Bisoprolol was Associated with Better Cardiac Outcomes in Hemodialysis Patients – A Comparison with Carvedilol

Introduction

Patients with end-stage renal disease undergoing maintenance dialysis (MHD) are often prescribed with beta-blockers for several prophylactic and therapeutic indications. However, the evidence for their clinical effectiveness in scarce in this special population. Particularly, the trials of comparative clinical effectiveness are lacking for the most commonly used beta-blockers in MHD patients.

There is a growing understanding of the heterogeneity of the pharmacokinetics and clinical actions of different beta-blockers in the general population. Furthermore, the choice of beta-blockers in the MHD patients is additionally complicated by the differential dialyzability profiles (clearance) and intradialytic hypotension potentials of different beta-blockers.

Bisoprolol and carvedilol are among the two commonly used beta-blockers in the clinical practice. They differ in their Beta-1 selectivity, action on the Aplha-1 receptors, and dialyzability profiles. Wu et al.1 hypothesized that bisoprolol may offer clinical advantages over carvedilol in this special population of MHD patients because of its cardioselectivity and moderate dialyzability with a relatively lower intradialytic hypotension potential.

Aims

In the light of the existing paucity of clinical data for beta-blocker usage in this special population, Wu and colleagues1 aimed to compare the cardiovascular outcomes associated with carvedilol or bisoprolol use in the MHD patients from a nationwide database, in order to inform the clinicians about their comparative clinical effectiveness.

Methods

This analysis was based on the data registered with the Taiwan National Health Insurance Research Database. This analysis enrolled adult patients who underwent chronic MHD for over 90 days and were prescribed beta-blockers between January 2004 and December 2011. The results were analyzed for patients who received their first prescription of bisoprolol or carvedilol only after MHD i.e., no beta-blocker prescription were active for the patients within 90 days before MHD..

Based on the dosage of bisoprolol or carvedilol, the patients were classified into low-dose or high-dose groups as follows: high-dose bisoprolol (≥10 mg/day), low-dose bisoprolol (1.25–<10 mg/day), high-dose carvedilol (≥50 mg/day) and low-dose carvedilol (6.25–<50 mg/day).

The main study outcomes included all-cause mortality and major adverse CV events (MACEs); MACE was defined as hospital admission primarily due to acute myocardial infarction, heart failure, or ischemic stroke. The follow-up continued until death, deregistration, dialysis modality change, renal transplantation, events or until 2 years. The main analysis followed an intention-to-treat (ITT) design.

Several secondary analyses were conducted to reduce the impact of confounding and to assess the robustness of the results, including 1:1 propensity-score matching, subgroup analysis by baseline coronary artery disease, sensitivity analysis by extending the definition of new user duration to 120 and 180 days, censoring patients at drug discontinuation or switching (as-treated analyses), and the assessment of residual confounding by using the E-value methodology.

Results and Discussion

A total of 9,305 and 11,171 patients in the bisoprolol and carvedilol groups, respectively were included in the primary analysis. There were several baseline differences between the two groups favoring the bisoprolol group, including age, sex, dialysis vintage, proportion of hypertension and hyperlipidemia, drug use of statins and antiplatelets, proportion of heart failure, and digoxin use. To minimize the impact of confounding due to these differences, 4,107 patients from each group were included in the propensity-score matching analysis (Figure 1). After matching, the mean patient age in both groups was 55.4, 51.6% were men, 39.9% had diabetes and 78.6% had hypertension.

Figure 1. Patient Flow¹

The results for the primary outcomes for the full cohort are shown in Figure 2; it can be seen that significantly lower mortality and MACEs were noted in the bisoprolol group. Additionally, compared with patients who took low-dose carvedilol, those who were prescribed low- or high-dose bisoprolol had a lower risk of all-cause mortality, MACEs, and heart failure.

Figure 2. Results of Primary analysis for the full cohort. A) Survival and B) Major adverse cardiovascular events.¹

Additionally, in the multivariate analysis, bisoprolol had a relatively lower mortality risk [adjusted hazard ratio [HR] 0.66 [95% confidence interval (CI) 0.60–0.73], and  risk of MACEs [HR 0.85 (95% CI 0.80–0.91)] compared with patients using carvedilol, mainly attributed to a lower risk of heart failure [HR 0.83 (95% CI 0.77–0.91)] and ischemic stroke [HR 0.84 (95% CI 0.72–0.97)]. After P-S matching, the results remained unaffected (Figure 3).

Figure 3. ITT analysis for cardiac outcomes in full and P-S matched cohorts.¹

Moreover, all sensitivity analyses attested to the robustness of the results. The E-values indicated that unmeasured confounding of a considerable strength might only affect the observed associations, which is unlikely, thereby validating the robustness of these findings.

The authors suggested that though the use of beta-blockers offers cardio-protection and improves survival in MHD patients; however, BB classes possess different pharmacologic and pharmacokinetic properties, vasodilatory capabilities, and beta-adrenergic receptor selectivity, which might explain the differences in the cardiovascular outcomes observed in this study in the favor of bisoprolol.

Conclusion

The authors concluded that in this large nationwide cohort of MHD patients, the initiation of bisoprolol was associated with significantly lower risks of mortality and MACEs compared with carvedilol. Since the insights from comparative clinical trials are unavailable and are likely to remain as such, these novel insights might help clinicians to make more informed decisions regarding the initiation of beta-blockers in this high-risk population of MHD patients.

Reference

1. Ping-Hsun Wu, Yi-Ting Lin, Jia-Sin Liu, Yi-Chun Tsai, Mei-Chuan Kuo, Yi-Wen Chiu, Shang-Jyh Hwang, Juan-Jesus Carrero, Comparative effectiveness of bisoprolol and carvedilol among patients receiving maintenance hemodialysis, Clinical Kidney Journal, Volume 14, Issue 3, March 2021, Pages 983–990, https://doi.org/10.1093/ckj/sfaa248