Beta-blockers for prevention of atrial fibrillation in cardiac surgery

Atrial fibrillation following cardiac surgery is one of the most frequent complications, associated with increased hospital length of stay, haemodynamic instability, and a higher risk of stroke and mortality (1). Among these arrhythmias, physicians should distinguish chronic atrial fibrillation, which results from cardiac remodeling, from de novo atrial fibrillation—referred to as postoperative atrial fibrillation (POAF)—which is secondary to acute factors such as inflammation, sympathetic activation, and oxidative stress (2).

In cardiac surgery, and more broadly in cardiothoracic surgery (2), new-onset atrial fibrillation occurs frequently. Although patients may have no prior history of arrhythmia, the incidence of de novo atrial fibrillation has been reported to range between 30% and 50% (3). The exact pathophysiology of POAF remains incompletely understood, and two main hypotheses have been proposed (Figure 1).

Figure 1.

Two hypothesis of de novo POAF following cardiac surgery. The POAF episode could result of a chronic remodeling of the heart with an increased risk of stroke in contrast with the second hypothesis where POAF is secondary to acute inflammation, adrenergic responses and oxidative stress with no specific risk of stroke at long term. POAF, post-operative atrial fibrillation.

The first hypothesis suggests an interaction between acute perioperative factors and chronic structural remodeling or ageing of the heart (e.g., fibrosis or left atrial enlargement), leading to an increased long-term risk of stroke (2).

The second hypothesis involves only acute factors related to surgery, particularly inflammation, sympathetic activation, and oxidative stress. Indeed, the time course of C-reactive protein parallels that of POAF, with a peak incidence on postoperative day 2. Moreover, cardiac surgery with cardiopulmonary bypass induces marked activation of the sympathetic–adrenal system, resulting in a significant increase in circulating catecholamines, particularly norepinephrine and epinephrine (4). Finally, oxidative stress results from ischemia–reperfusion injury induced by cardiopulmonary bypass, increasing the production of reactive oxygen species and leading to acute electrical remodeling (2).

Given the sympathetic activation induced by cardiac surgery with cardiopulmonary bypass, beta-blockers have been proposed to reduce this trigger and have been strongly associated with a reduction in POAF in clinical studies (1,5). Accordingly, beta-blockers are recommended as first-line therapy for POAF prevention following cardiac surgery (6,7).

However, the optimal timing and modalities of administration remain unclear. For example, continuation of oral beta-blockers on the day of surgery was not associated with a reduced incidence of POAF but was linked to increased vasopressor use and adverse postoperative renal events (8). The postoperative initiation of oral beta-blockers is also debated due to variable bioavailability and prolonged duration of action, which may increase the risk of hypotension or bradycardia.

New intravenous highly selective β1-blockers with ultra-short onset of action may help reduce sympathetic activation, thereby decreasing POAF incidence, while allowing safe and flexible use according to their pharmacokinetic properties. Among these agents, landiolol has been shown to have a strong negative chronotropic effect with limited negative inotropic effects compared with other short-acting β1-selective blockers such as esmolol (9,10).

Clinical studies have shown that landiolol can reduce the incidence of POAF following cardiac surgery in Asian populations (1). However, these findings cannot be directly extrapolated to non-Asian populations, as Asian patients may exhibit increased sensitivity to beta-blockers at the β-adrenergic receptor level (11).

In Caucasian populations, a randomized controlled pilot study evaluated incremental doses of intravenous landiolol (0.5 to 10 µg/kg/min) initiated within two hours after cardiac surgery (12). The authors reported a significant reduction in heart rate in the landiolol group compared with placebo, while mean arterial pressure and stroke volume remained unchanged. No significant effects were observed on left or right ventricular systolic or diastolic function, nor on metabolic parameters (12). However, this pilot study was not designed to assess POAF prevention.

The LANDIPROTECT study was conducted to evaluate the effect of low-dose landiolol for POAF prevention in non-Asian patients undergoing cardiac surgery (13). Between January 2021 and July 2023, 318 patients were randomized in three French intensive care units (ICUs) to receive either an intravenous infusion of landiolol at 2 µg/kg/min initiated within four hours after ICU admission and continued for at least 24 hours, or placebo, while maintaining mean arterial pressure (MAP) ≥65 mmHg and heart rate ≥50 bpm. From 12 hours postoperatively, oral bisoprolol (or the patient’s usual beta-blocker) was introduced twice daily when heart rate was <100 bpm, with the aim of tapering and discontinuing the intravenous treatment.

The study showed that landiolol safely reduced heart rate during the first 24 hours after surgery but did not reduce the incidence of POAF (13).

Several explanations can be proposed. First, the dose of landiolol (2 µg/kg/min) may have been insufficient for POAF prevention. In addition, the administration strategy (timing, duration, dosing, and heart rate targets) may have contributed to the lack of efficacy. Initiation of landiolol earlier—during weaning from cardiopulmonary bypass (14)—and/or the use of higher doses (≥5 µg/kg/min) could be more effective in reducing sympathetic activation (12,15). Furthermore, the duration of landiolol infusion may have been insufficient, as oral beta-blockers may not achieve effective bioavailability until 48 hours postoperatively. This suggests that prolonged infusion [72 hours (16) or even 96 hours (17)] may be beneficial.

Second, the inclusion of patients undergoing mitral or complex cardiac surgery may have introduced a population with significant structural remodeling (fibrosis, atrial enlargement), representing a substrate for chronic atrial fibrillation rather than true POAF, with a different pathophysiology.

Several perspectives emerge from this work. First, optimal landiolol administration strategies (timing, dose, and heart rate targets) should be evaluated in large randomized trials in non-Asian populations, likely using higher doses (≥2 µg/kg/min) and longer durations (≥48 hours).

Second, transdermal bisoprolol represents an interesting alternative, either alone for POAF prevention (18) or in combination with oral beta-blockers to improve heart rate control during POAF episodes (19). A retrospective study conducted in Japan suggested that transdermal bisoprolol was more effective than oral formulations in reducing POAF after cardiac surgery (20), possibly due to more reliable bioavailability in the postoperative setting.

Finally, given the multifactorial nature of POAF, a bundled approach combining beta-blockers with antiarrhythmic and/or anti-inflammatory strategies—such as posterior left pericardiotomy—should be evaluated (21).

In conclusion, the LANDIPROTECT trial demonstrated that landiolol at 2 µg/kg/min is safe in non-Asian patients undergoing cardiac surgery but does not reduce POAF incidence. The optimal modalities of beta-blocker administration in this setting remain to be defined. At present, routine use of landiolol for POAF prevention in non-Asian populations cannot be recommended.

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