UMIN-CTR Clinical Trial

Public title

Effect of Long-Acting vs. Short-Acting Loop Diuretics and Neurohormonal Agents on Patients' Quality-of-Life Among Patients with Heart Failure

Acronym

LAQUA-HF Trial

Scientific Title

Effect of Long-Acting vs. Short-Acting Loop Diuretics and Neurohormonal Agents on Patients' Quality-of-Life Among Patients with Heart Failure

Scientific Title:Acronym

LAQUA-HF Trial

Region

Japan

Condition

Heart failure

Classification by specialty

Medicine in general

Cardiology

Classification by malignancy

Others

Genomic information

YES

Narrative objectives1

LAQUA-HF is a pragmatic, randomized, with a 2x2 factorial design to compare 1) torsemide versus furosemide and 2) angiotensin receptor II blocker/neprilysin inhibitor (sacubitril/valsartan) versus sodium-glucose cotransporter 2 inhibitors (dapagliflozin 10 mg); the primary objective is to compare the patients' reported outcomes over 6 months after randomization in patients with heart failure with reduced ejection fraction.

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Pragmatic

Developmental phase

Not applicable

Primary outcomes

The mean changes in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score from the start of the intervention to 6 months.

Key secondary outcomes

- The hierarchical composite endpoint consisting of the time to all-cause death, total number of worsening HFEs, the time to first HFEs within 6 months, and non-improvement in KCCQ-OSS of less than 5 points from baseline to 6 months, assessed by the win ratio.
- The composite of all-cause death and the non-improvement in KCCQ-OS score (less than 5 points) from the start of the intervention to 6 months.
The mean changes in the NT-proBNP levels from baseline to 6 months.
- The composite of all-cause death and non-improvement in the NT-proBNP levels (less than 20%) from the start of the intervention to 6 months.
- The composite of all-cause death, heart failure hospitalization, non-improvement in KCCQ-OS score (less than 5 points), and non-improvement in the NT-proBNP levels (less than 20%) from the start of the intervention to 6 months.
- The incidence of all-cause death, cardiovascular death, heart failure hospitalization, unscheduled office visits for worsening heart failure with an increasing dose of diuretics or intravenous infusion from the start of the intervention to 6 months.
- The mean changes in the KCCQ-clinical summary (KCCQ-CS) score and non-improvement in the KCCQ-CS score (less than 5 points) from the start of the intervention to 6 months.
- The mean changes in the KCCQ- total symptom score (KCCQ-TS) and non-improvement in the KCCQ-TS score (less than 5 points) from the start of the intervention to 6 months.
- The mean changes in left ventricular ejection fraction (LVEF) from the start of the intervention to 6 months.
- The mean changes in estimated glomerular filtration ratio (eGFR) from the start of the intervention to 6 months.
- The incidence of all-cause death, cardiovascular death, and heart failure hospitalization from the start of the intervention to 2 years.

Study type

Interventional

Basic design

Factorial

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -but assessor(s) are blinded

Control

Active

Stratification

YES

Dynamic allocation

YES

Institution consideration

Institution is considered as adjustment factor in dynamic allocation.

Blocking

NO

Concealment

Central registration

No. of arms

4

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Torsemide (oral dosing of torsemide compared to furosemide will be 1mg: 2.5-5mg) with sacubitril/valsartan 50 mg b.i.d. as started dose, after every 2-4 weeks dose will be up titrated to the goal of 200 mg b.i.d
Other heart failure medications (except for an ACE inhibitor or ARB) will be continued during the trial.

Interventions/Control_2

Furosemide with sacubitril/valsartan 50 mg b.i.d. as started dose, after every 2-4 weeks dose will be up titrated to the goal of 200 mg b.i.d.
Other heart failure medications (except for an ACE inhibitor or ARB) will be continued during the trial.

Interventions/Control_3

Torsemide (oral dosing of torsemide compared to furosemide will be 1mg: 2.5-5.0mg) with dapagliflozin 10mg once a day.
Other heart failure medications (except for a sacubitril/valsartan) will be continued during the trial.

Interventions/Control_4

Furosemide with dapagliflozin 10mg once a day.
Other heart failure medications (except for a sacubitril/valsartan) will be continued during the trial.

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

1) Patients with chronic heart failure with/without hospitalization within 1 year before enrollment
A. Patients hospitalized with worsening of chronic heart failure, or new diagnosis of heart failure within 1 year before enrollment AND has an elevated natriuretic peptide level (either NT-proBNP greater than or equal to 300 pg/mL or BNP greater than or equal to 100 pg/mL) with the most recent value used to determine eligibility. (In patients with atrial fibrillation, the level of NT-proBNP will be greater than or equal to 450 pg/mL or BNP greater than or equal to 150 pg/mL)
B. Patients with chronic heart failure without hospitalization within 1 year before enrollment AND have an elevated natriuretic peptide level (either NT-proBNP greater than or equal to 600 pg/mL or BNP greater than or equal to 150 pg/mL) with the most recent value used to determine eligibility. (In patients with atrial fibrillation, the level of NT-proBNP will be greater than or equal to 900 pg/mL or BNP greater than or equal to 225 pg/mL)
2) Patients with heart failure (NYHA functional class II, III, or IV) receiving oral loop diuretic.
3) Patients whose left ventricular ejection fraction is less than or equal to 50% within 1 year before enrollment.
4) Above 20 years of age
5) Able to consent for the trial.

Key exclusion criteria

1) Symptomatic hypotension and/or a systolic blood pressure < 100 mmHg at screening
2) Serum potassium greater than or equal to5.4 mEq/L at screening
3) eGFR < 30 ml/min/1.73m or end-stage renal disease requiring renal replacement therapy at the time of screening
4) Pregnant or nursing women, or history of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, as well as known or suspected contraindications to the study drugs.
5) Inability or unwillingness to comply with the study requirements
6) Patients who are unable to obtain written consent or require a substitute.

Target sample size

240

Name of lead principal investigator

1st name	Shun
Middle name
Last name	Kohsaka

Organization

Keio University School of Medicine

Division name

Department of Cardiology

Zip code

160-8582

Address

35 Shinanomachi, Shinjuku-ku, Tokyo

TEL

03-5843-6702

Email

sk@keio.jp

Name of contact person

1st name	Yasuyuki
Middle name
Last name	Shiraishi

Organization

Keio University School of Medicine

Division name

Department of Cardiology

Zip code

160-8582

Address

35 Shinanomachi, Shinjuku-ku, Tokyo

TEL

03-5843-6702

Homepage URL

Email

yasshiraishi@keio.jp

Institute

Keio University School of Medicine, Department of Cardiology

Institute

Department

Personal name

Organization

Japan Society for the Promotion of Science

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

Japan

Co-sponsor

None

Name of secondary funder(s)

Organization

Keio University, School of medicine, Independent Ethics Committee

Address

35 Shinanomachi, Shinjuku-ku, Tokyo

Tel

03-5363-3503

Email

med-rinri-jimu@adst.keio.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

慶應義塾大学病院（東京都）
榊原記念病院（東京都）
防衛医科大学校病院（埼玉県）
東京都済生会中央病院（東京都）
済生会宇都宮病院（栃木県）
埼玉医科大学国際医療センター（埼玉県）
杏林大学医学部付属病院（東京都）
東京慈恵会医科大学附属病院（東京都）
独立行政法人 国立病院機構 埼玉病院（埼玉県）
独立行政法人 国立病院機構 東京医療センター（東京都）
浜松医科大学医学部附属病院（静岡県）
足利赤十字病院（栃木県）
川崎市立川崎病院（神奈川県）
国際医療福祉大学成田病院（千葉県）

Date of disclosure of the study information

2021

Year

08

Month

24

Day

URL releasing protocol

https://bmjopen.bmj.com/content/14/2/e076519

Publication of results

Published

URL related to results and publications

https://heart.bmj.com/content/early/2026/05/13/heartjnl-2025-327642.long

Number of participants that the trial has enrolled

240

Results

In 231 outpatients with symptomatic HF and LVEF <50% randomized in a 2x2 factorial design, 6-month change in KCCQ OSS did not differ between sacubitril/valsartan and dapagliflozin (adjusted mean difference 2.53, 95% CI -1.81 to 6.88; P=0.25) or between torsemide and furosemide (0.25, 95% CI -4.10 to 4.59; P=0.91). Hierarchical composite outcomes were also similar. No treatment showed superiority, although modest differences cannot be excluded.

Results date posted

2026

Year

08

Month

21

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

2026

Year

05

Month

05

Day

Baseline Characteristics

Among the 231 randomised patients, the median age was 73 years, 51 patients (22.1%) were women, and the median body mass index was 22.8 kg/m2. Overall, 84.0% of patients were in New York Heart Association functional class II, and 66 patients (28.6%) had been hospitalised for heart failure requiring urgent treatment within 1 month before enrolment. The median left ventricular ejection fraction was 36.0% (interquartile range, 31.0 to 41.9), and the median NT-proBNP level was 1101 pg/mL (interquartile range, 609 to 2135). The prevalence of diabetes and atrial fibrillation was 27.7% and 35.1%, respectively. At baseline, 99.1% of patients were receiving an ACE inhibitor or angiotensin receptor blocker, 98.3% a beta-blocker, and 63.6% a mineralocorticoid receptor antagonist. Baseline characteristics were generally balanced between the treatment groups in both randomised comparisons.

Participant flow

A total of 238 patients were assessed for eligibility, of whom 7 were excluded: 3 did not meet the eligibility criteria, 3 declined participation, and 1 was excluded for another reason. The remaining 231 patients were randomised to sacubitril/valsartan (n=118) or dapagliflozin (n=113), and simultaneously to torsemide (n=111) or furosemide (n=120).

A total of 228 patients (98.7%) initiated the assigned treatment and completed at least one KCCQ assessment after treatment initiation and were included in the intention-to-treat analysis. The analysis populations comprised 118 patients assigned to sacubitril/valsartan, 110 assigned to dapagliflozin, 111 assigned to torsemide, and 117 assigned to furosemide. No patient was lost to follow-up, and 3 patients withdrew consent. No treatment crossover between sacubitril/valsartan and dapagliflozin occurred during the 6-month study period.

Adverse events

The safety analysis populations comprised 117 patients assigned to sacubitril/valsartan, 113 assigned to dapagliflozin, 111 assigned to torsemide, and 120 assigned to furosemide. In each factorial comparison, a total of 15 patients discontinued the assigned intervention: 9 in the sacubitril/valsartan group, 6 in the dapagliflozin group, 11 in the torsemide group, and 4 in the furosemide group. Reasons for treatment discontinuation included death in 3 patients (2 deaths from cancer and 1 cardiac death), non-fatal cardiac events or stroke in 4, hypotension in 2, other medical reasons in 4, and non-medical reasons in 2. Because of the 2x2 factorial design, the same patient-level event was represented in both the disease-modifying therapy comparison and the loop-diuretic comparison.

Outcome measures

The primary outcome was the change in the KCCQ-OSS from baseline through 6 months. KCCQ-OSS ranges from 0 to 100, with higher scores indicating better health status. A change of at least 5 points was considered clinically meaningful. KCCQ assessments were performed at baseline and at 3 and 6 months. The adjusted between-group difference in KCCQ-OSS change was 2.53 points (95% CI, -1.81 to 6.88; p=0.25) for sacubitril/valsartan versus dapagliflozin and 0.25 points (95% CI, -4.10 to 4.59; p=0.91) for torsemide versus furosemide.

The key secondary outcome was a 6-month hierarchical composite assessed using the win ratio, with comparisons performed in the following order: Time to all-cause death; total number of worsening heart failure events; time to the first worsening heart failure event; and failure to achieve a clinically meaningful improvement of at least 5 points in KCCQ-OSS

A worsening heart failure event was defined as heart failure hospitalization, an urgent emergency department visit for heart failure, or an unplanned outpatient visit requiring intensification of heart failure therapy because of worsening signs or symptoms. The win ratio was 1.15 (95% CI, 0.71 to 1.88) for sacubitril/valsartan versus dapagliflozin and 1.15 (95% CI, 0.70 to 1.85) for torsemide versus furosemide, with no significant difference in either comparison.

Other secondary outcomes included the composite of all-cause death or failure to achieve clinically meaningful improvement in KCCQ-OSS; all-cause death; cardiovascular death; heart failure hospitalization; urgent or unplanned visits for heart failure; and changes in the KCCQ Clinical Summary Score, NT-proBNP, left ventricular ejection fraction, and estimated glomerular filtration rate.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Main results already published

Date of protocol fixation

2021

Year

07

Month

30

Day

Date of IRB

2021

Year

07

Month

30

Day

Anticipated trial start date

2022

Year

01

Month

01

Day

Last follow-up date

2024

Year

02

Month

05

Day

Date of closure to data entry

2024

Year

03

Month

13

Day

Date trial data considered complete

2024

Year

03

Month

31

Day

Date analysis concluded

2024

Year

04

Month

30

Day

Other related information

Registered date

2021

Year

08

Month

23

Day

Last modified on

2026

Year

08

Month

21

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000051667