The potential effects discussed in the previous paragraphs may often be difficult to distinguish clinically and therefore be less convincing. Clinical endpoints are of paramount importance in assessing measurable impact significance and the impact resulting from the integration of therapeutic modalities into the healthcare system. Therefore, we have decided to emphasize the research focusing on the endpoints disregarding the minor effects. Translating into the currently prevailing terminology based on 2021 ESC guidelines [2], patients undergoing the aforementioned analysis of the SWEDIC study [17] can be divided into the HFmrEF (EF 41–49%) and HFpEF (EF ≥ 50%) subgroups. The results of a recent study showed that treatment with beta-blockers may be associated with reduced risk of hospitalization and death only in the HFmrEF patient group. In the HFpEF group, there is a lack of significant reduction in the risk of hospitalization, or survival benefit, particularly in the subgroup with an EF > 60% [18].

The study focusing on the association between the use of beta-blockers and different outcomes in patients with HFpEF revealed that the use of beta-blockers was associated with lower all-cause mortality but did not reduce combined all-cause mortality or HF hospitalizations. With a median follow-up of 709 days in the matched cohort, 1-year survival was 80% vs 79% for treated vs untreated patients, and 5-year survival was 45% vs 42%, with 2279 (41%) vs 1244 (45%) total deaths and 177 vs 191 deaths per 1000 patient-years; moreover, beta-blockers use did not reduce combined mortality or heart failure hospitalizations—3368 (61%) vs 1753 (64%) total for first events, with 371 vs 378 first events per 1000 patient-years. To highlight the differences between the different phenotypes of HF, it is worth mentioning that in the matched HFrEF cohort, beta-blockers reduced mortality and also reduced combined mortality or heart failure hospitalization [19].

In the fully adjusted first model of the TOPCAT trial analysis, patients with an ejection fraction of 50% or greater who were receiving beta-blockers had a higher relative risk of heart failure hospitalization compared to those not receiving beta-blockers. In a second sensitivity analysis involving propensity score-matched cohorts, beta-blocker use was also associated with a higher number of hospitalizations due to heart failure among patients with an ejection fraction of 50% or greater [20].

The SENIORS trial with nebivolol [21] included HF patients regardless of EF and demonstrated a beneficial beta-blocker effect independent of EF [22]. In a meta-analysis comprising 25 RCTs, beta-blockers exhibited a decrease in both all-cause and cardiovascular mortality when compared to a placebo in patients with an ejection fraction greater than 40% (The American College of Cardiology defined a group of patients with 41 to 49% EF as borderline HFpEF at the time of this meta-analysis being undertaken) [23]. The value of this study in assessing the use of beta-blockers for treating HFpEF may be limited due to the inclusion criteria; in the 25 studies analyzed, 7 studies included patients with EF > 40%, 9 studies included patients with EF > 45%, and only 9 studies focused on patients with EF > 50%. Additionally, some of the studies had only a 12-week follow-up period.

The current scientific discourse emphasizes the importance of both duration and dose in the context of beta-blocker administration [24].

The findings from the J-DHF study indicate that the administration of the standard carvedilol dose of 7.5 mg/day in patients with EJ ≥ 50% did not demonstrate a reduction of the risk of any composite outcomes. However, the risks for a composite of cardiovascular or all-cause death and unplanned hospitalization for any cardiovascular causes tended to be reduced when compared with the control group [25].

An analysis of the Medicare-linked OPTIMIZE-HF data, that included 26,376 patients, of which 8873 had HFpEF, defined as ejection fraction ≥ 50%, revealed that among hospitalized elderly patients with HFpEF and a discharge heart rate > 70 bpm, the utilization of high-dose beta-blockers is linked to a reduced risk of all-cause readmission and the combined endpoint of all-cause readmission or all-cause mortality; nevertheless, the use of high-dose beta-blockers did not translate to a significant reduction of HF hospital readmissions [26].

In the context of the evaluation of a nationwide sample of 13,533 applicable patients with the diagnosis of HFpEF, the administration of beta-blocker therapy revealed a non-significant trend in survival benefits after 1 year. However, a statistically significant improvement in survival outcomes was observed after 3 years of treatment. The observed reduction in mortality with beta-blockers, when contrasted with the more pronounced effects of statins and renin–angiotensin–aldosterone system inhibitors, suggests a substantial proportion of patients with underlying coronary artery disease. This highlights the heterogeneity of HFpEF populations in older cohorts and raises important considerations about the potential confounding effects of comorbidities such as coronary artery disease on these outcomes [27].

Yndigegn et al. [28] in their recently published study highlighted that the widespread use of beta-blockers post-myocardial infarction is based on research conducted prior to the era of biomarker-driven diagnostics and intravascular interventions and modern pharmaceuticals, questioning their current relevance. A randomized clinical trial aimed at assessing the impact of long-term beta-blocker therapy in patients post-myocardial infarction with accompanying HFpEF revealed that patients treated according to current guidelines did not derive benefit compared to the group not receiving beta-blockers, considering the composite primary end point of death from any cause or new myocardial infarction [28].

In a single-center retrospective cohort study of 20,206 patients with left ventricular ejection fraction (EF) ≥ 50% hospitalized for decompensated heart failure, beta-blocker therapy was associated with reduced all-cause mortality at 30 days, 1 year, and 3 years (p < 0.0001). This mortality benefit was further confirmed through a propensity score-matched analysis. Additionally, a secondary analysis demonstrated that the combination of beta-blockers with either spironolactone (p = 0.0359) or ACEi/ARBs (p < 0.0001) significantly reduced mortality at 3 years, even in patients with comorbid conditions such as hypertension, coronary artery disease, or atrial fibrillation [29].

The STRONG-HF trial was terminated early due to its remarkable results, demonstrating significant benefits of intensive treatment. It included patients across the spectrum of LVEF, including those with HFpEF. Beta-blockers were up-titrated more aggressively in the high-intensity care group, with 49% of patients reaching full doses by day 90 compared to 4% in the usual care group. Subgroup analysis showed that the intensive treatment strategy, including beta-s, was equally effective in patients with HFpEF as in those with HFrEF or HFmrEF. The study also demonstrated a significant reduction in the primary endpoint (180-day heart failure readmission or all-cause death), suggesting the potential benefits of beta-blockers in HFpEF when up-titrated effectively [30].

It is important to keep in mind that RCTs have shown that mortality decreases as ejection fraction improves. This contrasts with heart failure with HFpEF, where mortality is largely driven by non-cardiovascular causes, emphasizing the complex and multifactorial nature of the condition. Consequently, most studies prioritize total mortality rather than focusing solely on cardiovascular mortality.

To provide a clearer representation of the cited study results, they have been consolidated into Table 1.

It is noteworthy that certain referenced studies originate from periods during which alternative classifications and guidelines were in force, thus constraining their contemporary applicability [31,32,33,34,35,36].