The prevalence of heart failure (HF) with preserved ejection fraction (HFpEF) increases with age and is higher in females across the spectrum of old age.1,2 Currently, no treatment has been shown to improve the prognosis of HFpEF.3,4 This lack of evidence has not prevented these patients’ attending physicians from prescribing therapies with benefits proven only for HF with reduced ejection fraction (HFrEF), especially when other comorbidities appear to provide a justification for their use.

The use of beta-adrenergic receptor blockers (beta-blockers) is therefore common in patients with HFpEF, although scientific doubts about their benefits have been raised.3,5,6 Controlled studies assessing the clinical effects of beta-blockers in HFpEF have shown inconsistent and heterogeneous results.7–9 However, data from current registries show high rates (ranging from 50% to 80%) of beta-blocker prescription in these patients, regardless of baseline heart rhythm.10,11 In our setting, in the RICA registry, which assesses the characteristics and trajectories of elderly HF patients (mean age 80 years) cared for by internists during an episode of decompensation, the percentage of beta-blocker prescription on discharge was 53%, with a sizable proportion of such patients also suffering from atrial fibrillation (AF).12

To analyze the clinical effect of beta-blockers in elderly patients with HFpEF in more detail, avoiding the confounding effect of age-prevalent concomitant arrhythmias, we investigated whether this class of drugs modifies the risk of mortality or readmission after an acute episode of HF decompensation focusing only on the subset of HFpEF patients presenting with sinus rhythm on admission.

Patients with HFpEF were divided into two groups according to whether or not they were discharged with a prescription of any beta-blocker with a guideline-recommended use for chronic HFrEF (carvedilol, bisoprolol, metoprolol succinate, or nebivolol) regardless of dose.4 The primary endpoints of our study were one-year all-cause mortality (after index admission discharge) and the composite endpoint of all-cause mortality or HF readmission.

The study complied with the principles outlined in the Declaration of Helsinki. The study protocol (155/2007) was approved by the Ethics Committee of University Hospital Reina Sofia in Cordoba, Spain. All patients provided written informed consent at inclusion.

A descriptive analysis of the sample was performed using mean and standard deviation for quantitative variables and frequency and percentage for categorical variables. The baseline characteristics of the groups were compared using the t test and Fisher's exact test for quantitative and categorical variables, respectively. Multivariate logistic regression analysis was used to identify predictors of beta-blocker prescription at discharge. Mortality and readmission were analyzed at one-year follow-up, and predictive differences between groups were analyzed with cumulative episode curves using the Kaplan-Meier method. Multivariate Cox regression analysis was carried out to asses mortality risks, using the backward conditional method for all variables shown in univariate analysis to be significantly associated with a higher probability of readmission or death. The covariates included in the final multivariate model were those associated with statistical significance in univariate analysis in addition to those related to the use of beta-blockers. The C-statistic of the final model was 0.664. A similar analysis was performed to analyze the combination of overall mortality or HF readmission. The C-statistic of this other final model was 0.626. The level of statistical significance was established as p<0.05. The data were analyzed using IBM SPSS, version 21.0, Armonk, NY, USA.

Of the total of 5312 RICA patients, 3315 fulfilled the inclusion criteria, and of these, 2042 had HFpEF (61.6%). Of these, 1078 (52.8%) were in sinus rhythm and were included in this study. At the time of hospital discharge, 531 (49.3%) were on beta-blocker therapy; 289 (54%) patients received bisoprolol, 43 (27%) carvedilol, 51 (9.6%) nebivolol, seven (1.2%) metoprolol succinate, and 8.1% others.

The mean age at inclusion was 79.3±8.8 years, and 419 (39%) were male. The baseline characteristics of these patients and the differences according to discharge beta-blocker use are summarized in Tables 1 and 2.

Factors associated with all-cause mortality

A total of 161 patients (15%) died within 12 months of follow-up. Table 3 shows the factors associated with HF-related mortality. After multivariate adjustment, beta-blockers were not associated with total mortality (hazard ratio [HR] 0.83, 95% CI 0.61-1.13; p=0.236). Covariates associated with mortality were male gender, higher heart rate, valvular disease, higher comorbidity, poor physical performance, poor renal function, and treatment with loop diuretics. Figure 1 shows the Kaplan-Meier survival curve for one-year all-cause mortality according to beta-blocker prescription status (log-rank p=0.235).

Table 3.

Factors associated with one-year all-cause mortality.

Variable	Univariate analysis		Multivariate analysis
	HR (95% CI)	p	HR (95% CI)	p
Age	1.02 (1.00-1.04)	0.043
Male gender	1.22 (0.89-1.66)	0.218	1.54 (1.10-2.16)	0.012
Heart rate	1.01 (1.00-1.02)	0.036	1.01 (1.00-1.02)	0.022
Hypertension	1.14 (0.64-2.00)	0.659
Diabetes	1.03 (0.76-1.40)	0.850
Ischemic heart disease	1.70 (1.21-2.39)	0.002
SBP	0.99 (0.99-1.00)	0.063
Etiology
Ischemic	1.09 (0.75-1.57)	0.656
Hypertensive	0.72 (0.52-0.99)	0.041
Valvular	1.96 (1.36-2.81)	<0.001	2.40 (1.66-3.48)	<0.001
Institutionalized	0.99 (0.50-1.94)	0.974
Charlson index	1.11 (1.05-1.17)	<0.001	1.08 (1.01-1.15)	0.026
Stroke	1.49 (0.99-2.24)	0.056
COPD	1.35 (0.96-1.90)	0.084
Barthel index	0.99 (0.98-0.99)	<0.001	0.99 (0.98-0.99)	<0.001
Pfeiffer index	1.13 (1.05-1.21)	<0.001
NYHA functional class
I-II	0.66 (0.48-0.90)	0.010
III-IV	1.52 (1.11-2.10)	0.010
Hemoglobin, g/dl	0.94 (0.87-1.01)	0.098
eGFR, <60 ml/min	1.73 (1.23-2.42)	0.002	1.68 (1.18-2.41)	0.004
Sodium, mmol/l	1.01 (0.97-1.04)	0.720
Potassium, mmol/l	1.22 (0.98-1.53)	0.082
Treatment at discharge
ACEIs and/or ARBs	0.86 (0.62-1.19)	0.352
Beta-blockers	0.83 (0.61-1.13)	0.236
Loop diuretics	0.86 (0.55-1.36)	0.527	0.60 (0.38-0.95)	0.030
Thiazides	0.81 (0.49-1.34)	0.415
Aldosterone antagonists	1.33 (0.92-1.92)	0.128

ACEIs: angiotensin-converting enzyme inhibitors; ARBs: angiotensin receptor blockers; CI: confidence interval; COPD: chronic obstructive pulmonary disease; eGFR MDRD: estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula; HR: hazard ratio; NHYA: New York Heart Association; SBP: systolic blood pressure.

Figure 1.

Kaplan-Meier survival curve for all-cause mortality at one year according to discharge beta-blocker prescription. Log-rank p=0.235.

(0.09MB).

Factors associated with one-year all-cause mortality or readmission for heart failure

At one year of follow-up, 314 (29%) patients had either died or been readmitted. Figure 2 shows the Kaplan-Meier curve for one-year all-cause mortality or HF-related admission according to beta-blocker prescription, which again did not significantly influence these outcomes (log-rank p=0.882).

Figure 2.

Kaplan-Meier curve for all-cause mortality or heart failure-related admission at one year according to beta-blocker prescription. Log-rank p=0.882.

(0.08MB).

Table 4 shows the factors associated with one-year all-cause mortality or HF readmission. Multivariate analysis confirmed that beta-blocker therapy was not related to this combined endpoint (HR 0.98, 95% CI 0.79-1.23; p=0.882). Instead, a prior history of coronary heart disease, HF due to ischemic or valvular etiology, higher comorbidity burden, past stroke history, poor cognitive status and higher potassium levels were associated with a worse prognosis.

Table 4.

Factors associated with one-year all-cause mortality and/or heart failure readmission.

Variable	Univariate analysis		Multivariate analysis
	HR (95% CI)	p	HR (95% CI)	p
Age	1.01 (1.00-1.02)	0.096
Male gender	1.02 (0.81-1.28)	0.864
Heart rate	1.00 (1.00-1.01)	0.644
Hypertension	1.48 (0.95-2.30)	0.084
Diabetes	1.09 (0.87-1.36)	0.450
Ischemic cardiopathy	1.72 (1.35-2.18)	<0.001	1.39 (1.07-1.79)	0.012
SBP	1.00 (0.99-1.00)	0.219
Etiology	1.01 (1.00-1.02)	0.096
Ischemic	1.33 (1.03-1.70)	0.028	1.38 (1.04-1.83)	0.024
Hypertensive	0.74 (0.59-0.93)	0.009
Valvular	1.43 (1.08-1.90)	0.013	1.61 (1.17-2.21)	0.003
Institutionalized	0.76 (0.45-1.30)	0.322
Charlson index	1.10 (1.06-1.15)	<0.001	1.08 (1.03-1.13)	0.001
Stroke	1.62 (1.22-2.16)	<0.001	1.43 (1.04-1.96)	0.028
COPD	1.42 (1.11-1.81)	0.005
Barthel index	0.99 (0.99-1.00)	<0.001
Pfeiffer index	1.09 (1.03-1.15)	0.002	1.06 (1.01-1.13)	0.027
NYHA functional class
I-II	0.71 (0.56-0.90)	0.005
III-IV	1.40 (1.11-1.77)	0.005
Hemoglobin, g/dl	0.93 (0.88-0.98)	0.006
eGFR, <60 ml/min	1.53 (1.21-1.94)	<0.001
Sodium, mmol/l	0.99 (0.97-1.01)	0.349
Potassium, mmol/l	1.26 (1.07-1.48)	0.005	1.20 (1.00-1.42)	0.004
Treatment at discharge
ACEIs and/or ARBs	1.10 (0.87-1.38)	0.436
Beta-blockers	0.98 (0.79-1.23)	0.882
Thiazides	0.80 (0.56-1.15)	0.225
Aldosterone antagonists	1.02 (0.77-1.35)	0.902

ACEIs: angiotensin-converting enzyme inhibitors; ARBs: angiotensin receptor blockers; COPD: chronic obstructive pulmonary disease; NHYA: New York Heart Association; eGFR MDRD: estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula; SBP: systolic blood pressure.

The main result of our study is that nearly half of the elderly HF patients in the RICA cohort with HFpEF in sinus rhythm (20.3% of the total RICA sample) were discharged with a beta-blocker. These patients’ profile was defined by a previous history of hypertension, a higher comorbidity burden (including prior ischemic heart disease), and better functional status, but a lower prevalence of COPD. These patients also had lower heart rate and were more often prescribed with ACEIs/ARBs/ARNIs and loop diuretics. In this cohort, being on beta-blockers did not improve the risks of either all-cause mortality or the combined outcome of all-cause mortality plus HF-related readmission in the short to mid term (one year).

Regarding the use of beta-blockers in patients with HFpEF, in the recent PARAGON trial13 75% of the participants were pre-treated with beta-blockers (32% of the total included patients also had a diagnosis of AF), a percentage similar to the 79% found in the TOPCAT trial (34% again with a concomitant diagnosis of AF)14 and higher than the 59% found in I-PRESERVE (29% AF),15 56% of CHARM-preserved16 (29% AF) and 55% of PEP-CHF17 (21% AF). These latter percentages, of just over half of the study being treated with beta-blockers, are similar to those reported in our RICA registry (53%), in which the percentage of patients receiving beta-blockers in cases of HFpEF was similar (p=0.182) for both the group without (51%) and with AF (55%).8 In the TOPCAT trial, 42.6% of patients receiving beta-blockers had an AF diagnosis.19 These figures, showing that beta-blocker prescription rates are higher than the proportion of patients with HF and AF, confirm that our sample follows the same prescription trend, even though there is no scientific evidence for beta-blocker use in HFpEF.

Regarding prognosis, many previous studies included patients with intermediate ejection fraction (EF) (40-50%), a subset of HF for which beta-blockers might be clinically useful. Lund et al.,19 using data from the Swedish Heart Failure Registry, reported that among HFpEF patients (EF ≥40%), beta-blocker use was associated with lower all-cause mortality (one-year survival 84% vs. 78%) but not with reduction of combined all-cause mortality or heart failure hospitalization. A secondary analysis of the TOPCAT trial reported that for patients with EF ≥50%, beta-blocker use was associated with an increased risk of HF hospitalizations but not of cardiovascular disease mortality, whereas for patients with EF between 45% and 49% no such association was found.18 The SENIORS study was underpowered to analyze the subgroup of patients with EF ≥50%.20

Beta-blockers are frequently prescribed in patients without indications for associated comorbidities (tachyarrhythmias or exertional angina), likely based on extrapolations of pathophysiological pathways that have not been well clarified in HFpEF and may sometimes be paradoxical. Sympathetic antagonism may promote a reduction in myocardial oxygen demand and have anti-ischemic, antiarrhythmic and antiremodeling effects, besides reducing blood pressure and prolonging ventricular filling time, among other possible beneficial mechanisms.21 However, cardiac output in a hypertrophic and rigid myocardium is highly dependent on heart rate, and therefore any slowing might hinder an appropriate increase in output that is needed for exertion.22 Furthermore, slowing heart rate leads to prolongation of diastolic filling, which increases end-systolic volumes and pressures, contributing to significant stress on the myocardial wall.23 Manbiar et al.24 have shown that beta-blocker withdrawal in stable patients with HFpEF was associated with a significant reduction in natriuretic peptides, a marker of myocardial stress.

Current evidence in patients with HFpEF and ischemic heart disease only supports the prescription of beta-blockers in the early phase after an acute coronary syndrome and for the management of angina.9 Data from the TOPCAT study showed that the use of beta-blockers in patients without prior myocardial infarction was associated with poorer health outcomes (increased risk of all-cause death, major cardiovascular events, and hospitalization for HF).18 In our real-world data, however, we did not find this negative association.

New techniques, such as assessment of myocardial global longitudinal strain (GLS), may help select HFpEF patients who could potentially benefit more from beta-blockade. For patients with HF and LVEF ≥40%, beta-blocker use is associated with improved survival in those with GLS <14%.25 Chronotropic incompetence, on the other hand, is very common among the elderly and is associated with a poor maximum functional capacity.26,27

The main strength of our study is that it is based on prospective data from a multicenter, homogeneous real-world elderly HFpEF cohort who have experienced an episode of AHF, a subset of HF patients for whom clinical information derived from clinical trials is almost non-existent. Nevertheless the study has several limitations. First, it is a cohort study, not a randomized trial, and thus may be subject to various selection biases. For instance, patients who die during the index admission are not included in the registry. Second, biomarkers were available for only a subgroup of our patients. Third, other than recording treatment at discharge, we did not analyze how post-discharge management or intervening incidents may have affected mortality or readmission risk. Fourth, the reasons behind the choice (and type) of beta-blocker prescription were not recorded, and neither were data on further up-titration, dose modification or withdrawal. Also, we did not analyze medications used before the index admission, so the possible legacy effect of beta-blocker prescription was not accounted for.

In conclusion, the use of beta-blockers in elderly patients with HFpEF in sinus rhythm does not seem to influence major clinical outcomes (death or HF readmission) within a year following an AHF admission. Whether these results might affect prescription habits in this subset of HF patients remains to be tested in appropriate trials.

The authors have no conflicts of interest to declare.