a b s t r a c t

Aims: Treating patients with acute heart failure is difficult at the local hospitals in medically depopulated areas where cardiologists are generally absent. These patients require long-distance and time-consuming transporta- tion to the intensive care units. It is well known that tolvaptan is effective for the treatment of congestive heart failure, but the effect of prehospital tolvaptan use in patients is not well evaluated. The aim of this study was to evaluate the efficacy and safety of prehospital tolvaptan use in patients with Acute congestive heart failure who require long-distance and time-consuming transportation.

Methods: This retrospective study included 30 patients who were newly diagnosed with acute heart failure at Wakkanai City Hospital and transported to Nayoro City General Hospital between January 2013 and May 2020. The patients were classified into those who received tolvaptan (tolvaptan group, n = 18) and did not receive tolvaptan (control group, n = 12).

Results: The percentage of patient survival at discharge did not show a statistically significant difference between the groups (100% [tolvaptan] vs. 91% [control], p = 0.414). During transportation, the percentage of patients in the tolvaptan group who required increased oxygen doses was statistically significantly lower than that in the control group (0% vs. 36%, p = 0.0181). Patients in the tolvaptan group had statistically significantly shorter in- tensive care unit stays (median: 2 days vs. 6 days, p = 0.0376), less days to discontinuation of oxygen (median: 2.8 days vs. 6.9 days, p < 0.00125), and less days to ambulation (median: 1.5 days vs. 7.5 days, p = 0.0362) com- pared with the control group.

In the tolvaptan group, blood pressure was not different; however, heart rate was statistically significantly re- duced (99 +- 21 vs. 88 +- 21 beats per minute, p = 0.016) during transportation.

Conclusion: The use of tolvaptan in patients with acute heart failure requiring long-distance transport is safe and may show better clinical course compared with conventional therapies.

(C) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://

creativecommons.org/licenses/by/4.0/).

1. Introduction

The treatment of acute cardiovascular diseases is extremely difficult in medically depopulated areas where cardiologists are generally absent. Critically ill patients need to be transported over long distances to receive intensive care. In addition, if the patient’s condition

Abbreviations: ADHF, acute decompensated heart failure; CS, clinical scenario; ICU, intensive care unit; LV, left ventricular; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; WRF, worsening renal function; BNP, brain natriuretic peptide.

* Corresponding author.

E-mail addresses: [email protected] (S. Iwata), [email protected] (M. Okada).

deteriorates during transport, treatment in the ambulance is limited. Wakkanai City is located in the northernmost part of Japan and has a population of approximately 30,000. Because of the absence of cardiol- ogists in the city, general physicians provide cardiovascular care. There- fore, patients with acute heart failure need transportation to Nayoro City to receive intensive care. However, it requires approximately

2.5 h to transport a patient by ambulance over a distance of approxi- mately 175 km in summer. In winter, it takes 3 h owing to snow- covered and rough roads. There is a concern that long-distance trans- portation under these conditions may worsen the patient’s condition. The average length of hospital stay for patients with heart failure is 21 days in Japan [1] compared with 9 days in Europe and the US [2]. This discrepancy is because of the difference in the calculation method. Unlike in Western countries, where only the Acute stage of

https://doi.org/10.1016/j.ajem.2021.09.082

0735-6757/(C) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

hospitalization is considered, in Japan, the period of hospitalization for long-term care owing to heart failure is also considered, except same- day discharge. Furthermore, in cold regions, the length of hospital stay is even longer in winter. Irrespective of these reasons, it is clear that early ambulation leads to shorter hospital stays [3].

For the treatment of acute decompensated heart failure , the use of Loop diuretics to relieve congestion is the primary treatment strategy [4]; their delayed use increases in-hospital mortality [5]. By contrast, the use of loop diuretics could potentially lead to a high prev- alence of worsening renal function (WRF) [6].

The vasopressin receptor antagonist tolvaptan has a different mech- anism of action from salt excretion diuretics and based on the results of the QUEST study, tolvaptan has been covered by health insurance in Japan since 2010 for treating patients with fluid overload who respond poorly to loop diuretics [7]. In patients with ADHF, the addition of tolvaptan to loop diuretics reduces weight, increases Sodium levels, im- proves respiratory status, and prevents WRF. Furthermore, it is ex- pected to avoid the overuse of loop diuretics and improve the outcome of patients with ADHF [8]. In the TACT-ADHF study, tolvaptan administered within 24 h of admission to patients with ADHF resulted in diuresis without any worsening of renal function compared with a group of patients who received increased doses of loop diuretics [9]. Likewise, the use of tolvaptan in patients with congestive heart failure and renal dysfunction resulted in increased urine output over 48 h and faster improvement in dyspnea compared with conventional ther- apy [10]. It has also been reported that the early use of tolvaptan in patients with decompensated heart failure, within 3 days of hospitaliza- tion, increased urine output, thereby resulting in significantly shorter time to ambulation and start of rehabilitation [11]. Therefore, the ad- ministration of tolvaptan before hospitalization may have clinical ad- vantages for the patients who need long-distance transportation. This study aimed to evaluate the impact of tolvaptan administration during long-distance transportation on the clinical outcomes of ADHF patients.

1. Material and methods
   1. Study patients and protocol

This was a retrospective study, conducted at Nayoro City General Hospital in northern Hokkaido, Japan. This hospital has a total of seven cardiologists. In addition, approximately 50 patients with ADHF are transported to this hospital annually from the surrounding areas. In this study, only patients transported from Wakkanai City, the most dis- tant location, were enrolled.

We included 59 patients with ADHF who were diagnosed with acute heart failure at Wakkanai City Hospital and transported to Nayoro City General Hospital between January 2013 and May 2020. Acute heart fail- ure and ADHF were diagnosed based on the Framingham Criteria [12]. The patients were excluded based on the following criteria: no diuretics used during the treatment period, no diuretics used before transfer, acute coronary syndrome, maintenance dialysis, and shock. At the Wakkanai City Hospital, general physicians provided initial medical care and triaged patients with suspected severe heart failure. Then, after consultation with cardiologists at Nayoro City General Hospital, patients who needed intensive care were transported.

Patients eligible for ADHF were those with first-episode heart failure classified as New York Heart Association (NYHA) class III or IV, with the evidence of congestion on chest radiographs and brain natriuretic pep- tide (BNP) level of >=100 pg/mL [5]. The type of diuretics to be used and its doses were determined by the physician of the initial treatment.

• 1. Data collection

Data on baseline patient characteristics, previous medical history, prehospitalization medications, and discharge medications were ob- tained from the patients’ medical records. Blood sample was collected

from all patients before and after transportation; moreover, they underwent electrocardiography and chest radiography before and after transportation. Furthermore, all patients underwent coronary an- giography, coronary computed tomography angiography, or myocardial scintigraphy to assess for the presence of myocardial ischemia.

The patient condition was defined as worsening when the volume of Oxygen administration exceeded baseline (i.e., when leaving the Wakkanai City Hospital) after arrival to our hospital, as stable when it was the same as baseline after arrival to our hospital, and as improved when it was below baseline after arrival to our hospital. We adopted a clinical classification system (i.e., clinical scenario [CS]) based on the systolic blood pressure before transportation; in particular, systolic blood pressure > 140 mmHg was regarded as CS1, systolic blood pres- sure >= 100 mmHg and <= 140 mmHg as CS2, and systolic blood pres- sure < 100 mmHg as CS3 [13]. Blood samples were collected before leaving the Wakkanai City Hospital and on arrival to the Nayoro City General Hospital. Transthoracic echocardiography was performed by a laboratory technician, and left ventricular ejection fraction (LVEF) was assessed by the Modified SImpson method. WRF was defined as creati- nine >0.3 mg/dL or a > 50% increase from baseline within 48 h of onset. The Estimated glomerular filtration rate was calculated based on the calculation formulas proposed by the Japanese Society of Nephrol- ogy. Chronic kidney disease was defined as eGFR <60 (mL/min/ 1.73 m²). The dose of loop diuretics was changed to furosemide- equivalent doses based on previous studies [14].

The study conformed to the principles outlined in the Declaration of Helsinki and was approved by the ethics committees of the Nayoro City General Hospital and the Wakkanai City Hospital (2020-16; Nayoro City General Hospital, R2-8; Wakkanai City Hospital). All patients gave writ- ten informed consent.

• 1. Patient and public involvement

Patients were not involved in the design, conduct, reporting, or dis- semination plans of this research.

• 1. Endpoints

The primary endpoint was survival at hospital discharge. Secondary endpoints included oxygen dose before and after transport, length of stay in the intensive care unit (ICU), total number of days of hospitaliza- tion, number of days until ambulation (being able to walk to the rest- room), number of days until oxygen administration was discontinued, urine volume during transport, and 24-h urine volume after hospitaliza- tion. In addition, blood pressure; heart rate; cardiopulmonary ratio; and serum sodium, potassium, chloride, and Creatinine levels were evalu- ated before and after transport.

• 1. Statistical analyses

Continuous normally distributed data were reported as means +- standard deviations and non-normally distributed data were expressed as medians (interquartile ranges). Continuous variables were evaluated using paired or unpaired t-tests; if the variance was heterogeneous, Welch’s t-test was used. Categorical variables were analyzed using Fisher’s exact test. The Confidence level was set at 95%, and p < 0.05 in- dicated statistical significance. The statistical software EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) was used for data analyses.

1. Results

Among 59 ADHF patients, the following patients were excluded: no diuretics used during the treatment period (7 patients), no diuretics used before transfer (10 patients), acute coronary syndrome (7 patients), maintenance dialysis (3 patients), and shock (2 patients).

Excluding these 29 patients, the remaining 30 patients were assigned to 2 groups: those who received loop diuretics before transfer (control group, n = 12) and those who received tolvaptan in addition to loop di- uretics (tolvaptan group, n = 18). Table 1 shows the baseline data of the study patients. Nearly all patients in both groups belonged to NYHA class IV. Mean LVEF levels in the tolvaptan and control groups were 36 +- 12% and 40 +- 9%, respectively.

The administration of diuretics included any of the following: intra- venous dose or oral dose of furosemide (20, 40, or 80 mg), oral dose of torasemide (4 or 8 mg), or oral dose of azosemide (30 mg). In addition to these regimens, tolvaptan (7.5 or 15 mg) was administered (7.5 mg, 11 patients; 15 mg, 7 patients). Tolvaptan was additionally given to 18 patients who were possibly at an increased risk of worsening heart fail- ure during transportation, which was determined by a physician at the Wakkanai City Hospital and via the proposal from a cardiologist at our hospital. Tolvaptan 15 mg and 7.5 mg was administered to 7 patients (38%) by the physician of the initial treatment and other 11 patients (62%), respectively (Tables 2, 3).

Fig. 1 shows the CS of each group. No patient was classified into CS4 and CS5 in this study. In addition, there was no statistically significant difference in the proportion of CSs between the two groups. The etiolo-

Table 2

Dose of diuretics before transportation (Tolvaptan group n = 18)

Patients	Furosemide (mg)	Azosemide (mg)	Torasemide (mg)	Tolvaptan (mg)
1	40	0	0	15
2	20	30	0	15
3	0	0	8	15
4	20	30	0	15
5	40	0	0	15
6	20	0	0	7.5
7	0	0	4	7.5
8	20	0	0	7.5
9	40	0	0	7.5
10	20	0	0	7.5
11	20	0	0	7.5
12	20	0	0	7.5
13	20	0	0	7.5
14	20	0	0	7.5
15	0	30	0	15
16	20	0	0	15
17	20	0	0	7.5
18	20	0	0	7.5

gies of acute heart failure included ischemic heart disease (7 patients), tachyarrhythmia (10 patients), cardiomyopathy (7 patients), and

valve diseases (6 patients).

Table 1

Patient characteristics on admission.

Characteristic	Tolvaptan group	Control group
	(n = 18)	(n = 12)
Age (years)	73 +- 8	69 +- 9
Male sex (%)	66	66
Body weight (kg)	61 +- 13	65 +- 14
Body mass index, kg/m2	23 +- 4	26 +- 4
NYHA class IV (%)	94	100
Atrial fibrillation (%)	72	41
Hypertension (%)	83	91
Coronary artery disease (%)	38	41
Diabetes mellitus (%)	44	41
Dyslipidemia (%)	58	55
Prior smoking (%)	72	75
Prior myocardial infarction (%)	33	16
Oral medications

Loop diuretics dose (mg) 25 (20-35) 23(20-20)

Spironolactone (%) 11 8

ACE inhibitor/ARB (%) 44 58

?-blocker (%) 61 25

Intravenous agents

Vasodilators (%) 22 25

Carperitide (%) 22 16

NPPV (%) 16 9

Heart rate (beats/min) 88 +- 21 85 +- 20

Systolic blood pressure (mmHg) 132 +- 19 140 +- 22

Diastolic blood pressure (mmHg) 79 +- 17 82 +- 16

LVEF (%) 36 +- 12 40 +- 9

Cardio-thoracic ratio (%) 60 +- 5 63 +- 6 Laboratory data

Table 4 shows changes in blood pressure, heart rate, and blood test results before and after transportation in the tolvaptan group. There was no statistically significant difference in systolic and diastolic blood pressures before and after transportation; however, the heart rate de- creased statistically significantly after transportation (99 +- 21 vs. 88 +- 21 beats per minute, p = 0.016). There was statistically signifi- cantly decrease in serum potassium after transportation (4.2 vs. 3.8 mEq/L, p = 0.0133). The cardiothoracic ratio statistically signifi- cantly improved after transportation (63% vs. 60%, p = 0.00272).

Table 5 shows changes in the vital signs and blood test results of pa- tients who received only loop diuretics before and after transportation. No statistically significant difference was found in systolic and diastolic blood pressures as well in heart rate. Of all serum electrolyte levels, only Chloride levels increased after transportation (103.5 +- 2.1 vs. 105.7 +- 2.9 mEq/L, p = 0.0222).

Oxygen flow rates during transfer are shown in Fig. 2. In the control group, the oxygen flow rate was not changed before and after transpor- tation (3.9 +- 3.0 L/min vs. 4.3 +- 4.3 L/min, p = 0.459). By contrast, in the tolvaptan group, the oxygen flow rate was statistically significantly decreased (4.1 +- 3.9 L/min vs. 1.7 +- 1.6 L/min, p = 0.007). Indeed, 36% of patients in the control group required increased oxygen flow, whereas none of the patients in the tolvaptan group required increased oxygen flow during transfer (p = 0.0181).

The outcomes of this study are shown in Tables 6 and 7. Urine vol- ume during transportation was statistically significantly higher in the tolvaptan group, but no statistically significant difference was observed in the 24-h urine volume between the groups. There was no statistically

Table 3

Dose of diuretics before transportation (Control group n = 12)

eGFR (mL/min/1.73 m )

Hemoglobin (g/dL)	12.1 +- 2.4	12.6 +- 2.8
Sodium (mEq/L)	142.3 +- 3.2	141.0 +- 3.2
Potassium (mEq/L)	3.8 +- 0.5	3.8 +- 0.5
Chloride (mEq/L)	105.5 +- 4.5	103.5 +- 2.1
Creatinine (mg/dL)	0.97 +- 0.45	1.15 +- 0.75
BUN (mg/dL)	19.6 +- 11.1	22.5 +- 16.2
2	63.5 +- 31.8	58.3 +- 24.8

Patients Furosemide (mg)

Azosemide (mg)

Torasemide (mg)

Tolvaptan (mg)

CKD (%)	61	50	1	0	30	0	0
BNP (pg/mL)	793 +- 663	976 +- 678	2	10	0	0	0
AST (IU/L)	27.4 +- 18.4	30.5 +- 17.9	3	20	0	0	0
ALT (IU/L)	17.6 +- 12.3	24.6 +- 18.6	4	20	0	0	0
transportation time (min)	132 +- 27	129 +- 36	5	20	0	0	0

NYHA, New York Heart Association; ACE, angiotensin-converting enzyme; ARB, angioten- sin II type 1 receptor blocker; NPPV, noninvasive positive pressure ventilation; LVEF, left ventricular ejection fraction; BUN, blood urea nitrogen; eGFR, estimated glomerular filtra-

6	80	0	0	0
7	20	0	0	0
8	20	0	0	0
9	20	0	0	0
10	20	0	0	0
11	20	0	0	0
12	10	0	0	0

tion rate; CKD, chronic kidney disease; BNP, brain natriuretic peptide; AST, aspartate ami-

notransferase; ALT, alanine aminotransferase.

Data presented as mean +- standard deviations or number (%).

The baseline data were collected at the Nayoro City General Hospital.

Fig. 1. Breakdown of patient number and ratio by clinical scenario classification.

A. Tolvaptan group (n = 18); B. Control group (n = 12); CS, clinical scenario.

Table 4

Variation between transportation (Tolvaptan group n = 18)

	Before transportation	After transportation	p value
Heart rate (beats/min)	99 +- 21	88 +- 21	0.016
Systolic blood pressure (mmHg)	128 +- 17	132 +- 19	0.4
Diastolic blood pressure (mmHg)	76 +- 15	79 +- 17	0.432
Cardio-thoracic ratio (%)	63 +- 6	60 +- 5	0.00272
Laboratory data Hemoglobin (g/dL)	11.9 +- 2.3	12.1 +- 2.4	0.269
Sodium (mEq/L)	141.9 +- 2.7	142.3 +- 3.2	0.556
Potassium (mEq/L)	4.2 +- 0.8	3.8 +- 0.5	0.0133
Chloride (mEq/L)	106.3 +- 3.3	105.5 +- 4.5	0.224
Creatinine (mg/dL)	0.95 +- 0.42	0.97 +- 0.45	0.446
BUN (mg/dL)	21.3 +- 12.2	19.6 +- 11.1	0.182
BNP (pg/mL)	823.2 +- 606	859 +- 661	0.221
AST (IU/L)	27.2 +- 14.1	27.4 +- 18.4	0.968
ALT (IU/L)	20.7 +- 16.1	17.6 +- 12.3	0.206

BUN, blood urea nitrogen; BNP, brain natriuretic peptide; AST, aspartate aminotransfer- ase; ALT, alanine aminotransferase.

Data presented as mean +- standard deviations or number (%).

significant difference in the frequency of WRF between the groups. There was statistically significant body weight reduction during trans- portation in the tolvaptan group (-0.7 +- 0.3 vs. -0.4 +- 0.2, p = 0.00953) (Table 6). No statistically significant difference was observed in the proportion of patients who survived until hospital discharge be- tween the tolvaptan and control groups (100% vs. 91%, p = 0.414)

Table 5

Variation between transportation (Control group n = 12)

	Before transportation	After transportation	p value
Heart rate (beats/min)	89 +- 21	85 +- 20	0.315
Systolic blood pressure (mmHg)	140 +- 21	140 +- 22	0.956
Diastolic blood pressure (mmHg)	78 +- 18	82 +- 16	0.542
Cardio-thoracic ratio (%) Laboratory data	63 +- 6	63 +- 6	1
Hemoglobin (g/dL)	13.0 +- 2.5	12.6 +- 2.8	0.239
Sodium (mEq/L)	140.3 +- 3.0	141.0 +- 3.2	0.651
Potassium (mEq/L)	3.9 +- 0.5	3.8 +- 0.5	0.422
Chloride (mEq/L)	103.5 +- 2.1	105.7 +- 2.9	0.0222
Creatinine (mg/dL)	1.09 +- 0.7	1.15 +- 0.75	0.121
BUN (mg/dL)	22.8 +- 15.0	22.5 +- 16.2	0.734
BNP (pg/mL)	939 +- 552	976 +- 678	0.437
AST (IU/L)	27.2 +- 10.0	30.5 +- 17.9	0.347
ALT (IU/L)	23.3 +- 15.0	24.6 +- 18.6	0.467

BUN, blood urea nitrogen; BNP, brain natriuretic peptide; AST, aspartate aminotransfer- ase; ALT, alanine aminotransferase.

Data presented as mean +- standard deviations or number (%).

Fig. 2. Changes in oxygen flow rates during transport. The graph shows the oxygen flow rates of patients in the tolvaptan (A) and control groups

(B) during Patient transport.

*p < 0.05 for the tolvaptan and control group regarding the variation of oxygen flow rates.

(Table 7). One patient who received loop diuretics died during hospital- ization because of multiorgan failure associated with heart failure. The following parameters were statistically significantly shorter in the tolvaptan group than in the control group: the length of ICU stay (me- dian: 2 days vs. 6 days, p = 0.0376); total number of days of hospitali- zation (median: 18.5 days vs. 32.5 days, p = 0.0202); number of days until the discontinuation of oxygen administration (median: 2.8 days vs. 6.9 days, p = 0.00125); and number of days until ambulation (being able to walk to the restroom) (median: 1.5 days vs. 7.5 days, p = 0.0362).

1. Discussion

To the best of our knowledge, this is the first study to evaluate the effects of the use of tolvaptan before transfer with those of loop diuretics in patients with acute heart failure who require long-distance transpor- tation to receive intensive care. The main findings of this study are as follows: (1) The survival discharge ratio was not significantly different between the tolvaptan and control groups. (2) During transportation, the percentage of patients in the tolvaptan group who required in- creased oxygen doses was significantly lower than that in the control group. (3) In Tolvaptan group, blood pressure was not different; how- ever, heart rate was reduced significantly (99 +- 21 vs. 88 +- 21 beats per minute, p = 0.016) during transportation. (4) Patients in the tolvaptan group had significantly shorter ICU stays, less days to discon- tinuation of oxygen, and less days to ambulation.

Patients with acute heart failure require emergency hospitalization for symptom relief. The primary condition leading to hospitalization is usually congestion rather than a low cardiac output [15]. The main treatment for ADHF involves the use of loop diuretics to relieve

Table 6

Clinical outcomes during transportation between the tolvaptan and control groups

	Tolvaptan group (n = 18)	Control group (n = 12)	p value
Urine during transportation (ml)	906 +- 427	400 +- 222	0.000781
Urine 24 h after transportation (ml)	2542 +- 1261	2083 +- 909	0.287
WRF (%)	11.1	16.7	1.0
Weight reduction during transportation (kg)	0.7 +- 0.3	0.4 +- 0.2	0.00953
Oxygen depletion during transportation (%)	0	33.3	0.0181

WRF, worsening renal failure.

Data presented as mean +- standard deviations or number (%).

Table 7

Clinical outcomes after administration between tolvaptan group and control group

	Tolvaptan group (n = 18)	Control group (n = 12)	p value
Survival discharge ratio (%)	100	91	0.414
Length of ICU stay (day)	2 (2-3)	6 (2.25-8)	0.0376
length of hospitalization (day)	18.5 (15.25-23.25)	32.5 (25-39.75)	0.0202
Length of oxygen administration (day)	2.8 +- 2.7	6.9 +- 3.6	0.00125
Number of days until ambulation (day)	1.5 (0-3)	7.5 (3.75-11)	0.0362

ICU, intensive care unit.

Data presented as mean +- standard deviations or number (%).

congestion [4]. Moreover, the delayed use of diuretics has been reported to increase in-hospital mortality [5]. However, the half-life of furose- mide is 1-1.5 h, which is ineffective when prolonged transport is re- quired. In fact, some patients with ADHF who received only loop diuretics before transport experienced worsening of their condition during transfer. By contrast, the use of high doses of loop diuretics has been associated with the occurrence of WRF [16], which is a limitation of ambulance treatment. However, no study has yet evaluated the effect of tolvaptan before transfer in patients with ADHF requiring transporta- tion to another hospital.

Early tolvaptan use (within 3 days after admission) for patients with decompensated heart failure increases urine volume, resulting in a sig- nificantly shorter length of hospitalization till ambulation and the initi- ation of rehabilitation [11]. A previous study on patients with acute heart failure and renal function of <60 mL/min eGFR reported that, compared with loop diuretics alone, adding tolvaptan to loop diuretics led to a moderate-to-remarkable improvement in dyspnea within 12 h of therapy initiation [10]. A previous study comparing tolvaptan and furosemide in patients with severe heart failure (NYHA class IV) showed a lower incidence of WRF in the tolvaptan group [17]. The re- sults of a meta-analysis investigating the efficacy and clinical outcomes of tolvaptan in treating acute heart failure suggested that the use of tolvaptan as an additional treatment may reduce body weight, increase sodium levels, improve dyspnea, avoid the overdose of loop diuretics, and improve outcomes in patients with ADHF [8].

This study showed that urine volume during transportation in- creased statistically significantly more in patients who received tolvaptan along with a loop diuretic than in those who received only loop diuretics. In particular, the early improvement of congestion is nec- essary for patients with heart failure and severe respiratory distress re- quiring transport to another hospital because their symptoms may worsen owing to stress during transport. In this study, the group that re- ceived tolvaptan in addition to the loop diuretics before transfer had sig- nificantly shorter oxygen administration time and earlier start of ambulation than the control group. This was believed to be because tolvaptan enabled the excretion of a large amount of urine during trans- port, thereby improving congestion early. In fact, the decrease in CTR and heart rate immediately after transport indicated an improvement in heart failure. Therefore, we hypothesized that the addition of tolvaptan may contribute to achieving early ambulation and discharge. Tolvaptan often causes side effects associated with hypernatremia

[7]; however, in this study, there was no increase in sodium after

administration. It is also known that the lower the serum sodium con- centration, the more likely it is to lead to hypernatremia. In this study, the mean transport time was 132 min and the sodium concentration at the time of transport was 141.9 mEq/L. As a result, hypernatremia may not have been observed. Serum potassium was decreased in the tolvaptan group, but this was believed to have occurred because of the enhanced diuretic effect of loop diuretics.

The comparison of urine volume, weight loss, length of ICU stay, total number of days of hospitalization, and number of days until dis- continuation of oxygen administration by the type of CS showed that urine volume tended to be higher in CS2 than in CS1 [13], but there was no significant difference among CSs. This may have been because of the small sample size. The aggressive use of diuretics in patients with CS1 may be controversial. Mebazaa et al. state that CS1 is a “vascu- lar disorder” that represents inappropriate vasoconstriction and that the mainstream treatment is vasodilators rather than diuretics [13]. By contrast, real-world data from Japan showed that nearly 70% of patients with CS1 ADHF used diuretics. This has been explained by the fact that the Japanese diet is characterized by high salt intake, particularly among the elderly, which leads to sodium retention and volume over- load. Given the increased stiffness of the left ventricular (LV) wall asso- ciated with atherosclerosis due to LV-arterial coupling, volume overload can easily lead to increased LV end-diastolic pressure and even blood pressure [18]. In the present study, tolvaptan and loop di- uretics were used in 17% of patients and diuretics were used in 50% of patients. In the situation of requiring long-distance transportation, con- sidering the risk of worsening symptoms, the use of tolvaptan and di- uretics together, with caution, may be considered acceptable to reduce volume reduction.

The management of patients in regions that require long-distance transport is an important issue when specialized treatment is required. In patients with acute heart failure, the use of tolvaptan before transport was shown to improve symptoms and shorten hospital stay. In addition, this study reconfirmed the efficacy and safety of tolvaptan in patients with heart failure. Further prospective studies are needed to determine the efficacy of this drug when used for treating heart failure.

• 1. Limitations

There are several limitations in this study. First, this was a retrospec- tive study with a small sample size, and there was wide variability in the data obtained. Second, the administration and dose of tolvaptan was

determined at the discretion of the physician of the initial treatment. In other words, there were no specific criteria for the administration of tolvaptan. Third, we did not accurately assess volume overload before diuretic administration. In patients with severe aortic stenosis or peri- cardial effusion, echocardiography should be performed prior to the use of tolvaptan in patients newly diagnosed with ADHF because of the risk of extreme hypotension. In the future, prospective studies with a larger sample size that consider these factors are warranted.

Contributors

Shuko Iwata drafted the manuscript; Masaru Yamaki, Hirotsuka Sakai and Motoi Okada finalized manuscript; Takeshi Nishiura, Keita Nakagawa and Shota Tokuno helped with the data collection; Shuko Iwata and Motoi Okada take full responsibility for the study and the manuscript. All authors contributed substantially to its revision.

Data availability statement

Data are available upon reasonable request.

Ethics approval statement

The study conformed to the principles outlined in the Declaration of Helsinki and was approved by the ethics committees of the Nayoro City General Hospital and the Wakkanai City Hospital (2020-16; Nayoro City General Hospital, R2-8; Wakkanai City Hospital). All patients gave writ- ten informed consent.

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

Shuko Iwata – No conflicts of interest. Masaru Yamaki – No conflicts of interest. Takeshi Nishiura – No conflicts of interest. Keita Nakagawa – No conflicts of interest. Shota Tokuno – No conflicts of interest.

Hirotsuka Sakai – No conflicts of interest. Motoi Okada – No conflicts of interest.

Acknowledgements

The authors express a deep sense of gratitude to physicians in Wakkanai City Hospital for enrolling patients.

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