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
Resting heart rate (RHR) is a well-established predictor of total mortality and hospitalization due to heart failure in patients with hypertension. Bisoprolol fumarate, a second-generation beta-adrenoreceptor blocker (β-blocker), is commonly prescribed to manage hypertension. This study aimed to retrospectively evaluate changes in the average RHR and its association with cardiovascular outcomes in bisoprolol-treated coronary artery disease (CAD) patients with comorbid hypertension, based on data from the BISO-CAD study.
Introduction
Hypertension, characterized by persistently high blood pressure (BP), is a major risk factor for cardiovascular diseases (CVD). Elevated BP contributes significantly to global all-cause mortality. Clinical studies have demonstrated a strong, continuous, and linear relationship between elevated BP and CVD. A meta-analysis revealed that every 10 mmHg reduction in systolic BP (SBP) significantly reduces the risk of CVD, coronary artery disease, stroke, heart failure, and all-cause mortality. Resting heart rate (RHR) is considered a strong predictor of total mortality and hospitalization due to heart failure in hypertensive patients. Data from the Framingham cohort showed that RHR is an independent risk factor for cardiovascular events, particularly heart failure and all-cause death. Higher RHR is also associated with poor long-term outcomes in CAD patients who underwent percutaneous coronary intervention.
Beta-blockers are commonly prescribed to manage hypertension. They are categorized into three generations based on their activity. First-generation β-blockers non-selectively bind β1 or β2 adrenoreceptors, while second-generation β-blockers are cardio-selective with higher affinity for β1 adrenoreceptors. Third-generation β-blockers are vasodilators that block α1 adrenoreceptors, stimulate β2 adrenoreceptors, generate nitric oxide, and have anti-inflammatory properties. Beta-blockers lower RHR, cardiac output, and renin release, reducing sympathetic nervous system (SNS) activity. They are prescribed for myocardial infarction, angina pectoris, and left ventricular dysfunction.
However, the Joint National Committee guidelines do not recommend β-blockers as first-line therapy for hypertension due to increased stroke incidence observed in atenolol-treated patients. Recent European Society of Cardiology (ESC) and European Society of Hypertension guidelines recommend the use of β-blockers in combination with other anti-hypertensive drugs for conditions requiring heart rate control, post-myocardial infarction, and symptomatic angina. Recent randomized controlled trials and meta-analyses have shown that β-blockers are as effective as other classes of anti-hypertensive drugs in preventing major cardiovascular events, except for stroke.
Bisoprolol fumarate, a second-generation β1-blocker, is commonly prescribed for hypertension. The Cardiac Insufficiency Bisoprolol Study (CIBIS I) showed that bisoprolol significantly reduces all-cause mortality in patients with heart failure. CIBIS II confirmed that bisoprolol improves survival in heart failure patients, irrespective of their baseline heart rate. The BISO-ART study demonstrated that bisoprolol lowers central SBP and aortic pulse pressure more significantly than atenolol in hypertensive patients. However, there is limited evidence on the effect of bisoprolol-induced lowering of RHR on cardiovascular outcomes in patients with primary or comorbid hypertension. This study aimed to fill this gap by analyzing the subgroup of hypertensive patients from the BISO-CAD study.
Methods
The BISO-CAD study was a phase IV, multinational, multicenter, single-arm, observational study conducted from October 2011 to July 2015 across China, South Korea, and Vietnam. The study aimed to evaluate the association between RHR and composite cardiac clinical outcomes (CCCO) in Chinese CAD patients receiving bisoprolol. Patients were followed up at 6, 12, and 18 months from baseline. Inclusion criteria included age ≥20 years, CAD diagnosis, stable or unstable angina, type 2 diabetes mellitus, or ≥3 risk factors (e.g., hypertension, dyslipidemia, smoking, family history of CAD, obesity), office RHR ≥70 beats/min, and prior bisoprolol treatment. Exclusion criteria included hypersensitivity or contraindications to bisoprolol, acute myocardial infarction within the preceding month, active myocarditis, coronary heart failure, impaired renal or hepatic function, severe or uncontrolled hypertension (SBP >180 mmHg or DBP >110 mmHg), complete revascularization for a single CAD, implanted pacemaker, and pregnancy or lactation.
This subgroup analysis included CAD patients with comorbid hypertension (resting SBP ≥140 mmHg and/or DBP ≥90 mmHg or using anti-hypertensive treatment). Patients were treated with bisoprolol at baseline, and clinical parameters were evaluated after 6, 12, and 18 months of treatment. Bisoprolol was administered orally at doses ranging from 1.25 to 10 mg/day, with dose adjustments based on cardiovascular health.
Study Outcomes
The primary outcome was the occurrence of CCCO, including cardiovascular mortality, non-fatal acute myocardial infarction, and hospitalization due to unstable angina or revascularization, up to 18 months. Secondary outcomes included changes in heart function parameters (e.g., ejection fraction, left ventricular end-systolic dimension), carotid artery intima-media thickness (CIMT), all-cause mortality, cardiovascular mortality, hospitalizations due to acute coronary syndrome (ACS), and coronary artery revascularization. Safety was evaluated in all enrolled patients.
Results
A total of 681 hypertensive patients (mean age: 64.77 ± 10.33 years; 69.0% male) were included in the intent-to-treat (ITT) set. Baseline mean SBP and DBP were 134.2 ± 15.2 mmHg and 78.5 ± 10.5 mmHg, respectively. Baseline RHR was 75.7 ± 6.8 beats/min in the ITT set and 75.5 ± 6.6 beats/min in the efficacy analysis (EA) set. Bisoprolol improved CCCOs in CAD patients with comorbid hypertension, particularly in those with RHR <65 and <70 beats/min compared to those with RHR ≥65 and ≥75 beats/min. Bisoprolol lowered RHR in both ITT and EA groups after 6, 12, and 18 months of treatment. RHR of 70 to 74 beats/min resulted in a significantly higher risk of CCCOs in the EA set (adjusted odds ratio [OR]: 4.34; 95% confidence interval [CI]: 1.19–15.89; P = 0.03). Hospitalization due to ACS was higher in patients with RHR 69 to 74 beats/min compared to those with RHR <69 beats/min in the ITT set.
Bisoprolol reduced RHR from 75.7 ± 6.8 beats/min at baseline to 68.9 ± 8.4, 69.3 ± 8.1, and 68.8 ± 9.7 beats/min after 6, 12, and 18 months of treatment, respectively, in the ITT set. Similar reductions were observed in the EA set. The percentage of patients with controlled BP (SBP <140 mmHg and DBP <90 mmHg) increased from baseline after 6 and 18 months of treatment.
The mean bisoprolol dose in the ITT population was 3.7 ± 1.9 mg/day, with 43.9% of patients receiving 2.5 mg/day and 40.1% receiving 5 mg/day. Patients received bisoprolol for an average of 520.9 ± 135.4 days in the ITT set and 541.5 ± 96.6 days in the EA set. Higher RHR positively affected left ventricular end-systolic dimension (LVESD) and Tei index, while RHR ≥75 beats/min negatively affected the E/A ratio and CIMT.
Multivariate analysis showed that RHR in the range of 70 to 74 beats/min in the EA set was associated with a significantly higher risk of CCCOs (adjusted OR: 4.34; 95% CI: 1.19–15.89; P = 0.03). Age, gender, concomitant diabetes, and BMI did not significantly affect the odds of CCCOs.
Safety Evaluation
A total of 163 (23.9%) patients reported adverse events (AEs), including nine (1.3%) related to bisoprolol administration. Serious AEs occurred in 83 (12.2%) patients, with ten (1.5%) proving fatal (two due to cardiovascular abnormalities).
Discussion
This study demonstrated that bisoprolol effectively reduces RHR and improves CCCOs in CAD patients with comorbid hypertension, independent of its BP-lowering effect. The findings are consistent with previous studies showing that higher RHR is associated with poor cardiovascular outcomes. Bisoprolol reduced RHR from baseline to 18 months of treatment, with the majority of patients achieving controlled BP. The study highlights the importance of controlling RHR in hypertensive patients, as higher RHR was associated with increased cardiovascular events.
The results are supported by previous studies, including the CIBIS trials, which showed that bisoprolol improves survival in heart failure patients, and the BEAUTIFUL study, which demonstrated that higher RHR increases the risk of cardiovascular outcomes in CAD patients. The study also aligns with the EUROPA trial, which reported increased mortality and hospitalization rates in patients with RHR >75 beats/min.
Limitations
The study has several limitations, including the highly varied number of patients in the ITT and EA sets, the lack of inclusion of medical history and concomitant medications, and the relatively short study duration of 18 months. Additionally, the majority of patients received bisoprolol at doses ≤5 mg/day, limiting the assessment of higher doses’ effects on cardiovascular outcomes.
Conclusion
Bisoprolol effectively reduces RHR and improves CCCOs in CAD patients with comorbid hypertension, independent of its BP-lowering effect. The study underscores the importance of controlling RHR in hypertensive patients to improve cardiovascular outcomes. Further research is needed to explore the long-term effects of bisoprolol and the impact of higher doses on cardiovascular outcomes in this patient population.
doi.org/10.1097/CM9.0000000000000802
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