Mechanisms of landiolol-mediated positive inotropy in critical care settings.

PURPOSE: To present the potential mechanisms by which landiolol enhances a positive inotropic response in critically ill patients. METHODS: Analysis of preclinical, animal, and clinical data to provide novel knowledge and translate research findings into potential clinical application. RESULTS: The super-selective ß1-antagonist landiolol may increase inotropy and may be associated with positive outcomes in critically ill patients with acute decompensated heart failure or sepsis. CONCLUSION: This review sheds light on the potential mechanisms by which landiolol enhances a positive inotropic response, potentially alleviating the long-held concern over possible negative hemodynamic effects in critically ill patients.

Landiolol for the prevention of postoperative atrial fibrillation after cardiac surgery: a systematic review and meta-analysis.

PURPOSE: Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery. Although the evidence suggests that beta blockers prevent POAF, they often cause hypotension. Landiolol, an ultra-short-acting ß1 blocker, may prevent POAF, without adverse hemodynamic consequences. SOURCE: We searched MEDLINE, CENTRAL, Embase, and trial registries between January 1970 and March 2022. We included randomized controlled trials (RCTs) that evaluated the effect of landiolol for the prevention of POAF after cardiac surgery. Two reviewers independently assessed eligibility, extracted data, and assessed risk of bias using the Risk of Bias 2.0 tool. We pooled data using random-effects models. We used the Grading of Recommendations, Assessment, Development and Evaluations framework to assess certainty of evidence. PRINCIPAL FINDINGS: Nine RCTs including 868 participants met the eligibility criteria. Patients randomized to landiolol (56/460) had less POAF compared with controls (133/408) with a relative risk (RR) of 0.40 (95% confidence interval [CI], 0.30 to 0.54; I2 = 0%;) and an absolute risk of 12.2% vs 32.6% (absolute risk difference, 20.4%; 95% CI, 15.0 to 25.0). Landiolol resulted in a shorter hospital length-of-stay (LOS) (268 patients; mean difference, -2.32 days; 95% CI, -4.02 to -0.57; I2 = 0%). We found no significant difference in bradycardia (RR, 1.11; 95% CI, 0.48 to 2.56; I2 = 0%). No hypotension was reported with landiolol. We judged the certainty of evidence as moderate for POAF (because of indirectness as outcomes were not clearly defined) and low for LOS (because of imprecision and concern of reporting bias). CONCLUSION: In patients undergoing cardiac surgery, landiolol likely reduces POAF and may reduce LOS. A definitive large RCT is needed to confirm these findings. STUDY REGISTRATION: PROSPERO (CRD42021262703); registered 25 July 2021.

RéSUMé: OBJECTIF: La fibrillation auriculaire postopératoire (FAPO) est une complication fréquente après une chirurgie cardiaque. Bien que les données probantes suggèrent que les bêta-bloqueurs préviennent la FAPO, ces agents provoquent souvent une hypotension. Le landiolol, un ß1-bloqueur à action ultra-courte, pourrait prévenir la FAPO sans conséquences hémodynamiques indésirables. SOURCES: Nous avons effectué des recherches dans les bases de données MEDLINE, CENTRAL et Embase, et dans les registres d'études publiées entre janvier 1970 et mars 2022. Nous avons inclus les études randomisées contrôlées (ERC) évaluant l'effet du landiolol pour la prévention de la FAPO après une chirurgie cardiaque. Deux personnes ont indépendamment révisé l'éligibilité, extrait les données et évalué le risque de biais à l'aide de l'outil Risque de biais 2.0. Nous avons regroupé les données à l'aide de modèles à effets aléatoires. Nous avons utilisé le système de notation GRADE (Grading of Recommendations Assessment, Development, and Evaluation) pour évaluer la certitude des données probantes. CONSTATATIONS PRINCIPALES: Neuf ERC incluant 868 personnes remplissaient les critères d'éligibilité. Les patient·es randomisé·es dans le groupe landiolol (56/460) présentaient moins de FAPO que les témoins (133/408), avec un risque relatif (RR) de 0,40 (intervalle de confiance [IC] à 95 %, 0,30 à 0,54; I2 = 0 %) et un risque absolu de 12,2 % vs 32,6 % (différence de risque absolue, 20,4 %; IC 95 % 95 %, 15,0 à 25,0). Le landiolol a entraîné une durée de séjour hospitalier plus courte (268 patient·es; différence moyenne, −2,32 jours; IC 95 %, −4,02 à −0,57; I2 = 0 %). Nous n'avons trouvé aucune différence significative en matière de bradycardie (RR, 1,11; IC 95 %, 0,48 à 2,56; I2 = 0 %). Aucune hypotension n'a été rapportée avec le landiolol. Nous avons jugé que la certitude des données probantes était modérée pour la FAPO (en raison du caractère indirect car les critères d'évaluation n'étaient pas clairement définis) et faible pour la durée de séjour hospitalier (en raison de l'imprécision et de questionnements concernant le biais de déclaration). CONCLUSION: Chez les patient·es bénéficiant d'une chirurgie cardiaque, le landiolol réduit probablement la FAPO et peut réduire la durée de séjour hospitalier. Une ERC définitive à grande échelle est nécessaire pour confirmer ces résultats. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42021262703); enregistrée le 25 juillet 2021.

A novel survival rat model of hyperkalemia and landiolol induced cardioplegic arrest and resuscitation via cardiopulmonary bypass.

OBJECTIVE: A small animal model would be an effective tool for research on the pathophysiology of cardiopulmonary bypass (CPB). However, numerous CPB models do not involve myocardial arrest and resuscitation. The aim of this research is to establish an easily achievable myocardial arrest and resuscitation CPB model through hyperkalemia and landiolol, simulating clinical cardiac surgery. MATERIALS AND METHODS: Ten Sprague-Dawley rats were chosen for CPB. Rats underwent sevoflurane inhalation induction anesthesia and were sustained in an anesthesia state by intubation and intraperitoneal injection's of esketamine and propofol. The entire CPB circuit include a reservoir, a membrane oxygenator and a roller pump, which were connected into a complete loop via silicon tubes and infusion tube.After CPB was established through the tail artery and internal jugular vein, cardioplegic arrest was induced and maintained for 5 min at a rectum temperature of 28.5 ± 0.5°C with hyperkalemia and landiolol. Calcium chloride, epinephrine and insulin were then used for resuscitation. RESULT: All rats successfully finished cardioplegic arrest, resuscitation procedure and survived 2 h postoperatively. Mean hematocrit during CPB was significantly lower than physiologic values of the baseline. The mean time of arrest-resuscitation and CPB was 5.4 ± 0.8 min and 98.5 ± 5.0 min. The blood gas at each detection point were in range with the normal standard requirement of CPB. CONCLUSION: The establishment of cardioplegic arrest and resuscitation procedure via hyperkalemia and landiolol during CPB of WD rat could be achieved successfully. This animal model could be an alternative organ injury research on organ injury of patients undergoing cardiac surgery.

Control of Heart Rate in Infant and Child Tachyarrhythmia With Reduced Cardiac Function Using Landiolol (HEARTFUL)　- Results of a Prospective, Multicenter, Uncontrolled Clinical Study.

BACKGROUND: The prospective Control of HEART rate in inFant and child tachyarrhythmia with reduced cardiac function Using Landiolol (HEARTFUL) study investigated the effectiveness and safety of landiolol, a short-acting ß1 selective blocker, in children.Methods and Results: Twenty-five inpatients aged ≥3 months to <15 years who developed supraventricular tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardia, and inappropriate sinus tachycardia) were treated with landiolol. The primary endpoint, the percent of patients with a reduction in heart rate ≥20% from the initial rate of tachycardia, or termination of tachycardia at 2 h after starting landiolol, was achieved in 12/25 patients (48.0%; 95% CI 28.4-67.6), which exceeded the predetermined threshold (38.0%). At 2 h after starting landiolol administration, heart rate had decreased by ≥20% in 45.8% (11/24) and recovery to sinus rhythm was achieved in 40.0% (6/15) of the patients. Adverse reactions (ARs) occurred in 24.0% (6/25) of patients, and the study was discontinued in 4.0% (1/25) of the patients; however, none of these ARs were considered serious. The most common AR was hypotension (20.0% [5/25] of patients). CONCLUSIONS: The HEARTFUL study has demonstrated the efficacy of landiolol, by reducing heart rate or terminating tachycardia, in pediatric patients with supraventricular tachyarrhythmias. Although serious ARs and concerns were not identified in this study, physicians should be always cautious of circulatory collapse due to hypotension.

Prognostic Impact of Landiolol in Patients with Acute Heart Failure and Atrial Fibrillation with Rapid Ventricular Rates: A Pilot Observational Study.

INTRODUCTION: Guidelines recommend ventricular rate control to <130 bpm during atrial fibrillation (AF) in patients with acute decompensated heart failure (ADHF) to avoid aggravating deteriorations in cardiac outputs. We aimed to evaluate the prognostic impact of landiolol in patients with ADHF and AF. METHODS: This observational study included 60 patients who were urgently hospitalized with ADHF and presented with AF and a heart rate (HR) ≥130 bpm at admission. The patients were assigned to the landiolol group (n = 37) or the reference group (n = 23) based on their intravenous landiolol use within 24 h after admission. The primary endpoint was death from any cause. RESULTS: The groups' baseline characteristics were similar. A significant HR reduction occurred in the landiolol group at 2 h after admission. Compared with the reference group, the HR was significantly lower (111.6 vs. 97.9 bpm, p = 0.02) and the absolute HR reduction was greater (-32.2 vs. -50.0 bpm, p = 0.006) in the landiolol group at 48 h after admission. The landiolol group's mortality rate was significantly lower than that in the reference group (log-rank test, p = 0.032). landiolol use within 24 h after admission was independently associated with lower all-cause mortality (adjusted hazard ratio: 0.15, 95% confidence interval: 0.02-0.92). CONCLUSION: Patients with ADHF and AF who received landiolol for rate control during the acute phase had better prognoses than those who did not receive landiolol.

Landiolol for refractory tachyarrhythmias in the intensive care unit: case reports.

Tachyarrhythmias are common complications of critically ill patients treated on intensive care units. Landiolol is an ultra-short acting beta-blocker with a very high beta1-selectivity. Therefore, landiolol effectively reduces heart rate with only minimal negative effects on blood pressure and inotropy. This article describes two cases of successful treatment of supraventricular and ventricular tachycardias with landiolol in critically ill patients.

The role of landiolol in the management of atrial tachyarrhythmias in patients with acute heart failure and cardiogenic shock: case reports and review of literature.

Atrial tachyarrhythmias and worsening heart failure frequently coexist and potentially progress to a life threatening condition. Therapeutic approach requires simultaneous management of rapid ventricular response and heart failure symptom relief in order to improve haemodynamic stability and cardiac function. Landiolol is an ultra-short-acting b-adrenergic receptor blocker with high b1 selectivity incorporated in 2020 European Society of Cardiology guidelines for the management of atrial fibrillation. We provide a report of two cases with atrial fibrillation treated with landiolol in the acute setting of pulmonary oedema and cardiogenic shock, respectively. Additionally, we searched the international database PUBMED (MEDLINE, PubMed Central) to retrieve scientific evidence regarding its implementation in the treatment of atrial tachyarrhythmias in patients with cardiac dysfunction. Recent studies support the use of landiolol in patients with acute heart failure and atrial tachyarrhythmias. Compared to digoxin, landiolol proved to be more effective in controlling heart rate, with minimal adverse effects. Moreover, landiolol may be helpful in the conversion of atrial tachyarrhythmia to sinus rhythm. A more potent effect has been reported in patients with heart failure with preserved or mildly reduced ejection fraction, small left ventricular volume and high blood pressure. Likewise, administration of low doses of landiolol in patients with cardiogenic shock and atrial tachyarrhythmias reduced heart rate and pulmonary capillary wedge pressure and improved cardiac contractility without reducing blood pressure. Landiolol seems to be an attractive alternative in the acute management of patients with atrial tachyarrhythmias and cardiac dysfunction, though further clinical trials are needed to establish its role.

Effects of Landiolol on Macrocirculatory Parameters and Left and Right Ventricular Performances Following Cardiac Surgery: A Randomized Controlled Trial.

OBJECTIVES: Postoperative atrial fibrillation (POAF) is a major complication after cardiac surgery, and an early postoperative introduction of beta-blockers is recommended to reduce its incidence. Landiolol, a new intravenous short-acting beta-1 blocker, could present a useful and safe macrohemodynamic profile after cardiac surgery. Detailed metabolic and hemodynamic effects of landiolol on cardiac performance, however, remain poorly documented. The authors aimed to investigate the dose-dependent hemodynamic and metabolic effects of landiolol in that specific setting. DESIGN: A prospective, randomized, double-blind study versus placebo. SETTING: A tertiary university hospital. PARTICIPANTS: Adult patients scheduled for elective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Incremental doses of intravenous landiolol (0.5, 1, 2, 5, and 10 µg/kg/min) were given within the 2 hours after arrival in the intensive care unit. Macrocirculatory parameters and cardiac performances were derived from transpulmonary thermodilution and transthoracic echocardiography. Metabolic data were obtained from arterial blood tests. MEASUREMENTS AND MAIN RESULTS: From January to November 2019, 58 patients were analyzed and divided into a landiolol group (n = 30) and a control group (n = 28). Heart rate significantly decreased in the landiolol group (p < 0.01), whereas mean arterial pressure and stroke volume remained unchanged. No significant modification was found in both left and right systolic and diastolic performances. Metabolic variables were similar in both groups. New-onset POAF occurred in 9 (32%) versus 5 (17%) patients in the control and landiolol groups, respectively (p = 0.28). CONCLUSIONS: Infusion of landiolol in the range of 0.5-to-10 µg/kg/min during the early postoperative period presents a good macrohemodynamic safety profile in cardiac surgical patients and could be useful to prevent POAF.

Acute rate control in atrial fibrillation: an urgent need for the clinician.

Rate and rhythm control are still considered equivalent strategies for symptom control using the Atrial Fibrillation Better Care algorithm recommended by the recent atrial fibrillation guideline. In acute situations or critically ill patients, a personalized approach should be used for rapid rhythm or rate control. Even though electrical cardioversion is generally indicated in haemodynamically unstable patients or for rapid effective rhythm control in critically ill patients, this is not always possible due to the high percentage of failure or relapses in such patients. Rate control remains the background therapy for all these patients, and often rapid rate control is mandatory. Short and rapid-onset-acting beta-blockers are the most suitable drugs for acute rate control. Esmolol was the classical example; however, landiolol a newer very selective beta-blocker, recently included in the European atrial fibrillation guideline, has a more favourable pharmacokinetic and pharmacodynamic profile with less haemodynamic interference and is better appropriate for critically ill patients.

Benefits and safety of landiolol for rapid rate control in patients with atrial tachyarrhythmias and acute decompensated heart failure.

Atrial tachyarrhythmias often occur in patients with worsening heart failure (HF), and the development of atrial tachyarrhythmias in acute decompensated HF (ADHF) causes an uncontrolled heart rate (HR) and leads to further exacerbation of HF and persistence of a decompensated HF state. Landiolol, a short-acting intravenous beta-1 blocker, shows very high cardiac beta-1 selectivity and has a very short elimination half-life of approximately 4 min. As shown in several reports, the benefit of intravenous landiolol is that it lowers the ventricular rate early after the start of use without markedly deteriorating haemodynamics. After the cardiac status is stabilized by rapid control of HR, subsequent basic HF pharmacotherapy and rhythm control therapies will be effective for improving outcomes. Because of the pharmacokinetic properties of landiolol, if the patient suffers an adverse reaction such as hypotension or bradycardia, such effects can be quickly reversed by tapering the dose or discontinuing use altogether. Based on several clinical studies, this review discusses the efficacy, safety and role of intravenous landiolol in acute HR control in patients with atrial tachyarrhythmias and ADHF.

Short acting intravenous beta-blocker as a first line of treatment for atrial fibrillation after cardiac surgery: a prospective observational study.

Post-operative atrial fibrillation (POAF) defined as a new-onset of atrial fibrillation (AF) following surgery occurs frequently after cardiac surgery. For non-symptomatic patients, rate control strategy seems to be as effective as rhythm control one in surgical patients. Landiolol is a new highly cardio-selective beta-blocker agent with interesting pharmacological properties that may have some interest in this clinical situation. This is a prospective, monocentric, observational study. All consecutive adult patients (age >18 years old) admitted in the intensive care unit following cardiac surgery with a diagnosed episode of AF were eligible. Success of landiolol administration was defined by a definitive rate control from the beginning of infusion to the 72th h. We also evaluated rhythm control following landiolol infusion. Safety analysis was focused on haemodynamic, renal and respiratory side effects. From 1 January 2020 to 30 June 2021, we included 54 consecutive patients. A sustainable rate control was obtained for 49 patients (90.7%). Median time until a sustainable rate control was 4 h (1, 22). Median infusion rate of landiolol needed for a sustainable rate control was 10 µg/kg/min (6, 19). Following landiolol infusion, median time until pharmacological cardioversion was 24 h. During landiolol infusion, maintenance of mean arterial pressure target requires a concomitant very low dose of norepinephrine. We did not find any other side effects. Low dose of landiolol used for POAF treatment was effective and safe for a rapid and sustainable rate and rhythm control after cardiac surgery.

Dose-dependent scavenging activity of the ultra-short-acting ß1-blocker landiolol against specific free radicals.

Landiolol, a highly cardioselective ultra-short-acting ß1-blocker, prevents perioperative atrial fibrillation associated with systemic inflammation and oxidative stress. We evaluated the direct scavenging activity of landiolol against multiple free radical species. Nine free radical species (hydroxyl, superoxide anion, ascorbyl, tert-butyl peroxyl, tert-butoxyl, singlet oxygen, 2,2-diphenyl-1-picrylhydrazyl, nitric oxide, and tyrosyl radicals) were directly quantified using an X-band ESR spectrometer with the spin-trapping method. IC50 and reaction rate constants were estimated from the dose-response curve for each free radical. Landiolol scavenged six of the free radical species examined: hydroxyl radical (IC50 = 0.76 mM, k landiolol = 1.4 × 10|10 M|-1 s|-1, p<0.001), superoxide anion (58 mM, 2.1 M|-1 s|-1, p = 0.044), tert-butoxyl radical (4.3 mM, k landiolol/k CYPMPO = 0.77, p<0.001), ascorbyl free radical (0.31 mM, p<0.001), singlet oxygen (0.69 mM, k landiolol/k 4-OH |TEMP = 2.9, p<0.001), and nitric oxide (15 mM, 1.7 × 10 M|-1 s|-1, p<0.001). This study is the first to report that landiolol dose-dependently scavenges multiple free radical species with different reaction rate constants. These results indicate the potential clinical application of landiolol as an antioxidative and anti-inflammatory agent in addition to its present clinical use as an anti-arrhythmic agent.

Suppression of amiodarone-induced torsade de pointes by landiolol in a patient with atrial fibrillation-mediated cardiomyopathy.

An elderly Japanese woman developed acute decompensated heart failure caused by persistent atrial fibrillation (AF) and left ventricular systolic dysfunction. Approximately 6 days after starting intravenous administration of amiodarone (600 mg/day) for maintaining sinus rhythm after cardioversion of AF, electrocardiograms revealed a prolonged QT interval associated with torsade de pointes (TdP). The amiodarone-induced TdP disappeared after intravenous administration of landiolol plus magnesium and potassium, without discontinuation of amiodarone or overdrive cardiac pacing, although the prolonged QT interval persisted. To the best of our knowledge, this is the first report that landiolol could be effective for amiodarone-induced TdP.

Efficacy and Safety of Early Intravenous Landiolol on Myocardial Salvage in Patients with ST-segment Elevation Myocardial Infarction before Primary Percutaneous Coronary Intervention: A Randomized Study.

Early treatment with an oral ß-blocker is recommended in patients with a ST-segment-elevation myocardial infarction (STEMI). In this multicenter study, we evaluated the effects of a continuous administration of landiolol, an ultrashort-acting ß-blocker, before primary percutaneous coronary intervention (PCI) on myocardial salvage and its safety in STEMI patients. A total of 47 Japanese patients with anterior or lateral STEMI undergoing a primary PCI within 12 h of symptom onset were randomized to receive intravenous landiolol (started at 3 µg/min/kg dose and continued to a total of 50 mg; n=23) or not (control; n=24). Patients with Killip class III or more were excluded. The primary outcome was the myocardial salvage index on cardiac magnetic resonance imaging (MRI) performed 5-7 days after the PCI. Cardiac MRI was performed in 35 patients (74%). The myocardial salvage index in the landiolol group was significantly greater than that in the control group (44.4±14.6% vs. 31.7±18.9%, respectively; p=0.04). There were no significant differences in adverse events at 24 h between the landiolol and control groups. A continuous administration of landiolol before a primary PCI may increase the degree of myocardial salvage without additional hemodynamic adverse effects within the first 24 h after STEMI.

Safety and Efficacy of Landiolol Hydrochloride in Children with Tachyarrhythmia of Various Etiologies.

The safety and efficacy of landiolol have not been fully elucidated in pediatric patients. This study aimed to clarify the safety and efficacy of landiolol in a pediatric cohort. We retrospectively assessed the clinical features of 21 pediatric patients who were administered landiolol at our hospital. We also investigated the rates of sinus rhythm conversion and heart rate response. The median patient age was 7 months (interquartile range 1-13 months). The etiology of tachyarrhythmia was junctional ectopic tachycardia in 10 patients (47.6%), atrial tachycardia in 10 patients (47.6%), and ventricular tachycardia in 1 patient (4.8%). Of the 21 children, 18 (85.7%) had congenital heart defects, including 14 (77.8%) in whom a landiolol infusion was performed perioperatively. The landiolol infusion was effective in 18 pediatric patients (85.7%), as measured by the conversion to sinus rhythm or a reduced heart rate. Atrial tachycardia in the perioperative period was terminated in all patients. Of 7 patients with tachyarrhythmias unrelated to the perioperative period, landiolol was effective in 5. No adverse effects were reported in any patient. Landiolol infusion is effective and safe in pediatric patients with tachyarrhythmia of various etiologies, especially those with atrial tachyarrhythmia during the perioperative period.

Randomized controlled trial of landiolol, a short-acting beta-1 adrenergic receptor blocker, illustrating changes in high-molecular weight adiponectin levels after elective percutaneous coronary intervention.

Adiponectin (APN) has cardioprotective properties and bisoprolol has been reported to increase myocardial APN expression and reduce myocardial damage. Administration of landiolol, which has a higher cardio-selectivity and shorter half-life than bisoprolol, during the percutaneous coronary intervention (PCI) may increase serum APN and high-molecular weight (HMW)-APN, an active form of APN, in patients with stable angina pectoris (SAP). We recruited 70 patients with SAP and randomized them to intravenous landiolol during PCI (N = 35) or control group (N = 35). The primary endpoint was serum APN and HMW-APN level 3 days after PCI. There was no difference in the primary endpoint between the landiolol and control groups (8.93 ± 5.24 vs. 10.18 ± 5.81 µg/mL, p = 0.35 and 3.36 ± 2.75 vs. 4.28 ± 3.13 µg/mL, p = 0.20) for APN and HMW-APN levels, respectively. APN and HMW-APN level were significantly decreased 1 day after PCI [-0.55 ± 0.92 µg/mL (9.87-9.32 µg/mL), p < 0.001 and -0.20 ± 0.45 µg/mL (3.89-3.69 µg/mL), p < 0.001, respectively]. Additionally, the absolute change in HMW-APN was significantly smaller in the landiolol group compared to the control group (-0.08 ± 0.27 vs. -0.31 ± 0.55 µg/mL, p = 0.031). Multiple linear regression analysis showed that use of landiolol was an independent predictor of change in HMW-APN (ß = 0.276, p = 0.014). Serum APN and HMW-APN level 3 days after PCI were similar between patients treated with and without landiolol. APN and HMW-APN decreased 1 day after PCI in the SAP and landiolol mitigated decrease in HMW-APN.

Cost-Effectiveness Analysis of Landiolol, an Ultrashort-Acting Beta-Blocker, for Prevention of Postoperative Atrial Fibrillation for the Germany Health Care System.

OBJECTIVES: Landiolol is an ultrashort-acting beta-blocker with high beta-1 receptor affinity and less blood pressure-lowering properties than other beta-blockers available for intravenous use in Germany. The present analysis aimed to determine whether perioperative treatment with landiolol in cardiac surgical patients is cost-effective under the conditions of the German Diagnosis-Related Groups health cost reimbursement system. DESIGN: On the basis of clinical outcome data from a meta-analysis that included 622 patients from 7 randomized controlled trials, a decision-model was developed to determine the cost-effectiveness of landiolol versus standard-of-care (SoC). SETTING: Hospital setting. PARTICIPANTS: Hospital patients undergoing a representative mix of cardiac surgical procedures (MIX-CS) and isolated coronary artery bypass grafting (CABG). INTERVENTIONS: Landiolol versus SoC in prevention of atrial fibrillation immediately after cardiac surgery. MEASUREMENTS AND MAIN RESULTS: The model benefit was expressed in a reduction of postoperative atrial fibrillation (POAF) episodes and reduced complications. The model calculated total inpatient costs over the hospital length of stay. Costs from published sources were used for the German hospital perspective. SoC was associated with POAF rates of 36.0% to 39.2% and 24.4% to 30.1% in the MIX-CS and CABG populations, respectively. Patients with POAF had a higher morbidity and mortality. Estimated total costs for SoC patients in the MIX-CS and CABG groups were 28.792 € and 25.630 €, respectively. Landiolol reduced the incidence of POAF to 12.6% in the MIX-CS and 12.1% in the CABG groups. This was associated with a cost reduction of 2.209 € and 1.470 €. CONCLUSIONS: This analysis suggests that preventing POAF with landiolol is highly cost-effective. Additional studies are needed to assess whether a comparable reduction in POAF and associated cost savings may be achieved using conventional intravenous beta-blockers or amiodarone.

Efficacy and Safety of the Ultra-Short-Acting ß1-Selective Blocker Landiolol in Patients With Recurrent Hemodynamically Unstable Ventricular Tachyarrhymias　- Outcomes of J-Land II Study.

BACKGROUND: We aimed to investigate the efficacy and safety of landiolol in Japanese patients with recurrent hemodynamically unstable ventricular tachycardia or recurrent ventricular fibrillation (recurrent VT/VF).Methods and Results:This was an open-label, uncontrolled, multicenter study. Patients with hemodynamically unstable VT or VF 24 h prior to providing informed consent, and who were refractory to class III antiarrhythmic drugs, were enrolled. Landiolol was started at a dose of 1 µg/kg/min, after VT/VF was suppressed with electrical defibrillation. Landiolol was titrated up to 10 µg/kg/min in 1 h and adjusted between 1 and 40 µg/kg/min for the efficacy assessment (1-49 h). The primary efficacy endpoint was the proportion of patients free from recurrent VT/VF. Secondary efficacy endpoints included the number of recurrent VT/VF events and the survival rate 30 days after the start of landiolol treatment. Adverse events (AEs) were assessed for safety; 27 and 29 patients were analyzed for efficacy and safety, respectively. The proportion of patients free from recurrent VT/VF was 77.8% (95% CI 57.1-89.3). The mean (±standard deviation) number of recurrent VT/VF events was 9.3±7.9. The survival rate was 96.3%. The overall incidence of AEs and of serious AEs was 72.4% and 6.9%, respectively. CONCLUSIONS: Landiolol may be useful for Japanese patients with recurrent VT/VF who do not respond to class III antiarrhythmic drugs.

Open-Label Two-Dose Pilot Study of Landiolol for the Treatment of Atrial Fibrillation/Atrial Flutter in Caucasian Patients.

BACKGROUND: We investigated for the first time the suitability of landiolol, an ultra-short-acting ß1-specific ß-blocker, for the treatment of atrial fibrillation/atrial flutter (AF/AFL) in Caucasian patients.Methods and Results:The 20 study patients received landiolol as a continuous infusion (starting dose 40 µg/kg/min) with (B+CI) or without (CI) a preceding bolus dose (100 µg/kg/min administered over 1 min) in a prospective open-label study. The primary endpoint was the proportion of patients with sustained heart rate (HR) reduction ≥20% or to <90 beats/min within 16 min of starting the CI. Secondary endpoints were the pharmacodynamics, pharmacokinetics, AF/AFL symptoms, safety and tolerability of landiolol. At 16 min, HR was reduced in all patients treated with landiolol. The primary endpoint was met by 60% of patients in the CI group and 40% in the B+CI group without a significant group difference. Overall reduction of AF/AFL symptoms at 16 min was 72%. Safety and local tolerability of landiolol were excellent, and no serious adverse events occurred. CONCLUSIONS: Continuous infusion of landiolol with a starting dose of 40 µg/kg/min is suitable for the acute treatment of tachycardic AF/AFL in Caucasian patients. Administration of a preceding bolus seems unnecessary.

Differential Effectiveness of Landiolol Between Atrial Fibrillation and Atrial Flutter/Atrial Tachycardia Patients With Left Ventricular Dysfunction.

BACKGROUND: Landiolol, an ultra-short acting ß1-selective blocker, is more effective for controlling the heart rate (HR) than digoxin in patients with atrial tachyarrhythmias and left ventricular (LV) dysfunction. The impact of the type of atrial tachyarrhythmias on the effectiveness of landiolol is uncertain. We evaluated the efficacy and safety of landiolol on tachycardiac atrial fibrillation (AF) and tachycardiac atrial flutter/atrial tachycardia (AFl/AT) in patients with reduced LV function. Methods and Results: Seventy-seven patients treated with landiolol were retrospectively analyzed. There were no significant differences in the baseline characteristics between the AF group (n=65) and AFl/AT group (n=12). Despite a higher dosage, the %change in HR from baseline to 12 and 24 h was only -10.2±12.7% and -16.1±19.4% in the AFl/AT group, while it was -28.3±13.2% and -31.3±11.3% in the AF group (P<0.02), respectively. The prevalence of the responders to landiolol treatment was much greater in the AF group than in the AFl/AT group (P<0.001). Alternative treatments such as i.v. amiodarone and electrical cardioversion were required in 83% of the AFl/AT patients. CONCLUSIONS: Landiolol was ineffective in the majority of AFl/AT patients. An alternative management to prevent any worsening of heart failure might be considered in those patients.