Association between the beta‐blockers, calcium channel blockers, all‐cause mortality and length of hospitalization in patients with heart failure with preserved ejection fraction: A meta‐analysis of randomized controlled trials

Abstract Purpose To establish an association between beta‐blockers (BBs), calcium channel blockers (CCBs), all‐cause mortality, and hospitalization in patients with Heart failure with preserved Ejection Fraction (HFpEF). Methods The present meta‐analysis has been performed as per the guidelines of (PRISMA). An inclusive literature search was made without any limitations on language using the electronic databases Cochrane Library, EMBASE, and PubMed up to November 2022. The outcomes evaluated in this meta‐analysis involved all‐cause mortality and hospitalization due to heart failure. The number of patients with HFpEF and their positive outcomes was extracted and analyzed using RevMan software. Results In total, 10 articles were included in the present meta‐analysis, with a pooled sample size of 12 940 HFpEF patients. In comparison with placebo, both BB and CCB substantially reduced the risk of all‐cause mortality and hospitalization. However, BB are more effective because they provide a significant reduction in all‐cause mortality (risk ratio (RR) = 0.60; 95% confidence interval [CI] = 0.43–0.83; p = .002] and hospitalization (RR = 0.54; 95% CI = 0.37–0.80; p = .002) as compared with CCB with a risk ratio of all‐cause mortality (RR = 0.77; 95% CI = 0.60–0.98; p = .03) and hospitalization (RR = 0.63; 95% CI = 0.44–0.90; p < .00001). A random‐effects model was used because of high heterogeneity between the studies (I 2 > 70%). Conclusions The current meta‐analysis suggests that BBs were more beneficial than CCB in reducing all‐cause mortality and hospitalization duration in patients with HFpEF.


| INTRODUCTION
Heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) is defined as the presence of heart failure in the absence of any evidence of reduced LV ejection fraction. 1,2 This type of heart failure is also known as heart failure with intact left ventricular (LV) function. The incidence of HFpEF is on the rise, and research has linked it to an increase in the number of patients who require hospitalization. 3 Numerous studies on patients with chronic heart failure have shown that this syndrome has a high mortality and morbidity rate. 4 However, evidence from clinical studies revealing improvements in mortality has been variable and essentially unbiased; a few investigations suggest that pharmacological therapy may improve the tolerance for exercise and quality of life of these people. 5 Given that patients with heart failure with intact left ventricular ejection fraction (LVEF) are more likely to be older and have a greater number of comorbidities than their counterparts, 6,7 the efficacy of pharmacological treatment may be best assessed by its impact on hospitalization and associated symptoms. This condition can be treated with neprilysin inhibitors, sacubitril, valsaltran, an interleukin-1 blocker, Spironolactone, a RAAS blocker, a beta-blocker (BB), Sildenafil, an aldosterone antagonist, empagliflozin, and calcium channel blockers (CCBs). [7][8][9][10] Even though there is a paucity of evidence supporting their advantages, BBs are often recommended for HFpEF. BBs, or beta-adrenergic blocking medications, works by inhibiting the release of stress chemicals adrenaline and noradrenaline in specific regions, which decreases the heart rate and the force with which blood is pushed throughout the body. In their research articles, Yum et al. 11 and Xu et al. 12

| MATERIALS AND METHODS
The present meta-analysis was undertaken following the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

| Data sources and searches
An inclusive literature search was conducted without any limitations on the year and language of publication utilizing the electronic databases Cochrane Library, EMBASE, and PubMed up to September 30, 2022 using the following search criteria: (I) "heart failure with preserved ejection fraction " OR "HFpEF"; (II) "beta-blockers" OR BB; (III) "calcium channel blockers" OR "CCB"; (IV) "all-cause mortality"; (V) Length of hospitalization; (VI) and "cardiovascular outcomes." Within the context of the search strategy, the Boolean operator "AND" was used to combine the Medical Subject Headings (MeSH) with the text keywords. First, duplicate articles were deleted from the search results, followed by a title and abstract screening of the remaining articles. Finally, the full texts of all the qualified studies were retrieved and reviewed for inclusion and exclusion based on the inclusion-exclusion criteria.

| Study selection
The literature search was conducted separately by two authors.
Through discussion, a consensus was obtained in the event of dispute. The following conditions must be met for a study to qualify: (a) randomized controlled trials (RCTs) examining the efficacy of BBs and CCBs; (b) studies that evaluate at least one of the following two outcomes: all-cause mortality, or hospitalization for cardiovascular causes. Exclusion criteria included clinical trials with a follow-up time of smaller than one month. Studies that were led on healthy volunteers or on those who suffered from disorders other than HFpEF were also not considered. In the end, studies that compared medications other than BBs and CCBs were not included in this metaanalysis.

| Data extraction
A computerized data extraction form was developed in Microsoft Excel and utilized for the purpose of listing the fundamental information of the studies 15-24 selected for the meta-analysis. This included the first author's name, the year of publication, the intervention, the sample size in each group, the duration of followup, and the outcomes. The data were extracted by two different authors in an independent process, and then the results of both authors' extractions were compared. In the event that there was a difference of opinion, a consensus was reached through debate.
Third author was also included in the event whenever necessary.

| Quality assessment of the included studies
The Cochrane Risk of Bias tool was applied to evaluate the methodological validity of each and every study that was incorporated into the meta-analysis. During the process of data extraction, selected articles were given a score, and the RevMan version 5.4 software 25 was used to construct a quality evaluation graph.

| Data analysis
For the process of data analysis RevMan version 5.4.0 and MedCalc software 26 were utilized. For the purpose of assessing the pooled risk ratio in addition to the 95% confidence interval (CI) for both two outcomes, the Mantel-Haenszel technique with the random effect model 27 was utilized. A statistically significant result was regarded to have a p-value of < .05. 28 To graphically depict the risk ratio along with the 95% CI, forest plots 29 were utilized. I 2 statistics were utilized to ascertain the degree of heterogeneity present among the study's findings, 30 and for comparison of BBs and CCBs in terms of all-cause mortality, and length of hospitalization was done using metaregression analysis.  Table S1. 31 The main characteristics of all included trials, including 12 940 patients with HFpEF are displayed in Table 1. Five publications evaluated the effectiveness of BBs, 15,16,19,20,24 while five articles evaluated the effectiveness of CCBs. 17,18,[21][22][23] In all included investigations, the median follow-up time ranged from 1 month to 42 months.

| Assessment of risk of bias and publication bias
A pre-designed questionnaire was used for assessment of risk of bias and results are shown in Table S2. Figure S2 depicts the risk of bias summary, whereas Figure S3 depicts the risk of bias graph. Five of the 10 included studies were associated with low risk of bias whereas; three had a moderate risk attributable to allocation concealment and selective reporting. The other two studies posed a high risk of reporting bias. Figure 1

| Efficacy outcomes
All 10 trials with a total of 12 940 individuals provided data on allcause mortality and length of hospitalization. Figure 2   CCBs for all-cause mortality and length of hospitalization was done via meta-regression analysis as shown in Figure 4, and we found that BBs were more effective than CCBs, since the risk of all-cause death was 45% lesser in patients who took BBs as compared with those patients who took CCBs. Nevertheless, BBs are more effective than CCBs, as hospitalization for cardiac reasons was 73% lower in patients getting BBs as opposed to CCBs.

| DISCUSSION
Since heart failure is a leading cause of death worldwide, it's a matter of grave medical concern to understand all of its facets. With a greater understanding of the best medication, its mortality and morbidity can be minimized, and the overall survival rate can be improved. According to the guidelines published by the European Society of Cardiology, it is essential to lessen the problem of readmission for those patients who have HFpEF. 33 Due to the fact that patients with HFpEF (heart failure with preserved ejection fraction) have a higher probability of being older than those with HFrEF, they are more likely to be hospitalized for cardiac reasons, which is linked with an inferior quality of life and an advanced mortality rate. 34 Similarly, Xu et al. 45

| LIMITATIONS
The present meta-analysis has a number of limitations, such as a lack of data comparing different therapies; hence, we were unable to compare the therapies. Another restriction is the definition of HFpEF, which in some research is defined as heart failure with LVEF below 50% and in many trials as heart failure with LVEF between 40% and 49%. Aside from this, risk ratio values were predominantly used to identify the relationship between medicines, which may induce bias F I G U R E 4 Regression analysis of betablocker (BB) versus calcium channel blocker (CCB).

| CONCLUSIONS
When compared with CCBs, the results of this meta-analysis of randomized controlled trials involving HFpEF patients showed that the BB drugs considerably reduced the risk of mortality from any cause as well as the need for hospitalization among these patients.
This meta-analysis concluded that BBs were more effective in HFpEF patients based on statistically significant results.

ACKNOWLEDGMENTS
None declared. No funding was received.

CONFLICT OF INTEREST STATEMENT
The authors declare that they have no conflict of interest.

DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
Ethical approval was not required as this study was based on publicly available data.