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Annual heart failure hospitalizations exceed 1 million in both the United States and Europe, and more than 90% are due to symptoms and signs of fluid overload. Additionally, up to one in four patients (24%) are readmitted within 30 days, and one in two patients (50%) are readmitted within 6 months. Acute decompensated heart failure (ADHF) remains the leading cause of hospitalization in patients > 65 years old and has the highest rate of 30-day rehospitalization among all medical conditions. Recurrent fluid overload in heart failure has been associated with worse outcomes independently of age and renal function. Deranged hemodynamics, neurohormonal activation, excessive tubular sodium reabsorption, inflammation, oxidative stress, and nephrotoxic medications are important drivers of harmful cardiorenal interactions in patients with heart failure. Central venous pressure elevation is rapidly transmitted to the renal veins, causing increased interstitial and tubular hydrostatic pressure, which decreases net glomerular filtration. Venous congestion itself can produce endothelial activation, the up-regulation of inflammatory cytokines, hepatic dysfunction, and intestinal villi ischemia. Thus, the foremost goal in managing acutely decompensated heart failure is to effectively resolve fluid overload.
- acute decompensated heart failure
- fluid overload
- loop diuretics
- diuretic resistance
- mineralocorticoid
- SGLT2 inhibitors
- ultrafiltration
1. Heart Failure
Heart failure represents a clinical syndrome that consists mainly of symptoms like shortness of breath, orthopnea, ankle swelling, and fatigue and can be accompanied by signs of congestion like increased central venous pressure, pulmonary crackles, or lower-limb edema [8]. It can be the result of either a structural or functional abnormality leading to decreased cardiac output, increased intraventricular pressure, and decreased tolerance to exercise. Coronary artery disease and diabetes mellitus have become the predominant predisposing factors for heart failure. Other structural causes of congestive heart failure (CHF) include hypertension, valvular heart disease, uncontrolled arrhythmia, myocarditis, and congenital heart disease. Finally, diastolic heart failure with impaired ventricular filling can also be caused by restrictive cardiomyopathy and constrictive pericarditis [9]. A rapid increase in blood pressure (afterload), particularly in patients with diastolic dysfunction, may precipitate severe pulmonary congestion.
In recent years, interest has fallen on the right ventricle (RV) and how it can participate in the phenotype of HF. It is well known that a failing left ventricle (LV) can lead to an increase in the pulmonary capillary wedge pressure (PCWP) and transpulmonary pressure and eventually increase the afterload of the RV. This increase in pressure will lead to RV distention as a response mechanism in order to maintain adequate cardiac output. This distention will eventually affect contractility to aggravate tricuspid regurgitation, increase ventricular interdependence, impair LV filling and cardiac output (CO) reduction, and multi-organ dysfunction [10]. In fact, a recent retrospective study that included six hundred and seventy-seven severely ill patients with acute COVID-19 patients admitted to an ICU showed that one-third of those presented right ventricle systolic dysfunction. This presentation was attributed to positive mechanical ventilation with high positive end-expiratory pressure (PEEP) due to severe ARDS, hypercapnia, and pulmonary embolism [11]. One of the major factors causing PE is the significant increase in the capillary hydrostatic pressure of the pulmonary circulation, following the Frank–Starling law. Normal pulmonary circulation is a system of high flow, low resistance, and low pressure under normal conditions. Factors that cause abnormal pulmonary circulation will eventually cause a mismatch between the right heart and the flow in the circulatory bed leading to PE. Considering the role of the pressure generated by the right ventricle in maintaining the capillary hydrostatic pressure, it is understood that its failure will lead to congestion [12].
In spite of the great variety of clinical profiles and the heterogeneity of the underlying cause of HF, the majority of patients with AHF will present signs and symptoms of pulmonary congestion with or without systemic congestion. This presentation may not be connected to decreased cardiac output (CO). Congestion will lead to dyspnea, which is the major symptom among patients with AHF [13]. However, the initiation of diuretic treatment might not always lead to dyspnea relief [14]. Moreover, increased PCWP is not always associated with dyspnea severity, in such a manner that high PCWP may cause mild dyspnea, while lower PCWP can cause severe dyspnea [15].
An imbalance between the forces that drive fluid into the alveoli and the removal mechanism, leads to pulmonary edema. Two fundamental processes may lead to alveolar-capillary barrier dysfunction in AHF: (a) mechanical injury of the barrier due to increased hydrostatic pulmonary capillary pressures and (b) inflammatory and oxidative lung injury.
Pulmonary endothelium can induce several intracellular signaling pathways, leading to increased inflammatory cytokine production, macrophage activation, acute inflammation, and barrier dysfunction [16]. This oxidative and inflammatory lung injury further damages the alveolar-capillary barrier and increases its permeability leading to a decrease in pulmonary fluid accumulation by the capillary hydrostatic pressure. This could partially explain the recurrence that the AHF patients present.
Another cause of acute decompensation of HF is hypoalbuminemia, which results in low serum colloid osmotic pressure (COP), facilitating the onset of pulmonary edema in patients with diastolic heart failure (DHF). Reduced COP allows more fluid to leak out of the blood vessels, while elevated PAWP indicates increased pressure in the pulmonary capillaries, promoting the movement of fluid into the lung tissue. Hypoalbuminemia, as a sign of cachexia, can be present in HF patients during the evolution of the disease and is exacerbated when other organs become involved, like the liver, due to congestion.
It has been shown that a major role in the decompensation of Heart failure is attributed to inadequate drug treatment, failure to comply with the dietary sodium restriction, and decreased physical activity [17].
In the primary stages of congestive heart failure, the heart muscle uses several compensatory mechanisms in order to maintain cardiac output in an attempt to keep up with the systemic demands. These mechanisms include changes in myocyte regeneration, myocardial hypertrophy and hypercontractility, and the Frank–Starling mechanism, which increases cardiac output. The increasing wall stress will force the myocardium to compensate via eccentric remodeling, leading to fibrosis and eventually affecting the loading conditions and wall stress [17].
The most commonly used heart failure classification is based on the left ventricle ejection function. The rationale behind this old classification is based on the fact that treatment has a bigger benefit to the lowest ejection fraction [18] (Table 1).
Table 1. HF types according to Left Ventricular Ejection Fraction (LVEF).
| Types of Heart Failure | Criteria |
|---|---|
| Heart Failure with reduced ejection fraction (HFrEF) | Symptoms ± Signs |
| LVEF ≤ 40% | |
| Heart Failure with mildly reduced ejection fraction (HFmrEF) | Symptoms ± Signs |
| LVEF 40–49% | |
| Heart Failure with preserved ejection fraction (HFpEF) | Symptoms ± Signs |
| LVEF ≥ 50% |
Heart failure can present either as a chronically decompensated status (CHF), where the diagnosis is set and the symptoms build up throughout the years of the disease evolution, or as an acute decompensation, which could lead to a decrease in the cardiac output either at a rapidly or slowly evolving pace. These two types necessitate the use of a decongestion treatment either in a conservative form with the use of diuretics alone or with the aid of ultrafiltration.
Finally, NYHA classification categorizes heart failure patients according to their functional status starting from class I, where the patient is almost completely functional, up to class IV, where the patient has reached the last stage of the disease and, unless transplanted or mechanically supported, will have very poor prognosis (Table 2).
Table 2. NYHA functional classification of HF.
| Class I | No limitation of physical activity. Ordinary physical activity does not cause undue breathlessness, fatigue, or palpitations. |
| Class II | Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue, or palpitations |
| Class II | Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity results undue breathlessness, fatigue, or palpitations. |
| Class IV | Unable to carry on any physical activity without discomfort. Symptoms at rest can be present. If any physical activity is undertaken, discomfort is increased. |
2. Diuretics in Heart Failure: Historical Perspective
The first ever HF case described belonged to 3500-year-old mummified remains found in the Valley of the Queens by the Italian Egyptologist Ernesto Schiaparelli [78]. Andreas Nerlich, a pathologist from Germany who performed the histologic examinations of the lungs, concluded, by exclusion, that the leading cause of death was pulmonary edema, likely due to HF [79].
Over the centuries, many civilizations have managed to describe the presence of fluid accumulation but without any understanding of the cause behind it [80], not making the connection between the symptom and the heart. The breakthrough occurred in 1918 when E.H. Starling [81] published his ‘Law of the Heart’. The demonstration that increasing end-diastolic volume enhances cardiac performance contradicted the 19th-century view that dilatation weakened the heart. Until the 1980s, the treatment was based on fluid restriction, rest, and the use of digitalis and diuretics, underlying the clear orientation of the scientific community towards kidney function rather than that of the heart. HF was finally recognized as a neuroendocrine disease in the 1980s and treatment with diuretics, vasodilators, and inotropes was put under discussion as it would keep the patient hostage in the vicious circle of the endocrine response present in HF [82].
The goal of keeping the patient in a euvolemic status remains, and this is exactly the treatment given when the patient decompensates, besides the optimal medical treatment that has been discovered throughout the years with potent agents like ACE inhibitors, ARNIs, b-blockers, MRAs, and SGLT 2 inhibitors. Although routine diuretic treatment of HF may appear uncomplicated, questions have arisen about the optimal use of diuretics, particularly in settings of ADHF and diuretic resistance (DR).
2.1. Challenges in Diuretic Therapy
Heart–kidney disorders caused by variable etiologies and precipitated by factors such as hemodynamic, neurohormonal, and inflammatory disorders can lead to cardiorenal syndrome (CRS) [83]. The clinical profile is characterized by decreased glomerular filtration, sodium avidity, and diuretic resistance (DR) [84].
2.2. Diuretic Resistance (DR)
Mortality, pump failure death, and sudden death present independent associations with diuretic resistance (DR). It may be defined as a non-satisfactory rate of diuresis/natriuresis despite an adequate diuretic regimen [85]. The diuretic resistance definition includes persistent congestion, despite adequate and escalating doses of diuretic agents equivalent to ≥80 mg/day furosemide; the amount of sodium excretion as a percentage of filtered load below 0.2% and failure to excrete at least 90 mmol of sodium within 72 h of a 160-mg twice-daily dose of furosemide. Other proposed parameters include weight loss achieved per 40 mg of furosemide or equivalent; net fluid loss per milligram of loop diuretic agent; and natriuretic response to furosemide as the urinary sodium-to-urinary furosemide ratio [86]. In HF patients, the prevalence of diuretic resistance (DR) is estimated at 20–30% [87]. It is vital to differentiate the homeostatic mechanism of the kidneys to protect themselves from a hypovolemic status and present a poor response to diuretics even in patients naive to diuretics [88]. Diuretic efficiency integrates the diuretic response in the context of the loop diuretic dose, dividing fluid output, weight change, or sodium output by the loop diuretic dose administered [89]. Diuretic efficiency is underscored in clinical practice since a modest response to a low-dose diuretic can result in good diuretic efficiency that is clinically unimportant if inadequate to bring the patient into a euvolemic status. It was proposed to be a mechanism of resistance according to anatomic location and significance [76]. When extra tubular, the mechanism can be venous congestion, increased intra-abdominal pressure or kidney vasoconstriction and hypoperfusion, decreased cardiac output, hypoalbuminemia, and high sodium intake. Even though gut edema and low duodenal blood flow do not typically affect furosemides’ oral bioavailability, they slow absorption, leading to reduced peak plasma levels, and therefore contribute to diuretic resistance. When tubular, it can be divided into the loop of Henle or the post-loop of Henle. In the former, an inadequate loop diuretic dose or rightward shift in the loop diuretic dose response curve should be checked, while for the latter compensatory distal tubular sodium reabsorption, hypochloremic alkalosis or specific transporters should be controlled [85]. Finally, the extent of natriuresis following a defined dose of diuretics decreases over time, even in normal subjects. This is called the ‘braking phenomenon’, and it is the result of both hemodynamic changes in the glomerulus and adaptive changes in the distal nephron. Loop diuretics are ‘threshold drugs’. The dose–response curve is shifted downwards and right due to heart failure. In other words, a higher dose of loop diuretics is needed in order to achieve the same level of sodium excretion.
The clinical presentation of diuretic resistance consists of insignificant relief of symptoms, further decompensation of heart failure besides the in-hospital treatment, increased mortality post-discharge, and up to three times higher rate of rehospitalization [86]. In the Acute Decompensated Heart Failure National Registry (ADHERE), 33% of the 50,000 patients enrolled that were treated with conventional diuretics lost around 2.3 kg, 16% gained weight while in hospital, and half of them were discharged with persistent congestion [90]. Moreover, in the Diuretic Optimization Strategies Evolution (DOSE) trial, 42% of participants with acute heart failure reached the end point of death or an unprogrammed visit to the hospital at 60 days irrespective of the treatment followed [91].
2.3. Treatment Strategies to Tackle DR
Once initiated, the effect of diuretic treatment needs to be monitored. For this purpose, an indicator needs to be used easily in daily clinical practice. There are two indicators that are used currently, the net fluid output and body weight changes. Weight assessment is technically challenging, and fluctuations seen in weight during hospitalization might not represent changes in volume redistribution. Further more, there is no clear correlation between fluid output and weight loss [92].
2.3.1. Loop Diuretics
Intravenous loop diuretics exert their effect within the first couple of hours, and a return to baseline sodium excretion is noticed by 6–8 h. In this timeframe, early evaluation of the diuretic response can take place and will identify patients with a poor diuretic response [89,93]. It is known that thiazide and thiazide-like diuretics may partially overcome distal increased sodium avidity accompanied by chronic loop diuretic use [94]. In contrast to conventional knowledge, more recent evidence does support the effectiveness of thiazides in patients with a reduced glomerular filtration rate (<30 mL/min) [95].
In the DOSE-AHF trial, high loop diuretic dose, defined as 2.5 times the home dose and not less than 80 mg of furosemide per day, had a more favorable effect than the equal-to-home dose and this led to clinical improvement with dyspnea relief and a decrease in body weight and extravascular volume [71]. Renal dysfunction, defined as an increase in creatinine by more than 0.3 mg/dL, occurred more in the high-dose group. However, this increase did not affect the outcome as was shown by a post-hoc analysis of the DOSE-AHF trial [96]. Furthermore, a better outcome was seen in the high-dose group when adjusted for the total amount of loop diuretics received, suggesting that the adequacy of loop diuretic dosing to reach the ‘ceiling’ threshold is key [97]. The individual ceiling dose in each patient is difficult to determine and can be influenced by many factors, such as non-naivety with loop diuretics, body composition, the extent of volume overload, and renal function. Nonetheless, intravenous doses ranging between 400 and 600 mg furosemide vs. 10–15 mg bumetanide are generally considered the maximal total daily dose. When exceeded, additional natriuresis should be expected but this will lead to an increase in the side effects. Intravenous loop diuretics should be administered as soon as possible since early loop diuretic administration is associated with lower in-hospital mortality [98]. In the DOSE-AHF trial, no difference was seen in the primary endpoint between continuous or bolus infusion. If bolus infusion is chosen, doses should be administered in at least 6 h intervals to maximize the time above the natriuretic threshold and to avoid rebounding sodium retention [99].
Over the years, many efforts have been made to decrease both the resistance and the side effects of LD. Another well-investigated approach is that of changing the diuretic agent to torasemide. It is known to have the longest half-life at 3 to 4 h and can be as long as 5 to 6 h in patients with renal/hepatic dysfunction or heart failure. Bumetanide and torsemide exhibit higher and more consistent oral bioavailability (>90%) and do not exhibit absorption-limited kinetics, making oral and intravenous doses more comparable. In a recent meta-analysis, Miles et al. described a reduction in intermediate-term heart failure readmissions and improvement in the New York Heart Association class driven by torsemide compared with furosemide, which was not associated with a reduced mortality risk [100]. The TRANSFORM HF trial recruited 2859 participants hospitalized with heart failure and directly compared the novel loop diuretic torsemide (n = 1431) with furosemide (n = 1428) with investigator-selected dosages. Among patients discharged after hospitalization for heart failure, torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months [101]. Similar results were seen also in the ASCEND-HF trial where furosemide was also compared with torsemide and showed that torsemide use was not associated with significantly improved outcomes. However, in this trial, patients receiving torsemide had more comorbidities than those receiving furosemide. The landmark study on torsemide is the TORIC study, which compared torsemide to furosemide and found that after an average of 9 months, there was a significant 51.5% reduction in the risk of overall mortality, a 59.7% reduction in cardiac mortality, and a significant improvement in functional status within the torsemide group [102]. Unfortunately, the limitations of the study design included that they did not proceed to randomization, the sample population was mainly rural non-hospital based, and the use of other standard HF-pharmacotherapies such as beta-blockers and ACE inhibitors was low (~9.5% and ~30%, respectively).
2.3.2. Mineralocortiocoid
Mineralocorticoid antagonists such as spironolactone improve mortality in heart failure with a reduced ejection fraction but need to be used at low doses of 25 mg in order to avoid hyperkalemia. Several small studies suggested that when mineralocorticoid antagonists are given in higher doses, called “natriuretic doses”, they might improve decongestion in ADHF [103]. The ATHENA study randomized 360 patients with ADHF and congestion to 96 h of spironolactone (100 mg daily) or placebo, but with a low dose of spironolactone continued [104]. Spironolactone did not improve either the primary endpoint of decongestion, measured by the change in NT-proBNP, or secondary endpoints, including symptom amelioration and decongestion. In contrast to the anticipated increase in potassium levels, the plasma potassium concentration was not affected, suggesting incomplete mineralocorticoid receptor blockade.
2.3.3. Carbonic Anhydrase Inhibitor
As described above, one of the targets in heart failure is sodium reabsorption in the proximal tubules. Firstly, in a state of decompensated heart failure, sodium is reabsorbed mostly in the proximal nephron. Secondly, greater delivery of chloride to the macula densa cells increases, leading to a decrease in renin production, which reduces neurohumoral activation. Third, endogenous natriuretic peptides will possibly regain their cardioprotective effects. The carbonic anhydrase inhibitor acetazolamide acts in the proximal tubules inhibiting sodium reabsorption. An observational study in patients with decompensated heart failure and significant fluid overload showed that adding acetazolamide (500 mg intravenous bolus on top of loop diuretic) improved the loop diuretic response with approximately 100 mmol Na+ excreted per 40 mg of furosemide dose equivalents [105]. This synergic effect of acetazolamide with loop diuretics was also observed in a small, randomized trial with 24 patients, presenting with acute fluid overload resistant to loop diuretic therapy [106]. A multicenter, randomized, double-blind, clinical trial of the diuretic effects of Acetazolamide in Decompensated heart failure with Volume Overload (ADVOR) investigated whether acetazolamide can improve the efficiency of loop diuretics leading to faster and more efficient decongestion in ADHF. A total of 519 patients underwent randomization. In total, 108 of 256 in the treatment arm (42.2%) were successfully decongested as compared with 79 out of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; p < 0.001). The death rate and the rehospitalization rate were similar in both groups (29.7% vs. 27.8%) The treatment group had higher urine output and natriuresis, presenting an overall better diuretic effect. Adverse events, expressed by worsening kidney function, hypokalemia, and hypotension, were similar in both groups [107].
2.3.4. SGLT2 Inhibitors
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel glucose-lowering treatment that blocks the SGLT2 protein, which is located in the proximal convoluted tubule of the nephron in type 2 adult patients. The substances are canagliflozin, dapagliflozin, and empagliflozin [108]. The Empagliflozin Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) among patients with cardiovascular disease history indicated a significant reduction in the composite risk of cardiovascular death, myocardial infarction, or stroke by 14%. Overall, the risk of all-cause mortality was reduced by 32% during a follow-up period of 3.1 years [109]. Whether SGLT2 inhibitors provide clinical benefits in patients with AHF is being thoroughly explored. A total of 1831 patients took part in three different trials with their baseline characteristics mostly similar between interventional and control groups. The drug of choice was Empagliflozin in EMPULSE [110] and EMPA-RESPONSE-WHF [111] and Sotagiflozin in SOLOIST-WHF [112]. Compared with the placebo group, the risk of mortality was reduced by 27% in the intervention group (RR: 0.73, 95% CI: 0.49–1.09, p = 0.12, I2 = 18%). The mortality risk reduction was 15% in patients with Acute Decompensated Congestive Heart Failure (ADCHF) who took SGLT2 inhibitors compared to placebo (RR: 0.85, 95% CI: 0.62–1.15, p = 0.39, I2 = 0%). Compared to the placebo group, the intervention group had a significant risk reduction in Heart Failure Events (HFEs) of 62% (RR: 0.66, 95% CI: 0.58–0.75, p < 0.0001, I2 = 0%), defined as a hospitalization or visits to the emergency department, or an outpatient visit necessitating the intensification of treatment. Serious events were slightly lower in the intervention group by 15%, demonstrating a favorable safety profile in the three SGLT2 trials in acute heart failure (RR: 0.85, 95% CI: 0.70–1.03, p = 0.1, I2 = 44%). By the end of 2022, 15 clinical trials will have been conducted, testing the efficacy and safety of SGLT2 inhibitors on heart failure, diabetes mellitus type 2, acute myocardial infarction, and chronic kidney disease. The controlled substances are Empagliflozin of 10 and 20 mg, Dapagliflozin of 10 mg, and Canagliflozin. Control and group standard care consist of either placebo or loop diuretics, vasodilators, inotropic agents, digoxin, and/or vasopressors.
2.3.5. Miscellaneous Approaches (Oral Vasopressin-2 Receptor Antagonist, Hypertonic Solutions, Dopamine)
Hyponatremia, reflecting water accumulation, is common in heart failure patients and is a poor prognostic indicator [113]. The oral vasopressin-2 receptor antagonist tolvaptan inhibits the action of antidiuretic hormone and increases free water excretion [114]. The EVEREST study, which evaluated hospitalized heart failure patients (with or without hyponatremia), did not demonstrate the superiority of tolvaptan over placebo in terms of long-term clinical outcomes. However, a beneficial effect on volume status and symptoms was observed on the initial treatment days [115]. Smaller trials focused on tolvaptan use in patients with lower serum sodium levels to achieve short-term decongestion did not show significant improvement in symptoms or clinical outcomes, despite leading to greater weight and fluid loss [116].
A randomized, single-blind study evaluated the effects of the combination of high-dose furosemide and small-volume hypertonic saline solution (HSS) infusion in the treatment of refractory New York Heart Association (NYHA) class IV CHF and a normal sodium diet during follow-up [117]. Patients were randomized into two groups. Patients in group 1 received an intravenous (IV) infusion of furosemide (500–1000 mg) plus HSS twice a day for 30 min. Patients in group 2 received an IV bolus of furosemide (500–1000 mg) twice a day, without HSS, during a period lasting 6 to 12 days. The results showed an improvement in quality of life, a delay in upscaling diuretic treatment, and a trend toward decreasing mortality.
When renal blood flow decreases, it contributes to sodium retention in ADHF. The proposed mechanism is limited Na+ filtration, increased Na+ reabsorption, and reduced renal diuretic delivery to the proximal tubule. Dopamine increases renal blood flow and was shown to cause urinary Na+ excretion at low doses [118] and therefore enhances natriuresis. The ROSE-AHF study randomized 360 patients hospitalized for ADHF with impaired renal function to furosemide plus either dopamine infusion (2 μg/kg/min), nesiritide (0.005 μg/kg/min), or placebo [119]. Urine volume or changes in cystatin C levels for 72 h were not affected by the two drugs. Dopamine infusion was associated with tachycardia (7% for dopamine vs. 1% for placebo, p > 0.001), even at this low dose. A post hoc subgroup analysis suggested that the low-dose dopamine effect could be different according to the heart failure subtype; in patients with heart failure with a reduced ejection fraction (HFrEF), dopamine may improve decongestion and prognosis [120].
3. Ultrafiltration Strategy (UF)
For years, the concept of a rapid decongestant performed mechanically by an ultrafiltration (UF) device has been under thorough investigation. UF presents many advantages over the classic diuretic treatment. These consist of precise control of the rate and amount of fluid removal, restoration of fluid responsiveness, removal of isotonic plasma water, no effect on the plasma concentration of potassium and magnesium, and finally, it does not exert direct neurohormonal activation. The disadvantages of the method are the need for anticoagulation, a peripheral or central venous catheter, and an extracorporeal circuit [121]. UNLOAD, CARRESS-HF, CUORE, and AVOID-HF are trials that investigated the role of UF in Acutely Decompensated Congestive Heart Failure (ADCHF). The key lessons from these trials are that UF can restore diuretic agent responsiveness, but overly aggressive fluid removal can convert nonoliguric renal dysfunction into oliguric failure and dialysis dependence.
The UNLOAD (UF vs. IV Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure, n = 200) trial [122] was a multicenter, single-session, UF therapy for ADHF within 24 h. The trial showed that, compared with patients receiving intravenous (iv) Loop Diuretics (LD), those randomized to the ultrafiltration arm had greater weight and net fluid loss at 48 h and a 53% reduction in the 90-day risk of hospitalization and unscheduled visits for heart failure (p = 0.0037). In decompensated HF, UF can more safely produce weight and fluid loss than IV diuretics, reduces 90-day resource utilization for HF, and is an effective alternative therapy.
In contrast to the results of the UNLOAD trial, which tested the effects of early decongestive strategies, the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure, n = 188) trial [123] showed that a stepped pharmacologic therapy algorithm was both superior and safer than a fixed 200 mL/h UF rate for the preservation of renal function at 96 h. The use of diuretics was superior to a strategy of UF for the preservation of renal function at 96 h, with a similar amount of weight loss on the two approaches. UF was associated with a higher rate of adverse events.
The AVOID-HF (Aquapheresis vs. IV Diuretics and Hospitalization for HF, n = 227) trial [124] showed that the Adjustable Ultrafiltration (AUF) group, compared with the Adjustable Loop Diuretic (ALD) group, had a non-statistically significant trend toward a longer time to first HF event after index hospitalization, significantly fewer patients rehospitalized, and shorter hospitalization times for HF or CV causes at 30 days. Whereas 90-day mortality did not differ between groups, the number of patients experiencing an adverse event of special interest or a serious product-related side effect was greater in the AUF than in the ALD group. The study was prematurely terminated by the sponsor. Nevertheless, the results of the AVOID-HF trial suggest that decongestion with UF requires careful evaluation of the benefit of reducing HF rehospitalizations with the risk of UF-related adverse events.
The CUORE trial [125], a small (n = 56), prospective, randomized, unblinded study, compared ultrafiltration and standard medical treatment. It did not include patients with acutely decompensated heart failure or cardiogenic shock. Moreover, randomization took place 24 h post admission, and fluid removal could not exceed 75% of the estimated initial weight increase. The intravenous dosage of diuretics that started before randomization was left unchanged in both groups.
This entry is adapted from the peer-reviewed paper 10.3390/jcm13010012
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