Better Natriuresis With IV Furosemide and Metolazone in Chronic HF Patients

LISBON, Portugal—The use of intravenous furosemide plus the thiazide-like diuretic metolazone resulted in significantly better natriuresis, as well as greater increase in urine volume and a larger reduction in body weight, when compared with IV furosemide alone, according to a study conducted in patients with ambulatory congestive heart failure (HF).

The addition of IV acetazolamide to furosemide, on the other hand, did not result in better natriuresis or urine volume excretion.

These results, which were presented this past weekend at the European Society of Cardiology’s Heart Failure 2024 Congress, should help direct the use of diuretics in patients with severe chronic HF experiencing refractory congestion, say investigators.

“For years, what we have done is we extrapolated the data from the acute heart failure patients to the chronic patients,” senior investigator Oren Caspi, MD, PhD (Rambam Health Care Campus, Haifa, Israel), told TCTMD. “Also, this study was conducted in chronic heart failure patients treated with contemporary medical therapy. Here, we need to think about contemporary in two ways: the guideline-directed medical therapy [GDMT] that modulates the natural history of the disease and the decongestive therapy.”

Lead investigator Aharon Abbo, MD (Rambam Health Care Campus), told TCTMD they included patients with refractory congestion, those “at an advanced stage of disease where they are on maximally tolerated guideline-directed medical therapy but still need a lot of diuretics.”

These patients were treated weekly in the ambulatory setting with intravenous diuretic administration over 3 to 6 hours. Ambulatory care has been shown to be safe and effective in prior studies for promoting substantial urine output, weight loss, and natriuresis, say investigators, and it’s been suggested that a daycare HF setting could be one way to manage congestion-refractory HF patients instead of admitting them to hospital.

“This is a unique concept,” said Caspi. “There are few places in the US or Europe that do it this way, but these patients don’t have any other alternative. They are on maximally tolerated GDMT and they are on a very high dose of furosemide. Otherwise, we’d see them in the outpatient clinics and in between those visits they would decompensate and be admitted to hospital.”

The study, known as DEA-HF, was published simultaneously online in JACC: Heart Failure.

Have Metolazone on Call

In this intra-patient, crossover study, 42 patients (mean age 72 years; 60% female) were randomized into six groups based on the sequence of treatment and treated with one of three diuresis regimens:

• IV furosemide 250 mg alone
• IV furosemide 250 mg plus oral metolazone 5 mg
• IV furosemide 250 mg plus IV acetazolamide 500 mg

The vast majority (93%) of patients had NYHA class III/IV symptoms and significantly elevated NT-proBNP levels at baseline (median 3,558 pg/mL). Nearly all were treated with beta-blockers, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists, and all patients were on high-dose oral loop diuretics at baseline (background furosemide 160 mg daily). Half of patients had HF with preserved ejection fraction. 

The amount of sodium excretion, the study’s primary endpoint, was significantly greater with furosemide and metolazone (4,691 mg) compared with furosemide and furosemide plus acetazolamide (3,835 and 3,584 mg, respectively). Urine volume was also greater with the furosemide/metolazone combination (1.84 vs 1.71 L with furosemide alone and 1.58 L with furosemide plus acetazolamide).

Worsening renal function—defined as a 0.3-mg/dL or greater increase in serum creatinine or 20% or greater decrease in estimated glomerular filtration rate—was significantly higher with furosemide and metolazone, but it didn’t lead to any events requiring hospitalization. In this monitored setting, there were no signs of hyponatremia, dyskalemia, or symptomatic hypotension.   

“We need to think of metolazone as an effective therapy,” said Caspi. “For those that actually reach a ceiling, the maximal diuretic efficacy of loop diuretics, we need to have metolazone on call. There are some adverse events like the worsening of renal function, but this did not translate into clinically significant events. So, I think this is a viable option for those patients.”

Additionally, “we know now that intravenous acetazolamide is not effective as an addition to furosemide,” said Caspi. “That’s important, especially in the context of high rates of guideline-directed medical therapy.”

Results Conflict With ADVOR Trial

In the ADVOR trial, a study of patients with acute decompensated HF with volume overload, adding acetazolamide to loop diuretic therapy led to a greater incidence of successful decongestion compared with furosemide alone.

To TCTMD, both Caspi and Abbo said the differing results between their trial and ADVOR might be explained by the patient population (acute vs chronic HF patients), but also because they included patients treated with SGLT2 inhibitors. Both acetazolamide and SGLT2 inhibitors act on the proximal nephron of the kidneys, with the SGLT2 inhibitors potentially diminishing the action of acetazolamide.

Kevin Damman, MD, PhD (University of Groningen, the Netherlands), the discussant following the presentation, said he still doesn’t completely understand why adding acetazolamide wasn’t effective at lowering urinary volume and sodium excretion. While DEA-HF adds yet more evidence on the best diuretic strategy for patients with congestion, he questioned why these patients were treated in an ambulatory setting.  

“Why would you admit a patient just for 6 hours to get rid of fluid, weight, and sodium?” he said. “If you think that a patient needs IV diuretics, admit the patient, perhaps for nurse-led, natriuresis-guided therapy and decongest appropriately so that you can actually have a lower use of diuretics in a stabilized patient. This is important because the high-dose furosemide background therapy actually results in distal tubular hypertrophy.”

This background therapy, plus recurrent furosemide treatments, makes patients “extremely diuretic-resistant,” said Damman. Acetazolamide, on the other hand, prevents diuretic resistance, but it’s unlikely to be effective in the DEA-HF patients given their background use of high-dose furosemide. In this distinct phenotype, only thiazide-like diuretics, such as metolazone, appear to have beneficial add-on effects, but use does come at the expense of worsening renal function, he said.    

To TCTMD, Caspi emphasized that treatment in the ambulatory setting is not for all chronic HF patients, just those in need of regular diuresis to prevent hospitalization for decompensation. He noted there are questions around its scalability, but this might be overcome with greater use of nurses to guide natriuresis. Moreover, DEA-HF study investigators are not advocating for the ambulatory setting, but noted the controlled environment was useful to rigorously test the various diuretic strategies. He said they are still attempting to determine if acetazolamide might be effective in some chronic HF patients.