Ivabradine in acute care: Revisiting the funny current in critical care context

Abstract

Ivabradine, a selective inhibitor of the funny current in the sinoatrial node, has emerged as a promising agent for heart rate modulation in acute and critical care settings. Unlike beta-blockers, ivabradine reduces heart rate without affecting myocardial contractility, making it a valuable option for patients contraindicated for traditional therapies. This review examines its mechanism of action, clinical applications, comparative efficacy, and safety profile. It incorporates recent literature to assess its expanding role in managing acute coronary syndrome, acute decompensated heart failure, and sepsis-induced tachycardia.

Key Words: Ivabradine; Heart rate control; Tachycardia; Heart failure; Beta blocker; Acute care

Core Tip: Ivabradine reduces heart rate by specifically inhibiting the funny current in the sinoatrial node, without impacting myocardial contractility or blood pressure. This distinctive characteristic renders it an appealing choice for critically sick patients for whom beta-blockers are contraindicated or poorly tolerated. Recent studies corroborate its significance in acute scenarios, including acute decompensated heart failure, acute coronary syndrome, and sepsis-induced tachycardia, where a higher heart rate exacerbates outcomes. This review looks at the mechanism of action, clinical uses, comparative effectiveness, and safety profile.

INTRODUCTION

Heart rate control is a critical determinant in managing acute cardiovascular conditions. Traditional agents like beta blockers achieve this but may cause hypotension and bradycardia, limiting their use in acute care, especially in patients with decompensated heart failure[1,2].

Ivabradine selectively inhibits the funny current, reducing heart rate without affecting myocardial contractility. Initially approved for the treatment of chronic heart failure, recent studies have investigated its efficacy in acute care settings (Figure 1). This review compiles recent studies to evaluate the growing significance of ivabradine in critical care settings.

Figure 1 Ivabradine in acute care. LV: Left ventricle; PCI: Percutaneous coronary intervention; ADHF: Acute decompensated heart failure; HR: Heart rate; MODS: Multi-organ dysfunction syndrome; RCT: Randomised controlled trial; ICU: Intensive care unit.

MECHANISM OF ACTION

The funny current (If) is a mixed sodium-potassium inward current contributing to spontaneous depolarisation in sinoatrial node cells. Ivabradine blocks the channel responsible for the cardiac pacemaker current, which regulates heart rate. This results in prolonged diastolic time and reduced heart rate[3]. Ivabradine selectively inhibits the If current, reducing heart rate without adverse inotropic effects. This unique mechanism offers advantages in acute cardiovascular conditions, where tachycardia worsens myocardial oxygen consumption and leads to hemodynamic instability (Figure 2 and Table 1)[4-12].

Figure 2 Mechanism of action of ivabradine. HR: Heart rate.

Table 1 Use of ivabradine in intensive care unit.

Ref.	Study population	Study type No. of patients	Outcome measured	Implications for clinical practice
Zheng et al[4], 2024	Sepsis	Prospective, multicenter, randomised, open-label (n = 172)	Difference in reduction in HR below 95 bpm and the effect of ivabradine on hemodynamics between the standard treatment group and the ivabradine group within the first 96 hours after randomisation	Trial ongoing
Colombo et al[5], 2022	Cardiogenic shock on mechanical circulatory support	Case series (n = 6)	HR, stroke volume, ECMO flow, vasopressor requirements	Significant reduction in HR observed after ivabradine administration. SV improvement allowing the reduction of ECMO flow support and vasopressors administration
Datta et al[6], 2021	Septic shock	RCT (n = 60)	HR, stroke volume, vasopressor dose, survival outcomes	Enteral ivabradine is effective in reducing HR, improving haemodynamic parameters, and cardiac function
Nguyen et al[7], 2018	Low cardiac output syndrome treated by dobutamine after elective coronary artery bypass surgery	Multicenter RCT (n = 19)	HR, cardiac index, continuous CO monitoring	IV ivabradine achieved effective and rapid correction of sinus tachycardia. Simultaneously, stroke volume and systolic blood pressure increased, suggesting a beneficial effect of this treatment on tissue perfusion
Nuding et al[8], 2018	Multiple organ dysfunction syndrome	Single-centre RCT (n = 70)	HR reduction ≥ 10 bpm at 96 hours, hemodynamics, disease severity, vasopressor use, mortality	HR reduction after oral ivabradine did not differ significantly between groups. It did not affect hemodynamics or disease severity
Barillà et al[9], 2016	STelevation myocardial infarction complicated by cardiogenic shock	Single-centre RCT (n = 58)	HR reduction, clinical, and hemodynamic outcomes	Associated with a short-term favourable outcome and can be effectively administered by nasogastric intubation
Gallet et al[10], 2014	Severe systolic dysfunction	RCT (n = 22)	HR, diastolic function, perfusion, cardiac output	Demonstrates the safety and potential benefit of as HR HR-lowering agent
De Santis et al[11], 2014	MODS	Case report (n = 3)	Hemodynamic variables	HR reduction in MODS patients
Franke et al[12], 2011	Acute heart failure due to myocarditis	Case report (n = 2)	Hemodynamic variables	Beneficially influence outcome by allowing optimisation of the patient′s HR
Swedberg et al[1], 2010	Chronic heart failure	Randomised placebo-controlled (n = 6558)	Composite of cardiovascular death or hospital admission for worsening heart failure	HR is reduced with improvement in clinical outcomes

HR: Heart rate; ECMO: Extracorporeal membrane oxygenation; SV: Stroke volume; MODS: Multi-organ dysfunction syndrome; RCT: Randomised controlled trial.

ACUTE CORONARY SYNDROME

An elevated heart rate in acute coronary syndrome (ACS) increases myocardial oxygen demand, thereby exacerbating ischemia. Ivabradine's ability to selectively lower heart rate has been evaluated in several trials. Calabrò et al[13] indicated its effectiveness in reducing heart rate and improving left ventricular function, particularly in patients undergoing primary percutaneous coronary intervention. They suggested that ivabradine also aids in left ventricular remodeling post-ST-segment elevation myocardial infarction.

ACUTE DECOMPENSATED HEART FAILURE

Sinus tachycardia worsens symptoms and prognosis in patients with acute decompensated heart failure. Beta-blockers are effective but poorly tolerated in patients with hypotension. Ivabradine provides an alternative by selectively controlling heart rate without affecting contractility. A clinical trial reported that ivabradine improved heart rate control and reduced hospital stay duration in acute decompensated heart failure patients who were refractory to beta-blockers[14].

SEPSIS AND MULTIPLE ORGAN DYSFUNCTION SYNDROME

Sepsis-induced tachycardia contributes to hemodynamic instability and worsens outcomes. Ivabradine’s selective heart rate reduction has been explored in septic patients. A prospective trial demonstrated improved hemodynamic parameters, including cardiac output and tissue perfusion, without increasing adverse effects[4].

COMPARATIVE EFFICACY: IVABRADINE VS BETA-BLOCKERS

A prospective study compared ivabradine to beta-blockers in patients with ACS, observing both to be equally effective in reducing heart rate. However, ivabradine was better tolerated in patients with contraindications to beta blockers[15]. Unlike beta-blockers, ivabradine does not affect blood pressure or contractility, making it suitable for specific patient populations.

SAFETY PROFILE

Ivabradine has a favourable safety profile, characterised by mild, reversible side effects. The most common adverse effects include bradycardia (often dose-dependent) and visual disturbances (transient effects due to retinal If channel inhibition). Importantly, ivabradine lacks the negative inotropic and vasodilatory properties of beta-blockers, making it a safer alternative in patients with hypotension or left ventricular dysfunction (Table 2)[16].

Table 2 Comparison of ivabradine and beta-blockers.

Variable	Ivabradine	Beta-blockers
Mechanism	Blocks If channels in SA node (reduces HR only)	Block β1/β2-adrenergic receptors (reduces HR + BP)
Common side effects	Luminous phenomena (visual brightness). Bradycardia. Headache. Rare: Atrial fibrillation	Fatigue. Cold. hands/feet. Bronchospasm (worsens COPD/asthma) Erectile dysfunction. Sleep disturbances. Depression
Metabolic effects	Neutral (no impact on glucose/Lipids)	May worsen: Insulin resistance. Triglycerides (↑). HDL (↓)
Contraindications	HR < 60 bpm. Acute heart failure. Pacemaker-dependent	Asthma/COPD. Severe bradycardia. Heart block (2nd/3rd degree)
Advantages	Pure HR control. Safe in lung diseases. No sexual dysfunction. No metabolic interference	Broader benefits (angina, HTN, post-MI). Lower cost
Uses	COPD/asthma patients. Diabetes patients. HR reduction without BP effects	Hypertension. Post-heart attack. Arrhythmias

HR: Heart rate; BP: Blood pressure; HDL: High-Density Lipoprotein; COPD: Chronic obstructive pulmonary disease; HTN: Hypertension, MI: Myocardial infarction; SA: Sinoatrial; If: Funny current.

LIMITATIONS AND FUTURE DIRECTIONS

Despite encouraging findings supporting ivabradine's role in acute care, several challenges persist, including the reliance on small sample sizes in clinical trials, which may limit the generalizability of results, the relatively short follow-up durations that restrict assessments of long-term effectiveness and safety, and the lack of comprehensive long-term efficacy data in critically ill patients. Future large-scale, multicenter, randomized controlled trials are needed to determine the definitive role of ivabradine in acute and critical care settings.

CONCLUSION

Ivabradine represents a novel approach to heart rate modulation in the acute care setting. Its selective inhibition of the If provides a heart rate reduction strategy without compromising myocardial contractility, differentiating it from beta-blockers. While current evidence suggests potential benefits in heart rate control without adverse hemodynamic effects, robust data from diverse patient populations are lacking. Future large-scale studies should aim to assess long-term outcomes, optimal dosing strategies, and potential interactions with other critical care medications to support the broader use of ivabradine in intensive care settings.