Department of Pharmacy Practice, Karnataka College of Pharmacy, Rajiv Gandhi University of Health Sciences, Bengaluru, Karnataka, India.
Heart rate (HR) is a key prognostic and modifiable risk factor in patients with acute coronary syndrome (ACS), yet comparative real-world data on different HR-lowering strategies remain limited. This prospective observational study evaluated the efficacy and safety of bisoprolol, ivabradine, and their combination in adult patients with ACS admitted to a tertiary care hospital. Over a six-month period, 50 patients were included and categorized according to in-hospital therapy: bisoprolol monotherapy (n = 17), ivabradine monotherapy (n = 17), or combination therapy (n = 16). The primary outcome was change in HR from admission to discharge, while secondary outcomes included changes in systolic and diastolic blood pressure (BP) and the incidence of adverse drug reactions (ADRs). All treatment groups demonstrated significant within-group HR reduction (p < 0.05). Between-group comparison revealed a statistically significant difference in HR reduction (one-way ANOVA, p = 0.018), with combination therapy achieving the greatest mean reduction. Bisoprolol was associated with significant BP reduction, whereas ivabradine showed a largely BP-neutral profile. ADRs were infrequent and mild; hypotension occurred only in the combination group, while bradycardia was limited to monotherapy groups. The study is limited by its observational design, small sample size, and short follow-up. Overall, bisoprolol remains effective for HR and BP control in ACS, while ivabradine, alone or in combination, offers a welltolerated option for enhanced HR reduction in selected patients.
Acute coronary syndrome (ACS) comprises a spectrum of clinical conditions caused by acute obstruction of coronary blood flow due to atherosclerotic disease, including ST-elevation myocardial infarction (STEMI), non–ST-elevation myocardial infarction (NSTEMI), and unstable angina [1]. It is characterized by myocardial ischemia, most commonly resulting from rupture of an atherosclerotic plaque with subsequent thrombus formation and reduced myocardial perfusion [2]. Comorbid conditions such as hypertension, diabetes mellitus, sleep apnoea, and renal disease substantially increase cardiovascular risk, while factors including smoking, physical inactivity, psychological stress, family history, and advancing age further contribute to the development and progression of ACS [3,4].
In patients presenting with ACS, early physiological parameters play a critical role in risk assessment and clinical decision-making. Among these, heart rate (HR) has been identified as a key prognostic indicator. Higher heart rates may reflect sympathetic activation, larger areas of ischemia, and greater myocardial oxygen demand, each contributing to poorer outcomes and has been consistently associated with increased in-hospital mortality, long-term mortality, and major adverse cardiovascular events, even in the contemporary percutaneous coronary intervention era [5]. Consistent with these findings, large multinational registries have shown that ACS patients presenting with rates above approximately 80 beats per minute had significantly higher in-hospital mortality than those with lower heart rates, independent of age, diabetes status, or atrial fibrillation [6]. Heart rate is therefore increasingly recognized not merely as a vital sign, but as a modifiable risk factor in ACS, reflected in contemporary risk stratification models such as the GRACE score, which incorporate admission heart rate as a predictor of mortality [5][7].
Recent guidelines have highlighted the importance of heart rate control in patients with heart failure and ACS, suggesting that optimal management of heart rate can reduce hospitalization and improve survival rates [8]. β-blocker, like bisoprolol, are well-established in the treatment of heart failure and ACS due to their ability to reduce heart rate and myocardial oxygen demand [9]. While βblocker remain the cornerstone of therapy, ivabradine, a selective If channel inhibitor, offers a unique mechanism of heart rate reduction without affecting myocardial contractility or blood pressure and has been shown to provide additional benefits, particularly in patients who remain symptomatic despite β-blocker therapy or who are intolerant to β-blockers. Given the central role of heart rate in the pathophysiology and prognosis of ACS, evaluation of different heart rate– lowering strategies, including bisoprolol, ivabradine, and their combination, may provide insights into heart rate control and safety outcomes in routine clinical practice.
MATERIALS AND METHODS
Study Design and Setting
This was a prospective observational study conducted over a period of six months in the coronary care unit (CCU) of a tertiary care hospital. The study evaluated the efficacy and safety of bisoprolol, ivabradine, and their combination in adult patients diagnosed with acute coronary syndrome (ACS).
Study Population and Treatment Groups
Adult patients aged ≥18 years admitted to the CCU with a confirmed diagnosis of ACS and receiving bisoprolol, ivabradine, or combination therapy as part of routine clinical care were enrolled. Treatment decisions were made by the treating physician.
A total of 50 patients were included and categorized based on the therapy received during hospitalization: Bisoprolol monotherapy (n = 17) Ivabradine monotherapy (n = 17), Combination therapy with bisoprolol and ivabradine (n = 16). Patients whose therapy was modified during hospitalization were assigned to the group corresponding to their final stable treatment regimen.
Inclusion and Exclusion Criteria
Inclusion criteria were age ≥18 years, diagnosis of ACS, and receiving bisoprolol, ivabradine, or combination therapy. Exclusion criteria included hemodynamic instability requiring inotropic support, severe baseline bradycardia, second- or third-degree atrioventricular block, severe hepatic impairment, pregnancy or lactation, and incomplete clinical records.
Outcome Measures
The primary outcome was to compare heart rate reduction from admission to discharge with ivabradine and bisoprolol, alone or in combination, in patients with acute coronary syndrome.
Secondary outcomes included changes in systolic and diastolic blood pressure, and the incidence of adverse drug reactions such as bradycardia and hypotension.
Statistical Analysis
Data were analysed using Microsoft Excel, with continuous variables expressed as mean ± standard deviation and categorical variables as frequencies and percentages; within-group changes in heart rate and blood pressure from admission to discharge were assessed using paired t-tests, while comparisons of mean heart rate and blood pressure reduction among the three treatment groups (bisoprolol, ivabradine, and combination therapy) were performed using one-way ANOVA, and gender, adverse drug reactions, and subgroup analyses based on age, gender, and comorbidities were analysed descriptively, with a p-value < 0.05 considered statistically significant.
RESULTS
Baseline demographic and clinical characteristics
Table 1 outlines baseline demographics of the study population. A total of 50 patients were included in the study, with a predominance of male participants. Elderly individuals constituted the majority of the study population, indicating that acute coronary syndrome primarily affected older patients in this cohort.
Acute coronary syndrome was the most frequently observed diagnosis. Among its subtypes, non– ST-elevation myocardial infarction was the most common presentation, followed by ST-elevation myocardial infarction and unstable angina. Further classification of ST-elevation myocardial infarction revealed anterior wall myocardial infarction as the predominant pattern, followed by inferior wall myocardial infarction, while no cases of lateral wall myocardial infarction were identified. A substantial burden of comorbidities was observed among the study population. Hypertension and type 2 diabetes mellitus were the most prevalent conditions, with renal dysfunction also commonly encountered. Other comorbidities, including hypothyroidism and dyslipidemia, were present in a smaller proportion of patients. Overall, these findings reflect the complex clinical profile of patients with acute coronary syndrome and heart failure.
During hospitalization, three patients died, with two deaths occurring in the bisoprolol group and one in the combination therapy group and were excluded from discharge heart rate and blood pressure analyses due to unavailable discharge data.
Table 1. Patient demographics
|
Baseline Characteristics |
N= 50 |
|
|
Gender |
N (%) |
|
|
Male Female |
29(58%) 21(42%) |
|
|
Age |
N (%) |
Mean ± SD |
|
Adults (18-59) Elders (>59) |
18(36) 32(64) |
53.2 ± 5.40 72.68 ± 8.12 |
|
Diagnosis |
N (%) |
|
|
ACS |
44(88%) |
|
|
NSTEMI STEMI UA |
29(58%) 13(26%) 2(4%) |
|
|
STEMI |
|
|
|
AWMI IWMI LWMI |
10(77%) 3(23%) 0 |
|
|
Comorbidities |
N (%) |
|
|
Hypertension Type 2 Diabetes Mellitus AKI/CKD Hypothyroidism Dyslipidemia |
35(70%) 44(88%) 18(36%) 7 (14%) 6(12%) |
|
ACS: Acute Coronary Syndrome, NSTEMI: Non-ST Elevated Myocardial Infarction, STEMI: ST Elevated Myocardial Infarction, UA: Unstable Angina, AWMI: Anterior Wall Myocardial Infarction, IWMI: Inferior Wall Myocardial Infarction, LWMI: Lateral Wall Myocardial Infarction, AKI: Acute Kidney Injury, CKD: Chronic Kidney Disease.
Heart rate reduction following treatment
A reduction in heart rate from admission to discharge was observed across all treatment groups. All groups showed statistically significant within-group reductions in heart rate (p < 0.05). Comparison of heart rate reduction among the three groups using one-way ANOVA demonstrated a statistically significant difference between treatments (F = 4.35, p = 0.018), indicating that the magnitude of heart rate reduction varied across treatment regimens. Patients receiving combination therapy exhibited a greater mean reduction in heart rate compared with those receiving monotherapy highlighting a potential additive or synergistic effect of combined treatment on heart rate control. (Table 2)
Table 2. Changes in Heart Rate from Admission to Discharge Across Treatment Groups
|
Therapy |
Admission HR (mean ± SD) |
Discharge HR (mean ± SD) |
HR Reduction (mean ± SD) |
p value |
|
Ivabradine (n = 17) |
103.4 ± 14.2 |
81.5 ± 6.0 |
21.9 ± 13.29 |
< 0.05 |
|
Bisoprolol (n = 15) |
94.6 ± 11.6 |
76.2 ± 10.0 |
18.4 ± 11.17 |
< 0.05 |
|
Combination therapy (n = 15) |
107.1 ± 17.6 |
74.1 ± 9.1 |
33.0 ± 17.5 |
< 0.05 |
HR: Heart Rate; Analysis was based on patients with paired admission and discharge heart rate data; patients who died during hospitalization were excluded from analysis
Changes in blood pressure across treatment groups
A reduction in both systolic and diastolic blood pressure from admission to discharge was observed across all treatment groups. However, statistical significance for within-group blood pressure reduction was achieved only in patients treated with bisoprolol, whereas the changes observed with ivabradine and combination therapy did not reach statistical significance (Table 3)
Between-group comparison of systolic blood pressure changes using one-way ANOVA did not show a statistically significant difference among the three treatment groups (F (2,44) = 1.77, p = 0.18), indicating comparable systolic blood pressure responses across therapies. Similarly, one-way ANOVA for diastolic blood pressure changes revealed no statistically significant difference between groups (F (2,44) = 2.18, p = 0.13).
Overall, while bisoprolol demonstrated a statistically significant reduction in blood pressure within its treatment group, intergroup analysis did not reveal a significant difference in blood pressure changes among ivabradine, bisoprolol, and combination therapy.
Table 3. Changes in Systolic and Diastolic Blood Pressure from Admission to Discharge Across Treatment Groups
|
Therapy |
Admission SBP (mean ± SD) |
Discharge SBP (mean ± SD) |
Mean SBP difference (mean ± SD) |
p value |
Admission DBP (mean ± SD) |
Discharge DBP (mean ± SD) |
Mean DBP difference (mean ± SD) |
p value |
|
Ivabradine (n = 17) |
120.1 ± 25.6 |
116.8 ± 17.6 |
3.3 ± 17.5 |
0.40 |
71.0 ± 13.4 |
67.2 ± 7.0 |
3.8 ± 13.6 |
0.27 |
|
Bisoprolol (n = 15) |
127.3 ± 19.8 |
111.3 ± 9.9 |
16.0 ± 18.4 |
< 0.05 |
75.3 ± 9.1 |
65.3 ± 7.4 |
10.0 ± 9.2 |
< 0.05 |
|
Combination therapy (n = 15) |
117.0 ± 22.8 |
107.6 ± 12.6 |
9.4 ± 21.12 |
0.10 |
72.0 ± 12.0 |
71.0 ± 9.4 |
1.0 ± 12.8 |
0.70 |
SBP: systolic blood pressure; DBP: diastolic blood pressure; SD: standard deviation. Analysis were based on patients with paired admission and discharge heart rate data; patients who died during hospitalization were excluded from analysis
Adverse drug reactions
Adverse drug reactions were infrequent across the study population. Hypotension was observed exclusively in patients receiving combination therapy, occurring in three cases, while no cases were reported among patients treated with ivabradine or bisoprolol monotherapy. Bradycardia was reported in one patient receiving ivabradine and in two patients receiving bisoprolol, whereas no cases of bradycardia were observed in the combination therapy group. All reported adverse drug reactions were mild to moderate in severity and were managed conservatively during hospitalization. No additional adverse events were documented during the study period.
DISCUSSION
This prospective observational study evaluated the comparative effects of bisoprolol, ivabradine, and their combination on heart rate (HR), blood pressure (BP), and tolerability in patients hospitalized with acute coronary syndrome (ACS). Given the established prognostic importance of HR in ACS, optimizing rate control remains a key therapeutic objective. Elevated admission and discharge HR have consistently been associated with increased short- and long-term mortality, recurrent ischemic events, and adverse cardiovascular outcomes, even in the era of early reperfusion and contemporary pharmacotherapy [10,11]. The present study adds real-world evidence on HR lowering strategies commonly employed in routine clinical practice.
In this cohort, all three treatment strategies produced statistically significant reductions in HR from admission to discharge. Ivabradine monotherapy achieved HR reduction comparable to bisoprolol, supporting prior evidence that ivabradine is effective for rate control in ACS and ischemic heart disease populations [10,12]. Ivabradine’s selective inhibition of the sinoatrial node I_f current allows targeted HR reduction without negative inotropic effects or significant influence on systemic blood pressure, distinguishing it pharmacologically from β-blockers [13]. This mechanism likely explains its clinical use in patients with borderline BP, reactive airway disease, or intolerance to βblockers. Consistent with prior systematic reviews, ivabradine demonstrated effective HR control in this study but was not associated with an assessment of mortality benefit, which remains inconclusive in ACS populations [10,18].
Bisoprolol monotherapy was associated with significant reductions in both HR and BP, reflecting its broader β-adrenergic blockade. The benefit of oral β-blockers in ACS is well established, with extensive evidence demonstrating reductions in myocardial oxygen demand, infarct size, malignant arrhythmias, and in-hospital mortality [14–16]. Contemporary guidelines continue to recommend early β-blocker initiation in hemodynamically stable ACS patients, particularly those with left ventricular systolic dysfunction [15]. The HR- and BP-lowering effects observed in the bisoprolol group in this study are consistent with these established benefits and reinforce its role as first-line therapy in ACS management.
Notably, combination therapy with bisoprolol and ivabradine resulted in the greatest magnitude of HR reduction among the three treatment groups. This additive effect is biologically plausible, as the two agents act through complementary mechanisms—β-blockers attenuate sympathetic activation, while ivabradine selectively slows sinus node depolarization. Prior studies in chronic stable coronary syndromes and heart failure have shown that adding ivabradine to background β-blocker therapy enables further HR reduction when β-blocker up-titration is limited by hypotension or bradycardia, with good tolerability [17]. The present findings suggest that similar benefits may extend to the ACS population, particularly in patients with persistent tachycardia despite β-blocker therapy.
Despite superior HR reduction with combination therapy, no clear advantage was observed in short term clinical outcomes, such as in-hospital complications or length of stay. This aligns with previous evidence indicating that while HR reduction improves myocardial efficiency and symptom burden, it does not consistently translate into short-term mortality benefits in ACS, particularly in observational analyses with limited follow-up [10]. These findings emphasize that HR control should be considered one component of comprehensive ACS management rather than an isolated determinant of prognosis.
Blood pressure responses differed meaningfully across treatment groups. Bisoprolol was associated with statistically significant reductions in systolic and diastolic BP, whereas ivabradine demonstrated a largely BP-neutral profile. These observations are consistent with prior pharmacological and clinical studies showing that ivabradine does not significantly affect myocardial contractility, vascular tone, or systemic BP [12,13]. Importantly, combination therapy did not result in a disproportionate additional decline in BP compared with bisoprolol alone, suggesting that ivabradine can enhance HR control without substantially increasing the risk of hypotension. This is clinically relevant in ACS patients with hemodynamic vulnerability, where excessive BP reduction may limit therapeutic options.
From a safety perspective, adverse drug reactions were infrequent and generally mild. Hypotension occurred only in the combination therapy group, while bradycardia was observed in small numbers with monotherapy. These findings are consistent with previous reports describing ivabradine as a hemodynamically well-tolerated agent and support its cautious use, alone or in combination, with appropriate patient selection [12,17].
Importantly, this study addresses a recognized literature gap. Direct comparative data evaluating bisoprolol, ivabradine, and their combination specifically in ACS remain limited, as most ivabradine evidence is derived from chronic coronary syndrome or heart failure populations. Existing systematic reviews highlight the safety and HR-lowering efficacy of ivabradine in ACS but emphasize the need for adequately powered randomized trials to determine its impact on clinically meaningful outcomes [10].
In conclusion, bisoprolol remains the cornerstone of HR management in ACS due to its established prognostic benefits and BP-lowering effects. Ivabradine provides a valuable alternative or adjunct for HR control, particularly in patients with β-blocker intolerance or low BP. Combination therapy offers enhanced HR reduction with acceptable tolerability, supporting a patient-centered, physiology-guided approach to HR management in ACS. Larger randomized controlled trials with longer follow-up are warranted to clarify the role of ivabradine, alone or in combination with βblockers, on long-term outcomes in this population.
LIMITATIONS
The findings of this study should be interpreted in the context of a small sample size and an observational design, with treatment allocation based on physician discretion, which may introduce selection bias. In-hospital deaths reduced the number of patients available for paired admission-to discharge analysis. Drug dose was not analyzed despite its potential influence on heart rate reduction. Outcomes were assessed only during hospitalization, limiting long-term interpretation, and the low incidence of adverse drug reactions restricted safety evaluation to descriptive analysis. Post-hoc testing following ANOVA was not performed due to the limited sample size and use of Microsoft Excel.
CONCLUSION
Heart rate control in patients with acute coronary syndrome was achieved with bisoprolol, ivabradine, and their combination, with distinct hemodynamic effects across treatment strategies. Combination therapy resulted in the greatest reduction in heart rate, while bisoprolol was associated with significant blood pressure lowering and ivabradine demonstrated a largely blood pressure– neutral profile. Adverse drug reactions were infrequent and generally mild across all groups, indicating acceptable in-hospital tolerability. These findings provide real-world evidence supporting ivabradine as an effective alternative or adjunct to β-blocker bfor heart rate control in selected patients with acute coronary syndrome. Further studies with larger sample sizes, randomized designs, and longer follow-up are required to determine the impact of different heart rate–lowering strategies on long-term clinical outcomes.
ABBREVIATIONS
ACS – Acute Coronary Syndrome; ADR – Adverse Drug Reaction; AKI – Acute Kidney Injury; ANOVA – Analysis of Variance; AWMI – Anterior Wall Myocardial Infarction; BP – Blood Pressure; CCU – Coronary Care Unit; CKD – Chronic Kidney Disease; DBP – Diastolic Blood Pressure; ESC – European Society of Cardiology; GRACE – Global Registry of Acute Coronary Events; HR – Heart Rate; IWMI – Inferior Wall Myocardial Infarction; LWMI – Lateral Wall Myocardial Infarction; MI – Myocardial Infarction; NSTEMI – Non–ST-Elevation Myocardial Infarction; PCI – Percutaneous Coronary Intervention; SBP – Systolic Blood Pressure; SD – Standard Deviation; STEMI – ST-Elevation Myocardial Infarction; UA – Unstable Angina.
DECLARATION
Funding
This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Competing interests
The authors have no relevant financial or non-financial interests to disclose. The authors declare no competing interests.
Ethics approval
This was an observational study based on routinely collected clinical data. As no intervention was performed and no identifiable patient information was used, formal ethical approval was not required. Patient confidentiality was maintained throughout the study in accordance with institutional policies and ethical standards..
REFERENCES
Biaktluangi, Blessy K George, Balakeshwa Ramaiah, C. Vanlalawmpuii, Comparative Heart Rate Control with Bisoprolol, Ivabradine, and Combination Therapy in Acute Coronary Syndrome, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 2, 2652-2660. https://doi.org/10.5281/zenodo.18670902
10.5281/zenodo.18670902
