Adjunctive pharmacologic therapies for diuretic resistance in acute decompensated heart failure: Systematic review of randomized trials

Table 1 Study-level effect estimates from included randomized controlled trials

Ref.	Population characteristics	Intervention (adjunct therapy)	Comparator	Sample size (intervention/comparator)	Primary outcome	Key findings	Statistical information1
Mullens et al[12]	Acute decompensated heart failure; volume overload; elevated natriuretic peptides	Acetazolamide 500 mg IV daily (proximal tubule) + standardized loop diuretics	Placebo + standardized loop diuretics	256/259	Successful decongestion at 72 hours	Higher decongestion rates; increased natriuresis and urine output	RR 1.46; 95%CI: 1.17-1.82
Cox et al[13]	Acute HF with documented loop resistance	Metolazone, IV chlorothiazide, or tolvaptan (distal tubule or V2 receptor) + loop diuretics	Active comparators	20/20/20	48-hour weight loss	All adjuncts improved diuretic response; no between-group superiority	Weight loss 4.1-5.8 kg (study-level range)
Trullàs et al[14]	Hospitalized acute HF; volume overload	Hydrochlorothiazide (distal tubule) + IV furosemide	Placebo + IV furosemide	115/115	72-hour body-weight change	Greater weight loss; improved diuresis; more renal impairment	Mean difference 114 kg; renal impairment 46.5% vs 17.2%
Cox et al[15]	Hypervolemic acute HF; hospitalized within 24 hours	Dapagliflozin 10 mg daily (proximal tubule via SGLT2) + protocolized diuretics	Structured usual care	120/120	Diuretic efficiency	No improvement in diuretic efficiency; reduced loop-diuretic needs; increased natriuresis	Odds ratio 0.65 for diuretic efficiency
Damman et al[16]	Acute decompensated HF with or without diabetes	Empagliflozin 10 mg daily (proximal tubule via SGLT2)	Placebo	40/40	Dyspnea and diuretic response	Higher urine output; fewer worsening-HF events	Composite events 10% vs 33%
Voors et al[17]	Stabilized acute HF; broad EF spectrum	Empagliflozin 10 mg daily	Placebo	265/265	Hierarchical composite	Significant clinical benefit; improved composite outcomes	Win ratio 1.36; 95%CI: 1.09-1.68
Butler et al[18]	Acute HF; elevated natriuretic peptides	High-dose spironolactone 100 mg daily	Placebo or usual-care spironolactone	180/180	Change in natriuretic peptide levels	No improvement in congestion or outcomes	Reported as non-significant in original trial
Chen et al[19]	Acute HF with renal dysfunction	Low-dose dopamine or low-dose nesiritide + loop diuretics	Placebo	122/119/119	Urine volume and renal biomarkers	No benefit in decongestion or renal outcomes	Reported as non-significant in original trial

¹Statistical information reflects study-level estimates only, extracted directly from individual trials, with no recalculation or pooling, consistent with narrative synthesis requirements.

HF: Heart failure; SGLT2: Sodium-glucose cotransporter 2; RR: Risk ratio; CI: Confidence interval.

Table 2 Risk of bias assessment of included randomized controlled trials (RoB 2.0)

Ref.	Randomization	Deviations from intended interventions	Missing data	Outcome measurement	Selective reporting	Overall risk
Mullens et al[12]	Low	Low	Low	Low	Low	Low
Cox et al[13]	Low	Low	Low	Low	Some concerns	Some concerns
Trullàs et al[14]	Low	Low	Low	Low	Low	Low
Cox et al[15]	Low	Some concerns	Low	Some concerns	Low	Some concerns
Damman et al[16]	Low	Low	Low	Low	Some concerns	Some concerns
Voors et al[17]	Low	Low	Low	Low	Low	Low
Butler et al[18]	Low	Low	Low	Low	Low	Low
Chen et al[19]	Low	Low	Low	Low	Low	Low