Differential Effectiveness of Landiolol Between Atrial Fibrillation and Atrial Flutter/Atrial Tachycardia Patients With Left Ventricular Dysfunction

Abstract

Background: Landiolol, an ultra-short acting β₁-selective blocker, is more effective for controlling the heart rate (HR) than digoxin in patients with atrial tachyarrhythmias and left ventricular (LV) dysfunction. The impact of the type of atrial tachyarrhythmias on the effectiveness of landiolol is uncertain. We evaluated the efficacy and safety of landiolol on tachycardiac atrial fibrillation (AF) and tachycardiac atrial flutter/atrial tachycardia (AFl/AT) in patients with reduced LV function.

Methods and Results: Seventy-seven patients treated with landiolol were retrospectively analyzed. There were no significant differences in the baseline characteristics between the AF group (n=65) and AFl/AT group (n=12). Despite a higher dosage, the %change in HR from baseline to 12 and 24 h was only −10.2±12.7% and −16.1±19.4% in the AFl/AT group, while it was −28.3±13.2% and −31.3±11.3% in the AF group (P<0.02), respectively. The prevalence of the responders to landiolol treatment was much greater in the AF group than in the AFl/AT group (P<0.001). Alternative treatments such as i.v. amiodarone and electrical cardioversion were required in 83% of the AFl/AT patients.

Conclusions: Landiolol was ineffective in the majority of AFl/AT patients. An alternative management to prevent any worsening of heart failure might be considered in those patients.

Atrial tachyarrhythmias such as atrial fibrillation (AF), atrial flutter (AFl), and atrial tachycardia (AT) often coexist in patients with reduced left ventricular (LV) function and heart failure (HF).¹ A persistent rapid ventricular response during AF might cause a worsening of the HF. Therefore, it is important to control the heart rate (HR) of atrial tachyarrhythmias within an optimal range.² I.v. digoxin or amiodarone has been recommended as the standard pharmacological therapy for atrial tachyarrhythmias in patients with reduced LV function.³ The effect of digoxin for controlling HR, however, is limited especially in patients with excessive sympathetic nervous activity due to congestive HF. In addition, i.v. non-dihydropyridine calcium blockers (i.e., diltiazem and verapamil) for HR control should be avoided, especially in patients with reduced LV function, because of their negative inotropic effect.^4,5 Recently, the J-Land study showed that landiolol, an ultra-short acting β₁-selective blocker, was more effective for controlling rapid HR than digoxin in patients with AF/AFl and reduced LV systolic function.⁶ The J-Land study included both AF and AFl, the mechanism of which differed, and the impact of the type of atrial tachyarrhythmia on the effectiveness of landiolol was uncertain. In addition, the majority of those patients treated with landiolol were admitted to the intensive care unit or cardiac care unit, where continuous invasive arterial blood pressure monitoring and mechanical ventilation were available. The purpose of the present study was to evaluate the efficacy and safety of landiolol treatment for tachycardiac AF and tachycardiac AFl/AT patients with LV dysfunction in a general cardiovascular ward.

Methods

Subjects

Seventy-seven consecutive patients with acute decompensated HF (ADHF) who were treated with landiolol for atrial tachyarrhythmia on the general ward of the Department of Cardiology at Nippon Medical School Hospital were retrospectively analyzed between November 2013 and March 2016. In this study, the patients were divided into 2 groups according to the mechanisms of the atrial tachyarrhythmia at the time of admission (Figure 1).

Figure 1.

Study design. ADHF, acute decompensated heart failure; AF, atrial fibrillation; AFl, atrial flutter; AT, atrial tachycardia; HR, heart rate; IABP, intra-aortic balloon pump; LV, left ventricular; NYHA, New York Heart Association; PCPS, percutaneous cardiopulmonary support system.

The main inclusion criteria were ADHF (New York Heart Association [NYHA] class III or IV and LV ejection fraction [EF] <50%) and HR ≥120 beats/min with an atrial tachyarrhythmia (AF/AFl/AT). The exclusion criteria were as follows: age <20 years, perioperative period, necessity for mechanical circulatory support devices such as an intra-aortic balloon pump (IABP) or percutaneous cardiopulmonary support system, mechanical ventilation by tracheal intubation, and cardiac shock (systolic blood pressure [SBP] <80 mmHg).

Study Protocol

All patients were admitted to the general ward of the Department of Cardiology for HF, and were treated with oxygen inhalation, vasodilators, diuretics, and/or i.v. low dose inotropic agents with dobutamine. The HR was continuously measured on ECG, and non-invasive blood pressure was measured every 10–15 min for the first 1 h after landiolol initiation, followed by measurement every 1–3 h. Continuous i.v. landiolol was initiated from 1 µg/kg/min and titrated by 1 µg/kg/min up to a maximum dose of 10 µg/kg/min according to the patient’s condition. Once the target HR (<110 beats/min) was reached, the dose of landiolol was not increased. Switching to oral β-blockers (bisoprolol or carvedilol) from i.v. landiolol depended on physician discretion (Figure 2). Patients who had already had oral β-blockers before admission continued taking them or at a reduced dose, in addition to the landiolol. Alternative therapy including electrical cardioversion and i.v. amiodarone were chosen in cases refractory to landiolol, to prevent any worsening of the HF.

Figure 2.

Study protocol. (A) Treatment regimen after landiolol in patients with atrial tachyarrhythmias. The timing of switch to oral β-blockers or an alternative therapy was left to the physician. (B) Example of the titration of landiolol. We started at 1 µg/kg/min (γ) and titrated by 1-γ increments to a maximum dose of 10 γ according to the patient’s condition. When the target heart rate (HR) was reached, the dose was not increased. BP, blood pressure; ECG, electrocardiogram; SpO2, saturation of percutaneous oxygen.

This study was approved by the institutional ethics committee at Nippon Medical School Hospital.

Endpoints

The primary endpoint of this study was the prevalence of patients with response to landiolol. Response was defined as decrease of HR <110 beats/min ≤24 h after the start of landiolol, and treatment could be switched to oral medication without any alternative management. The secondary endpoints were HR at 12 and 24 h after the initiation of landiolol, maximum dose and mean dose at each time point, dosing period of landiolol, and percentage of patients with both HR <110 beats/min and ≥20% decrease in HR from baseline 2 h after landiolol treatment, which was defined as the primary endpoint of the J-Land Study.⁶ Any adverse events of landiolol treatment, such as bradycardia, hypotension, or other serious events were recorded.

Statistical Analysis

Data are expressed as mean±SD or percentage of patients. Comparison between the 2 groups was performed using Student’s t-test for continuous variables and chi-squared or Fisher’s test for categorical variables. For time-dependent comparisons, a linear mixed-effects model was used. Bonferroni correction was used for multiple comparisons. Single-variable analysis was conducted first, followed by multivariable analysis adjusted for variables with single-variable P<0.10. Adjusted odds ratios (OR) and 95% CI were examined on binary logistic regression to determine the multiple predictors of non-response to landiolol. All tests were 2-sided and P<0.05 was considered statistically significant. All statistical analysis was conducted using IBM SPSS Statistics version 21 for Windows.

Results

Patient Characteristics

The baseline characteristics of the 77 patients are listed in Table 1. There were 65 patients in the AF group and 12 in the AFl/AT group. Paroxysmal AF was seen in 28 patients and persistent AF in 37. Five of the 12 patients in the AFl/AT group had typical AFl, and the other 7, AT. Around 45% of the patients were hospitalized with first-episode atrial tachyarrhymia in both groups (47.7% vs. 41.7% for the AF and AFl/AT groups, respectively, P=0.762). One of the patients in the AF group had HR 150 beats/min with a narrow QRS tachycardia suggesting AFl with 2:1 atrioventricular (AV) conduction during the first examination, but on ECG the AFl changed to AF using adenosine for a differential diagnosis before hospitalization. In contrast, in 1 patient in the AFl/AT group who had undergone radiofrequency catheter ablation of AF 1 month before development of incessant AT upon admission, the AT shifted to AF during landiolol treatment.

Table 1. Baseline Patient Characteristics

	Total (n=77)	AF (n=65)	AFl/AT (n=12)	P-value
Baseline characteristics and hemodynamic parameters
Age (years)	72.4±12.6	73.1±12.6	68.7±14.0	0.288
Male	54 (70.1)	45 (69.2)	9 (75.0)	1.000
Weight (kg)	58.0±14.6	57.4±14.9	61.7±12.6	0.354
Heart rate (beats/min)	143.1±15.2	142.0±15.7	149.2±10.8	0.137
SBP (mmHg)	120.2±20.9	120.3±21.3	119.8±19.2	0.931
DBP (mmHg)	73.4±15.6	72.8±16.3	76.8±6.7	0.420
LAD (mm)	47.1±10.0	47.4±10.2	45.5±8.4	0.550
LVDd (mm)	52.9±10.0	53.8±10.0	48.3±8.9	0.077
LVDs (mm)	41.5±11.5	42.4±11.2	36.2±12.7	0.139
LVEF (%)	33.1±13.7	34.3±13.0	26.8±15.9	0.083
BNP (pg/mL)	807.0±883.2	868.5±940.0	473.9±324.2	0.156
Creatinine (mg/dL)	1.2±0.8	1.3±0.9	0.9±0.2	0.145
Baseline arrhythmia
AF	65 (84.4)	65 (100)	0 (0.0)
Paroxysmal AF	28 (36.4)	28 (43.1)	0 (0.0)
Persistent AF	37 (48.1)	37 (56.9)	0 (0.0)
AFl	5 (6.5)	0 (0.0)	5 (41.7)
AT	7 (9.1)	0 (0.0)	7 (55.6)
First arrhythmia episode	36 (46.8)	31 (47.7)	5 (41.7)	0.762
Baseline cardiovascular disease
IHD	16 (20.8)	15 (23.1)	1 (8.3)	0.441
Valvular disease	25 (32.4)	23 (35.4)	2 (16.7)	0.317
DCM	6 (7.8)	6 (9.2)	0 (0.0)	0.582
HCM	2 (2.6)	2 (3.1)	0 (0.0)	1.000
TIC	26 (33.8)	17 (26.2)	9 (75.0)	0.002
HHD	1 (1.3)	1 (1.5)	0 (0.0)	1.000
Other	1 (1.3)	1 (1.5)	0 (0.0)	1.000
Treatment before admission
Diuretic (oral)	30 (39.0)	29 (44.6)	1 (8.3)	0.023
β-blocker (oral)	34 (44.2)	31 (47.7)	3 (25.0)	0.209
ACEI/ARB	34 (44.2)	32 (49.2)	2 (16.7)	0.056
Digitalis (oral)	2 (2.6)	2 (3.1)	0 (0.0)	1.000

Data given as mean±SD or n (%). ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; AFl/AT, atrial flutter/atrial tachycardia; ARB, angiotensin receptor blocker; BNP, brain natriuretic peptide; DBP, diastolic blood pressure; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HHD, hypertensive heart disease; IHD, ischemic heart disease; LAD, left atrial dimension; LVDd, left ventricular end-diastolic diameter; LVDs, left ventricular end-systolic diameter; SBP, systolic blood pressure; TIC, tachycardia-induced cardiomyopathy.

Mean patient age was 72.4±12.6 years, and 54 patients (70.1%) were male. Average HR at baseline was 142.0±15.7 beats/min in the AF group and 149.2±10.8 beats/min in the AFl/AT group (P=0.137). Mean LVEF was 34.3±13.0% and 26.8±15.9%, respectively, for the AF and AFl/AT groups (P=0.083). LV end-diastolic diameter tended to be greater in the AF than the AFl/AT group (53.8±10.0 mm vs. 48.3±8.9 mm, P=0.077). There were no significant differences in the baseline characteristics or hemodynamic parameters between the 2 groups.

Baseline underlying cardiovascular disease and baseline treatment before admission are also listed in Table 1. The cardiovascular diseases were ischemic heart disease in 16 patients (20.8%), valvular disease in 25 (32.4%), dilated and hypertrophic cardiomyopathy in 8 (10.4%), and tachycardia-induced cardiomyopathy (TIC) in 26 (33.8%). The diagnosis of TIC was made after demonstrating recovery of LV function after controlling the tachyarrhythmia in the absence of any other identifiable etiologies such as myocardial ischemia. There were significantly more patients with TIC in the AFl/AT group than in the AF group (P=0.002).

Before being hospitalized, the number of patients who had taken oral diuretics, oral β-blockers, angiotensin-converting enzyme inhibitors (ACEI)/angiotensin type 2 receptor blockers (ARB), and oral digitalis are also listed in Table 1. Although oral β-blockers had been used in both groups, diuretics and ACEI/ARB were more frequently used in the AF group because of a baseline cardiovascular disease.

Effects of Landiolol

The time course of HR during landiolol treatment is shown in Figure 3. Compared with the AFl/AT group, landiolol was significantly more effective for the AF group to control rapid HR. On multivariate linear mixed effect modeling, landiolol significantly decreased HR in the AF group at 2, 12, and 24 h (vs. baseline, P<0.05). The magnitude of the reduction in HR was significantly greater in the AF group than in the AFl/AT group (mixed-effects model: interaction [group×time], P<0.0001). Despite a significantly higher dosage at each time point, HR at 2, 12, and 24 h was significantly higher in the AFl/AT group than the AF group (Figure 3).

Figure 3.

(A) Time course of mean heart rate (HR) during landiolol treatment in the atrial fibrillation (AF) and atrial flutter/atrial tachycardia (AFl/AT) groups. A mixed-effects model was used to compare the data between the AF group and AFl/AT group. ^†P<0.0001 (interaction [group×time]), *P<0.05 vs. baseline. (B) Changes in mean landiolol dose. ^‡P<0.001.

As shown in Table 2, the percent decrease in HR from baseline to 12 h was −10.2±12.7% in the AFl/AT group and −28.3±13.2% in the AF group (P<0.001). The maximum dose was significantly higher in the AFl/AT group than the AF group (8.5±3.0 vs. 3.6±2.4 μg/kg/min, P<0.001). The dosing period was 1.2±1.3 days in the AFl/AT group and 2.5±2.2 days in the AF group (P=0.100).

Table 2. Landiolol Treatment Results

	AF (n=65)	AFl/AT (n=12)	P-value
Primary endpoints
Responder to landiolol treatment	47 (72.3)	2 (16.7)	<0.001
Alternative treatment	16 (24.6)	10 (83.3)	<0.001
I.v. amiodarone	6	5
Electrical cardioversion	10	4
I.v. diltiazem	2	1
Secondary endpoints
HR at 12 h after treatment (beats/min)	100.3±16.7	131.9±17.3	<0.001
%HR change at 12 h vs. baseline	−28.3±13.2	−10.2±12.7	<0.001
HR at 24 h after treatment (beats/min)	96.6±12.9	124.0±23.0	<0.001
%HR change at 24 h vs. baseline	−31.3±11.3	−16.1±19.4	0.018
Maximum dose (μg/kg/min)	3.6±2.4	8.5±3.0	<0.001
Dosing period (days)	2.5±2.2	1.2±1.3	0.100
HR at 2 h after treatment (beats/min)	114.9±17.4	139.2±16.8	<0.001
%HR change at 2 h vs. baseline	−19.0±10.6	−6.5±11.1	<0.001
Achieved J-Land primary endpoint†	23 (35.4)	1 (8.3)	0.091
Concomitant treatment after admission
Loop diuretics	26 (40.0)	4 (33.3)	0.756
Vasodilator	20 (30.1)	5 (41.7)	0.757
Low dose inotropes	12 (18.5)	0 (0.0)	0.195
I.v. digoxin	24 (36.9)	5 (41.7)	0.756
Non-invasive PPV	7 (10.8)	1 (8.3)	1.000

Data given as mean±SD or n (%). ^†HR <110 beats/min and a ≥20% decrease in HR from baseline at 2 h after landiolol treatment. HR, heart rate; PPV, positive pressure ventilation. Other abbreviations as in Table 1.

The primary endpoint is shown in Table 2 and Figure 4. The prevalence of response to landiolol treatment was much greater in the AF group than the AFl/AT group (72.3% vs. 16.7%, P=0.0004). To prevent any exacerbation in HF, the percentage of non-responders receiving alternative treatment was overwhelmingly higher in the AFl/AT group (P=0.0008). Ten of the 12 patients in the AFl/AT group required alternative management: i.v. amiodarone in 5 patients, electrical cardioversion in 4, and i.v. diltiazem in 1 (Table 2). The timing of switching to other treatment is also shown in Figure 4. More than half of the patients in the AFl/AT group abandoned landiolol in ≤24 h and required alternative treatment. The condition of the non-responders then improved. Electrical cardioversion was performed after the absence of any left atrial appendage thrombi was confirmed on transesophageal echocardiography and the appropriate anticoagulation therapy had been continued.

Figure 4.

Flowchart of treatment. Response to landiolol treatment was defined as decrease of heart rate <110 beats/min in the 24 h after the start of landiolol, and switch to oral medication without any alternative management. The timing to switch to oral therapy or alternative therapy was left to the physician. AF, atrial fibrillation; AFl/AT, atrial flutter/atrial tachycardia; AMD, i.v. amiodarone; DC, direct current cardioversion.

We also performed further statistical analysis by dividing the study subjects into 2 groups according to the effectiveness of landiolol (Table 3). Baseline characteristics and cardiovascular disease did not differ between the responder group (n=49) and non-responder group (n=28). There were significantly many more patients with persistent AF in the responder group than in the non-responder group (P=0.004). In contrast, most of the patients with AFl/AT belonged to the non-responder group (P=0.0004) and developed TIC. The proportion of patients who were hospitalized with first-episode arrhythmia was 38.8% in the responder group and 60.7% in the non-responder group, showing that there was no significant difference between the 2 groups (P=0.096). As shown in Table 4, on logistics regression analysis AFl/AT was an independent predictor of non-response to landiolol treatment (OR, 14.827; 95% CI: 2.498–88.011; P=0.003).

Table 3. Baseline Patient Characteristics vs. Landiolol Effectiveness

	Total (n=77)	Responder (n=49)	Non-responder (n=28)	P-value
Baseline characteristics and hemodynamic parameters
Age (years)	72.4±12.6	73.2±12.2	71.0±13.3	0.464
Male	54 (70.1)	33 (67.3)	21 (75.0)	0.607
Weight (kg)	58.0±14.6	57.7±14.6	58.6±14.8	0.807
Heart rate (beats/min)	143.1±15.2	142.6±16.7	144.1±12.6	0.677
SBP (mmHg)	120.2±20.9	121.9±22.7	117.3±16.9	0.359
DBP (mmHg)	73.4±15.6	74.3±16.5	71.8±14.1	0.508
LAD (mm)	47.1±10.0	47.6±10.9	46.3±8.2	0.578
LVDd (mm)	52.9±10.0	52.3±9.3	54.0±11.2	0.481
LVDs (mm)	41.5±11.5	40.2±10.7	45.4±12.3	0.200
LVEF (%)	33.1±13.7	35.3±13.4	29.3±13.5	0.060
BNP (pg/mL)	807.0±883.2	717.3±694.1	963.9±1,139.8	0.241
Creatinine (mg/dL)	1.2±0.8	1.3±0.7	1.2±1.0	0.875
Baseline arrhythmia
Paroxysmal AF	28 (36.4)	17 (34.7)	11 (39.3)	0.806
Persistent AF	37 (48.1)	30 (61.2)	7 (25.0)	0.004
AFl/AT	12 (15.6)	2 (4.1)	10 (35.7)	<0.001
First arrhythmia episode	36 (46.8)	19 (38.8)	17 (60.7)	0.096
Baseline cardiovascular disease
IHD	16 (20.8)	10 (20.4)	6 (21.4)	1.000
Valvular disease	25 (32.4)	19 (38.8)	6 (21.4)	0.137
DCM/HCM	8 (10.3)	5 (10.2)	3 (10.7)	1.000
TIC	26 (33.8)	13 (26.5)	13 (46.4)	0.086
HHD	1 (1.3)	1 (2.0)	0 (0.0)	1.000
Other	1 (1.3)	1 (2.0)	0 (0.0)	1.000
Treatment before admission
Diuretic (oral)	30 (39.0)	21 (42.9)	9 (32.1)	0.467
β-blocker (oral)	34 (44.2)	23 (46.9)	11 (39.3)	0.635
ACEI/ARB	34 (44.2)	23 (46.9)	11 (39.3)	0.635
Digitalis (oral)	2 (2.6)	2 (4.1)	0 (0.0)	1.000

Data given as mean±SD or n (%). Abbreviations as in Table 1.

Table 4. Predictors of Non-Response to Landiolol

	OR	95% CI	P-value
LVEF (%)	0.979	0.938–1.023	0.344
AFl/AT	14.827	2.498–88.011	0.003
First arrhythmia episode	3.021	0.941–9.704	0.063
TIC	1.099	0.336–3.597	0.876

LVEF, left ventricular ejection fraction. Other abbreviations as in Table 1.

Overall, 2 patients in the AF group died of infection during hospitalization. Only 3 patients (2 in the AF group), treated with landiolol on the general ward, needed intensive treatment in the cardiac care unit for septic shock and low output syndrome.

On comparison of HR at 2 h after initiation of landiolol, those in the AF group also had a lower HR than those in the AFl/AT group (114.9±17.4 vs. 139.2±16.8 beats/min, P<0.001). Mean HR, however, did not reach the target HR, and the proportion of patients who achieved the J-Land study primary endpoint did not differ between the 2 groups.

There was also no significant difference in the concomitant treatment, including digoxin, after admission (Table 2). I.v. digoxin was used in 24 patients in the AF group and in 5 in the AFl/AT group (P=0.756).

It was difficult for 3 patients in the AFl/AT group to continue landiolol due to hypotension, as well as due to uncontrolled HR. In contrast, although the rapid HR was able to be controlled, landiolol was discontinued in 6 patients in the AF group because of hypotension and in 1 because of bradycardia. SBP <80 mmHg and HR <50 beats/min were recorded as hypotension and bradycardia, respectively. No other adverse events, such as drug-induced renal dysfunction, bronchial asthma, or gastrointestinal symptoms (e.g., constipation and nausea/vomiting) were observed in either group.

Discussion

In the present study HR was effectively reduced by approximately 30%, 12 h after landiolol treatment in the AF group, whereas it was reduced by only approximately 10% in those with AFl/AT. The majority of the patients with tachycardiac AF with reduced LV function could be treated with landiolol without requiring intensive care such as mechanical ventilation and IABP. In contrast, in the majority of patients in the AFl/AT group (approximately 83%), alternative treatment instead of landiolol was required to control HR and HF.

Mechanisms of HR Reduction by Landiolol in Atrial Tachyarrhythmias

The mechanism of AV nodal conduction velocity slowing, leading to a prolongation of the RR interval during atrial tachyarrhythmias, was associated with an increased AV nodal effective refractory period (ERP) and concealed conduction in the AV node. The effect of β-blockers on the AV node is mainly associated with ERP prolongation rather than concealed conduction.⁷ A medium dose of diltiazem, however, increases the ERP of the AVN and the degree of concealed conduction in the AV node, and enhances the irregularity of the ventricular response during AF.^8,9 Therefore, it is suggested that the effect of landiolol on controlling HR was mainly due to the prolongation of the ERP of the AV node.

Differential Effectiveness of Landiolol

Although the clinical interrelationship between AF and AFl has been reported,¹⁰ the mechanisms of AF and AFl differ. AF can be maintained by multiple circuit reentry and/or rapid focal ectopic firing, whereas AFl can be sustained by a single macro-reentrant circuit in the atria.

Beta-blockers have a negative dromotropic effect on the AV node and lead to a prolongation of the AV nodal conduction time. In patients with AF, rapid fibrillatory excitation 400–500 beats/min in the atria can conduct to the AV node. The β-blockers more or less decrease the AV node conductivity, leading to a reduction in HR during AF, leading to increased cardiac output. In contrast, it was hard to control HR in the patients with AFl/AT if landiolol did not reduce the AV conduction ratio (i.e., from 2:1 AV conduction to 3:1 AV conduction). There is no intermediate effect of controlling HR in AFl/AT, which differs from AF. The effect of landiolol, without changing HR, might lead to a decompensation of the HF by its negative inotropic effect.

Long-Term Effect of Landiolol for Controlling HR

In the present study, landiolol effectively reduced HR in the patients with AF by 28.3% and 31.3% at 12 and 24 h after drug treatment, respectively. The treatment interval with landiolol in the AF group and AFl/AT group was 2.5±2.2 and 1.2±1.3 days, respectively. Of the total group, adverse events occurred in 10 patients (13.0%). The incidence of adverse events in this study was much lower than in the J-Land study. There were no fatal complications due to landiolol, because it has a very short half-life of only 4 min.

There was no venous phlebitis associated with long-term landiolol via a peripheral vein. Also, i.v. amiodarone, in patients with LV dysfunction or signs of congestive HF, was recommended as an option when the ventricular rate remained high despite treatment with the smallest-dose β-blockers.¹¹ The long term infusion of i.v. amiodarone should be given by central venous access for the prevention of venous phlebitis.^12,13 Therefore, i.v. landiolol might be a safe therapeutic option in patients with tachycardiac AF and LV dysfunction. Taking the medical economic burden into account, however, it is also important to make an effect judgment in a few days using an appropriate dosage of landiolol.

Alternative Therapy in Landiolol Refractoriness

It is reported that AF begets HF, and HF also begets AF.¹⁴ Higher admission HR is independently associated with worse outcomes,¹⁵ and the cardiac output also begins to decrease at HR >120 beats/min.² Persistent uncontrolled rapid HR has the potential to worsen HF. HR reduction from the acute phase to discharge on β-blocker treatment is a stronger predictor of the clinical outcome of future cardiac events in patients with ADHF.¹⁶ Therefore in the patients with AF who are not responsive to landiolol in 24 h, an alternative treatment should be considered. In addition, in the patients with tachycardiac AFl/AT, prompt alternative treatment might be considered in cases of landiolol refractoriness.

According to the ESC guidelines, i.v. amiodarone is also recommended for controlling HR in patients with HF and rapid AF,¹¹ but it is difficult to adjust the dose of amiodarone according to patient condition. We should pay attention to not only the acute adverse effects, such as hypotension, bradycardia, and QT prolongation, but also to the amiodarone-induced side-effects such as pulmonary fibrosis. There is individual variability in the action time after amiodarone treatment because it is a lipophilic drug. In a meta-analysis, the conversion rate to sinus rhythm for i.v. amiodarone was approximately 17% at 1–2 h, 56% at 6–8 h, and 82% at 24 h.¹⁷ Therefore, even if we intend to use i.v. amiodarone for the purpose of controlling a rapid HR during the acute phase, the probability of cardioversion of AF/AFl is relatively high. Thromboembolisms must be taken more seriously into consideration.

In most cases of abandonment of landiolol and switch to i.v. amiodarone, HR could be controlled without any adverse events. In more than half of the patients with amiodarone in both groups, amiodarone resulted in the restoration of sinus rhythm.

Because the majority of the patients in the AFl/AT group developed TIC, it is important to control acute HR more strictly. AFl, however, may not be well controlled by pharmacological therapies (digoxin, calcium channel blockers, and β-blockers) in some cases of not only reduced EF but also preserved EF, and it is sometimes necessary to use cardioversion to sinus rhythm. Potassium-channel blockers and pure class III anti-arrhythmic drugs are effective for the acute conversion of AFl. Nifekalant is effective for conversion of AFl, with a potent effect even in patients with structural heart disease.¹⁸ These anti-arrhythmic drugs, however, have a risk of QT prolongation and subsequent torsade de pointes. Linear catheter ablation of the inferior vena cava-tricuspid isthmus (CTI) is also recommended by the ACC/AHA/ESC guidelines as a class I indication treatment for the long-term management of AFl, and has become the standard treatment for typical AFl.^19,20 In approximately 95% of cases successful bilateral CTI block can be achieved without requiring much time for the procedure. We performed catheter ablation for typical AFl in 2 patients with recurrent AFl after electrical cardioversion as a quasi-emergency. Although HR adjustment is often difficult with AFl, catheter ablation of typical AFl is considered to be an effective treatment.

Study Limitations

This study was a retrospective and single-center study with a small population. The present study did not include any patients with severely hemodynamic compromise requiring intensive care management. The effect of landiolol in such patients still remains uncertain. Further multicenter studies with a large number of patients are needed to confirm those findings.

Conclusions

Landiolol was less effective for controlling rapid HR in patients with AFl/AT and LV dysfunction than in those with AF. Alternative management to prevent the worsening of HF should be considered in patients refractory to landiolol.

Acknowledgment

We thank Mr. John Martin for English-language assistance.

Disclosures

The authors declare no conflicts of interest.

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