advances in device therapy and the emergence of novel treatments, beta-blockers (BBs) remain a commonly prescribed medication in heart failure (HF). However, HF with preserved ejection fraction (HFpEF) is underdiagnosed and undertreated, and the specific role of BB therapy in this population remains controversial. A comprehensive search was conducted on PubMed, Embase, and Cochrane databases to identify studies evaluating the impact of BB use on clinical outcomes in patients with HFpEF. Data were pooled using a random-effects model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and heterogeneity was assessed using I² statistics. We identified 13 observational studies comprising 442,543 patients, of whom 48.3% were women, with a mean age of 76.0 ± 8.3 years. In pooled analyses, BB use was associated with a lower risk of all-cause mortality (HR 0.81, 95% CI 0.73–0.90, p < 0.001). BB therapy was also associated with lower risks of cardiovascular death (HR 0.76, 95% CI 0.64–0.90, p < 0.01), HF hospitalization (HR 0.88, 95% CI 0.78–1.00, p = 0.05), and the composite outcome of death or HF hospitalization (HR 0.89, 95% CI 0.82–0.98, p = 0.02). In conclusion, in this observational meta-analysis, BB use was associated with lower mortality risk in HFpEF, whereas associations with hospitalization outcomes were heterogeneous. These findings should be interpreted as hypothesis-generating and warrant confirmation in adequately powered randomized trials.
Graphical abstract
Abbreviations: CI: Confidence interval; HFpEF: Heart Failure with Preserved Ejection Fraction; LVEF: Left Ventricular Ejection Fraction.
Heart failure (HF) is a major global public health challenge, affecting >60 million individuals worldwide and imposing substantial morbidity, mortality, and economic burden. , HF with preserved ejection fraction (HFpEF) accounts for approximately 50% of HF cases and remains a significant clinical and therapeutic challenge. For many years, HFpEF lacked effective disease-modifying therapies. Diuretics improve symptoms but not survival, and agents proven to reduce mortality in HF with reduced ejection fraction (HFrEF), including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists—have not shown consistent benefit in HFpEF. ,,, More recently, sodium–glucose cotransporter-2 inhibitors demonstrated reductions in HF hospitalization and composite cardiovascular (CV) outcomes in HFpEF populations. , In contrast, although beta-blockers (BB) are well established in HFrEF, their role in HFpEF remains uncertain. Current 2021 European Society of Cardiology (ESC) and 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guidelines do not provide specific recommendations for BB use in HFpEF beyond comorbidity management. , Available evidence remains limited, heterogeneous, and predominantly observational. Therefore, this systematic review and meta-analysis aimed to evaluate the association between BB use and major clinical outcomes in adults with HFpEF.
Methods
This systematic review and meta-analysis were performed and reported per the Cochrane Collaboration Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement guidelines. , The protocol for this prospective meta-analysis was registered with PROSPERO on September 27, 2025, and assigned the registration number CRD420251156778.
Search strategy and selection process
A systematic literature search was conducted in PubMed, Embase, and Cochrane databases from inception to September 2025. The search strategy was developed based on the criteria of population, intervention, comparison, outcome, and study design. The following search terms were utilized in all three databases: (“Heart Failure, Diastolic” OR HFpEF OR “heart failure preserved ejection fraction” OR “heart failure with preserved ejection fraction” OR “heart failure with preserved systolic function” OR HFmrEF OR “mid-range ejection fraction”) AND (“Adrenergic Beta-Antagonists” OR beta-blocker OR “beta adrenergic antagonist” OR “adrenergic beta receptor antagonist” OR carvedilol OR bisoprolol OR metoprolol OR nebivolol OR atenolol OR propranolol OR nadolol OR labetalol OR sotalol OR esmolol OR pindolol OR acebutolol OR betaxolol OR celiprolol OR timolol OR alprenolol OR “beta adrenergic blocking agent”). The search strategy is reported in the Supplemental Material ( Appendix 1 , Supplemental Digital Content 1).
Additionally, the reference lists of all included studies and relevant reviews were manually screened to identify any additional eligible studies. Two researchers (M.W.S. and A.P.D) independently evaluated the data using predetermined search criteria and quality-assessment techniques. When disagreements arose between these two authors, they were resolved through discussion and consensus, with input from a third author (C.O.F.B).
Inclusion and exclusion criteria
Inclusion in this meta-analysis was limited to studies meeting all of the following eligibility criteria: (1) randomized controlled trials (RCTs), prospective or retrospective cohort studies; (2) adult population diagnosed with HFpEF, defined as a left ventricular ejection fraction (LVEF) ≥50%, or ≥45% when classified as HFpEF by the study authors, as well as studies combining HFpEF and HF with mildly reduced ejection fraction (HFmrEF) populations without separate data reporting; and (3) reporting at least one relevant clinical outcome.
Studies were excluded if they met any of the following criteria: (1) narrative reviews; (2) previous meta-analyses; (3) editorials; (4) letters or commentaries without original data; (5) descriptive epidemiological studies, such as case reports or case series; (6) conference abstracts without full-text publication; (7) animal studies; (8) studies including pediatric populations; (9) studies evaluating exclusively acute HF or HFrEF; (10) studies not reporting relevant clinical outcomes; (11) studies with overlapping populations; or (12) clinical guidelines or consensus statements.
Although RCTs were eligible, no adequately powered RCTs reporting time-to-event clinical outcomes in HFpEF met the inclusion criteria for quantitative synthesis; therefore, the pooled evidence reflects observational cohort data.
Data collection process
Data were manually extracted and recorded in a structured spreadsheet using the Google Sheets platform. Extracted information included study characteristics (author, year, design, population, interventions, and outcomes), as well as relevant details for methodological quality and risk of bias assessments. To ensure data accuracy, a second reviewer (P.B) independently verified a random sample of 20% of the extracted entries to identify potential inconsistencies.
As this was a study-level meta-analysis, missing individual patient data could not be retrieved or imputed. Outcomes were synthesized using adjusted hazard ratios (HRs) as reported. Baseline characteristics not provided were recorded as not available and were not imputed.
End points and sensitivity analysis
Outcomes assessed in this study included both primary and secondary end points. The primary outcome was (1) all-cause mortality. The secondary outcomes included: (2) CV death, (3) HF hospitalization, and (4) the composite end point of all-cause death or HF hospitalization. Sensitivity analyses were performed to assess the robustness of the findings, including leave-one-out (LOO) analysis for outcomes with I² values of 50% or higher, recalculating the pooled HR after sequentially removing each study to evaluate the stability of the results.
Quality assessment
The risk of bias in each study was assessed using the tool Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I). Two independent reviewers (M.W.S. and A.P.D.) conducted the assessments, and any disagreements were resolved through consensus after a full-text review of the articles.
Statistical analysis
The HRs and corresponding 95% confidence intervals (CIs) were pooled using a random-effects model to compare the association between BB therapy in patients with HFpEF and clinical outcomes. Heterogeneity across studies was assessed using Cochran’s Q test, I² statistic, and Tau-squared, estimated through the restricted maximum likelihood method. Heterogeneity was categorized as low (I² = 0–25%), moderate (I² = 26–50%), or high (I² > 50%). All statistical analyses were performed using R statistical software, version 4.5.0 (R Foundation for Statistical Computing). When continuous baseline variables were reported as medians and interquartile ranges, missing means and standard deviations were estimated using the method described by Wan et al, in accordance with guidance from the Cochrane Handbook. These estimates were used for descriptive purposes only and not for the pooling of HRs.
Results
Study selection and baseline characteristics
The search in the databases identified 607 articles. After removing duplicates and screening based on title and abstract, 25 full-text articles were reviewed for possible inclusion. Finally, 13 observational cohort studies met the predefined inclusion criteria and were incorporated into this meta-analysis. ,,,,,,,,,,,, The study selection process is illustrated in Figure 1 .
PRISMA flowchart illustrating the study screening and selection process for the systematic review.
Across these studies, all patients had a confirmed diagnosis of HFpEF. In total, the pooled population comprised 442,543 participants, with a median follow-up duration of 2.8 years and a mean age of 76.0 ± 8.3 years. Most patients were male (51.7%). The mean LVEF was 57.4% ± 9.2 ( Table 1 ).
Table 1
Baseline characteristics of included studies.
| Study | Study design | Intervention | Control | N° of patients B/ NB | Age B/ NB | Male (%) B/ NB | LVEF (%) B/NB | Hypertension (n) B/ NB | Diabetes (n) B/ NB | AF/Flutter (n) B/ NB |
|---|---|---|---|---|---|---|---|---|---|---|
| Arnold, 2023 | Cohort | β-blockers | No β-Blocker | 230607/ 129616 | 76.2 ± 7.8/ 76.0 ± 7.8 | 52.6%/ 50.5% | 56.8 ± 9.6/ 59.4 ± 9.1 | NA/NA | NA/NA | NA/NA |
| Bitar, 2021 | Cohort | β-blockers | No β-Blocker | 412/ 277 | NA/NA | 32.8%/ 40.5% | NA/NA | 354/230 | 147/97 | 175/116 |
| Formiga, 2022 | Cohort | β-blockers | No β-Blocker | 531/ 547 | 78.9 ± 8.9/ 79.7 ± 8.7 | 38.9%/38.7% | NA/NA | 493/ 482 | 283/ 263 | NA/NA |
| Gomez-Soto, 2011 | Cohort | β-blockers | No β-Blocker | 378/ 707 | 68.3 ± 7.7/ 72.3 ± 6.3 | 44.9%/ 27.8% | 58.5 ± 2.9/ 58.8 ± 3.3 | 249/ 456 | 178/ 326 | 111/ 204 |
| Ibrahim, 2024 | Cohort | β-blockers | No β-Blocker | 12514/ 7692 | 75.9 ± 12.2/ 75.7 ± 14.0 | 59.0%/ 64.2% | 56.6 ± 5.2/ 57.5 ± 5.4 | 8305/ 3094 | 3927/ 1272 | 4087/ 1111 |
| Lam, 2018 | Cohort | β-blockers | No β-Blocker | 640/640 | 76.0 ± 11.0/ 76.0 ± 12.0 | 33.9%/ 33.3% | 58.7 ± 7.0/ 59.0 ± 7.0 | 547/ 546 | 274/ 256 | 246/ 237 |
| Matsumoto, 2025 | Cohort | β-blockers | No β-Blocker | 9905/ 3495 | 72.1 ± 8.4/ 73.6 ± 8.5 | 45.5%/ 43.3% | 59.4 ± 7.1/ 61.0 ± 7.8 | 9191/ 3090 | 4068/ 1207 | 4904/ 1388 |
| Meyer, 2021 | Cohort | β-blockers | No β-Blocker | 11990/ 2444 | 78.3 ± 10.3/ 80.2 ± 10.3 | 48.4%/ 49.8% | 53.2 ± 3.7/ 55 +- 7.4 | 8635/ 1563 | 3389/ 595 | 7692/ 1160 |
| Nevzorov, 2012 | Cohort | β-blockers | No β-Blocker | 154/ 191 | 76.2 ± 10.3/ 77.8 ± 11.4 | 37.6%/ 43.9% | NA/NA | 118/ 123 | 76/62 | 65/ 90 |
| Peikert, 2023 | Cohort | β-blockers | No β-Blocker | 5177/ 1086 | 71.3 ± 9.4/ 73.5 ± 10.0 | 56.4%/ 54.8% | 53.8 ± 8.6/ 56 ± 9.2 | 4623/ 930 | 2349/ 457 | 2969/ 583 |
| Ruiz, 2016 | Cohort | β-blockers | No β-Blocker | 985/ 985 | 72.7 ± 7.3/ 72.6 ± 7.1 | 45.0%/ 45.1% | 58.5 ± 2.7/ 58.6 ± 3.0 | 655/ 658 | 425/425 | 348/ 349 |
| Seko, 2022 | Cohort | β-blockers | No β-Blocker | 216/ 374 | NA/NA | 51.0%/ 46.6% | 52.9 ± 9.6/ 58.7 ± 10.0 | NA/NA | NA/NA | NA/NA |
| Uijl, 2024 | Cohort | β-blockers | No β-Blocker | 17078/ 3902 | NA/NA | NA/NA | NA/NA | NA/NA | NA/NA | NA/NA |
AF = atrial fibrillation; B = beta-blocker therapy; LVEF = left ventricular ejection fraction; NA = not available; NB = no beta-blocker therapy.
Primary outcome
The primary outcome, all-cause mortality, was analyzed by extracting HR from individual studies and pooling them using a random-effects model. BB use was associated with a lower risk of all-cause mortality among patients with HFpEF or HFmrEF (HR 0.81, 95% CI 0.73–0.90, p < 0.01) ( Figure 2 ). On analyzing subgroups based on differentiating types of HF, BB use was associated with lower mortality in patients with HFpEF (HR 0.80, 95% CI 0.73–0.88, p < 0.001) and HFmrEF (HR 0.84, 95% CI 0.81–0.87, p < 0.001), with heterogeneity null in the HFmrEF group and high (I² = 94.6%) in the HFpEF group ( Figure 3 ).
Beta-blocker therapy was associated with a statistically significant reduction in all-cause mortality among patients with HFpEF or HFmrEF, as shown by the pooled hazard ratios (p < 0.01).
Subgroup analysis by heart failure phenotype demonstrated that beta-blocker therapy significantly reduced all-cause mortality in patients with HFpEF and HFmrEF (p < 0.001).
Secondary outcomes
Cardiovascular mortality
CV death is a clinically relevant outcome in patients with HF. In pooled analyses, BB use was associated with a lower risk of CV death (HR 0.76, 95% CI 0.64–0.90, p < 0.01) ( Figure 4 ). In subgroup analyses according to HF phenotype, BB use was associated with lower CV mortality among patients with HFpEF, based on six studies (HR 0.77, 95% CI 0.65–0.90, p < 0.001; I² = 87%). Only 1 study contributed data for the HFmrEF subgroup ( Figure 5 ).
Beta-blocker therapy significantly reduced CV mortality among patients with heart failure (p < 0.01).
Subgroup analysis demonstrated that beta-blocker therapy significantly decreased CV mortality in patients with HFpEF, while only one study included HFmrEF cases (p< 0.001).
HF hospitalization
The beta-blocker use was associated with a lower risk of HF hospitalization among patients with HFpEF or HFmrEF in pooled analyses (HR 0.88, 95% CI 0.78–1.00, p = 0.05; I² = 91.6%) ( Figure 6 ). In subgroup analyses, BB use was associated with a nonsignificant trend toward a lower risk of HF hospitalization in patients with HFpEF (HR 0.93, 95% CI 0.84–1.03, p = 0.15), accompanied by high heterogeneity (I² = 89.2%) and inconsistent findings across studies. In contrast, among patients with HFmrEF, BB use was associated with a lower risk of HF hospitalization (HR 0.79, 95% CI 0.74–0.83, p < 0.001), with no observed heterogeneity ( Figure 7 ).
Beta-blocker therapy was associated with a significant reduction in heart failure hospitalizations among patients with HFpEF and HFmrEF (p = 0.05).
Subgroup analysis showed a trend toward reduced HF hospitalizations in HFpEF and a significant reduction in HFmrEF (p = 0.15).
Composite outcome of HF or death
In pooled analyses, BB use was associated with a lower risk of the composite outcome of HF hospitalization or death (HR 0.89, 95% CI 0.82–0.98, p = 0.02) ( Figure 8 ). In subgroup analyses, BB use was associated with a lower risk of the composite outcome among patients with HFpEF (HR 0.90, 95% CI 0.83–0.98, p = 0.01), although heterogeneity was high (I² = 89.7%), with generally consistent findings across studies. Similarly, BB use was associated with a lower risk of the composite outcome in the HFmrEF subgroup (HR 0.83, 95% CI 0.80–0.86, p < 0.001), with no observed heterogeneity ( Figure 9 ).
