Kidney function and acid–base status as gatekeepers of natriuretic and diuretic responsiveness in chronic HF: insights from the DEA-HF clinical trial

AIMS: In chronic heart failure (HF), decongestion is hindered by reduced renal function and diuretic resistance. This study compared the effect of eGFR and serum bicarbonate on three diuretic regimens in congestion-refractory HF patients. METHODS AND RESULTS: This is a prespecified post-hoc analysis of DEA-HF, a randomized, crossover trial (n = 42). Patients received, in random order, weekly treatments of IV furosemide 250 mg; oral metolazone 5mg + IV furosemide 250 mg; and IV acetazolamide 500mg + IV furosemide 250 mg. Primary endpoint: 6h-Natriuresis; secondary: 6h-diuresis and decongestion measures at 7 ± 3 days. Mixed models assessed effect modification by eGFR (≤30 vs. > 30 mL/min/1.73m2) and by serum bicarbonate (≤vs.> median-29.6 mmol/L). Higher eGFR was associated with greater natriuresis and diuresis (4735 mg vs. 3211 mg, P = 0.0004; 1.93L vs. 1.49L, P = 0.0078). In patients with eGFR > 30, addition of metolazone to furosemide led to higher natriuresis compared to acetazolamide addition (5525 mg vs. 4379 mg, P = 0.04) or to furosemide monotherapy (5525 mg vs. 4303 mg, P = 0.014); no regimen differences were observed at eGFR ≤ 30. Independently, higher serum bicarbonate predicted greater natriuresis and diuresis (4858 mg vs. 3576 mg, P = 0.0008; 1.99 vs. 1.56L, P = 0.0014). There was no difference in clinical decongestion measures. All regimens were well-tolerated with comparable safety concerns regarding renal function, electrolyte disturbances, or hypotension. CONCLUSION: In ambulatory patients with congestion-refractory HF and eGFR > 30 mL/min/1.73m2, natriuretic and diuretic responses are augmented across all regimens, with metolazone providing additional improvement in natriuresis. When eGFR ≤ 30 mL/min/1.73m2, neither metolazone nor acetazolamide provides additional benefit. High serum bicarbonate predicts better natriuretic and diuretic response, as well as additional benefit from metolazone treatment. High-dose diuretics had comparable safety profiles across the eGFR spectrum.