Letter to the Editor: Beta-blockers vs calcium channel blockers in heart failure with preserved ejection fraction: An old question in need of new answers

Abstract

Heart failure with preserved ejection fraction (HFpEF) remains a complex and heterogeneous syndrome without robust disease-modifying therapies. In this context, the retrospective analysis comparing beta-blockers and calcium channel blockers offers intriguing signals that beta-blockers may reduce all-cause mortality and heart failure hospitalizations, albeit at the expense of increased symptomatic bradycardia and treatment discontinuation. While these findings are not definitive, they highlight the potential relevance of heart-rate control and autonomic modulation in selected HFpEF phenotypes. This article discusses the clinical implications and limitations of the study by Mansoor et al published in World Journal of Cardiology, emphasizing the need for precision-based treatment strategies and calling for prospective trials to clarify the true prognostic impact of beta-blockers in HFpEF. Ultimately, the study reinforces the notion that therapeutic decisions in HFpEF must be individualized, integrating hemodynamic, rhythm-related, and comorbidity-driven considerations.

Key Words: Heart failure with preserved ejection fraction; Beta-blockers; Calcium channel blockers; Phenotype-guided therapy; Heart rate control

Core Tip: Heart failure with preserved ejection fraction (HFpEF) remains a heterogeneous syndrome lacking robust disease-modifying therapies. This article critically examines the long-standing debate between beta-blockers and calcium channel blockers in HFpEF, integrating evidence from meta-analyses, observational studies, and a recent retrospective comparison. While beta-blockers may confer modest benefits in selected phenotypes - particularly in patients with atrial fibrillation or coronary artery disease - their potential to worsen chronotropic incompetence limits universal applicability. Calcium channel blockers appear largely safe and may reduce hospitalizations in specific settings. Overall, the analysis underscores the need for phenotype-driven, individualized treatment strategies and prospective trials to guide therapy in HFpEF.

TO THE EDITOR

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome[1,2]. Characterized by impaired diastolic function, elevated filling pressures, and a high burden of comorbidities, including hypertension, atrial fibrillation (AF), and coronary artery disease (CAD)[1-3]. Unlike heart failure with reduced ejection fraction, HFpEF lacks consistently effective disease-modifying therapies, and pharmacological management is largely driven by symptom control and treatment of associated conditions. Heart-rate modulation remains clinically relevant, particularly in patients with AF, although excessive rate reduction may worsen chronotropic incompetence and exercise intolerance[2,3]. In this context, the comparative role of beta-blockers and calcium channel blockers (CCBs) continues to be debated.

What do we know about beta-blockers and CCBs?

Mechanisms of action - beta-blockers vs CCBs: Beta-adrenergic blockers reduce heart rate, myocardial oxygen demand, and blood pressure, and may improve diastolic filling time. However, in HFpEF, excessive heart rate reduction can worsen chronotropic incompetence and limit exercise capacity[2,3]. CCBs act via inhibition of L-type calcium channels. Dihydropyridine CCBs (e.g., amlodipine) primarily cause vasodilation and lower blood pressure, while non-dihydropyridine CCBs (e.g., diltiazem, verapamil) also reduce heart rate and have negative inotropic effects[4,5]. Non-dihydropyridine CCBs may be preferred in patients with concomitant AF for rate control[4]. The Table 1[2-9] summarizes the knowledge about beta-blockers and CCBs in the context of HFpEF.

Table 1 Summary about beta-blockers and calcium channel blockers.

Topic	Ref.	Beta-blockers	Calcium channel blockers
Mechanism of action	Arnold et al[2], 2023; Wernhart et al[3], 2023; Meyer et al[4], 2023; Matsumoto et al[5], 2023	Reduce heart rate, myocardial oxygen demand, and blood pressure	Dihydropyridines cause vasodilation and BP reduction; non-dihydropyridines also reduce heart rate and have negative inotropic effects
Clinical use	Meyer et al[4], 2023; Matsumoto et al[5], 2023; Martin et al[7], 2021	Potential benefit in patients with concomitant CAD or AF	Non-dihydropyridines preferred for rate control in AF; dihydropyridines are mainly used for hypertension
Safety and adverse effects	Wernhart et al[3], 2023; Martin et al[7], 2021	Can worsen chronotropic incompetence and exercise intolerance, particularly in HFpEF without AF or CAD	Generally well tolerated; non-dihydropyridines may cause bradycardia and conduction disturbances
Efficacy in HFpEF	Meyer et al[4], 2023; Matsumoto et al[5], 2023; Wu et al[6], 2023; Martin et al[7], 2021; Liu et al[8], 2014; Bavishi et al[9], 2015	May modestly reduce cardiovascular mortality, but evidence certainty is low; inconsistent effects on all-cause mortality and HF hospitalization	Generally neutral or modestly protective for HF hospitalization and pump failure death, without increased mortality
Comparative outcomes	Arnold et al[2], 2023; Wernhart et al[3], 2023; Meyer et al[4], 2023; Martin et al[7], 2021	Benefits are more pronounced in HFpEF with CAD or AF; neutral or potentially harmful in patients without these comorbiditie	Non-dihydropyridines may be associated with lower HF hospitalization risk compared to beta-blockers, especially in HFpEF with AF
Strength of evidence	Joseph et al[1], 2019; Meyer et al[4], 2023; Wu et al[6], 2023; Martin et al[7], 2021; Liu et al[8], 2014; Bavishi et al[9], 2015	Meta-analyses, RCTs, and observational studies; results inconsistent	Mostly observational studies; limited RCT data
Clinical scenarios favoring use	Arnold et al[2], 2023; Meyer et al[4], 2023; Martin et al[7], 2021	HFpEF with AF or CAD	Hypertension, AF (rate control), or intolerance to beta-blockers due to exercise limitation

BP: Blood pressure; CAD: Coronary artery disease; AF: Atrial fibrillation; HFpEF: Heart failure with preserved ejection fraction; HF: Heart failure; RCT: Randomized controlled trial.

Safety considerations and adverse effects: Beta-blockers can worsen chronotropic incompetence and exercise intolerance, especially in HFpEF patients without AF or CAD[3,7]. CCBs, particularly dihydropyridines, are generally well tolerated, but non-dihydropyridines may increase the risk of bradycardia and conduction disturbances. CCB use has been associated with a higher risk of stroke, though the absolute risk is modest[5]. Clinical scenarios favoring beta-blockers include HFpEF with AF or CAD, while CCBs may be preferred in patients with hypertension, AF (for rate control), or those experiencing exercise intolerance with beta-blockers[2,4,7].

Limitations of current evidence and new findings

The evidence base is limited by the predominance of observational studies and underpowered randomized controlled trials, with significant heterogeneity in patient populations and endpoints[2,4,7,9]. The latest meta-analyses and randomized controlled trials reveal that beta-blockers do not consistently reduce all-cause mortality or heart failure hospitalization in patients with HFpEF, especially when stratified by comorbidities such as AF or CAD[4,9,10]. In pooled analyses, beta-blockers may offer benefit in HFpEF patients with concomitant CAD or AF, with meta-regression showing improved New York Heart Association class and B-type natriuretic peptides levels in these subgroups, but these findings are not robust across all studies and are limited by trial heterogeneity and low statistical power[9,10].

For patients with HFpEF and AF, beta-blockers are not superior to CCBs for reducing mortality or hospitalization. Observational data suggest that non-dihydropyridine CCBs (diltiazem, verapamil) may be associated with a lower risk of heart failure hospitalization compared to beta-blockers, but with a possible increase in all-cause mortality[4]. In large pooled analyses, CCBs - especially dihydropyridines - are not associated with worse heart failure outcomes and may reduce pump failure death, but may increase stroke risk[5]. Current guidelines from the American Heart Association, American College of Cardiology, and Heart Failure Society of America do not recommend beta-blockers or CCBs for HFpEF unless there is a separate indication, such as AF or CAD[11,12]. In summary, beta-blockers and CCBs should be selected based on comorbidities rather than for direct HFpEF benefit, with CCBs potentially preferred for rate control in AF and beta-blockers reserved for patients with CAD or other compelling indications[4,5,11].

According to the 2021 European Society of Cardiology Guidelines on HF, beta-blockers should be considered for short-term and long-term rate control in patients with HFpEF and AF (Class IIa, level of evidence B), while no specific recommendation is provided for CCBs in HFpEF outside of comorbidity-driven indications[13]. Importantly, the 2023 focused update of the European Society of Cardiology guidelines modified the therapeutic landscape of HFpEF by recommending sodium-glucose cotransporter-2 inhibitors (dapagliflozin or empagliflozin) to reduce the risk of heart failure hospitalization or cardiovascular death (class I, level of evidence A)[14]. Therefore, while beta-blockers and CCBs remain relevant for symptom control and comorbidity management, they should no longer be interpreted as disease-modifying therapies in isolation.

The paper published in World Journal of Cardiology by Mansoor et al[15] is a retrospective analysis comparing beta-blockers and CCBs that offers intriguing signals showing that beta-blockers may reduce all-cause mortality and heart failure hospitalizations, albeit at the expense of increased symptomatic bradycardia and treatment discontinuation. While these findings are not definitive, they highlight the potential relevance of heart-rate control and autonomic modulation in selected HFpEF phenotypes. A central and potentially outcome-defining limitation of this study is its reliance on simulated patient-level data rather than true individual patient records. Although the authors carefully calibrated simulations to real electronic medical records distributions and applied robust statistical techniques (including propensity score matching), simulations cannot reproduce the complex, non-random clinical decision-making that governs drug selection in HFpEF.

The large sample size and propensity score-matched design represent methodological strengths. However, the reliance on simulated patient-level data rather than true longitudinal clinical records introduces substantial limitations. Simulation cannot fully capture physician treatment selection, dose titration, adherence, or time-varying clinical trajectories, all of which are particularly relevant in a heterogeneous syndrome such as HFpEF. Consequently, residual confounding remains likely, and causal inference is inherently limited. These considerations may partially explain discrepancies between the reported findings and prior randomized or post-hoc trial data, underscoring the need for cautious interpretation.

This issue is especially relevant in HFpEF, a syndrome characterized by marked phenotypic heterogeneity and treatment-response discordance. Prior analyses from rigorously conducted randomized and post-hoc trial datasets (e.g., Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonis and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure)[12,16] have shown that beta-blockers exert neutral or even adverse effects on hospitalization and functional outcomes in subsets of HFpEF patients, underscoring how sensitive conclusions are to patient selection and unmeasured confounders. Without real-world longitudinal exposure data, adherence patterns, dose titration, or time-varying covariates, simulated cohorts risk overstating therapeutic consistency in a condition where none clearly exists. This limitation should temper interpretation of the reported mortality and hospitalization signals and reinforces the need for prospective, phenotype-stratified trials before translating these findings into clinical guidance.

Clinical implications

From a practical perspective, the findings reinforce a phenotype-driven approach to HFpEF management. Beta-blockers may be reasonable in patients with HFpEF and AF requiring rate control or in those with established CAD, provided that bradycardia and exercise intolerance are carefully monitored. In contrast, CCBs - particularly non-dihydropyridines - may be considered for rate control in AF when beta-blockers are poorly tolerated, while dihydropyridines remain appropriate for blood pressure control. Importantly, neither class should be viewed as a disease-modifying therapy in HFpEF, and contemporary management should prioritize guideline-recommended treatments such as sodium-glucose cotransporter-2 inhibitors alongside individualized control of comorbidities.

There is a need for improved patient stratification and larger, well-designed trials to clarify which HFpEF phenotypes benefit from beta-blockers or CCBs. Current consensus does not support routine use of either agent for HFpEF in the absence of alternative indications (e.g., AF, hypertension, CAD)[7].

CONCLUSION

In summary, beta-blockers may offer modest mortality benefit in HFpEF, particularly in patients with AF or CAD, but can worsen exercise intolerance in others. CCBs are generally safe and may reduce HF hospitalization, especially non-dihydropyridines in AF, without increasing mortality. Choice of agent should be individualized based on comorbidities and symptom profile.