Bisoprolol Improved Cardiac Outcomes in Patients with Coronary Artery Disease and Hypertension by Reducing the Resting Heart Rate

Introduction

Resting heart rate (RHR) is an important prognostic indicator in patients with coronary artery disease (CAD); a high RHR is strongly associated with poor prognosis in patients with CAD. In addition, a high RHR has been linked with elevated blood pressure levels. Furthermore, hypertension (HTN) by itself is one of the strongest indicators of poor prognosis in patients with CAD.

Bisoprolol, a second-generation beta-blocker, reduces the resting heart rate as well as blood pressure, suggesting its potential clinical benefits in patients having both CAD and HTN. However, the clinical evidence of the effectiveness of bisoprolol in patients having both CAD and HTN is limited. Moreover, it is unclear whether the main action of bisoprolol in this subgroup is through the reduction of RHR or via reduction of blood pressure, especially in those with well-controlled HTN.

The present study by Chen et al.1 attempts to bridge these evidence- and knowledge-gaps by analyzing the data of patients with CAD and HTN administered bisoprolol in a Phase IV trial.

Aims

This subgroup analysis of the BISO-CAD trial aimed to examine the effect of long-term administration of bisoprolol on RHR and blood pressure, and their association with the composite cardiac clinical outcomes (CCCO) to clarify the mode of action of bisoprolol in patients with CAD and HTN.

Methods

This retrospective analysis included all patients from the HTN subgroup among those enrolled in the BISO-CAD Phase IV study, which was conducted in 39 centers across South Korea, Vietnam, and China between 2011 to 2015 to evaluate the effectiveness of bisoprolol in patients with CAD. Patients with CAD and HTN were to receive oral bisoprolol, with dosage between 1.25 mg/day and 10 mg/day. Patients were assessed for endpoints at baseline, and after 6, 12, and 18 months.

CCCO, the primary composite endpoint, comprised of cardiovascular mortality, non-fatal acute MI, and hospitalization because of unstable angina, or for revascularization. Other important endpoints included RHR, blood pressure, and dosage of bisoprolol. Endpoint comparisons were made for patients based on their RHRs as follows: ≥75 beats/min (bpm) vs. <75 bpm; ≥70 bpm vs. <70 bpm; ≥65 bpm vs. <65 bpm; and ≥60 bpm vs. <60 bpm.

Patients with CAD and HTN who were given at least one dose of bisoprolol formed the intention to treat (ITT) set. In the ITT set, patients who continued with bisoprolol till end of the study formed the efficacy analysis (EA) set, which were assessed separately. Poison regression, logistic regression, Cox proportional hazard model, and multivariate regression were used for statistical testing.

Summary of Key Results

Of the 866 patients enrolled in the BISO-CAD study, 681 patients had comorbid HTN and were included in this analysis as the ITT set, of which 539 patients formed the EA set. In the ITT set, the mean age was 64 years and 69% of the participants were males, with a mean BMI of 25 and mean baseline systolic and diastolic blood pressures of 134 and 78, respectively, reflecting a good HTN control at baseline, which also persisted throughout the study.

The 2.5 mg/day and 5 mg/day were the most commonly used dosages (43.9% and 40.1%, respectively) in this study. Furthermore, a total of 84.1% patients and 95% patients received bisoprolol for ≥12 months in the ITT set and EA set, respectively.

This analysis revealed that bisoprolol administration reduced the RHR in both ITT and EA sets by an average of 6-7 bpm at six months, which also persisted throughout the study. However, there was no significant change in the systolic and diastolic blood pressures over the study duration (Figure 1).

Figure 1. No Significant Effect of Bisoprolol on Blood Pressure (A). Reduction in Resting Heart Rate With Bisoprolol (B).

Regarding the association of the change in RHR with CCCO events, the analysis revealed that the CCCO events increased significantly as the heart rate increased. For instance, the CCCO events in ≥60 bpm group (n = 646) and <60 bpm group (n = 35) were recorded to be 41 events and one event, respectively (estimate: 0.80; SE: 1.01; 95% CI: 1.19, 2.78) in the ITT set. Similar trends were noted across other RHR-based groups in both ITT and EA sets. This association of RHR with CCCO was further observed in the multivariate analysis, in which patients with RHR between 70 and 74 showed an adjusted odds ratio of 4.34 (95% CI: 1.19, 15.89; P = 0.03).

Conclusion

This analysis revealed that, in patients with CAD and well-controlled HTN at baseline, bisoprolol effectively reduced RHR and improved CCCOs, independent of its effect on blood pressure.

References

Chen YD, Yang XC, Pham VN, et al. Resting heart rate control and prognosis in coronary artery disease patients with hypertension previously treated with bisoprolol: a sub-group analysis of the BISO-CAD study. Chin Med J (Engl). 2020;133(10):1155-1165.

IN-CONCO-00023