Evaluating the Therapeutic Efficacy and Safety of Landiolol Hydrochloride for Management of Arrhythmia in Critical Settings: Review of the Literature

Figures & data

Table 1 Pharmacokinetics by Population

Study	M. Wang, Drug Res (Stuttg), 2014^Citation15		M Nakashima, J. Clin. Therap. Med, 2000^Citation1		Krumpl G, J. Cardiovasc. Pharmacol, 2016^Citation16
Population	Healthy Chinese		Healthy Japanese		Healthy Caucasians
Dosage	L(low): 0.125mg/kg/min (1min) load-ing→0.02mg/kg/min (20min) continuous.	H(high): 0.25mg/kg/min (1min) loading→0.04mg/kg/min (20min) continuous	0.04mg/kg/min (60min) continuous	0.25mg/kg/min (1min) loading→0.04mg/kg/min (60min) continuous	0.01mg/kg/min (120min) continuous	0.02mg/kg/min (120min) continuous	0.04mg/kg/min (20h) continuous
Participated number	10	10	5	5	12	12	12
Age	24 ± 3	22 ± 2	26 ± 2	-	34.3 ± 9.5	34.3 ± 9.5	34.3 ± 9.5
Female (%)	50	50	-	-	41.7	41.7	41.7
C max (ng/mL)	400 ± 110	731 ± 246	-	2008 ± 798	230 ± 46	520 ± 93	980 ± 147
C 21 min (ng/mL)	327 ± 109	508 ± 141	-	-	-	-	-
C 60 min (ng/mL)	-	-	1008 ± 303	-	-	-	-
C 61 min (ng/mL)	-	-	-	1237 ± 329	-	-	-
T max (min)	10.1 ± 6.5	6.2 ± 5.7	-	2	-	-	-
t 1/2 (min)	4.7 ± 1.6	6.5 ± 1.7	3.96 ± 0.46	3.47 ± 0.44	-	-	4.52 ± 0.99
T 80% (min)	-	-	-	-	30 (20, 60)	10 (6, 12)	6 (6, 8)
AUC 0–81min (μg/mL · min)	8.28 ± 1.12	14.49 ± 3.28	-	-	-	-	-
AUC 0–∞ (μg/mL · min)	8.30 ± 1.13	14.50 ± 3.28	59.34 ± 12.49	82.43 ± 23.52	-	-	153 ± 29
CL (mL/min/kg)	-	-	41.8 ± 8.3	-	58 ± 13	47 ± 8	52 ± 7
CL/F (mL/min/kg)	64 ± 9	76 ± 16	-	-	-	-	-
Vd (L/kg)	-	-	0.242 ± 0.067	-	-	-	-
Vd/F (L/kg)	0.425 ± 0.114	0.694 ± 0.171	-	-	-	-	-

Abbreviations: AUC0-t, area under the blood concentration–time curve from initiation until end of respective dose level; AUC0-∞, AUC from 0 hr to infinity; C 21min; C 60 min; C 61 min, the concentration at completion of continuous infusion at that time, T max, time point of maximum blood concentration; CL, total clearance; CL/F, CL by bioavailability; T 1/2, the elimination half-life; T80%, time until 80% of T max; VD, volume of distribution; VD/F:VD divided by bioavailability.

Table 2 Therapeutic and Prophylactic Effects of Landiolol During Cardiac Operation in Randomized Control Trials

Author	Year	Study Name	Type of Surgery	Landiolol Dose	Compare Drag	Participants	POAF	Adverse Effects
Treatment of POAF
Sakamoto et al^Citation42	2012	JL-KNIGHT Study	CABG, valve replacement	0.5–40μg/kg/min	DIL: bolus dose of 0.25 mg/kg over 2 min, 3–15 mg/h	LAN:35 DIL:36	Incidence: LAN:11.5% vs DIL:27.2%, Conversion to sinus rhythm (<8h): LAN:54.3% vs DIL:30.6%*, HR controlled, but not converted (<8): LAN:62.9% vs DIL:50%	Hypotension:LAN:11.4% vs DIL:30.6%*,Bradycardia: LAN:0% vs DIL:11.1%*, ICU stay (days): LAN:3.9 vs DIL:3.4. Bradycardia: LAN:0% vs DIL:11.1%*. ICU stay (days): LAN:3.9 vs DIL:3.4.
Prevention of POAF in CABG on CPB
Sezai A et al^Citation38	2011	PASCAL Trial	CABG on pump	Started at 2μg/kg/min and dis-continued after 48 h	Placebo	LAN:70 placebo:70	Incidence: LAN:10% vs Placebo:34.3%*	Mortality:0% vs.2.8%,Complications:4.2% vs 8.5%, Hospital stay (days): 11.2 vs 14.0*
Sezai A et al^Citation39	2012	BABYLON trial	CABG on pump	Group L: using LAN 5mg/kg/min for 3 days, Group LB:using LAN 5mg/kg/min for 3 days, then BIS 2.5mg/day PO for 2 days	Group C: placebo	Group L:34 Group LB:33 Group C:34	Incidence: Group L:14.7% vs Group LB:9.1%* vs Group C:34.3%	Mortality:Group L:2.9% vs Group LB:0% vs Group C:0%,Complications:Group L:5.8% vs Group LB:9% vs Group C:8.8%, Hospital stay (days): Group L:11.8 vs Group LB:11 vs Group C:12
Prevention of POAF in Off-Pump CABG
Fujii et al^Citation36	2012		CABG off pump	5 (range 0–10)μg/kg/min untill PO drug start then CAR 2.5–5mg/day PO continued postoperatively	Placebo untill PO drug start then CAR 2.5–5mg/day PO continued postoperatively	LAN:36 placebo:34	Incidence: LAN:11.1% vs Placebo:32.3%*	-
Ogawa S et al^Citation37	2012		CABG off pump	3–5μg/kg/min for 2 days	Not using LAN	LAN:68 control:68	Incidence: LAN:19% vs Control:37%*	Tachycardia:LAN:13% vs Control:32%*, Bradycardia:LAN:15% vs Control:13%,
Nagaoka et al^Citation35	2014		CABG off pump	0.5 to 2 μg/min/kg untill PO drug start	DIL:0.5 to 2 μg/min/kg untill PO drug start	LAN:21 DIL:22	Incidence: LAN:4.8% vs DIL:27%*	-
Prevention of POAF on Valve Surgery
Sakaguchi M et al^Citation40	2012		Valve Surgery	10μg/kg/min for 72h	Not using LAN	LAN:30 control:30	Incidence: LAN:20% vs Control:53.3%*	-
Prevention of POAF on Cardiac Surgery with LV Dysfunction
Sezai A et al^Citation41	2015	PLATON trial	Cardiac surgery under CPB and had LV dysfunction (EF >35%)	2μg/kg/min at least 2 days	Not using LAN	LAN:30 control:30	Incidence: LAN:10% vs Control:40%*	In-hospital death: LAN:0% vs Control:6.6%, Complications:LAN:3.3% vs Control:13.3%, ICU stay (days): LAN:4.1 vs Control:4.3, Hospital stay (days): 14.6 vs 19.4*

Note: *p<0.05, if the ones with no * are not statistically significant.

Abbreviations: BIS, bisoprolol; CABG, coronary artery bypass grafting; CAR, carvedilol; CPB, cardiopulmonary bypass; DIL, diltiazem; LAN, landiolol; PO, oral administration; ICU, Intensive care unit.

Table 3 Therapeutic Effect of Landiolol During Percutaneous Coronary Intervention in Randomized Control Trials

Author	Year	Landiolol Dose	Compare Drag	Timing of Dosage	Participants	Excluded	LV Function	Biomarkers in Acute Myocardial Injury	Arrhythmias	Adverse Effects
Hanada K^Citation46	2012	3 μg/kg/min without loading and continued for 24 h.	Non LAN	Just after PCI	LAN: 47 Control:49	Those with Killip class 3 or 4, bradycardia <50 beats/min, hypotension with systolic BP <90 mmHg, bronchospasm, or second- or third-degree atrioventricular block.	LVEF acute phase to chronic phase: LAN 49.1% to 52.0 (p=0.01), Control 50.2% to 50.2%, p=0.99).	-	Arrhythmias in first 24 h,Sustained VT/Vf: LAN:0% vs Control:0%,Unsustained VT:LAN:34% vs Control:22%, Newly developed AF:LAN:2% vs Control:2%	One patient in the landiolol group showed bradycardia at a rate of 50 beats/min at 12 h after administration, which recovered approximately 10 min after discontinuation of the drug.
ParkH^Citation47	2013	Intracoronary administration of landiolol (0.06 mg/kg)	Intracoronary administration of the same volume (5 mL) of saline	1 min via Over-the-Wire balloon catheter before and after balloon inflation. Intravenous administration of landiolol (0.02 mg/kg/min) or saline was started after the last stent deployment and continued for 6 h after PCI.	LAN: 35 Control: 35	Elevation of cardiac enzymes, NYHA ≧III or Killip class ≧III or an LV ejection fraction below 30%, BP below 100 mm Hg or a HR below 50 bpm without anti-hypertensive drugs or antiarrhythmic drugs, respectively, heart block or CKD ≧stage IV.	LV wall motion score index:Change from pre-PCI:LAN:0.00 vs Control: −0.01*	cTnI (ng/mL):LAN: 0.57 vs Control: 1.27, cTnI ≧0.05 ng/mL: LAN: 56% vs Control: 79%*, cTnI ≧0.12 ng/mL: LAN: 41% vs Control: 70%*, CK-MB (ng/mL): LAN: 3.17 vs Control: 7.09	-	-

Note: *p<0.05, if the ones with no * are not statistically significant.

Abbreviations: BP, blood pressure; cTnl, cardiac troponin-I; CKD, chronic kidney disease; HR, heart rate; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; LAN, landiolol; LV, left ventricular; LVEF, left ventricular ejection fraction; Vf, ventricular fibrillation; VT, ventricular tachycardia.

Table 4 Ongoing Randomized Control Trials in New Therapeutic Area

Author	Year	Study Name	Age	Disease of Eligible Patients	Landiolol Dose	Compare Drag	Sample Size	Primary Endpoint	Secondary Endpoint
Sepsis
Unger M et al^Citation79	2018-	LANDI-SEP study	Aged ≥ 18 years	Septic shock and tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization period of 24–36 h.	1–40μg/kg/min at intervals of at least 20 min to obtain and maintain a HR of 80–94 bpm.	Standard care	200	HR response (HR =80–94 bpm) and maintenance thereof without increase in vasopressor requirements during the first 24h.	ICU and 28-day mortality, ICU and hospital stay duration, SOFA score, and inotrope and vasopressor support requirements.
Pediatric Patients with Heart Failure
Sumitomo N et al^Citation87	2015–2021	HEARTFUL study	Aged ≧ 3 months and <15 years	Have tachyarrhythmia (AF, AFL, SVT) as well as heart failure.	1–10μg/kg/min	Not written	25	≧20% reduction from baseline heart rate or return to normal sinus rhythm within 2 h after starting intravenous administration.	HR, return to normal sinus rhythm, percentage of patients with 20% reduction in heart rate or return to normal sinus rhythm, and return to the resting HR before the arrhythmia attack.

Abbreviations: AF, atrial fibrillation; AFL, atrial flutter; HR, heart rate; ICU, Intensive care unit; SOFA, sequential organ failure assessment; SVT, supraventricular tachycardia.

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