Study Design: The main purpose of the IMP-OUTCOME trial (Clinical Trials.gov Identifier:NCT 05035459) is to investigate the impact of residual LU-BL at discharge on the outcome of HF patients and test the hypothesis that adding SGLT2 inhibitor and more frequent follow up including LU-BL assessment would improve the outcome of HF patients with residual LU-BL at discharge. HF Patients will be divided into < 3 LU-BL group and ≥ 3 LU-BL group according to LU assessment results within 48 hours before discharge. An 8-point method will be used[15]. Patients in the < 3 LU-BL group will receive standard HF medication and be followed up at 1, 3, and 6 months post discharge by HF nurses or cardiologists through telephone call or clinical visit, at 12 months post discharge by clinical visit. The group with ≥ 3 B-lines will be further divided into the conventional HF therapy group and the intensive HF therapy group at a 1:1 ratio. The intensive HF therapy group will be treated with an SGLT2 inhibitor beyond other standard HF medications, if not contraindicated. Patients in the intensive HF therapy group will be followed up at 1-month interval up to 12 months post discharge by HF nurses or cardiologists through the clinical visit. Patients in control HF therapy group will receive standard HF medication and followed up at 1, 3 months, 6 months, after discharge by HF-nurses or cardiologists through telephone call or clinical visit, and at 12 months post discharge by clinical visit. LU-BL will be assessed monthly post discharge in the intensive HF therapy group, and at 12 months post discharge for patients in the conventional HF therapy group and for patients with LU-BL < 3 at discharge. Echocardiography examination will be performed for all patients at 12 months post discharge (Fig. 1, Table 1).
LU-BL = lung ultrasound detected B-lines
Table 1
Study protocol and follow up timeline
| Conventional HF therapy group | Intensive HF therapy group |
| Month 1 | Month 3 | Month 6 | Month 12 | Month 1 to 11 | Month 12 |
Body Weight | x | x | x | x | x | x |
Medication | x | x | x | x | x | x |
DASI | x | x | x | x | x | x |
NT-proBNP | x | x | x | x | x | x |
6MWD | x | x | x | x | x | x |
LU-BL | | | | x | x | x |
Echocardiography | | | | x | | x |
DASI: the Duke Activity Status Index; NT-pro-BNP: N terminales pro brain natriuretic peptide; 6MWD: 6-minute working distance; LU-BL: Lung ultrasound detected B-lines |
Participant Selection
Eligibility requirements included age of at least 18 years. Hospitalized heart failure patients with objective heart failure evidence during or before hospitalization. New York Heart Association (NYHA) class II, III, or IV. Patients with NT-pro-BNP levels of at least 600pg/mL (or ≥ 400 pg/meal if they had been hospitalized for heart failure within the previous 12 months). Atrial fibrillation or atrial flutter patients with NT-pro BNP levels of at least 900 pg/ml, regardless of their history of HF hospitalization. Exclusion criteria included patients with a life expectancy of less than 1-year due to malignancy. Lung ultrasonography (LU) examination will be performed by qualified researchers with a national lung ultrasound certificate on commercially available ultrasound machines (Versana Premier, GE) within 48 hours before discharge and during follow up as indicated. LU examinations were be performed on the patient in the supine position. The ultrasound scanning of the anterior and lateral chest will be obtained and evaluated with the 8-point method offline[10]. Patients will be divided into LU-BL < 3 and ≥ 3 groups. After obtaining informed consent, inclusion and exclusion criteria will be evaluated and baseline information (including clinical, laboratory, and imaging results) will be collected from qualified participants. Follow-up will be made by telephone or clinical visit for patients with LU-BL < 3 at discharge and for patients in conventional HF therapy group during months 1, 3 and 6 post discharge and by clinical visit at month 12 post discharge. Patients will be followed up monthly by clinical visits for patients in the intensive HF therapy group.
Endpoints
The primary outcome consisted of readmission for worsening heart failure and all-cause death during follow-up. The secondary endpoint includes the patient's Duke Activity Status Index, NT-pro BNP and 6-minute walk distance values at each follow up, EF and number of LU-BL values during the follow up at month 12 post discharge.
Sample Size And Statistical Analysis
Event rates of the IMP-OUTCOME study is assumed based on the data of previous studies[15]. The study showed that the incidence of the composite outcome of worsening heart failure or all-cause death was 19.8% in the ༜3 B-lines group versus 45.8% in the ≥ 3 groups (hazard ratio, 4.08; 95% confidence interval (CI), 1.96 to 8.54; P < 0.001). Thus, we estimated that the difference in primary endpoint could be achieved by enrolling 186 patients (60 patients in ༜3 LU-BL groups and 126 patients in ≥ 3 LU-BL group). The power of the study is set at 90% with a 2-sided type I error rate of 0.05. Assuming that 2% of patients would withdraw or be lost to follow-up, the final sample size is determined to be 233 patients (75 patients in the༜3 LU-BL groups, 158 patients in the ≥ 3 LU-BL group). The level of significance to be used in the trial will be 0.05.
Study Administration And Management
The trial is registered as ClinicalTrails.gov identifier: NCT05035459. The local Institutional Review Board or Ethics Committee has approved the study, and all patients must provide written informed consent prior to enrollment. Funding is provided by the Department of Cardiology, the Xiangtan Central Hospital. An independent data monitoring committee (DMC), composed of three physicians from the fields of cardiology and interventional cardiology and one biostatistician, will review aggregate and individual patient data related to safety, data integrity, and overall conduct of the trial, on a periodic basis. The DMC may make recommendations to the steering committee and study sponsor based on monitoring activities. The study has not started enrollment, and we plan to complete the enrollment of all subjects between October 2021 and December 2022, and the follow-up will then be ended on December 2023, and primary results would be available by early 2024.