Highlight
• β-blockers are frequently prescribed in HFpEF, but their impact on patient-reported health status remains unclear.
• Analysis of 1,726 patients from the TOPCAT trial showed no significant association between β-blocker use and baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) scores.
• No meaningful modification by β-blockers was observed on spironolactone’s health status benefits at 4 months.
• Patients with LVEF ≥65% on β-blockers showed a nominally lower health status, warranting further investigation.
Study Background and Disease Burden
Heart failure with preserved ejection fraction (HFpEF) constitutes approximately half of the heart failure population and is characterized by symptoms of heart failure despite a preserved left ventricular ejection fraction (LVEF ≥45%). Unlike heart failure with reduced ejection fraction (HFrEF), for which evidence-based treatments including β-blockers have demonstrated survival and symptomatic benefit, management strategies for HFpEF remain less well-defined. Patients with HFpEF frequently experience impaired health-related quality of life and increased morbidity but therapeutic interventions had limited proven impact on patient-reported outcomes.
β-Blockers are widely used in HFpEF, mainly extrapolating from HFrEF trials and due to their benefits in comorbidities such as coronary artery disease and hypertension. However, their direct effects on health status in HFpEF remain poorly understood. The Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated heart failure-specific patient-reported outcome measure, quantifies symptoms, physical limitations, and social function, providing an insight into patients’ health status and quality of life. Understanding whether β-blocker use impacts health status could inform individualized treatment decisions in this heterogeneous HFpEF population.
Study Design
This study represents a secondary cohort analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) randomized clinical trial. The original trial enrolled 3,445 patients diagnosed with HFpEF (LVEF ≥45%) randomized to receive spironolactone or placebo.
For this analysis, patients enrolled from regions with concerns about data fidelity (Georgia and Russia) were excluded, as were those with missing baseline data on β-blocker use or KCCQ overall summary scores. The final analytic cohort included 1,726 patients recruited between August 10, 2006, and January 31, 2012. Baseline β-blocker use was recorded, and health status was assessed using baseline KCCQ-OS scores and changes at 4 months.
Multivariable linear regression models were employed to assess associations between β-blocker use and concurrent baseline KCCQ-OS, adjusting for demographics and clinical covariates. The interaction between β-blocker use and LVEF strata was tested. Additionally, a longitudinal model assessed whether β-blocker use modified changes in KCCQ-OS over 4 months, particularly in relation to spironolactone therapy.
Key Findings
Among the cohort (mean age 71.6 years, 49.9% women), 78.6% were on β-blockers at baseline. The mean LVEF was 58.1%.
1. Association with Baseline Health Status: β-blocker use was not significantly associated with baseline KCCQ-OS (mean difference -1.1 points; 95% CI, -3.7 to 1.4; P=0.38). This suggests that β-blockers neither improved nor worsened patient-reported health status at enrollment.
2. Effect Modification by LVEF: Although statistically non-significant (P=0.21 for interaction), patients with LVEF ≥65% on β-blockers had a numerically lower KCCQ-OS score (mean difference -6.1 points; 95% CI, -12.3 to 0.0) compared to those with intermediate LVEF strata (55–64% and 45–54%). This may indicate potential differential effects by LVEF subgroup requiring further exploration.
3. Longitudinal Changes and Interaction with Spironolactone: Over 4 months, β-blockers did not significantly modify the health status benefit associated with spironolactone (mean difference 2.9 points with β-blockers vs. 0.1 points without; P=0.20 for interaction). This indicates no synergistic or antagonistic effect on health status outcomes between these therapies in HFpEF.
4. Safety and Tolerability: The study did not directly report safety outcomes related to β-blocker use; however, the lack of worsening health status provides indirect reassurance about tolerability in this population.
Expert Commentary
The lack of clear benefit or harm in health status conferred by β-blockers in HFpEF contrasts with the established efficacy of β-blockers in HFrEF, highlighting the distinct pathophysiological mechanisms driving HFpEF. The nominally lower health status scores in patients with very high LVEF (≥65%) might reflect underlying heterogeneous myocardial or vascular factors or comorbidities not fully captured by this analysis.
Current HFpEF guidelines emphasize individualized care focusing on symptom management and comorbidity control. While β-blockers remain staples for associated conditions like ischemic heart disease and atrial fibrillation, their role as primary therapy for health status improvement in HFpEF is not supported by these findings.
This study’s strengths include a well-characterized clinical trial population and rigorous adjustment for confounders. Yet, limitations include its observational nature regarding β-blocker exposure, potential residual confounding, and exclusion of patients from regions with trial enrollment concerns. Additionally, health status changes were assessed over a relatively short duration (4 months), which may not fully capture long-term effects.
Conclusion
In this secondary analysis of the TOPCAT trial cohort, β-blocker use among patients with HFpEF was not associated with significant differences in baseline health status or modification of the health status benefits derived from spironolactone therapy over 4 months. These findings suggest that routine β-blocker use may not improve patient-reported health outcomes in HFpEF, although further research is needed to clarify effects in specific subgroups and over longer durations.
Clinicians should continue to individualize treatment based on comorbidities and symptomatic needs rather than expecting uniform health status improvement solely from β-blocker therapy in HFpEF. Ongoing and future clinical studies exploring novel therapies and patient-centered outcomes will be critical in refining the management of this complex syndrome.
References
1. Abdel Jawad M, Spertus JA, Cho YJ, Jones PG, Arnold SV. β-Blocker Use and Health Status Among Patients With Heart Failure With Preserved Ejection Fraction. JAMA Netw Open. 2025 Aug 1;8(8):e2529519. doi: 10.1001/jamanetworkopen.2025.29519. PMID: 40875231; PMCID: PMC12395312.
2. Paulus WJ, Tschöpe C, Sanderson JE, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2020 Jan 14;41(40):407-432. doi: 10.1093/eurheartj/ehz859.
3. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-3726. doi: 10.1093/eurheartj/ehab368.
