Acute Heart Failure is a Remitting–Relapsing Disorder and not a Step Towards Advanced Heart Failure: Implications for Decongestion Therapy

Acute heart failure (AHF) has been seen throughout the last decades of research as an inevitable step on the way to advanced heart failure (HF), as is evident from the graph presented in Figure 1, which is adapted from the 2022 AHA/ACC/HFSA guideline for the management of HF1 and has been presented in different shapes and forms over the last 20 plus years. Although this is the case in some patients who have advanced HF driven by very severe cardiac dysfunction, the evidence that AHF is a step towards advanced HF in most HF patients is scarce. First, if patients with AHF are in a precursor stage towards advanced HF, they should have the same characteristics as patients with advanced HF, with the main difference being a younger age. However – as evidenced by many AHF and chronic HF registries2-4 – patients with AHF are older by about 10 years than those with chronic advanced HF, and have a plethora of differing characteristics such as different proportion of women, prevalence of atrial fibrillation, ischaemic heart disease, etc. Moreover, patients with AHF have more significant neurohormonal inflammatory activation, that is different both quantitatively and qualitatively than in patients even with outpatient worsening of chronic HF.5 Even though the reasons for this activation are not known, it suggests that in most AHF patients neurohormonal, inflammatory, adrenergic activation plays a pivotal, core pathophysiological role in the genesis of decompensation. Second, patients with AHF when recovering from the acute episode mostly return quickly to a low New York Heart Association (NYHA) class stage, not advanced HF in most cases. For instance, in the RELAX-AHF study, congestion was quickly relieved during the hospitalization and 2 weeks after admission for the qualifying AHF event 34.4%, 44.8%, 18.7% and 2.1% of patients were in NYHA class I, II, III and IV, respectively. At 60 days post-discharge, the proportions in NYHA class I, II, III and IV were 36.1%, 41.8%, 19.0% and 3.1%, respectively. The same numbers were seen in the larger RELAX-AHF-2 study (NYHA class I, II, III, IV: 36.3%, 44.8%, 16.8% and 2.2%, respectively; Voors A, personal communication). In the STRONG-HF study, despite requiring high N-terminal pro-B-type natriuretic peptide levels at admission and discharge, 23%, 60%, 16% and 1% of patients were in NYHA class I, II, III and IV, respectively, 90 days after discharge.6 Hence, within days of admission for AHF >75% of patients were in NYHA class I (asymptomatic) or II (mildly symptomatic) and the number slightly increased to 80–85% of patients at day 60–90. Only <5% of patients were in NYHA class IV. Therefore, most patients with AHF do not have advanced HF or progress towards it in the weeks and months after an AHF admission, although some – probably in the range of 10–20% – do. Despite these commonly mild symptoms and probably less advanced HF, patients with AHF still have a very high rate of readmission and death, about 25% at day 180,6-15 probably related to more neurohormonal, inflammatory and adrenergic activation. These repeat AHF episodes lead to more AHF episodes and subsequently to death. The progression of the more ‘common’ patients with AHF, usually more elderly with mildly impaired to preserved ejection fraction, is probably better depicted as in Figure 2. These patients are largely treated in general medicine wards during admissions and by family physicians post discharge. HF experts see mostly the advanced, highly symptomatic younger patients, depicted in Figure 1. In these advanced HF patients, AHF is the culmination of progression of chronic advanced HF,16 possibly characterizing the trajectory towards stage C/D HF. In such patients,4 worsening of HF is a dire event signalling progression of the core advanced HF process which should alert the treating team that other interventions may be needed. If indeed AHF is a remitting–relapsing disorder in most patients, that between episodes is mostly associated with no or very mild chronic symptoms, what is the role of decongestion therapy post-AHF for such patients? Congestion is obviously a serious core driver of symptoms in patients with AHF and therefore intravenous (IV) diuretics followed by oral diuretics should be administered early during an acute heart failure episode to improve patients' symptoms. However, data from AHF studies such as RELAX-AHF and RELAX-AHF-2 suggest that for most patients a dose of furosemide 40–120 mg IV administered over about 2 days, followed by about 40 mg/day orally is enough to control those symptoms.9 This is consistent with the short-term effects and reversibility of congestion when properly and quickly treated. The fact that most AHF patients, are in NYHA class I or II despite being treated with minimal doses of diuretics further exemplifies the fact that only a small minority of AHF patients are in advanced HF weeks to months after discharge. When it comes to more decongestion therapy, it may indeed benefit those patients who cannot be decongested by IV and oral loop diuretics alone. Those patients with higher NYHA class, many of which have advanced HF could benefit from additional treatments such as acetazolamide.10 However, one should bear in mind that those therapies are only useful in symptom relief and should only be titrated towards that goal. Studies examining the use of higher doses of loop diuretics,17 acetazolamide,10 aquaretic agents11 or even ultrafiltration18 have not shown these therapies to reduce mortality or post-discharge readmissions, and some showed trends suggesting untoward effects on those endpoints. In many of these studies, adverse events such as worsening renal function, hypotension, and hypokalaemia were significantly increased. As suggested correctly by Packer and Butler,19 the rapid introduction of agents known to improve patient outcomes such as sodium–glucose cotransporter 2 (SGLT2) inhibitors (instead of more diuretics) is important and the only way to improve post-discharge outcomes. In this context, one must remember that SGLT2 inhibitors are not the only agents to exert such salutary effects in patients with AHF. Results of the SOLOIST-WHF,12 EMPULSE,13 PIONEER-HF14 and STRONG-HF6 studies suggest that rapid up-titration of four classes of medications – renin–angiotensin system inhibitors (RASi) such as angiotensin receptor–neprilysin inhibitors, beta-blockers (BB), SGLT2 or SGLT1/2 inhibitors and mineralocorticoid receptor antagonists (MRA) – should be undertaken at the end of admission for AHF and in the two following weeks aspiring to get the doses of these four classes of medications as close as possible to 100% of recommended doses, under strict safety monitoring including assessment of laboratory measures such as creatinine, potassium and natriuretic peptides. The implementation of these four pillars of HF therapy after an AHF event has led to treatment effects that are higher than those in chronic HF studies. This should be accompanied by IV iron where indicated.15 Those therapies (as shown in EMPULSE and STRONG-HF) can also assist in decongestion.6, 20 Patients with advanced HF will need more decongestion therapy to improve their symptoms, but these are the minority of AHF patients. For the majority of AHF patients, overzealous attempts to further decongest beyond a small dose of loop diuretics are not needed and may cause increases in creatinine levels and drops in blood pressure that slow down up-titration of guideline-directed medical therapy (GDMT) unnecessarily.21 Finally, patients who had an AHF episode are, as stated above, at high risk for recurrences. Therefore, they should be closely monitored by traditional and new technologies (both invasive and non-invasive as appropriate) to alert healthcare providers of potential new events.22 In conclusion, the majority of AHF patients are almost asymptomatic starting within days after discharge requiring only small doses of diuretics. Therefore, an approach of judicious decongestion early in the AHF admission utilizing small doses of loop diuretics, followed by rapid up-titration of guideline-recommended therapy at the end of admission (inclusive of a RASi, BB, MRA and SGLT inhibitor) and close monitoring is the best way to improve patients' symptoms short and longer term as well as their short- and longer-term outcomes. Additional decongestion therapies should be reserved for the minority of patients with more advanced HF who are more symptomatic in between AHF events despite full implementation of GDMT. Conflict of interest: G.C. and B.D. are directors of Heart Initiative, a non-profit organization and are employees of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics.