The SEEQUOIA-AHF (Safety and Efficacy of Early, seQUential oral dIuretic nephron blockAde in Acute Heart Failure) trial is a multicenter, randomized, open-label, parallel-arm trial assessing the impact of early sequential nephron blockade (i.e. a regimen based on the combination of four oral diuretics with different sites of action along the nephron at low doses) compared to a conventional approach with a high-dose loop diuretic in the treatment of congestion in patients hospitalized with acute heart failure (AHF).

In this study, after 24-72 hours of high-dose intravenous furosemide started at the time of hospital admission, patients admitted with AHF will be randomized to open-label oral treatment with either low-dose sequential nephron blockade or high-dose furosemide for 96 hours.

The primary end-point will be the bivariate change in body weight and serum creatinine value at 96 hours since randomization. Secondary endpoints will include clinical (e.g., total change in body weight during hospitalization, change in dyspnea score at 96 hours since randomization, 30-day readmission rate) and laboratory (e.g., change in BNP or NT-proBNP at discharge vs randomization) parameters, and safety (e.g., change in serum creatinine value at discharge versus randomization and up to 30 days from discharge) issues.

The SEEQUOIA-AHF trial is aimed at ascertaining if the early, oral administration of a combination of four diuretics with different sites of action along sequential nephron segments (i.e., sequential nephron blockade: proximal tubule, loop of Henle, distal tubule, cortical collecting duct) may achieve greater decrease in body weight and lower increase in serum creatinine values as compared with standard of care, i.e. a conventional diuretic therapy regimen based on high-dose oral furosemide. To assess the efficacy and safety of an early sequential nephron blockade, the study intervention will be initiated 24-72 hours after an algorithm-based treatment with high-dose intravenous furosemide started at the time of hospital admission to achieve patient stabilization.

After 24-72 hours of algorithm-based treatment with high-dose intravenous furosemide, eligible patients will be randomized to either control (furosemide-only) or intervention (early sequential nephron blockade) arm.

All patients will be put on a low sodium diet (< 70 mEq/24 hours), and will be allowed a fluid intake of < 1 L/day.

Following randomization patients will be started on oral diuretic therapy according to two different approaches, namely:

1. High-dose oral furosemide-only arm A furosemide oral dose equivalent to twice the intravenous dose of the last 24 hours will be given in two daily divided doses.

   Unless serum potassium value is higher than 5.0 mEq/L, oral spironolactone or potassium canrenoate will be added; dose will be established based on serum creatinine value Oral or intravenous potassium supplementation (potassium chloride at least 24 mEq/day) will be started if serum potassium value is lower than 4.0 mEq/L

2. Early sequential oral diuretic nephron blockade

   1. Furosemide A furosemide oral dose equivalent to the previous 24-hour intravenous dose will be given in two divided doses
   2. Metolazone. Dose will be established based on serum creatinine value
   3. Acetazolamide. Dose will be established based on serum creatinine value
   4. Spironolactone or Potassium Canrenoate. Unless serum potassium value is higher than 5.0 mEq/L, oral spironolactone or potassium canrenoate will be added; dose will be established based on serum creatinine value.

In both arms, if within the first 48 hours since randomization urine output is lower than 1.5 L/day and/or body weight decrease is less than 0.5 Kg/day, the oral dose of furosemide will be doubled, or the patient will be switched to intravenous administration at the discretion of the attending physician. If urinary output exceeds 50 ml/Kg/day current furosemide dose will be halved. Diuretics can be decreased or temporarily discontinued if there is a decrease in systolic blood pressure (> 25% of basal value) or worsening kidney function (WKF, defined as an increase in serum creatinine value ≥ 0.3 mg/dL or 25% from baseline value within 24-48 hours) that is felt as being be due to a transient episode of intravascular volume depletion. After the patient has stabilized, if congestion persists, diuretics will be reinitiated or their doses will be increased until the patient's fluid balance has been optimized. Investigators may opt-out of the treatment algorithm if they feel that it is in the interest of patient care.

The primary endpoint will be the bivariate change in body weight and serum creatinine value at 96 hours since patient randomization.

According to the data from the study of Grodin et al (J Card Fail 2016; 22:26-32), comparing subjects randomized to stepped-care diuretic treatment in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial with those developing the cardiorenal syndrome during standard treatment with intravenous furosemide in the Diuretic Optimization Strategies Evaluation Acute Heart Failure (DOSE-AHF) trial and the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) trial, the mean difference in body weight obtained with the stepped-care oral approach versus the intravenous approach was -1.2 Kg, with a standard deviation (SD) ranging between 1.5 and 2.4 Kg; the mean difference in serum creatinine was -0.1 mg/dL, with a SD of 0.3 mg/dL. Thus, the investigators estimated that the enrollment of 206 patients would yield a 90% power to detect a 0.5 effect size for either component of the bivariate primary endpoint (1.2/2.4 Kg and 0.15/0.30 mg, respectively) with a two-sided 0.05 alpha level.

Inclusion Criteria:

• Male or non-pregnant female patient, 18 years or older
• Patients admitted to Cardiology or Internal Medicine units with a diagnosis of acute decompensated heart failure and congestion: NT-proBNP > 1,000 pg/ml or BNP >250 pg/ml, dyspnea and at least two of the following clinical signs: 2+ pitting edema, pulmonary edema/pleural effusions at chest x-ray or US body weight increase above usual > 5% over the last 4 weeks
• Clinically stable patients that can be switched to oral diuretic therapy after 24-72 hours of an algorithm-based treatment with high-dose intravenous furosemide started at the time of hospital admission
• Patients capable to provide written informed consent

Exclusion Criteria:

• Serum creatinine levels > 3.5 mg per deciliter at admission to the hospital or usual estimated glomerular filtration rate (eGFR) < 20 ml/min/1.73 m2 by the MDRD or CKD-EPI formula
• Systolic blood pressure < 90 mmHg at time of enrollment and/or hemodynamic instability severe enough to require intravenous inotropes, intravenous vasodilators, or both
• Severe arrhythmias with hemodynamic instability or DC shock occurred prior to randomization
• Ascertained acute coronary syndrome (ACS), or ACS occurred within the last 4 weeks
• Hematocrit > 45%
• Use of iodinated radio contrast material occurred in the last 72 hours
• Current mechanical ventilator support
• Previous solid organ transplant
• Primary hypertrophic or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis or cardiac tamponade, severe valvular stenosis
• Complex congenital heart disease
• Liver disease (serum ALT or AST > 4, and/or total serum bilirubin > 3)
• Known bilateral renal artery stenosis
• Active sepsis or ongoing systemic infection
• Active gastrointestinal tract bleeding
• Enrollment in another clinical trial
• Locally advanced or metastatic cancer