Loop diuretics remain the mainstay of decongestion therapy. Still, their effectiveness can be reduced by inadequate dosing, reduced absorption of oral formulations, resistance to their pharmacologic actions, and compensatory changes in renal sodium reabsorption that often necessitate IV administration during ADHF. When loop diuretics are insufficient, adjuncts like thiazides, carbonic anhydrase inhibitors, or inotropes are used to boost diuresis, though, these combinations can increase electrolyte disturbances and renal dysfunction without consistently improving clinical outcomes. Recent outpatient studies have explored these strategies with mixed results (Table 1). In SALT-HF (2024), the addition of hypertonic saline to IV furosemide in 167 ambulatory worsening HF patients failed to improve short-term diuresis, congestion scores, or 30-day clinical outcomes compared to IV furosemide alone [3]. Conversely, the DEA-HF (2024) trial randomized 42 patients with worsening HF to combination regimens and demonstrated that IV furosemide plus oral metolazone produced significantly greater natriuresis and urinary output at six hours compared to IV furosemide alone or when combined with IV acetazolamide (Table 1) [4]. These data suggest that while some diuretic adjuncts may enhance natriuresis, results remain heterogeneous, highlighting the ongoing difficulty of achieving reliable, sustained decongestion in the outpatient setting. When these medical therapies are exhausted or unavailable, further treatment is limited to mechanical fluid removal with dialysis or other experimental invasive therapies that require hospitalization.

Beyond the pharmacologic challenges for successful decongestion with these agents, many logistical barriers prevent high throughput and effective outpatient management of ADHF. IV loop diuretics administered in the clinic are usually limited to a single dose or infusion, as arranging serial administrations is constrained by staffing, patient mobility, and insurance coverage. Sequential dosing of diuretics over multi-day periods can achieve potent fluid removal but requires close monitoring and patient compliance, raising safety concerns with heightened risk of complications. Consequently, hospitalization remains the default and most practical setting for decongestion, even among patients who may otherwise be safely managed in an outpatient clinic or at home.

To overcome these challenges, several outpatient trials are testing novel pharmacologic approaches. The TROUPER trial (NCT02476409) is evaluating whether adding tolvaptan to standard diuretic therapy, guided by copeptin levels, improves 48-hour weight loss in worsening HF outpatients [5]. Likewise, a phase 2 dose-finding study of the relaxin agonist R2R01 (NCT06264310) is enrolling outpatients with worsening HF to assess whether this vasodilatory peptide can enhance natriuresis and preserve renal function compared with standard care Table 1) [6]. Together, these efforts highlight a growing shift toward safe, scalable, physiology-guided outpatient therapies aimed at reducing HF admissions.