Neurohormonal-Centred Decongestion in Acute Heart Failure: Moving Beyond the Diuretic-Centered Paradigm

Introduction

• Congestion is the most common clinical presentation and cause of admission for acute heart failure (AHF).
  • Effective decongestion is a vital short-term goal because it can lead to rapid symptom relief, improved quality of life, and shorter hospital stay.
  • Euvolaemia at hospital discharge is clinically relevant and associated with better post-discharge outcomes, but is achieved in less than $50\%$ of patients.
• Central thesis: congestion is a consequence of complex pathophysiology, not a direct cause of HF itself; therefore, therapies that remove sodium/water alone (targeting symptoms) do not modify disease progression or prognosis.
• Aim of the paper: critique current decongestive strategies and propose a non-diuretic-centered paradigm that targets the underlying pathophysiology to improve congestion, prevent new decompensations, and favorably alter the disease course.

The pathophysiology of congestion development in heart failure

• Core disturbance: inability to control water-ion homeostasis due to neurohormonal drive and impaired kidney function, causing water/sodium retention (sodium avidity) and volume shifts leading to clinical congestion.
• Key mediators/pathways contributing to sodium avidity and congestion:
  • Sympathetic nervous system (SNS) activation
  • Renin–angiotensin–aldosterone system (RAAS)
  • Proinflammatory pathways
  • Non-osmotic vasopressin release
  • Peripheral resistance to natriuretic peptides
• Urine sodium (uNa+) as a marker of sodium avidity: reflects neurohormonal activity and outcomes, but interpretation depends on clinical context, patient fluid status, and diuretic dosing (Table 1).
• Why diuretic-focused strategies may fail long-term:
  • Removing sodium/water relieves congestion temporarily but does not address the root drivers of sodium avidity.
  • Neurohormonal modulation alone often does not fully prevent recurrent decompensation.
• Figure 1 (conceptual): major pathways contributing to congestion include SNS activation, RAAS, inflammatory signaling, vasopressin axis, and natriuretic peptide resistance, influencing kidney sodium handling and congestion risk.

Effects and limitations of direct water/sodium removers on outcomes in acute heart failure

• Direct sodium/water removers discussed: loop diuretics, non-loop diuretics (acetazolamide, HCTZ), vasopressin V2 antagonists, rolofylline, ultrafiltration (UF).
• Loop diuretics
  • Widely used as first-line therapy to relieve congestion due to rapid onset and efficacy in sodium/water removal.
  • No robust randomized data showing improvement in hard outcomes (mortality, rehospitalization) with loop diuretics in contemporary populations; one older meta-analysis was retracted.
  • Diuretic-induced natriuresis is not curative; loop diuretics can activate counter-regulatory mechanisms, notably RAAS, which can worsen diuretic response over time and promote diuretic resistance.
  • Mechanistic concern: loop diuretics block the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC) and can promote renin secretion, contributing to RAAS activation and volume-redistribution dynamics; chronic furosemide exposure may blunt tubular responsiveness requiring dose escalation, creating a vicious cycle.
  • Practical note: Peak uNa⁺ occurs roughly between $2\text{--}3\,\mathrm{h}$ after the initial diuretic dose.
• Non-loop diuretics (e.g., acetazolamide, hydrochlorothiazide)
  • Can augment decongestion by promoting natriuresis, but trials show no clear mortality or rehospitalization benefit and may increase renal function deterioration risk.
  • ADVOR trial: acetazolamide added for $72\,\mathrm{h}$ improved objective decongestion (42.2% vs 30.5%; p<0.001) but did not reduce all-cause mortality or HF rehospitalizations; higher incidence of transient worsening of renal function with acetazolamide (40.5% vs 18.9%).
  • CLOROTIC trial: adding hydrochlorothiazide to loop diuretics accelerated decongestion but did not improve post-discharge outcomes and increased WRF risk (46.5% vs 17.2%).
• Vasopressin-2 receptor antagonists (tolvaptan)
  • Mechanism: corrects dilutive hyponatremia by promoting aquaresis (water excretion without electrolyte loss).
  • EVEREST: tolvatpan improved decongestion markers and serum Na⁺ but did not improve long-term outcomes.
  • TACTICS-HF: tolvaptan addition enhanced short-term weight/edema reduction but did not improve dyspnea responder rates or long-term events.
• Rolofylline (adenosine A1 receptor antagonist)
  • Early weight loss observed, but no improvement in rehospitalization or mortality in PROTECT trial.
• Ultrafiltration (UF)
  • UNLOAD: UF achieved greater weight loss and net fluid removal and lowered HF rehospitalizations within $90\,\mathrm{days}$, with no mortality difference.
  • CARRESS-HF: UF proved inferior for the primary endpoint (change in serum creatinine and body weight at $96\,\mathrm{h}$).
  • Post-hoc analyses: UF associated with higher plasma renin activity at $96\,\mathrm{h}$, suggesting neurohormonal activation with UF may counter any short-term volume benefits.
  • Overall: UF has not shown mortality benefit and may carry renal and renal-renal physiology risks; no mortality reduction signal.
• Summary: Across diuretic- and non-diuretic-based decongestive strategies, while short-term decongestion can be achieved, there is no consistent evidence of improved mortality or reduced HF hospitalizations from these direct water/sodium removal approaches alone.

Neurohormonal blockade and the concept of sodium avidity

• Rationale: To counterbalance sodium avidity (the driver of congestion in HF) by modulating the neurohormonal drives (SNS, RAAS, vasopressin) rather than solely removing sodium/water.
• Early mechanistic observations (smaller studies):
  • ACE inhibitors may increase natriuresis without necessarily increasing diuresis; case with captopril showed natriuresis increase in some contexts (e.g., ascites) with variable results.
  • High-dose spironolactone (e.g., 200 mg bid) increased natriuresis, diuresis, and weight loss in certain settings; ACE inhibition plus MRA showed additive natriuretic effects in animal models and some diuretic-resistant cases.
  • Beta-blockers’ potential to cause sodium retention was not confirmed in clinical practice.
• Clinical trials showing the impact of neurohormonal blockade on congestion and diuretic needs:
  • PARADIGM-HF: sacubitril/valsartan (ARNI) reduced loop diuretic requirements and dose increases vs enalapril, reflecting improved congestion status.
  • CHARM programme: ARBs (and later observations) showed reduced diuretic requirements, suggesting improved congestion with RAAS blockade.
  • NATRIUM-HF: initiation of ARNi in chronic HF improved natriuresis and diuresis in response to a fluid/sodium challenge, with changes in NT-proBNP and weight trajectories suggesting better decongestion response.
  • STRONG-HF: rapid up-titration of GDMT (ACEi/ARB/ARNi, beta-blockers, MRA) post-hospitalization led to better congestion markers at day 90 despite lower loop diuretic doses; those with higher GDMT remained decongested, whereas those with lower GDMT were more likely to redevelop congestion.
  • BIOSTAT-CHF: up-titration of beta-blockers and RAAS inhibitors associated with reduced risk of recurrent hospitalizations.
• Mechanistic interpretation: neurohormonal blockade reduces sodium avidity, leading to long-term decongestion, less diuretic need, and lower decompensation risk.
• Summary: neurohormonal blockade, by attenuating systemic signals driving renal sodium handling, can shift the balance toward sustained decongestion and better outcomes than diuretic-centric strategies alone.

Sodium–glucose cotransporter 2 (SGLT-2) inhibitors and decongestion

• SGLT-2 inhibitors do not directly suppress neurohormonal drive but have demonstrable decongestive effects and reduce worsening HF risk.
• EMPULSE trial: empagliflozin started in hospital after stabilization of AHF showed significant improvements in congestion markers (weight, edema, orthopnea, NT-proBNP) and clinical status vs placebo; benefits observed during hospitalization and follow-up.
• EMPA-RESPONSE-AHF: randomized pilot study suggesting SGLT-2 inhibitors may influence clinical outcomes in acute decompensated HF; post-hoc analyses indicate reduced loop diuretic requirements in patients treated with SGLT-2 inhibitors, with a lower likelihood of diuretic initiation or higher likelihood of discontinuation when initiated.
• NATRIUM-HF (and related analyses): ARNi initiation associated with reductions in diuretic needs; SGLT-2 inhibitors show similar complementary effects by reducing congestion pressure and diuretic exposure in various cohorts.
• Semaglutide (GLP-1 receptor agonist) in obesity-related HFpEF: analysis showed a mean loop diuretic dose decrease of $17\%$ in active vs $2\%$ in placebo arms, indicating potential indirect decongestive effects via weight loss/diuretic-sparing mechanisms.
• Practical implications: SGLT-2 inhibitors contribute to decongestion without directly suppressing the nephron’s sodium-handling mechanisms; they may lower diuretic requirements and support sustained decongestion within a neurohormonal-centered management plan.

The current diuretic-centric paradigm and key clinical trials

• What the data collectively suggest:
  • Diuretics (loop and non-loop) rapidly relieve congestion but do not improve long-term outcomes when used alone; higher loop diuretic doses correlate with worse prognosis, likely reflecting underlying disease severity rather than a causal link to outcomes.
  • UF and vasopressin antagonists similarly achieve short-term decongestion but have not demonstrated consistent mortality or rehospitalization benefits.
  • Neurohormonal blockade, either alone or in combination with SGLT-2 inhibitors, reduces sodium avidity and diuretic needs, and improves congestion markers and outcomes in several trials.
• Notable trials and takeaways:
  • DOSE-AHF: high vs low diuretic strategy yielded greater symptom relief, urine output, and weight loss with higher doses but no difference in mortality, rehospitalization, or ED visits over $60\,\mathrm{days}$.
  • TRANSFORM-HF: torasemide vs furosemide post-discharge showed no difference in $12\text{-month}$ mortality.
  • ADVOR: acetazolamide added to standard therapy improved decongestion (relative improvement: $42.2\%$ vs $30.5\%$; p<0.001) but did not reduce mortality or rehospitalizations; higher transient renal function deterioration observed.
  • CLOROTIC: adding HCTZ to loop diuretics accelerated decongestion but did not improve post-discharge outcomes; higher WRF risk with thiazide.
  • UNLOAD: ultrafiltration reduced rehospitalization within $ext{90 days}$ but did not affect dyspnea improvement or mortality; greater weight loss with UF.
  • CARRESS-HF: UF was inferior for the primary endpoint (creatinine and weight at $96\,\mathrm{h}$).
  • EVEREST & TACTICS-HF: vasopressin antagonists provided short-term decongestion without long-term outcome gains.
  • STRONG-HF: aggressive GDMT up-titration post-discharge produced better congestion metrics at day $90$ with lower loop diuretic use, supporting a shift toward neurohormonal optimization.
  • PARADIGM-HF & CHARM: relapse-free decongestion associated with greater GDMT up-titration or diuretic reduction in ARNI-treated or RAAS-inhibited patients; natriuresis and diuresis improved with comprehensive neurohormonal blockade.
  • NATRIUM-HF: ARNi initiation associated with improved natriuresis and spontaneous diuresis.
  • EMPULSE: SGLT-2 inhibitors (empagliflozin) demonstrated decongestion signals in the acute phase and favorable clinical trajectories.
  • BIOSTAT-CHF: broader up-titration of GDMT linked with reduced recurrent HF hospitalizations.
• Overall conclusion from trials: strategies that rely solely on diuretic-based decongestion do not reliably translate into better survival or fewer hospitalizations; targeting the underlying pathophysiology via neurohormonal blockade and SGLT-2 inhibition yields more meaningful, durable decongestion and better prognosis.

A proposed paradigm shift: neurohormonal-centred decongestion with supportive agents

• Core idea: a comprehensive neurohormonal blockade, combined with SGLT-2 inhibitors, provides the best framework for sustained decongestion and favorable long-term outcomes.
• Practical framework (Figures 4 and 5):
  • In the acute hospital phase, use diuretics to treat overt volume overload (the first-line step).
  • Once volume overload is controlled, initiate and rapidly up-titrate GDMT (ACEi/ARB/ARNi, beta-blockers, MRA) and add SGLT-2 inhibitors to counterbalance sodium avidity, aiming to maintain euvolaemia with the lowest feasible diuretic dose.
  • The long-term objective is to sustain decongestion by modifying the disease process, not just by removing fluid; this should reduce subsequent decompensations and improve survival.
• Practical implications:
  • Early hospital initiation and rapid optimization of GDMT are safer and feasible, and in ambulatory settings, up-titration remains effective.
  • Minimizing diuretic exposure after stabilization helps mitigate dehydration, hypotension, and worsening renal function, which could otherwise delay GDMT optimization.
  • The deliberate reduction of diuretics over time is a potential outcome of successful neurohormonal and SGLT-2–driven decongestion.
• Conceptual analogies:
  • Diuretics are to decongestion what morphine is to STEMI pain relief: they address the symptom (edema/pain) but do not treat the underlying cause of the disease or improve survival.
  • Neurohormonal blockade plus SGLT-2 inhibitors targets the upstream drivers of congestion (sodium avidity) to achieve sustained, not just symptomatic, decongestion.

Practical algorithm for optimizing decongestion in decompensated HF (highlights)

• Stepwise approach for in-hospital to post-discharge management:
  • Step 1: Treat overt congestion with diuretics (loop diuretics as first-line) while monitoring for signs of dehydration, renal function, and electrolyte balance.
  • Step 2: Initiate and rapidly up-titrate GDMT (ACEi/ARB/ARNi, beta-blockers, MRA) as tolerated; monitor BP, renal function, and electrolytes; consider up-titration as soon as feasible.
  • Step 3: Start SGLT-2 inhibitor in hospital when appropriate; continue during transition to outpatient care.
  • Step 4: Use uNa+ guidance to tailor diuretic dosing where feasible (natriuresis-guided decongestion approaches like PUSH-AHF or ENACT-HF show improved diuresis and shorter hospitalization without clear mortality benefit).
  • Step 5: Aim for sustained decongestion with GDMT optimization; keep diuretic doses as low as possible once euvolemia is achieved to minimize adverse events and facilitate GDMT up-titration.
• Key markers to monitor decongestion and fluid status:
  • Oedema, jugular venous pressure, rales, orthopnea, weight changes, and NT-proBNP levels.
  • Weight trajectory and NT-proBNP changes often parallel improvements in congestion with optimized GDMT.
  • Urine sodium (uNa⁺) as a dynamic marker of natriuretic response and diuretic efficacy when using natriuresis-guided strategies.

Implications for clinical practice and ethics

• Ethical/practical implications:
  • A shift away from a purely diuretic-centric approach reduces exposure to diuretic-associated adverse events (dehydration, hypotension, WRF) and prioritizes disease-modifying therapies.
  • Early GDMT up-titration requires careful monitoring to avoid adverse effects but is feasible and beneficial in both inpatient and outpatient settings.
• Real-world relevance:
  • Implementing a neurohormonal/SGLT-2–based decongestion strategy may reduce rehospitalization rates and improve survival by addressing the root causes of congestion.
  • The approach aligns with contemporary guidelines prioritizing GDMT optimization and SGLT-2 inhibitors in HF management.

Conclusions

• Summary: Diuretic-centered decongestion alleviates symptoms but does not address the underlying drivers of congestion or disease progression; neurohormonal blockade (and SGLT-2 inhibition) reduces sodium avidity, promotes durable decongestion, and improves long-term outcomes.
• Practical takeaway: In managing congestion in HF, prioritize early initiation and rapid up-titration of GDMT and SGLT-2 inhibitors, use diuretics primarily for overt fluid overload, and aim to minimize diuretic exposure to enable sustained disease-modifying therapy; this integrated strategy offers the best potential for durable decongestion and improved prognosis.

Tables and figures referenced in the transcript (conceptual summaries)

• Table 1: Interpretation of urine sodium (uNa⁺) in special clinical settings; relationships to fluid status and diuretic response.
• Table 2: Overview of key decongestion studies and their mechanisms, including loop diuretics, UF, non-loop diuretics, vasopressin antagonists, MRAs, RAAS blockade, and SGLT-2 inhibitors; comparative effects on NT-proBNP, weight, dyspnea, safety, and outcomes.
• Table 3: Symptomatic (diuretic-centered) vs. etiological (neurohormonal/SGLT-2–centered) treatments.
• Figure 1: Pathophysiological pathways contributing to congestion development in HF (SNS, RAAS, vasopressin, inflammation, natriuretic peptide resistance).
• Figure 2: Mechanistic differences between direct sodium/water removers and neurohormonal/SGLT-2 approaches.
• Figure 3: Classic diuretic-centric decongestion pathway.
• Figure 4: Neurohormonal-centric approach to sustained decongestion (neurohormonal blockade + SGLT-2 inhibitors with minimized diuretic use after stabilization).
• Figure 5: Algorithm to optimize decongestion in decompensated HF (GDMT up-titration as the central pillar; uNa⁺–guided diuretic adjustments as a supplementary strategy).

Key terminology and abbreviations

• AHF: acute heart failure
• HF: heart failure
• GDMT: guideline-directed medical therapy
• RAAS: renin–angiotensin–aldosterone system
• SNS: sympathetic nervous system
• SGLT-2i: sodium–glucose cotransporter 2 inhibitors
• ARNi: angiotensin receptor–neprilysin inhibitor (e.g., sacubitril/valsartan)
• NT-proBNP: N-terminal pro-B-type natriuretic peptide
• uNa⁺: urine sodium
• WRF: worsening renal function
• UF: ultrafiltration
• DOSE-AHF: Diuretic Optimization Strategies Evaluation in Acute Heart Failure
• TRANSFORM-HF: Torsemide vs Furosemide in HF
• ADVOR: Acetazolamide in Decompensated Heart Failure with Volume Overload
• CLOROTIC: Combination of Loop with Thiazide-type Diuretics in Decompensated HF
• EVEREST: Efficacy of Vasopressin Antagonism in HF Outcome Study With Tolvaptan
• TACTICS-HF: Targeting Acute Congestion with Tolvaptan in Congestive HF
• PARADIGM-HF: ARNI vs ACEI in HF
• CHARM: Candesartan in HF; related analyses
• STRONG-HF: Safety, tolerability, and efficacy of up-titration of GDMT in acute HF
• NATRIUM-HF/NATRIUM-HF: natriuretic response to diuretic challenge and ARNi effects
• EMPULSE: EMPagliflozin in patients hospitalized with acUTE HF
• NATRIUM-HF: Natriuretic response to expansion and diuretics in HF
• STEP: references to trial-associated endpoints and statistical outcomes formatted in the text (e.g., p<0.001, $60\,\mathrm{days}$, $90\,\mathrm{days}$, $12\text{-month}$).