Bisoprolol Shows a Superior Reduction in Heart Rate and a Non-Inferior Reduction in Blood Pressure Versus Metoprolol
Bisoprolol Shows a Superior Reduction in Heart Rate and a Non-Inferior Reduction in Blood Pressure Versus Metoprolol
Introduction
Hypertension (HTN) is one of the most important cardiovascular disease risk factors and a public health problem worldwide. Adequate HTN control remains an effective strategy to minimize cardiovascular complications, including target organ damage. In addition, elevated resting heart rate (HR) and 24-hour blood pressure (BP) variability are other important risk factors for cardiovascular diseases and target organ damage. Therefore, while choosing antihypertensive agents, it has been recommended to consider the potential to reduce resting HR and 24-hour BP variability.
Bisoprolol and extended-release formulations of metoprolol (metoprolol succinate) are both cardio- selective beta-blockers that are widely used as anti-hypertensive agents. However, there are significant pharmacokinetic and pharmacodynamic differences between the two. Bisoprolol has a longer elimination half-life (9-12 hours) and is particularly suited for once-daily dosing than the extended-release metoprolol succinate, which is released for only about 20 hours. In addition, bisoprolol has a higher beta-1 selectivity than metoprolol (75:1 vs. 20:1 selectivity for beta-1 and beta-2 receptors, respectively). However, whether these pharmacokinetic advantages of bisoprolol vs. metoprolol translate into clinical advantages, particularly in terms of heart rate and dynamic BP reduction, remains unknown.
Aims
This ambulatory BP monitoring (ABPM)-based Phase-IV study by Yang et al.1 aimed to compare the 24-hour BP control and HR reduction capacities of bisoprolol and extended-release metoprolol in hypertensive patients. More specifically, this study aimed to compare their efficacies in lowering the dynamic BP and HR, especially during the last 4, and 24 hours of the study.
Methods
This study was a 12-week randomized parallel-group open-label trial conducted in seven Chinese hospitals between 2011 and 2014. The study included adults aged 18-70 years with mild to moderate HTN (systolic BP 140-179 and diastolic BP 90-109) and resting HR of 70 or more beats per minute. The participants had to be not on any antihypertensive agent at enrolment. However, those with mild HTN were enrolled after a 2-week drug washout. The patients with following conditions were excluded: moderate HTN receiving antihypertensive drugs, secondary HTN, concomitant heart diseases, a cardiovascular event in the preceding 6-month period, hepatic, and renal impairment.
Patients had a baseline 24-hour ABPM evaluation and were randomized to receive either 5 mg once daily bisoprolol or 47.5 mg once daily extended-release metoprolol at approximately 8 AM each day. In case of persistent elevated BP readings at 4 weeks, the doses were up-titrated to 7.5 mg and
71.25 mg, respectively. If the BP was uncontrolled even after 8 weeks, the doses were again up- titrated to reach the maximal study doses of 10 mg and 95 mg, respectively. A 24-hour ABPM evaluation was again conducted at study completion. Intention-to-treat (ITT), per-protocol (PPS), and safety-set analyses were conducted. In addition, a clinical BP response was defined as diastolic BP ≤90 mm Hg or a ≥10 mm Hg decrease in the diastolic BP from baseline; while a ≥10% decrease in HR was considered as HR response. This study was conducted in compliance with the Declaration of Helsinki, and was registered at clinicaltrials.gov (NCT01508325).
Summary of Key Results
A total of 186 patients, 93 in each group, were enrolled in this study. Seventy-five patients in the bisoprolol group and 72 in the metoprolol group finished the per-protocol treatment. Both groups had similar baseline characteristics except for proportion of males (bisoprolol group: 61.29% vs. metoprolol group: 39.78%; p=0.003). A majority of patients (bisoprolol group: 72% vs. metoprolol group: 58%) received a low-dose of the study drugs (5mg or 47.5 mg per day). Only 3% and 5% of patients required high-dose of study drugs (10 mg and 95 mg per day) in the bisoprolol and metoprolol groups, respectively .
In the ITT set, the reduction in the mean dynamic HR in the last 4 hours of the study was significantly higher in the bisoprolol group (−8.04 bpm) than that in the metoprolol group (−4.75 bpm) (LSmeans of difference (97.5% CI)= −3.79 b.p.m. (−7.45, − 0.14); p=0.0202) (Figure 1a). However, both bisoprolol and metoprolol had significant reductions int the mean dynamic diastolic BP in the last 4 hours of the study (bisoprolol: −4.45 mm Hg, p=0.0014; metoprolol: −3.39, p=0.0168). Of note, it was shown that bisoprolol was non-inferior to metoprolol in lowering the mean dynamic diastolic BP (LSmeans of difference (97.5% CI) = − 1.00 (−4.79, 2.78); p=0.5495; the upper limit of the 97.5% CI was less than the 4 mm Hg non-inferiority margin) (Figure 1b). PPS analysis yielded similar results.
Figure 1. Primary endpoint of the study a) reduction in HR; b) reduction in diastolic BP. 1
Moreover, greater HR reduction with bisoprolol was confirmed in the 24-hour ABPM analysis
in the ITT set. In addition, the stratification of 24-hour HR reductions into daytime and night-
time reductions yielded similar results with consistently greater efficacy with bisoprolol vs.
metoprolol (daytime: −9.60 vs. −3.85 bpm, p=0.0012; night-time: −4.72 vs. −1.50 bpm,
p=0.0347). Additionally, subgroup analysis showed that the greater HR reduction with
bisoprolol was even higher for patients with a resting HR of ≥ 80 bpm (bisoprolol: −12.97
bpm; metoprolol: −6.13 bpm; P=0.0281).
The analysis on treatment response rate in the ITT set revealed that response rates were
not statistically different between the bisoprolol and metoprolol groups in terms of both
diastolic BP (bisoprolol group: 86.67%; metoprolol group: 83.33%; p=0.5487; Figure 2a) as
well as HR (bisoprolol group: 72.00%; metoprolol group: 55.56%; p=0.0527; Figure 2b)
although the inter-group difference for HR was close to statistical significance (study not
adequately powered for secondary endpoints).
Figure 2. Treatment Response Rate over the Study. a) For systolic BP, b) For HR.
Discussion and Conclusion
The authors highlighted
Therefore, the authors proposed that bisoprolol may be preferred over metoprolol in
hypertensive patients with elevated sympathetic activity.
Reference
1. Yang T, Jiang Y, Hao Y, et al. Comparison of bisoprolol to a metoprolol CR/ZOK tablet for control of heart rate
and blood pressure in mild-to-moderate hypertensive patients: the CREATIVE study. Hypertens Res.
2017;40(1):79-86.
Code
IN-CONCO-00058