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

Abstract

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 β₁ 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.

Various tachyarrhythmias may occur after surgical repair of congenital heart disease (CHD) and they may be potentially fatal.^1,2 Following onset, emergency therapy to control and terminate the tachycardia, and to prevent circulatory deteriorations, is usually mandatory. In patients with tachyarrhythmia resistant to pharmacological therapy, non-pharmacological treatments, such as catheter ablation or implantation of a cardioverter defibrillator, are an option for adult patients.^3,4 However, non-pharmacological approaches are sometimes difficult in some types of CHD, or after surgical procedures for anatomical reasons in children.^2,5 Amiodarone and nifekalant have been used for acute control of tachyarrhythmias, but β-blockers were also recommended in the current Japanese guidelines for controlling tachyarrhythmia in patients experiencing cardiac failure.^5,6

Landiolol is a short-acting β₁ selective blocker that is already marketed in Japan, where it has been used for many years to treat tachyarrhythmias in adults. Preclinical studies have demonstrated that landiolol is a highly selective β₁ receptor antagonist, with a selectivity exceeding that of another β₁ selective blocker, esmolol.^7–10 Because the elimination half-life of landiolol is approximately 4 min, its dose can be easily adjusted during administration to achieve the desired heart rate and avoid excessive heart rate lowering and hypotension.

Abundant clinical studies in adults have since demonstrated the efficacy and safety of landiolol in various settings,^11–19 resulting in a broad range of indications for heart rate control.²⁰ However, only a few studies of landiolol use in children have been reported.^21–25 Those were retrospective studies and involved patients treated at individual hospitals. Furthermore, only 2 of those studies had been published when we were planning our trial. Therefore, a prospective, multicenter clinical study to evaluate the efficacy and safety of landiolol in children was started.

The prospective Control of HEART rate in inFant and child tachyarrhythmia with reduced cardiac function Using Landiolol (HEARTFUL) phase II/III study was designed to investigate the efficacy and safety of landiolol in children.

Methods

Ethics

The design of the HEARTFUL study is comprehensively described in our previous report.²⁶ The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice, and was approved by the Institutional Review Boards at 15 participating institutions. The study was registered in the JapicCTI database (JapicCTI-152911; http://www.japic.or.jp/). The study sites are listed in the Supplementary Appendix.

Patients

Japanese inpatients with cardiac dysfunction and supraventricular tachyarrhythmias (SVTs) aged ≥3 months to <15 years were invited to participate in this study. Patients who developed SVTs (atrial fibrillation, atrial flutter, supraventricular tachycardia, and inappropriate sinus tachycardia) with a heart rate of ≥160 beats/min (<1 year of age) or ≥120 beats/min (≥1 year of age) for ≥10 min were eligible for this study if they met one of the following criteria for decreased cardiac function: (1) systemic ventricular ejection fraction prior to the occurrence of arrhythmia was 25–50%; (2) patients receiving continuous intravenous adrenergic stimulants or adrenergic receptor agonists to maintain their circulation before the onset of tachycardia; or (3) patients under control of a cardiopulmonary assist device such as left ventricular assist device, pump oxygenator, or extracorporeal membrane oxygenation before the onset of tachycardia. The type of arrhythmia was diagnosed by the individual investigators at each institution based on electrocardiography during tachycardia, the response to adenosine triphosphate, or electrophysiological studies.

The major exclusion criteria were: (1) systemic ventricular ejection fraction of <25% during tachycardia; (2) patients who required cardioversion to terminate tachycardia; (3) severe valvular stenosis; (4) presence of or suspected hyperthyroidism; (5) after implantation of a permanent pacemaker and/or implantable cardioverter defibrillator (except patients with temporary epicardial wire implantations during surgery); (6) atrial fibrillation with Wolff–Parkinson–White syndrome; (7) cardiogenic shock; (8) diabetic ketoacidosis or metabolic acidosis; (9) atrioventricular block (second degree or greater) or sick sinus syndrome; (10) right ventricular failure due to pulmonary hypertension; (11) patients with or suspected pheochromocytoma; and (12) patients undergoing surgery.

Other eligibility criteria are described in our prior report.²⁶

Written informed consent was obtained from all of the parents/guardians, or from the patient if considered appropriate.

Treatment

Eligible patients who provided consent were enrolled using an online database. Patients started an intravenous infusion of landiolol (in saline) beginning at a rate of 1 μg/kg/min, and their heart rate was monitored for 15–20 min by electrocardiogram (ECG) or an ECG monitor. If the heart rate did not decrease or tachycardia was not terminated, the dose of landiolol was increased by 1 μg/kg/min every 15–20 min until a decrease in heart rate by ≥20% from the rate at onset of tachycardia, or termination of the tachycardia. Once either of these criteria were achieved, the dose of landiolol was to be continued until the patient stabilized. The maximum dose in this study was 10 μg/kg/min. The dose of landiolol could be decreased at any time depending on the patient’s condition. The minimum duration of administration was 2 h and landiolol could be continued for up to 72 h depending on the patient’s condition. After the administration of landiolol, the patient could be switched to an oral β-blocker if deemed appropriate by the investigator. If the systolic blood pressure decreased by ≥20% from the level at the start of the study, the investigator could decide whether to terminate any further landiolol dose increases or to terminate landiolol administration.

Concomitant use of antiarrhythmic drugs, adrenergic stimulants, adrenergic receptor antagonists, defibrillator, catheter ablation, and pacemaker therapy was prohibited from the start of landiolol administration to completion of all observations 2 h later. Prior oral β-blockers (carvedilol or bisoprolol) or oral digitalis preparations for underlying heart diseases (including arrhythmias) could be continued during the study. Likewise, adrenergic stimulants and intravenous digitalis could be continued if they were being used to preserve cardiac function and hemodynamics, and if their doses remained unchanged. The use of sedatives was also permitted, providing their doses remained unchanged, in principle, for the first 2 h of landiolol administration.

Assessments

The study comprised of screening, treatment, and post-treatment periods.²⁶ The treatment period comprised a mandatory period of landiolol administration (2 h) with optional administration for up to 72 h. ECG monitoring was to continue from the onset of arrhythmia attack until 48 h after terminating landiolol administration. Heart rate, blood pressure, and oxygen saturation were sequentially recorded immediately after starting landiolol administration, 0.5, 1, 2, 3, 6, 12, 24, 48, and 72 h (or at the end of administration) after starting landiolol, and at 0.5, 1, and 48 h (or at the end of the protocol) after terminating administration. Twelve-lead ECG was recorded just before starting the study, at 2 and 72 h (or at the end of the administration) after starting landiolol, and at 48 h (or at the end of the protocol) after terminating administration. Blood samples for the pharmacokinetic analysis were collected at a single time-point between the completion of all observations 2 h after starting landiolol administration and at the end of its administration, providing its dose had been stable for ≥30 min prior to blood sampling. The blood landiolol concentration was measured by high-performance liquid chromatography at LSI Medience Corporation. Total clearance was calculated using the following equation: total clearance (mL/min/kg) = dose (μg/kg/min) / drug concentration (ng/mL) × 1,000.

Endpoints

The primary endpoint was the percentage of patients with a reduction in heart rate of ≥20% from baseline or the termination of tachycardia at 2 h after starting landiolol administration.

Secondary endpoints included a sequentially recorded heart rate, the percentage of patients who returned from a non-sinus rhythm to a normal sinus rhythm, the percentage of patients whose heart rate decreased by ≥20% from baseline among patients who continued administration of landiolol for ≥2 h, and the percentage of patients whose heart rate returned to the resting heart rate before the arrhythmia attack (for patients whose heart rate was recorded before the arrhythmia attack).

Safety endpoints included the frequencies of adverse events (AEs) and adverse reactions (ARs; defined as AEs with a causal relationship to the study drug), laboratory tests, percutaneous oxygen saturation, 12-lead ECG, systemic ventricular ejection fraction, cardiothoracic ratio (on chest X-ray), cardiac function evaluated using the New York Heart Association (NYHA) or Ross classification, and renal function. Both AEs and ARs were classified according to system organ class and preferred term using the Medical Dictionary for Regulatory Affairs (MedDRA) version 24.0/J (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use).

Pharmacokinetic endpoints included the blood concentrations and total systemic clearance of landiolol.

Statistical Analyses

We planned to enroll 25 patients, which would provide 86.0% power for the primary endpoint with an efficacy threshold rate of 38.0%.²⁶ The efficacy threshold rate was determined based on the results of a randomized controlled trial in adults that compared the efficacy of landiolol with that of digoxin as a control.¹³ The efficacy rate for landiolol was 48.8% compared with 13.9% for digoxin. The lower limit of the 2-sided 95% confidence interval (CI) for the efficacy rate in the landiolol group was 38%; this value was selected as the efficacy threshold rate in our study. To provide a homogeneous distribution of patients by age, we planned to enroll 10 patients aged ≥3 months to <1 year, 10 patients aged ≥1 to <7 years, and 5 patients aged ≥7 to <15 years. The results are expressed as a percentage with a 2-sided 95% CI. Other efficacy and safety endpoints were assessed using appropriate summary statistics, including the number (percentage) of patients, and presented as or the mean±standard deviation (SD). Kaplan–Meier analysis was used to determine the cumulative percentages of patients with recovery to sinus rhythm or achievement of an appropriate heart rate, as described in the Endpoints section. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

Patients

Between July 2015 and March 2021, informed consent was obtained for 504 patients aged ≥3 months to <15 years, mainly before surgery for CHD. Thirty patients were enrolled in the study and 25 were eligible and started treatment with landiolol (Figure 1). There were 15 males and 10 females with a mean age of 2.2±3.4 years; 9 were aged ≥3 months to <1 year, 13 were aged ≥1 to <7 years, and 3 were aged ≥7 to <15 years (Table 1). In 12 patients, the ejection fraction was ≥50.0% before starting landiolol because they were treated with intravenous adrenergic stimulants to maintain their circulatory conditions. The NYHA/Ross functional classification was III in 15 patients and IV in 10 patients. All patients had SVTs, including atrial tachycardia in 9 patients, inappropriate sinus tachycardia in 8 patients, and junctional ectopic tachycardia (JET) in 6 patients. This study included both postoperative and non-perioperative pediatric patients. Among 21 patients with histories of surgery for CHD, arrhythmias developed within 3 days after CHD surgery in 19 patients. The characteristics of the individual patients are shown in Supplementary Table 1.

Figure 1.

Patient disposition. ^aConsent to participate was obtained prior to arrhythmia attack from at-risk patients (e.g., before surgery); only patients who experienced tachyarrhythmia were enrolled.

Table 1. Patient Characteristics (N=25)

	Value
Sex
Male	15 (60.0)
Female	10 (40.0)
Age (years)	2.2±3.4
≥3 months to <1	9 (36.0)
≥1 to <7	13 (52.0)
≥7 to <15	3 (12.0)
Body weight (kg)	11.8±10.6
Systemic ventricular ejection fraction (%)	54.2±12.2
30 to <40	1 (4.0)
≥40 to <50	12 (48.0)
≥50	12 (48.0)
NYHA/Ross HF functional classification
Class III	15 (60.0)
Class IV	10 (40.0)
Diagnosis
Atrial tachycardia	9 (36.0)
Inappropriate sinus tachycardia	8 (32.0)
JET	6 (24.0)
AVNRT	1 (4.0)
JET, AVNRT	1 (4.0)
Timing of arrhythmia onset
≤3 days after surgery for CHD	19 (76.0)
Othera	6 (24.0)
Underlying heart diseaseb	22 (88.0)
Double-outlet right ventricle	8 (32.0)
Univentricular heart	4 (16.0)
Pulmonary artery atresia with VSD	4 (16.0)
Tricuspid atresia	2 (8.0)
VSD	1 (4.0)
Tetralogy of Fallot	1 (4.0)
Coarctation of the aorta	1 (4.0)
Hypoplastic left heart syndrome	1 (4.0)
No underlying heart disease	3 (12.0)
Wolff–Parkinson–White syndrome	1 (4.0)
Supraventricular tachycardia	1 (4.0)
Ectopic atrial tachycardia	1 (4.0)
Surgical procedures for CHDs (within 3 days before arrhythmia attack)c
Fontan operation	7 (28.0)
Rastelli operation	3 (12.0)
VSD closure	3 (12.0)
Pulmonary angioplasty	3 (12.0)
Intracardiac repair	3 (12.0)
RVOT reconstruction	2 (8.0)
Ross procedure	1 (4.0)
Repair of corrected transposition of the great arteries	1 (4.0)
Mitral valve repair	1 (4.0)
Arterial switch operation	1 (4.0)
Ductus arteriosus ligation	1 (4.0)
Atrioventricular valvuloplasty	1 (4.0)
Surgery for double-outlet right ventricle (with RVOT reconstruction)	1 (4.0)
Bidirectional Glenn procedure	1 (4.0)
No applicable surgery	6 (24.0)

Data are presented as n (%) or mean±standard deviation. AVNRT, atrioventricular nodal re-entrant tachycardia; CHD, congenital heart disease; HF, heart failure; JET, junctional ectopic tachycardia; NYHA, New York Heart Association; RVOT, right ventricular outflow tract; VSD, ventricular septal defect. ^aIncludes 2 patients who underwent CHD surgery more than 3 days earlier, 1 patient without surgical history for CHD, and 3 patients who had no underlying heart diseases. ^bIf the patient had more than 1 underlying heart disease, the major disease term was selected. ^cSurgical procedures for CHD performed within 3 days before arrhythmia attack were compiled (including cases with multiple procedures).

The mean±SD doses of landiolol at 0.5, 1, and 2 h post-treatment initiation were 2.8±1.3, 5.3±2.4, and 7.6±3.2 μg/kg/min, respectively. The mean±SD total administration time was 22.4±24.0 h.

Efficacy

The primary endpoint, a reduction in heart rate of ≥20% from baseline or termination of tachycardia at 2 h after the start of landiolol administration, was achieved in 48.0% of the patients (12/25 patients, 95% CI 28.4–67.6), which exceeded the predetermined threshold efficacy rate of 38.0% (Table 2). The percentages of patients who achieved the primary endpoint were relatively consistent across subgroups by sex, age, and NYHA/Ross functional classification (Table 3). In other subgroups, the percentage was highest in patients with a heart rate of <140 beats/min prior to the start of treatment (80.0%, 4/5), patients with ejection fraction of ≥40 to <50% (66.7%, 8/12), and patients without prior treatment with adrenergic stimulants (80.0%, 4/5) compared with the other subgroups of patients. The percentage of responders according to the type of SVT was 44.4% (4/9) for atrial tachycardia, 37.5% (3/8) for inappropriate sinus tachycardia, and 50.0% (3/6) for JET. The other 2 patients, 1 patient with atrioventricular nodal re-entrant tachycardia (AVNRT) and 1 patient with JET and AVNRT, were responders (Supplementary Table 1).

Table 2. Percentage of Patients Achieving the Efficacy Endpoints

	n/N (%)
Patients who achieved the primary endpointa	12/25 (48.0) [95% CI 28.4–67.6]
Secondary endpoints at 2 h
Percent reduction in heart rate ≥20%b	11/24 (45.8)
Termination of tachycardiac	6/15 (40.0)

CI, confidence interval. ^aThe primary endpoint was the proportion of patients who achieved a reduction in heart rate of ≥20% from baseline or termination of tachycardia at 2 h after the start of landiolol administration. ^bThe decrease in heart rate at 2 h after starting the study drug was evaluated in 24 of 25 patients administered landiolol. The other patient discontinued the study within 2 h after starting administration and was excluded from the analysis. ^cThis analysis was conducted using patients who were not in sinus rhythm before the administration of landiolol. Of the 10 patients excluded from the analysis, 8 presented with inappropriate sinus tachycardia whose ECG waveform indicated sinus rhythm, 1 returned to sinus rhythm immediately before administration of landiolol, and 1 discontinued the study within 2 h after starting administration.

Table 3. Subgroup Analysis of Patients Achieving the Primary Endpoint^a (N=25)

	n/N (%)
Total	12/25 (48.0)
Sex
Male	7/15 (46.7)
Female	5/10 (50.0)
Age (years)
≥3 months to <1	4/9 (44.4)
≥1 to <7	6/13 (46.2)
≥7 to <15	2/3 (66.7)
NYHA/Ross HF functional classification
Class III	7/15 (46.7)
Class IV	5/10 (50.0)
Heart rate prior to the start of treatment (beats/min)
<140	4/5 (80.0)
≥140 to <160	2/7 (28.6)
≥160	6/13 (46.2)
SBP prior to the start of treatment (mmHg)
<80	2/8 (25.0)
≥80 to <100	7/12 (58.3)
≥100	3/5 (60.0)
Ejection fraction (%)
≥30 to <40	0/1 (0.0)
≥40 to <50	8/12 (66.7)
≥50	4/12 (33.3)
Prior treatment with an adrenergic stimulant
No	4/5 (80.0)
Yes	8/20 (40.0)

HF, heart failure; NYHA, New York Heart Association; SBP, systolic blood pressure. ^aReduction in heart rate of ≥20% from baseline or termination of tachycardia at 2 h after the start of landiolol administration.

Changes in the secondary endpoints are presented in Figure 2. Of 15 patients with non-sinus rhythm at baseline, sinus rhythm was achieved in 6 (40.0%; Table 2 and Figure 2A). Among 24 patients who continued the study for ≥2 h, a reduction in heart rate of ≥20% was achieved at 2 h after starting landiolol administration in 11 (45.8%; Table 2 and Figure 2B). As indicated in Figure 2C, there were steady reductions in heart rate over 2 h in all patients and in patients divided by age group. The changes in blood pressure are shown in Figure 2D; the systolic and diastolic blood pressures remained relatively stable in each age group, except for decreases in systolic and diastolic blood pressure over time in those aged ≥7 to <15 years. The percentage of patients with a return to the resting heart rate before the arrhythmia attack at 2 h after starting landiolol administration was 69.2% (9/13).

Figure 2.

Secondary endpoints. Cumulative percentages of patients with a reduction in heart rate of ≥20% (A) or recovery of sinus rhythm (B) for up to 120 h after starting landiolol. Changes in heart rate (C) and blood pressure (D) for up to 120 min after starting landiolol for all patients and in patients divided by age. Values in (C) and (D) are shown as the mean±standard deviation. bpm, beats/min; DBP, diastolic blood pressure; h, hour; min, minute; mo, month; SBP, systolic blood pressure; yr, year.

The relationship between the landiolol dose at 2 h after the start of administration and clinical efficacy is shown in the Supplementary Figure. The doses at the response varied among the individual patients. Three patients responded to landiolol at a dose of 1 μg/kg/min, but 7 out of 9 patients did not respond to landiolol even at a dose of 10 μg/kg/min.

Safety

The safety of landiolol was assessed in terms of AEs and ARs among all the 25 patients. AEs occurred in 40.0% of the patients, and led to treatment discontinuation in 4.0% (Table 4). ARs occurred in 24.0% of patients, and led to treatment discontinuation in 4.0%. None of the AEs or ARs were considered serious. The ARs were hypotension (including blood pressure decreased as a preferred term) in 20.0% of the patients and peripheral coldness in 4.0% of the patients. Hypotension was the only AE/AR that led to treatment discontinuation. AEs were more frequent in males than in females, and in patients with NYHA/Ross class IV than class III. By age, AEs were reported in 22.2%, 46.2%, and 66.7% of patients aged ≥3 months to <1 year, ≥1 to <7 years, and ≥7 to <15 years, respectively (Table 5).

Table 4. Incidence of AEs and ARs in Pediatric Patients With Tachyarrhythmia and Ventricular Dysfunction Treated With Landiolol (N=25)

	n (%)
	AEs	ARsa
All	10 (40.0)	6 (24.0)
Leading to discontinuation	1 (4.0)	1 (4.0)
Serious	0	0
By MedDRA preferred term
Hypotensionb	6 (24.0)	5 (20.0)
Pyrexia	2 (8.0)	0
Restlessness	2 (8.0)	0
Peripheral coldness	1 (4.0)	1 (4.0)
Blood urea increased	1 (4.0)	0
Puncture site swelling	1 (4.0)	0
Pleural effusion	1 (4.0)	0
Respiratory failure	1 (4.0)	0
Use of accessory respiratory muscles	1 (4.0)	0
Erythema	1 (4.0)	0
Urticaria	1 (4.0)	0
Cyanosis	1 (4.0)	0
Sedation complication	1 (4.0)	0

AE, adverse event; AR, adverse reaction; MedDRA, Medical Dictionary for Regulatory Affairs. ^aAEs with a causal relationship to landiolol. ^bIncludes blood pressure decreased as a preferred term.

Table 5. Subgroup Analysis of AEs (N=25)

	n/N (%)
Total	10/25 (40.0)
Sex
Male	8/15 (53.3)
Female	2/10 (20.0)
Age (years)
≥3 months to <1	2/9 (22.2)
≥1 to <7	6/13 (46.2)
≥7 to <15	2/3 (66.7)
NYHA/Ross HF functional classification
Class III	5/15 (33.3)
Class IV	5/10 (50.0)
Heart rate prior to the start of treatment (beats/min)
<140	1/5 (20.0)
≥140 to <160	3/7 (42.9)
≥160	6/13 (46.2)
SBP prior to the start of treatment (mmHg)
<80	2/8 (25.0)
≥80 to <100	4/12 (33.3)
≥100	4/5 (80.0)
Ejection fraction (%)
<40	0/1 (0.0)
≥40 to <50	6/12 (50.0)
≥50	4/12 (33.3)
Prior treatment with an adrenergic stimulant
No	3/5 (60.0)
Yes	7/20 (35.0)

AE, adverse event; HF, heart failure; NYHA, New York Heart Association; SBP, systolic blood pressure.

The changes in the hemodynamic parameters, renal function, and NYHA/Ross class at the final observation are shown in Supplementary Table 2. None of the above parameters became serious from starting landiolol to the end of this study. There were no particular concerns regarding the general laboratory tests or 12-lead ECG findings.

Pharmacokinetics

Total systemic clearance of landiolol was assessed in 21 patients. The median (range) clearance was 43.0 (27.8–206) mL/min/kg in the overall population, and was generally comparable among patients aged ≥3 months to <1 year (47.2 [32.4–206] mL/min/kg), ≥1 to <7 years (41.7 [27.8–115] mL/min/kg), and ≥7 to <15 years (42.6 [39.7–48.3] mL/min/kg) (Figure 3).

Figure 3.

Total systemic clearance of landiolol in all patients and according to age. X represents the mean; error bars represent the SD; the horizontal line represents the median; the box represents the interquartile range; circles represent the individual data. mo, month; SD, standard deviation; yr, year.

Discussion

A guideline on the pharmacotherapy of cardiac arrhythmias was recently published,²⁷ but the efficacy of landiolol for JET in children was only described in this guideline using a case-based study,²⁵ and there was no prospective study of landiolol for tachyarrhythmias in children until now.

The HEARTFUL study was performed to evaluate the efficacy and safety of landiolol for tachyarrhythmia with reduced cardiac function in patients aged ≥3 months to <15 years. We observed appropriate heart rate controlling effects of landiolol in this group of children, similar to that observed in adults in the J-Land study.¹³ In this study, the effective dose of landiolol in the individual patients ranged from 1 to 10 μg/kg/min. A range of effective doses was also reported in the individual patients in the prior adult study.¹³

Interestingly, the present study suggested better outcomes of landiolol in pediatric patients than in adults in terms of the return to normal sinus rhythm. A possible explanation is that the adult study included patients with atrial fibrillation and atrial flutter, whereas this pediatric study was limited to patients with atrial tachycardia, inappropriate sinus tachycardia, and JET, which are among the most common types of tachycardia that occur after surgery for CHD in children. Atrial fibrillation and atrial flutter were reported to be caused by random or ordered reentry. By contrast, the arrhythmias in the pediatric patients enrolled in this study are considered to be due to abnormal automaticity or triggered activity.

It is important to consider that the J-Land study did not include postoperative patients, whereas the majority (76.0%) of the patients enrolled in the HEARTFUL study experienced arrhythmia within 3 days after surgical treatment of CHD. Therefore, sympathetic nerve activity might be increased in these postoperative patients. Considering this background, we believe that landiolol, which suppresses the sympathetic nervous system, might contribute to the return to normal sinus rhythm in these patients.

Another reason for the high percentage of patients with a return to normal sinus rhythm might relate to the fact that all of the patients in this study had acute-onset tachycardia. In the J-Land study,¹³ the underlying arrhythmias were chronic atrial fibrillation and chronic atrial flutter in 48.4% (45/93) and 5.4% (5/93) of patients, respectively, but only 2 patients in the HEARTFUL study had SVT as an underlying arrhythmia. The effects of landiolol in terms of appropriate control of heart rate and the high success rate of a return to sinus rhythm were similar to those reported in previous retrospective studies of landiolol in children.^21,24,25

The efficacy of amiodarone, a class III antiarrhythmic drug, and ivabradine, an I_f channel inhibitor, for the treatment of JET after surgery for CHD has been reported.²⁸ However, ivabradine is an oral medication, which may not be suitable for the acute control of tachycardia or in postsurgical situations. Amiodarone is characterized by slow clearance (90–158 mL/h/kg) and long terminal elimination half-life (20–47 days).²⁹ It is usually used for patients with tachycardia that cannot be controlled by other antiarrhythmic medications, or in patients with life-threatening arrhythmia. By contrast, landiolol has pharmacokinetic properties permitting dose titration to achieve the target heart rate with strong support for acute control of tachyarrhythmias.^19,30

We also investigated the safety of landiolol in pediatric patients. Overall, the AE profile in this study was similar to that reported in the J-Land study,¹³ and no other new concerns specific to children were identified. The most frequent AR was hypotension, which occurred in 20.0% of the patients. This value was numerically greater than the value reported in the J-Land study (4.3%).¹³ Because of the limited number of patients in the HEARTFUL study, we could not perform detailed analysis to examine this difference, but the high frequency of hypotension might be due to the unstable hemodynamic conditions in these patients, particularly acute postsurgical conditions. Hypotension occurred in 3 patients who had recently undergone surgery and in 1 patient who was on a high dose of a diuretic agent. The degree of hypotension in these cases was classified as mild or moderate; none of them were considered to be severe. Two patients recovered following fluid infusion or pacing, and 3 patients recovered without treatment. Landiolol was discontinued in 1 patient. The blood pressure recovered in the other 4 patients who continued landiolol without a change in its dose. We speculated that the decrease in heart rate may increase the stroke volume due to sufficient contraction of the atrium, resulting in increases in cardiac output and hence blood pressure.

The median total systemic clearance in the present study was 43.0 mL/min/kg, which was quite similar to the total systemic clearance of 41.8±8.3 mL/min/kg in healthy adult males.²⁰ Based on the efficacy, safety, and pharmacokinetic results, we consider that pediatric patients can be treated with the same dose of landiolol as adult patients. Two patients had higher total systemic clearance values than the other patients. Because high systemic clearance will result in rapid elimination of landiolol from the body, it will not affect the safety profile of landiolol in such patients.

Study Limitations

There are several limitations that warrant discussion. First, this study enrolled a low number of patients. The sample size was planned in the protocol based on the calculated sample size and predicted response. As we predicted, only 25 patients were administered landiolol among 504 patients for whom informed consent was obtained during the enrollment period of approximately 6 years. Of course, a larger study may have allowed more detailed analyses and detection of other potential AEs/ARs. Second, this study lacked a control group; however, in reduced cardiac function patients with tachyarrhythmia, a placebo group would be unethical.

Conclusions

In conclusion, the results of the HEARTFUL study have demonstrated the efficacy of landiolol in terms of reducing heart rate or terminating tachycardia in pediatric patients with SVTs. Although serious ARs and concerns were not identified in this study, physicians should be cautious of circulatory collapse due to hypotension.

Acknowledgments

The authors thank all the patients and their families, the investigators, and the site staff who participated in the present study. The authors acknowledge the support from Mari Iwamoto (Department of Pediatrics, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan), Motoki Takamuro (Department of Pediatric Cardiology, Hokkaido Medical Center for Child Health and Rehabilitation, Sapporo, Japan), and Chiho Tokunaga (Department of Cardiovascular Surgery, Saitama Medical University International Medical Center, Saitama, Japan) as members of the safety evaluation committee; and Tetsuji Nagano (Ono Pharmaceutical Co., Ltd.) for drafting the study protocol. This study was funded by Ono Pharmaceutical Co., Ltd. The authors thank Nicholas D. Smith (EMC K.K.) for medical writing support, which was funded by Ono Pharmaceutical Co., Ltd.

Disclosures

Eiichiro Morishima and Kaori Oki are employees of Ono Pharmaceutical Co., Ltd. The other authors have no conflicts of interest to disclose.

IRB Information

The present study was approved by the central institutional review board or the institutional review board at each of the following participating centers: Review Board of Human Rights and Ethics for Clinical Studies (reference no. 2015-6-19 for Ibaraki Children’s Hospital and Nagano Children’s Hospital), Tokyo Metropolitan Children’s Medical Center (reference no. ONO-1101-31), National Center for Child Health and Development (reference no. A27001), Kanagawa Children’s Medical Center (reference no. 2015-6-19), Shizuoka Children’s Hospital (reference no. DY150601), Japan Community Healthcare Organization Chukyo Hospital (reference no. 15-008), Osaka City General Hospital (reference no. 2324), Fukuoka Children’s Hospital (reference no. fcho201502), Okinawa Prefectural Nanbu Medical Center & Children’s Medical Center (reference no. N2015-002), Saitama Children’s Medical Center (reference no. CT2020-1), Kyusyu Hospital (reference no. 2020-3-16), Osaka University Hospital (reference no. 200003-B), Juntendo University Hospital (reference no. 2020-009), and Osaka Women’s and Children’s Hospital (reference no. 2020-5-11).

Author Contributions

K.O. and N.S. conceived the study. E.M., K.O., and N.S. designed the study and were responsible for data analysis. K.S., T.S., K.T., M.M., H.U., H.H., H.O., N.O., S.S., H.F., and H.A. were responsible for data collection. A.M. and H.S. were responsible for data interpretation. K.S., T.S., K.T., M.M., H.U., H.H., H.O., N.O., N.S., S.S., H.F., H.A., A.M., H.S., E.M., and K.O. drafted and revised the manuscript, approved the final draft, and take responsibility for the accuracy and/or integrity of the work.

Data Availability

The deidentified participant data will not be shared. For more information on Ono Pharma’s Policy for the Disclosure of Clinical Study Data, please refer to the following website: https://www.ono.co.jp/eng/rd/policy.html.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0967

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