Historically, many patients admitted with congestion due to heart failure have been treated with furosemide monotherapy.  However, a strategy of furosemide monotherapy has numerous drawbacks: 

Adding one or two additional diuretics with varying mechanisms of action may alleviate some of these drawbacks.  Bihari et al. performed a small RCT in 2016 involving randomization of critically ill patients to receive furosemide versus furosemide plus 5 mg/day of indapamide (a thiazide-like diuretic).  The dual diuretic therapy improved sodium excretion and diuretic efficacy (more on this trial here). 

ADVOR is a large, multicenter, double-blind RCT which adds to our understanding of multi-agent diuresis.  The subjects were 519 patients with congestion due to heart failure who had been on furosemide prior to admission.  Patients were randomized to receive 500 mg IV acetazolamide daily versus placebo (both in combination with furosemide).  The addition of acetazolamide caused more effective decongestion, with a greater fraction of patients achieving successful decongestion after three days (42% vs. 30%; p<0.001). 

This was largely driven by more effective natriuresis (as shown below, acetazolamide had a greater impact on sodium excretion than merely the volume of urine produced).

For the sake of thoroughness, a few limitations are worth noting:

Regardless of these weaknesses, ADVOR is a robust multicenter RCT that should affect management.  In conjunction with Bihari et al, this study supports the concept that multi-agent diuresis may improve natriuresis and thus improve clinical decongestion. 

Numerous questions remain regarding the optimal diuretic(s) to combine with furosemide (e.g., thiazide versus acetazolamide).  Currently, the ADVOR trial is the most robust evidence regarding combination diuretic therapy in heart failure – which could suggest that acetazolamide might be a front-line therapy in this context.  However, for patients with unusual comorbidities or electrolyte abnormalities, a tailored approach might be more appropriate (e.g., furosemide plus indapamide could be more appropriate for a patient with low baseline bicarbonate levels).

For a more complete discussion of diuresis, see the IBCC chapter on diuresis here.  This is a hot take, so if it turns out that I missed something big about this study I will update the post. 

Photo by Mike Lewis HeadSmart Media on Unsplash

Josh Farkas
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