Post-Marketing Surveillance of the Safety of Landiolol in Patients With Recurrent Hemodynamically Unstable Ventricular Tachyarrhythmias

Abstract

Background: Landiolol is a short-acting, intravenously administered β₁-adrenergic receptor blocker that can rapidly control heart rate in refractory and urgent fatal arrhythmias (ventricular fibrillation [VF] and hemodynamically unstable ventricular tachyarrhythmia [VT]). This indication was approved in Japan in 2019 based on results of the J-Land II clinical trial. We conducted post-marketing surveillance (PMS) to assess the safety and effectiveness of landiolol in real-world settings in Japan.

Methods and Results: This PMS examined the safety, focusing on adverse drug reactions (ADRs) related to the safety specifications (_SS), namely hypotension-decreased blood pressure_SS, bradycardia_SS, and heart failure_SS, and effectiveness (physician-rated) in patients treated with landiolol for the target indication. Among 253 registered patients, 13.0% experienced ADRs related to the safety specifications: bradycardia_SS (7.1%), hypotension-decreased blood pressure_SS (6.7%), and heart failure_SS (1.2%). Serious ADRs related to the safety specifications occurred in 6.7% of patients, including those related to bradycardia_SS (3.2%), hypotension-decreased blood pressure_SS (3.2%), and heart failure_SS (1.2%). The effectiveness of landiolol within 48 h after starting treatment was rated as effective (52.4%), slightly effective (27.0%), not effective (18.7%), and indeterminate (2.0%).

Conclusions: The safety profile of landiolol in this PMS was similar to that observed in a prior clinical trial, and no new safety signals were identified. Landiolol is an option for treating refractory and potentially fatal VF or hemodynamically unstable VT.

Ventricular arrhythmias include ventricular ectopy, ventricular fibrillation (VF), and ventricular tachycardia (VT). Sustained VF and VT are associated with a poor prognosis and account for approximately 80% of sudden cardiac deaths.¹ These arrhythmias lead to hemodynamic deterioration, and can cause syncope and sudden death, particularly in patients with structural heart disease and low systolic function.^2–5

Landiolol hydrochloride (landiolol) is a short-acting, intravenously infused drug that binds to and blocks the β₁-adrenergic receptor in the sympathetic nervous system to antagonize catecholamine activity, and thereby lowers heart rate.^6,7 Landiolol has been approved for 6 indications in Japan, including for refractory and urgent fatal arrhythmia (VF and hemodynamically unstable VT), which was added in 2019.⁸ The use of landiolol is recommended by the Japan Circulation Society/Japanese Heart Rhythm Society guidelines for managing recurrent VT associated with organic heart disease for which antiarrhythmic drugs, such as amiodarone and nifekalant, are ineffective.^2,3

The approval of landiolol for refractory and urgent fatal arrhythmia (VF and hemodynamically unstable VT) was based on the results of the J-Land II clinical trial (study ONO-1101-30), which demonstrated the efficacy and safety of landiolol in patients with VF/VT refractory to Class III antiarrhythmic drugs.⁶ However, owing to the small sample size of 29 patients and the limited variety of patients, which may not reflect actual clinical practice, the Ministry of Health, Labour and Welfare requested post-marketing surveillance (PMS) after landiolol was approved for this indication. Therefore, this PMS was conducted in Japan to determine the safety of landiolol and its effectiveness in patients with refractory fatal arrhythmia (VF and hemodynamically unstable VT) in real-world clinical practice. This PMS focused on detecting adverse events (AEs), defined in the risk management plan for landiolol as adverse drug reactions (ADRs) or serious ADRs that occurred during or after treatment, and were related to the following safety specifications (denoted “_SS”): hypotension-decreased blood pressure_SS, bradycardia_SS, and heart failure_SS.

Methods

Study Design

This PMS was a prospective observational survey that registered consecutive patients with cardiac dysfunction who were treated with landiolol for VF and/or hemodynamically unstable VT in the real-world setting. This PMS was conducted in compliance with the Ministerial Ordinance on Good Post-Marketing Study Practice for Drugs, which does not require ethics review board approval for surveys of this type. It was registered with the Japan Registry of Clinical Trials (ID: jRCT1080225340).

Patients

Patients who met the indications for landiolol (i.e., refractory and urgent fatal arrhythmia [VF and hemodynamically unstable VT]) and were candidates for new treatment with landiolol or had already started treatment with landiolol were eligible for this PMS. It was planned to register 200 patients across 50 institutions in Japan that included cardiology and emergency departments. Patients were centrally registered. Informed consent was obtained from patients at institutions where it was required according to institution-specific requirements. Landiolol was to be administered in accordance with the package insert.⁸ All treatment decisions were at the discretion of the attending physician.

Patients were included in the safety analysis population if their case report forms were completed, excluding patients with incomplete documents (agreement form, enrollment form, and case report form), patients who started landiolol treatment outside the registration period specified in the agreement or outside the registration period, duplicated patients, patients for whom the use of landiolol was unknown, patients for whom the presence or absence of AEs was unknown or unrecorded, and patients who had previously received landiolol for the target indication of this PMS.

The effectiveness analysis population included all patients in the safety analysis population, excluding patients with off-label use or those whose indication for use was unknown or not recorded, and patients whose overall assessment of effectiveness or outcome was not recorded by the physician.

Assessments

All data were captured using case report forms, which covered patient demographics/clinical characteristics, safety (AEs/ADRs), effectiveness (overall response to treatment rated by the physicians), and patient outcomes (including survival).

Patient demographics/clinical characteristics included basic information (sex, age, inpatient/outpatient status), presence of underlying heart diseases (myocardial infarction, angina), heart function tests (New York Heart Association [NYHA] functional classification, left ventricular ejection fraction [LVEF]), and comorbidities/complications. Renal and liver dysfunction were identified using a combination of Medical Dictionary for Regulatory Activities (MedDRA) search terms and relevant formulas.

Safety included AEs, ADRs, infections, and abnormal laboratory values that occurred during the observation period. The safety specifications covered 3 categories of AEs/ADRs, as those related to hypotension-decreased blood pressure_SS, bradycardia_SS, and heart failure_SS, as coded by relevant MedDRA preferred terms. The case report forms recorded the presence/absence of AEs (including those defined in the safety specifications), AE duration, timing of onset, dose of landiolol at the time of onset, severity, causal relationship to landiolol, any suspected factors other than landiolol, action taken with landiolol, other interventions for the AE, outcome of the AE (including timing of outcome), clinical course and rationale for the assessment of causal relationship of AE (the time course of the landiolol dose from onset to date and time of outcome [date and time of change, dose in μg/kg/min] if the landiolol dose at the time of onset was >10 μg/kg/min), blood pressure (systolic/diastolic; for AEs related to hypotension-decreased blood pressure_SS), and heart rate (for AEs related to bradycardia_SS).

AEs included in the safety specifications and serious AEs were to be recorded throughout the observation period (i.e., from the start of treatment with landiolol to 48 h after treatment discontinuation or through to 168 h if landiolol was used for more than 120 h). AEs that required treatment discontinuation, dose reduction, or dose interruption of landiolol were recorded from the start of treatment through to treatment discontinuation or until 168 h after the start of treatment (whichever came first).

The indication for using landiolol, past medical history, comorbidities, and AEs (including those related to the safety specifications) were coded using MedDRA/J version 26.0.

The effectiveness of landiolol was assessed in terms of the overall response during the observational period of landiolol use (up to 48 h after the start of treatment or earlier if landiolol was discontinued before 48 h). Patients whose ventricular tachyarrhythmias had terminated at the time of landiolol initiation were classified by the attending physician into 3 grades according to the period of inhibition of recurrent ventricular arrhythmia episodes after landiolol administration as follows: effective, no recurrence during the observation period; slight effect, suppressed recurrence during part of the observation period; and no effect, failed to suppress recurrence during the observation period. Persistent ventricular tachyarrhythmias at the start of landiolol were classified by the attending physician into 3 grades according to the number of ventricular arrhythmia episodes after landiolol administration as follows: effective, disappearance of arrhythmia episodes; slightly effective, decreased number of arrhythmia episodes; or not effective, no decrease in the number of arrhythmia episodes (Supplementary Table 1). The patient’s status (alive, dead, or unknown) at 168 h after the start of landiolol treatment was also recorded.

Statistical Analysis

The sample size of the safety analysis population was set at 200 patients. This was calculated after considering prior Japanese clinical trials in which the incidence of the ADRs (by preferred term) hypotension, bradycardia, and cardiac failure were 20.69% (6/29 patients), 3.45% (1/29 patients), and 3.45% (1/29 patients), respectively.⁶ This planned sample size would provide a probability of 99.91% to detect 1 event of an individual ADR occurring with an incidence of 3.45%, and was therefore considered appropriate for detecting the safety specifications and feasible to enroll the planned number of patients.

Patient demographics and clinical characteristics were summarized using appropriate statistics, including the frequency and proportion (component ratio) or the mean±standard deviation (SD), median, and range (minimum–maximum).

Regarding safety outcomes, any AE/ADR (by preferred term) that occurred more than once in the same patient was only counted once in that patient. If ≥2 AEs/ADRs with different preferred terms within the same safety specification were observed in the same patient, the patient was only counted once. ADRs were analyzed descriptively to determine their frequencies, proportions, and number of events. The overall incidence of ADRs listed in the safety specifications was also stratified by baseline factors (including demographics/clinical characteristics) with 95% confidence intervals (CI) calculated using an exact test. The incidence of ADRs among each stratification factor were compared using Fisher’s exact test or Wilcoxon’s rank-sum test.

The overall effectiveness of landiolol by 48 h and patient outcomes at 168 h were analyzed descriptively to determine the number of patients together with the frequency (component ratio) for all patients and according to the indication (i.e., to prevent recurrence of the episode or to terminate the episode).

Data analyses were conducted using SAS version 9.4. (SAS Institute, Cary, NC, USA).

Results

Patients

A total of 253 patients across 72 sites started treatment with landiolol in the period September 2019–February 2022, and were registered in the PMS. The survey period was completed in August 2023. All 253 patients satisfied the eligibility criteria and were included in the safety analysis set. For 1 patient, landiolol was administered off-label; this patient was excluded from the effectiveness analysis set, which therefore comprised 252 patients (Supplementary Figure).

The characteristics of the safety analysis population are presented in Table 1. The majority of patients were male (80.2%). The mean±SD age was 64.9±15.6 years, and approximately half the patients were aged ≥65 years (58.1%). The indications for using landiolol were VF in 28.5%, hemodynamically unstable VT in 64.8%, VF+hemodynamically unstable VT in 6.3%, and others in 0.4% (paroxysmal atrial fibrillation). The NYHA functional class was I in 36.0% of patients and II in 19.0% of patients. LVEF was recorded for 193 patients, and was <40% in 40.3% of patients, 40% to <50% in 17.4% of patients, and ≥50% in 18.6% of patients; the mean±SD LVEF was 39.18±14.87%. Overall, 77.5% of patients received premedication for ventricular arrhythmia (prior to starting landiolol treatment), which included Class III antiarrhythmic drugs in 63.2% of patients.

Table 1.

Patient Characteristics (Safety Analysis Population; N=253)

Characteristic		Value
Sex	Male	203 (80.2)
	FemaleA	50 (19.8)
Age (years)	<15	1 (0.4)
	15 to <65	105 (41.5)
	≥65	147 (58.1)
	Mean±SD	64.9±15.6
	Median (minimum–maximum)	68.0 (5–93)
Weight (kg)	<50	43 (17.0)
	50 to <60	59 (23.3)
	60 to <70	73 (28.9)
	≥70	78 (30.8)
	Mean±SD	63.72±14.87
	Median (minimum–maximum)	62.30 (22.4–115.0)
Indication for treatment with landiolol	VF	72 (28.5)
	VTB	164 (64.8)
	VF+VT	16 (6.3)
	OthersC	1 (0.4)
Inpatient/outpatient status	Inpatient	196 (77.5)
	Emergency outpatient	57 (22.5)
Any comorbid/concurrent disorder		242 (95.7)
Type of comorbid/concurrent disorder	Renal dysfunction	49 (19.4)
	Liver dysfunction	6 (2.4)
	Underlying heart disease	237 (93.7)
	Type of underlying heart diseaseD
	Myocardial infarction	117 (46.2)
	Angina pectoris	45 (17.8)
	Cardiomyopathy	65 (25.7)
	Valvular heart disease	39 (15.4)
	Heart failure	151 (59.7)
	Hypertension	113 (44.7)
	Persistent atrial fibrillation	34 (13.4)
	Other heart disease	44 (17.4)
	Ischemic heart disease	140 (55.3)
NYHA functional classification	Class I	91 (36.0)
	Class II	48 (19.0)
	Class III	37 (14.6)
	Class IV	39 (15.4)
	Unknown	38 (15.0)
LVEF (%)	<40	102 (40.3)
	40 to <50	44 (17.4)
	≥50	47 (18.6)
	Unknown	60 (23.7)
	Mean±SD	39.18±14.87 (n=193)
	Median (minimum–maximum)	38.00 (8.0–87.9) (n=193)
Status of ventricular arrhythmia at the start of using landiolol	Terminated	139 (54.9)
	Not terminated	114 (45.1)
Premedication for ventricular arrhythmia	No	57 (22.5)
	Yes	196 (77.5)
	Class III antiarrhythmic agents	160 (63.2)
	EffectiveE	69 (27.3)
	IneffectiveE	63 (24.9)
	UnknownE	28 (11.1)

Values are n (%) unless otherwise stated. ^ANone of the females was pregnant or breastfeeding at the time of landiolol administration. ^BThis includes 1 patient whose indication was recorded in the case report form as both “hemodynamically unstable VT” and “other.” ^CIncludes patients whose indication was recorded in the case report form as “other” only. ^DMultiple types were possible. ^EIf multiple Class III antiarrhythmic agents were used as premedication, they were regarded as “effective” if at least 1 agent was “effective,” as “ineffective” if no agent was effective and at least 1 agent was “ineffective”, or as “unknown.” LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SD, standard deviation; VF, ventricular fibrillation; VT, hemodynamically unstable ventricular tachycardia.

Landiolol Usage

Table 2 presents the dose of landiolol and reasons for discontinuation within 48 h. The starting dose of landiolol was <1, 1, and >1 μg/kg/min in 5.9%, 34.0%, and 60.1% of patients, respectively, with a mean±SD dose of 2.07±1.45 μg/kg/min. The highest dose of landiolol during the observation period was ≤10 μg/kg/min in 94.9%, >10 μg/kg/min in 4.7%, and unknown in 0.4% of patients. The mean±SD maintenance dose from the start of treatment to 48 h or to discontinuation, if earlier, was 3.40±2.71 μg/kg/min.

Table 2.

Landiolol Usage (Safety Analysis Population; N=253)

Status		Value
Starting dose of landiolol (μg/kg/min)	<1	15 (5.9)
	1	86 (34.0)
	>1	152 (60.1)
	Mean±SD	2.07±1.45
	Median (minimum–maximum)	1.85 (0.3–10.0)
Highest dose of landiolol during the observation period (μg/kg/min)	≤10	240 (94.9)
	>10	12 (4.7)
	Unknown	1 (0.4)
Maintenance dose from the start of treatment to 48 h after the start of treatment or to discontinuation if earlier (μg/kg/min)	Mean±SD	3.40±2.71
	Median (minimum–maximum)	2.50 (0.1–15.0)
Highest dose of landiolol from the start of treatment to 48 h after the start of treatment or to discontinuation if earlier (μg/kg/min)	≤10	241 (95.3)
	>10	12 (4.7)
	Mean±SD	4.38±3.46
	Median (minimum–maximum)	3.00 (0.4–20.0)
Treatment duration (h)	≤48	130 (51.4)
	>48 to <168	85 (33.6)
	168	35 (13.8)
	Unknown	3 (1.2)
	Mean±SD	66.93±57.02
	Median (minimum–maximum)	46.37 (0.3–168.0)
Discontinuation within 48 h after starting treatmentA		133 (52.6)
Reason for discontinuation	AEs listed in the safety specificationsB	23 (17.3)
	AEs not listed in the safety specificationsB	4 (3.0)
	Good response	66 (49.6)
	Inadequate response	22 (16.5)
	Other reason	24 (18.0)

Values are n (%) unless otherwise stated. ^AMultiple reasons for discontinuation were possible. ^BAEs related to the safety specifications hypotension-blood pressure decreased_SS, bradycardia_SS, or heart failure_SS, where “_SS” denotes safety specification category. AE, adverse event; SD, standard deviation.

The treatment duration was recorded for 250 patients (unknown in 3 patients), and was ≤48 h in 51.4% of patients, >48 to <168 h in 33.6%, and 168 h in 13.8%. The mean±SD treatment duration was 66.93±57.02 h.

Overall, 133 (52.6%) patients discontinued landiolol within 48 h after the start of treatment. The reasons for treatment discontinuation included AEs related to the safety specifications in 17.3%, other AEs in 3.0%, a good response to treatment in 49.6%, an inadequate response to treatment in 16.5%, and other reasons in 18.0%.

Safety

A total of 39 ADRs related to the safety specifications (identified from relevant preferred terms) were recorded in 33 patients, with an incidence of 13.0% (Table 3). ADRs related to the safety specifications of bradycardia_SS, hypotension-decreased blood pressure_SS, and heart failure_SS occurred in 7.1%, 6.7%, and 1.2% of patients, respectively. The most common ADRs related to these categories of safety specifications (by preferred term) were bradycardia (6.3%), blood pressure decreased (4.0%), hypotension (2.4%), cardiac failure (0.8%), and low cardiac output syndrome (0.8%).

Table 3.

Incidence of ADRs Listed in the Safety Specifications (Safety Analysis Population; N=253)

Category/safety specification	MedDRA preferred term	All ADRs	Serious ADRs
Patients with an ADR		33 (13.0)	17 (6.7)
No. of ADRs		39	20
Type of ADR
Hypotension-decreased blood pressureSS	All ADRs	17 (6.7)	8 (3.2)
	Blood pressure decreased	10 (4.0)	4 (1.6)
	Hypotension	6 (2.4)	3 (1.2)
	Ventricular fibrillation	1 (0.4)	1 (0.4)
	Ventricular tachycardia	1 (0.4)	1 (0.4)
BradycardiaSS	All ADRs	18 (7.1)	8 (3.2)
	Bradycardia	16 (6.3)	7 (2.8)
	Heart rate decreased	1 (0.4)	0
	Ventricular fibrillation	1 (0.4)	1 (0.4)
	Ventricular tachycardia	1 (0.4)	1 (0.4)
Heart failureSS	All ADRs	3 (1.2)	3 (1.2)
	Cardiac failure	2 (0.8)	2 (0.8)
	Low cardiac output syndrome	2 (0.8)	2 (0.8)

Values are n (%) unless otherwise specified. ADRs were grouped by MedDRA/J Ver.26.0 and preferred term. Multiple occurrences of each ADR were counted once per patient. Patients with ≥2 ADRs with different preferred terms in the same category of safety specification were counted once. Only ADRs that occurred during the observation period were counted. ADRs, adverse drug reactions; MedDRA, Medical Dictionary for Regulatory Activities; _SS, safety specification category.

Regarding the ADR bradycardia (preferred term), which occurred in 16 patients, landiolol treatment was continued in 4 patients, its administration was interrupted in 2 patients, its dose was reduced in 6 patients, and it was discontinued in 4 patients. For all these patients, the outcome of the ADR was recorded as resolved or resolving.

Twenty serious ADRs related to the safety specifications were reported in 17 (6.7%) patients. By preferred term, these ADRs included bradycardia in 2.8% of patients, blood pressure decreased in 1.6%, hypotension in 1.2%, cardiac failure in 0.8%, and low cardiac output syndrome in 0.8% (Table 3).

Table 4 presents the overall incidence of ADRs related to the safety specifications according to patient characteristics, including the indication for use and the dose of landiolol. By indication, ADRs related to the safety specifications occurred in 23.6% (17/72) of patients with VF, 9.1% (15/164) of patients with hemodynamically unstable VT, and 6.3% (1/16) of patients with VF+hemodynamically unstable VT; the difference in the incidence of ADRs among these groups was statistically significant (P=0.017).

Table 4.

Incidence of Adverse Drug Reactions Listed in the Safety Specifications According to Patient Characteristics (Safety Analysis Population; N=253)

Characteristic		Incidence rate: n/N (%) [95% confidence interval]A	P valueB
Sex	Male	25/203 (12.3) [8.1–17.6]	0.486
	Female	8/50 (16.0) [7.2–29.1]
Age group (years)	<15	0/1 (0.0) [0.0–97.5]	1.000
	≥15	33/252 (13.1) [9.2–17.9]
	<65	12/106 (11.3) [6.0–18.9]	0.572
	≥65	21/147 (14.3) [9.1–21.0]
Indication for treatment with landiolol	VF	17/72 (23.6) [14.4–35.1]	0.017
	VT	15/164 (9.1) [5.2–14.6]
	VF+VT	1/16 (6.3) [0.2–30.2]
	Others	0/1 (0.0) [0.0–97.5]
Any comorbid/concurrent disorder	No	2/11 (18.2) [2.3–51.8]	0.640
	Yes	31/242 (12.8) [8.9–17.7]
Type of comorbid/concurrent disorder
Renal dysfunction	No	25/204 (12.3) [8.1–17.6]	0.479
	Yes	8/49 (16.3) [7.3–29.7]
Liver dysfunction	No	32/247 (13.0) [9.0–17.8]	0.571
	Yes	1/6 (16.7) [0.4–64.1]
Underlying heart disease	No	2/16 (12.5) [1.6–38.3]	1.000
	Yes	31/237 (13.1) [9.1–18.0]
Hypertension	No	15/140 (10.7) [6.1–17.1]	0.261
	Yes	18/113 (15.9) [9.7–24.0]
Ischemic heart disease	No	14/113 (12.4) [6.9–19.9]	0.852
	Yes	19/140 (13.6) [8.4–20.4]
Status of ventricular arrhythmia at the start of using landiolol	Terminated	17/139 (12.2) [7.3–18.9]	0.710
	Not terminated	16/114 (14.0) [8.2–21.8]
Premedication with Class III antiarrhythmic agents for ventricular arrhythmias	No	13/93 (14.0) [7.7–22.7]	0.846
	Yes	20/160 (12.5) [7.8–18.6]
Starting dose of landiolol (μg/kg/min)	<1	1/15 (6.7) [0.2–31.9]	0.208
	1	9/86 (10.5) [4.9–18.9]
	>1	23/152 (15.1) [9.8–21.8]
Concomitant use of Class III antiarrhythmic agents for ventricular arrhythmia	No	14/94 (14.9) [8.4–23.7]	0.563
	Yes	19/159 (11.9) [7.4–18.0]

See Table 1 for definitions. ^AThe denominator was the number of patients in each subgroup. ^BFisher’s test was used except for the starting dose of landiolol (Wilcoxon rank-sum test).

By landiolol dose (Table 5), ADRs related to the safety specifications occurred in 16.7% (2/12) of patients who received a maximum dose of landiolol of >10 μg/kg/min. The ADRs (by preferred term) in these 2 patients were VF and VT in 1 patient, and blood pressure decreased and bradycardia in the other patient.

Table 5.

Incidence of ADRs Listed in the Safety Specifications According to the Maximum Dose of Landiolol (Safety Analysis Population; N=253)

Category/safety specification	MedDRA preferred term	Maximum dose (μg/kg/min)A
		>10	≤10
No. of patients		12	240
Patients with an ADR		2 (16.7)	31 (12.9)
No. of ADRs		4	35
Type of ADR
Hypotension-decreased blood pressureSS	All ADRs	2 (16.7)	15 (6.3)
	Blood pressure decreased	1 (8.3)	9 (3.8)
	Hypotension	0	6 (2.5)
	Ventricular fibrillation	1 (8.3)	0
	Ventricular tachycardia	1 (8.3)	0
BradycardiaSS	All ADRs	2 (16.7)	16 (6.7)
	Bradycardia	1 (8.3)	15 (6.3)
	Heart rate decreased	0	1 (0.4)
	Ventricular fibrillation	1 (8.3)	0
	Ventricular tachycardia	1 (8.3)	0
Heart failureSS	All ADRs	0	3 (1.3)
	Cardiac failure	0	2 (0.8)
	Low cardiac output syndrome	0	2 (0.8)

See Table 3 for definitions. Values are n (%) unless otherwise specified. ^AThe starting dose of landiolol was unknown for 1 patient, for which no ADRs listed in the safety specifications were reported.

Among patients for whom LVEF data were available, there was no significant difference in the incidence of ADRs between patients with LVEF <40% and those with LVEF ≥40% (9.8% [10/102] vs. 8.8% [8/91], respectively).

There were 4 serious ADRs, other than those defined in the safety specifications, in 2 (0.8%) patients (Supplementary Table 2). One patient experienced cerebral haemorrhage and platelet count decreased, and the other patient had aortic valve disease with cardiac output decreased. The first patient had concurrent unstable angina and chronic heart failure, and was being treated with intravenous amiodarone and intravenous heparin. The platelet count was 9.3×10⁴ cells/µL at approximately 31 h and the cerebral haemorrhage occurred approximately 37 h after starting landiolol treatment. The administration of landiolol was continued after the onset of both events. Neither event was reported to have resolved. Two (0.8%) patients required treatment discontinuation, dose reduction, or dose interruption of landiolol due to ADRs that were not defined in the safety specifications (Supplementary Table 2).

Overall Effectiveness of Landiolol and Survival at 168 h

The overall effectiveness during landiolol treatment was assessed by the attending physician according to its indication and whether it was being used to prevent ventricular arrhythmic episodes from recurring or to terminate ventricular arrhythmic episodes. The responses were determined among all 252 patients included in the effectiveness analysis population. The proportion of patients with a response to treatment was 79.4% (effective in 52.4% and slightly effective in 27.0%; Table 6). The response was reported as non-effective in 18.7% and indeterminate in 2.0%. The response rate was 83.4% in 138 patients who received landiolol to prevent recurrence and 74.6% in 114 patients who initiated landiolol without prior termination of the ventricular arrhythmic episode (to terminate the episode).

Table 6.

Effectiveness of Landiolol and Patient Outcomes (Effectiveness Analysis Population; N=252)

		Intended use
		All patients	Prevent recurrence	Terminate episode
No. of patientsA		252 (100.0)	138 (54.8)	114 (45.2)
Effectiveness by 48 h after starting treatmentB	Effective	132 (52.4)	96 (69.6)	36 (31.6)
	Slightly effective	68 (27.0)	19 (13.8)	49 (43.0)
	Not effective	47 (18.7)	21 (15.2)	26 (22.8)
	Indeterminate	5 (2.0)	2 (1.4)	3 (2.6)
Patient outcome at 168 h after starting treatmentC	Alive	227 (90.1)	127 (92.0)	100 (87.7)
	Dead	24 (9.5)	11 (8.0)	13 (11.4)
	Unknown	1 (0.4)	0	1 (0.9)

Values are n (%). ^ADenominator used to calculate percentages. ^BThe overall response was reported by the physician up to 48 h after starting landiolol treatment, or to discontinuation if landiolol was discontinued within 48 h, according to the status of ventricular arrhythmia at the time of starting landiolol treatment (Table 1). ^CRecorded at 168 h after starting landiolol treatment.

Table 7 presents the overall effectiveness of landiolol according to patient background characteristics. The proportion of patients in whom landiolol was considered to be effective or slightly effective combined was 82.6% (76/92) in patients with no premedication and 77.5% (124/160) in patients who had received premedication with Class III antiarrhythmic drugs for ventricular tachyarrhythmia. By indication, the proportion of patients in whom landiolol was rated as effective or slightly effective combined was 79.2% (57/72) in patients treated with landiolol for VF, 77.4% (127/164) in patients treated for hemodynamically unstable VT, and 100.0% (16/16) in patients treated for VF+hemodynamically unstable VT.

Table 7.

Effectiveness of Landiolol Treatment According to Patient Characteristics

Characteristic		Total	Effective	Slightly effective	Not effective	Indeterminate
All patients		252	132 (52.4)	68 (27.0)	47 (18.7)	5 (2.0)
Sex	Male	202 (80.2)	105 (52.0)	54 (26.7)	38 (18.8)	5 (2.5)
	Female	50 (19.8)	27 (54.0)	14 (28.0)	9 (18.0)	0
Age group (years)	<15	1 (0.4)	1 (100.0)	0	0	0
	15 to <65	105 (41.7)	54 (51.4)	29 (27.6)	21 (20.0)	1 (1.0)
	≥65	146 (57.9)	77 (52.7)	39 (26.7)	26 (17.8)	4 (2.7)
Indication for treatment with landiolol	VF	72 (28.6)	31 (43.1)	26 (36.1)	12 (16.7)	3 (4.2)
	VT	164 (65.1)	88 (53.7)	39 (23.8)	35 (21.3)	2 (1.2)
	VF+VT	16 (6.3)	13 (81.3)	3 (18.8)	0	0
Any comorbid/concurrent disorder	No	11 (4.4)	5 (45.5)	2 (18.2)	4 (36.4)	0
	Yes	241 (95.6)	127 (52.7)	66 (27.4)	43 (17.8)	5 (2.1)
Type of comorbid/concurrent disorder
Renal dysfunction	No	203 (80.6)	112 (55.2)	54 (26.6)	33 (16.3)	4 (2.0)
	Yes	49 (19.4)	20 (40.8)	14 (28.6)	14 (28.6)	1 (2.0)
Liver dysfunction	No	246 (97.6)	129 (52.4)	66 (26.8)	46 (18.7)	5 (2.0)
	Yes	6 (2.4)	3 (50.0)	2 (33.3)	1 (16.7)	0
Underlying heart disease	No	16 (6.3)	10 (62.5)	2 (12.5)	4 (25.0)	0
	Yes	236 (93.7)	122 (51.7)	66 (28.0)	43 (18.2)	5 (2.1)
Ischemic heart disease	No	113 (44.8)	57 (50.4)	31 (27.4)	24 (21.2)	1 (0.9)
	Yes	139 (55.2)	75 (54.0)	37 (26.6)	23 (16.5)	4 (2.9)
Premedication with Class III antiarrhythmic agents for ventricular arrhythmias	No	92 (36.5)	51 (55.4)	25 (27.2)	15 (16.3)	1 (1.1)
	Yes	160 (63.5)	81 (50.6)	43 (26.9)	32 (20.0)	4 (2.5)
Concomitant use of Class III antiarrhythmic agents for ventricular arrhythmias	No	93 (36.9)	55 (59.1)	26 (28.0)	11 (11.8)	1 (1.1)
	Yes	159 (63.1)	77 (48.4)	42 (26.4)	36 (22.6)	4 (2.5)

See Table 1 for definitions. Values are n (%).

Regarding patient outcomes at 168 h after starting landiolol treatment, 90.1% of patients were alive, 9.5% had died, and the status was unknown in 0.4% (Table 6).

Discussion

This PMS was performed to assess the safety and effectiveness of landiolol among patients with VF or hemodynamically unstable VT in the real-world setting, following an earlier clinical trial in this setting.⁶

Safety

Among the 253 registered patients, 13.0% experienced ADRs defined in the safety specifications, of which only the incidence of 1 ADR, namely bradycardia (6.3%; preferred term) exceeded the incidence reported in the prior clinical trial (3.4%).⁶ All these cases of bradycardia were categorized as resolved or resolving following dose adjustment, including discontinuation of landiolol, while monitoring heart rates. Therefore, bradycardia appears to be a manageable ADR in patients treated with landiolol.

We also analyzed the safety data according to the indication for using landiolol; ADRs related to the safety specifications were reported for 23.6% of patients with VF, 9.1% of patients with hemodynamically unstable VT, and 6.3% of patients with VF+hemodynamically unstable VT, a statistically significant difference (P=0.017). These findings may be influenced by the differences in indications, particularly the poor condition of patients with VF.

In addition, we investigated the safety of landiolol according to the highest administered dose. In the J-Land II clinical trial,⁶ only 1 patient was treated with landiolol at doses >10 μg/kg/min, which limited that study’s ability to examine its safety at high doses. In this PMS, 12 patients were treated with landiolol at doses >10 μg/kg/min, and ADRs defined in the safety specifications occurred in 16.7% (2/12). Among 240 patients treated with landiolol at doses ≤10 μg/kg/min, the incidence of ADRs defined in the safety specifications was 12.9% (31/240), showing no major difference. According to the package insert, landiolol can be administered at doses of up to 40 μg/kg/min.⁸ The maximum dose of landiolol administered to patients in this PMS was 20 μg/kg/min. Therefore, it is recommended that caution be exercised when administering higher doses of landiolol, above 10 μg/kg/min, due to the potential for ADRs.

Overall Effectiveness of Landiolol Treatment

Among 252 patients, treatment with landiolol was considered by the attending physicians to be effective or slightly effective in 200 (79.4%). Although we cannot simply compare the effectiveness due to the different evaluation criteria among studies, we believe that the effectiveness in this PMS is comparable to that reported in J-Land II, in which 77.8% of patients were free from recurrent VT/VF.⁶ Notably, in that study, in the event of VF or hemodynamically unstable VT before treatment with landiolol, measures such as electrical cardioversion were immediately implemented in principle, and landiolol was administered after restoration of sinus rhythm.⁶

The current PMS included 114 (45.2%) patients in whom the ventricular arrhythmia episodes had not been terminated before starting landiolol. Among these patients, landiolol was rated as effective in 31.6% for terminating the ventricular arrhythmia episodes and in 43.0% for reducing the number of the episodes. Therefore, our data suggest that landiolol reduces the number of ventricular arrhythmia episodes in patients whose episodes have not been terminated. Landiolol also prevented recurrence.

Among 138 patients treated with landiolol to prevent recurrence, recurrence was prevented in 69.6% and landiolol was considered to be slightly effective in 13.8%. The PMS included patients with VF (28.6%), hemodynamically unstable VT (65.1%), and VF+hemodynamically unstable VT (6.3%). In contrast, the clinical trial included only 2 patients with VF (6.9%), which limited insight into the effectiveness of landiolol in patients with VF.⁶ Therefore, the results reported here provide valuable evidence regarding the clinical effectiveness of landiolol, as evaluated by the physicians, for these indications based on data from larger populations of patients with VF and/or hemodynamically unstable VT.

Influence of Atrial Fibrillation

The PMS included 41 (16.2%) patients with persistent or paroxysmal atrial fibrillation. ADRs occurred in 14.6% of these patients, and the attending physician considered landiolol to be effective or slightly effective in 90.2%. Therefore, these data suggest that the presence of atrial fibrillation does not influence the safety and effectiveness of landiolol.

Survival After Landiolol Treatment

The survival rate at 168 h after the start of landiolol treatment was 90.1%. In the prior study, the survival rate at 30 days after the start of treatment was 96.3%.⁶ Together, the results of this PMS and the prior clinical trial suggest that landiolol may be effective for patients with refractory and urgent, potentially fatal, VF or hemodynamically unstable VT.

New Findings of This PMS

The prior clinical trial enrolled patients who had been treated with an intravenous or oral antiarrhythmic drug (amiodarone, nifekalant, or sotalol).⁶ In this PMS, 63.2% of patients had received premedication with a Class III antiarrhythmic drug. The other patients (36.8%) had not received pretreatment with Class III antiarrhythmic drugs. Notably, the effectiveness of landiolol treatment in these patients was comparable to that of premedicated patients. Consequently, we provide new information regarding the effectiveness of landiolol in a group of patients who were not included in prior clinical studies of landiolol, specifically patients who are not premedicated with Class III antiarrhythmic drugs.

Study Limitations

There are 4 main limitations to this survey, consistent with other PMS, including its observational design without a control group and the potential that some survey items are poorly controlled because physicians make decisions based on the patient’s condition. Because this PMS was conducted in routine clinical practice, the safety and effectiveness data may be affected by factors other than landiolol. Furthermore, because this PMS was primarily designed to collect safety information for landiolol in clinical practice, the evaluation of efficacy was based on the overall assessment by the attending physician and is therefore subject to certain limitations.

Conclusions

The safety profile of landiolol in this PMS was similar to that observed in a prior clinical trial, and no new risks defined in the safety specifications were identified. Landiolol is one of the therapeutic options for treating refractory and potentially fatal VF or hemodynamically unstable VT.

Acknowledgments

The authors thank the patients and healthcare professionals who participated in this PMS. The authors also thank Nicholas D. Smith (LESPEDEZA, a division of EMC K.K.) for medical writing support, which was funded by Ono Pharmaceutical Co., Ltd.

Sources of Funding

This PMS was funded by Ono Pharmaceutical Co., Ltd.

Disclosures

T.S. has received research funds from Ono Pharmaceutical Co., Ltd. M.S., R.T., R.M., and M.F. are employees of Ono Pharmaceutical Co., Ltd.

Author Contributions

All authors contributed to data interpretation, critical revisions of the manuscript, approved the final draft, and take accountability for the accuracy and integrity of the work. R.M. and M.F. contributed to drafting the manuscript; M.S. contributed to data analysis.

IRB Information

This PMS was conducted in compliance with the Ministerial Ordinance on Good Post-Marketing Study Practice for Drugs. According to Japanese regulations and laws related to PMS, ethics approval and informed consent were not required. However, consent to use the clinical data was obtained from the participating institutions. All institutions enrolled in the PMS signed agreements with Ono Pharmaceutical Co., Ltd. All treatment decisions were made by the physicians and patients in actual clinical practice. All data were pseudo-anonymized. The PMS was registered with the Japan Registry of Clinical Trials (ID: jRCT1080225340).

Data Availability

Qualified researchers may request Ono Pharmaceutical Co., Ltd. to disclose individual patient-level data from clinical studies through the following website: https://www.clinicalstudydatarequest.com/. For more information on Ono Pharmaceutical’s Policy for the Disclosure of Clinical Study Data, please see the following website: https://www.ono-pharma.com/en/company/policies/clinical_trial_data_transparency_policy.html.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0898

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