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:
- Furosemide tends to stimulate production of dilute urine, leading to a greater amount of water loss than sodium loss. Predominant loss of water may cause loss of volume from the intracellular compartment (rather than from the extracellular compartment, which is what we’re striving for). Patients often produce lots of urine, but this may be dilute urine with a relatively low sodium content. Thus, treating teams may be fooled into thinking that the patient is responding well, when in fact the voluminous urine output is partially reflective of dehydrating the patient (an undesirable side effect).
- Furosemide causes a contraction alkalosis, which may become problematic over time for various reasons. Practitioners inexperienced with large-volume diuresis may misinterpret the alkalosis as a signal that further volume removal is contraindicated. It’s also theoretically conceivable that hypochloremia could cause diuretic resistance (more on this here).
- IV furosemide lasts about six hours. In between doses of furosemide, patients may retain sodium due to up-regulation of distal tubular sodium reabsorption. Thus, furosemide alone that is given once or twice daily may fail to work.
- Patients are often admitted to the hospital due to failure of furosemide to work on an outpatient basis. It’s illogical to continue using the same basic medication strategy that the patient has already failed to respond to.
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:
- The furosemide regimen included a single dose on the first day, followed by twice-daily administration. It’s conceivable that a more aggressive furosemide strategy with frequent dose-adjustment and q6hr dosing could have worked more effectively (thereby reducing the impact of acetazolamide).
- Patients receiving SGLT2 inhibitors were excluded from the trial. Although SGLT2 inhibitors do have a diuretic effect, it’s doubtful that chronic use of an SGLT2 inhibitor would have a major effect on diuresis. Nonetheless, the generalizability of these results among patients on SGLT2 inhibitors remains unclear.
- Patients with baseline renal dysfunction and GFR <20 ml/min were excluded from the trial. Patients with severe chronic renal failure and pre-existing metabolic acidosis could be at increased risk of metabolic acidosis due to acetazolamide. Thus, the role of acetazolamide among these patients is unclear.
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.
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