The Impact of Beta Blockers on Survival in Heart Transplant Recipients: Insights from the Zabrze HTx Registry

Introduction The data assessing the impact of beta blocker (BB) medication on survival in patients after heart transplantation (HTx) are scarce and unequivocal; therefore, we investigated this population. Methods We retrospectively analyzed the HTx Zabrze Registry of 380 consecutive patients who survived the 30-day postoperative period. Results The percentage of patients from the entire cohort taking BBs was as follows: atenolol 24 (17%), bisoprolol 67 (49%), carvedilol 11 (8%), metoprolol 28 (20%), and nebivolol 8 (6%). The patients receiving BBs were older (56.94 ± 14.68 years vs. 52.70 ± 15.35 years, p=0.008) and experienced an onset of HTx earlier in years (11.65 ± 7.04 vs. 7.24 ± 5.78 p ≤ 0.001). They also had higher hematocrit (0.40 ± 0.05 vs. 0.39 ± 0.05, p=0.022) and red blood cells (4.63 (106/μl) ± 0.71 vs. 4.45 (106/μl) ± 0.68, p=0.015). Survival according to BB medication did not differ among the groups (p=0.655) (log-rank test). Univariate Cox proportional hazard regression analysis revealed that the following parameters were associated with unfavorable diagnosis: serum concentration of albumin (g/l) HR: 0.87, 95% CI (0.81–0.94), p=0.0004; fibrinogen (mg/dl) HR: 1.006, 95% CI (1.002–1.008), p=0.0017; and C-reactive protein (mg/l) HR: 1.014, 95% CI (1.004–1.023), p=0.0044. Conclusions The use of BBs in our cohort of patients after HTx was not associated with survival benefits.


Introduction
Heart transplantation (HTx), which is the gold standard of treatment at the end stage of heart failure, is associated with denervation of the donor's heart. Since the reinnervation is reported in approximately fifty percent of cases and rarely affects the parasympathetic nervous system, the donors have increased heart rates [1,2]. Physiological studies have shown that the exercise capacity of a denervated heart is determined by the increase in stroke volume through the Frank-Starling mechanism, and the raised heart rate (HR) contributes only later, at the peak of exercise [3]. e older studies have indicated that the use of nonselective beta blocker (BB) (propranolol) during physical activity resulted in reduced exercise tolerance and capacity [3,4]. erefore, BBs were advised to be used with caution; nonetheless, the early concerns about their use were recently challenged. Hence, a growing body of evidence shows that the elevated HR is associated with increased mortality and that the use of HR-decreasing medication in the selected group of patients may improve the short-and midterm results [5,6]. Data on the use of BBs in HTx recipients in the clinical setting are scarce and unequivocal; therefore, we sought to investigate the impact of these drugs in the population of patients included in the institutional HTx Registry [7].

Aim.
To test the hypothesis that HTx recipients who receive BBs during follow-up have a better prognosis.

Methods
A total of 380 consecutive adult patients (≥18 years) receiving HTx at the Silesian Center of Heart Diseases between January 1, 2000, and December 31, 2018, who survived the in-hospital postoperative period and were hospitalized between May 1, 2017, and December 31, 2018, were retrospectively analyzed. e study complies with the Declaration of Helsinki and was approved by the local ethical committee which waived the need for informed consent (approval numberŚIL.KB.790. 19). e follow-up between May 1, 2017, and October 31, 2019, was conducted in a typical manner in the outpatient clinic, using the phone contact or the digital information from the National Insurance System. e study flowchart is depicted in Figure 1. As the decision on the type of medication to implement was left at the physician's discretion, the authors did not interfere with this decision at any time point. e 4587 records of patients were collected using a computer software called the Retrieval Project, which was designed for this purpose. If the patient was eligible for the BB treatment, but it was discontinued for any reason and reported as such in a six-to twelve-month interval, the patient was described as not treated; this occurred in only three cases. e software was validated, and the data were manually verified to check if it was correctly retrieved.

Statistical Analysis.
Distributions of the examined parameters were analyzed using the Shapiro-Wilk test. Categorical variables were expressed as n and percentage. Continuous variables were expressed as the mean ± standard deviation (SD). Linear variables with normal distribution were compared using Student's t-test. Variables with abnormal distribution were compared using the Mann-Whitney U test. Categorical variables were compared using the chi-square test. A Kaplan-Meier analysis was used to demonstrate the frequency of death due to any cause during the follow-up. Log-rank test was used to compare the survival curves based on BB use. Cox proportional hazard uni/multivariate regression approach was used to evaluate the risk of death. Independent predictors were presented as the hazard ratio (HR) with a confidence interval (CI). Differences between the values were considered statistically significant if p < 0.05. Analyses were performed using R statistical environment.

Cardiology Research and Practice
Over ninety percent of patients in the cohort completed the follow-up. e cumulative survival rate is depicted in Figure 3.
Kaplan-Meier survival curves did not show statistically significant differences between those who received BBs and those who did not: p � 0.655 (log-rank test). e Kaplan-Meier curves are shown in Figure 4.

Discussion
is paper has two major clinical implications. Firstly, the prognosis of the HTx patients who survived the in-hospital postoperative period in the eastern European country may not differ significantly from the western countries despite the substantial differences in the organization and funding of the healthcare systems [8,9]. Secondly, we could not document the beneficial effect of BB administration on survival in the real-life clinical setting. Several aspects might have played a role. ese include the older age of the patients receiving BBs compared to the control group (56.94 ± 14.68 vs. 52.70 ± 15.35, p � 0.008); the more complex clinical profile of patients with more than one indication for the therapy (94 patients (68%) vs. 54 patients (22%), p ≤ 0.001); and the higher incidence of patients with the impairment of the systolic function of the heart (40 patients (29%) vs. 30 patients (12%), p ≤ 0.001).
In our cohort, BBs were mainly initiated in the treatment of supraventricular and ventricular tachycardia and in patients with impaired LVEF. Moreover, we reported a large number of patients receiving atenolol (n � 24, 17%) which has a lesser impact on hypertension, but not on heart rate, compared to bisoprolol [10][11][12]. e clinical practice at our center shows that BBs were introduced as a third or fourth line of drugs in the treatment of hypertension and frequently coadministered with calcium channel blockers (62 patients (45%) vs. 85 patients (35%), p � 0.059); however, this difference was statistically insignificant. It is likely that using BBs in the cohort of older patients with higher incidence of comorbidities weakened or waived its potentially beneficial effect on survival [13,14].
Despite the early controversies, there is a rising consensus that an increased heart rate stimulates coronary artery vasculopathy (CAV) and reduces survival after HTx [5][6][7][22][23][24][25][26]. We found that the most advanced form of CAV, according to the ISHLT recommendations, occurred more often in patients receiving BBs than those who did not (13% vs. 7%, p � 0.073), notwithstanding the difference was not statistically significant [27].
Nevertheless, it should be highlighted that the CAV, despite being present in half of the patients ten years after HTx, contributes only partially to the total mortality along with malignancies, infections, rejections, and renal insufficiencies [28,29]. is contribution tends to be even lower in centers providing careful follow-up with annual invasive assessments and early revascularization of narrow stenoses [30]. erefore, we cannot provide substantial evidence that the use of BBs in the patients without effective heart rate reduction has a beneficial effect on survival. Moreover, with the positive impact of diltiazem and ivabradine on cardiac remodeling and exercise tolerance, it would be interesting to compare their efficacy alone or in combination; thus, further investigations are warranted [31][32][33].

Limitations of the Study.
e study is limited by the fact that only a part of the population of HTx patients has been analyzed due to technical reasons related to the automatic data acquisition. Moreover, we did not address the diastolic function of the heart and immunological agents which could have influenced the results.

Conclusions
e use of BB in our cohort of patients after HTx was not associated with improved survival. Further investigations including the use of other HR-decreasing agents like ivabradine or diltiazem, alone or in combination with BBs, are mandatory in the HTx patient population.

Data Availability
e data used to support the findings of this study are restricted by the local ethical board (approval numbeŕ SIL.KB.790. 19) in order to protect patient privacy. Data are available from the corresponding author through gkubiak@ sccs.pl for researchers who meet the criteria for access to confidential data.

Additional Points
e free trial version of the ProjectRetrieval ® software is available to download at the http://retrieval-project.com.pl. Its functionality is limited. Any potential users are kindly requested to contact the authors prior to the use of the software in order to set a consensus considering the donation and citation details.

Conflicts of Interest
e authors declare that they have no conflicts of interest.