Editorial: Terlipressin Induced Bradycardia

Abstract

Hepatorenal syndrome (HRS) is a devastating form of acute renal failure precipitated by haemodynamic dysregulation associated with end-stage liver disease. HRS often has a progressive course that results in the need for renal replacement therapy (dialysis) which can have grave impact on prognosis [1]. In 2022, terlipressin was approved by the FDA for the treatment of HRS in the United States [2]. Terlipressin induces splanchnic and systemic vasoconstriction. The resultant increase in mean arterial pressure (MAP) stimulates reflexive bradycardia. Previous studies have suggested that terlipressin is associated with other arrhythmias and ischaemic events [3]. Whether terlipressin treatment was associated with significant cardiac adverse events (AE) in patients enrolled in large phase III clinical trials is unclear. Bajaj et al. analyse the cardiac AEs that were reported in three North American-centric Phase III randomised placebo-controlled trials examining terlipressin treatment of HRS (OT-0401, REVERSE, CONFIRM) [4].

Bradycardia was the only cardiac AE occurring more frequently in patients treated with terlipressin compared to placebo. Bradycardia led to low rates of dose reduction or interruption but did not result in treatment discontinuation. Other arrhythmias, including atrial fibrillation, were similar in both treatment groups, likely reflecting the general haemodynamic instability of patients with HRS [1].

This study presents several important findings. There was a trend towards higher baseline serum albumin levels in terlipressin-treated patients who experienced bradycardia compared to those who did not, correlating with higher doses of pre-treatment albumin administered to these patients. While the potential role of albumin in promoting bradycardia is unclear, this finding is in congruence with guidance recommendations for judicious albumin utilisation in diagnosing and treating HRS [5]. Importantly, the incidence of bradycardia was not associated with a decrease in MAP or systemic blood pressure and did not influence response rates to treatment.

This study also raises several important points of discussion. While the authors note that no bradycardia AEs were considered serious (SAE), the AE was considered severe (defined as discomfort sufficient to renderer a patient unable to perform normal daily activities) in 68% and 100% of terlipressin and placebo-treated patients, respectively. While this symptomatic bradycardia did not result in treatment discontinuation in the clinical trial setting, it may in real-world settings. Secondly, while patients with severe cardiovascular disease were excluded from the trial and the FDA recommends avoiding terlipressin in patients with a history of severe cardiovascular, cerebrovascular, or ischaemic disease [2], it remains to be seen if patients with preexisting risk factors for arrhythmia will be at increased risk for symptomatic or CV significant complications with terlipressin. The authors mention low rates of arrhythmia in previous terlipressin studies, including those utilising continuous infusion. It would be interesting to learn if larger studies utilising continuous terlipressin infusion could reduce the incidence of arrhythmia (and other treatment-related side effects) compared to bolus dosing that may induce more volatile haemodynamic changes.

Ultimately, the low incidence of arrhythmia with terlipressin treatment in this and previous studies supports the notion that this medication can be used safely without continuous cardiac or ICU monitoring.