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Dose-Finding Study of Landiolol Hydrochloride: A Short-Acting β1-Blocker for Controlling Heart Rate During Coronary Computed-Tomography Angiography in Japan

Introduction Coronary computed-tomography angiography (CCTA) has high diagnostic performance, but it sometimes does not allow evaluation because of artifacts. Currently, the use of a β-blocker is recommended to prevent motion artifacts, but the β-blocker (metoprolol, propranolol, etc.) commonly used has a slow onset and long duration of action. Landiolol hydrochloride is an intravenous β1-blocker with a very short half-life. We investigated the efficacy and optimal dose of this drug for reduction of heart rate in patients undergoing CCTA. Methods Eighty-seven subjects with ischemic heart disease were divided into three groups to receive landiolol hydrochloride at a dose of 0.125 (Group L), 0.25 (Group M), or 0.5 mg/kg (Group H). CCTA was performed at 3–7 min after administration, and heart rate, blood pressure, and image quality were assessed. Results Heart rate decreased rapidly after completion of landiolol hydrochloride administration in all groups, with a heart rate reduction of 15.55 ± 6.56% in Group L, 16.48 ± 7.80% in Group M, and 21.49 ± 6.13% in Group H (Group L vs Group H, P = 0.0008; Group M vs Group H, P = 0.0109). Since there was no significant difference in heart rate during imaging among the three groups, although there was a significant difference between groups L and H and groups M and H in terms of percent change in heart rate, coronary stenosis was diagnosable in all groups with no significant difference. Conclusion Landiolol hydrochloride showed a rapid onset and short β-blocking effect, and was most effective at a dose of 0.5 mg/kg. However, the diagnosable proportion had no significant differences among the three groups in CCTA. Therefore, the clinically recommended dose was 0.125 mg/kg or less, considering the heart rate of patients with suspected coronary stenosis during CCTA.


INTRODUCTION
Coronary angiography (CAG) has been used for the diagnosis of coronary stenosis or occlusion, which causes ischemic heart disease, including angina pectoris and acute myocardial infarction. With the development of medical devices, marked progress has been made recently in non-invasive diagnostic imaging.
In particular, coronary computed-tomography angiography (CCTA), using multidetector row computed tomography (MDCT), has proved to be an excellent imaging modality for the diagnosis of cardiovascular disease as it not only has high spatial resolution, but also allows imaging with only one breath hold [1][2][3]. Using a non-invasive approach, CCTA provides morphological information equivalent to that obtained by CAG, and also has very high diagnostic performance for cardiovascular disease. However, although CCTA has high diagnostic performance in clinical settings, it does not allow assessment in some patients because of artifacts associated with calcification (beam-hardening effect) or the influence of heart beat (motion artifact) [4][5][6]. Solutions to these artifacts have been sought and attempts have been made to eliminate artifacts due to calcification using dual energy [7,8] or subtraction [9][10][11]. As well as eliminating motion artifacts, sufficient time resolution is required to visualize the beating heart in a resting state. Time resolution of computed tomography (CT) equipment depends on the rotation speed of the X-ray tube and detector.
Since the rotation speed is eventually limited, images are likely to be affected by heart beats in patients with a high heart rate [12]. In order to reduce the time resolution by half, dual source CT equipment with two tubes and two detectors has been developed [13]. However, it has not proved popular, because its use is limited to heart imaging only. Current CCTA guidelines published by the Society of Cardiovascular Computed Tomography recommend the use of b-blockers to prevent motion artifacts due to heart beats [14][15][16][17][18][19]. However, metoprolol, a commonly prescribed highly b 1 -selective drug, achieves its maximum b-blocking effect at 1-2 h after administration, with a duration of at least 6-8 h [20,21].

Study Population
Prior to CCTA, 90 Japanese patients aged

Dose Selection
In a Phase I study in healthy volunteers, a landiolol hydrochloride dose of 0.5 mg/kg was found to be the maximum dose that did not cause any abnormalities or variations in signs/ symptoms, ECG findings, physiological tests, or laboratory tests, and was well tolerated [26]. On this basis, a landiolol hydrochloride dose of 0.5 mg/kg was selected for the high-dose group in the current study.
In a phase III study [27] in patients with atrial fibrillation/flutter, the optimal dose of landiolol hydrochloride in terms of efficacy and safety was 0.25 mg/kg. For the low-dose group, a landiolol hydrochloride dose that was equivalent to half the optimal dose was selected (i.e. 0.125 mg/kg). Accordingly, three dose levels of 0.125 mg/kg (Group L), 0.25 mg/kg (Group M), and 0.5 mg/kg (Group H) were selected for the present study to find the optimal dose of landiolol hydrochloride for patients undergoing CCTA.

CCTA
CCTA was conducted at 3-7 min after completion of administration of the study drug, to assess the improvement in coronary visualization achieved after administration of landiolol hydrochloride (Fig. 1). The SOMATOM Sensation Cardiac 64 CT system (Siemens Japan CO., LTD., Tokyo, Japan) was used and operated at the following settings: X-ray tube voltage 120 kV, tube current 770-850 mA s, collimation 32 rows 9 0.6 mm, X-ray tube rotation speed 0.33 s/rot, helical pitch 0.2, and field of view 200 mm. A non-ionic contrast medium, iopamidol (370 mg I/mL), was administered IV at 3-4.5 mL/s using a 2-channel injector, followed by an IV infusion of saline (20-30 mL) using a bolus tracking system. was performed according to the retrospective ECG-gated reconstruction method [28], under optimal conditions at each study center, using a slice thickness for reconstruction of 0.75 mm.

Image Analysis
At the core laboratory, volume-rendering images, curved multi-planar reformation (MPR) images, interactive oblique MPR images, thin maximum intensity projection (MIP) images and cross-sectional images were prepared using the images reconstructed at each study center. All images of the 15 coronary segments, based on the American Heart Association classification [29], were assessed and classified by a central coronary visualization judgment committee which consisted of three independent radiodiagnostic specialists. The images were given a quality score of either 1 (motion artifact(s) present and impossible to diagnose); 2 (motion artifact(s) present but diagnosable); or 3 (no motion artifact and diagnosable).
Preparation of the images as well as assessment of the diagnosable proportion was performed using a workstation, Aquarius NET Server (TeraRecon, Inc. California, USA).

Endpoints
The primary efficacy endpoint was the diagnosable proportion (proportion of subjects whose coronary stenosis was diagnosable in reconstructed images). Additional endpoints investigated included: the extent and duration of effect of landiolol hydrochloride on heart rate [mean, the achieve proportion (proportion of subjects who achieved the threshold of 60, 65 or 70 beats/ min), and percent change] and blood pressure, percutaneous oxygen saturation (SpO 2 ), ECG parameters, and adverse events. Heart rate (Holter ECG), blood pressure and SpO 2 were monitored before study initiation (baseline: measured on the day of CCTA), on admission to the CT room, immediately before administration of nitroglycerin, immediately before administration of the study drug, and at 1-min intervals from 0 to 10 min, and at 15 and 30 min, after completion of study drug administration, In addition, a 12-lead ECG was performed and laboratory values were measured before study initiation (baseline) and within 3 days after completion of study drug administration. And, we investigated the relationship between the diagnosable proportion and heart rate in order to confirm the image quality-improving effect of administration of landiolol hydrochloride.
Adverse events (AEs) were recorded from the start of study drug administration until the end of the monitoring period (within 3 days after completion of study drug administration).

Statistical Analysis
The study population was selected based on the assumption that the heart rate reduction was 10.0 ± 12.0%, using paired t test (significance level: 0.05, two-tailed) with a power of 80%, so that subjects with a significant difference could be detected. Analysis of the primary efficacy endpoint, was based on the per protocol analysis set (PPS) and the safety analysis was based on the full analysis set (FAS). PPS is restricted to the participants who fulfill the protocol in the terms of the eligibility, interventions, and outcome assessment. FAS was restricted to the participants who fulfill the main protocol in the terms of the eligibility, interventions, and outcome assessment.

Subject Disposition and Baseline
Characteristics All 90 subjects enrolled in the study received the study drug, without any withdrawals or dropouts. However, two subjects did not meet the inclusion criteria, and one subject had incomplete data for assessment. As a result, 87 subjects were included in the PPS analysis set (low-dose, n = 29; medium-dose, n = 28; high-dose, n = 30) (Fig. 2). There was no significant difference among the three groups for patient baseline characteristics (Table 1).
Heart Rate During CCTA The data of heart rate during CCTA is shown in  Table 2).

Heart Rate Evaluation
Heart rate began to decrease immediately after completion of study drug administration in all three dose groups (Fig. 3). The lowest heart rate

Blood Pressure Evaluation
In all three dose groups, both systolic and diastolic blood pressure showed the greatest decrease at 3-4 min after completion of landiolol hydrochloride administration, although the percent decrease was minimal ( Fig. 4). Systolic and diastolic blood pressure returned to baseline levels in all groups at 30 min after completion of administration.

Image Quality
The percentage of subjects with an image quality score of C2 was 61.5% (n = 16) in Group L, 44.4% (n = 12) in Group M and Values are mean ± SD. There was no significant difference between treatment groups for any of the parameters   55.2% (n = 16) in Group H. There was no significant difference between the three dose groups, indicating that image quality was sufficiently improved in the low-dose group ( Table 3).
Analysis of image quality by coronary vessel revealed a significant difference between Group L and Group M (Wilcoxon rank sum test, P = 0.0461), whereas analysis by coronary segment revealed a significant difference   between Group L and Group H (P = 0.0007). Since there was no significant difference in heart rate during imaging among the three groups, although there was a significant difference between groups L and H and groups M and H in terms of percent change in heart rate, the subjects were classified by heart rate to determine the  NS not significant a Two-tailed test (* P\0.05; NS P C 0.05) b One-tailed test (* P\0.025; NS P C 0.025) percentage of subjects with an image quality score of C2. Using this approach, a definite correlation was noted between reduction in heart rate and image quality score (C2) (Fig. 5).

Safety
There was no dose-dependent increase in the incidence of AEs, adverse drug reactions or decreased blood pressure, showing no significant difference among the three groups

DISCUSSION
CCTA has high diagnostic performance in diagnosable cases, but does not allow assessment in some patients because of artifacts due to calcification or heart beats [4][5][6]. Imaging of the beating heart requires sufficient time resolution to allow imaging of the heart in a resting state. However, many models of CT  in United States [30,31]. Therefore, in order to improve relative time resolution, it is necessary to reduce heart rate using b-blockers [14][15][16].
In other words, during CCTA imaging, a b-blocker that is able to reduce the heart rate from approximately 75 beats/min to less than 65 beats/min is necessary. The present study showed that the heart rate-lowering effect of landiolol hydrochloride was dose dependent, but the clinically recommended dose was concluded to be 0.125 mg/kg or less, considering the heart rate of patients with suspected coronary stenosis during CCTA. Landiolol hydrochloride is a b 1 -blocker characterized by a very short half-life of approximately 4 min [26]. Since traditional b-blockers have long half-lives and a prolonged effect after CCTA imaging, they have been associated with safety problems, such as a reduction of blood pressure. However, landiolol hydrochloride showed a rapid onset of heart rate lowering after administration, with rapid recovery of heart rate after completion of the examination. Since this drug decreased heart rate only during CCTA, owing to its rapid onset and short duration of b-blocking effect, it seems to be a suitable b-blocking agent for use prior to CCTA. The diagnosable proportion had no significant difference between the three dose groups in CCTA for assessment of the severity of coronary stenosis.
Beta-blockers with a heart rate-lowering effect were originally used as antihypertensive agents, suggesting that a decrease in blood pressure is inevitable with the use of b-blockers.
In this respect, landiolol hydrochloride differs markedly from conventional b-blockers in that it produces only a very small decrease in blood pressure [22,23]. In the present study, landiolol hydrochloride did not cause a large decrease in blood pressure during CCTA imaging.
Furthermore, owing to its very short half-life, the effect of this drug was rapidly eliminated even if a subject experienced a transient decrease of blood pressure, indicating the safety of this drug. Actually, in the present study, the patients with a mild decrease of blood pressure in a middle-dose group has recovered soon without any treatment. In the safety evaluation, landiolol hydrochloride was not repeated to cause any serious adverse events. Therefore, landiolol hydrochloride is considered to be well tolerated at doses between 0.125 and 0.5 mg/kg.
There was no significant difference in the proportion of subjects with image quality scores of 2 or more among the three groups. Image quality has been reported to correlate with a reduction in heart rate to some extent [1][2][3][4]. After administration of landiolol hydrochloride during the present study, although there was a significant difference between groups L and H and groups M and H in terms of percent change in heart rate, no significant difference was noted in the heart rate during imaging among the three groups. Therefore, it was a natural outcome that no significant difference in image quality was detected among the three groups. The limitations of the present study was that we did not directly compare the safety and efficacy between this drug and conventional betablockers (oral or intravenous) or placebo, which is expected to be evaluated in further studies.

CONCLUSION
Landiolol hydrochloride showed a rapid onset and short duration of heart rate lowering, and was found to be most effective at a dose of 0.5 mg/kg. However, the diagnosable proportion did not show significant differences among the three groups in CCTA. Therefore, the clinically recommended dose was 0.125 mg/kg or less, considering the heart rate of patients with suspected coronary stenosis during CCTA.

ACKNOWLEDGMENTS
The authors thank all the investigators (listed below) and site staff who participated in this clinical trial. Dr. Masaharu Hirano is the guarantor for this article, and takes responsibility for the integrity of the work as a whole. Sponsorship and article processing charges for this study was funded by Ono Pharmaceutical Co. Ltd. and reproduction in any medium, provided the original author(s) and the source are credited.