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For patients with chronic heart failure (HF) who have persistent congestion despite high doses of oral loop diuretics, the right way to intensify diuretics in the outpatient setting may be narrowed, based on a small randomized crossover study.

Comparing the potency of three diuretic regimens in ambulatory congestion-refractory patients, investigators in the reported significantly more total sodium excretion at 6 hours with high-dose IV furosemide plus oral metolazone (4,691 mg), which beat furosemide alone (3,835 mg, P=0.015) and furosemide plus acetazolamide (3,584 mg, P=0.001).

As for total urinary volume excreted, the best results were seen with furosemide plus metolazone (1.84 L) and furosemide alone (1.71 L), compared with furosemide plus acetazolamide (1.58 L, P=0.039), reported Oren Caspi, MD, PhD, of Rambam Health Care Campus in Haifa, Israel, and colleagues in .

The investigators said their overall results support the older CLOROTIC and 3T trials.

However, the modest difference in urine volumes with and without metolazone led Paula Rambarat, MD, and G. Michael Felker, MD, MHS, both of Duke University School of Medicine in Durham, North Carolina, to question the clinical significance of the sodium excretion data.

"Demonstrating a significant increase in natriuresis between two treatment arms is perhaps purely academic if a subsequent improvement in important clinical endpoints such as markers of congestion or rates of hospitalizations cannot be achieved," they wrote in an .

Additionally, there was a downside to furosemide plus metolazone: a significantly higher rate of worsening renal function (39%) versus furosemide alone (16%) and furosemide plus acetazolamide (2.6%). Nevertheless, this did not translate into more hospital admissions attributable to acute kidney injury as the primary cause, study authors noted.

In any case, acetazolamide did not result in better natriuresis, urine volume, or weight reduction as an add-on to high-dose IV furosemide, according to Caspi's team -- in contrast to the ADVOR trial, which found that lower-dose furosemide plus acetazolamide did indeed provide a benefit.

The diminishing returns of this combination in the present trial may be related to furosemide having been tested at a higher dose in DEA-HF, they theorized, or the greater preponderance of background SGLT2 inhibitor (SGLT2i) use precluding the ability of acetazolamide to show a benefit.

"From a physiological perspective, SGLT2is and acetazolamide both block sodium reabsorption in the proximal tubule of the nephron ... On a background of high SGLT2i use, the addition of intravenous acetazolamide to a loop diuretic may not be as effective at augmenting diuresis," wrote Rambarat and Felker.

Also complicating the choice of diuretics is the availability of a relatively new subcutaneous formulation of furosemide that can be self-administered by patients at home.

"Future studies are needed to compare outcomes with subcutaneous furosemide vs combination therapy with intravenous furosemide in the ambulatory, congestion-refractory HF population. In addition, whether combination therapy with metolazone in addition to subcutaneous furosemide improves outcomes is unknown," Rambarat and Felker urged.

"Importantly, although the proof of diuretic effect is in the urine, these future prospective studies should ideally be adequately powered to assess symptom burden and HF hospitalizations as important clinical endpoints. It is only through such important work that the role of outpatient parenteral diuretic therapy in the management of the congestion-refractory HF patient can be established," the editorialists concluded.

DEA-HF was a prospective study conducted in 2023 in a single day-care heart failure unit located in-hospital.

Eligible patients were chronic HF patients with New York Heart Association class II to IV symptoms and at least one sign of congestion while taking at least two HF drugs. Additionally, they had to show estimated glomerular filtration rates greater than 20 mL/ min/1.73 m² and have no history of renal replacement therapy or ultrafiltration 30 days before randomization.

In their crossover study, investigators had 42 people subjected to a random sequence of weekly treatment with IV furosemide 250 mg, IV furosemide 250 mg plus oral metolazone 5 mg, or IV furosemide 250 mg plus IV acetazolamide 500 mg. Treatments were administered once a week for overall study participation lasting 3 consecutive weeks in total.

The proportion of people completing the entire sequence of treatments and follow-up reached 88%.

Among all enrolled patients, mean age was 72 years, and 40% were women. Half had left ventricular ejection fraction 50% or higher. Three-quarters were in New York Heart Association class III. All were on high-dose oral loop diuretic agents at baseline and most patients were on guideline-directed medical therapy including SGLT2 inhibitors.

The incidence of electrolyte abnormalities and symptomatic hypotension was similar between groups.

Caspi and colleagues acknowledged the possibility of carryover effects between treatments despite finding no statistical evidence of this. With DEA-HF as a single-center study, it is also limited in its generalizability to other settings, and attempts to conduct it as a multicenter trial would be impractical, the authors cautioned.

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