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

Guenter Stix; Michael Wolzt; Hans Domanovits; Pavla Kadlecová; Bernhard Husch; Michaela Trebs; Juri Hodisch; Martin Unger; Guenther Krumpl

doi:10.1253/circj.CJ-19-0661

Abstract

Background: We investigated for the first time the suitability of landiolol, an ultra-short-acting β1-specific β-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.

Atrial fibrillation (AF) is the most frequent serious cardiac rhythm disturbance encountered in clinical practice. More than 8.8 million patients in the European Union, mainly persons aged more than 65 years old, have AF.¹

The elevated heart rate (HR) and irregularity of the rhythm precipitated by the uncoordinated atrial activation can cause symptoms and severe hemodynamic distress. AF is associated with a reduction in the quality of life and with significantly increased morbidity and mortality.² Recent guidelines of the European Society of Cardiology for the management of AF recommend intravenous administration of β-blockers in order to decrease the HR in the acute setting.³

Landiolol, an ultrashort-acting β-blocker highly selective for β₁-adrenoceptors, has been used for the acute treatment of AF/AFL in Japanese patients.⁴^–⁹ Based on previous clinical trials,¹⁰^–¹² dosing recommendations for the treatment of AF/AFL in Japan vary according to the patient’s cardiac status and the clinical setting (intraoperative/postoperative). In patients with normal cardiac function, a bolus dose of 60–125 µg/kg/min administered over 1 min, followed by maintenance doses of 10–40 µg/kg/min are recommended. In patients with left ventricular (LV) dysfunction, landiolol administration should be initiated at 1 µg/kg/min and adjusted between 1 and 10 µg/kg/min without a preceding bolus dose.¹²^,¹³ In Europe, landiolol is registered with the same dose range as used in Japan (1–10 µg/kg/min and no bolus for LV dysfunction and 10–40 µg/kg/min in cases of normal LV function, but the optional bolus dose is 100 µg/kg/min for 1 min). We report the results of a clinical study investigating for the first time the effects of landiolol in the treatment of AF/AFL in Caucasian patients using a high-dose landiolol regimen with or without bolus.

Methods

We conducted our phase II clinical trial at the hospital of the Medical University of Vienna (Vienna General Hospital) between February 2015 and February 2016 in compliance with the Declaration of Helsinki, current GCP guidelines and local laws after approval of the study protocol by the independent Ethics Committee of the Medical University of Vienna. The study was registered at EudraCT under study ID 2014-001905-42. Participants provided written informed consent before the conduct of any study-related procedures. The main inclusion criteria were: in- and outpatients ≥18 years of age, AF or AFL, HR between 100 and 200 beats/min and clinical symptoms, and systolic blood pressure (SBP) ≥100 mmHg. The main exclusion criteria were: NYHA class III or IV, cardiogenic shock or heart failure requiring inotropic agents or intubation, unstable angina, myocardial infarction, sick sinus syndrome and 2nd- or 3rd-degree atrioventricular block. The baseline characteristics of the study population are presented in Table 1. Apart from the sex distribution, baseline values – particularly HR, SBP and diastolic blood pressure (DBP) – were not significantly different between treatment groups. Most patients suffered from hypertension, and a history of transthoracic cardioversion or ablation therapy was also frequent. Concomitant medication was in line with these comorbidities.

Table 1. Baseline Characteristics (Demography, Comorbidities/Risk Factors and Comedications) of the Patient Population (Full Analysis Set)

Characteristic	Inclusion criterion	All (n=20)	B+CI (n=10)	CI (n=10)
Demography
Ethnicity	–
European White, n (%)		20 (100.0)	10 (100.0)	10 (100.0)
Sex	–
Female, n (%)		8 (40.0)	6 (60.0)	2 (20.0)
Male, n (%)		12 (60.0)	4 (40.0)	8 (80.0)
Diagnosis
AF, n (%)		17 (85.0)	8 (80.0)	9 (90.0)
AFL, n (%)		3 (15.0)	2 (20.0)	1 (10.0)
Age, years (mean±SD)	≥18	67.4±9.1	70.9±9.9	63.9±7.0
Weight, kg (mean±SD)	–	85.7±16.9	80.2±15.9	91.2±16.7
BMI, kg/m² (mean±SD)	–	27.5±4.0	27.6±3.3	27.3±4.8
Creatinine, mg/dL (mean±SD)	–	0.99±0.27	1.05±0.31	0.92±0.20
eGFR, mL/min/1.73 m² (mean±SD)	–	91.1±39.3	74.3±32.6	107.8±38.4
Pre-dose HR, beats/min (median [range])	[100, 200] (inclusive)	126.5 [101, 145]	125.0 [101, 143]	132.0 [102, 145]
Pre-dose SBP, mmHg (median [range])	≥100	140.5 [97*, 163]	144.5 [109, 162]	137.5 [97*, 163]
Pre-dose DBP, mmHg (median [range])	–	95.5 [58, 129]	103.5 [68, 129]	94 [58, 107]
Comorbidities
Hypertension			9	6
Overweight/obesity			8	7
Hypercholesterolemia			2	5
Valve defects (corrected or present)			0	4
History of cardiac ablation			2	2
History of cardioversion			3	1
History of MI			0	1
CAD			0	1
Heart failure			0	1
COPD			0	1
CKD			0	1
Pleural effusion			1	0
Thyroid hypofunction			3	3
Drug hypersensitivity			1	3
Psychiatric disorder			3	1
Comedications
Anticoagulants			9	10
Amiodarone			2	2
Cardioselective CCBs			1	1
Antihypertensive drugs
β-blockers			4	5
Drugs acting on the RAS (ACEI, ARB)			9	5
Dihydropyridine CCBs			6	3
Thiazide diuretics			6	1
Other diuretics			1	4
α-blockers			1	2
Statins			2	5
Thyroid hormone replacement			3	3
Psychotropics			3	2
Gastric acid inhibitors			4	2

*Protocol violation. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotesin II receptor blockers; CAD, coronary artery disease; CCB, calcium-channel blocker; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; HR, heart rate; MI, myocardial infarction; RAS, renin-angiotensin system.

Study Design

Our prospective single-center open-label pilot clinical trial included 20 patients and compared 2 administration schemes of landiolol for the treatment of AF or AFL: 10 patients each received landiolol either as a continuous infusion (CI) or as a bolus dose followed by CI (B+CI). The primary endpoint of the study was the proportion of patients in whom administration of landiolol resulted in HR control, defined as sustained HR reduction by ≥20% from baseline or to <90 beats/min within 16 min from initiation of continuous administration. Secondary endpoints were the pharmacodynamics, pharmacokinetics, safety and tolerability of the study drug.

Study Treatment

Lyophilized landiolol hydrochloride (Rapibloc Lyo, 600 mg), provided by AOP Orphan Pharmaceuticals AG (Vienna, Austria), was reconstituted in 50 mL of 0.9% NaCl solution prior to use.

The basic administration schemes were either CI at 40 µg/kg/min (maximum total administration time 210 min) or CI at 40 µg/kg/min preceded by a bolus dose of 100 µg/kg administered over 1 min (B+CI; maximum total administration time 211 min). If the HR target was achieved after 16 min CI of landiolol at 40 µg/kg/min, administration was continued at the same rate; otherwise, the rate was increased to 80 µg/kg/min. If the HR target was met 30 min after initiation of continuous administration, the infusion was continued at an unchanged rate. If HR control was not achieved at 30 min, the infusion was stopped and patients were switched to a rescue treatment at the investigator’s discretion. Transition to oral medication (preferably bisoprolol) was initiated after 180 min of landiolol CI if HR control but not conversion to sinus rhythm had been achieved. The administration rate of landiolol was reduced by 50% 10 min later (190 min), and after another 20 min (210 min) the infusion was terminated.

Data Acquisition

12-lead ECG was monitored continuously from at least 10 min before initiation of administration of landiolol until at least 1 h after discontinuation of administration. Supine BP and ECG runs were recorded at 0, 4, 8, 12, 16, 20, 30, 45, 60, 75, 90, 120, 150, 180, 190 and 210 min after initiation of the CI. After discontinuation of administration, data were recorded at 4, 8, 12, 16, 20, 30 and 60 min.

Venous blood samples were collected according to the same schedule except for time points 45, 75, 90 and 150 min during infusion. Samples were processed as previously described.¹⁴

AF/AFL symptoms were recorded before landiolol infusion (baseline), at 16 min and at 30 min after initiation of the CI, at the end of infusion and at the end-of-study examination 1 day later.

Analytical Procedure

Landiolol and its 2 main metabolites, LM1 and LM2, were quantitated in supernatants of ethanol-precipitated whole blood with a validated HPLC-MS/MS method.¹⁴

Statistical Analysis

Time courses of the variables were evaluated in terms of absolute values and the changes from baseline on both an individual basis and by descriptive statistics. Non-compartmental pharmacokinetic analysis and statistical evaluation were performed with the validated software package SAS (version 9.4, SAS Institute Inc., Cary, NC, USA). The 2-sided Wilcoxon signed-rank test, 2-tailed t-test and Fisher’s exact test were used for exploratory comparisons as appropriate. P≤0.05 was considered significant.

Results

Efficacy

HR was swiftly reduced in all patients treated with landiolol (median of individual reductions and reduction of median HR by 20.5 beats/min, corresponding to −17.2%, at 16 min). The primary endpoint (sustained HR reduction by ≥20% or to ≤90 beats/min within 16 min) was met by 60% of patients in the CI group and 40% in the B+CI group without a significant difference between the groups (P=0.66); 53% of patients (CI, 67%; B+CI, 38%) met the primary endpoint in the AF subgroup (n=17). In the AFL subgroup (n=3), the primary endpoint was achieved in 1 of 2 patients in the B+CI group but not in the patient in the CI group. 2 patients met the HR reduction criterion transiently, 1 patient achieved the targeted HR reduction later than 16 min, and 7 patients (35%) missed the HR target. Median time to achievement of HR reduction criterion was 12 min. Subgroup analyses by age (</>65 years), sex or pre-dose SBP (</>130 mmHg) did not reveal any significant differences.

Clinical Response

AF/AFL symptoms were substantially reduced (between 46% and 100% for individual symptoms, 72% overall) after 16 min (Table 2). The reduction was similar in patients meeting or missing the primary endpoint (Figure 1).

Table 2. Time Course of Symptom Response (Combined Analysis)

Symptom	Baseline	16 min		30 min
Symptom	n	n	Change from baseline	n	Change from baseline
Palpitations	12	2	−83%	2	−83%
Rapid heartbeat	11	2	−82%	1	−91%
Irregular pulse	11	6	−46%	6	−46%
Fatigue	8	3	−63%	3	−63%
Shortness of breath	8	1	−88%	1	−88%
Dizziness	5	2	−60%	2	−60%
Sweating	2	0	−100%	0	−100%
Other	1	0	−100%	0	−100%
Total score (n=20)	2.90	0.80		0.75

Figure 1.

Time course of symptom response (baseline, 16 min, 30 min). (Light gray) Patients meeting the primary endpoint; (dark gray) patients missing the primary endpoint.

Pharmacodynamics

Because there was no significant difference between treatment groups in HR, SBP or DBP until 30 min when the infusion was stopped or continued depending on whether patients had met the HR target, the time courses of HR and BP response were evaluated for the combined administration schemes (Figure 2).

Figure 2.

Time course of median heart rate (open diamonds) and blood pressure (SBP, solid squares; DBP, solid circles) combined. Note the 2 discontinuities in the graph: values in the time window after 30 min until 210 min reflect data from patients meeting the primary endpoint only, because infusion in patients missing the primary endpoint was terminated at 30 min. bpm, beats/min.

The HR showed a swift response: 4 min after initiation of landiolol CI it was reduced from the baseline median value of 126.5 beats/min to 113.5 beats/min (−10.8%), and further to 106.0 beats/min (−17.2%) after 16 min. Afterwards, median HR continued to decrease to 100.0 beats/min (−18.7%) at 30 min and 96.0 beats/min (−24.5%) at 60 min. The values at 60 min and beyond were based exclusively on the patients meeting the primary endpoint because patients missing the HR reduction target after 30 min had already been switched to rescue treatment. After 180 min of CI, when the transition to oral medication was initiated, the median HR was 90.0 beats/min. At 190 min, when the administration rate of landiolol was reduced by 50%, median HR was 86.0 beats/min, and 88.0 beats/min at 210 min when landiolol administration was ceased. The maximum value of the median HR during follow-up after discontinuation of landiolol (112.0 beats/min) was observed 60 min after ceasing the infusion. Median HR at the end-of-study examination (i.e., 24 h after landiolol infusion) was 94 beats/min.

Median SBP was reduced during infusion of landiolol from 140.5 mmHg (baseline) by between 1.0 and 14.0 mmHg (with the largest median of individual changes −17.0 mmHg observed at 60 min); the decrease from baseline was significant from 12 min onwards until 180 min. SBP was unchanged or slightly increased after the start of oral medication at 190 min and before termination of landiolol infusion at 210 min, but significantly lower compared with baseline (median reduction up to 8 mmHg) during the landiolol washout period. At 30 min after discontinuation until the end-of-study examination, SBP was not significantly different from baseline.

DBP showed little or clinically irrelevant changes from the median baseline value of 95.5 mmHg during the study, with the lowest median value of 89.0 mmHg recorded 4 min after discontinuation of administration. Median DBP at the end-of-study examination was 86.0 mmHg.

Safety and Tolerability

There were 12 treatment-emergency adverse events occurred during the study in 8 of the 20 patients (40%): 3 hypotensive episodes, 2 hematomas, 1 hypertensive episode, 3 local reactions (1 pain, 2 erythema; all rated mild), 1 nasopharyngitis, 1 fatigue and 1 acute kidney injury. Apart from the acute kidney injury that developed 5 days after the administration of landiolol and subsequent cardioversion, all adverse events had resolved completely on day 1 after the study. None of the adverse events was rated as serious.

Pharmacokinetics

The blood concentration of landiolol reached steady state after 20 min in both treatment groups. No relevant differences in pharmacokinetic parameters were observed between the CI and B+CI groups except for Cmax, which was almost double in the latter group (1.15 vs. 2.20 µg/ml; P<0.01). Terminal elimination half-life was 4.8 min, volume of distribution (Vd) 268 mL/kg, and total body clearance (CL) 39.0 mL/(kg*min) (all values are geometric means, Table 3).

Table 3. Pharmacokinetic Parameters (Full Analysis Set)

Landiolol, geometric mean (SD of logs)	All	CI	B+CI	P value
Cmax [μg/mL]	1.59 (0.54)	1.15 (0.51)	2.20 (0.36)	<0.01
T1/2 [min]	4.77 (0.24)	4.65 (0.33)	4.87 (0.14)	0.70
Total body clearance [mL/(kg*min)]	38.97 (0.30)	46.60 (0.26)	33.18 (0.25)	<0.01
Volume of distribution [mL/kg]	267.91 (0.32)	312.84 (0.36)	233.02 (0.22)	0.04

The blood concentrations of the pharmacologically inactive metabolites, LM1 and LM2, increased continuously until the end of administration. Metabolite LM1 reached 5.26 µg/mL at 210 min. The volume of distribution was 493 mL/kg, and total body clearance was 3.2 mL/(kg*min) (all values are geometric means). Metabolite LM2 was below the limit of quantitation until 30 min of administration; the maximum geometric mean concentration of 235 µg/mL was observed shortly after the end of administration. Estimates for the volume of distribution and total body clearance could be calculated for 1 patient, with values of 9,290 mL/kg and 291 mL/(kg*min), respectively.

Exploratory Analyses by Primary Endpoint

Primary analysis per treatment group and prespecified subpopulation analyses did not identify relevant differences. We therefore performed separate exploratory analyses of the baseline characteristics and the time courses of hemodynamic variables for both treatment groups combined, depending on whether patients met or missed the primary endpoint.

The median HR in the patient group that met the primary endpoint showed a marked reduction from baseline until 16 min (from 126.5 beats/min to 104.0 and 89.0 beats/min at 8 and 16 min, respectively; relative change: −17.8% and −29.6%). The corresponding changes in median SBP and DBP were from 144.5 mmHg to 146 and 132.0 mmHg (relative change: +1.0% and −8.7%) and from 100.5 mmHg to 101.5 and 98.5 mmHg (relative change: +1.0% and −2.0%). The change in median HR from baseline until 16 min in the patient group missing the primary endpoint was less pronounced but still clinically relevant (from 126.5 beats/min to 114.5 beats/min and 115.5 beats/min at 8 and 16 min, respectively; relative change: −9.5% and −8.9%), whereas the changes in SBP and DBP were from 132.0 mmHg to 120 and 117.5 mmHg (relative change: −9.1% and −11.0%) and from 79.0 mmHg to 96.5 and 84.0 mmHg (relative change: +22.2% and +7.3%), respectively.

Baseline HR was similar between the groups meeting and missing the primary endpoint, whereas there was a noticeable difference between groups in baseline SBP and even more so in baseline DBP (144.5 vs. 132.0 mmHg (−8.7%; NS) and 100.5 vs. 79.0 mmHg (−21.4%; P<0.02), respectively) (Table 4).

Table 4. Baseline Characteristics (Demography, Comorbidities/Risk Factors and Comedications) of the Patient Population by Primary Endpoint (Full Analysis Set)

Demographic variable	Inclusion criterion	All (n=20)	Endpoint met (n=10)	Endpoint missed (n=10)
Demography
Sex	–
Female, n (%)		8 (40.0)	1 (10.0)	7 (70.0)
Male, n (%)		12 (60.0)	9 (90.0)	3 (30.0)
Diagnosis
AF, n (%)		17 (85.0)	9 (90.0)	8 (80.0)
AFL, n (%)		3 (15.0)	1 (10.0)	2 (20.0)
Age, years (mean±SD)	≥18	67.4±9.1	65.3±7.4	69.5±10.5
Weight, kg (mean±SD)	–	85.7±16.9	96.1±14.4	75.3±12.3
Pre-dose HR, beats/min (median [range])	[100, 200] (inclusive)	126.5 [101, 145]	126.5 [102, 145]	126.5 [101, 143]
Pre-dose SBP, mmHg (median [range])	≥100	140.5 [97*, 163]	144.5 [129, 163]	132.0 [97*, 163]
Pre-dose DBP, mmHg (median [range])	–	95.5 [58, 129]	100.5 [89, 129]	79.0 [58, 107]
Comorbidities
Hypertension			7	8
Overweight/obesity			9	6
Hypercholesterolemia			4	3
Valve defects (corrected or present)			1	3
History of cardiac ablation			2	2
History of cardioversion			1	3
History of MI			1	0
CAD			1	0
Heart failure			0	1
COPD			1	0
CKD			1	0
Pleural effusion			1	0
Thyroid hypofunction			2	4
Drug hypersensitivity			1	3
Psychiatric disorder			2	2
Comedications
Antihypertensive drugs
β-blockers			3	6
Dihydropyridine CCBs			6	3
Diuretics			5	7
α-blockers			2	1
Statins			4	3
Thyroid hormone replacement			2	4
Gastric acid inhibitors			2	4

*Protocol violation. CAD, coronary artery disease; CCB, calcium-channel blocker; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; HR, heart rate; MI, myocardial infarction.

Analysis of comorbidities and comedications in the patient groups meeting or missing the primary endpoint suggested a trend towards a reduced HR effect in patients receiving concomitant β-blockers or antihypertensive drugs, but there was no evidence for an effect of concurrent antiarrhythmic drugs (Table 4). Graphical illustration of the interrelationship between hypertension diagnosis, β-blocker use, pre-dose SBP and the odds of meeting the primary endpoint showed a conspicuous cluster of patients that missed the primary endpoint while sharing the combination of hypertension diagnosis, β-blocker use and low pre-dose SBP (Figure 3).

Figure 3.

Relationship of comorbidities, β-blocker use, pre-dose systolic blood pressure and heart rate response as reflected by primary endpoint (light gray, patients meeting the primary endpoint; dark gray, patients missing the primary endpoint). AF(L), atrial fibrillation/atrial flutter.

Discussion

Clinical Response and Pharmacodynamics

A fast, excellent clinical response was seen even in patients who did not meet the primary endpoint. All patients showed some reduction in HR, with 10 patients meeting the primary endpoint, and 7 other patients missing the HR target value by a few beats only or achieving it earlier or later than 16 min. Bolus administration of landiolol prior to CI did not lead to significant differences in HR, SBP or DBP compared with CI alone, despite differences in mean blood concentrations of landiolol in the early phase of treatment (Table 5). The mean blood concentration of 0.41 μg/mL in the CI group led to a significant HR reduction at 8 min, comparable to the B+CI group with a mean blood concentration of 0.97 μg/mL. The blood concentration of landiolol at the time of HR control was similar in both treatment groups: 0.62 μg/mL in the CI group vs. 0.73 μg/mL in the B+CI group (Table 5). The difference in maximum blood concentration between treatment groups, 1.15 μg/mL in the CI group and 2.20 μg/mL in the B+CI group, was mainly related to dose increases to 80 µg/kg/min. Only 1 patient responded to this dose escalation. Thus, it seems that in this setting higher blood concentrations, achieved with a bolus dose and/or further dose escalation, did not lead to higher treatment success (i.e., HR control). These findings indicate that lower dosages of landiolol may be sufficient to achieve adequate HR control as also observed in recent clinical trials.¹²^,¹³ However, these results must also be seen in connection with the limited sample size.

Table 5. Time Course of Hemodynamic Parameters and Blood Concentrations of Landiolol in the Early Treatment Phase (Full Analysis Set)

	CI	B+CI	P value
Heart rate [beats/min], mean (SD)
0 min	125.8 (16.48)	124.1 (13.68)	0.71
8 min	107.8 (14.77)	108.5 (11.03)	1.0
16 min	104.4 (17.86)	103.1 (13.78)	1.0
SBP [mmHg], mean (SD)
0 min	135.2 (20.7)	139.3 (17.93)	0.55
8 min	122.4 (24.49)	140.8 (20.64)	0.06
16 min	117.9 (16.88)	135.9 (19.03)	0.02
DBP [mmHg], mean (SD)
0 min	90.1 (14.70)	96.3 (21.52)	0.47
8 min	91.5 (18.05)	97.6 (9.14)	0.57
16 min	85.5 (17.53)	93.3 (12.54)	0.11
Landiolol concentration [μg/mL], geometric mean (SD of logs)
8 min	0.41 (0.53)	0.97 (0.31)	<0.01
16 min	0.67 (0.44)	1.09 (0.39)	0.02
At heart rate control	0.62 (0.67)	0.73 (0.48)	0.65
Cmax	1.15 (0.51)	2.20 (0.36)	<0.01

DBP, diastolic blood pressure; SBP, systolic blood pressure.

The pharmacodynamic effects of landiolol have been studied in Japanese patients suffering from AF, AFL and other supraventricular tachyarrhythmias.⁴^,⁵ In contrast to our elderly, slightly overweight, multimorbid and polymedicated population (75% of whom had a diagnosis of hypertension), patients in the Japanese studies were younger, only 20% were hypertensive, and approximately 70% received no comedications. In the dose-finding trial, the dose range studied was a 63, 125 or 250 µg/kg/1 min bolus followed by CI at infusion rates of 20, 40 or 80 µg/kg/min for 10 min,⁴ while in the subsequent high-dose trial a 250 µg/kg/1 min bolus was followed by 80 µg/kg/min CI for 10 min.⁵ The primary endpoint in those studies (conversion to sinus rhythm or HR reduction by >20%) was met in 55–69% in the dose-finding study and 60% (AF) and 78% (AFL) in the high-dose study. HR decreased within 11 min from mean values between 110–124 to 97–108 beats/min in the pilot study and from 118.4±26.0 to 94.5±28.6 beats/min in the high-dose trial. No significant decreases in SBP and DBP were observed in either study. Subjective symptom improvement rates using a 7-grade scale were between 15% and 50% in the dose-finding study and 56% (shortness of breath), 74% (palpitation) and 75% (chest tightness) in the high-dose study. Comparison of these results with our findings shows that the cardiovascular response was similar between patients of Japanese or European ancestry despite the substantially higher proportion of patients with diagnosed hypertension and other comorbidities in our European population.

Landiolol has been studied for prophylaxis of AF after cardiac surgery,¹⁵ and especially also the treatment of AF in the perioperative phase after cardiac⁷^,⁹ and non-cardiac surgery.⁶^,¹⁶ Because of the different pathomechanisms involved, the success rate with landiolol in regard to HR control is higher (between 70% and 90%) in the latter setting than in the emergency department setting.

Although some patients with normal or elevated BP missed the primary endpoint in our study, a lack of adequate HR response appears more likely in patients with low BP that may be associated with comedication of β-blockers or attributed to LV dysfunction (Figure 3). It is interesting to note that the scheduled dose increase after 16 min in the patients missing the primary endpoint did not result in a relevant effect on HR. In the given setting, this might be explained by sympathetic counter regulation which, as shown with esmolol, may even lead to increased HR.¹⁷^,¹⁸

HR control in AF and AFL with other selective short-acting β-blockers such as esmolol has previously been investigated in a limited number of studies in which patients with diabetes, anemia, chronic obstructive pulmonary disease and especially premedication with β-blockers were excluded, whereas – in contrast to our setting – postoperative patients who generally responded better were also included.¹⁹^–²³ Endpoint criteria varied and were overall less stringent with respect to response threshold and time. The dosing approach was different as well: We started with a high dose as opposed to the former studies in which the study drug was titrated from a low dose. The clinical efficacy in the former studies and the current study is similar, but the incidence rate of hypotensive episodes in the current study with landiolol (15%) was substantially lower than observed with esmolol (up to 47%). The likely reason for this discrepancy is the well-known additional BP-reducing effect of esmolol,²⁴^,²⁵ which is not through its β-blocking properties but mediated via renin decrease²⁶ and effects on Na, Ca and K channels.²⁷^–²⁹

Transition to oral medication in patients with HR control was initiated at 180 min by administering bisoprolol or, in 1 case, nebivolol. As can be seen in Figure 2, there was a slight HR increase after termination of landiolol, which indicates that the starting dose of the oral β-blocker (bisoprolol between 1.25 and 5 mg, nebivolol 5 mg) should be chosen individually and may require readjustment in some cases.

Safety

Compared with esmolol, landiolol has a higher β₁-selectivity and a lower effect on BP.³⁰^,³¹ In line with this, the incidence of cardiovascular adverse events (15% hypotensive episodes) in the current study was low, especially considering that the patients received a high number of concomitant antihypertensive drugs, which increased the likelihood of hypotensive episodes. The 3 hypotensive episodes occurred in patients with concomitant antihypertensive medication; 2 of them had very low SBP at baseline, and the 3rd patient had a labile hypertension that presented as fluctuation of the SBP between 160 and 120 mmHg in the pre-administration phase. In 2 cases the hypotensive episodes occurred with the 80 µg/kg/min dose but the 3rd patient was not escalated. All recovered rapidly after dose reduction despite the high dose administered. All 3 patients missed the HR target by a few beats only (5 and 4 beats/min in the first cases, the 3rd patient achieved the HR target value after 12 min and missed it at 16 min by 5 beats/min) and would not have been subjected to a higher dose in a normal clinical setting. Considering the good responses demonstrated with a lower landiolol dose range of 1–10 µg/kg/min in patients with reduced LV function,¹²^,¹³ lower dosages would be used in these patients under individual clinical treatment settings. These patients could therefore be considered “protocol victims” rather than true treatment failures.

The case of acute kidney injury diagnosed 5 days after the study was assessed as possibly related to the study drug. However, this patient underwent electrical cardioversion subsequent to administration of landiolol. Renal failure is a common complication of electrical cardioversion after AF and is observed in up to 17% of patients.³² A causal relationship with the study drug is therefore unlikely.

Pharmacokinetics

The pharmacokinetics of landiolol have been studied in Japanese patients with arrhythmias,³³ hepatic impairment,³⁴ and during cardiovascular surgery.³⁵ We have studied the pharmacokinetics in healthy Caucasian individuals both after bolus application and long-term infusion.¹⁴^,³⁶^–³⁸ Half-life values in the Japanese studies, as well as in our studies in healthy Caucasians and in the current study, were approximately 4 min. It is important to note that we have measured the steady-state pharmacokinetics after hours of CI whereas the parameter estimates in Japanese individuals were derived from data obtained after administration for 5 and 15 min,³³ or after addition in vitro.³⁵ Only the data published by Takahata et al³⁴ are based on a 1-h infusion and is the only study that assessed Vd (141 mL/kg) and CL (24.2 mL/(min*kg), which are lower than those obtained in our study. A similar discrepancy between data in Japanese and European volunteers has been observed,¹⁴^,³⁶^–⁴⁰ and higher Vd and higher CL values have been reported in Chinese volunteers.⁴¹ Part of these differences may be explained by differences in analytical methodology.

In summary, the half-life and thus elimination of landiolol in patients of European ancestry is similar to that in European volunteers and also in line with results obtained in Asiatic individuals.

Conclusions

Treatment of tachycardic AF or AFL in patients of European ancestry with a CI of landiolol with or without a preceding bolus resulted in excellent control of HR within a short time frame in our open-label study. HR was reduced in all patients receiving landiolol. The primary endpoint of the study (sustained HR reduction by ≥20% or to <90 beats/min within 16 min) was achieved in 50% of patients, and clinical symptoms improved in 85% of patients. Bolus administration of landiolol prior to CI seems not to be required. Safety was excellent; only 3 patients developed transient hypotension that resolved upon dose reduction. Rapid transition to an oral β-blocker in responding patients was managed successfully.

Acknowledgments

We thank Mrs Carola Fuchs and Mrs Claudia Eder for their excellent technical assistance during the clinical part of the study.

Statement of Ethics

All subjects gave their written informed consent prior to inclusion in the study. The study was approved by the independent Ethics Committee of the Medical University of Vienna.

Disclosures

M.U., G.K., J.H. and M.T. are employees of the sponsor AOP Pharmaceuticals AG. All other authors declare no conflicts of interest regarding this publication.

Funding

AOP Orphan Pharmaceuticals AG sponsored the trial.

Author Contributions

G.S., M.U., G.K., B.H. drafted the manuscript. G.K., J.H., M.T. conceived the study protocol. G.S., M.W., H.D. were responsible for the clinical part of the study. All authors made substantial contributions to critical review of the manuscript. All authors approved the final version.

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