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

Kubiak, Grzegorz M.; Kwieciński, Radosław; Ciarka, Agnieszka; Tukiendorf, Andrzej; Przybyłowski, Piotr; Hrapkowicz, Tomasz; Zembala, Michał O.

doi:https://doi.org/10.1155/2020/5190248

Cardiology Research and Practice

On this page

Abstract Introduction Methods Results Discussion Conclusions Data Availability Additional Points Conflicts of Interest Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2020 | Article ID 5190248 | https://doi.org/10.1155/2020/5190248

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

Grzegorz M. Kubiak,^1,2Radosław Kwieciński,¹Agnieszka Ciarka,²Andrzej Tukiendorf,³Piotr Przybyłowski,¹Tomasz Hrapkowicz,¹and Michał O. Zembala¹

Academic Editor: Michael S. Wolin

Received31 Mar 2020

Accepted16 Jun 2020

Published23 Jul 2020

Abstract

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, ) and experienced an onset of HTx earlier in years (11.65 ± 7.04 vs. 7.24 ± 5.78 ). They also had higher hematocrit (0.40 ± 0.05 vs. 0.39 ± 0.05, ) and red blood cells (4.63 (10⁶/μl) ± 0.71 vs. 4.45 (10⁶/μl) ± 0.68, ). Survival according to BB medication did not differ among the groups () (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), ; fibrinogen (mg/dl) HR: 1.006, 95% CI (1.002–1.008), ; and C-reactive protein (mg/l) HR: 1.014, 95% CI (1.004–1.023), . Conclusions. The use of BBs in our cohort of patients after HTx was not associated with survival benefits.

1. 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]. The 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]. Therefore, 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].

1.1. Aim

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

2. 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. The study complies with the Declaration of Helsinki and was approved by the local ethical committee which waived the need for informed consent (approval number ŚIL.KB.790.19). The 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. The 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. The 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. The software was validated, and the data were manually verified to check if it was correctly retrieved.

2.1. 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 . Analyses were performed using R statistical environment.

3. Results

The patients were more prone to receive BBs if they were diagnosed with supraventricular tachycardia 90 (65%) vs. 12 (5%) () and ventricular tachycardia 14 (10%) vs. 6 (2%) (). BBs were also more frequently used in patients suffering from reduced left ventricular ejection fraction (LVEF) below fifty-five percent 40 (29%) vs. 30 (12%) (). Notwithstanding, the use of BBs among patients diagnosed with hypertension or atrial fibrillation did not differ between the groups (114 (83%) vs. 188 (78%), = ns, and 10 (7%) vs. 18 (7%), = ns, respectively). Complex clinical characteristic (described as two or more indications) was common in both the BB and non-BB groups, 94 (68%) and 54 (22%), . Dilated cardiomyopathy was less frequently reported as a reason for HTx in those patients who received BBs compared to those who did not 42 (30%) vs. 107 (44%), . Compared to patients who were not on BBs, the patients receiving BBs were older (mean: 56.94 ± 14.68 years vs. 52.70 ± 15.35 years, ). They also had an earlier onset of HTx (mean: 11.65 ± 7.04 years vs. 7.24 ± 5.78 years, ) and higher initial HR (101.09 ± 12.26 (1/min) vs. 90.88 ± 12.32 (1/min), ). Other differences among the groups were statistically insignificant. The data are presented in Table 1.

Bisoprolol was used in 67 patients (49%), carvedilol in 11 patients (8%), metoprolol in 28 patients (20%), and nebivolol in 8 patients (6%). The data are depicted in Figure 2.

The patients receiving BBs had higher hematocrit and red blood cells than the non-BB patients (0.40 ± 0.05 vs. 0.39 ± 0.05, and 4.63 (10⁶/μl) ± 0.71 vs. 4.45 (10⁶/μl) ± 0.68, , respectively). They also had lower platelets: 201.73 (10³/μl) ± 62.39 vs. 220.44 (10³/μl) ± 76.77, . Additionally, the patients receiving BBs had decreased level of tacrolimus 8.45 (ng/ml) ± 3.63 vs. 9.40 (ng/ml) ± 3.83, , and cyclosporin 110.60 (ng/ml) ± 32.04 vs. 141.01 (ng/ml) ± 49.76, . Other differences including differences in biochemical, hematological, and coagulation parameters were statistically insignificant. All data are shown in Table 2.

Over ninety percent of patients in the cohort completed the follow-up. The 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: (log-rank test). The Kaplan–Meier curves are shown in Figure 4.

Univariate Cox proportional hazard regression analysis revealed that the following parameters were associated with unfavorable prognosis: decreased albumin (g/l) HR: 0.87, 95% CI (0.81–0.94), ; increased fibrinogen (mg/dl) HR: 1.006, 95% CI (1.002–1.008), ; and increased CRP (mg/l) HR: 1.014, 95% CI (1.004–1.023), . Multivariate Cox proportional hazard regression model of survival did not show any significant predictors of death for any cause because the variables were too closely associated. The uni/multivariate Cox proportional hazard regression analysis is presented in Table 3.

4. Discussion

This 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. These include the older age of the patients receiving BBs compared to the control group (56.94 ± 14.68 vs. 52.70 ± 15.35, ); the more complex clinical profile of patients with more than one indication for the therapy (94 patients (68%) vs. 54 patients (22%), ); and the higher incidence of patients with the impairment of the systolic function of the heart (40 patients (29%) vs. 30 patients (12%), ).

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 [10–12]. The 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%), ); 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].

Ciarka et al. reported that BB treatment had beneficial effects on survival after HTx, which may be associated with its antiarrhythmic properties, especially given that it reduces the incidence of atrial fibrillation in the general population and after heart surgery [15–18]. In their study, patients receiving BB were older (52 ± 11 years vs. 49 ± 15 years, ) and had higher serum concentrations of total cholesterol (TC) (216 ± 53 vs. 204 ± 50 mg/dl, ) and low-density lipoprotein cholesterol (LDL-C) (120 ± 44 mg/dl vs. 107 ± 40 mg/dl, ). These results are in line with our observations. Patients receiving BBs in our study were also older (56.94 ± 14.68 years vs. 52.70 ± 15.35 years, ) and had higher concentrations of TC and LDL-C levels although without statistical significance (4.35 ± 1.34 vs. 4.25 ± 0.97 mmol/l and 2.21 ± 1.06 vs. 2.12 ± 0.84 mmol/l, = ns, respectively). We observed that the patients receiving BBs had different blood morphology which was expressed by elevated red blood cells (RBC) (4.63 ± 0.71 vs. 4.45 ± 0.68 (10⁶/μl), ), elevated hematocrit (0.40 ± 0.05 vs. 0.39 ± 0.05, ), and decreased platelets (201.73 ± 62.39 vs. 220.44 ± 76.77 (10³/μl), ). It was reported that the hemoglobin concentration and hematocrit are raised in hypertensive patients [19, 20]. It has been proved in animal studies that the hemoglobin reduces the nitric oxide availability for the smooth muscle cells which implies vasoconstriction [21].

Despite the early controversies, there is a rising consensus that an increased heart rate stimulates coronary artery vasculopathy (CAV) and reduces survival after HTx [5–7, 22–26]. 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%, ), 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]. This contribution tends to be even lower in centers providing careful follow-up with annual invasive assessments and early revascularization of narrow stenoses [30]. Therefore, 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 [31–33].

4.1. Limitations of the Study

The 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.

5. Conclusions

The 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

The data used to support the findings of this study are restricted by the local ethical board (approval number ŚIL.KB.790.19) in order to protect patient privacy. Data are available from the corresponding author through [email protected] for researchers who meet the criteria for access to confidential data.

Additional Points

The 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

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors thank Mrs. Wiktoria Świątek for the English language editing and Dr. Kuczaj and Dr. Małyszek-Tumidajewicz for providing careful care in the outpatient clinic. They would like to express their special acknowledgments to Prof. Zakliczyński for the experience and invaluable remarks he shared. The publication of the manuscript was funded by the Medical University of Silesia.

References

F. Buendia-Fuentes, L. Almenar, C. Ruiz et al., “Sympathetic reinnervation 1 year after heart transplantation, assessed using iodine-123 metaiodobenzylguanidine imaging,” Transplantation Proceedings, vol. 43, no. 6, pp. 2247-2248, 2011.
View at: Publisher Site | Google Scholar
S.-R. Lee, D.-Y. Kang, Y. Cho et al., “Early parasympathetic reinnervation is not related to reconnection of major branches of the vagus nerve after heart transplantation,” Korean Circulation Journal, vol. 46, no. 2, pp. 197–206, 2016.
View at: Publisher Site | Google Scholar
R. S. Bexton, J. R. Milne, R. Cory-Pearce, T. A. English, and A. J. Camm, “Effect of beta blockade on exercise response after cardiac transplantation,” Heart, vol. 49, no. 6, pp. 584–588, 1983.
View at: Publisher Site | Google Scholar
S. S. Kushwaha, N. R. Banner, N. Patel, A. Cox, H. Patton, and M. H. Yacoub, “Effect of beta blockade on the neurohumoral and cardiopulmonary response to dynamic exercise in cardiac transplant recipients,” Heart, vol. 71, no. 5, pp. 431–436, 1994.
View at: Publisher Site | Google Scholar
R. Rivinius, M. Helmschrott, A. Ruhparwar et al., “Control of cardiac chronotropic function in patients after heart transplantation: effects of ivabradine and metoprolol succinate on resting heart rate in the denervated heart,” Clinical Research in Cardiology, vol. 107, no. 2, pp. 138–147, 2018.
View at: Publisher Site | Google Scholar
M. Liebo, J. Newman, A. Joshi et al., “Elevated heart rate following heart transplantation is associated with increased graft vasculopathy and mortality,” Journal of Cardiac Failure, vol. 25, no. 4, pp. 249–256, 2019.
View at: Publisher Site | Google Scholar
M. Pazdernik, D. Wichterle, Z. Chen et al., “Heart rate and early progression of cardiac allograft vasculopathy: a prospective study using highly automated 3-D optical coherence tomography analysis,” Clinical Transplantation, vol. 34, no. 2, Article ID e13773, 2020.
View at: Publisher Site | Google Scholar
L. E. Zijlstra, A. A. Constantinescu, O. Manintveld et al., “Improved long-term survival in Dutch heart transplant patients despite increasing donor age: the Rotterdam experience,” Transplant International, vol. 28, no. 8, pp. 962–971, 2015.
View at: Publisher Site | Google Scholar
T. Deuse, F. Haddad, M. Pham et al., “Twenty-year survivors of heart transplantation at stanford university,” American Journal of Transplantation, vol. 8, no. 9, pp. 1769–1774, 2008.
View at: Publisher Site | Google Scholar
J. M. Neutel, D. H. G. Smith, C. V. S. Ram, M. P. Lefkowitz, M. K. Kazempour, and M. A. Weber, “Comparison of bisoprolol with atenolol for systemic hypertension in four population groups (young, old, black and nonblack) using ambulatory blood pressure monitoring,” The American Journal of Cardiology, vol. 72, no. 1, pp. 41–46, 1993.
View at: Publisher Site | Google Scholar
R. Lewis, D. Maclean, C. Ioannides, A. Johnston, and D. McDevitt, “A comparison of bisoprolol and atenolol in the treatment of mild to moderate hypertension,” British Journal of Clinical Pharmacology, vol. 26, no. 1, pp. 53–59, 1988.
View at: Publisher Site | Google Scholar
W.-J. Zhou, R.-Y. Wang, Y. Li et al., “A randomized controlled study on the effects of bisoprolol and atenolol on sympathetic nervous activity and central aortic pressure in patients with essential hypertension,” PLoS ONE, vol. 8, no. 9, Article ID e72102, 2013.
View at: Publisher Site | Google Scholar
M. R. Costanzo, A. Dipchand, R. Starling et al., “The international society of heart and lung transplantation guidelines for the care of heart transplant recipients,” The Journal of Heart and Lung Transplantation: The Official Publication of the International Society for Heart Transplantation, vol. 29, no. 8, pp. 914–956, 2010.
View at: Publisher Site | Google Scholar
M. R. Mehra, C. E. Canter, M. M. Hannan et al., “The 2016 international society for heart lung transplantation listing criteria for heart transplantation: a 10-year update,” The Journal of Heart and Lung Transplantation, vol. 35, no. 1, pp. 1–23, 2016.
View at: Publisher Site | Google Scholar
A. Ciarka, L. H. Lund, J. Van Cleemput, G. Voros, W. Droogne, and J. Vanhaecke, “Effect of heart rate and use of beta blockers on mortality after heart transplantation,” The American Journal of Cardiology, vol. 118, no. 12, pp. 1916–1921, 2016.
View at: Publisher Site | Google Scholar
H. Fröhlich, L. Torres, T. Täger et al., “Bisoprolol compared with carvedilol and metoprolol succinate in the treatment of patients with chronic heart failure,” Clinical Research in Cardiology, vol. 106, no. 9, pp. 711–721, 2017.
View at: Publisher Site | Google Scholar
G. Marazzi, F. Iellamo, M. Volterrani et al., “Comparison of effectiveness of carvedilol versus bisoprolol for prevention of postdischarge atrial fibrillation after coronary artery bypass grafting in patients with heart failure,” The American Journal of Cardiology, vol. 107, no. 2, pp. 215–219, 2011.
View at: Publisher Site | Google Scholar
M. Konishi, G. Haraguchi, S. Kimura et al., “Comparative effects of carvedilol vs bisoprolol for severe congestive heart failure,” Circulation Journal, vol. 74, no. 6, pp. 1127–1134, 2010.
View at: Publisher Site | Google Scholar
M. Emamian, S. M. Hasanian, M. Tayefi et al., “Association of hematocrit with blood pressure and hypertension,” Journal of Clinical Laboratory Analysis, vol. 31, no. 6, Article ID e22124, 2017.
View at: Publisher Site | Google Scholar
S.-G. Lee, J. H. Rim, and J.-H. Kim, “Association of hemoglobin levels with blood pressure and hypertension in a large population-based study: the Korea National Health and Nutrition Examination Surveys 2008-2011,” Clinica Chimica Acta, vol. 438, pp. 12–18, 2015.
View at: Publisher Site | Google Scholar
P. Cabrales, G. Han, P. Nacharaju, A. J. Friedman, and J. M. Friedman, “Reversal of hemoglobin-induced vasoconstriction with sustained release of nitric oxide,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 300, no. 1, pp. H49–H56, 2011.
View at: Publisher Site | Google Scholar
L. Gullestad, H. Ross, J. Myers et al., “Importance of decreased heart rate in predicting transplant coronary artery disease,” Clinical Transplantation, vol. 11, no. 6, pp. 628–632, 1997.
View at: Google Scholar
L. A. Weinrauch and J. A. D’Elia, “Use of calcium channel blockers after heart transplantation,” The American Journal of Cardiology, vol. 120, no. 3, p. 512, 2017.
View at: Publisher Site | Google Scholar
A. B. Shah, J. K. Patel, M. Rafiei, R. P. Morrissey, M. M. Kittleson, and J. A. Kobashigawa, “The impact of mean first-year heart rate on outcomes after heart transplantation: does it make a difference?” Clinical Transplantation, vol. 27, no. 5, 2013.
View at: Publisher Site | Google Scholar
Á. López-Sainz, E. Barge-Caballero, G. Barge-Caballero et al., “Late graft failure in heart transplant recipients: incidence, risk factors and clinical outcomes,” European Journal of Heart Failure, vol. 20, no. 2, pp. 385–394, 2018.
View at: Publisher Site | Google Scholar
J. Schilling and J. Vader, “Be still my beating heart: should heart rate be a target of therapy after heart transplantation?” Journal of Cardiac Failure, vol. 25, no. 4, pp. 257-258, 2019.
View at: Publisher Site | Google Scholar
M. R. Mehra, M. G. Crespo-Leiro, A. Dipchand et al., “International society for heart and lung transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010,” The Journal of Heart and Lung Transplantation, vol. 29, no. 7, pp. 717–727, 2010.
View at: Publisher Site | Google Scholar
M. J. Wilhelm, “Long-term outcome following heart transplantation: current perspective,” Journal of Thoracic Disease, vol. 7, no. 3, pp. 549–551, 2015.
View at: Publisher Site | Google Scholar
L. H. Lund, L. B. Edwards, A. Y. Kucheryavaya et al., “The registry of the international society for heart and lung transplantation: thirty-first official adult heart transplant report-2014; focus theme: retransplantation,” The Journal of Heart and Lung Transplantation, vol. 33, no. 10, pp. 996–1008, 2014.
View at: Publisher Site | Google Scholar
H. R. C. Biefer, S. H. Sündermann, M. Y. Emmert et al., “Surviving 20 years after heart transplantation: a success story,” The Annals of Thoracic Surgery, vol. 97, no. 2, pp. 499–504, 2014.
View at: Publisher Site | Google Scholar
S. Varnado, Y. Peled-Potashnik, A. Huntsberry et al., “Effect of diltiazem on exercise capacity after heart transplantation,” Clinical Transplantation, vol. 31, no. 8, Article ID e12997, 2017.
View at: Publisher Site | Google Scholar
E. Lage-Gallé, N. Romero-Rodríguez, J. Nevado-Portero et al., “Safety and effectiveness of ivabradine after cardiac transplantation,” Transplantation Proceedings, vol. 42, no. 8, pp. 3191-3192, 2010.
View at: Publisher Site | Google Scholar
A. Doesch, S. Mueller, C. Gleissner et al., “Heart rate reduction for 36 months with ivabradine reduces left ventricular mass in cardiac allograft recipients: a long-term follow-up study,” Drug Design, Development and Therapy, vol. 7, pp. 1323–1328, 2013.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2020 Grzegorz M. Kubiak et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1634

Downloads

774

Citations